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copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
Preclinical Road map for Neuroscience Drug Discovery Research at Boston
Childrenrsquos Hospital Contact Robin Kleiman PhD
Director of Preclinical Research
Translational Neuroscience Center Boston Childrenrsquos Hospital
robinkleimanchildrensharvardedu
The goal of a drug discovery project team is to help clinical investigators design a successful clinical trial
This requires high confidence identification of all of the following
Correct target
Correct molecule
Correct dose
Correct duration of drug treatment
Correct subset of patients
Correct stage of disease
Correct sample size
Correct endpoints
Acceptable side effect profile
The Translational Neuroscience Center at Boston Childrenrsquos Hospital offers a range of support for researchers addressing
critical decision points required to develop a drug discovery program and enable successful therapeutic clinical trials This
roadmap provides researchers with a strategic frame work for considering key project-specific issues and where to identify
resources to help address these issues Many resources are available in public databases via collaboration with industry
partners and via the coordination of services through the Translational Neuroscience Center at Boston Childrenrsquos Hospital
All feedback and suggestions are welcome
Other factors to consider
Phenotypic ScreensDrug Repurposing
Collaborating with Industry Preserving Intellectual Property
Funding Opportunities for Drug Discovery Projects Clinical Trials
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
main menu
Target identification and Validation resources
Drug targets for human disease emerge from basic research into mechanisms of disease biology Validated molecular drug
targets require that the project team address issues related to Rationale Druggability Mechanism and Safety The
Commercial viability of the approach may also be critical for recruiting industry partners at key junctures to support
development
The Molecular Target is the protein that will bind directly to the proposed drug A validated target has
Rationale
A human genetic or pharmacological link to a selected disease population
bull Modulation of the target has been shown to produce therapeutic benefit in an in vivo animal model of the disease
population or of the relevant circuit dysfunction using a directly translatable and quantifiable endpoint
Druggability
bull A tool compound exists to modulate the target or a family member
bull Biochemical and cellular assays exist to support development of SAR for on-target and off-target activities
Well-Defined Mechanism of Action
bull A clear set of laboratory objectives that specify required mode and degree of target engagement needed for
efficacy
bull Pharmacodynamic measures of target engagement are available to monitor activity in animals and people
bull Disease induced changes in target expression or distribution have been examined
bull Common human SNPs in target documented and functional consequences considered
Safety Risk Assessment
bull Known pharmacological risks associated with target mechanism are documented
bull The tissue distribution of the target is understood in preclinical species humans and patients
bull The most likely off-target activities associated with closest sequence homology are identified and considered for
safety risks
Commercial Potential
bull Competitive differentiation strategy suggests improvement over standard of care
bull Viable intellectual property and product development plan
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
Download a short guide to Acronyms and Terminology associated with Drug Discovery
ACRONYMSampTERMpdf
Download an Introductory Slide Deck on the Drug Discovery Process for Neuroscience
roadmapoverviewkleimanpdf
Download an Introductory slide deck on the Role of the Biology Team in a drug discovery program
drug discovery biologykleimanpdf
Below are listed databases and other resources that can help address questions about rationale distribution of target or its
relationship to other disease genes
RNA expression data sets
GEO- Gene Expression Omnibus data base of all published RNA expression data sets
httpwwwncbinlmnihgovgeo
Allen Brain Atlas- database of brain RNA expression data httpwwwbrain-maporg
Brain Span database-Brain RNA expression data including transcriptome and ISH for human brain
httpwwwbrainspanorg
Human genome resources at NCBI
httpwwwncbinlmnihgovgenomeguidehuman
OMIM- human genes and inherited disorders maintained by Johnrsquos Hopkins
Gene Database- database of genes and associated information
dbSNP- a database of SNP and other nucleotide variations
dbGaP- database of Genotypes and Phenotypes
NextBio Free Harvard enterprise account
Mine transcriptional profiling studies for changes in your target
Search connectivity map for compounds that modulate your target
Correlate human data to animal models and cell lines
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
Compare disease profiles across cohorts and stages of disease
wwwnextbiocom
iHOP--information Hyperlinked Over Proteins
A portal for searching literature by gene or gene Interactions httpwwwihop-netorgUniPubiHOP
Ingenuity Pathway Analysis
Available from research computing Find disease related literature for your target
httpwwwingenuitycomproductsipa
TISSUES database of Expression of targets (RNA and Protein)
TISSUES is a frequently updated web resource that integrates evidence on tissue expression from manually curated
literature proteomics and transcriptomics screens and automatic text mining They map all evidence to common
protein identifiers and Brenda Tissue Ontology terms and further unify it by assigning confidence scores that facilitate
comparison of the different types and sources of evidence Finally these scores are visualized on a schematic human
body to provide a convenient overview
httptissuesjensenlaborgSearch
Refrence Literature related to target identification and validation
Bunnage ME Gilbert AM Jones LH Hett EC Know your target know your molecule Nature chemical biology 2015
11(6)368-372 httpwwwncbinlmnihgovpubmed15718163
Grover MP Ballouz S Mohanasundaram KA George RA Sherman CD Crowley TM Wouters MA Identification of
novel therapeutics for complex diseases from genome-wide association data BMC medical genomics 2014 7 Suppl
1S8 httpwwwncbinlmnihgovpubmed25077696
Plenge RM Scolnick EM Altshuler D Validating therapeutic targets through human genetics Nature reviews Drug
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
main menu
Resources available at BCH Assay Development Screening Funnel development Chemical compound files Assistance
with identification of academic and industry partners for collaborative SAR campaigns
Identification of the correct molecule requires a clearly defined set of laboratory objectives and a well-designed screening
funnel to select the molecule that will meet those objectives Laboratory objectives for a molecule include specific criteria
for the mode of binding to target (eg agonist partial agonist inverse agonist non-competitive inhibitor) the potency
(eg Ki lt30nM) selectivity (eg gt30X selectivity over family member target XY and Z) brain penetration (yesno) dosing
paradigm ( eg oral once daily intravenous once monthly) and duration of expected treatment (eg sub-chronic daily
treatment for 2 weeks chronic treatment for years) Each of these laboratory objectives will have bearing on the design of
the screening funnel required to identify the molecule
The screening funnel requires a robust high-throughput (HTS) biochemical assay capable of testing gt100000 compounds
good sensitivity (Zrsquogt05) and an appropriate orthogonal assay (usually cell based) to confirm functional activity of the
compound at the target which can be used to weed out false positives and primary HTS artifacts Critical features defined
by the laboratory objectives may require additional in vitro absorption and metabolism data from compounds slated to
progress in vivo to ensure that structure activity relationships being developed will support expected dosing profiles and
target organ disposition A collection of critical off target assays to ensure required selectivity of the candidate drug must
be available to test molecules progressing from functional assays Compounds expected to be tested in vivo will require
pharmacokinetic studies to ensure target organ exposure in concentration ranges needed to support hypothesis testing
Link to sample Screening Funnels
httpswwwnimhnihgovresearchprioritiestherapeutics
The types of information needed to Characterize a Lead Compound are summarized here
Download an introductory slide deck on Medicinal Chemistry Structure Activity Relationship (SAR) campaign courtesy Dr
Johnny Bennett Merck
Childrens MedChem 29Jul2015pdf
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
Resources for assay development
The Assay Guidance Manual httpwwwncbinlmnihgovbooksNBK53196
This is a key resource for design and qualification of all types of biochemical and cell based assays It covers many
different modes of assay development and optimization as well as troubleshooting guides Do not run a screen
without consulting the manual first
The Assay Development Screening Facility (ADSF) at BCH Hourly access to equipment and technical assistance
consultations compound libraries- live cell medium throughput screening For more information contact Dr Lee Barrett
The ICCB at Longwood Project based access to equipment and expertise for design and execution of high-throughput
screens access to wide collection of chemical and genomic libraries For more information contact Dr Caroline Shamu
caroline_shamuhmsharvardedu
Website httpiccbmedharvardedu
Databases and references with information about activity and properties of small molecule compounds
PubChem provides information on the biological activities of small molecules PubChem is organized as three linked
databases within the NCBIs Entrez information retrieval system These are PubChem Substance PubChem Compound and
PubChem BioAssay Links from PubChems chemical structure records to other Entrez databases provide information on
biological properties These include links to PubMed scientific literature and NCBIs protein 3D structure resource Links to
PubChems bioassay database present the results of biological screening Links to depositor web sites provide further
information A PubChem FTP site Download Facility Power User Gateway(PUG) Standardization Service Score Matrix
Service Structure Clustering and Deposition Gateway are also available Home page is here
httpspubchemncbinlmnihgov
httpspubchemncbinlmnihgovsearch
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
DrugBank The DrugBank database is a unique bioinformatics and cheminformatics resource that combines detailed drug
(ie chemical pharmacological and pharmaceutical) data with comprehensive drug target (ie sequence structure and
pathway) information The database contains 7759 drug entries including 1602 FDA-approved small molecule drugs 161
FDA-approved biotech (proteinpeptide) drugs 89 nutraceuticals and over 6000 experimental drugs Additionally 4300
non-redundant protein (ie drug targetenzymetransportercarrier) sequences are linked to these drug entries Each
DrugCard entry contains more than 200 data fields with half of the information being devoted to drugchemical data and
the other half devoted to drug target or protein data Homepage is here httpwwwdrugbankca
Protein Data Bank archive Targets with protein crystal structures are more attractive targets for structure based drug design
Determine if your target has a known crystal structure by looking it up in the protein database- A Structural View of Biology
This resource is powered by the Protein Data Bank archive-information about the 3D shapes of proteins nucleic acids and
complex assemblies that helps students and researchers understand all aspects of biomedicine and agriculture from
protein synthesis to health and disease Homepage is here httpwwwrcsborgpdbhomehomedo
High Quality Chemical tools are required for testing biological hypothesis Find chemical tools that are fit for purpose by
virtue of target potency and selectivity needed to test hypothesis The dangers of using inadequate chemical tools are
detailed here httpwwwnaturecomnchembiojournalv11n8fullnchembio1867html To support the needs of the
biology community the industrial chemistry research community has joined a pre-competitive effort to provide
characterization data for high quality chemical probes That data is stored here httpwwwchemicalprobesorgprotein-
family
ChemNavigator The National Institutes of Health (NIH) has formed an agreement with ChemNavigator to provide the NIH
with a current and comprehensive database of commercially accessible drug discovery screening compounds to be
made available to all NIH researchers ChemNavigator is pleased to serve NIH affiliated scientific researchers in compound
sample procurement As an NIH researcher you have full access to use the iResearch System All you need to do is take a
few minutes to register in the system Then you will be able to perform chemical structure searches for compound samples
of interest and purchase these samples through this on-line system Link is here httpwwwchemnavigatorcomnihasp
Additional References related to biological activity of compounds
Edwards AM Bountra C Kerr DJ Willson TM Open access chemical and clinical probes to support drug discovery Nature
chemical biology 2009 5(7)436-440
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
Wang Y Suzek T Zhang J Wang J He S Cheng T Shoemaker BA Gindulyte A Bryant SH PubChem BioAssay 2014 update
Nucleic acids research 2014 42(Database issue)D1075-1082
Wang Y Bolton E Dracheva S Karapetyan K Shoemaker BA Suzek TO Wang J Xiao J Zhang J Bryant SH An overview of
the PubChem BioAssay resource Nucleic acids research 2010 38(Database issue)D255-266
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
main menu
Pharmacokinetic tutorial drug exposure measurement services pharmacokinetic data references
Selecting the correct dose to achieve exposure of drug that are adequate to test a hypothesis in preclinical species
requires that you know the potency of the molecule at the desired drug target and the dose of compound required to
achieve target organ exposure that will result in the free (not bound by protein) concentration of drug required to engage
the molecular target within the target organ compartment Estimates of Drug potency can be found in many of the
databases listed under correct molecule The free concentration of a drug is determined in the plasma by multiplying the
concentration of drug in the plasma by the fraction unbound This must be measured for each compound A literature
reference that provides the measured plasma protein binding (PPB) values for many common drugs is provided here
Zhang Xue Shao and Jia (2012) Compilation of 222 drugsrsquo plasma protein binding data and guidance for study designs
Drug Discovery Today Vol 17 Issue 9-10 Pages 476-485 httpwwwncbinlmnihgovpubmed22210121
If your drug target is the brain then you must also understand the kinetics of drug disposition and clearance including blood
brain barrier (BBB) penetration in your test species to select a dose of compound adequate to test your hypothesis
Download a tutorial deck on basic principles of drug disposition and their application in small molecule drug discovery
courtesy of Dr Chris Shaffer Pfizer
150805DMPKTutorial(CLSBCHCourse)pdf
Pharmacometrics Research Core and Pharmacokinetics Service The Pharmacometrics Research Core is directed by Dr Luis
Pereira and provides analytical services for assaying drugsmetabolites in biological matrices (eg plasma serum blood
urine CSF saliva tissues) The Core provides pharmacokinetic and pharmacodynamic analyses for current and future
clinical trials and research projects (including contract services) It conducts stability and potency studies for pediatric
formulations compounded at BCH as per recent demand from FDA and CMS Finally the Core fosters grant applications
and research collaborations both intra and extramural The TNC can additionally provide investigators with consultation in
the identification of resources for pharmacodynamic assay development and contract research organizations able to
provide bioanalysis of preclinical samples needed to support animal clinical trials Contact Dr Luis Pereira for more
information LuisPereirachildrensharvardedu
article on importance of understanding drug exposure in preclinical drug studies here
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
References on Pharmacokinetics and Brain Penetration of Small Molecules
Di L Rong H Feng B Demystifying brain penetration in central nervous system drug discovery Miniperspective Journal of
medicinal chemistry 2013 56(1)2-12
Reichel A Addressing central nervous system (CNS) penetration in drug discovery basics and implications of the evolving
new concept Chemistry amp biodiversity 2009 6(11)2030-2049
Smith DA Di L Kerns EH The effect of plasma protein binding on in vivo efficacy misconceptions in drug discovery Nature
reviews Drug discovery 2010 9(12)929-939
Moda TL Torres LG Carrara AE Andricopulo AD PKDB database for pharmacokinetic properties and predictive in silico
ADME models Bioinformatics 2008 24(19)2270-2271
Law V Knox C Djoumbou Y Jewison T Guo AC Liu Y Maciejewski A Arndt D Wilson M Neveu V et al DrugBank 40
shedding new light on drug metabolism Nucleic acids research 2014 42(Database issue)D1091-1097
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
main menu
Formulations advice and assistance with preclinical drug delivery Neurodevelopmental Behavioral Core
To effectively deliver drug to preclinical species for the duration of a study researchers must choose a dose a formulation
and a route of administration that will support target organ exposure long enough to test a therapeutic hypothesis Since
most drugs developed for humans are optimized for human metabolism parameters many compounds developed for
humans are rapidly metabolized and cleared in rodents requiring alternative formulations and routes of preclinical
administration (see tutorial under Correct Dose)
Proper formulation of drugs and vehicles to ensure appropriate drug exposure is a critical factor in preclinical study design
The Neurodevelopmental Behavioral Core may provide advice on standard formulations Preclinical assistance and
training across many routes of administration including IV cannulation osmotic minipumps oral gavage sc and ip is also
available through the Neurodevelopmental Behavioral Core
Contact is Dr Nick Andrews NickAndrewschildrensharvardedu
Custom formulation used for human studies are supported on a case by case basis by the Pharmacometrics Research Core
or Clinical Research Pharmacy Contact for the Pharmacometrics Core is Dr Luis Pereira LuisPereirachildrensharvardedu
The Clinical Research Pharmacy can provide advice on unusual formulations Contact is Dr Rocco Anzaldi
RoccoAnzaldichildrensharvardedu
idspharmacy-dlchildrensharvardedu
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
main menu
Stratification Biomarker development and resources patient sample repositories requests for collection of new types of
patient samples development of patient specific iPSC lines and neurons Genetic databases RNA expression databases
Humans are diverse Not only do patients come in different sizes ages genders and ethnic backgrounds but the same
disease diagnosis often develops in people as a function of different environmental insults and genetic predispositions
Finding biomarkers that will segregate similarly diagnosed patients into subsets of biologically more homogenous
populations is a critical feature of good clinical trial design A lsquostratification biomarkerrsquo can be a biochemical measure from
patient samples a structural or a functional feature of a human imaging technology or a functional measure of an
electrophysiological readout
The Translational Neuroscience Center can help investigators access advice and assistance for investigators with vendors
experienced in profiling DNA RNA or protein across a range of platforms httpwwwchildrenshospitalorgresearch-and-
Neurophysiology Services can assist investigators with identification of biomarkers to stratify patients based on EEG
signatures Contact Drs Charles Nelson and Jurriaan Peters Co-Directors
CharlesNelsonchildrensharvardedu
JurriaanPeterschildrensharvardedu
MRIRadiology Imaging Core can assist with identification of biomarkers to stratify patients by functional or structural deficits
in brain circuitry Contact Dr Simon Warfield Director SimonWarfieldchildrensharvardedu
Molecular Genetics core can assist investigators with identification of genetic stratification biomarkers or gene expression-
based stratification biomarkers Contact Drs Louis Kunkel and Christopher Walsh Co-Directors
LouisKunkelchildrensharvardedu
ChristopherWalshchildrensharvardedu
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
The Human Neuron Differentiation Service within the Translational Neuroscience Center can help investigators recruit
specific subtypes of patients to be consented for reprogramming of blood or fibroblast cells into iPSC lines that will support
differentiation into human neurons for phenotypic analysis and screening ContactDr Robin Kleiman
RobinKleimanchildrensharvardedu
Translab can assist with routine processes as well as complex laboratory-‐developed tests They place special emphasis on
assay development for use in clinical trials Translab website with contact information can be viewed here
httpwwwtranslabbostonorg
TransLab Flyer 2 2015pdf
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
main menu
Patient sample repositoryBiobank Patient registry
Disease processes are dynamic The molecular underpinnings of disease differ between inception progression and
response of the body to disease Thus each stage of disease may require alternative therapeutic strategies Understanding
which stage of disease is best suited to testing a specific therapeutic approach will require information about disease from
patient samples collected at different stages of disease well as an ability to collect and recruit patients at relevant stages of
disease
To locate human RNA profiling data in the public domain from disease samples and tissues at specific stages of disease
search databases referenced in the Correct Target section of this document
The Translational Neuroscience Center offers multiple services that can assist with identification of the correct patients The
Core Repository for Neurological Disorders stores a wide variety of patient samples from many stages of disease The
biorepository is directed by Dr Mustafa Sahin and these samples and de-identified clinical data can be searched and
requested through the Translational Neuroscience Center
The Biobank Core Lab serves as a core resource that ensures top-level specimen handling and services to the Boston
Childrens Hospital research community It serves as both a service core and a biorepository providing an institutional
perspective on the presence of specimens that may be available for use to foster collaborations and accelerate research
and discovery
The Clinical Research and Regulatory Affairs Service can provide assistance to investigators in identifying patients andor
repository samplesdata Contact Co-Directors Stephanie Brewster and Kira Dies for more information about access to
these resources
StephanieBrewsterchildrensharvardedu
KiraDieschildrensharvardedu
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
main menu
Statistical support clinical trialsgov
Determining the correct sample size to support preclinical and clinical studies requires power calculations that take into
account the variability of the endpoint being measured Statistical support for preclinical studies is available on a
department by department basis Neurology and Neurobiology requests for preclinical biostatistics support can be made
through the CRC website
httpredcap-qiredcap_edcsurveyss=Rma5u83qKC
Clinical statistical support for all departments is also available through the CRC Design and Analysis Core For more
information contact Michael Monuteaux michaelmonuteauxchildrensharvardedu
Clinical datasets that provide data for supporting power calculations can be found by searching through clinical trialsgov
database All studies in the clinical trials data base are required to describe the study design the endpoints under
evaluation and the treatments as well as links to publications of the studies The studies can be searched by topic This can
be a good way to find historical data to help you evaluate variability of endpoint measures in clinical populations This will
be needed to support sample size power calculations httpsclinicaltrialsgov
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
main menu
Understanding RDoC Human Neurobehavioral Core Service IRB assistance with clinical protocols
Different stages of clinical trials have different goals for selecting endpoints Early stage clinical trials are typically in search
of a translatable pharmacodynamic or target engagement endpoint to ensure that the molecule in question will be
competent to test a clinical hypothesis in humans Developing translatable measures of target engagement in preclinical
species and humans is critical to developing data sets that will enable subsequent therapeutic efficacy trials The earliest
trials require endpoints that can be measured in a functionally equivalent manner across species Therefore it is critical for
preclinical researchers to develop dose-responsive data sets in preclinical species using quantitative endpoints such as EEG
visual or auditory evoked potentials PET ligands plasma or CSF based biochemical measures or translatable task based
behaviors Preclinical data must be a developed with an eye towards what the equivalent measure will be in the clinic
Toward that end the NIMH has initiated the Research Domain Criteria (RDoC) that is aimed at characterizing mental health
disorders across many different dimensions across species A big focus of the RDoC initiative is the identification of
translatable endpoints for evaluating pharmacodynamics and efficacy in Neuroscience Drug Discovery Preclinical
Neuroscience researchers should be familiar with the RDoC framework For advice on in vivo characterization of preclinical
endpoints with translational potential for Neuroscience related disorders contact Dr Robin Kleiman at the TNC
robinkleimanchildrensharvardedu
The Human Neurobehavioral Core Service of the Translational Neuroscience Center can provide guidance to investigators
on the appropriate tests that will provide the best translation from animal studies to human studies The Service also offers
human neurobehavioral assessment services Contact-Drs Charles Nelson and Deborah Waber Co-Directors
CharlesNelsonchildrensharvardedu
DeborahWaberchildrensharvardedu
Developing clinical protocols and obtaining IRB approval for human study of translatable endpoints can be supported by
the Translational Neuroscience Center Clinical Research and Regulatory Affairs Service Contact-Kira Dies and Stephanie
Brewster Co-Directors
KiraDieschildrensharvardedu
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
StephanieBrewsterchildrensharvardedu
Background Information on RDoC httpswwwnimhnihgovresearch-prioritiesrdocindexshtml
Casey BJ Oliveri ME Insel T A neurodevelopmental perspective on the research domain criteria (RDoC) framework
Cuthbert BN Insel TR Toward the future of psychiatric diagnosis the seven pillars of RDoC BMC Med 2013 11126
httpwwwncbinlmnihgovpmcarticlesPMC3653747
Insel T Cuthbert B Garvey M Heinssen R Pine DS Quinn K Sanislow C Wang P Research domain criteria (RDoC)
toward a new classification framework for research on mental disorders The American journal of psychiatry 2010
167(7)748-751 httpwwwncbinlmnihgovpubmed20595427
Insel TR The NIMH Research Domain Criteria (RDoC) Project precision medicine for psychiatry The American journal
of psychiatry 2014 171(4)395-397 httpwwwncbinlmnihgovpubmed24687194
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
main menu
Body atlases for expression of mRNA and protein guides to chemical alerts guidance for preclinical toxicology studies for
Investigational New Drug (IND) applications
Discovery scientists must consider the distribution of the proposed drug target across the entire body in human samples in
order to understand potential safety risks to be monitored during preclinical toxicological testing Teams also have to be
aware of differences in distribution of the target and related family members in preclinical species Many of the target
expression databases listed in the Correct Target section of this document are useful in this regard Assays that can be used
to monitor any potential safety risks are critical to the development of a suitable testing funnel needed to advance
compounds
Many chemical classes of compounds that are identified in screens are not suitable for drug development due to the
presence of structural alerts that are known to cause chemical toxicity Databases that house information of structural alerts
can be used to de-prioritize structural series early in the life of a program Some toxicology databases that can help
deprioritize toxic chemotypes include httppubsacsorgdoiabs101021ci300245q
Some web resources for identifying side effects of known compounds httpintsideirbbarcelonaorg
Once a potential clinical candidate molecule is identified GLP-qualified toxicology studies must be carried out with a
qualified vendor to support regulatory filings of an Investigational New Drug (IND) application For a short tutorial on studies
needed to support preclinical toxicology testing and guidance on evaluating contract research organizations that are
qualified to perform this work see attached tutorial courtesy of Dr Joe Brady Pfizer
Brady boston childrens hosp talk aug2015 IND toxpdf
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
main menu
FAQs
Industry partners and collaborators can bring tremendous expertise and complementary resources to bear on research
projects with therapeutic applications These may include medicinal chemistry expertise pharmacology expertise access
to unique and undisclosed chemical probe molecules assay development and high-throughput screening resources
antibody and other reagent development pharmacokinetic analysis pharmacokinetic and pharmacodynamics
modeling formulation expertise post-doctoral training programs and in some cases financial support There is a wide range
of models of interacting with industry in a range of different capacities Some frequently asked questions about types of
relationships and the responsibilities associated with those interactions can be found in the following document
Download Frequently Asked Questions about working with Industry
Translation of basic research into new marketed drugs will require a transition from exploring scientific principles and testing
hypotheses into commercial products Industry partners capable of developing these potential products need to be able
to license the intellectual property required to sell the product in order to justify investment in building programs around new
ideas This requires that scientific researchers protect and patent potential inventions from their work to enable future
commercialization by partners with appropriate expertise To ensure that researchers are appropriately documenting their
work in a manner that will support preservation of intellectual property all investigators are encouraged to consult with TIDO
before any public disclosures of new research Similarly the following documentation provides guidance for documenting
your work according to standards that will support patent applications
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
Download the compliance manual for BCH for Intellectual property policy
cm_021_intellectual_propertydocx
Download a summary of laboratory notebook Dorsquos and Donrsquot
Dosdontsnotebookspdf
Link to TIDO Technology Innovation and Development Office
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
main menu
A phenotypic screen requires a biologically robust assay that represents a significant aspect of disease-relevant human
biology It can be used to identify molecular targets for target validation studies through the use of well-annotated
bioactive molecules or genomic libraries (eg RNAi CRISPER) Alternatively phenotypic screens can be used to identify
novel compounds that must subsequently be lsquoDE convolutedrsquo to identify novel targets using lsquowarheadsrsquo These screens rely
on identification and manipulation of a functional deficit or phenotype using a patient-derived cellular system
The strengths of this approach
Use of human systems can improve translatability
Identified compounds may empirically balance therapeutic activity at multiple required targets
Well-suited to drug repurposing
Phenotypic screens can be used to identify compounds or targets for mechanism based drug discovery programs
Many CNS drugs have been discovered using a phenotypic repurposing screen (Swinney and Anthony 2011)
Drawbacks to this approach
Assays are slow low throughput and more expensive as compared to cell-free assays
Cell-based assays may not predict circuit level or brain phenotypes
Furthermore as a primary screening approach
Precludes leveraging strengths in uHTS SBDD and parallel design
Every molecule must be de-risked independently thus safety can be very hard to predict
Drug Repurposing Drug Repurposing is a strategic pillar of the National Center for Advancing Translational Science (NCATS)
Details on resources and funding opportunities can be found here httpsncatsnihgovntu
Chemogenomic Files from industry partners Many companies have well designed and annotated chemical files that are
designed to cover the druggable genome with small molecule compounds from their proprietary collections Each
company has different criteria and stipulations associated with use of the library It is advisable to consult with TIDO
regarding terms and conditions associated with individual companies
ICCB-LongwoodKirby ADSF The ICCB screening center and the Kirby ADSF have multiple collections of compounds that
include bioactive or FDA approved molecules available for screening
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
Kirby ADSF libraries contact Dr Lee Barrett LeeBarrettchildrensharvardedu
References related to phenotypic screens and Drug Repurposing
Vincent F Loria P Pregel M Stanton R Kitching L Nocka K Doyonnas R Steppan C Gilbert A Schroeter T
and MC Peakman Developing predictive assays The phenotypic screening ldquorule of 3rdquo Sci Transl Med 7 293ps15
(2015)
Langedijk J Mantel-Teeuwisse AK Slijkerman DS Schutjens MH Drug repositioning and repurposing terminology and
definitions in literature Drug Discov Today (2015)
Swinney DC and J Anthony How were new medicines discovered Nature Reviews Drug Discovery 10 507-
519 (July 2011) | doi101038nrd3480
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
main menu
TNC Clinical Research and Regulatory Affairs Service Research Participant Registry CRC
Glossary of Terms
Glossary-of-Clinical-Trials-Termspdf
Clinical Research and Regulatory Affairs Service This Translational Neuroscience Center service facilitates the mission of the
Translational Neuroscience Center providing coordination among studies communications resource development and
implementation of new or ongoing preclinical and clinical studies The service is led by experts in protocol development
and launching of new studies The directors are available to guide TNC researchers in designing human studies including
the preparation of Institutional Review Board (IRB) and FDA submissions Additionally staff of the Clinical Research and
Regulatory Affairs Service will help researchers with recruitment plans budget development supervision of study
coordinators study monitoring and audit preparation For more information contact Co-Directors Kira Dies ScM CGC and
Stephanie Brewster MS CGC
KiraDieschildrensharvardedu
StephanieBrewsterchildrensharvardedu
Clinical Research Center (CRC) Assists investigators at BCH with research project initiation and implementation resources
in the CTSU for the conduct of clinical research visits and ancillary services education on research methods and practices
The CRC has biostatisticians project managers research specialists clinical trials specialists research coordinators and
highly skilled nurses and nurse project managers who work every day to facilitate the many research needs of the BCH
community httpwwwchildrenshospitalorgresearch-and-innovationresearchclinicalclinical-research-center
Clinical and Translational Study Unit (CTSU) The CTSU provides clinical research infrastructure for investigators in the design
initiation conduct and reporting of clinical research with the goal of translating scientific knowledge into new therapies for
pediatric conditions httpweb2tchharvardeductsu
Clinical Research Roadmap This clinical research map is designed to serve as a guide for investigators study coordinators
and research nurses at Boston Childrenrsquos Hospital The research map outlines the key steps in preparing to launch a
research study and provides embedded links to institutional resources tools and documents
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
Clinical Research Mappdf
main menu
Office of Sponsored Programs Research Administration TIDO
Many government and foundation grant opportunities are available for developing Drug Discovery Projects updated lists of
funding options exist on OSP and Research Administration web sites
Some good options for finding relevant requests for proposals
Translational Research Program annual call for proposals
Boston Childrenrsquos Hospital ndash Broad Institute Collaboration Grants Proposals will be reviewed by a joint Childrenrsquos Hospitalndash
Broad Institute committee Additional submission dates are expected for 2016
BCH_Broad collaborative grant 852015docx
Kirby Neurobiology Screening Pilot awards- available to Kirby Neurobiology PIs as funding is available
Translational Neuroscience Center- Pilot awards supported by trust sponsored donations as available Distributed through
TNC e-mail lists
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
ADDF The ADDF Academic Drug Discovery and Development Program seeks to create and support innovative translational
research programs for Alzheimerrsquos disease related dementias and cognitive aging in academic medical centers and
universities Biomarker development studies and innovative proof of concept pilot clinical trials of new approaches to
treatment prevention and early detection are also supported
Department of Defense ALSRP The FY15 Defense Appropriations Act provides $75 million (M) to the Department of Defense
Amyotrophic Lateral Sclerosis Research Program (ALSRP) to support innovative high-impact Amyotrophic Lateral Sclerosis
research As directed by the Office of the Assistant Secretary of Defense for Health Affairs the Defense Health Agency
Research Development and Acquisition (DHA RDA) Directorate manages and executes the Defense Health Program
(DHP) Research Development Test and Evaluation (RDTampE) appropriation The executing agent for the anticipated
Program AnnouncementsFunding Opportunities is the Congressionally Directed Medical Research Programs (CDMRP)
httpcdmrparmymilpubspress201515alsrppreannshtml
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
Michael J Fox Foundation Therapeutic Pipeline Program Supports Parkinsons disease therapeutic development along the
pre-clinical and clinical path (both drug and non-pharmacological therapeutics including gene therapy biological
surgical and non-invasive approaches) The Michael J Fox Foundation seeks applications with potential for fundamentally
altering disease course andor significantly improving treatment of symptoms above and beyond current standards of care
Proposals must have a well-defined plan for moving toward clinical utility for patients The Therapeutic Pipeline Program is
open to industry and academic investigators proposing novel approaches or repositioning approved or clinically safe
therapies from non-PD indications httpswwwmichaeljfoxorgresearchgrant-detailphpid=28
NINDS The Blueprint Neurotherapeutics Network (BPN) Provides the neuroscience community access to a complete and
seamless pipeline for preclinical drug development beginning with chemical optimization and concluding after phase I
clinical trials Participants in the BPN will receive funding to conduct bioactivity and efficacy testing in their own laboratories
as well as access to millions of dollars in NIH-contracted drug development services including medicinal chemistry
pharmacology toxicology and phase 1 clinical trials NIH will also provide drug development consultants who have had
years of experience working at a senior level in industry Because the Blueprint is establishing a network of drug
development service providers that typically cater to biopharmaceutical companies neuroscientists who join the BPN can
readily plug in to all of the drug development expertise that typically resides in industry The projects supported through the
network will be highly collaborative and the researchers who initiate the projects will serve as the principal investigators
(PIs) directing their projects through the development pipeline with the help of industry consultants The PIs and their
institutions will have the opportunity to attain assignment of intellectual property rights from all other network participants
who may have intellectual input into their projects This will allow the PIs to retain control of the intellectual property for drug
candidates developed through the network and eventually pursue licensing and commercialization partnerships
httpneuroscienceblueprintnihgovbpdrugs
NeuroNEXT Will establish a consortium of clinical sites capable of forming disease-specific cadres of investigators in order to
develop and implement trials rapidly in a wide range of neurological disorders that affect adults andor children With a
stable and experienced research staff a central IRB model and master trial agreements NeuroNEXT will streamline the
administrative processes for clinical trials and reduce start-up times NeuroNEXT will also be able to design and implement
evidence-based measures to improve patient recruitment into clinical trials httpswwwneuronextorgresearchers
NIMH Many grant options see overview here httpwwwnimhnihgovresearch-prioritiestherapeuticsindexshtml
Building on High Impact Basic Neurobiology Through Assay Development Advancing Tools for Therapeutic Discovery (R01) -
See more at httpgrantsnihgovgrantsguidepa-filesPAR-15-066htmlsthashs1HMWjWudpuf
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
NCATS many grant options see overview here httpwwwncatsnihgovprograms
Bridging Interventional Development Gaps (BrIDGs) Program Makes available on a competitive basis certain critical
resources needed for the development of new therapeutic agents for both common and rare diseases Investigators do not
receive grant funds through this program Instead successful applicants receive access to NIH experts and contractors who
conduct pre-clinical studies at no cost to the investigator In general synthesis formulation pharmacokinetic and
toxicology services in support of investigator-held IND applications to the Food and Drug Administration (FDA) are available
httpwwwncatsnihgovbridgsworksolicitation
NCATS Discovering New Therapeutic Uses for Existing Molecules (New Therapeutic Uses) A collaborative program designed
to develop partnerships between pharmaceutical companies and the biomedical research community to advance
therapeutics development This innovative program matches researchers with a selection of pharmaceutical industry
assets to test ideas for new therapeutic uses with the ultimate goal of identifying promising new treatments for patients
httpwwwncatsnihgovntu
Pfizer Centers for Therapeutic Innovation (CTI) Suitable for biotherapeutic or small molecule projects with a strong project
rationale (demonstrated association between target biology pathway and disease mechanism) CTIrsquos areas of interest
include inflammation autoimmunity tissue remodeling oncology cancer immunology rare or genetic diseases
cardiovascular and metabolic diseases and neuroscience Selected projects are undertaken by a joint team with BCH
members and Pfizer CTI drug development experts located on the 18th floor of CLS working towards agreed common
goals The Pfizer CTIBCH collaboration program is managed by a Joint Steering Committee with representation from both
Boston Childrenrsquos and CTI httpswwwpfizercticom Calls for proposals come through TIDO three times a year in January
May and September httpwwwchildrensinnovationsorgPagesHighlightsHighlights-83aspx
Shire-BCH Collaborative Program Development The Joint Steering Committee of the Shire Alliance extends a call for ldquoPre-
Proposalsrdquo with defined objectives from time to time generally annually in the late fall or winter That call is publicized
through emails from BCH Research Administration and TIDO Following review by the JSC a full proposal may be requested
Unsolicited proposals may also be considered from time to time
ACRONYMS
HTS- High-throughput Screen run with 96 well 384 well 1536 wells or 3456 well capacity- screen has capacity to run through a library of 1-3Million compounds in total
uHTS- Ultra High-throughput Screen ndash arbitrary cut off to denote capability to measure 100s of thousands of assays per day with automation and high density plate readers
HCS- High Content Screen usually a cell based assay that is able to monitor multiple endpoints reflective of different cellular processes in a single well of cells treated with a compound May be biochemical or image based endpoints
SAR- Structure-Activity Relationship ie relationship of modifications to chemical structure on relevant activity SPR-Structure-Property Relationship ie relationship of modifications of chemical structure on physicochemical
properties
PK- Pharmacokinetic measure of drug levels in a body compartment
PD- Pharmacodynamic a measure of functional activity of a drug
PKPD- PharmacoKinetic PharmacoDynamic relationship- how drug levels relate to drug response in a system
DDI-Drug-Drug Interactions- occurs when one drug affects the activity of another drug when co- administered Often due to changes in ADME properties of one of the co-administered drugs (ie for example induction by one drug of enzymes that will metabolize the second drug )
DMPK- Drug Metabolism and PharmacoKinetics
ADME- Absorption Distribution Metabolism amp Excretion
PDM-pharmacokinetics dynamics and metabolism GLP- Good Laboratory Practice- regulations that govern toxicology studies required by the FDA to support IND
and NDA
POM- Proof of Mechanism clinical studies to demonstrate hit the target and elicited a biological response
POC- Proof of Concept Clinical studies to demonstrate a clinically meaningful outcome measure improved
PoP-Proof of Principal usually preclinical studies that demonstrate that engaging target in a disease model produced efficacy
FIH- First in Human clinical trial to evaluate new molecule in humans for safety and PK- Ph1
FIP-First in Patient first clinical trial to evaluate new molecule in patients hERG (the human Ether-agrave-go-go-Related Gene) is a gene KCNH2 that codes for a subunit of Kv111 and
contributes to the repolarizing current in the heart that coordinates the hearts beating When compromised by application drugs or by rare mutations in some families it can result in a potentially fatal disorder called long QT syndrome A number of clinically successful drugs in the market have had the tendency to inhibit hERG and create a concomitant risk of sudden death as a side-effect which has made hERG inhibition an important anti-target that must be avoided during drug development
IND-Investigational New Drug Application- formal application to FDA to evaluate a NCE in people
NME- New Molecular Entity- a new FDA approved drug
NCE-New Chemical Entity-an investigational drug that is not yet a FDA approved NME NDA- New Drug Application (A lsquoFilingrsquo)- a formal application for approval of a new drug
CAN-(Pfizer-specific shorthand )-Clinical Candidate- a molecule competent to be tested in humans IB- Investigators Brochure- basic information on an investigational drug and its mechanism for clinicans involved
in conducting a clinical trial Provides background information on the hypothesis being tested and the types of patients that should be included excluded and risks and how the drug should be administered It must be updated continually by the sponsor to include all new findings
SOC- Standard of Care- in our context it is the drug treatment that a clinican should prescribe for a particular type of patient used as a benchmark for comparing new entities
MTD- Maximum Tolerated Dose- first identified in GLP safety studies during preclinical development AE- Adverse Event- a side effect that causes safety concerns
TI- Therapeutic Index -ratio of the concentration of drug needed to produce efficacy and the concentration of drug that is safely tolerated ( also called ldquoSafety Marginrdquo)
Questions Contact Robin Kleiman- email RobinKleimanchildrensharvardedu office CLS 13070
Terms that relate to Targets Molecular target- the protein that binds drug to produce efficacy Off-Target- other proteins that bind the drug that do not relate to efficacy and may produce Adverse Events (AEs) Druggable target ndashcomes from a class of proteins that has successfully been targeted with small molecule drugs in
the past Primarily transporters enzymes receptors ion channels (Not protein-protein interactions transcription factors RNA binding proteins etc)
Druggable genome- about 3000 genes encoding all druggable proteins Druggability- the presence of protein folds (quarternary structures) that favor specific interactions with drug-like
molecules Exploratory target- Hypothesis that a modulating a target via a particular mode of action will be beneficial to a
particular patient population Validated target- Hypothesis regarding a target also has in vivo efficacy data for a disease or a disease model- along
with a complete understanding of how the target mechanism relates to disease- (also called lsquoProof of Principlersquo) Phenotypic screen- a screen for compounds that will reverse a phenotype the molecular target may not be known Systems pharmacology target(s)-a precisely defined combination or lsquofingerprintrsquo of molecular targets to be
modulated to correct a phenotype (Poly-pharmacology)
Terms that relate to programs
Biomarker- a physiological pathological or anatomical characteristic that is measured by an automated process or algorithm as an indicator of the normal biological process pathological process or biological response to a therapeutic intervention Many types of Biomarkers target engagement biomarkers stratification biomarkers efficacy biomarkers pharmacodynamic biomarkers etchellip
Laboratory Objectives-Criteria established at the start of the program to define the desired pharmacological properties of the molecule with regard to potency selectivity mode of action frequency and route of administration For antibodies would include minimal criteria for knock down stability etc
Therapeutic Modality- small molecule biologic RNAi stem cell etc
Screening tree Screening funnel- A decision tree for utilizing a panel of assays to identify molecules that meet the laboratory objectives
Terms that relate to molecules
Drug-like molecule- has physicochemical properties in line with known oral medications The molecule will be largely rule of 5 (RO5) compliant therefore small and moderately lipophilic Not related to pharmacological activity
Rule of Five (RO5)=Chris Lipinskirsquos rule of 5 states that a drug like molecule will have the following properties Molecular Weight of less than 500 a clogP lt5 fewer than 5 H-bond donors and the number of H-bond acceptors ( which is the sum of N and O atoms) is less than 10
Physicochemical properties- key properties of molecules include (calculated)Molecular Weight number of H bond acceptors and donors (measured) kinetic solubility pKa lipophilicity (logD logP)
Chemical tool -a compound with good potency and selectivity for a specified molecular target but fails to meet all criteria for safety PK or potency needed to become a clinical candidate Suitable for preclinical testing of hypothesis and proof of principal studies but not for lsquopreclinical developmentrsquo
Active molecule describes an individual chemical entity with measurable dose-dependent activity in a biological screening assay
Hit molecule refers to a molecule plus its related structural analogs for which there is an understanding of the structure-properties and structure-activity relationships (SPR and SAR) for a specific biological context Additionally preliminary drug disposition data (both in vitro and in vivo) provide an assessment of pharmacokinetic properties The available data provide a basis for further optimization of the hit series
Lead molecule refers to a molecule plus its related structural analogs that demonstrate o Sufficient exposure at pharmacologically relevant doses by the intended route of administration to explore
intended pharmacology in a relevant in vivo disease or pharmacodynamic model o Proof-of-principle or efficacy in a in vivo model that will be used to establish a margin of safety
Clinical candidate an optimized individual chemical entity derived from a lead series that demonstrates o a dose-response relationship via intended route and schedule of administration in relevant disease model o an exposure-based margin of safety in toxicology studies o In summary a clinical candidate is a molecule that is deemed competent for testing the primary disease
intervention hypothesis in humans
A laboratory notebook is a vital record of events leading to a patentable invention Therecorded information can establish dates of conception and reduction to practice of atechnology as well as the inventorship of a patent claiming the technology Below arefourteen rules you should follow when keeping lab notebooks
1 mdash Do use bound booksInventors should use permanently bound notebooks eg notebooks with spiral or glue bindings If loose-leaf sheets are used they should be consecutively numbered and eachpage should be dated signed and witnessed
2 mdash Do sign and date Each notebook should be signed and dated on the inside front cover to indicate the firstday the recipient started using the notebook Each entry should be dated and signed orinitialed
An independent witness ie someone who understands the technology but will not benamed as a co-inventor of the invention should sign and date each entry after the state-ment ldquoRead and understood by rdquo (The witness should preferably sign theentries on a contemporaneous or fairly contemporaneous basis but entries can also bereviewed signed and dated on a periodic eg weekly or monthly basis)
3 mdash Do use inkNotebook entries should be made in ink and in chronological order Entries should not beerased or ldquowhited outrdquo If an entry contains an error a line should be drawn through theerror and new text should continue in the next available space
4 mdash Donrsquot leave blank spacesBlank gaps between entries should be avoided If a blank space is left on a page a line orcross should be drawn through the blank space and the page dated to prevent subsequententries
5 mdash Donrsquot modifyPrior entries should not be modified at a later date If data were omitted the new datacan be entered under a new date and cross-referenced to the previous entry Record exper-iments when they are performed
6 mdash Do use past tenseUse the past tense (eg ldquowas heatedrdquo) to describe the experiments that were actually performed
Fish amp Richardson pc
Dorsquos and Don rsquo ts forKeeping Lab Notebooks
Boston
Dallas
Delaware
New York
San Diego
Silicon Valley
Twin Cities
Washington dc
FR
7 mdash Do explain abbreviations and special termsExplain all abbreviations and terms that are nonstandard Explain in context in a table ofabbreviations or in a glossary
8 mdash Do staple attachmentsAttachments such as graphs or computer printouts should be permanently attached to pagesin the notebook (eg by stapling) and both the attachment and the notebook page signedand dated If the attachment cannot be stapled it should be placed in an envelope and theenvelope stapled to the notebook page The envelope and page should then be signed andwitnessed making reference to the attachment being placed in the envelope
9 mdash Donrsquot remove originalsNo original pages should be removed from the notebook
10 mdash Do outline new experimentsWhen a new project or experiment is started the objective and rationale should be brieflyoutlined (eg in a short paragraph or by providing a flowchart)
11 mdash Do record lab meeting discussionsRelevant discussions from lab meetings should be recorded as should ideas or suggestionsmade by others The names of the people making the ideas and suggestions should be care-fully documented This information may be important in establishing inventorship
12 mdash Do provide detailRecord test descriptions including preferred operating conditions control conditionsoperable and preferred ranges of conditions and alternate specific materials Also recordtest results and an explanation of the results as well as photos or sketches of the resultsandor the test device Any conclusions should be short and supported by the factual dataOpinions or speculation about the invention should be avoided
13 mdash Do track notebooksIdeally each lab should maintain a catalog of notebooks in which each notebook is assigneda number and the name of the author of each notebook is recorded In addition the datethe author received the notebook as well as the date the notebook was completed andreturned should be recorded Upon leaving the lab the author should return all notebookschecked out by or to him
14 mdash Do save completed notebooksAll completed notebooks should be indexed (eg by number by author andor by subjectarea) and kept safely in a central repository together with corresponding patent applica-tions or patents Lab notebooks that relate to inventions on which patents have been grant-ed should be kept for the life of the patent plus six years
By J Peter Fasse
Fish amp Richardson pcIntellectual property complex litigation technology law800 818-5070wwwfrcominfofrcom
P ER SP EC T I V E
PHARMACOK INET I CS
Data gaps limit the translational potentialof preclinical researchRobin J Kleiman1 and Michael D Ehlers2
The absence of mouse pharmacokinetic reference data hinders translation An analysis ofrecent literature highlights a systematic lack of discussion regarding rationale for the selec-tion of dosing paradigms in preclinical studies and in particular for neuroscience studies inwhich the lack of brain penetration can limit target-organ exposure We propose solutionsto improve study design
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nloaded from
Despite widespread use of pharmacologicalagents in mouse models of human diseasethe literature lacks comprehensive pharmaco-kinetic profiles for such studies Coupled witha paucity of suitable data are shortcomingsin the training of experimental biologists inthe application of pharmacometric principlesto experimental study design Many authorssimply cite previously published studies tosupport the selection of a particular dose evenwhen the cited paper lacks drug exposuredata There is an assumption on the part ofresearchers that if a referenced study demon-strates a biological effectmdashthat is any measur-able physiological or behavioral effectmdashin arodent at a given dose then that same dosewill also effectively perturb disease-relevantmechanistic biology in a different study Thedanger occurs when the observed therapeuticeffects are not linked to drug-induced mecha-nistic alterations at the level of the target organLack of a drug exposurendashresponse relationshipin a target organ casts doubt on mechanisticinterpretations In addition any changes inthe route of drug administration vehicle prep-aration species used (rat versus mouse versusprimate) age or strain of animal transgenicmodification time points under investigationduration of dosing or organ targeted for inter-vention (for example brain versus a periph-eral tumor) can alter the relation between doseexposure and measured response In suchcases assumptions regarding the mechanisticbasis for observed therapeutic effects may nothold true
Preclinical pharmacological experimentsthat do not measure drug concentrations in
1Translational Neuroscience Center Kirby NeurobiologyCenter Department of Neurology Boston ChildrenrsquosHospital Harvard Medical School Boston MA 02115USA 2Neuroscience amp Pain Research Unit BioTherapeu-tics Worldwide Research and Development Pfizer IncCambridge MA 02139 USACorresponding author E-mail robinkleimanchildrensharvardedu (RJK) michaelehlerspfizercom (MDE)
the target organ run the risk of producing ex-posures that are too low or too high to inter-pret a mechanistic hypothesis Most drugs arenot selective over a large exposure range for asingle molecular target Confident evaluationof a therapeutic hypothesis requires an under-standing of the drugrsquos penetration and kineticswithin the target tissue as well as its potencyand selectivity for specific molecular targetsFurther investigators must consider the con-centration of the unbound fraction of drugthat is available to interact with the targetPublished reports often overlook the fact thatmany small molecules are more than 90bound to plasma or tissue proteins whichgreatly decreases the fraction of drug availableto bind to the intended target Thus in casesin which drug binding has a slow off-rate anorganismrsquos total drug exposure is not a predic-tor of drug available to interact with its target(1) The failure of some academic scientists toobtain relevant pharmacokinetic data impairsthe interpretation of preclinical research resultsand likely contributes to the acknowledgeddifficulties in replicating some academic liter-ature as reported by industry scientists (2 3)
Drug discovery teams in industry settingsroutinely collect pharmacokinetic data to aidin the mechanistic interpretation of in vivopreclinical data and to project optimal dosingparadigms for efficacy and toxicology studiesData required to evaluate brain penetrationare not typically collected by industry-baseddrug-discovery teams for compounds origi-nally developed for therapeutic indicationsthat do not obviously implicate the centralnervous system making this information es-pecially hard to find for many otherwise well-described drugs In addition because mousedata are not required for preclinical toxicologystudies (the more common small animal spe-cies for preclinical toxicology being rats)industry scientists do not often obtain pharma-cokinetic data from mouse experiments These
wwwScienceTranslationalMedicineo
issues are especially relevant for older drugsthat are potentially suitable for repurposingMany older drugs were discovered and char-acterized before routine pharmacokinetic-pharmacodynamic (PK-PD) modeling ofpreclinical drug exposure and its applicationto predicting human dosing became standardpractice Last pharmacokinetic data are notconsidered innovative and these studies gen-erally do not achieve publication in peer-reviewed journals even when the data havebeen generated When such data are pub-lished it is often relegated to the unsearchableblack hole of supplementary materials Thusmouse neuroPK profiles are not readily avail-able for many drugs that are frequently usedin conjunction with mouse models of humanbrain disorders
DOCUMENTING DOSING STRATEGIES
To evaluate the potential impact of insufficientpharmacokinetic data on dose selection in asample of recent published neuroscience liter-ature we conducted an analysis of papersidentified by means of a PubMed search usingthe search terms ldquodrugrdquo and ldquobrainrdquo for the pub-lication year 2014 from eight journals (Table 1)This list was culled to include only primaryresearch reports that included systemic adminis-tration of a pharmacological agent a pharma-cological therapeutic or a biological therapeuticas part of the study design The search yielded100 articles published between 1 January and30 December 2014 that used systemic drug de-livery with the intended goal of targeting thebrain of rodents (table S1) Each publicationwas examined for the stated rationale behindthe dose selection of study drugs (Table 1)
The reported rationale for dosing strategiesfell into several broad categories including(from lowest confidence to highest) (i) dose se-lected rationale not discussed (ii) literaturecitations of another study in which reportsranged from citation of exposure in the samespecies exposure in a different strain or spe-cies a dose conversion from the human liter-ature to rodent or reports of effects on rodentbehavior in another study (iii) demonstrationof an effect on rodent behavior or function inthe current study (iv) demonstration of adose-responsive biological effect in the currentstudy (v) measurement of drug levels in bloodor plasma in the current study and (vi) mea-surement of drug levels in the target organ(that is the brain) in the current study In onlytwo instances were publications identifiedthat considered the impact of drug binding
rg 6 January 2016 Vol 8 Issue 320 320ps1 1
P ER SP EC T I V E
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nloaded from
to plasma or brain proteins on the free expo-sure of drug available to interact with the tar-get This is a critical flaw in most publishedstudies that use small molecules for functionaleffects in the brain because many centralnervous system (CNS) drugs that penetratethe blood-brain barrier exhibit high proteinbinding leaving a small fraction of the totaldrug measured in plasma or brain unbound
and free to interact with the molecular targetFurthermore most studies used evidence of abiological activity to justify dose selection with-out consideration for how exposure of theagent relates to the potency of the compoundat known molecular targets which would berequired to test a mechanistic hypothesis
The lack of pharmacokinetic considera-tion does not imply that every study used an
wwwScienceTranslationalMedicineo
inappropriate dose of drug to test their hypoth-esis It does illustrate that a clear rationale wasnot provided for dose selection in most pub-lications Furthermore all 11 of the 100 publi-cations that measured total brain exposureincluded an author from the pharmaceutical in-dustry (n=5) an academic drug screening group(n = 3) or a pharmacologyndashpharmaceuticalsciences department (n = 3) This observationlikely reflects the limited presence of pharma-cology and pharmacometrics departmentswithinmost academic institutions and limitedaccess to the mass spectrometry and otheranalytical resources needed to measure druglevels in study samples Outsourcing the bio-analysis of samples collected from study ani-mals is feasible but the use of contract researchorganizations to support such studies is oftentoo costly for most academic grant budgets toaccommodate
DATABASES AND REPURPOSINGRecent years have seen increasing efforts toinvestigate approved or clinically tested drugsfor new indications (4ndash8) Such repurposinghas been touted as a means to accelerate ther-apeutic development (4) For example a stra-tegic pillar of the US National Institutes ofHealthrsquos (NIHrsquos) translational roadmap callsfor the academic community to actively par-ticipate in the repurposing of drugs approvedby the US Food and Drug Administration(FDA) or investigational drugs that havepassed safety hurdles but failed in clinicaltrials because of lack of efficacy (9ndash11) To havea meaningful impact in neurological and psy-chiatric disorders such drug repurposingefforts will require access to neuropharma-cokinetic (neuroPK) data sets in mice to guidethe testing of new therapeutic hypotheses ingenetically engineered disease models A re-cently published consensus evaluation of drugrepositioning opportunities for Alzheimerrsquosdisease identified 15 potential drug candidatesThese were further prioritized for testing onthe basis of available evidence to produce ashortlist of seven compounds reviewed by in-dustry experts to provide insight into the via-bility of these candidates The most commonshortcoming identified for the compoundsconsidered were issues related to insufficientbrain penetration or the lack of informationabout optimal dosing strategies (11)
The repurposing of statins illustrateshow the neuroPK knowledge gap limits progressStatins were developed as 3-hydroxy-3-methylglutarylndashcoenzyme A (HMG-CoA) reduc-tase inhibitors to lower cholesterol and reduce
Table 1 Preclinical dosing strategies The rationale for drug-dosing strategies was extractedfrom the literature through the analysis of 100 peer-reviewed studies published in2014 from eight journals that cover research on mechanisms of brain function disease andtherapeutic approaches to CNS disorders (Cell Neuron Nature Nature Neuroscience NatureMedicine Neurobiology of Disease Neuropsychopharmacology and Science TranslationalMedicine) (table S1) Forty-four of the 100 publications selected were studies of potentialtherapeutic approaches to disease whereas the remaining were studies of basic neurobiology ormechanisms of disease Each publication was examined to discern how authors selected thedosage of pharmacological tools or therapeutic compounds used in the design of studies toprobe brain function A relatively small number of studies considered what the concentrationof drug available in the brain after administration would be in the context of theirexperimental studies The most common method for selecting a dose of drug was tocite a previous study that demonstrated a biological effect of the drug on someaspect of rodent behavior
Rationale for studyrsquos drug-dose selection
Therapeutic
studies
Number of papers from the100 published studies
analyzed
bull No exposure or rationale for dose selection provided
5
22
bull Rodent dose extrapolated from human studies
0
1
bull Doses are similar to what was used previously toproduce a biological effect
8
23
bull Literature reports cited for multiple functionaleffects of drug at selected dose
4
5
bull Brain penetration evaluated but exposure notmeasured
2
2
bull Literature report of mismatched drug exposure
0
1
bull Observation of a biological effect at a single dosein current study
3
6
bull Observation of dose-responsive biological effectin current study
5
16
bull Brain exposure to drug was measured with routeof administration that differed from the oneused in the efficacy study
1
1
bull Plasma drug concentrations measured literaturereport of brain exposure cited and target-organpharmacodynamic effect observed in the currentstudy
1
1
bull Plasma drug concentrations measured
4
7
bull Brain pharmacodynamic effect of drug observed
2
4
bull Brain drug concentrations measured (totalconcentration)
6
7
bull Unbound brain drug concentrations measured
1
2
bull Brain drug concentrations measured and brainpharmacodynamic effect of drug observed
2
2
Total
44
100
rg 6 January 2016 Vol 8 Issue 320 320ps1 2
P ER SP EC T I V E
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risk of cardiovascular disease (12) FDA hasapproved at least nine different statins andmost are commonly prescribed nearly one-third of Americans ages 55 to 64 took a pre-scription cholesterol-lowering drug between2009 and 2012 (wwwcdcgovnchsdatahushus14pdf) The widespread availability andsafety profile of statins has lured researchersinto evaluating their potential for repurpos-ing (13) Statins have been profiled extensive-ly in preclinical research to test for potentialtherapeutic benefit in Alzheimerrsquos disease(14ndash19) Fragile X syndrome (20) Rett syn-drome (21 22) epilepsy (23) Huntingtonrsquos dis-ease (24) Parkinsonrsquos disease (25 26) stroke(27) and brain injury (28 29)
A search of the literature reveals no sys-tematic neuroPK studies in any mouse strainthat would enable direct comparisons of CNSexposure across the various statins In silicopredictions based on the drugsrsquo molecularproperties suggest that the nine most widelyprescribed statins each have a different poten-tial to penetrate the blood-brain barrier differ-ent potencies against the HMG-CoA reductaseenzyme and different ldquooff-targetrdquo activity pro-files (30) On the basis of available data thereis reason to believe that simvastatin has thebest overall profile for inhibiting HMG-CoAreductase in the brain (30) A recent study re-ported that lovastatin is able to reverse a rangeof phenotypes in a mouse model of Fragile Xsyndrome (20) However the design of an op-timal clinical trial will require the collection ofmouse pharmacokinetic data to understandhow much CNS drug exposure is required toproduce efficacy in the disease model Thereare at least two possible scenarios Giventhat simvastatin is more potent at inhibitingHMG-CoA reductase than are other statinsand likely to be more brain penetrant inboth mice and humans one would expectthat simvastatin will be more potent than lo-vastatin in ameliorating symptoms in bothmice and humans if the observed efficacy stemsfrom inhibition of HMG-CoA reductase activ-ity in the brain by lovastatin The advantage ofthis outcome would be that better brain pen-etration and potency would lead to a loweroverall dose requirement to achieve efficacyand thus likely a better safety profile
A second scenario could be that lovastatin ismore potent than simvastatin in the mousemodel of Fragile X syndrome because of anadditional biological activity inherent to thelovastatinmolecule whichmaynot yet be doc-umented in the literature In either case un-derstanding the CNS exposure of lovastatin
required to produce efficacy in themouse willdetermine whether there is a safe therapeuticindex for achieving the required concentra-tion in patients Previous attempts to discernuseful neuroPK parameters from the litera-ture for the use of statins in rodent modelshave highlighted the lack of critical data asthe looming roadblock to progress in the field(31 32) Until these data exist the transla-tional potential of preclinical research maybe limited And this is but one example ofone drug class
The creation of a centralized database isneeded for the entire translational researchcommunity and would establish a new mech-anism for academia funding agencies founda-tions and industry to pool resources If studiesare donewell the first time and documented inan open-access resource it will reduce redun-dant efforts and improve the quality of decisionmaking by scientists considering innovativesolutions to our biggest health problems
FILL THE GAPSManuscript submission practices for severalhigh-impact journals now include require-ments that authors include detailed informa-tion regarding study design and statisticalanalysis with each submission A reasonableextension of this checklist should includethe stated rationale for doses selected for studydrugs Information should include a discus-sion of data highlighted in Table 2 Authorsshould be expected to reference a relevant
wwwScienceTranslationalMedicineo
data set from a high-quality database or pub-lication or provide the data in the current study(Table 3)
Industry biologists learn basic principlesof medicinal chemistry pharmacokineticsand drug disposition while working on drugdiscovery project teams Academic groupsare playing an increasing role in transla-tional therapeutics and in particular drugrepurposing Academic programs need toaugment training in pharmacokinetics andpharmacodynamics so as to increase the rigor ofpreclinical work and to ensure that investigator-initiated clinical studies are testing hypotheseseffectively Institutions without a departmentof pharmacology or pharmacometrics mightlack the organizational knowledge needed toconduct drug studies and must identify re-sources or collaborators to patch these defi-cits Formal coursework and Web-basedresources and tutorials are needed to train andsupport translational researchers Manuscriptand grant reviewers need to demand higherstandards for preclinical studies with respect toreporting on drug exposure associated withbiological effects Ethics committees responsi-ble for review of animal protocols should re-quire investigators to provide rationale fordose selections in proposed studies Similarlyscientific review boards at academic medicalcenters need to include clinical pharmacologistswho are able to review investigator-initiatedclinical studies to ensure that proposed dosingstrategies will test a meaningful hypothesis
Table 2 Recommendations for use of pharmacokinetic data The first column includes a listof recommended data sets to aid reviewers of submitted articles in the interpretation ofpreclinical findings The second column includes a list of useful reference data that wouldsupport improved preclinical study design in mice if available in a public database
Literature reports that evaluate studydrugs should include
Compound-specific data that shouldbe included in a rodent
pharmacokinetic database
bull Expected or measured plasma exposure of thestudy drug in the preclinical species during thestudy
bull Elimination half-life (T12)bull Systemic clearance (CL)bull Fraction of drug that is protein bound (fb)
bull Expected or measured target organ exposureof the study drugs in the preclinical speciesduring the study
Maximum plasma concentration after drug admin-istration (Cmax) and time to reach maximum plas-ma concentration (Tmax) for a standardized doseand route of administration
bull Expected or measured free fraction (unboundby protein) of the study drugs in the targetorgan of the preclinical species during thestudy
bull The ratio of drug in brain to that in plasma (BP)bull The ratio of drug found free in brain (Cub) to thatfound free in the plasma (Cup) defined as CubCupbull Any potential impact of drug transporters (foundon the rodent blood-brain barrier) in limiting brainexposure
bull Expected or measured potency of the studydrug against the hypothesized activity in vitro
Expected ormeasured potency of molecule at knownbiological targets
rg 6 January 2016 Vol 8 Issue 320 320ps1 3
P ER SP EC T I V E
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A central repository that contains brainpenetration protein binding and pharmaco-kinetic profiles of drugs and pharmacologicaltools in rodents is needed to effectively sup-port translational research This databaseshould also provide basic tutorials that de-fine primary pharmacokinetic parameterswith examples to illustrate how data are usedto predict optimal dosing strategies The min-imum data set needed for each compoundin a useful rodent database is highlighted inTable 2 Access to this information and sup-porting materials will have an immediateimpact on the quality of translational drug re-purposing efforts across brain disorders andwill support the development of new thera-peutic approaches to neurological disordersand mental illness Existing databases man-aged by NIH or precompetitive consortia couldbe reinforced with donated pharmacokineticdata sets and tutorials
Industry and government scientists shouldwork precompetitively to collect and curatepharmacokinetic data sets in conjunction withsupporting educational materials Mouse phar-macokinetic data exist inside pharmaceuti-cal companies for a wide range of publicallydisclosed molecules and literature standardsRelease of these data into a public databasewould provide several benefits to companiesincluding (i) increased scientific rigor in theliterature with a higher probability of repro-ducibility (ii) increased appreciation by theacademic biology community for the diffi-culty inherent in generating molecules withpotency and pharmacokinetic profiles suit-able for in vivo work opening the door forin-kind collaboration with academic groups
and (iii) direct comparison of data collectedin-house to that collected at other compa-nies or institutions to enable better internalquality control Comprehensive pharmaco-kinetic data sets will benefit all therapeuticareas regardless of whether the brain is thetarget organ because peripheral and cen-tral exposure data can be generated fromthe same experiments Moreover the prin-ciples described above for the CNS apply toother target tissues in which vascular bar-riers metabolic processes or active transportalter the distribution of systemically admin-istered drugs
Key to ensuring that preclinical mousestudies test the hypotheses they aim to eval-uate is an understanding of the unboundfraction of drug present in the target organat an appropriate time point under studyGrant and journal reviewers need to care-fully consider whether authors of propos-als and manuscripts are providing adequaterationale for their choices of preclinical dos-ing paradigms Importantly the collectionand centralization of rodent pharmacoki-netic datasets will promote efficient genera-tion of future data reduce the collection ofredundant data and improve the return oninvestment for research funds that are de-voted to preclinical studies aimed towardclinical translation
SUPPLEMENTARY MATERIALS
wwwsciencetranslationalmedicineorgcgicontentfull8320320ps1DC1Table S1 One hundred publications that used systemic drugdelivery with the goal of targeting rodent brains
wwwScienceTranslationalMedicineo
REFERENCES AND NOTES1 A Reichel Addressing central nervous system (CNS) penetra-
tion in drug discovery Basics and implications of the evolv-ing new concept Chem Biodivers 6 2030ndash2049 (2009)
2 F Prinz T Schlange K Asadullah Believe it or not Howmuch can we rely on published data on potential drugtargets Nat Rev Drug Discov 10 712 (2011)
3 C G Begley L M Ellis Drug development Raisestandards for preclinical cancer research Nature 483531ndash533 (2012)
4 P Nair Second act Drug repurposing gets a boost asacademic researchers join the search for novel uses ofexisting drugs Proc Natl Acad Sci USA 110 2430ndash2432(2013)
5 T I Oprea J Mestres Drug repurposing Far beyond newtargets for old drugs AAPS J 14 759ndash763 (2012)
6 S M Strittmatter Overcoming drug development bot-tlenecks with repurposing Old drugs learn new tricksNat Med 20 590ndash591 (2014)
7 K Xu T R Coteacute Database identifies FDA-approved drugswith potential to be repurposed for treatment of orphandiseases Brief Bioinform 12 341ndash345 (2011)
8 X Bosch European researchers drug companies joinforces against rare diseases JAMA 294 2014ndash2015 (2005)
9 F S Collins Mining for therapeutic gold Nat Rev DrugDiscov 10 397 (2011)
10 P Vallance P Williams C Dollery The future is much closercollaboration between the pharmaceutical industry andacademic medical centers Clin Pharmacol Ther 87525ndash527 (2010)
11 A Corbett J Pickett A Burns J Corcoran S B DunnettP Edison J J Hagan C Holmes E Jones C KatonaI Kearns P Kehoe A Mudher A Passmore N ShepherdF Walsh C Ballard Drug repositioning for Alzheimerrsquosdisease Nat Rev Drug Discov 11 833ndash846 (2012)
12 J L Goldstein M S Brown A century of cholesterol andcoronaries From plaques to genes to statins Cell 161161ndash172 (2015)
13 A M Malfitano G Marasco M C Proto C Laezza P GazzerroM Bifulco Statins in neurological disorders An overviewand update Pharmacol Res 88 74ndash83 (2014)
14 T Kurata K Miyazaki M Kozuki N Morimoto Y OhtaY Ikeda K Abe Progressive neurovascular disturbances inthe cerebral cortex of Alzheimerrsquos disease-model miceProtection by atorvastatin and pitavastatin Neuroscience197 358ndash368 (2011)
15 H Kurinami N Sato M Shinohara D Takeuchi S TakedaM Shimamura T Ogihara R Morishita Prevention ofamyloid beta-induced memory impairment by fluvastatinassociated with the decrease in amyloid beta accumulationand oxidative stress in amyloid beta injection mousemodel Int J Mol Med 21 531ndash537 (2008)
16 M Shinohara N Sato H Kurinami D Takeuchi S TakedaM Shimamura T Yamashita Y Uchiyama H RakugiR Morishita Reduction of brain beta-amyloid (Abeta)by fluvastatin a hydroxymethylglutaryl-CoA reductaseinhibitor through increase in degradation of amyloidprecursor protein C-terminal fragments (APP-CTFs) andAbeta clearance J Biol Chem 285 22091ndash22102 (2010)
17 G J Siegel N B Chauhan D L Feinstein G Li E B LarsonJ C Breitner T J Montine Statin therapy is associated withreduced neuropathologic changes of Alzheimer diseaseNeurology 71 383 author reply 383 (2008)
18 X-K Tong C Lecrux P Rosa-Neto E Hamel Age-dependentrescue by simvastatin of Alzheimerrsquos disease cerebrovascularand memory deficits J Neurosci 32 4705ndash4715 (2012)
19 X K Tong N Nicolakakis P Fernandes B Ongali J BrouilletteR Quirion E Hamel Simvastatin improves cerebrovascularfunction and counters soluble amyloid-beta inflammationand oxidative stress in aged APP mice Neurobiol Dis35 406ndash414 (2009)
Table 3 Recommendations to improve translation through the use of preclinicalpharmacokinetic data
Journalsbull Require authors to provide explicit rationale for dosing strategies usedbull Rationale should include consideration of the unbound drug exposure in target organas best practices
Educationbull Include basic pharmacology and pharmacokinetic principles in formal coursework requiredfor basic preclinical and clinical research scientists
bull Develop tutorials and on-line calculators for rodent dose projections to support appropriateuse of published pharmacological tools
Databasesbull Reinforce public chemical databases with mouse pharmacokinetic data that includes brainexposure
Precompetitive consortiabull Create precompetitive consortia to solicit mouse pharmacokinetic data sets from industry andfoundation partners for database expansion
bull Targeted data collection for compounds already in the public domain
rg 6 January 2016 Vol 8 Issue 320 320ps1 4
P ER SP EC T I V E
20 E K Osterweil S C Chuang A A Chubykin M SidorovR Bianchi R K Wong M F Bear Lovastatin corrects ex-cess protein synthesis and prevents epileptogenesis in amouse model of fragile X syndrome Neuron 77 243ndash250(2013)
21 C M Buchovecky S D Turley H M Brown S M KyleJ G McDonald B Liu A A Pieper W Huang D M KatzD W Russell J Shendure M J Justice A suppressorscreen in Mecp2 mutant mice implicates cholesterol me-tabolism in Rett syndrome Nat Genet 45 1013ndash1020(2013)
22 M J Justice C M Buchovecky S M Kyle A Djukic A rolefor metabolism in Rett syndrome pathogenesis Newclinical findings and potential treatment targets RareDis 1 e27265 (2013)
23 F Scicchitano A Constanti R Citraro G De Sarro E RussoStatins and epilepsy Preclinical studies clinical trials andstatin-anticonvulsant drug interactions Curr Drug Targets16 747ndash756 (2015)
24 M L Ferlazzo L Sonzogni A Granzotto L Bodgi O LartinC Devic G Vogin S Pereira N Foray Mutations of theHuntingtonrsquos disease protein impact on the ATM-dependentsignaling and repair pathways of the radiation-inducedDNA double-strand breaks Corrective effect of statins andbisphosphonates Mol Neurobiol 49 1200ndash1211 (2014)
25 E K Tan L C Tan Holding on to statins in Parkinsondisease Neurology 81 406ndash407 (2013)
26 B Friedman A Lahad Y Dresner S Vinker Long-termstatin use and the risk of Parkinsonrsquos disease Am J ManagCare 19 626ndash632 (2013)
27 M S Elkind Stroke A step closer to statin therapy forstroke Nat Rev Neurol 9 242ndash244 (2013)
28 E E Abrahamson M D Ikonomovic C E Dixon S T DeKoskySimvastatin therapy prevents brain trauma-inducedincreases in beta-amyloid peptide levels Ann Neurol66 407ndash414 (2009)
29 E F Wible D T Laskowitz Statins in traumatic brain injuryNeurotherapeutics 7 62ndash73 (2010)
wwwScienceTranslationalMedicineo
30 S Sierra M C Ramos P Molina C Esteo J A VaacutezquezJ S Burgos Statins as neuroprotectants A comparativein vitro study of lipophilicity blood-brain-barrier penetra-tion lowering of brain cholesterol and decrease of neuroncell death J Alzheimers Dis 23 307ndash318 (2011)
31 W G Wood G P Eckert U Igbavboa W E Muumlller Statinsand neuroprotection A prescription to move the fieldforward Ann N Y Acad Sci 1199 69ndash76 (2010)
32 W G Wood W E Muumlller G P Eckert Statins and neuro-protection Basic pharmacology needed Mol Neurobiol50 214ndash220 (2014)
101126scitranslmedaac9888
Citation R J Kleiman M D Ehlers Data gaps limit thetranslational potential of preclinical research Sci Transl Med8 320ps1 (2016)
D
rg 6 January 2016 Vol 8 Issue 320 320ps1 5
on January 6 2016httpstm
sciencemagorg
ownloaded from
101126scitranslmedaac9888] (320) 320ps1 [doi8Science Translational Medicine
Robin J Kleiman and Michael D Ehlers (January 6 2016) Data gaps limit the translational potential of preclinical research
Editors Summary
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httpstmsciencemagorgcontent8320320ps1article tools Visit the online version of this article to access the personalization and
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is a registered trademark of AAASMedicineScience TranslationalAssociation for the Advancement of Science all rights reserved The title
Science 1200 New York Avenue NW Washington DC 20005 Copyright 2016 by the Americanweekly except the last week in December by the American Association for the Advancement of
(print ISSN 1946-6234 online ISSN 1946-6242) is publishedScience Translational Medicine
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sciencemagorg
Dow
nloaded from
Boston Childrenrsquos Hospital ndash Broad Institute Collaboration Grants
Background Meeting the challenges of biomedicine requires bringing together creative scientists exceptional technological resources and world-class expertise across many disciplines that rarely exist within a single institution This guiding principle is the basis for a funding opportunity to support Boston Childrenrsquos Hospital investigators performing research in collaboration with Broad scientists
Goals The fundamental goal of this new award is to spark new collaborations between Boston Childrenrsquos Hospital and the Broad Institute The grants will be awarded to address a very wide range of scientific questions but are specifically designated for projects with the following characteristics
middot Projects where engagement with the Broad would benefit Childrenrsquos Hospital investigators projects that can uniquely benefit from being done at the Broad Institute
middot Projects that create new scientific collaborations and bring together diverse scientific backgrounds projects that spark new scientific directions or technologies and are not currently being pursued at Childrenrsquos Hospital
middot Projects that pilot new approaches that researchers at Childrenrsquos the Broad and the greater scientific community can benefit from in the future the purpose of these awards is not to provide gap or extension funding of existing projects but to initiate new projects
Eligibility Individuals with Principal Investigator status at Boston Childrenrsquos Hospital are eligible Applicants need not be Associate Members of the Broad Institute
Broad Platforms and Scientists Broadrsquos Platforms (Genomics Imaging Metabolite Profiling Proteomics Genomic Perturbation and the Broad Technology Labs) are collaborative organizations that provide scientific leadership and cutting edge technologies in support of project goals Collaborations can also be established with other groups at the Broad including the Klarman Cell Observatory the Stanley Center for Psychiatric Research or the Center for the Development of Therapeutics
Budgets Grants will provide $60000 direct support for 1 year plus philanthropic overhead It is expected that most grants will fund work performed at the Broad Institute either through interaction with Broadrsquos Platforms or via collaboration with a Broad scientist however the work may also occur at Boston Childrenrsquos if it is important to meet the scientific goals of the collaboration
Deadline and Review process Final proposals are due by September 1 2015 Funding decisions are expected to be reached by October 1 2015 Proposals will be reviewed by a joint Childrenrsquos HospitalndashBroad Institute committee Additional submission dates are expected for 2016
Submission Applicants are strongly encouraged to discuss potential applications in advance with the office of the Chief Scientific Officer at the Broad Questions should be directed to Alex Burgin ( 617-714-7124)
Proteomics Genomic Perturbation and the Broad Technology Labs) are collaborative
organizations that provide scientific leadership and cutting edge technologie
s in support of
project goals Collaborations can also be established with other groups at the Broad including
the Klarman Cell Observatory the Stanley Center for Psychiatric Research or the Center for the
Development of Therapeutics
Budgets
Grants wi
ll provide $60000 direct support for 1 year plus philanthropic overhead It
is expected that most grants will fund work performed at the Broad Institute either through
interaction with Broadrsquos Platforms or via collaboration with a Broad scientist howev
er the
work may also occur at Boston Childrenrsquos if it is important to meet the scientific goals of the
collaboration
Deadline and Review process
Final proposals are due by September 1 2015 Funding
decisions are expected to be reached by October 1 201
5 Proposals will be reviewed by a joint
Childrenrsquos Hospital
ndash
Broad Institute committee Additional submission dates are expected for
2016
Submission
Applicants are
strongly encouraged to discuss potential applications in
advance
with the office of the Chief Sc
ientific Officer at the Broad
Questions should be
directed to Alex Burgin (
aburginbroadinstituteorg
617
-
714
-
7124
)
Boston Childrenrsquos Hospital ndash Broad Institute Collaboration Grants
Background Meeting the challenges of biomedicine requires bringing together creative
scientists exceptional technological resources and world-class expertise across many
disciplines that rarely exist within a single institution This guiding principle is the basis for a
funding opportunity to support Boston Childrenrsquos Hospital investigators performing research
in collaboration with Broad scientists
Goals The fundamental goal of this new award is to spark new collaborations between Boston
Childrenrsquos Hospital and the Broad Institute The grants will be awarded to address a very wide
range of scientific questions but are specifically designated for projects with the following
characteristics
Projects where engagement with the Broad would benefit Childrenrsquos Hospital
investigators projects that can uniquely benefit from being done at the Broad Institute
Projects that create new scientific collaborations and bring together diverse scientific
backgrounds projects that spark new scientific directions or technologies and are not
currently being pursued at Childrenrsquos Hospital
Projects that pilot new approaches that researchers at Childrenrsquos the Broad and the
greater scientific community can benefit from in the future the purpose of these awards
is not to provide gap or extension funding of existing projects but to initiate new
projects
Eligibility Individuals with Principal Investigator status at Boston Childrenrsquos Hospital are
eligible Applicants need not be Associate Members of the Broad Institute
Broad Platforms and Scientists Broadrsquos Platforms (Genomics Imaging Metabolite Profiling
Proteomics Genomic Perturbation and the Broad Technology Labs) are collaborative
organizations that provide scientific leadership and cutting edge technologies in support of
project goals Collaborations can also be established with other groups at the Broad including
the Klarman Cell Observatory the Stanley Center for Psychiatric Research or the Center for the
Development of Therapeutics
Budgets Grants will provide $60000 direct support for 1 year plus philanthropic overhead It
is expected that most grants will fund work performed at the Broad Institute either through
interaction with Broadrsquos Platforms or via collaboration with a Broad scientist however the
work may also occur at Boston Childrenrsquos if it is important to meet the scientific goals of the
collaboration
Deadline and Review process Final proposals are due by September 1 2015 Funding
decisions are expected to be reached by October 1 2015 Proposals will be reviewed by a joint
Childrenrsquos HospitalndashBroad Institute committee Additional submission dates are expected for
2016
Submission Applicants are strongly encouraged to discuss potential applications in
advance with the office of the Chief Scientific Officer at the Broad Questions should be
directed to Alex Burgin (aburginbroadinstituteorg 617-714-7124)
Clinical Trials Glossary
ADME an acronym for absorption distribution metabolism and elimination ADME
studies determine how a drug is absorbed by the body the chemical changes that it may
undergo and how it is eliminated from the body
Adverse event (AE) a bothersome event that occurs in a study participant AEs may be
related to the treatment being tested or may be due another cause (eg another treatment
another medical condition an accident or a surgery)
Arm a specific type of treatment to which a group of clinical trial participants is
assigned Some clinical trials have one arm and some have two arms while others have
three or more arms For example a clinical trial comparing two different doses of an
investigational drug versus a placebo would have three arms participants receiving a
higher dose of the investigational drug participants receiving a lower dose of the
investigational drug and participants receiving the placebo
Baseline a point in time at the beginning of a clinical trial before the study participants
receive any treatment At the baseline participants usually have certain types of tests
During and after treatment the same tests may be performed and the results compared
with the baseline results to see if the drug has caused changes
Bias a factor ndash such as a preconceived idea about the effects of the benefits and risks of a
treatment or a lack of balance in selection of patients for a study ndash that reduces the
likelihood that the study results are true Methods such as blinding and randomization
are used to limit the potential for bias
Bioavailability the portion of the dose of a drug that reaches the bloodstream For
example if the drug is administered intravenously its bioavailability is 100 percent
however if the drug is administered in any other way such as orally topically or
through intramuscular injection its bioavailability will decrease due to incomplete
absorption
Bioequivalence study a test performed to compare the portion of a drug in the
bloodstream when administered in different dosage forms
Biologic product any substance that can be used in prevention treatment or cure of
disease Some examples include vaccines blood virus toxin antitoxin and therapeutic
serum
Biopsy the removal of cells or tissue from a patient for examination which is usually
done under a microscope A tissue sample might be taken for genetic studies Sometimes
there is a difference between the blood genotype and the skin or other tissue genotype
This term can also refer to the tissue sample that has been obtained by such a procedure
2
Blinding a process used to prevent the participants the researchers or both from
knowing what specific treatment is being given to participants in a clinical trial The
process of blinding helps to reduce bias because study participants and researchers are
less likely to be unconsciously influenced by the knowledge of what the study participant
is actually receiving If only the participants are blinded the study is called a single-
blind study If both participants and researchers are blinded the study is called a double-
blind study
Carcinogenicity studies long-term studies conducted in animal models to determine a
drugrsquos likelihood of causing cancer
Clinical efficacy a compoundrsquos ability to produce the desired effect
Clinical pharmacology a science that studies properties of drugs in relation to their
therapeutic value in humans
Clinical study or Clinical trial a medical experiment in human beings that helps to
determine how a disease drug or medical device affects study participants Clinical
studies are necessary to answer specific questions about how to better diagnose prevent
or treat a disease or condition
Cohort a group of study participants who have certain characteristics in common such
as female sex a defined age range or particular severity of disease Dividing study
participants into cohorts is often done as part of the analyses of study data
Contraindication a factor that makes the use of a particular drug inadvisable For
example a person who has had an allergic reaction to penicillin in the past is considered
to have a contraindication to using penicillin in the future
Control group a group of participants not receiving the investigational drug but instead
receiving a standard treatment for their disease or receiving a placebo The results
observed in the group of patients receiving the investigational drug are compared with the
results observed in the control group
Crossover study a study design with two or more arms where participants receive one
treatment for a period of time and then switch over to a second treatment for a period of
time Such a study design allows the effects of the two treatments to be compared in the
same patient
Data Monitoring Committee (DMC) or Data Safety and Monitoring Board (DSMB)
A committee of experts that periodically reviews the accumulating data from an ongoing
multicenter clinical trial Members of a DMCDSMB must be independent ie they
cannot be participating as investigators in the clinical trial Based on their review the
DMCDSMB experts advise the sponsor regarding whether it is safe and acceptable to
continue with the study or whether the data suggest that the study should be modified or
stopped A DMCDSMB may recommend that a trial be stopped if there are safety
concerns or if the trial objectives have been achieved
3
Dose-ranging study a clinical trial in which two or more doses of an investigational
drug are tested to determine which dose is likely to offer the best combination of safety
and efficacy in later clinical trials or in medical care
Efficacy or effectiveness the ability of a drug to prevent cure or slow a disease process or to alleviate the symptoms of a disease or condition
Eligibility a determination made during the screening period for a clinical study of
whether a personrsquos participation in the trial is likely to be safe and can contribute data
that will help achieve the study goals
Endpoint occurrence of a disease symptom sign or test result that constitutes one of the
target outcomes of a clinical trial
Inclusionexclusion criteria the factors defined in the protocol of a study that determine
whether a personrsquos participation in a clinical trial is likely to be safe and can contribute
data that will help achieve the study goals Study candidates undergo evaluation during
the study screening period to determine if they meet all of the inclusion criteria and do
not meet any of the exclusion criteria as defined in the protocol These criteria usually
consider such factors as age sex type of disease stage of disease previous treatment
history and other medical conditions in determining eligibility for the study
Informed consent (assent) a process by which medical researchers provide necessary
information to a person about a clinical study and the person voluntarily confirms his or
her willingness to participate in the study Children who are considered old enough to
have a basic understanding of the study may need to provide assent to be involved in the
study a parent or legal guardian must also give informed consent for such a child to
participate
Informed consent (assent) form a document that describes a clinical study to the
participants (or their parentsguardians) The informed consent (assent) form includes
information about the goals of the study the study design and duration the types of tests
to be performed the potential risks and inconveniences the potential benefits the
possible costs or payments associated with study participation the available alternative
therapies the rights and responsibilities of the participant and the people to contact if the
participant has questions The informed consent (assent) form must be reviewed and
signed before the participant has any study tests or treatment including the tests
performed during the screening period at the beginning of the study Participants are
given a copy of the informed consent (assent) form to take home
Institutional Review Board (IRB) or Independent Ethics Committee (IEC) a board
of physicians statisticians researchers community advocates and others who are
responsible for ensuring the protection of the rights safety and well-being of participants
in a clinical trial at a study center This board is called an IRB in the United States and is
often called an IEC in other countries IRBIECs review and approve important study
documents (eg protocols informed consent forms study advertisements and patient
4
brochures) before the start of the study and periodically review the progress of the study
while it is ongoing
Investigational Drug a drug that is being tested as a potential treatment for a disease or
condition but has not yet been proven safe and effective for that use
Investigator a physician or other health care worker who carries out a clinical trial by enrolling treating and monitoring participants and recording the results
In vitro testing testing conducted in test tubes or other artificial environments
In vivo testing testing conducted in living animals or humans
Longitudinal study a clinical study that involves observations of the same items over
long periods often many decades Because longitudinal studies track the same people
they are often used to study trends across the life span to uncover predictors of certain
diseases or to track the effects of a particular treatment on a patientrsquos condition over
time
Multicenter study a study conducted at more than one location Multicenter clinical
studies are generally performed when each individual clinical trial site does not have
enough study candidates to complete a large trial
Natural history study a study of the natural development of a disease or condition over
a period of time Natural history studies are usually longitudinal studies
New Drug Application (NDA) the registration document through which a
pharmaceutical company formally proposes that the FDA approve a new drug for
manufacturing and sale The application includes detailed reports of pharmacology
toxicology manufacturing and chemistry as well as data from clinical trials
Open-label study a study in which the participants and the investigators know which
treatment is being given In an open-label study there is no blinding and none of the participants receives a placebo
Orphan disease a disease or condition that affects a relatively small number of people
In the US this defined as fewer than 200000 people In Europe this is defined as fewer
than five in 110000 people
Orphan drug a drug intended to treat an orphan disease
Participant or subject a patient or healthy volunteer who participates in a clinical trial
Phase 1 the initial phase of testing of an investigational drug in humans Usually a
Phase 1 clinical study is conducted in a small number of healthy volunteers or patients
with a disease for which the drug may be useful Generally the study is designed to
determine the side effects of the drug and its pharmacokinetics Some information
5
regarding drug efficacy may be collected if patients with a disease participate A phase
frequently encompasses more than one clinical trial Phase 1 sometimes is sub-divided
into Phases 1a and 1b for example when the first set of Phase 1 trials (Phase 1a) is
performed in healthy volunteers and a second set of Phase 1 trials (Phase 1b) is
performed in patients with a disease
Phase 2 the intermediate phase of testing of an investigational drug in humans Usually
a Phase 2 clinical study conducted in patients with a disease for which the drug may be
useful Generally the study is designed to evaluate dosing to obtain preliminary data on
the effectiveness of the drug and to acquire more safety information Phase 2 sometimes
is sub-divided into Phases 2a and 2b Phase 2a studies typically are smaller and shorter
in duration and evaluate different drug doses to see how they affect certain tests that can
indicate whether the drug is working as expected Phase 2b studies typically enroll more
patients are of longer duration and evaluate whether the drug is offering clinical benefits to patients Phase 2b studies sometimes are considered pivotal or registration-directed
Phase 3 the final phase of testing an investigational drug in humans before regulatory
approval Phase 3 studies are usually conducted in a large population of patients and are
generally designed to confirm the effectiveness of the drug and to evaluate the overall
risk-benefit ratio Phase 3 studies usually test the investigational drug in comparison with
a standard treatment for the disease or a placebo
Phase 4 testing of a drug in humans after it has already been approved by regulatory
authorities and can be used in medical practice Phase 4 studies may be conducted to
compare the drug to a similar type of drug to explore whether it may help patients with
other diseases to further study the long-term safety of the drug or for other reasons
Pivotal study a study that is designed to generate the data required by regulatory
authorities to decide whether to approve an investigational drug A pivotal study is
usually a large randomized Phase 2b or Phase 3 study and often is blinded and uses a
placebo as a control Sometimes a pivotal study is described as a registration-directed
study
Placebo an inactive version of an investigational drug A placebo has a similar
appearance to the investigational drug but is expected to have no therapeutic value A
placebo is used as a comparison treatment to reduce bias in randomized studies
Preapproval access program an umbrella term for programs that allow seriously ill
patients to receive an investigational drug when they are unable to participate in clinical
trials and there is no alternative treatment This is sometimes referred to as
compassionate use Types of pre-approval access programs include expanded access
parallel-track named patient program single-patient exemption and treatment IND The
timing for starting an expanded access program usually depends upon what is known
about the risk-benefit of the drug and whether the drug can be provided in a manner that
is fair to patients with the disease
6
Preclinical (nonclinical) testing testing of a drug in test tubes or in animals A drug
undergoes preclinical testing before being tested in humans to make sure that it shows
evidence of desired effects and is sufficiently safe for study in people Preclinical testing
sometimes also helps to determine the doses of the drug that should be evaluated in
humans Preclinical testing is sometimes called nonclinical testing
Protocol a document describing what types of people may participate in a clinical study
and the objectives treatments measurements statistical methods timing and
organization of a clinical trial The protocol must be prepared in advance of the study
and must be reviewed and approved by review committees and regulatory authorities
before the study is started Investigators must follow the protocol to carry out the study
Randomization assignment of participants to treatment arms based on chance This is
usually done by a computer program in a way that does not allow either the participants
or the investigators to choose who is assigned to which arm Randomization is used to
reduce bias in clinical trials
Risk-benefit ratio the balance of the risk of side effects expected with use of a drug
versus the potential for benefit with the use of that drug A drug with a good risk-benefit
ratio has few side effects and is very effective
Serious adverse event (SAE) an adverse event that is life-threatening requires inpatient
hospitalization or lengthens a hospital stay leads to substantial disability leads to a birth
defect or results in death
Side effect any effect of a drug other than the desired effect Side effects are often
unwanted and may be bothersome Other names for a bothersome side effect are adverse
drug reaction (ADR) or drug toxicity
Screening period a period at the beginning of a clinical trial when candidates for the
study are evaluated to determine if their participation is likely to be safe and can
contribute data that will help achieve the study goals
Significant or statistically significant an outcome in a clinical trial is likely to result
from a real difference (eg due to an effect of a treatment) and is unlikely to be due to
chance alone The level of statistical significance is often expressed in terms of a p-
value which indicates the probability that a difference is not due to chance alone
Usually a p-value smaller 005 is considered statistically significant
Sponsor the organization responsible for financing and coordinating a clinical trial
Most often this is a pharmaceutical or biotechnology company
Standard treatment a treatment currently in wide use often approved by regulatory
agencies and generally considered effective in the treatment of a specific disease or
condition
7
Toxicity a side effect produced by a drug that is bothersome to the person taking the
drug
Toxicology the study of the adverse effects of chemicals conducted in animal models to
predict potential adverse effects in humans Some studies are conducted during clinical
development to evaluate dosing regimens
Boston Childrenrsquos Hospital Clinical Research Map 1 Mouse over for additional info Bold = hyperlink
CLINICAL RESEARCH MAP
Boston Childrenrsquos Hospital Clinical Research Map 2 Mouse over for additional info Bold = hyperlink
ObjectiveThis clinical research map is designed to serve as a guide for investigators study coordinators and research nurses at Boston Childrenrsquos Hospital The research map outlines the key steps in preparing to launch a research study and provides embedded links to institutional resources tools and documents
An investigator need not follow the steps on the Clinical Research Map in any particular order There is flexibility and the steps followed will in part de-pend on the type of research study
For new as well as more experienced investigators the Clinical Research Map can be used as a checklist or an inves-tigator can use the steps on the map as points for consideration as they are developing a protocol and launching a study
This tool is not intended to substitute for the important collaboration be-tween a junior investigator and a senior investigatormentor A senior investiga-tor plays a pivotal role in coaching and advising a junior investigator regarding the many subtleties and variations that apply to designing and implementing a protocol
This process map cannot be inclusive of every possible task or step but is intended as a general guide for investi-gators and their study teams
ResourcesThere are many institutional resources at Boston Childrenrsquos Hospital designed to support investigators and their clini-cal research teams In addition to links to resources tools and documents that are embedded in the steps of the clini-cal research map the last page of this document contains website addresses that will take you to additional helpful institutional resources
Acknowledgements Cindy Williams DNP RN PNP NE-BC Nursing Director CTSU Clinical Research Nursing
Ellen McGrath MSN RN CPNP Nurse Practitioner Department of Surgery
Grace Yoon MSN RN CNNP Research Nurse Department of Ophthalmology
Laura Feloney BA Lab Technician
ContentsOverview Four stages 3
1st Stage Protocol development 4
1st Stage Protocol development contrsquod 5
2nd Stage Implementation planning 6
3rd stage Study launch7
4th stage Statistical analysis reporting and dissemination 8
Discarded specimens Additional steps 9
Chart review Steps if you are completing a chart review 10
Appendix A Resources for researchers 11
Boston Childrenrsquos Hospital Clinical Research Map 3 Mouse over for additional info Bold = hyperlink
Overview Four stages
Protocol development
Implementation planning
Study launch
Statistical analysis reporting and dissemination
1
2
3
4
Boston Childrenrsquos Hospital Clinical Research Map 4 Mouse over for additional info Bold = hyperlink
1st Stage Protocol development
Explore resources
CRIT
CRC
EQuIP
CTSU
Harvard Catalyst
Complete training
CITI training
EQUiP
Consult research pharmacistResearch Pharmacy
Rocco Anzaldi
Consult statistician
CRC
Draft a protocol
Protocol guidelines
Study personnel
FDA Guidance for Investigators
Consult Clinical Research Center
CRC
Bio Bank
Start IRB application
TransLab
Consider applying for grants
securing funding
Office of Sponsored Programs
If INDIDE application to FDA
Does my study need an INDIDE
Regulatory resources
Arrange a consultation with
CRIT
ConsultationTasks for investigators and study teams
Boston Childrenrsquos Hospital Clinical Research Map 5 Mouse over for additional info Bold = hyperlink
Respond to IRB questionsrequests
for clarification
1st Stage Protocol development contrsquod
Departmental Scientific Review
Organize DSMB design DSMP
DSMPDSMB
Templates for Research Study
Documents and Tools
Study Templates and Tools
Investigators who sponsor an FDA regulated trial
ClinicalTrialsgov
Create regulatory binder
Regulatory Binder Template
Submit the grant application to OSP
OSP
TIDO
CTBO
Consult Office Intellectual Property
Technology and Innovation
Development Office
TIDO
IRB approval
Consider blood volume for research
Research blood volume policy
Confidentiality plan
Confidentiality guidelines
Boston Childrenrsquos Hospital Clinical Research Map 6 Mouse over for additional info Bold = hyperlink
Develop Case Report Forms
(CRFs)
CRF guidelines
Establish electronic shared
folder or study binder for study
documents
CRIT
Set date for trial launch
Develop fast fact sheet for bedside staff
Consult programmer re database
CRIT
Research study resource manual
for the clinical unit
Confirm study drug
in pharmacy
Rocco Anzaldi
Clarify system for screening
and enrolling patients
Recruitment guideline
Updated protocol to
nurse manager
Consult MDsNPs on unitclinic
2nd Stage Implementation planning
Tasks for investigators and study teams
Study logistics Documentation logistics
Data storage
Confidentiality plan
Confidentiality guidelines
Create study orderset
Consider blood volume for research
Research blood volume policy
Create Manual of Operations
MOO Guide
Study implementation
meeting
Develop study logstools
EQUIP
Finalize tracking sheet
Research Administration
Fernando Valles
Boston Childrenrsquos Hospital Clinical Research Map 7 Mouse over for additional info Bold = hyperlink
3 Document informed consent
Informed Consent
Consent library
Schedule weekly study team meeting
Communicate to department faculty
and multidisciplinary
team announcing trial launch
Steps before trial launch
3rd stage Study launch
Patient flow
1 Seek permission
to approach potential subjects
2 Screenenroll
patients
EQUIP
5 Send Study
Tracking Sheet (STS)
6 Collection of
patient data and assessing for
adverse events
7 Study
documents and data handling
4 Datetime study tests
Create a checklist outlining study action items for each subject
Boston Childrenrsquos Hospital Clinical Research Map 8 Mouse over for additional info Bold = hyperlink
Annual IRB Report
Annual Progress ReportStaff Report
raquo Maintain Interest of Staff
raquo Important to See Study Progress
Write Abstract
Dissemination of Research Results
raquo Conference raquo Internal Presentation for Colleagues
raquo Publication
Plan DSMB MeetingInterim
Analysis
4th stage Statistical analysis reporting and dissemination
Data Entry
When Enrollment Complete Data
Cleaning
Monitor Subjects to Identify
Adverse Events (CCI sponsor
DSMB)
Report Adverse Events
Update MOO Based on Experience
with First Several Patients Enrolled
Weekly Study Team Meeting
Report study findings to
subjects and stakeholders
Data management Trial management
Reporting Dissemination
Regular Review of Data
to Identify Deviations
and Workflow Improvements
Consult Statistician When Approaching Target Enrollment
Discarded specimens Additional steps
Boston Childrenrsquos Hospital Clinical Research Map 9 Mouse over for additional info Bold = hyperlink
Send IRB Approval to lab manager
Maureen Samson
Educate staff in areasunits about sample collection
Locate the discarded samples
Locate the accession number in PowerChart
Retrieve specimen
Mark Kellogg
Follow Shipping Rules and Procedures
IATAShipping with dry ice instructions
Communicate with laboratory staff
Contact Dr Mark Kellogg to discuss specimen retrieval
Consult with Biorepository
Biorepository
Chart review Steps if you are completing a chart review
Boston Childrenrsquos Hospital Clinical Research Map 10 Mouse over for additional info Bold = hyperlink
7 8
4321
Databaserecord review guidelines
5 6
Consult programmer re database
CRC Request
Respond to IRB questions
requests for clarification
Departmental Scientific Review
Complete training
CITI Training
Draft a protocol
Protocol Guidelines
Prepare IRB Application
Information about the CCI
IRB Application
Develop Case Report Forms (CRFs)
CRF Guidelines
IRB Review
Boston Childrenrsquos Hospital Clinical Research Map 11 Mouse over for additional info Bold = hyperlink
Clinical Research Center (CRC) x84720
Committee on Clinical Investigation (CCI IRB) x57052
Research Pharmacist x52014
Clinical and Translational Science Unit (CTSU) x57541
Education and Quality Improvement Program (EQUIP) x57052
Clinical Trials Office Central Budgeting x4-2714
Office of Sponsored Programs x4-2723
Technology and Innovation Development Office 617-919-3079
Research Finance x8-3517
Harvard Catalyst 617-432-7810
Regulatory Affairs x4-2777
Appendix A Resources for researchers
RES_4446_ClinicalResearchMap-FINAL FOR LINKS 1
RES_4446_ClinicalResearchMap-FINAL FOR LINKS 10
Overview Four stages
1st Stage Protocol development
1st Stage Protocol development contrsquod
2nd Stage Implementation planning
3rd stage Study launch
4th stage Statistical analysis reporting and dissemination
Discarded specimens Additional steps
Chart reviewSteps if you are completing a chart review
Appendix A Resources for researchers
RES_4446_ClinicalResearchMap-FINAL FOR LINKS 11
RES_4446_ClinicalResearchMap-FINAL FOR LINKS 2
RES_4446_ClinicalResearchMap-FINAL FOR LINKS 3
RES_4446_ClinicalResearchMap-FINAL FOR LINKS 4
RES_4446_ClinicalResearchMap-FINAL FOR LINKS 5
RES_4446_ClinicalResearchMap-FINAL FOR LINKS 6
RES_4446_ClinicalResearchMap-FINAL FOR LINKS 7
RES_4446_ClinicalResearchMap-FINAL FOR LINKS 8
RES_4446_ClinicalResearchMap-FINAL FOR LINKS 9
RES_4446_ClinicalResearchMap-PAGE 5pdf
Overview Four stages
1st Stage Protocol development
1st Stage Protocol development contrsquod
2nd Stage Implementation planning
3rd stage Study launch
4th stage Statistical analysis reporting and dissemination
Discarded specimens Additional steps
Chart reviewSteps if you are completing a chart review
Appendix A Resources for researchers
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MOUSE OVER
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Page 98
COVER BUTTON
Previous Page
Page 118
Page 2
Page 31
Page 63
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Page 96
Page 1
Button 91
Button 92
Button 94
IRB review
Button 102
Develop Case Report Forms
Button 136
Consult clinical research center
INDIDE 1
Explore resources
Button 1016
Bio Bank p
4
Consult statistician
Consult research pharmacist
Study personnel
Complete training
Consider grantsfunding
Draft a Protocal 2
Arrange a consutlations with CRIT
Next Page 1
Previous Page 1
TransLab
Start IRB application 3
Develop study logs
Updatedd protocol
Confirm study drug
Establish electronic shared
COnsult programmer
Clarify system
Research study resrouce manual
Develop case report forms
MOO
Set date for trial launch
Button 44
Study implementation meeting
Finalize tracking sheet
Data storage
Confidentiality
Blood volume 3
Develop fast fact
Consult MDs
Schedule weekly
Communicate early
Button 71
Screenenroll patients
Document informed consent
Datetime tests
Send study tracking sheets
Collection patient data
Button 77
Dissemination
Button 87
Button 124
Button 125
Communicate with lab staff
Button 106
Button 109
Button 1010
Shipping page 9
Button 1012
Button 99
Button 133
Button 134
Button 135
Biorepository
Locate assession number
Retrieve specimen
Button 30
Consult office
Negotiate Contract
Organizing DSMB
Submit Grant
Respond to IRB questions
Button 66
Create regulatory binder
Templates for research stufy
Clinical Trials Business Office
Blood volume 2
Confidentiality plan
Investigators who sponsor
clinicaltrials
gov
BPN Project
Drug Discovery amp Development Testing Funnel
Tier 1 2 3
Tier 6 7 8
Tier 5
Tier 4
Example Drug Discovery amp Development Testing Funnel
Cytotoxicity
Grant
Project
Example Drug Discovery amp Development Testing Funnel
TIER 1A ndash Primary Screen
Chemical purity and identity of active compounds
Primary bioactivity screen
Cell viability (When Appropriate)
ScaffoldsMoiety Chemical liabilities (for example Michael acceptor GSH reactive)
Calculated properties CLogP
PSA
Molecular Weight
rotatable bonds
H-bond donors and acceptors
permeability
pKa
Solubility
TIER 1B
Confirm EC50 determinations for actives compounds in primary screen with fresh
compounds from the original stock Confirm EC50 determinations for the lead (most
active) compound in primary screen with a new sample either repurchased purified
and characterized in-house or independently synthesized in-house
Compounds with IC50s (EC50s) less than X advance to Tier 2
TIER 2A ndash Activity Confirmation
Secondary screen
TIER 2B
Repeat EC50 determinations for actives in secondary screen with fresh
compounds from the original stock
Compounds with IC50s (EC50s) less than X advance to Tier 3
Example Drug Discovery amp Development Testing Funnel
TIER 3 ndash Drug-like Properties Specificity
IC50 selectivity in selectivity screen
CYP450 Inhibition competitive and time-dependent if structural alerts exist
(spot check illustrative examples from compound series)
Measured solubility
Measured protein binding (spot check illustrative examples from
compound series)
Test of Permeability in vitro permeability [indicate assay eg Caco2 orand
PAMPA] (spot check illustrative examples from compound series)
hERG
Cytoxicity assays
All compounds with no significant issues (Define Minimum Conditions for
Advancement) to advance to Tier 4
Example Drug Discovery amp Development Testing Funnel
TIER 4 ndash Scale-up Synthesis and Preliminary PK
Scale-up synthesis
Purity determination gt98 with no single impurity gt1
Rodent bioavailability and PK (define target delivery route) Tmax
Cmax
AUC
Bioavailibility
Vss CL T12 MRT
Brain to Plasma ratios
P-glycoprotein transport MDCK-MDR1 and MDCK-mdr1a
Plasma Protein Binding (species)
Microsomal Stability ndash rodent and human
Defineplan Patent Protection Strategy
All compounds with no significant issues (Define
Minimum Conditions for Advancement) advance
in parallel to Tiers 5AampB
Example Drug Discovery amp Development Testing Funnel
TIER 5A ndash In Vivo Bioactivity
Animal efficacy
Validate Biomarker
Target engagement
Advance to Tier 6 if (Define Minimum Conditions for advancement)
TIER 5B ndash Advanced Drug-like Properties
Microsomal stability in multiple
species
Chemical Stability
CYP450 induction
CYP reaction phenotyping
Metabolism ndash human
hepatocytesmicrosomes
Metab ID define major human rat dog and
non-human primates (NHP) metabolites
In vitro Tox Ames
Chromosome Aberration
CNS effects
Example Drug Discovery amp Development Testing Funnel
TIER 6 ndash Liability Assessment
Broad Pharmacological Profile and Toxicology
PK in second species
TIER 7
Non-GLP exposure studies single and multiple dose
Advance to late stage pre-clinical development (Define Minimum
Conditions for advancement)
Example Drug Discovery amp Development Testing Funnel
Principal InvestigatorProgram Director (Last First Middle)
enspenspenspenspensp
DETAILED BUDGET FOR INITIAL BUDGET PERIOD
DIRECT COSTS ONLY
FROM
THROUGH
enspenspenspenspensp
enspenspenspenspensp
PERSONNEL
DOLLAR AMOUNT REQUESTED (omit cents)
NAME
ROLE ONPROJECT
TYPEAPPT (months)
EFFORTONPROJ
INSTBASESALARY
SALARYREQUESTED
FRINGEBENEFITS
TOTAL
enspenspenspenspensp
PrincipalInvestigator
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
SUBTOTALS
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
CONSULTANT COSTS
enspenspenspenspensp
enspenspenspenspensp
EQUIPMENT (Itemize)
enspenspenspenspensp
enspenspenspenspensp
SUPPLIES (Itemize by category)
enspenspenspenspensp
enspenspenspenspensp
TRAVEL
enspenspenspenspensp
enspenspenspenspensp
PATIENT CARE COSTS
INPATIENT
enspenspenspenspensp
enspenspenspenspensp
OUTPATIENT
enspenspenspenspensp
enspenspenspenspensp
ALTERATIONS AND RENOVATIONS (Itemize by category)
enspenspenspenspensp
enspenspenspenspensp
OTHER EXPENSES (Itemize by category)
enspenspenspenspensp
enspenspenspenspensp
SUBTOTAL DIRECT COSTS FOR INITIAL BUDGET PERIOD
$
enspenspenspenspensp
CONSORTIUMCONTRACTUAL COSTS
DIRECT COSTS
enspenspenspenspensp
FACILITIES AND ADMINISTRATIVE COSTS
enspenspenspenspensp
TOTAL DIRECT COSTS FOR INITIAL BUDGET PERIOD
$
enspenspenspenspensp
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
main menu
Target identification and Validation resources
Drug targets for human disease emerge from basic research into mechanisms of disease biology Validated molecular drug
targets require that the project team address issues related to Rationale Druggability Mechanism and Safety The
Commercial viability of the approach may also be critical for recruiting industry partners at key junctures to support
development
The Molecular Target is the protein that will bind directly to the proposed drug A validated target has
Rationale
A human genetic or pharmacological link to a selected disease population
bull Modulation of the target has been shown to produce therapeutic benefit in an in vivo animal model of the disease
population or of the relevant circuit dysfunction using a directly translatable and quantifiable endpoint
Druggability
bull A tool compound exists to modulate the target or a family member
bull Biochemical and cellular assays exist to support development of SAR for on-target and off-target activities
Well-Defined Mechanism of Action
bull A clear set of laboratory objectives that specify required mode and degree of target engagement needed for
efficacy
bull Pharmacodynamic measures of target engagement are available to monitor activity in animals and people
bull Disease induced changes in target expression or distribution have been examined
bull Common human SNPs in target documented and functional consequences considered
Safety Risk Assessment
bull Known pharmacological risks associated with target mechanism are documented
bull The tissue distribution of the target is understood in preclinical species humans and patients
bull The most likely off-target activities associated with closest sequence homology are identified and considered for
safety risks
Commercial Potential
bull Competitive differentiation strategy suggests improvement over standard of care
bull Viable intellectual property and product development plan
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
Download a short guide to Acronyms and Terminology associated with Drug Discovery
ACRONYMSampTERMpdf
Download an Introductory Slide Deck on the Drug Discovery Process for Neuroscience
roadmapoverviewkleimanpdf
Download an Introductory slide deck on the Role of the Biology Team in a drug discovery program
drug discovery biologykleimanpdf
Below are listed databases and other resources that can help address questions about rationale distribution of target or its
relationship to other disease genes
RNA expression data sets
GEO- Gene Expression Omnibus data base of all published RNA expression data sets
httpwwwncbinlmnihgovgeo
Allen Brain Atlas- database of brain RNA expression data httpwwwbrain-maporg
Brain Span database-Brain RNA expression data including transcriptome and ISH for human brain
httpwwwbrainspanorg
Human genome resources at NCBI
httpwwwncbinlmnihgovgenomeguidehuman
OMIM- human genes and inherited disorders maintained by Johnrsquos Hopkins
Gene Database- database of genes and associated information
dbSNP- a database of SNP and other nucleotide variations
dbGaP- database of Genotypes and Phenotypes
NextBio Free Harvard enterprise account
Mine transcriptional profiling studies for changes in your target
Search connectivity map for compounds that modulate your target
Correlate human data to animal models and cell lines
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
Compare disease profiles across cohorts and stages of disease
wwwnextbiocom
iHOP--information Hyperlinked Over Proteins
A portal for searching literature by gene or gene Interactions httpwwwihop-netorgUniPubiHOP
Ingenuity Pathway Analysis
Available from research computing Find disease related literature for your target
httpwwwingenuitycomproductsipa
TISSUES database of Expression of targets (RNA and Protein)
TISSUES is a frequently updated web resource that integrates evidence on tissue expression from manually curated
literature proteomics and transcriptomics screens and automatic text mining They map all evidence to common
protein identifiers and Brenda Tissue Ontology terms and further unify it by assigning confidence scores that facilitate
comparison of the different types and sources of evidence Finally these scores are visualized on a schematic human
body to provide a convenient overview
httptissuesjensenlaborgSearch
Refrence Literature related to target identification and validation
Bunnage ME Gilbert AM Jones LH Hett EC Know your target know your molecule Nature chemical biology 2015
11(6)368-372 httpwwwncbinlmnihgovpubmed15718163
Grover MP Ballouz S Mohanasundaram KA George RA Sherman CD Crowley TM Wouters MA Identification of
novel therapeutics for complex diseases from genome-wide association data BMC medical genomics 2014 7 Suppl
1S8 httpwwwncbinlmnihgovpubmed25077696
Plenge RM Scolnick EM Altshuler D Validating therapeutic targets through human genetics Nature reviews Drug
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
main menu
Resources available at BCH Assay Development Screening Funnel development Chemical compound files Assistance
with identification of academic and industry partners for collaborative SAR campaigns
Identification of the correct molecule requires a clearly defined set of laboratory objectives and a well-designed screening
funnel to select the molecule that will meet those objectives Laboratory objectives for a molecule include specific criteria
for the mode of binding to target (eg agonist partial agonist inverse agonist non-competitive inhibitor) the potency
(eg Ki lt30nM) selectivity (eg gt30X selectivity over family member target XY and Z) brain penetration (yesno) dosing
paradigm ( eg oral once daily intravenous once monthly) and duration of expected treatment (eg sub-chronic daily
treatment for 2 weeks chronic treatment for years) Each of these laboratory objectives will have bearing on the design of
the screening funnel required to identify the molecule
The screening funnel requires a robust high-throughput (HTS) biochemical assay capable of testing gt100000 compounds
good sensitivity (Zrsquogt05) and an appropriate orthogonal assay (usually cell based) to confirm functional activity of the
compound at the target which can be used to weed out false positives and primary HTS artifacts Critical features defined
by the laboratory objectives may require additional in vitro absorption and metabolism data from compounds slated to
progress in vivo to ensure that structure activity relationships being developed will support expected dosing profiles and
target organ disposition A collection of critical off target assays to ensure required selectivity of the candidate drug must
be available to test molecules progressing from functional assays Compounds expected to be tested in vivo will require
pharmacokinetic studies to ensure target organ exposure in concentration ranges needed to support hypothesis testing
Link to sample Screening Funnels
httpswwwnimhnihgovresearchprioritiestherapeutics
The types of information needed to Characterize a Lead Compound are summarized here
Download an introductory slide deck on Medicinal Chemistry Structure Activity Relationship (SAR) campaign courtesy Dr
Johnny Bennett Merck
Childrens MedChem 29Jul2015pdf
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
Resources for assay development
The Assay Guidance Manual httpwwwncbinlmnihgovbooksNBK53196
This is a key resource for design and qualification of all types of biochemical and cell based assays It covers many
different modes of assay development and optimization as well as troubleshooting guides Do not run a screen
without consulting the manual first
The Assay Development Screening Facility (ADSF) at BCH Hourly access to equipment and technical assistance
consultations compound libraries- live cell medium throughput screening For more information contact Dr Lee Barrett
The ICCB at Longwood Project based access to equipment and expertise for design and execution of high-throughput
screens access to wide collection of chemical and genomic libraries For more information contact Dr Caroline Shamu
caroline_shamuhmsharvardedu
Website httpiccbmedharvardedu
Databases and references with information about activity and properties of small molecule compounds
PubChem provides information on the biological activities of small molecules PubChem is organized as three linked
databases within the NCBIs Entrez information retrieval system These are PubChem Substance PubChem Compound and
PubChem BioAssay Links from PubChems chemical structure records to other Entrez databases provide information on
biological properties These include links to PubMed scientific literature and NCBIs protein 3D structure resource Links to
PubChems bioassay database present the results of biological screening Links to depositor web sites provide further
information A PubChem FTP site Download Facility Power User Gateway(PUG) Standardization Service Score Matrix
Service Structure Clustering and Deposition Gateway are also available Home page is here
httpspubchemncbinlmnihgov
httpspubchemncbinlmnihgovsearch
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
DrugBank The DrugBank database is a unique bioinformatics and cheminformatics resource that combines detailed drug
(ie chemical pharmacological and pharmaceutical) data with comprehensive drug target (ie sequence structure and
pathway) information The database contains 7759 drug entries including 1602 FDA-approved small molecule drugs 161
FDA-approved biotech (proteinpeptide) drugs 89 nutraceuticals and over 6000 experimental drugs Additionally 4300
non-redundant protein (ie drug targetenzymetransportercarrier) sequences are linked to these drug entries Each
DrugCard entry contains more than 200 data fields with half of the information being devoted to drugchemical data and
the other half devoted to drug target or protein data Homepage is here httpwwwdrugbankca
Protein Data Bank archive Targets with protein crystal structures are more attractive targets for structure based drug design
Determine if your target has a known crystal structure by looking it up in the protein database- A Structural View of Biology
This resource is powered by the Protein Data Bank archive-information about the 3D shapes of proteins nucleic acids and
complex assemblies that helps students and researchers understand all aspects of biomedicine and agriculture from
protein synthesis to health and disease Homepage is here httpwwwrcsborgpdbhomehomedo
High Quality Chemical tools are required for testing biological hypothesis Find chemical tools that are fit for purpose by
virtue of target potency and selectivity needed to test hypothesis The dangers of using inadequate chemical tools are
detailed here httpwwwnaturecomnchembiojournalv11n8fullnchembio1867html To support the needs of the
biology community the industrial chemistry research community has joined a pre-competitive effort to provide
characterization data for high quality chemical probes That data is stored here httpwwwchemicalprobesorgprotein-
family
ChemNavigator The National Institutes of Health (NIH) has formed an agreement with ChemNavigator to provide the NIH
with a current and comprehensive database of commercially accessible drug discovery screening compounds to be
made available to all NIH researchers ChemNavigator is pleased to serve NIH affiliated scientific researchers in compound
sample procurement As an NIH researcher you have full access to use the iResearch System All you need to do is take a
few minutes to register in the system Then you will be able to perform chemical structure searches for compound samples
of interest and purchase these samples through this on-line system Link is here httpwwwchemnavigatorcomnihasp
Additional References related to biological activity of compounds
Edwards AM Bountra C Kerr DJ Willson TM Open access chemical and clinical probes to support drug discovery Nature
chemical biology 2009 5(7)436-440
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
Wang Y Suzek T Zhang J Wang J He S Cheng T Shoemaker BA Gindulyte A Bryant SH PubChem BioAssay 2014 update
Nucleic acids research 2014 42(Database issue)D1075-1082
Wang Y Bolton E Dracheva S Karapetyan K Shoemaker BA Suzek TO Wang J Xiao J Zhang J Bryant SH An overview of
the PubChem BioAssay resource Nucleic acids research 2010 38(Database issue)D255-266
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
main menu
Pharmacokinetic tutorial drug exposure measurement services pharmacokinetic data references
Selecting the correct dose to achieve exposure of drug that are adequate to test a hypothesis in preclinical species
requires that you know the potency of the molecule at the desired drug target and the dose of compound required to
achieve target organ exposure that will result in the free (not bound by protein) concentration of drug required to engage
the molecular target within the target organ compartment Estimates of Drug potency can be found in many of the
databases listed under correct molecule The free concentration of a drug is determined in the plasma by multiplying the
concentration of drug in the plasma by the fraction unbound This must be measured for each compound A literature
reference that provides the measured plasma protein binding (PPB) values for many common drugs is provided here
Zhang Xue Shao and Jia (2012) Compilation of 222 drugsrsquo plasma protein binding data and guidance for study designs
Drug Discovery Today Vol 17 Issue 9-10 Pages 476-485 httpwwwncbinlmnihgovpubmed22210121
If your drug target is the brain then you must also understand the kinetics of drug disposition and clearance including blood
brain barrier (BBB) penetration in your test species to select a dose of compound adequate to test your hypothesis
Download a tutorial deck on basic principles of drug disposition and their application in small molecule drug discovery
courtesy of Dr Chris Shaffer Pfizer
150805DMPKTutorial(CLSBCHCourse)pdf
Pharmacometrics Research Core and Pharmacokinetics Service The Pharmacometrics Research Core is directed by Dr Luis
Pereira and provides analytical services for assaying drugsmetabolites in biological matrices (eg plasma serum blood
urine CSF saliva tissues) The Core provides pharmacokinetic and pharmacodynamic analyses for current and future
clinical trials and research projects (including contract services) It conducts stability and potency studies for pediatric
formulations compounded at BCH as per recent demand from FDA and CMS Finally the Core fosters grant applications
and research collaborations both intra and extramural The TNC can additionally provide investigators with consultation in
the identification of resources for pharmacodynamic assay development and contract research organizations able to
provide bioanalysis of preclinical samples needed to support animal clinical trials Contact Dr Luis Pereira for more
information LuisPereirachildrensharvardedu
article on importance of understanding drug exposure in preclinical drug studies here
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
References on Pharmacokinetics and Brain Penetration of Small Molecules
Di L Rong H Feng B Demystifying brain penetration in central nervous system drug discovery Miniperspective Journal of
medicinal chemistry 2013 56(1)2-12
Reichel A Addressing central nervous system (CNS) penetration in drug discovery basics and implications of the evolving
new concept Chemistry amp biodiversity 2009 6(11)2030-2049
Smith DA Di L Kerns EH The effect of plasma protein binding on in vivo efficacy misconceptions in drug discovery Nature
reviews Drug discovery 2010 9(12)929-939
Moda TL Torres LG Carrara AE Andricopulo AD PKDB database for pharmacokinetic properties and predictive in silico
ADME models Bioinformatics 2008 24(19)2270-2271
Law V Knox C Djoumbou Y Jewison T Guo AC Liu Y Maciejewski A Arndt D Wilson M Neveu V et al DrugBank 40
shedding new light on drug metabolism Nucleic acids research 2014 42(Database issue)D1091-1097
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
main menu
Formulations advice and assistance with preclinical drug delivery Neurodevelopmental Behavioral Core
To effectively deliver drug to preclinical species for the duration of a study researchers must choose a dose a formulation
and a route of administration that will support target organ exposure long enough to test a therapeutic hypothesis Since
most drugs developed for humans are optimized for human metabolism parameters many compounds developed for
humans are rapidly metabolized and cleared in rodents requiring alternative formulations and routes of preclinical
administration (see tutorial under Correct Dose)
Proper formulation of drugs and vehicles to ensure appropriate drug exposure is a critical factor in preclinical study design
The Neurodevelopmental Behavioral Core may provide advice on standard formulations Preclinical assistance and
training across many routes of administration including IV cannulation osmotic minipumps oral gavage sc and ip is also
available through the Neurodevelopmental Behavioral Core
Contact is Dr Nick Andrews NickAndrewschildrensharvardedu
Custom formulation used for human studies are supported on a case by case basis by the Pharmacometrics Research Core
or Clinical Research Pharmacy Contact for the Pharmacometrics Core is Dr Luis Pereira LuisPereirachildrensharvardedu
The Clinical Research Pharmacy can provide advice on unusual formulations Contact is Dr Rocco Anzaldi
RoccoAnzaldichildrensharvardedu
idspharmacy-dlchildrensharvardedu
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
main menu
Stratification Biomarker development and resources patient sample repositories requests for collection of new types of
patient samples development of patient specific iPSC lines and neurons Genetic databases RNA expression databases
Humans are diverse Not only do patients come in different sizes ages genders and ethnic backgrounds but the same
disease diagnosis often develops in people as a function of different environmental insults and genetic predispositions
Finding biomarkers that will segregate similarly diagnosed patients into subsets of biologically more homogenous
populations is a critical feature of good clinical trial design A lsquostratification biomarkerrsquo can be a biochemical measure from
patient samples a structural or a functional feature of a human imaging technology or a functional measure of an
electrophysiological readout
The Translational Neuroscience Center can help investigators access advice and assistance for investigators with vendors
experienced in profiling DNA RNA or protein across a range of platforms httpwwwchildrenshospitalorgresearch-and-
Neurophysiology Services can assist investigators with identification of biomarkers to stratify patients based on EEG
signatures Contact Drs Charles Nelson and Jurriaan Peters Co-Directors
CharlesNelsonchildrensharvardedu
JurriaanPeterschildrensharvardedu
MRIRadiology Imaging Core can assist with identification of biomarkers to stratify patients by functional or structural deficits
in brain circuitry Contact Dr Simon Warfield Director SimonWarfieldchildrensharvardedu
Molecular Genetics core can assist investigators with identification of genetic stratification biomarkers or gene expression-
based stratification biomarkers Contact Drs Louis Kunkel and Christopher Walsh Co-Directors
LouisKunkelchildrensharvardedu
ChristopherWalshchildrensharvardedu
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
The Human Neuron Differentiation Service within the Translational Neuroscience Center can help investigators recruit
specific subtypes of patients to be consented for reprogramming of blood or fibroblast cells into iPSC lines that will support
differentiation into human neurons for phenotypic analysis and screening ContactDr Robin Kleiman
RobinKleimanchildrensharvardedu
Translab can assist with routine processes as well as complex laboratory-‐developed tests They place special emphasis on
assay development for use in clinical trials Translab website with contact information can be viewed here
httpwwwtranslabbostonorg
TransLab Flyer 2 2015pdf
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
main menu
Patient sample repositoryBiobank Patient registry
Disease processes are dynamic The molecular underpinnings of disease differ between inception progression and
response of the body to disease Thus each stage of disease may require alternative therapeutic strategies Understanding
which stage of disease is best suited to testing a specific therapeutic approach will require information about disease from
patient samples collected at different stages of disease well as an ability to collect and recruit patients at relevant stages of
disease
To locate human RNA profiling data in the public domain from disease samples and tissues at specific stages of disease
search databases referenced in the Correct Target section of this document
The Translational Neuroscience Center offers multiple services that can assist with identification of the correct patients The
Core Repository for Neurological Disorders stores a wide variety of patient samples from many stages of disease The
biorepository is directed by Dr Mustafa Sahin and these samples and de-identified clinical data can be searched and
requested through the Translational Neuroscience Center
The Biobank Core Lab serves as a core resource that ensures top-level specimen handling and services to the Boston
Childrens Hospital research community It serves as both a service core and a biorepository providing an institutional
perspective on the presence of specimens that may be available for use to foster collaborations and accelerate research
and discovery
The Clinical Research and Regulatory Affairs Service can provide assistance to investigators in identifying patients andor
repository samplesdata Contact Co-Directors Stephanie Brewster and Kira Dies for more information about access to
these resources
StephanieBrewsterchildrensharvardedu
KiraDieschildrensharvardedu
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
main menu
Statistical support clinical trialsgov
Determining the correct sample size to support preclinical and clinical studies requires power calculations that take into
account the variability of the endpoint being measured Statistical support for preclinical studies is available on a
department by department basis Neurology and Neurobiology requests for preclinical biostatistics support can be made
through the CRC website
httpredcap-qiredcap_edcsurveyss=Rma5u83qKC
Clinical statistical support for all departments is also available through the CRC Design and Analysis Core For more
information contact Michael Monuteaux michaelmonuteauxchildrensharvardedu
Clinical datasets that provide data for supporting power calculations can be found by searching through clinical trialsgov
database All studies in the clinical trials data base are required to describe the study design the endpoints under
evaluation and the treatments as well as links to publications of the studies The studies can be searched by topic This can
be a good way to find historical data to help you evaluate variability of endpoint measures in clinical populations This will
be needed to support sample size power calculations httpsclinicaltrialsgov
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
main menu
Understanding RDoC Human Neurobehavioral Core Service IRB assistance with clinical protocols
Different stages of clinical trials have different goals for selecting endpoints Early stage clinical trials are typically in search
of a translatable pharmacodynamic or target engagement endpoint to ensure that the molecule in question will be
competent to test a clinical hypothesis in humans Developing translatable measures of target engagement in preclinical
species and humans is critical to developing data sets that will enable subsequent therapeutic efficacy trials The earliest
trials require endpoints that can be measured in a functionally equivalent manner across species Therefore it is critical for
preclinical researchers to develop dose-responsive data sets in preclinical species using quantitative endpoints such as EEG
visual or auditory evoked potentials PET ligands plasma or CSF based biochemical measures or translatable task based
behaviors Preclinical data must be a developed with an eye towards what the equivalent measure will be in the clinic
Toward that end the NIMH has initiated the Research Domain Criteria (RDoC) that is aimed at characterizing mental health
disorders across many different dimensions across species A big focus of the RDoC initiative is the identification of
translatable endpoints for evaluating pharmacodynamics and efficacy in Neuroscience Drug Discovery Preclinical
Neuroscience researchers should be familiar with the RDoC framework For advice on in vivo characterization of preclinical
endpoints with translational potential for Neuroscience related disorders contact Dr Robin Kleiman at the TNC
robinkleimanchildrensharvardedu
The Human Neurobehavioral Core Service of the Translational Neuroscience Center can provide guidance to investigators
on the appropriate tests that will provide the best translation from animal studies to human studies The Service also offers
human neurobehavioral assessment services Contact-Drs Charles Nelson and Deborah Waber Co-Directors
CharlesNelsonchildrensharvardedu
DeborahWaberchildrensharvardedu
Developing clinical protocols and obtaining IRB approval for human study of translatable endpoints can be supported by
the Translational Neuroscience Center Clinical Research and Regulatory Affairs Service Contact-Kira Dies and Stephanie
Brewster Co-Directors
KiraDieschildrensharvardedu
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
StephanieBrewsterchildrensharvardedu
Background Information on RDoC httpswwwnimhnihgovresearch-prioritiesrdocindexshtml
Casey BJ Oliveri ME Insel T A neurodevelopmental perspective on the research domain criteria (RDoC) framework
Cuthbert BN Insel TR Toward the future of psychiatric diagnosis the seven pillars of RDoC BMC Med 2013 11126
httpwwwncbinlmnihgovpmcarticlesPMC3653747
Insel T Cuthbert B Garvey M Heinssen R Pine DS Quinn K Sanislow C Wang P Research domain criteria (RDoC)
toward a new classification framework for research on mental disorders The American journal of psychiatry 2010
167(7)748-751 httpwwwncbinlmnihgovpubmed20595427
Insel TR The NIMH Research Domain Criteria (RDoC) Project precision medicine for psychiatry The American journal
of psychiatry 2014 171(4)395-397 httpwwwncbinlmnihgovpubmed24687194
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
main menu
Body atlases for expression of mRNA and protein guides to chemical alerts guidance for preclinical toxicology studies for
Investigational New Drug (IND) applications
Discovery scientists must consider the distribution of the proposed drug target across the entire body in human samples in
order to understand potential safety risks to be monitored during preclinical toxicological testing Teams also have to be
aware of differences in distribution of the target and related family members in preclinical species Many of the target
expression databases listed in the Correct Target section of this document are useful in this regard Assays that can be used
to monitor any potential safety risks are critical to the development of a suitable testing funnel needed to advance
compounds
Many chemical classes of compounds that are identified in screens are not suitable for drug development due to the
presence of structural alerts that are known to cause chemical toxicity Databases that house information of structural alerts
can be used to de-prioritize structural series early in the life of a program Some toxicology databases that can help
deprioritize toxic chemotypes include httppubsacsorgdoiabs101021ci300245q
Some web resources for identifying side effects of known compounds httpintsideirbbarcelonaorg
Once a potential clinical candidate molecule is identified GLP-qualified toxicology studies must be carried out with a
qualified vendor to support regulatory filings of an Investigational New Drug (IND) application For a short tutorial on studies
needed to support preclinical toxicology testing and guidance on evaluating contract research organizations that are
qualified to perform this work see attached tutorial courtesy of Dr Joe Brady Pfizer
Brady boston childrens hosp talk aug2015 IND toxpdf
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
main menu
FAQs
Industry partners and collaborators can bring tremendous expertise and complementary resources to bear on research
projects with therapeutic applications These may include medicinal chemistry expertise pharmacology expertise access
to unique and undisclosed chemical probe molecules assay development and high-throughput screening resources
antibody and other reagent development pharmacokinetic analysis pharmacokinetic and pharmacodynamics
modeling formulation expertise post-doctoral training programs and in some cases financial support There is a wide range
of models of interacting with industry in a range of different capacities Some frequently asked questions about types of
relationships and the responsibilities associated with those interactions can be found in the following document
Download Frequently Asked Questions about working with Industry
Translation of basic research into new marketed drugs will require a transition from exploring scientific principles and testing
hypotheses into commercial products Industry partners capable of developing these potential products need to be able
to license the intellectual property required to sell the product in order to justify investment in building programs around new
ideas This requires that scientific researchers protect and patent potential inventions from their work to enable future
commercialization by partners with appropriate expertise To ensure that researchers are appropriately documenting their
work in a manner that will support preservation of intellectual property all investigators are encouraged to consult with TIDO
before any public disclosures of new research Similarly the following documentation provides guidance for documenting
your work according to standards that will support patent applications
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
Download the compliance manual for BCH for Intellectual property policy
cm_021_intellectual_propertydocx
Download a summary of laboratory notebook Dorsquos and Donrsquot
Dosdontsnotebookspdf
Link to TIDO Technology Innovation and Development Office
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
main menu
A phenotypic screen requires a biologically robust assay that represents a significant aspect of disease-relevant human
biology It can be used to identify molecular targets for target validation studies through the use of well-annotated
bioactive molecules or genomic libraries (eg RNAi CRISPER) Alternatively phenotypic screens can be used to identify
novel compounds that must subsequently be lsquoDE convolutedrsquo to identify novel targets using lsquowarheadsrsquo These screens rely
on identification and manipulation of a functional deficit or phenotype using a patient-derived cellular system
The strengths of this approach
Use of human systems can improve translatability
Identified compounds may empirically balance therapeutic activity at multiple required targets
Well-suited to drug repurposing
Phenotypic screens can be used to identify compounds or targets for mechanism based drug discovery programs
Many CNS drugs have been discovered using a phenotypic repurposing screen (Swinney and Anthony 2011)
Drawbacks to this approach
Assays are slow low throughput and more expensive as compared to cell-free assays
Cell-based assays may not predict circuit level or brain phenotypes
Furthermore as a primary screening approach
Precludes leveraging strengths in uHTS SBDD and parallel design
Every molecule must be de-risked independently thus safety can be very hard to predict
Drug Repurposing Drug Repurposing is a strategic pillar of the National Center for Advancing Translational Science (NCATS)
Details on resources and funding opportunities can be found here httpsncatsnihgovntu
Chemogenomic Files from industry partners Many companies have well designed and annotated chemical files that are
designed to cover the druggable genome with small molecule compounds from their proprietary collections Each
company has different criteria and stipulations associated with use of the library It is advisable to consult with TIDO
regarding terms and conditions associated with individual companies
ICCB-LongwoodKirby ADSF The ICCB screening center and the Kirby ADSF have multiple collections of compounds that
include bioactive or FDA approved molecules available for screening
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
Kirby ADSF libraries contact Dr Lee Barrett LeeBarrettchildrensharvardedu
References related to phenotypic screens and Drug Repurposing
Vincent F Loria P Pregel M Stanton R Kitching L Nocka K Doyonnas R Steppan C Gilbert A Schroeter T
and MC Peakman Developing predictive assays The phenotypic screening ldquorule of 3rdquo Sci Transl Med 7 293ps15
(2015)
Langedijk J Mantel-Teeuwisse AK Slijkerman DS Schutjens MH Drug repositioning and repurposing terminology and
definitions in literature Drug Discov Today (2015)
Swinney DC and J Anthony How were new medicines discovered Nature Reviews Drug Discovery 10 507-
519 (July 2011) | doi101038nrd3480
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
main menu
TNC Clinical Research and Regulatory Affairs Service Research Participant Registry CRC
Glossary of Terms
Glossary-of-Clinical-Trials-Termspdf
Clinical Research and Regulatory Affairs Service This Translational Neuroscience Center service facilitates the mission of the
Translational Neuroscience Center providing coordination among studies communications resource development and
implementation of new or ongoing preclinical and clinical studies The service is led by experts in protocol development
and launching of new studies The directors are available to guide TNC researchers in designing human studies including
the preparation of Institutional Review Board (IRB) and FDA submissions Additionally staff of the Clinical Research and
Regulatory Affairs Service will help researchers with recruitment plans budget development supervision of study
coordinators study monitoring and audit preparation For more information contact Co-Directors Kira Dies ScM CGC and
Stephanie Brewster MS CGC
KiraDieschildrensharvardedu
StephanieBrewsterchildrensharvardedu
Clinical Research Center (CRC) Assists investigators at BCH with research project initiation and implementation resources
in the CTSU for the conduct of clinical research visits and ancillary services education on research methods and practices
The CRC has biostatisticians project managers research specialists clinical trials specialists research coordinators and
highly skilled nurses and nurse project managers who work every day to facilitate the many research needs of the BCH
community httpwwwchildrenshospitalorgresearch-and-innovationresearchclinicalclinical-research-center
Clinical and Translational Study Unit (CTSU) The CTSU provides clinical research infrastructure for investigators in the design
initiation conduct and reporting of clinical research with the goal of translating scientific knowledge into new therapies for
pediatric conditions httpweb2tchharvardeductsu
Clinical Research Roadmap This clinical research map is designed to serve as a guide for investigators study coordinators
and research nurses at Boston Childrenrsquos Hospital The research map outlines the key steps in preparing to launch a
research study and provides embedded links to institutional resources tools and documents
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
Clinical Research Mappdf
main menu
Office of Sponsored Programs Research Administration TIDO
Many government and foundation grant opportunities are available for developing Drug Discovery Projects updated lists of
funding options exist on OSP and Research Administration web sites
Some good options for finding relevant requests for proposals
Translational Research Program annual call for proposals
Boston Childrenrsquos Hospital ndash Broad Institute Collaboration Grants Proposals will be reviewed by a joint Childrenrsquos Hospitalndash
Broad Institute committee Additional submission dates are expected for 2016
BCH_Broad collaborative grant 852015docx
Kirby Neurobiology Screening Pilot awards- available to Kirby Neurobiology PIs as funding is available
Translational Neuroscience Center- Pilot awards supported by trust sponsored donations as available Distributed through
TNC e-mail lists
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
ADDF The ADDF Academic Drug Discovery and Development Program seeks to create and support innovative translational
research programs for Alzheimerrsquos disease related dementias and cognitive aging in academic medical centers and
universities Biomarker development studies and innovative proof of concept pilot clinical trials of new approaches to
treatment prevention and early detection are also supported
Department of Defense ALSRP The FY15 Defense Appropriations Act provides $75 million (M) to the Department of Defense
Amyotrophic Lateral Sclerosis Research Program (ALSRP) to support innovative high-impact Amyotrophic Lateral Sclerosis
research As directed by the Office of the Assistant Secretary of Defense for Health Affairs the Defense Health Agency
Research Development and Acquisition (DHA RDA) Directorate manages and executes the Defense Health Program
(DHP) Research Development Test and Evaluation (RDTampE) appropriation The executing agent for the anticipated
Program AnnouncementsFunding Opportunities is the Congressionally Directed Medical Research Programs (CDMRP)
httpcdmrparmymilpubspress201515alsrppreannshtml
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
Michael J Fox Foundation Therapeutic Pipeline Program Supports Parkinsons disease therapeutic development along the
pre-clinical and clinical path (both drug and non-pharmacological therapeutics including gene therapy biological
surgical and non-invasive approaches) The Michael J Fox Foundation seeks applications with potential for fundamentally
altering disease course andor significantly improving treatment of symptoms above and beyond current standards of care
Proposals must have a well-defined plan for moving toward clinical utility for patients The Therapeutic Pipeline Program is
open to industry and academic investigators proposing novel approaches or repositioning approved or clinically safe
therapies from non-PD indications httpswwwmichaeljfoxorgresearchgrant-detailphpid=28
NINDS The Blueprint Neurotherapeutics Network (BPN) Provides the neuroscience community access to a complete and
seamless pipeline for preclinical drug development beginning with chemical optimization and concluding after phase I
clinical trials Participants in the BPN will receive funding to conduct bioactivity and efficacy testing in their own laboratories
as well as access to millions of dollars in NIH-contracted drug development services including medicinal chemistry
pharmacology toxicology and phase 1 clinical trials NIH will also provide drug development consultants who have had
years of experience working at a senior level in industry Because the Blueprint is establishing a network of drug
development service providers that typically cater to biopharmaceutical companies neuroscientists who join the BPN can
readily plug in to all of the drug development expertise that typically resides in industry The projects supported through the
network will be highly collaborative and the researchers who initiate the projects will serve as the principal investigators
(PIs) directing their projects through the development pipeline with the help of industry consultants The PIs and their
institutions will have the opportunity to attain assignment of intellectual property rights from all other network participants
who may have intellectual input into their projects This will allow the PIs to retain control of the intellectual property for drug
candidates developed through the network and eventually pursue licensing and commercialization partnerships
httpneuroscienceblueprintnihgovbpdrugs
NeuroNEXT Will establish a consortium of clinical sites capable of forming disease-specific cadres of investigators in order to
develop and implement trials rapidly in a wide range of neurological disorders that affect adults andor children With a
stable and experienced research staff a central IRB model and master trial agreements NeuroNEXT will streamline the
administrative processes for clinical trials and reduce start-up times NeuroNEXT will also be able to design and implement
evidence-based measures to improve patient recruitment into clinical trials httpswwwneuronextorgresearchers
NIMH Many grant options see overview here httpwwwnimhnihgovresearch-prioritiestherapeuticsindexshtml
Building on High Impact Basic Neurobiology Through Assay Development Advancing Tools for Therapeutic Discovery (R01) -
See more at httpgrantsnihgovgrantsguidepa-filesPAR-15-066htmlsthashs1HMWjWudpuf
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
NCATS many grant options see overview here httpwwwncatsnihgovprograms
Bridging Interventional Development Gaps (BrIDGs) Program Makes available on a competitive basis certain critical
resources needed for the development of new therapeutic agents for both common and rare diseases Investigators do not
receive grant funds through this program Instead successful applicants receive access to NIH experts and contractors who
conduct pre-clinical studies at no cost to the investigator In general synthesis formulation pharmacokinetic and
toxicology services in support of investigator-held IND applications to the Food and Drug Administration (FDA) are available
httpwwwncatsnihgovbridgsworksolicitation
NCATS Discovering New Therapeutic Uses for Existing Molecules (New Therapeutic Uses) A collaborative program designed
to develop partnerships between pharmaceutical companies and the biomedical research community to advance
therapeutics development This innovative program matches researchers with a selection of pharmaceutical industry
assets to test ideas for new therapeutic uses with the ultimate goal of identifying promising new treatments for patients
httpwwwncatsnihgovntu
Pfizer Centers for Therapeutic Innovation (CTI) Suitable for biotherapeutic or small molecule projects with a strong project
rationale (demonstrated association between target biology pathway and disease mechanism) CTIrsquos areas of interest
include inflammation autoimmunity tissue remodeling oncology cancer immunology rare or genetic diseases
cardiovascular and metabolic diseases and neuroscience Selected projects are undertaken by a joint team with BCH
members and Pfizer CTI drug development experts located on the 18th floor of CLS working towards agreed common
goals The Pfizer CTIBCH collaboration program is managed by a Joint Steering Committee with representation from both
Boston Childrenrsquos and CTI httpswwwpfizercticom Calls for proposals come through TIDO three times a year in January
May and September httpwwwchildrensinnovationsorgPagesHighlightsHighlights-83aspx
Shire-BCH Collaborative Program Development The Joint Steering Committee of the Shire Alliance extends a call for ldquoPre-
Proposalsrdquo with defined objectives from time to time generally annually in the late fall or winter That call is publicized
through emails from BCH Research Administration and TIDO Following review by the JSC a full proposal may be requested
Unsolicited proposals may also be considered from time to time
ACRONYMS
HTS- High-throughput Screen run with 96 well 384 well 1536 wells or 3456 well capacity- screen has capacity to run through a library of 1-3Million compounds in total
uHTS- Ultra High-throughput Screen ndash arbitrary cut off to denote capability to measure 100s of thousands of assays per day with automation and high density plate readers
HCS- High Content Screen usually a cell based assay that is able to monitor multiple endpoints reflective of different cellular processes in a single well of cells treated with a compound May be biochemical or image based endpoints
SAR- Structure-Activity Relationship ie relationship of modifications to chemical structure on relevant activity SPR-Structure-Property Relationship ie relationship of modifications of chemical structure on physicochemical
properties
PK- Pharmacokinetic measure of drug levels in a body compartment
PD- Pharmacodynamic a measure of functional activity of a drug
PKPD- PharmacoKinetic PharmacoDynamic relationship- how drug levels relate to drug response in a system
DDI-Drug-Drug Interactions- occurs when one drug affects the activity of another drug when co- administered Often due to changes in ADME properties of one of the co-administered drugs (ie for example induction by one drug of enzymes that will metabolize the second drug )
DMPK- Drug Metabolism and PharmacoKinetics
ADME- Absorption Distribution Metabolism amp Excretion
PDM-pharmacokinetics dynamics and metabolism GLP- Good Laboratory Practice- regulations that govern toxicology studies required by the FDA to support IND
and NDA
POM- Proof of Mechanism clinical studies to demonstrate hit the target and elicited a biological response
POC- Proof of Concept Clinical studies to demonstrate a clinically meaningful outcome measure improved
PoP-Proof of Principal usually preclinical studies that demonstrate that engaging target in a disease model produced efficacy
FIH- First in Human clinical trial to evaluate new molecule in humans for safety and PK- Ph1
FIP-First in Patient first clinical trial to evaluate new molecule in patients hERG (the human Ether-agrave-go-go-Related Gene) is a gene KCNH2 that codes for a subunit of Kv111 and
contributes to the repolarizing current in the heart that coordinates the hearts beating When compromised by application drugs or by rare mutations in some families it can result in a potentially fatal disorder called long QT syndrome A number of clinically successful drugs in the market have had the tendency to inhibit hERG and create a concomitant risk of sudden death as a side-effect which has made hERG inhibition an important anti-target that must be avoided during drug development
IND-Investigational New Drug Application- formal application to FDA to evaluate a NCE in people
NME- New Molecular Entity- a new FDA approved drug
NCE-New Chemical Entity-an investigational drug that is not yet a FDA approved NME NDA- New Drug Application (A lsquoFilingrsquo)- a formal application for approval of a new drug
CAN-(Pfizer-specific shorthand )-Clinical Candidate- a molecule competent to be tested in humans IB- Investigators Brochure- basic information on an investigational drug and its mechanism for clinicans involved
in conducting a clinical trial Provides background information on the hypothesis being tested and the types of patients that should be included excluded and risks and how the drug should be administered It must be updated continually by the sponsor to include all new findings
SOC- Standard of Care- in our context it is the drug treatment that a clinican should prescribe for a particular type of patient used as a benchmark for comparing new entities
MTD- Maximum Tolerated Dose- first identified in GLP safety studies during preclinical development AE- Adverse Event- a side effect that causes safety concerns
TI- Therapeutic Index -ratio of the concentration of drug needed to produce efficacy and the concentration of drug that is safely tolerated ( also called ldquoSafety Marginrdquo)
Questions Contact Robin Kleiman- email RobinKleimanchildrensharvardedu office CLS 13070
Terms that relate to Targets Molecular target- the protein that binds drug to produce efficacy Off-Target- other proteins that bind the drug that do not relate to efficacy and may produce Adverse Events (AEs) Druggable target ndashcomes from a class of proteins that has successfully been targeted with small molecule drugs in
the past Primarily transporters enzymes receptors ion channels (Not protein-protein interactions transcription factors RNA binding proteins etc)
Druggable genome- about 3000 genes encoding all druggable proteins Druggability- the presence of protein folds (quarternary structures) that favor specific interactions with drug-like
molecules Exploratory target- Hypothesis that a modulating a target via a particular mode of action will be beneficial to a
particular patient population Validated target- Hypothesis regarding a target also has in vivo efficacy data for a disease or a disease model- along
with a complete understanding of how the target mechanism relates to disease- (also called lsquoProof of Principlersquo) Phenotypic screen- a screen for compounds that will reverse a phenotype the molecular target may not be known Systems pharmacology target(s)-a precisely defined combination or lsquofingerprintrsquo of molecular targets to be
modulated to correct a phenotype (Poly-pharmacology)
Terms that relate to programs
Biomarker- a physiological pathological or anatomical characteristic that is measured by an automated process or algorithm as an indicator of the normal biological process pathological process or biological response to a therapeutic intervention Many types of Biomarkers target engagement biomarkers stratification biomarkers efficacy biomarkers pharmacodynamic biomarkers etchellip
Laboratory Objectives-Criteria established at the start of the program to define the desired pharmacological properties of the molecule with regard to potency selectivity mode of action frequency and route of administration For antibodies would include minimal criteria for knock down stability etc
Therapeutic Modality- small molecule biologic RNAi stem cell etc
Screening tree Screening funnel- A decision tree for utilizing a panel of assays to identify molecules that meet the laboratory objectives
Terms that relate to molecules
Drug-like molecule- has physicochemical properties in line with known oral medications The molecule will be largely rule of 5 (RO5) compliant therefore small and moderately lipophilic Not related to pharmacological activity
Rule of Five (RO5)=Chris Lipinskirsquos rule of 5 states that a drug like molecule will have the following properties Molecular Weight of less than 500 a clogP lt5 fewer than 5 H-bond donors and the number of H-bond acceptors ( which is the sum of N and O atoms) is less than 10
Physicochemical properties- key properties of molecules include (calculated)Molecular Weight number of H bond acceptors and donors (measured) kinetic solubility pKa lipophilicity (logD logP)
Chemical tool -a compound with good potency and selectivity for a specified molecular target but fails to meet all criteria for safety PK or potency needed to become a clinical candidate Suitable for preclinical testing of hypothesis and proof of principal studies but not for lsquopreclinical developmentrsquo
Active molecule describes an individual chemical entity with measurable dose-dependent activity in a biological screening assay
Hit molecule refers to a molecule plus its related structural analogs for which there is an understanding of the structure-properties and structure-activity relationships (SPR and SAR) for a specific biological context Additionally preliminary drug disposition data (both in vitro and in vivo) provide an assessment of pharmacokinetic properties The available data provide a basis for further optimization of the hit series
Lead molecule refers to a molecule plus its related structural analogs that demonstrate o Sufficient exposure at pharmacologically relevant doses by the intended route of administration to explore
intended pharmacology in a relevant in vivo disease or pharmacodynamic model o Proof-of-principle or efficacy in a in vivo model that will be used to establish a margin of safety
Clinical candidate an optimized individual chemical entity derived from a lead series that demonstrates o a dose-response relationship via intended route and schedule of administration in relevant disease model o an exposure-based margin of safety in toxicology studies o In summary a clinical candidate is a molecule that is deemed competent for testing the primary disease
intervention hypothesis in humans
A laboratory notebook is a vital record of events leading to a patentable invention Therecorded information can establish dates of conception and reduction to practice of atechnology as well as the inventorship of a patent claiming the technology Below arefourteen rules you should follow when keeping lab notebooks
1 mdash Do use bound booksInventors should use permanently bound notebooks eg notebooks with spiral or glue bindings If loose-leaf sheets are used they should be consecutively numbered and eachpage should be dated signed and witnessed
2 mdash Do sign and date Each notebook should be signed and dated on the inside front cover to indicate the firstday the recipient started using the notebook Each entry should be dated and signed orinitialed
An independent witness ie someone who understands the technology but will not benamed as a co-inventor of the invention should sign and date each entry after the state-ment ldquoRead and understood by rdquo (The witness should preferably sign theentries on a contemporaneous or fairly contemporaneous basis but entries can also bereviewed signed and dated on a periodic eg weekly or monthly basis)
3 mdash Do use inkNotebook entries should be made in ink and in chronological order Entries should not beerased or ldquowhited outrdquo If an entry contains an error a line should be drawn through theerror and new text should continue in the next available space
4 mdash Donrsquot leave blank spacesBlank gaps between entries should be avoided If a blank space is left on a page a line orcross should be drawn through the blank space and the page dated to prevent subsequententries
5 mdash Donrsquot modifyPrior entries should not be modified at a later date If data were omitted the new datacan be entered under a new date and cross-referenced to the previous entry Record exper-iments when they are performed
6 mdash Do use past tenseUse the past tense (eg ldquowas heatedrdquo) to describe the experiments that were actually performed
Fish amp Richardson pc
Dorsquos and Don rsquo ts forKeeping Lab Notebooks
Boston
Dallas
Delaware
New York
San Diego
Silicon Valley
Twin Cities
Washington dc
FR
7 mdash Do explain abbreviations and special termsExplain all abbreviations and terms that are nonstandard Explain in context in a table ofabbreviations or in a glossary
8 mdash Do staple attachmentsAttachments such as graphs or computer printouts should be permanently attached to pagesin the notebook (eg by stapling) and both the attachment and the notebook page signedand dated If the attachment cannot be stapled it should be placed in an envelope and theenvelope stapled to the notebook page The envelope and page should then be signed andwitnessed making reference to the attachment being placed in the envelope
9 mdash Donrsquot remove originalsNo original pages should be removed from the notebook
10 mdash Do outline new experimentsWhen a new project or experiment is started the objective and rationale should be brieflyoutlined (eg in a short paragraph or by providing a flowchart)
11 mdash Do record lab meeting discussionsRelevant discussions from lab meetings should be recorded as should ideas or suggestionsmade by others The names of the people making the ideas and suggestions should be care-fully documented This information may be important in establishing inventorship
12 mdash Do provide detailRecord test descriptions including preferred operating conditions control conditionsoperable and preferred ranges of conditions and alternate specific materials Also recordtest results and an explanation of the results as well as photos or sketches of the resultsandor the test device Any conclusions should be short and supported by the factual dataOpinions or speculation about the invention should be avoided
13 mdash Do track notebooksIdeally each lab should maintain a catalog of notebooks in which each notebook is assigneda number and the name of the author of each notebook is recorded In addition the datethe author received the notebook as well as the date the notebook was completed andreturned should be recorded Upon leaving the lab the author should return all notebookschecked out by or to him
14 mdash Do save completed notebooksAll completed notebooks should be indexed (eg by number by author andor by subjectarea) and kept safely in a central repository together with corresponding patent applica-tions or patents Lab notebooks that relate to inventions on which patents have been grant-ed should be kept for the life of the patent plus six years
By J Peter Fasse
Fish amp Richardson pcIntellectual property complex litigation technology law800 818-5070wwwfrcominfofrcom
P ER SP EC T I V E
PHARMACOK INET I CS
Data gaps limit the translational potentialof preclinical researchRobin J Kleiman1 and Michael D Ehlers2
The absence of mouse pharmacokinetic reference data hinders translation An analysis ofrecent literature highlights a systematic lack of discussion regarding rationale for the selec-tion of dosing paradigms in preclinical studies and in particular for neuroscience studies inwhich the lack of brain penetration can limit target-organ exposure We propose solutionsto improve study design
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Despite widespread use of pharmacologicalagents in mouse models of human diseasethe literature lacks comprehensive pharmaco-kinetic profiles for such studies Coupled witha paucity of suitable data are shortcomingsin the training of experimental biologists inthe application of pharmacometric principlesto experimental study design Many authorssimply cite previously published studies tosupport the selection of a particular dose evenwhen the cited paper lacks drug exposuredata There is an assumption on the part ofresearchers that if a referenced study demon-strates a biological effectmdashthat is any measur-able physiological or behavioral effectmdashin arodent at a given dose then that same dosewill also effectively perturb disease-relevantmechanistic biology in a different study Thedanger occurs when the observed therapeuticeffects are not linked to drug-induced mecha-nistic alterations at the level of the target organLack of a drug exposurendashresponse relationshipin a target organ casts doubt on mechanisticinterpretations In addition any changes inthe route of drug administration vehicle prep-aration species used (rat versus mouse versusprimate) age or strain of animal transgenicmodification time points under investigationduration of dosing or organ targeted for inter-vention (for example brain versus a periph-eral tumor) can alter the relation between doseexposure and measured response In suchcases assumptions regarding the mechanisticbasis for observed therapeutic effects may nothold true
Preclinical pharmacological experimentsthat do not measure drug concentrations in
1Translational Neuroscience Center Kirby NeurobiologyCenter Department of Neurology Boston ChildrenrsquosHospital Harvard Medical School Boston MA 02115USA 2Neuroscience amp Pain Research Unit BioTherapeu-tics Worldwide Research and Development Pfizer IncCambridge MA 02139 USACorresponding author E-mail robinkleimanchildrensharvardedu (RJK) michaelehlerspfizercom (MDE)
the target organ run the risk of producing ex-posures that are too low or too high to inter-pret a mechanistic hypothesis Most drugs arenot selective over a large exposure range for asingle molecular target Confident evaluationof a therapeutic hypothesis requires an under-standing of the drugrsquos penetration and kineticswithin the target tissue as well as its potencyand selectivity for specific molecular targetsFurther investigators must consider the con-centration of the unbound fraction of drugthat is available to interact with the targetPublished reports often overlook the fact thatmany small molecules are more than 90bound to plasma or tissue proteins whichgreatly decreases the fraction of drug availableto bind to the intended target Thus in casesin which drug binding has a slow off-rate anorganismrsquos total drug exposure is not a predic-tor of drug available to interact with its target(1) The failure of some academic scientists toobtain relevant pharmacokinetic data impairsthe interpretation of preclinical research resultsand likely contributes to the acknowledgeddifficulties in replicating some academic liter-ature as reported by industry scientists (2 3)
Drug discovery teams in industry settingsroutinely collect pharmacokinetic data to aidin the mechanistic interpretation of in vivopreclinical data and to project optimal dosingparadigms for efficacy and toxicology studiesData required to evaluate brain penetrationare not typically collected by industry-baseddrug-discovery teams for compounds origi-nally developed for therapeutic indicationsthat do not obviously implicate the centralnervous system making this information es-pecially hard to find for many otherwise well-described drugs In addition because mousedata are not required for preclinical toxicologystudies (the more common small animal spe-cies for preclinical toxicology being rats)industry scientists do not often obtain pharma-cokinetic data from mouse experiments These
wwwScienceTranslationalMedicineo
issues are especially relevant for older drugsthat are potentially suitable for repurposingMany older drugs were discovered and char-acterized before routine pharmacokinetic-pharmacodynamic (PK-PD) modeling ofpreclinical drug exposure and its applicationto predicting human dosing became standardpractice Last pharmacokinetic data are notconsidered innovative and these studies gen-erally do not achieve publication in peer-reviewed journals even when the data havebeen generated When such data are pub-lished it is often relegated to the unsearchableblack hole of supplementary materials Thusmouse neuroPK profiles are not readily avail-able for many drugs that are frequently usedin conjunction with mouse models of humanbrain disorders
DOCUMENTING DOSING STRATEGIES
To evaluate the potential impact of insufficientpharmacokinetic data on dose selection in asample of recent published neuroscience liter-ature we conducted an analysis of papersidentified by means of a PubMed search usingthe search terms ldquodrugrdquo and ldquobrainrdquo for the pub-lication year 2014 from eight journals (Table 1)This list was culled to include only primaryresearch reports that included systemic adminis-tration of a pharmacological agent a pharma-cological therapeutic or a biological therapeuticas part of the study design The search yielded100 articles published between 1 January and30 December 2014 that used systemic drug de-livery with the intended goal of targeting thebrain of rodents (table S1) Each publicationwas examined for the stated rationale behindthe dose selection of study drugs (Table 1)
The reported rationale for dosing strategiesfell into several broad categories including(from lowest confidence to highest) (i) dose se-lected rationale not discussed (ii) literaturecitations of another study in which reportsranged from citation of exposure in the samespecies exposure in a different strain or spe-cies a dose conversion from the human liter-ature to rodent or reports of effects on rodentbehavior in another study (iii) demonstrationof an effect on rodent behavior or function inthe current study (iv) demonstration of adose-responsive biological effect in the currentstudy (v) measurement of drug levels in bloodor plasma in the current study and (vi) mea-surement of drug levels in the target organ(that is the brain) in the current study In onlytwo instances were publications identifiedthat considered the impact of drug binding
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to plasma or brain proteins on the free expo-sure of drug available to interact with the tar-get This is a critical flaw in most publishedstudies that use small molecules for functionaleffects in the brain because many centralnervous system (CNS) drugs that penetratethe blood-brain barrier exhibit high proteinbinding leaving a small fraction of the totaldrug measured in plasma or brain unbound
and free to interact with the molecular targetFurthermore most studies used evidence of abiological activity to justify dose selection with-out consideration for how exposure of theagent relates to the potency of the compoundat known molecular targets which would berequired to test a mechanistic hypothesis
The lack of pharmacokinetic considera-tion does not imply that every study used an
wwwScienceTranslationalMedicineo
inappropriate dose of drug to test their hypoth-esis It does illustrate that a clear rationale wasnot provided for dose selection in most pub-lications Furthermore all 11 of the 100 publi-cations that measured total brain exposureincluded an author from the pharmaceutical in-dustry (n=5) an academic drug screening group(n = 3) or a pharmacologyndashpharmaceuticalsciences department (n = 3) This observationlikely reflects the limited presence of pharma-cology and pharmacometrics departmentswithinmost academic institutions and limitedaccess to the mass spectrometry and otheranalytical resources needed to measure druglevels in study samples Outsourcing the bio-analysis of samples collected from study ani-mals is feasible but the use of contract researchorganizations to support such studies is oftentoo costly for most academic grant budgets toaccommodate
DATABASES AND REPURPOSINGRecent years have seen increasing efforts toinvestigate approved or clinically tested drugsfor new indications (4ndash8) Such repurposinghas been touted as a means to accelerate ther-apeutic development (4) For example a stra-tegic pillar of the US National Institutes ofHealthrsquos (NIHrsquos) translational roadmap callsfor the academic community to actively par-ticipate in the repurposing of drugs approvedby the US Food and Drug Administration(FDA) or investigational drugs that havepassed safety hurdles but failed in clinicaltrials because of lack of efficacy (9ndash11) To havea meaningful impact in neurological and psy-chiatric disorders such drug repurposingefforts will require access to neuropharma-cokinetic (neuroPK) data sets in mice to guidethe testing of new therapeutic hypotheses ingenetically engineered disease models A re-cently published consensus evaluation of drugrepositioning opportunities for Alzheimerrsquosdisease identified 15 potential drug candidatesThese were further prioritized for testing onthe basis of available evidence to produce ashortlist of seven compounds reviewed by in-dustry experts to provide insight into the via-bility of these candidates The most commonshortcoming identified for the compoundsconsidered were issues related to insufficientbrain penetration or the lack of informationabout optimal dosing strategies (11)
The repurposing of statins illustrateshow the neuroPK knowledge gap limits progressStatins were developed as 3-hydroxy-3-methylglutarylndashcoenzyme A (HMG-CoA) reduc-tase inhibitors to lower cholesterol and reduce
Table 1 Preclinical dosing strategies The rationale for drug-dosing strategies was extractedfrom the literature through the analysis of 100 peer-reviewed studies published in2014 from eight journals that cover research on mechanisms of brain function disease andtherapeutic approaches to CNS disorders (Cell Neuron Nature Nature Neuroscience NatureMedicine Neurobiology of Disease Neuropsychopharmacology and Science TranslationalMedicine) (table S1) Forty-four of the 100 publications selected were studies of potentialtherapeutic approaches to disease whereas the remaining were studies of basic neurobiology ormechanisms of disease Each publication was examined to discern how authors selected thedosage of pharmacological tools or therapeutic compounds used in the design of studies toprobe brain function A relatively small number of studies considered what the concentrationof drug available in the brain after administration would be in the context of theirexperimental studies The most common method for selecting a dose of drug was tocite a previous study that demonstrated a biological effect of the drug on someaspect of rodent behavior
Rationale for studyrsquos drug-dose selection
Therapeutic
studies
Number of papers from the100 published studies
analyzed
bull No exposure or rationale for dose selection provided
5
22
bull Rodent dose extrapolated from human studies
0
1
bull Doses are similar to what was used previously toproduce a biological effect
8
23
bull Literature reports cited for multiple functionaleffects of drug at selected dose
4
5
bull Brain penetration evaluated but exposure notmeasured
2
2
bull Literature report of mismatched drug exposure
0
1
bull Observation of a biological effect at a single dosein current study
3
6
bull Observation of dose-responsive biological effectin current study
5
16
bull Brain exposure to drug was measured with routeof administration that differed from the oneused in the efficacy study
1
1
bull Plasma drug concentrations measured literaturereport of brain exposure cited and target-organpharmacodynamic effect observed in the currentstudy
1
1
bull Plasma drug concentrations measured
4
7
bull Brain pharmacodynamic effect of drug observed
2
4
bull Brain drug concentrations measured (totalconcentration)
6
7
bull Unbound brain drug concentrations measured
1
2
bull Brain drug concentrations measured and brainpharmacodynamic effect of drug observed
2
2
Total
44
100
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risk of cardiovascular disease (12) FDA hasapproved at least nine different statins andmost are commonly prescribed nearly one-third of Americans ages 55 to 64 took a pre-scription cholesterol-lowering drug between2009 and 2012 (wwwcdcgovnchsdatahushus14pdf) The widespread availability andsafety profile of statins has lured researchersinto evaluating their potential for repurpos-ing (13) Statins have been profiled extensive-ly in preclinical research to test for potentialtherapeutic benefit in Alzheimerrsquos disease(14ndash19) Fragile X syndrome (20) Rett syn-drome (21 22) epilepsy (23) Huntingtonrsquos dis-ease (24) Parkinsonrsquos disease (25 26) stroke(27) and brain injury (28 29)
A search of the literature reveals no sys-tematic neuroPK studies in any mouse strainthat would enable direct comparisons of CNSexposure across the various statins In silicopredictions based on the drugsrsquo molecularproperties suggest that the nine most widelyprescribed statins each have a different poten-tial to penetrate the blood-brain barrier differ-ent potencies against the HMG-CoA reductaseenzyme and different ldquooff-targetrdquo activity pro-files (30) On the basis of available data thereis reason to believe that simvastatin has thebest overall profile for inhibiting HMG-CoAreductase in the brain (30) A recent study re-ported that lovastatin is able to reverse a rangeof phenotypes in a mouse model of Fragile Xsyndrome (20) However the design of an op-timal clinical trial will require the collection ofmouse pharmacokinetic data to understandhow much CNS drug exposure is required toproduce efficacy in the disease model Thereare at least two possible scenarios Giventhat simvastatin is more potent at inhibitingHMG-CoA reductase than are other statinsand likely to be more brain penetrant inboth mice and humans one would expectthat simvastatin will be more potent than lo-vastatin in ameliorating symptoms in bothmice and humans if the observed efficacy stemsfrom inhibition of HMG-CoA reductase activ-ity in the brain by lovastatin The advantage ofthis outcome would be that better brain pen-etration and potency would lead to a loweroverall dose requirement to achieve efficacyand thus likely a better safety profile
A second scenario could be that lovastatin ismore potent than simvastatin in the mousemodel of Fragile X syndrome because of anadditional biological activity inherent to thelovastatinmolecule whichmaynot yet be doc-umented in the literature In either case un-derstanding the CNS exposure of lovastatin
required to produce efficacy in themouse willdetermine whether there is a safe therapeuticindex for achieving the required concentra-tion in patients Previous attempts to discernuseful neuroPK parameters from the litera-ture for the use of statins in rodent modelshave highlighted the lack of critical data asthe looming roadblock to progress in the field(31 32) Until these data exist the transla-tional potential of preclinical research maybe limited And this is but one example ofone drug class
The creation of a centralized database isneeded for the entire translational researchcommunity and would establish a new mech-anism for academia funding agencies founda-tions and industry to pool resources If studiesare donewell the first time and documented inan open-access resource it will reduce redun-dant efforts and improve the quality of decisionmaking by scientists considering innovativesolutions to our biggest health problems
FILL THE GAPSManuscript submission practices for severalhigh-impact journals now include require-ments that authors include detailed informa-tion regarding study design and statisticalanalysis with each submission A reasonableextension of this checklist should includethe stated rationale for doses selected for studydrugs Information should include a discus-sion of data highlighted in Table 2 Authorsshould be expected to reference a relevant
wwwScienceTranslationalMedicineo
data set from a high-quality database or pub-lication or provide the data in the current study(Table 3)
Industry biologists learn basic principlesof medicinal chemistry pharmacokineticsand drug disposition while working on drugdiscovery project teams Academic groupsare playing an increasing role in transla-tional therapeutics and in particular drugrepurposing Academic programs need toaugment training in pharmacokinetics andpharmacodynamics so as to increase the rigor ofpreclinical work and to ensure that investigator-initiated clinical studies are testing hypotheseseffectively Institutions without a departmentof pharmacology or pharmacometrics mightlack the organizational knowledge needed toconduct drug studies and must identify re-sources or collaborators to patch these defi-cits Formal coursework and Web-basedresources and tutorials are needed to train andsupport translational researchers Manuscriptand grant reviewers need to demand higherstandards for preclinical studies with respect toreporting on drug exposure associated withbiological effects Ethics committees responsi-ble for review of animal protocols should re-quire investigators to provide rationale fordose selections in proposed studies Similarlyscientific review boards at academic medicalcenters need to include clinical pharmacologistswho are able to review investigator-initiatedclinical studies to ensure that proposed dosingstrategies will test a meaningful hypothesis
Table 2 Recommendations for use of pharmacokinetic data The first column includes a listof recommended data sets to aid reviewers of submitted articles in the interpretation ofpreclinical findings The second column includes a list of useful reference data that wouldsupport improved preclinical study design in mice if available in a public database
Literature reports that evaluate studydrugs should include
Compound-specific data that shouldbe included in a rodent
pharmacokinetic database
bull Expected or measured plasma exposure of thestudy drug in the preclinical species during thestudy
bull Elimination half-life (T12)bull Systemic clearance (CL)bull Fraction of drug that is protein bound (fb)
bull Expected or measured target organ exposureof the study drugs in the preclinical speciesduring the study
Maximum plasma concentration after drug admin-istration (Cmax) and time to reach maximum plas-ma concentration (Tmax) for a standardized doseand route of administration
bull Expected or measured free fraction (unboundby protein) of the study drugs in the targetorgan of the preclinical species during thestudy
bull The ratio of drug in brain to that in plasma (BP)bull The ratio of drug found free in brain (Cub) to thatfound free in the plasma (Cup) defined as CubCupbull Any potential impact of drug transporters (foundon the rodent blood-brain barrier) in limiting brainexposure
bull Expected or measured potency of the studydrug against the hypothesized activity in vitro
Expected ormeasured potency of molecule at knownbiological targets
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A central repository that contains brainpenetration protein binding and pharmaco-kinetic profiles of drugs and pharmacologicaltools in rodents is needed to effectively sup-port translational research This databaseshould also provide basic tutorials that de-fine primary pharmacokinetic parameterswith examples to illustrate how data are usedto predict optimal dosing strategies The min-imum data set needed for each compoundin a useful rodent database is highlighted inTable 2 Access to this information and sup-porting materials will have an immediateimpact on the quality of translational drug re-purposing efforts across brain disorders andwill support the development of new thera-peutic approaches to neurological disordersand mental illness Existing databases man-aged by NIH or precompetitive consortia couldbe reinforced with donated pharmacokineticdata sets and tutorials
Industry and government scientists shouldwork precompetitively to collect and curatepharmacokinetic data sets in conjunction withsupporting educational materials Mouse phar-macokinetic data exist inside pharmaceuti-cal companies for a wide range of publicallydisclosed molecules and literature standardsRelease of these data into a public databasewould provide several benefits to companiesincluding (i) increased scientific rigor in theliterature with a higher probability of repro-ducibility (ii) increased appreciation by theacademic biology community for the diffi-culty inherent in generating molecules withpotency and pharmacokinetic profiles suit-able for in vivo work opening the door forin-kind collaboration with academic groups
and (iii) direct comparison of data collectedin-house to that collected at other compa-nies or institutions to enable better internalquality control Comprehensive pharmaco-kinetic data sets will benefit all therapeuticareas regardless of whether the brain is thetarget organ because peripheral and cen-tral exposure data can be generated fromthe same experiments Moreover the prin-ciples described above for the CNS apply toother target tissues in which vascular bar-riers metabolic processes or active transportalter the distribution of systemically admin-istered drugs
Key to ensuring that preclinical mousestudies test the hypotheses they aim to eval-uate is an understanding of the unboundfraction of drug present in the target organat an appropriate time point under studyGrant and journal reviewers need to care-fully consider whether authors of propos-als and manuscripts are providing adequaterationale for their choices of preclinical dos-ing paradigms Importantly the collectionand centralization of rodent pharmacoki-netic datasets will promote efficient genera-tion of future data reduce the collection ofredundant data and improve the return oninvestment for research funds that are de-voted to preclinical studies aimed towardclinical translation
SUPPLEMENTARY MATERIALS
wwwsciencetranslationalmedicineorgcgicontentfull8320320ps1DC1Table S1 One hundred publications that used systemic drugdelivery with the goal of targeting rodent brains
wwwScienceTranslationalMedicineo
REFERENCES AND NOTES1 A Reichel Addressing central nervous system (CNS) penetra-
tion in drug discovery Basics and implications of the evolv-ing new concept Chem Biodivers 6 2030ndash2049 (2009)
2 F Prinz T Schlange K Asadullah Believe it or not Howmuch can we rely on published data on potential drugtargets Nat Rev Drug Discov 10 712 (2011)
3 C G Begley L M Ellis Drug development Raisestandards for preclinical cancer research Nature 483531ndash533 (2012)
4 P Nair Second act Drug repurposing gets a boost asacademic researchers join the search for novel uses ofexisting drugs Proc Natl Acad Sci USA 110 2430ndash2432(2013)
5 T I Oprea J Mestres Drug repurposing Far beyond newtargets for old drugs AAPS J 14 759ndash763 (2012)
6 S M Strittmatter Overcoming drug development bot-tlenecks with repurposing Old drugs learn new tricksNat Med 20 590ndash591 (2014)
7 K Xu T R Coteacute Database identifies FDA-approved drugswith potential to be repurposed for treatment of orphandiseases Brief Bioinform 12 341ndash345 (2011)
8 X Bosch European researchers drug companies joinforces against rare diseases JAMA 294 2014ndash2015 (2005)
9 F S Collins Mining for therapeutic gold Nat Rev DrugDiscov 10 397 (2011)
10 P Vallance P Williams C Dollery The future is much closercollaboration between the pharmaceutical industry andacademic medical centers Clin Pharmacol Ther 87525ndash527 (2010)
11 A Corbett J Pickett A Burns J Corcoran S B DunnettP Edison J J Hagan C Holmes E Jones C KatonaI Kearns P Kehoe A Mudher A Passmore N ShepherdF Walsh C Ballard Drug repositioning for Alzheimerrsquosdisease Nat Rev Drug Discov 11 833ndash846 (2012)
12 J L Goldstein M S Brown A century of cholesterol andcoronaries From plaques to genes to statins Cell 161161ndash172 (2015)
13 A M Malfitano G Marasco M C Proto C Laezza P GazzerroM Bifulco Statins in neurological disorders An overviewand update Pharmacol Res 88 74ndash83 (2014)
14 T Kurata K Miyazaki M Kozuki N Morimoto Y OhtaY Ikeda K Abe Progressive neurovascular disturbances inthe cerebral cortex of Alzheimerrsquos disease-model miceProtection by atorvastatin and pitavastatin Neuroscience197 358ndash368 (2011)
15 H Kurinami N Sato M Shinohara D Takeuchi S TakedaM Shimamura T Ogihara R Morishita Prevention ofamyloid beta-induced memory impairment by fluvastatinassociated with the decrease in amyloid beta accumulationand oxidative stress in amyloid beta injection mousemodel Int J Mol Med 21 531ndash537 (2008)
16 M Shinohara N Sato H Kurinami D Takeuchi S TakedaM Shimamura T Yamashita Y Uchiyama H RakugiR Morishita Reduction of brain beta-amyloid (Abeta)by fluvastatin a hydroxymethylglutaryl-CoA reductaseinhibitor through increase in degradation of amyloidprecursor protein C-terminal fragments (APP-CTFs) andAbeta clearance J Biol Chem 285 22091ndash22102 (2010)
17 G J Siegel N B Chauhan D L Feinstein G Li E B LarsonJ C Breitner T J Montine Statin therapy is associated withreduced neuropathologic changes of Alzheimer diseaseNeurology 71 383 author reply 383 (2008)
18 X-K Tong C Lecrux P Rosa-Neto E Hamel Age-dependentrescue by simvastatin of Alzheimerrsquos disease cerebrovascularand memory deficits J Neurosci 32 4705ndash4715 (2012)
19 X K Tong N Nicolakakis P Fernandes B Ongali J BrouilletteR Quirion E Hamel Simvastatin improves cerebrovascularfunction and counters soluble amyloid-beta inflammationand oxidative stress in aged APP mice Neurobiol Dis35 406ndash414 (2009)
Table 3 Recommendations to improve translation through the use of preclinicalpharmacokinetic data
Journalsbull Require authors to provide explicit rationale for dosing strategies usedbull Rationale should include consideration of the unbound drug exposure in target organas best practices
Educationbull Include basic pharmacology and pharmacokinetic principles in formal coursework requiredfor basic preclinical and clinical research scientists
bull Develop tutorials and on-line calculators for rodent dose projections to support appropriateuse of published pharmacological tools
Databasesbull Reinforce public chemical databases with mouse pharmacokinetic data that includes brainexposure
Precompetitive consortiabull Create precompetitive consortia to solicit mouse pharmacokinetic data sets from industry andfoundation partners for database expansion
bull Targeted data collection for compounds already in the public domain
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P ER SP EC T I V E
20 E K Osterweil S C Chuang A A Chubykin M SidorovR Bianchi R K Wong M F Bear Lovastatin corrects ex-cess protein synthesis and prevents epileptogenesis in amouse model of fragile X syndrome Neuron 77 243ndash250(2013)
21 C M Buchovecky S D Turley H M Brown S M KyleJ G McDonald B Liu A A Pieper W Huang D M KatzD W Russell J Shendure M J Justice A suppressorscreen in Mecp2 mutant mice implicates cholesterol me-tabolism in Rett syndrome Nat Genet 45 1013ndash1020(2013)
22 M J Justice C M Buchovecky S M Kyle A Djukic A rolefor metabolism in Rett syndrome pathogenesis Newclinical findings and potential treatment targets RareDis 1 e27265 (2013)
23 F Scicchitano A Constanti R Citraro G De Sarro E RussoStatins and epilepsy Preclinical studies clinical trials andstatin-anticonvulsant drug interactions Curr Drug Targets16 747ndash756 (2015)
24 M L Ferlazzo L Sonzogni A Granzotto L Bodgi O LartinC Devic G Vogin S Pereira N Foray Mutations of theHuntingtonrsquos disease protein impact on the ATM-dependentsignaling and repair pathways of the radiation-inducedDNA double-strand breaks Corrective effect of statins andbisphosphonates Mol Neurobiol 49 1200ndash1211 (2014)
25 E K Tan L C Tan Holding on to statins in Parkinsondisease Neurology 81 406ndash407 (2013)
26 B Friedman A Lahad Y Dresner S Vinker Long-termstatin use and the risk of Parkinsonrsquos disease Am J ManagCare 19 626ndash632 (2013)
27 M S Elkind Stroke A step closer to statin therapy forstroke Nat Rev Neurol 9 242ndash244 (2013)
28 E E Abrahamson M D Ikonomovic C E Dixon S T DeKoskySimvastatin therapy prevents brain trauma-inducedincreases in beta-amyloid peptide levels Ann Neurol66 407ndash414 (2009)
29 E F Wible D T Laskowitz Statins in traumatic brain injuryNeurotherapeutics 7 62ndash73 (2010)
wwwScienceTranslationalMedicineo
30 S Sierra M C Ramos P Molina C Esteo J A VaacutezquezJ S Burgos Statins as neuroprotectants A comparativein vitro study of lipophilicity blood-brain-barrier penetra-tion lowering of brain cholesterol and decrease of neuroncell death J Alzheimers Dis 23 307ndash318 (2011)
31 W G Wood G P Eckert U Igbavboa W E Muumlller Statinsand neuroprotection A prescription to move the fieldforward Ann N Y Acad Sci 1199 69ndash76 (2010)
32 W G Wood W E Muumlller G P Eckert Statins and neuro-protection Basic pharmacology needed Mol Neurobiol50 214ndash220 (2014)
101126scitranslmedaac9888
Citation R J Kleiman M D Ehlers Data gaps limit thetranslational potential of preclinical research Sci Transl Med8 320ps1 (2016)
D
rg 6 January 2016 Vol 8 Issue 320 320ps1 5
on January 6 2016httpstm
sciencemagorg
ownloaded from
101126scitranslmedaac9888] (320) 320ps1 [doi8Science Translational Medicine
Robin J Kleiman and Michael D Ehlers (January 6 2016) Data gaps limit the translational potential of preclinical research
Editors Summary
This information is current as of January 6 2016 The following resources related to this article are available online at httpstmsciencemagorg
Article Tools
httpstmsciencemagorgcontent8320320ps1article tools Visit the online version of this article to access the personalization and
s sitesScienceThe editors suggest related resources on
PermissionshttpwwwsciencemagorgaboutpermissionsdtlObtain information about reproducing this article
is a registered trademark of AAASMedicineScience TranslationalAssociation for the Advancement of Science all rights reserved The title
Science 1200 New York Avenue NW Washington DC 20005 Copyright 2016 by the Americanweekly except the last week in December by the American Association for the Advancement of
(print ISSN 1946-6234 online ISSN 1946-6242) is publishedScience Translational Medicine
on January 6 2016httpstm
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Dow
nloaded from
Boston Childrenrsquos Hospital ndash Broad Institute Collaboration Grants
Background Meeting the challenges of biomedicine requires bringing together creative scientists exceptional technological resources and world-class expertise across many disciplines that rarely exist within a single institution This guiding principle is the basis for a funding opportunity to support Boston Childrenrsquos Hospital investigators performing research in collaboration with Broad scientists
Goals The fundamental goal of this new award is to spark new collaborations between Boston Childrenrsquos Hospital and the Broad Institute The grants will be awarded to address a very wide range of scientific questions but are specifically designated for projects with the following characteristics
middot Projects where engagement with the Broad would benefit Childrenrsquos Hospital investigators projects that can uniquely benefit from being done at the Broad Institute
middot Projects that create new scientific collaborations and bring together diverse scientific backgrounds projects that spark new scientific directions or technologies and are not currently being pursued at Childrenrsquos Hospital
middot Projects that pilot new approaches that researchers at Childrenrsquos the Broad and the greater scientific community can benefit from in the future the purpose of these awards is not to provide gap or extension funding of existing projects but to initiate new projects
Eligibility Individuals with Principal Investigator status at Boston Childrenrsquos Hospital are eligible Applicants need not be Associate Members of the Broad Institute
Broad Platforms and Scientists Broadrsquos Platforms (Genomics Imaging Metabolite Profiling Proteomics Genomic Perturbation and the Broad Technology Labs) are collaborative organizations that provide scientific leadership and cutting edge technologies in support of project goals Collaborations can also be established with other groups at the Broad including the Klarman Cell Observatory the Stanley Center for Psychiatric Research or the Center for the Development of Therapeutics
Budgets Grants will provide $60000 direct support for 1 year plus philanthropic overhead It is expected that most grants will fund work performed at the Broad Institute either through interaction with Broadrsquos Platforms or via collaboration with a Broad scientist however the work may also occur at Boston Childrenrsquos if it is important to meet the scientific goals of the collaboration
Deadline and Review process Final proposals are due by September 1 2015 Funding decisions are expected to be reached by October 1 2015 Proposals will be reviewed by a joint Childrenrsquos HospitalndashBroad Institute committee Additional submission dates are expected for 2016
Submission Applicants are strongly encouraged to discuss potential applications in advance with the office of the Chief Scientific Officer at the Broad Questions should be directed to Alex Burgin ( 617-714-7124)
Proteomics Genomic Perturbation and the Broad Technology Labs) are collaborative
organizations that provide scientific leadership and cutting edge technologie
s in support of
project goals Collaborations can also be established with other groups at the Broad including
the Klarman Cell Observatory the Stanley Center for Psychiatric Research or the Center for the
Development of Therapeutics
Budgets
Grants wi
ll provide $60000 direct support for 1 year plus philanthropic overhead It
is expected that most grants will fund work performed at the Broad Institute either through
interaction with Broadrsquos Platforms or via collaboration with a Broad scientist howev
er the
work may also occur at Boston Childrenrsquos if it is important to meet the scientific goals of the
collaboration
Deadline and Review process
Final proposals are due by September 1 2015 Funding
decisions are expected to be reached by October 1 201
5 Proposals will be reviewed by a joint
Childrenrsquos Hospital
ndash
Broad Institute committee Additional submission dates are expected for
2016
Submission
Applicants are
strongly encouraged to discuss potential applications in
advance
with the office of the Chief Sc
ientific Officer at the Broad
Questions should be
directed to Alex Burgin (
aburginbroadinstituteorg
617
-
714
-
7124
)
Boston Childrenrsquos Hospital ndash Broad Institute Collaboration Grants
Background Meeting the challenges of biomedicine requires bringing together creative
scientists exceptional technological resources and world-class expertise across many
disciplines that rarely exist within a single institution This guiding principle is the basis for a
funding opportunity to support Boston Childrenrsquos Hospital investigators performing research
in collaboration with Broad scientists
Goals The fundamental goal of this new award is to spark new collaborations between Boston
Childrenrsquos Hospital and the Broad Institute The grants will be awarded to address a very wide
range of scientific questions but are specifically designated for projects with the following
characteristics
Projects where engagement with the Broad would benefit Childrenrsquos Hospital
investigators projects that can uniquely benefit from being done at the Broad Institute
Projects that create new scientific collaborations and bring together diverse scientific
backgrounds projects that spark new scientific directions or technologies and are not
currently being pursued at Childrenrsquos Hospital
Projects that pilot new approaches that researchers at Childrenrsquos the Broad and the
greater scientific community can benefit from in the future the purpose of these awards
is not to provide gap or extension funding of existing projects but to initiate new
projects
Eligibility Individuals with Principal Investigator status at Boston Childrenrsquos Hospital are
eligible Applicants need not be Associate Members of the Broad Institute
Broad Platforms and Scientists Broadrsquos Platforms (Genomics Imaging Metabolite Profiling
Proteomics Genomic Perturbation and the Broad Technology Labs) are collaborative
organizations that provide scientific leadership and cutting edge technologies in support of
project goals Collaborations can also be established with other groups at the Broad including
the Klarman Cell Observatory the Stanley Center for Psychiatric Research or the Center for the
Development of Therapeutics
Budgets Grants will provide $60000 direct support for 1 year plus philanthropic overhead It
is expected that most grants will fund work performed at the Broad Institute either through
interaction with Broadrsquos Platforms or via collaboration with a Broad scientist however the
work may also occur at Boston Childrenrsquos if it is important to meet the scientific goals of the
collaboration
Deadline and Review process Final proposals are due by September 1 2015 Funding
decisions are expected to be reached by October 1 2015 Proposals will be reviewed by a joint
Childrenrsquos HospitalndashBroad Institute committee Additional submission dates are expected for
2016
Submission Applicants are strongly encouraged to discuss potential applications in
advance with the office of the Chief Scientific Officer at the Broad Questions should be
directed to Alex Burgin (aburginbroadinstituteorg 617-714-7124)
Clinical Trials Glossary
ADME an acronym for absorption distribution metabolism and elimination ADME
studies determine how a drug is absorbed by the body the chemical changes that it may
undergo and how it is eliminated from the body
Adverse event (AE) a bothersome event that occurs in a study participant AEs may be
related to the treatment being tested or may be due another cause (eg another treatment
another medical condition an accident or a surgery)
Arm a specific type of treatment to which a group of clinical trial participants is
assigned Some clinical trials have one arm and some have two arms while others have
three or more arms For example a clinical trial comparing two different doses of an
investigational drug versus a placebo would have three arms participants receiving a
higher dose of the investigational drug participants receiving a lower dose of the
investigational drug and participants receiving the placebo
Baseline a point in time at the beginning of a clinical trial before the study participants
receive any treatment At the baseline participants usually have certain types of tests
During and after treatment the same tests may be performed and the results compared
with the baseline results to see if the drug has caused changes
Bias a factor ndash such as a preconceived idea about the effects of the benefits and risks of a
treatment or a lack of balance in selection of patients for a study ndash that reduces the
likelihood that the study results are true Methods such as blinding and randomization
are used to limit the potential for bias
Bioavailability the portion of the dose of a drug that reaches the bloodstream For
example if the drug is administered intravenously its bioavailability is 100 percent
however if the drug is administered in any other way such as orally topically or
through intramuscular injection its bioavailability will decrease due to incomplete
absorption
Bioequivalence study a test performed to compare the portion of a drug in the
bloodstream when administered in different dosage forms
Biologic product any substance that can be used in prevention treatment or cure of
disease Some examples include vaccines blood virus toxin antitoxin and therapeutic
serum
Biopsy the removal of cells or tissue from a patient for examination which is usually
done under a microscope A tissue sample might be taken for genetic studies Sometimes
there is a difference between the blood genotype and the skin or other tissue genotype
This term can also refer to the tissue sample that has been obtained by such a procedure
2
Blinding a process used to prevent the participants the researchers or both from
knowing what specific treatment is being given to participants in a clinical trial The
process of blinding helps to reduce bias because study participants and researchers are
less likely to be unconsciously influenced by the knowledge of what the study participant
is actually receiving If only the participants are blinded the study is called a single-
blind study If both participants and researchers are blinded the study is called a double-
blind study
Carcinogenicity studies long-term studies conducted in animal models to determine a
drugrsquos likelihood of causing cancer
Clinical efficacy a compoundrsquos ability to produce the desired effect
Clinical pharmacology a science that studies properties of drugs in relation to their
therapeutic value in humans
Clinical study or Clinical trial a medical experiment in human beings that helps to
determine how a disease drug or medical device affects study participants Clinical
studies are necessary to answer specific questions about how to better diagnose prevent
or treat a disease or condition
Cohort a group of study participants who have certain characteristics in common such
as female sex a defined age range or particular severity of disease Dividing study
participants into cohorts is often done as part of the analyses of study data
Contraindication a factor that makes the use of a particular drug inadvisable For
example a person who has had an allergic reaction to penicillin in the past is considered
to have a contraindication to using penicillin in the future
Control group a group of participants not receiving the investigational drug but instead
receiving a standard treatment for their disease or receiving a placebo The results
observed in the group of patients receiving the investigational drug are compared with the
results observed in the control group
Crossover study a study design with two or more arms where participants receive one
treatment for a period of time and then switch over to a second treatment for a period of
time Such a study design allows the effects of the two treatments to be compared in the
same patient
Data Monitoring Committee (DMC) or Data Safety and Monitoring Board (DSMB)
A committee of experts that periodically reviews the accumulating data from an ongoing
multicenter clinical trial Members of a DMCDSMB must be independent ie they
cannot be participating as investigators in the clinical trial Based on their review the
DMCDSMB experts advise the sponsor regarding whether it is safe and acceptable to
continue with the study or whether the data suggest that the study should be modified or
stopped A DMCDSMB may recommend that a trial be stopped if there are safety
concerns or if the trial objectives have been achieved
3
Dose-ranging study a clinical trial in which two or more doses of an investigational
drug are tested to determine which dose is likely to offer the best combination of safety
and efficacy in later clinical trials or in medical care
Efficacy or effectiveness the ability of a drug to prevent cure or slow a disease process or to alleviate the symptoms of a disease or condition
Eligibility a determination made during the screening period for a clinical study of
whether a personrsquos participation in the trial is likely to be safe and can contribute data
that will help achieve the study goals
Endpoint occurrence of a disease symptom sign or test result that constitutes one of the
target outcomes of a clinical trial
Inclusionexclusion criteria the factors defined in the protocol of a study that determine
whether a personrsquos participation in a clinical trial is likely to be safe and can contribute
data that will help achieve the study goals Study candidates undergo evaluation during
the study screening period to determine if they meet all of the inclusion criteria and do
not meet any of the exclusion criteria as defined in the protocol These criteria usually
consider such factors as age sex type of disease stage of disease previous treatment
history and other medical conditions in determining eligibility for the study
Informed consent (assent) a process by which medical researchers provide necessary
information to a person about a clinical study and the person voluntarily confirms his or
her willingness to participate in the study Children who are considered old enough to
have a basic understanding of the study may need to provide assent to be involved in the
study a parent or legal guardian must also give informed consent for such a child to
participate
Informed consent (assent) form a document that describes a clinical study to the
participants (or their parentsguardians) The informed consent (assent) form includes
information about the goals of the study the study design and duration the types of tests
to be performed the potential risks and inconveniences the potential benefits the
possible costs or payments associated with study participation the available alternative
therapies the rights and responsibilities of the participant and the people to contact if the
participant has questions The informed consent (assent) form must be reviewed and
signed before the participant has any study tests or treatment including the tests
performed during the screening period at the beginning of the study Participants are
given a copy of the informed consent (assent) form to take home
Institutional Review Board (IRB) or Independent Ethics Committee (IEC) a board
of physicians statisticians researchers community advocates and others who are
responsible for ensuring the protection of the rights safety and well-being of participants
in a clinical trial at a study center This board is called an IRB in the United States and is
often called an IEC in other countries IRBIECs review and approve important study
documents (eg protocols informed consent forms study advertisements and patient
4
brochures) before the start of the study and periodically review the progress of the study
while it is ongoing
Investigational Drug a drug that is being tested as a potential treatment for a disease or
condition but has not yet been proven safe and effective for that use
Investigator a physician or other health care worker who carries out a clinical trial by enrolling treating and monitoring participants and recording the results
In vitro testing testing conducted in test tubes or other artificial environments
In vivo testing testing conducted in living animals or humans
Longitudinal study a clinical study that involves observations of the same items over
long periods often many decades Because longitudinal studies track the same people
they are often used to study trends across the life span to uncover predictors of certain
diseases or to track the effects of a particular treatment on a patientrsquos condition over
time
Multicenter study a study conducted at more than one location Multicenter clinical
studies are generally performed when each individual clinical trial site does not have
enough study candidates to complete a large trial
Natural history study a study of the natural development of a disease or condition over
a period of time Natural history studies are usually longitudinal studies
New Drug Application (NDA) the registration document through which a
pharmaceutical company formally proposes that the FDA approve a new drug for
manufacturing and sale The application includes detailed reports of pharmacology
toxicology manufacturing and chemistry as well as data from clinical trials
Open-label study a study in which the participants and the investigators know which
treatment is being given In an open-label study there is no blinding and none of the participants receives a placebo
Orphan disease a disease or condition that affects a relatively small number of people
In the US this defined as fewer than 200000 people In Europe this is defined as fewer
than five in 110000 people
Orphan drug a drug intended to treat an orphan disease
Participant or subject a patient or healthy volunteer who participates in a clinical trial
Phase 1 the initial phase of testing of an investigational drug in humans Usually a
Phase 1 clinical study is conducted in a small number of healthy volunteers or patients
with a disease for which the drug may be useful Generally the study is designed to
determine the side effects of the drug and its pharmacokinetics Some information
5
regarding drug efficacy may be collected if patients with a disease participate A phase
frequently encompasses more than one clinical trial Phase 1 sometimes is sub-divided
into Phases 1a and 1b for example when the first set of Phase 1 trials (Phase 1a) is
performed in healthy volunteers and a second set of Phase 1 trials (Phase 1b) is
performed in patients with a disease
Phase 2 the intermediate phase of testing of an investigational drug in humans Usually
a Phase 2 clinical study conducted in patients with a disease for which the drug may be
useful Generally the study is designed to evaluate dosing to obtain preliminary data on
the effectiveness of the drug and to acquire more safety information Phase 2 sometimes
is sub-divided into Phases 2a and 2b Phase 2a studies typically are smaller and shorter
in duration and evaluate different drug doses to see how they affect certain tests that can
indicate whether the drug is working as expected Phase 2b studies typically enroll more
patients are of longer duration and evaluate whether the drug is offering clinical benefits to patients Phase 2b studies sometimes are considered pivotal or registration-directed
Phase 3 the final phase of testing an investigational drug in humans before regulatory
approval Phase 3 studies are usually conducted in a large population of patients and are
generally designed to confirm the effectiveness of the drug and to evaluate the overall
risk-benefit ratio Phase 3 studies usually test the investigational drug in comparison with
a standard treatment for the disease or a placebo
Phase 4 testing of a drug in humans after it has already been approved by regulatory
authorities and can be used in medical practice Phase 4 studies may be conducted to
compare the drug to a similar type of drug to explore whether it may help patients with
other diseases to further study the long-term safety of the drug or for other reasons
Pivotal study a study that is designed to generate the data required by regulatory
authorities to decide whether to approve an investigational drug A pivotal study is
usually a large randomized Phase 2b or Phase 3 study and often is blinded and uses a
placebo as a control Sometimes a pivotal study is described as a registration-directed
study
Placebo an inactive version of an investigational drug A placebo has a similar
appearance to the investigational drug but is expected to have no therapeutic value A
placebo is used as a comparison treatment to reduce bias in randomized studies
Preapproval access program an umbrella term for programs that allow seriously ill
patients to receive an investigational drug when they are unable to participate in clinical
trials and there is no alternative treatment This is sometimes referred to as
compassionate use Types of pre-approval access programs include expanded access
parallel-track named patient program single-patient exemption and treatment IND The
timing for starting an expanded access program usually depends upon what is known
about the risk-benefit of the drug and whether the drug can be provided in a manner that
is fair to patients with the disease
6
Preclinical (nonclinical) testing testing of a drug in test tubes or in animals A drug
undergoes preclinical testing before being tested in humans to make sure that it shows
evidence of desired effects and is sufficiently safe for study in people Preclinical testing
sometimes also helps to determine the doses of the drug that should be evaluated in
humans Preclinical testing is sometimes called nonclinical testing
Protocol a document describing what types of people may participate in a clinical study
and the objectives treatments measurements statistical methods timing and
organization of a clinical trial The protocol must be prepared in advance of the study
and must be reviewed and approved by review committees and regulatory authorities
before the study is started Investigators must follow the protocol to carry out the study
Randomization assignment of participants to treatment arms based on chance This is
usually done by a computer program in a way that does not allow either the participants
or the investigators to choose who is assigned to which arm Randomization is used to
reduce bias in clinical trials
Risk-benefit ratio the balance of the risk of side effects expected with use of a drug
versus the potential for benefit with the use of that drug A drug with a good risk-benefit
ratio has few side effects and is very effective
Serious adverse event (SAE) an adverse event that is life-threatening requires inpatient
hospitalization or lengthens a hospital stay leads to substantial disability leads to a birth
defect or results in death
Side effect any effect of a drug other than the desired effect Side effects are often
unwanted and may be bothersome Other names for a bothersome side effect are adverse
drug reaction (ADR) or drug toxicity
Screening period a period at the beginning of a clinical trial when candidates for the
study are evaluated to determine if their participation is likely to be safe and can
contribute data that will help achieve the study goals
Significant or statistically significant an outcome in a clinical trial is likely to result
from a real difference (eg due to an effect of a treatment) and is unlikely to be due to
chance alone The level of statistical significance is often expressed in terms of a p-
value which indicates the probability that a difference is not due to chance alone
Usually a p-value smaller 005 is considered statistically significant
Sponsor the organization responsible for financing and coordinating a clinical trial
Most often this is a pharmaceutical or biotechnology company
Standard treatment a treatment currently in wide use often approved by regulatory
agencies and generally considered effective in the treatment of a specific disease or
condition
7
Toxicity a side effect produced by a drug that is bothersome to the person taking the
drug
Toxicology the study of the adverse effects of chemicals conducted in animal models to
predict potential adverse effects in humans Some studies are conducted during clinical
development to evaluate dosing regimens
Boston Childrenrsquos Hospital Clinical Research Map 1 Mouse over for additional info Bold = hyperlink
CLINICAL RESEARCH MAP
Boston Childrenrsquos Hospital Clinical Research Map 2 Mouse over for additional info Bold = hyperlink
ObjectiveThis clinical research map is designed to serve as a guide for investigators study coordinators and research nurses at Boston Childrenrsquos Hospital The research map outlines the key steps in preparing to launch a research study and provides embedded links to institutional resources tools and documents
An investigator need not follow the steps on the Clinical Research Map in any particular order There is flexibility and the steps followed will in part de-pend on the type of research study
For new as well as more experienced investigators the Clinical Research Map can be used as a checklist or an inves-tigator can use the steps on the map as points for consideration as they are developing a protocol and launching a study
This tool is not intended to substitute for the important collaboration be-tween a junior investigator and a senior investigatormentor A senior investiga-tor plays a pivotal role in coaching and advising a junior investigator regarding the many subtleties and variations that apply to designing and implementing a protocol
This process map cannot be inclusive of every possible task or step but is intended as a general guide for investi-gators and their study teams
ResourcesThere are many institutional resources at Boston Childrenrsquos Hospital designed to support investigators and their clini-cal research teams In addition to links to resources tools and documents that are embedded in the steps of the clini-cal research map the last page of this document contains website addresses that will take you to additional helpful institutional resources
Acknowledgements Cindy Williams DNP RN PNP NE-BC Nursing Director CTSU Clinical Research Nursing
Ellen McGrath MSN RN CPNP Nurse Practitioner Department of Surgery
Grace Yoon MSN RN CNNP Research Nurse Department of Ophthalmology
Laura Feloney BA Lab Technician
ContentsOverview Four stages 3
1st Stage Protocol development 4
1st Stage Protocol development contrsquod 5
2nd Stage Implementation planning 6
3rd stage Study launch7
4th stage Statistical analysis reporting and dissemination 8
Discarded specimens Additional steps 9
Chart review Steps if you are completing a chart review 10
Appendix A Resources for researchers 11
Boston Childrenrsquos Hospital Clinical Research Map 3 Mouse over for additional info Bold = hyperlink
Overview Four stages
Protocol development
Implementation planning
Study launch
Statistical analysis reporting and dissemination
1
2
3
4
Boston Childrenrsquos Hospital Clinical Research Map 4 Mouse over for additional info Bold = hyperlink
1st Stage Protocol development
Explore resources
CRIT
CRC
EQuIP
CTSU
Harvard Catalyst
Complete training
CITI training
EQUiP
Consult research pharmacistResearch Pharmacy
Rocco Anzaldi
Consult statistician
CRC
Draft a protocol
Protocol guidelines
Study personnel
FDA Guidance for Investigators
Consult Clinical Research Center
CRC
Bio Bank
Start IRB application
TransLab
Consider applying for grants
securing funding
Office of Sponsored Programs
If INDIDE application to FDA
Does my study need an INDIDE
Regulatory resources
Arrange a consultation with
CRIT
ConsultationTasks for investigators and study teams
Boston Childrenrsquos Hospital Clinical Research Map 5 Mouse over for additional info Bold = hyperlink
Respond to IRB questionsrequests
for clarification
1st Stage Protocol development contrsquod
Departmental Scientific Review
Organize DSMB design DSMP
DSMPDSMB
Templates for Research Study
Documents and Tools
Study Templates and Tools
Investigators who sponsor an FDA regulated trial
ClinicalTrialsgov
Create regulatory binder
Regulatory Binder Template
Submit the grant application to OSP
OSP
TIDO
CTBO
Consult Office Intellectual Property
Technology and Innovation
Development Office
TIDO
IRB approval
Consider blood volume for research
Research blood volume policy
Confidentiality plan
Confidentiality guidelines
Boston Childrenrsquos Hospital Clinical Research Map 6 Mouse over for additional info Bold = hyperlink
Develop Case Report Forms
(CRFs)
CRF guidelines
Establish electronic shared
folder or study binder for study
documents
CRIT
Set date for trial launch
Develop fast fact sheet for bedside staff
Consult programmer re database
CRIT
Research study resource manual
for the clinical unit
Confirm study drug
in pharmacy
Rocco Anzaldi
Clarify system for screening
and enrolling patients
Recruitment guideline
Updated protocol to
nurse manager
Consult MDsNPs on unitclinic
2nd Stage Implementation planning
Tasks for investigators and study teams
Study logistics Documentation logistics
Data storage
Confidentiality plan
Confidentiality guidelines
Create study orderset
Consider blood volume for research
Research blood volume policy
Create Manual of Operations
MOO Guide
Study implementation
meeting
Develop study logstools
EQUIP
Finalize tracking sheet
Research Administration
Fernando Valles
Boston Childrenrsquos Hospital Clinical Research Map 7 Mouse over for additional info Bold = hyperlink
3 Document informed consent
Informed Consent
Consent library
Schedule weekly study team meeting
Communicate to department faculty
and multidisciplinary
team announcing trial launch
Steps before trial launch
3rd stage Study launch
Patient flow
1 Seek permission
to approach potential subjects
2 Screenenroll
patients
EQUIP
5 Send Study
Tracking Sheet (STS)
6 Collection of
patient data and assessing for
adverse events
7 Study
documents and data handling
4 Datetime study tests
Create a checklist outlining study action items for each subject
Boston Childrenrsquos Hospital Clinical Research Map 8 Mouse over for additional info Bold = hyperlink
Annual IRB Report
Annual Progress ReportStaff Report
raquo Maintain Interest of Staff
raquo Important to See Study Progress
Write Abstract
Dissemination of Research Results
raquo Conference raquo Internal Presentation for Colleagues
raquo Publication
Plan DSMB MeetingInterim
Analysis
4th stage Statistical analysis reporting and dissemination
Data Entry
When Enrollment Complete Data
Cleaning
Monitor Subjects to Identify
Adverse Events (CCI sponsor
DSMB)
Report Adverse Events
Update MOO Based on Experience
with First Several Patients Enrolled
Weekly Study Team Meeting
Report study findings to
subjects and stakeholders
Data management Trial management
Reporting Dissemination
Regular Review of Data
to Identify Deviations
and Workflow Improvements
Consult Statistician When Approaching Target Enrollment
Discarded specimens Additional steps
Boston Childrenrsquos Hospital Clinical Research Map 9 Mouse over for additional info Bold = hyperlink
Send IRB Approval to lab manager
Maureen Samson
Educate staff in areasunits about sample collection
Locate the discarded samples
Locate the accession number in PowerChart
Retrieve specimen
Mark Kellogg
Follow Shipping Rules and Procedures
IATAShipping with dry ice instructions
Communicate with laboratory staff
Contact Dr Mark Kellogg to discuss specimen retrieval
Consult with Biorepository
Biorepository
Chart review Steps if you are completing a chart review
Boston Childrenrsquos Hospital Clinical Research Map 10 Mouse over for additional info Bold = hyperlink
7 8
4321
Databaserecord review guidelines
5 6
Consult programmer re database
CRC Request
Respond to IRB questions
requests for clarification
Departmental Scientific Review
Complete training
CITI Training
Draft a protocol
Protocol Guidelines
Prepare IRB Application
Information about the CCI
IRB Application
Develop Case Report Forms (CRFs)
CRF Guidelines
IRB Review
Boston Childrenrsquos Hospital Clinical Research Map 11 Mouse over for additional info Bold = hyperlink
Clinical Research Center (CRC) x84720
Committee on Clinical Investigation (CCI IRB) x57052
Research Pharmacist x52014
Clinical and Translational Science Unit (CTSU) x57541
Education and Quality Improvement Program (EQUIP) x57052
Clinical Trials Office Central Budgeting x4-2714
Office of Sponsored Programs x4-2723
Technology and Innovation Development Office 617-919-3079
Research Finance x8-3517
Harvard Catalyst 617-432-7810
Regulatory Affairs x4-2777
Appendix A Resources for researchers
RES_4446_ClinicalResearchMap-FINAL FOR LINKS 1
RES_4446_ClinicalResearchMap-FINAL FOR LINKS 10
Overview Four stages
1st Stage Protocol development
1st Stage Protocol development contrsquod
2nd Stage Implementation planning
3rd stage Study launch
4th stage Statistical analysis reporting and dissemination
Discarded specimens Additional steps
Chart reviewSteps if you are completing a chart review
Appendix A Resources for researchers
RES_4446_ClinicalResearchMap-FINAL FOR LINKS 11
RES_4446_ClinicalResearchMap-FINAL FOR LINKS 2
RES_4446_ClinicalResearchMap-FINAL FOR LINKS 3
RES_4446_ClinicalResearchMap-FINAL FOR LINKS 4
RES_4446_ClinicalResearchMap-FINAL FOR LINKS 5
RES_4446_ClinicalResearchMap-FINAL FOR LINKS 6
RES_4446_ClinicalResearchMap-FINAL FOR LINKS 7
RES_4446_ClinicalResearchMap-FINAL FOR LINKS 8
RES_4446_ClinicalResearchMap-FINAL FOR LINKS 9
RES_4446_ClinicalResearchMap-PAGE 5pdf
Overview Four stages
1st Stage Protocol development
1st Stage Protocol development contrsquod
2nd Stage Implementation planning
3rd stage Study launch
4th stage Statistical analysis reporting and dissemination
Discarded specimens Additional steps
Chart reviewSteps if you are completing a chart review
Appendix A Resources for researchers
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Develop Case Report Forms
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Consult clinical research center
INDIDE 1
Explore resources
Button 1016
Bio Bank p
4
Consult statistician
Consult research pharmacist
Study personnel
Complete training
Consider grantsfunding
Draft a Protocal 2
Arrange a consutlations with CRIT
Next Page 1
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TransLab
Start IRB application 3
Develop study logs
Updatedd protocol
Confirm study drug
Establish electronic shared
COnsult programmer
Clarify system
Research study resrouce manual
Develop case report forms
MOO
Set date for trial launch
Button 44
Study implementation meeting
Finalize tracking sheet
Data storage
Confidentiality
Blood volume 3
Develop fast fact
Consult MDs
Schedule weekly
Communicate early
Button 71
Screenenroll patients
Document informed consent
Datetime tests
Send study tracking sheets
Collection patient data
Button 77
Dissemination
Button 87
Button 124
Button 125
Communicate with lab staff
Button 106
Button 109
Button 1010
Shipping page 9
Button 1012
Button 99
Button 133
Button 134
Button 135
Biorepository
Locate assession number
Retrieve specimen
Button 30
Consult office
Negotiate Contract
Organizing DSMB
Submit Grant
Respond to IRB questions
Button 66
Create regulatory binder
Templates for research stufy
Clinical Trials Business Office
Blood volume 2
Confidentiality plan
Investigators who sponsor
clinicaltrials
gov
BPN Project
Drug Discovery amp Development Testing Funnel
Tier 1 2 3
Tier 6 7 8
Tier 5
Tier 4
Example Drug Discovery amp Development Testing Funnel
Cytotoxicity
Grant
Project
Example Drug Discovery amp Development Testing Funnel
TIER 1A ndash Primary Screen
Chemical purity and identity of active compounds
Primary bioactivity screen
Cell viability (When Appropriate)
ScaffoldsMoiety Chemical liabilities (for example Michael acceptor GSH reactive)
Calculated properties CLogP
PSA
Molecular Weight
rotatable bonds
H-bond donors and acceptors
permeability
pKa
Solubility
TIER 1B
Confirm EC50 determinations for actives compounds in primary screen with fresh
compounds from the original stock Confirm EC50 determinations for the lead (most
active) compound in primary screen with a new sample either repurchased purified
and characterized in-house or independently synthesized in-house
Compounds with IC50s (EC50s) less than X advance to Tier 2
TIER 2A ndash Activity Confirmation
Secondary screen
TIER 2B
Repeat EC50 determinations for actives in secondary screen with fresh
compounds from the original stock
Compounds with IC50s (EC50s) less than X advance to Tier 3
Example Drug Discovery amp Development Testing Funnel
TIER 3 ndash Drug-like Properties Specificity
IC50 selectivity in selectivity screen
CYP450 Inhibition competitive and time-dependent if structural alerts exist
(spot check illustrative examples from compound series)
Measured solubility
Measured protein binding (spot check illustrative examples from
compound series)
Test of Permeability in vitro permeability [indicate assay eg Caco2 orand
PAMPA] (spot check illustrative examples from compound series)
hERG
Cytoxicity assays
All compounds with no significant issues (Define Minimum Conditions for
Advancement) to advance to Tier 4
Example Drug Discovery amp Development Testing Funnel
TIER 4 ndash Scale-up Synthesis and Preliminary PK
Scale-up synthesis
Purity determination gt98 with no single impurity gt1
Rodent bioavailability and PK (define target delivery route) Tmax
Cmax
AUC
Bioavailibility
Vss CL T12 MRT
Brain to Plasma ratios
P-glycoprotein transport MDCK-MDR1 and MDCK-mdr1a
Plasma Protein Binding (species)
Microsomal Stability ndash rodent and human
Defineplan Patent Protection Strategy
All compounds with no significant issues (Define
Minimum Conditions for Advancement) advance
in parallel to Tiers 5AampB
Example Drug Discovery amp Development Testing Funnel
TIER 5A ndash In Vivo Bioactivity
Animal efficacy
Validate Biomarker
Target engagement
Advance to Tier 6 if (Define Minimum Conditions for advancement)
TIER 5B ndash Advanced Drug-like Properties
Microsomal stability in multiple
species
Chemical Stability
CYP450 induction
CYP reaction phenotyping
Metabolism ndash human
hepatocytesmicrosomes
Metab ID define major human rat dog and
non-human primates (NHP) metabolites
In vitro Tox Ames
Chromosome Aberration
CNS effects
Example Drug Discovery amp Development Testing Funnel
TIER 6 ndash Liability Assessment
Broad Pharmacological Profile and Toxicology
PK in second species
TIER 7
Non-GLP exposure studies single and multiple dose
Advance to late stage pre-clinical development (Define Minimum
Conditions for advancement)
Example Drug Discovery amp Development Testing Funnel
Principal InvestigatorProgram Director (Last First Middle)
enspenspenspenspensp
DETAILED BUDGET FOR INITIAL BUDGET PERIOD
DIRECT COSTS ONLY
FROM
THROUGH
enspenspenspenspensp
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PERSONNEL
DOLLAR AMOUNT REQUESTED (omit cents)
NAME
ROLE ONPROJECT
TYPEAPPT (months)
EFFORTONPROJ
INSTBASESALARY
SALARYREQUESTED
FRINGEBENEFITS
TOTAL
enspenspenspenspensp
PrincipalInvestigator
enspenspenspenspensp
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SUBTOTALS
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CONSULTANT COSTS
enspenspenspenspensp
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EQUIPMENT (Itemize)
enspenspenspenspensp
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SUPPLIES (Itemize by category)
enspenspenspenspensp
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TRAVEL
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PATIENT CARE COSTS
INPATIENT
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OUTPATIENT
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ALTERATIONS AND RENOVATIONS (Itemize by category)
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OTHER EXPENSES (Itemize by category)
enspenspenspenspensp
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SUBTOTAL DIRECT COSTS FOR INITIAL BUDGET PERIOD
$
enspenspenspenspensp
CONSORTIUMCONTRACTUAL COSTS
DIRECT COSTS
enspenspenspenspensp
FACILITIES AND ADMINISTRATIVE COSTS
enspenspenspenspensp
TOTAL DIRECT COSTS FOR INITIAL BUDGET PERIOD
$
enspenspenspenspensp
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
Download a short guide to Acronyms and Terminology associated with Drug Discovery
ACRONYMSampTERMpdf
Download an Introductory Slide Deck on the Drug Discovery Process for Neuroscience
roadmapoverviewkleimanpdf
Download an Introductory slide deck on the Role of the Biology Team in a drug discovery program
drug discovery biologykleimanpdf
Below are listed databases and other resources that can help address questions about rationale distribution of target or its
relationship to other disease genes
RNA expression data sets
GEO- Gene Expression Omnibus data base of all published RNA expression data sets
httpwwwncbinlmnihgovgeo
Allen Brain Atlas- database of brain RNA expression data httpwwwbrain-maporg
Brain Span database-Brain RNA expression data including transcriptome and ISH for human brain
httpwwwbrainspanorg
Human genome resources at NCBI
httpwwwncbinlmnihgovgenomeguidehuman
OMIM- human genes and inherited disorders maintained by Johnrsquos Hopkins
Gene Database- database of genes and associated information
dbSNP- a database of SNP and other nucleotide variations
dbGaP- database of Genotypes and Phenotypes
NextBio Free Harvard enterprise account
Mine transcriptional profiling studies for changes in your target
Search connectivity map for compounds that modulate your target
Correlate human data to animal models and cell lines
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
Compare disease profiles across cohorts and stages of disease
wwwnextbiocom
iHOP--information Hyperlinked Over Proteins
A portal for searching literature by gene or gene Interactions httpwwwihop-netorgUniPubiHOP
Ingenuity Pathway Analysis
Available from research computing Find disease related literature for your target
httpwwwingenuitycomproductsipa
TISSUES database of Expression of targets (RNA and Protein)
TISSUES is a frequently updated web resource that integrates evidence on tissue expression from manually curated
literature proteomics and transcriptomics screens and automatic text mining They map all evidence to common
protein identifiers and Brenda Tissue Ontology terms and further unify it by assigning confidence scores that facilitate
comparison of the different types and sources of evidence Finally these scores are visualized on a schematic human
body to provide a convenient overview
httptissuesjensenlaborgSearch
Refrence Literature related to target identification and validation
Bunnage ME Gilbert AM Jones LH Hett EC Know your target know your molecule Nature chemical biology 2015
11(6)368-372 httpwwwncbinlmnihgovpubmed15718163
Grover MP Ballouz S Mohanasundaram KA George RA Sherman CD Crowley TM Wouters MA Identification of
novel therapeutics for complex diseases from genome-wide association data BMC medical genomics 2014 7 Suppl
1S8 httpwwwncbinlmnihgovpubmed25077696
Plenge RM Scolnick EM Altshuler D Validating therapeutic targets through human genetics Nature reviews Drug
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
main menu
Resources available at BCH Assay Development Screening Funnel development Chemical compound files Assistance
with identification of academic and industry partners for collaborative SAR campaigns
Identification of the correct molecule requires a clearly defined set of laboratory objectives and a well-designed screening
funnel to select the molecule that will meet those objectives Laboratory objectives for a molecule include specific criteria
for the mode of binding to target (eg agonist partial agonist inverse agonist non-competitive inhibitor) the potency
(eg Ki lt30nM) selectivity (eg gt30X selectivity over family member target XY and Z) brain penetration (yesno) dosing
paradigm ( eg oral once daily intravenous once monthly) and duration of expected treatment (eg sub-chronic daily
treatment for 2 weeks chronic treatment for years) Each of these laboratory objectives will have bearing on the design of
the screening funnel required to identify the molecule
The screening funnel requires a robust high-throughput (HTS) biochemical assay capable of testing gt100000 compounds
good sensitivity (Zrsquogt05) and an appropriate orthogonal assay (usually cell based) to confirm functional activity of the
compound at the target which can be used to weed out false positives and primary HTS artifacts Critical features defined
by the laboratory objectives may require additional in vitro absorption and metabolism data from compounds slated to
progress in vivo to ensure that structure activity relationships being developed will support expected dosing profiles and
target organ disposition A collection of critical off target assays to ensure required selectivity of the candidate drug must
be available to test molecules progressing from functional assays Compounds expected to be tested in vivo will require
pharmacokinetic studies to ensure target organ exposure in concentration ranges needed to support hypothesis testing
Link to sample Screening Funnels
httpswwwnimhnihgovresearchprioritiestherapeutics
The types of information needed to Characterize a Lead Compound are summarized here
Download an introductory slide deck on Medicinal Chemistry Structure Activity Relationship (SAR) campaign courtesy Dr
Johnny Bennett Merck
Childrens MedChem 29Jul2015pdf
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
Resources for assay development
The Assay Guidance Manual httpwwwncbinlmnihgovbooksNBK53196
This is a key resource for design and qualification of all types of biochemical and cell based assays It covers many
different modes of assay development and optimization as well as troubleshooting guides Do not run a screen
without consulting the manual first
The Assay Development Screening Facility (ADSF) at BCH Hourly access to equipment and technical assistance
consultations compound libraries- live cell medium throughput screening For more information contact Dr Lee Barrett
The ICCB at Longwood Project based access to equipment and expertise for design and execution of high-throughput
screens access to wide collection of chemical and genomic libraries For more information contact Dr Caroline Shamu
caroline_shamuhmsharvardedu
Website httpiccbmedharvardedu
Databases and references with information about activity and properties of small molecule compounds
PubChem provides information on the biological activities of small molecules PubChem is organized as three linked
databases within the NCBIs Entrez information retrieval system These are PubChem Substance PubChem Compound and
PubChem BioAssay Links from PubChems chemical structure records to other Entrez databases provide information on
biological properties These include links to PubMed scientific literature and NCBIs protein 3D structure resource Links to
PubChems bioassay database present the results of biological screening Links to depositor web sites provide further
information A PubChem FTP site Download Facility Power User Gateway(PUG) Standardization Service Score Matrix
Service Structure Clustering and Deposition Gateway are also available Home page is here
httpspubchemncbinlmnihgov
httpspubchemncbinlmnihgovsearch
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
DrugBank The DrugBank database is a unique bioinformatics and cheminformatics resource that combines detailed drug
(ie chemical pharmacological and pharmaceutical) data with comprehensive drug target (ie sequence structure and
pathway) information The database contains 7759 drug entries including 1602 FDA-approved small molecule drugs 161
FDA-approved biotech (proteinpeptide) drugs 89 nutraceuticals and over 6000 experimental drugs Additionally 4300
non-redundant protein (ie drug targetenzymetransportercarrier) sequences are linked to these drug entries Each
DrugCard entry contains more than 200 data fields with half of the information being devoted to drugchemical data and
the other half devoted to drug target or protein data Homepage is here httpwwwdrugbankca
Protein Data Bank archive Targets with protein crystal structures are more attractive targets for structure based drug design
Determine if your target has a known crystal structure by looking it up in the protein database- A Structural View of Biology
This resource is powered by the Protein Data Bank archive-information about the 3D shapes of proteins nucleic acids and
complex assemblies that helps students and researchers understand all aspects of biomedicine and agriculture from
protein synthesis to health and disease Homepage is here httpwwwrcsborgpdbhomehomedo
High Quality Chemical tools are required for testing biological hypothesis Find chemical tools that are fit for purpose by
virtue of target potency and selectivity needed to test hypothesis The dangers of using inadequate chemical tools are
detailed here httpwwwnaturecomnchembiojournalv11n8fullnchembio1867html To support the needs of the
biology community the industrial chemistry research community has joined a pre-competitive effort to provide
characterization data for high quality chemical probes That data is stored here httpwwwchemicalprobesorgprotein-
family
ChemNavigator The National Institutes of Health (NIH) has formed an agreement with ChemNavigator to provide the NIH
with a current and comprehensive database of commercially accessible drug discovery screening compounds to be
made available to all NIH researchers ChemNavigator is pleased to serve NIH affiliated scientific researchers in compound
sample procurement As an NIH researcher you have full access to use the iResearch System All you need to do is take a
few minutes to register in the system Then you will be able to perform chemical structure searches for compound samples
of interest and purchase these samples through this on-line system Link is here httpwwwchemnavigatorcomnihasp
Additional References related to biological activity of compounds
Edwards AM Bountra C Kerr DJ Willson TM Open access chemical and clinical probes to support drug discovery Nature
chemical biology 2009 5(7)436-440
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
Wang Y Suzek T Zhang J Wang J He S Cheng T Shoemaker BA Gindulyte A Bryant SH PubChem BioAssay 2014 update
Nucleic acids research 2014 42(Database issue)D1075-1082
Wang Y Bolton E Dracheva S Karapetyan K Shoemaker BA Suzek TO Wang J Xiao J Zhang J Bryant SH An overview of
the PubChem BioAssay resource Nucleic acids research 2010 38(Database issue)D255-266
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
main menu
Pharmacokinetic tutorial drug exposure measurement services pharmacokinetic data references
Selecting the correct dose to achieve exposure of drug that are adequate to test a hypothesis in preclinical species
requires that you know the potency of the molecule at the desired drug target and the dose of compound required to
achieve target organ exposure that will result in the free (not bound by protein) concentration of drug required to engage
the molecular target within the target organ compartment Estimates of Drug potency can be found in many of the
databases listed under correct molecule The free concentration of a drug is determined in the plasma by multiplying the
concentration of drug in the plasma by the fraction unbound This must be measured for each compound A literature
reference that provides the measured plasma protein binding (PPB) values for many common drugs is provided here
Zhang Xue Shao and Jia (2012) Compilation of 222 drugsrsquo plasma protein binding data and guidance for study designs
Drug Discovery Today Vol 17 Issue 9-10 Pages 476-485 httpwwwncbinlmnihgovpubmed22210121
If your drug target is the brain then you must also understand the kinetics of drug disposition and clearance including blood
brain barrier (BBB) penetration in your test species to select a dose of compound adequate to test your hypothesis
Download a tutorial deck on basic principles of drug disposition and their application in small molecule drug discovery
courtesy of Dr Chris Shaffer Pfizer
150805DMPKTutorial(CLSBCHCourse)pdf
Pharmacometrics Research Core and Pharmacokinetics Service The Pharmacometrics Research Core is directed by Dr Luis
Pereira and provides analytical services for assaying drugsmetabolites in biological matrices (eg plasma serum blood
urine CSF saliva tissues) The Core provides pharmacokinetic and pharmacodynamic analyses for current and future
clinical trials and research projects (including contract services) It conducts stability and potency studies for pediatric
formulations compounded at BCH as per recent demand from FDA and CMS Finally the Core fosters grant applications
and research collaborations both intra and extramural The TNC can additionally provide investigators with consultation in
the identification of resources for pharmacodynamic assay development and contract research organizations able to
provide bioanalysis of preclinical samples needed to support animal clinical trials Contact Dr Luis Pereira for more
information LuisPereirachildrensharvardedu
article on importance of understanding drug exposure in preclinical drug studies here
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
References on Pharmacokinetics and Brain Penetration of Small Molecules
Di L Rong H Feng B Demystifying brain penetration in central nervous system drug discovery Miniperspective Journal of
medicinal chemistry 2013 56(1)2-12
Reichel A Addressing central nervous system (CNS) penetration in drug discovery basics and implications of the evolving
new concept Chemistry amp biodiversity 2009 6(11)2030-2049
Smith DA Di L Kerns EH The effect of plasma protein binding on in vivo efficacy misconceptions in drug discovery Nature
reviews Drug discovery 2010 9(12)929-939
Moda TL Torres LG Carrara AE Andricopulo AD PKDB database for pharmacokinetic properties and predictive in silico
ADME models Bioinformatics 2008 24(19)2270-2271
Law V Knox C Djoumbou Y Jewison T Guo AC Liu Y Maciejewski A Arndt D Wilson M Neveu V et al DrugBank 40
shedding new light on drug metabolism Nucleic acids research 2014 42(Database issue)D1091-1097
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
main menu
Formulations advice and assistance with preclinical drug delivery Neurodevelopmental Behavioral Core
To effectively deliver drug to preclinical species for the duration of a study researchers must choose a dose a formulation
and a route of administration that will support target organ exposure long enough to test a therapeutic hypothesis Since
most drugs developed for humans are optimized for human metabolism parameters many compounds developed for
humans are rapidly metabolized and cleared in rodents requiring alternative formulations and routes of preclinical
administration (see tutorial under Correct Dose)
Proper formulation of drugs and vehicles to ensure appropriate drug exposure is a critical factor in preclinical study design
The Neurodevelopmental Behavioral Core may provide advice on standard formulations Preclinical assistance and
training across many routes of administration including IV cannulation osmotic minipumps oral gavage sc and ip is also
available through the Neurodevelopmental Behavioral Core
Contact is Dr Nick Andrews NickAndrewschildrensharvardedu
Custom formulation used for human studies are supported on a case by case basis by the Pharmacometrics Research Core
or Clinical Research Pharmacy Contact for the Pharmacometrics Core is Dr Luis Pereira LuisPereirachildrensharvardedu
The Clinical Research Pharmacy can provide advice on unusual formulations Contact is Dr Rocco Anzaldi
RoccoAnzaldichildrensharvardedu
idspharmacy-dlchildrensharvardedu
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
main menu
Stratification Biomarker development and resources patient sample repositories requests for collection of new types of
patient samples development of patient specific iPSC lines and neurons Genetic databases RNA expression databases
Humans are diverse Not only do patients come in different sizes ages genders and ethnic backgrounds but the same
disease diagnosis often develops in people as a function of different environmental insults and genetic predispositions
Finding biomarkers that will segregate similarly diagnosed patients into subsets of biologically more homogenous
populations is a critical feature of good clinical trial design A lsquostratification biomarkerrsquo can be a biochemical measure from
patient samples a structural or a functional feature of a human imaging technology or a functional measure of an
electrophysiological readout
The Translational Neuroscience Center can help investigators access advice and assistance for investigators with vendors
experienced in profiling DNA RNA or protein across a range of platforms httpwwwchildrenshospitalorgresearch-and-
Neurophysiology Services can assist investigators with identification of biomarkers to stratify patients based on EEG
signatures Contact Drs Charles Nelson and Jurriaan Peters Co-Directors
CharlesNelsonchildrensharvardedu
JurriaanPeterschildrensharvardedu
MRIRadiology Imaging Core can assist with identification of biomarkers to stratify patients by functional or structural deficits
in brain circuitry Contact Dr Simon Warfield Director SimonWarfieldchildrensharvardedu
Molecular Genetics core can assist investigators with identification of genetic stratification biomarkers or gene expression-
based stratification biomarkers Contact Drs Louis Kunkel and Christopher Walsh Co-Directors
LouisKunkelchildrensharvardedu
ChristopherWalshchildrensharvardedu
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
The Human Neuron Differentiation Service within the Translational Neuroscience Center can help investigators recruit
specific subtypes of patients to be consented for reprogramming of blood or fibroblast cells into iPSC lines that will support
differentiation into human neurons for phenotypic analysis and screening ContactDr Robin Kleiman
RobinKleimanchildrensharvardedu
Translab can assist with routine processes as well as complex laboratory-‐developed tests They place special emphasis on
assay development for use in clinical trials Translab website with contact information can be viewed here
httpwwwtranslabbostonorg
TransLab Flyer 2 2015pdf
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
main menu
Patient sample repositoryBiobank Patient registry
Disease processes are dynamic The molecular underpinnings of disease differ between inception progression and
response of the body to disease Thus each stage of disease may require alternative therapeutic strategies Understanding
which stage of disease is best suited to testing a specific therapeutic approach will require information about disease from
patient samples collected at different stages of disease well as an ability to collect and recruit patients at relevant stages of
disease
To locate human RNA profiling data in the public domain from disease samples and tissues at specific stages of disease
search databases referenced in the Correct Target section of this document
The Translational Neuroscience Center offers multiple services that can assist with identification of the correct patients The
Core Repository for Neurological Disorders stores a wide variety of patient samples from many stages of disease The
biorepository is directed by Dr Mustafa Sahin and these samples and de-identified clinical data can be searched and
requested through the Translational Neuroscience Center
The Biobank Core Lab serves as a core resource that ensures top-level specimen handling and services to the Boston
Childrens Hospital research community It serves as both a service core and a biorepository providing an institutional
perspective on the presence of specimens that may be available for use to foster collaborations and accelerate research
and discovery
The Clinical Research and Regulatory Affairs Service can provide assistance to investigators in identifying patients andor
repository samplesdata Contact Co-Directors Stephanie Brewster and Kira Dies for more information about access to
these resources
StephanieBrewsterchildrensharvardedu
KiraDieschildrensharvardedu
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
main menu
Statistical support clinical trialsgov
Determining the correct sample size to support preclinical and clinical studies requires power calculations that take into
account the variability of the endpoint being measured Statistical support for preclinical studies is available on a
department by department basis Neurology and Neurobiology requests for preclinical biostatistics support can be made
through the CRC website
httpredcap-qiredcap_edcsurveyss=Rma5u83qKC
Clinical statistical support for all departments is also available through the CRC Design and Analysis Core For more
information contact Michael Monuteaux michaelmonuteauxchildrensharvardedu
Clinical datasets that provide data for supporting power calculations can be found by searching through clinical trialsgov
database All studies in the clinical trials data base are required to describe the study design the endpoints under
evaluation and the treatments as well as links to publications of the studies The studies can be searched by topic This can
be a good way to find historical data to help you evaluate variability of endpoint measures in clinical populations This will
be needed to support sample size power calculations httpsclinicaltrialsgov
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
main menu
Understanding RDoC Human Neurobehavioral Core Service IRB assistance with clinical protocols
Different stages of clinical trials have different goals for selecting endpoints Early stage clinical trials are typically in search
of a translatable pharmacodynamic or target engagement endpoint to ensure that the molecule in question will be
competent to test a clinical hypothesis in humans Developing translatable measures of target engagement in preclinical
species and humans is critical to developing data sets that will enable subsequent therapeutic efficacy trials The earliest
trials require endpoints that can be measured in a functionally equivalent manner across species Therefore it is critical for
preclinical researchers to develop dose-responsive data sets in preclinical species using quantitative endpoints such as EEG
visual or auditory evoked potentials PET ligands plasma or CSF based biochemical measures or translatable task based
behaviors Preclinical data must be a developed with an eye towards what the equivalent measure will be in the clinic
Toward that end the NIMH has initiated the Research Domain Criteria (RDoC) that is aimed at characterizing mental health
disorders across many different dimensions across species A big focus of the RDoC initiative is the identification of
translatable endpoints for evaluating pharmacodynamics and efficacy in Neuroscience Drug Discovery Preclinical
Neuroscience researchers should be familiar with the RDoC framework For advice on in vivo characterization of preclinical
endpoints with translational potential for Neuroscience related disorders contact Dr Robin Kleiman at the TNC
robinkleimanchildrensharvardedu
The Human Neurobehavioral Core Service of the Translational Neuroscience Center can provide guidance to investigators
on the appropriate tests that will provide the best translation from animal studies to human studies The Service also offers
human neurobehavioral assessment services Contact-Drs Charles Nelson and Deborah Waber Co-Directors
CharlesNelsonchildrensharvardedu
DeborahWaberchildrensharvardedu
Developing clinical protocols and obtaining IRB approval for human study of translatable endpoints can be supported by
the Translational Neuroscience Center Clinical Research and Regulatory Affairs Service Contact-Kira Dies and Stephanie
Brewster Co-Directors
KiraDieschildrensharvardedu
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
StephanieBrewsterchildrensharvardedu
Background Information on RDoC httpswwwnimhnihgovresearch-prioritiesrdocindexshtml
Casey BJ Oliveri ME Insel T A neurodevelopmental perspective on the research domain criteria (RDoC) framework
Cuthbert BN Insel TR Toward the future of psychiatric diagnosis the seven pillars of RDoC BMC Med 2013 11126
httpwwwncbinlmnihgovpmcarticlesPMC3653747
Insel T Cuthbert B Garvey M Heinssen R Pine DS Quinn K Sanislow C Wang P Research domain criteria (RDoC)
toward a new classification framework for research on mental disorders The American journal of psychiatry 2010
167(7)748-751 httpwwwncbinlmnihgovpubmed20595427
Insel TR The NIMH Research Domain Criteria (RDoC) Project precision medicine for psychiatry The American journal
of psychiatry 2014 171(4)395-397 httpwwwncbinlmnihgovpubmed24687194
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
main menu
Body atlases for expression of mRNA and protein guides to chemical alerts guidance for preclinical toxicology studies for
Investigational New Drug (IND) applications
Discovery scientists must consider the distribution of the proposed drug target across the entire body in human samples in
order to understand potential safety risks to be monitored during preclinical toxicological testing Teams also have to be
aware of differences in distribution of the target and related family members in preclinical species Many of the target
expression databases listed in the Correct Target section of this document are useful in this regard Assays that can be used
to monitor any potential safety risks are critical to the development of a suitable testing funnel needed to advance
compounds
Many chemical classes of compounds that are identified in screens are not suitable for drug development due to the
presence of structural alerts that are known to cause chemical toxicity Databases that house information of structural alerts
can be used to de-prioritize structural series early in the life of a program Some toxicology databases that can help
deprioritize toxic chemotypes include httppubsacsorgdoiabs101021ci300245q
Some web resources for identifying side effects of known compounds httpintsideirbbarcelonaorg
Once a potential clinical candidate molecule is identified GLP-qualified toxicology studies must be carried out with a
qualified vendor to support regulatory filings of an Investigational New Drug (IND) application For a short tutorial on studies
needed to support preclinical toxicology testing and guidance on evaluating contract research organizations that are
qualified to perform this work see attached tutorial courtesy of Dr Joe Brady Pfizer
Brady boston childrens hosp talk aug2015 IND toxpdf
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
main menu
FAQs
Industry partners and collaborators can bring tremendous expertise and complementary resources to bear on research
projects with therapeutic applications These may include medicinal chemistry expertise pharmacology expertise access
to unique and undisclosed chemical probe molecules assay development and high-throughput screening resources
antibody and other reagent development pharmacokinetic analysis pharmacokinetic and pharmacodynamics
modeling formulation expertise post-doctoral training programs and in some cases financial support There is a wide range
of models of interacting with industry in a range of different capacities Some frequently asked questions about types of
relationships and the responsibilities associated with those interactions can be found in the following document
Download Frequently Asked Questions about working with Industry
Translation of basic research into new marketed drugs will require a transition from exploring scientific principles and testing
hypotheses into commercial products Industry partners capable of developing these potential products need to be able
to license the intellectual property required to sell the product in order to justify investment in building programs around new
ideas This requires that scientific researchers protect and patent potential inventions from their work to enable future
commercialization by partners with appropriate expertise To ensure that researchers are appropriately documenting their
work in a manner that will support preservation of intellectual property all investigators are encouraged to consult with TIDO
before any public disclosures of new research Similarly the following documentation provides guidance for documenting
your work according to standards that will support patent applications
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
Download the compliance manual for BCH for Intellectual property policy
cm_021_intellectual_propertydocx
Download a summary of laboratory notebook Dorsquos and Donrsquot
Dosdontsnotebookspdf
Link to TIDO Technology Innovation and Development Office
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
main menu
A phenotypic screen requires a biologically robust assay that represents a significant aspect of disease-relevant human
biology It can be used to identify molecular targets for target validation studies through the use of well-annotated
bioactive molecules or genomic libraries (eg RNAi CRISPER) Alternatively phenotypic screens can be used to identify
novel compounds that must subsequently be lsquoDE convolutedrsquo to identify novel targets using lsquowarheadsrsquo These screens rely
on identification and manipulation of a functional deficit or phenotype using a patient-derived cellular system
The strengths of this approach
Use of human systems can improve translatability
Identified compounds may empirically balance therapeutic activity at multiple required targets
Well-suited to drug repurposing
Phenotypic screens can be used to identify compounds or targets for mechanism based drug discovery programs
Many CNS drugs have been discovered using a phenotypic repurposing screen (Swinney and Anthony 2011)
Drawbacks to this approach
Assays are slow low throughput and more expensive as compared to cell-free assays
Cell-based assays may not predict circuit level or brain phenotypes
Furthermore as a primary screening approach
Precludes leveraging strengths in uHTS SBDD and parallel design
Every molecule must be de-risked independently thus safety can be very hard to predict
Drug Repurposing Drug Repurposing is a strategic pillar of the National Center for Advancing Translational Science (NCATS)
Details on resources and funding opportunities can be found here httpsncatsnihgovntu
Chemogenomic Files from industry partners Many companies have well designed and annotated chemical files that are
designed to cover the druggable genome with small molecule compounds from their proprietary collections Each
company has different criteria and stipulations associated with use of the library It is advisable to consult with TIDO
regarding terms and conditions associated with individual companies
ICCB-LongwoodKirby ADSF The ICCB screening center and the Kirby ADSF have multiple collections of compounds that
include bioactive or FDA approved molecules available for screening
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
Kirby ADSF libraries contact Dr Lee Barrett LeeBarrettchildrensharvardedu
References related to phenotypic screens and Drug Repurposing
Vincent F Loria P Pregel M Stanton R Kitching L Nocka K Doyonnas R Steppan C Gilbert A Schroeter T
and MC Peakman Developing predictive assays The phenotypic screening ldquorule of 3rdquo Sci Transl Med 7 293ps15
(2015)
Langedijk J Mantel-Teeuwisse AK Slijkerman DS Schutjens MH Drug repositioning and repurposing terminology and
definitions in literature Drug Discov Today (2015)
Swinney DC and J Anthony How were new medicines discovered Nature Reviews Drug Discovery 10 507-
519 (July 2011) | doi101038nrd3480
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
main menu
TNC Clinical Research and Regulatory Affairs Service Research Participant Registry CRC
Glossary of Terms
Glossary-of-Clinical-Trials-Termspdf
Clinical Research and Regulatory Affairs Service This Translational Neuroscience Center service facilitates the mission of the
Translational Neuroscience Center providing coordination among studies communications resource development and
implementation of new or ongoing preclinical and clinical studies The service is led by experts in protocol development
and launching of new studies The directors are available to guide TNC researchers in designing human studies including
the preparation of Institutional Review Board (IRB) and FDA submissions Additionally staff of the Clinical Research and
Regulatory Affairs Service will help researchers with recruitment plans budget development supervision of study
coordinators study monitoring and audit preparation For more information contact Co-Directors Kira Dies ScM CGC and
Stephanie Brewster MS CGC
KiraDieschildrensharvardedu
StephanieBrewsterchildrensharvardedu
Clinical Research Center (CRC) Assists investigators at BCH with research project initiation and implementation resources
in the CTSU for the conduct of clinical research visits and ancillary services education on research methods and practices
The CRC has biostatisticians project managers research specialists clinical trials specialists research coordinators and
highly skilled nurses and nurse project managers who work every day to facilitate the many research needs of the BCH
community httpwwwchildrenshospitalorgresearch-and-innovationresearchclinicalclinical-research-center
Clinical and Translational Study Unit (CTSU) The CTSU provides clinical research infrastructure for investigators in the design
initiation conduct and reporting of clinical research with the goal of translating scientific knowledge into new therapies for
pediatric conditions httpweb2tchharvardeductsu
Clinical Research Roadmap This clinical research map is designed to serve as a guide for investigators study coordinators
and research nurses at Boston Childrenrsquos Hospital The research map outlines the key steps in preparing to launch a
research study and provides embedded links to institutional resources tools and documents
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
Clinical Research Mappdf
main menu
Office of Sponsored Programs Research Administration TIDO
Many government and foundation grant opportunities are available for developing Drug Discovery Projects updated lists of
funding options exist on OSP and Research Administration web sites
Some good options for finding relevant requests for proposals
Translational Research Program annual call for proposals
Boston Childrenrsquos Hospital ndash Broad Institute Collaboration Grants Proposals will be reviewed by a joint Childrenrsquos Hospitalndash
Broad Institute committee Additional submission dates are expected for 2016
BCH_Broad collaborative grant 852015docx
Kirby Neurobiology Screening Pilot awards- available to Kirby Neurobiology PIs as funding is available
Translational Neuroscience Center- Pilot awards supported by trust sponsored donations as available Distributed through
TNC e-mail lists
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
ADDF The ADDF Academic Drug Discovery and Development Program seeks to create and support innovative translational
research programs for Alzheimerrsquos disease related dementias and cognitive aging in academic medical centers and
universities Biomarker development studies and innovative proof of concept pilot clinical trials of new approaches to
treatment prevention and early detection are also supported
Department of Defense ALSRP The FY15 Defense Appropriations Act provides $75 million (M) to the Department of Defense
Amyotrophic Lateral Sclerosis Research Program (ALSRP) to support innovative high-impact Amyotrophic Lateral Sclerosis
research As directed by the Office of the Assistant Secretary of Defense for Health Affairs the Defense Health Agency
Research Development and Acquisition (DHA RDA) Directorate manages and executes the Defense Health Program
(DHP) Research Development Test and Evaluation (RDTampE) appropriation The executing agent for the anticipated
Program AnnouncementsFunding Opportunities is the Congressionally Directed Medical Research Programs (CDMRP)
httpcdmrparmymilpubspress201515alsrppreannshtml
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
Michael J Fox Foundation Therapeutic Pipeline Program Supports Parkinsons disease therapeutic development along the
pre-clinical and clinical path (both drug and non-pharmacological therapeutics including gene therapy biological
surgical and non-invasive approaches) The Michael J Fox Foundation seeks applications with potential for fundamentally
altering disease course andor significantly improving treatment of symptoms above and beyond current standards of care
Proposals must have a well-defined plan for moving toward clinical utility for patients The Therapeutic Pipeline Program is
open to industry and academic investigators proposing novel approaches or repositioning approved or clinically safe
therapies from non-PD indications httpswwwmichaeljfoxorgresearchgrant-detailphpid=28
NINDS The Blueprint Neurotherapeutics Network (BPN) Provides the neuroscience community access to a complete and
seamless pipeline for preclinical drug development beginning with chemical optimization and concluding after phase I
clinical trials Participants in the BPN will receive funding to conduct bioactivity and efficacy testing in their own laboratories
as well as access to millions of dollars in NIH-contracted drug development services including medicinal chemistry
pharmacology toxicology and phase 1 clinical trials NIH will also provide drug development consultants who have had
years of experience working at a senior level in industry Because the Blueprint is establishing a network of drug
development service providers that typically cater to biopharmaceutical companies neuroscientists who join the BPN can
readily plug in to all of the drug development expertise that typically resides in industry The projects supported through the
network will be highly collaborative and the researchers who initiate the projects will serve as the principal investigators
(PIs) directing their projects through the development pipeline with the help of industry consultants The PIs and their
institutions will have the opportunity to attain assignment of intellectual property rights from all other network participants
who may have intellectual input into their projects This will allow the PIs to retain control of the intellectual property for drug
candidates developed through the network and eventually pursue licensing and commercialization partnerships
httpneuroscienceblueprintnihgovbpdrugs
NeuroNEXT Will establish a consortium of clinical sites capable of forming disease-specific cadres of investigators in order to
develop and implement trials rapidly in a wide range of neurological disorders that affect adults andor children With a
stable and experienced research staff a central IRB model and master trial agreements NeuroNEXT will streamline the
administrative processes for clinical trials and reduce start-up times NeuroNEXT will also be able to design and implement
evidence-based measures to improve patient recruitment into clinical trials httpswwwneuronextorgresearchers
NIMH Many grant options see overview here httpwwwnimhnihgovresearch-prioritiestherapeuticsindexshtml
Building on High Impact Basic Neurobiology Through Assay Development Advancing Tools for Therapeutic Discovery (R01) -
See more at httpgrantsnihgovgrantsguidepa-filesPAR-15-066htmlsthashs1HMWjWudpuf
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
NCATS many grant options see overview here httpwwwncatsnihgovprograms
Bridging Interventional Development Gaps (BrIDGs) Program Makes available on a competitive basis certain critical
resources needed for the development of new therapeutic agents for both common and rare diseases Investigators do not
receive grant funds through this program Instead successful applicants receive access to NIH experts and contractors who
conduct pre-clinical studies at no cost to the investigator In general synthesis formulation pharmacokinetic and
toxicology services in support of investigator-held IND applications to the Food and Drug Administration (FDA) are available
httpwwwncatsnihgovbridgsworksolicitation
NCATS Discovering New Therapeutic Uses for Existing Molecules (New Therapeutic Uses) A collaborative program designed
to develop partnerships between pharmaceutical companies and the biomedical research community to advance
therapeutics development This innovative program matches researchers with a selection of pharmaceutical industry
assets to test ideas for new therapeutic uses with the ultimate goal of identifying promising new treatments for patients
httpwwwncatsnihgovntu
Pfizer Centers for Therapeutic Innovation (CTI) Suitable for biotherapeutic or small molecule projects with a strong project
rationale (demonstrated association between target biology pathway and disease mechanism) CTIrsquos areas of interest
include inflammation autoimmunity tissue remodeling oncology cancer immunology rare or genetic diseases
cardiovascular and metabolic diseases and neuroscience Selected projects are undertaken by a joint team with BCH
members and Pfizer CTI drug development experts located on the 18th floor of CLS working towards agreed common
goals The Pfizer CTIBCH collaboration program is managed by a Joint Steering Committee with representation from both
Boston Childrenrsquos and CTI httpswwwpfizercticom Calls for proposals come through TIDO three times a year in January
May and September httpwwwchildrensinnovationsorgPagesHighlightsHighlights-83aspx
Shire-BCH Collaborative Program Development The Joint Steering Committee of the Shire Alliance extends a call for ldquoPre-
Proposalsrdquo with defined objectives from time to time generally annually in the late fall or winter That call is publicized
through emails from BCH Research Administration and TIDO Following review by the JSC a full proposal may be requested
Unsolicited proposals may also be considered from time to time
ACRONYMS
HTS- High-throughput Screen run with 96 well 384 well 1536 wells or 3456 well capacity- screen has capacity to run through a library of 1-3Million compounds in total
uHTS- Ultra High-throughput Screen ndash arbitrary cut off to denote capability to measure 100s of thousands of assays per day with automation and high density plate readers
HCS- High Content Screen usually a cell based assay that is able to monitor multiple endpoints reflective of different cellular processes in a single well of cells treated with a compound May be biochemical or image based endpoints
SAR- Structure-Activity Relationship ie relationship of modifications to chemical structure on relevant activity SPR-Structure-Property Relationship ie relationship of modifications of chemical structure on physicochemical
properties
PK- Pharmacokinetic measure of drug levels in a body compartment
PD- Pharmacodynamic a measure of functional activity of a drug
PKPD- PharmacoKinetic PharmacoDynamic relationship- how drug levels relate to drug response in a system
DDI-Drug-Drug Interactions- occurs when one drug affects the activity of another drug when co- administered Often due to changes in ADME properties of one of the co-administered drugs (ie for example induction by one drug of enzymes that will metabolize the second drug )
DMPK- Drug Metabolism and PharmacoKinetics
ADME- Absorption Distribution Metabolism amp Excretion
PDM-pharmacokinetics dynamics and metabolism GLP- Good Laboratory Practice- regulations that govern toxicology studies required by the FDA to support IND
and NDA
POM- Proof of Mechanism clinical studies to demonstrate hit the target and elicited a biological response
POC- Proof of Concept Clinical studies to demonstrate a clinically meaningful outcome measure improved
PoP-Proof of Principal usually preclinical studies that demonstrate that engaging target in a disease model produced efficacy
FIH- First in Human clinical trial to evaluate new molecule in humans for safety and PK- Ph1
FIP-First in Patient first clinical trial to evaluate new molecule in patients hERG (the human Ether-agrave-go-go-Related Gene) is a gene KCNH2 that codes for a subunit of Kv111 and
contributes to the repolarizing current in the heart that coordinates the hearts beating When compromised by application drugs or by rare mutations in some families it can result in a potentially fatal disorder called long QT syndrome A number of clinically successful drugs in the market have had the tendency to inhibit hERG and create a concomitant risk of sudden death as a side-effect which has made hERG inhibition an important anti-target that must be avoided during drug development
IND-Investigational New Drug Application- formal application to FDA to evaluate a NCE in people
NME- New Molecular Entity- a new FDA approved drug
NCE-New Chemical Entity-an investigational drug that is not yet a FDA approved NME NDA- New Drug Application (A lsquoFilingrsquo)- a formal application for approval of a new drug
CAN-(Pfizer-specific shorthand )-Clinical Candidate- a molecule competent to be tested in humans IB- Investigators Brochure- basic information on an investigational drug and its mechanism for clinicans involved
in conducting a clinical trial Provides background information on the hypothesis being tested and the types of patients that should be included excluded and risks and how the drug should be administered It must be updated continually by the sponsor to include all new findings
SOC- Standard of Care- in our context it is the drug treatment that a clinican should prescribe for a particular type of patient used as a benchmark for comparing new entities
MTD- Maximum Tolerated Dose- first identified in GLP safety studies during preclinical development AE- Adverse Event- a side effect that causes safety concerns
TI- Therapeutic Index -ratio of the concentration of drug needed to produce efficacy and the concentration of drug that is safely tolerated ( also called ldquoSafety Marginrdquo)
Questions Contact Robin Kleiman- email RobinKleimanchildrensharvardedu office CLS 13070
Terms that relate to Targets Molecular target- the protein that binds drug to produce efficacy Off-Target- other proteins that bind the drug that do not relate to efficacy and may produce Adverse Events (AEs) Druggable target ndashcomes from a class of proteins that has successfully been targeted with small molecule drugs in
the past Primarily transporters enzymes receptors ion channels (Not protein-protein interactions transcription factors RNA binding proteins etc)
Druggable genome- about 3000 genes encoding all druggable proteins Druggability- the presence of protein folds (quarternary structures) that favor specific interactions with drug-like
molecules Exploratory target- Hypothesis that a modulating a target via a particular mode of action will be beneficial to a
particular patient population Validated target- Hypothesis regarding a target also has in vivo efficacy data for a disease or a disease model- along
with a complete understanding of how the target mechanism relates to disease- (also called lsquoProof of Principlersquo) Phenotypic screen- a screen for compounds that will reverse a phenotype the molecular target may not be known Systems pharmacology target(s)-a precisely defined combination or lsquofingerprintrsquo of molecular targets to be
modulated to correct a phenotype (Poly-pharmacology)
Terms that relate to programs
Biomarker- a physiological pathological or anatomical characteristic that is measured by an automated process or algorithm as an indicator of the normal biological process pathological process or biological response to a therapeutic intervention Many types of Biomarkers target engagement biomarkers stratification biomarkers efficacy biomarkers pharmacodynamic biomarkers etchellip
Laboratory Objectives-Criteria established at the start of the program to define the desired pharmacological properties of the molecule with regard to potency selectivity mode of action frequency and route of administration For antibodies would include minimal criteria for knock down stability etc
Therapeutic Modality- small molecule biologic RNAi stem cell etc
Screening tree Screening funnel- A decision tree for utilizing a panel of assays to identify molecules that meet the laboratory objectives
Terms that relate to molecules
Drug-like molecule- has physicochemical properties in line with known oral medications The molecule will be largely rule of 5 (RO5) compliant therefore small and moderately lipophilic Not related to pharmacological activity
Rule of Five (RO5)=Chris Lipinskirsquos rule of 5 states that a drug like molecule will have the following properties Molecular Weight of less than 500 a clogP lt5 fewer than 5 H-bond donors and the number of H-bond acceptors ( which is the sum of N and O atoms) is less than 10
Physicochemical properties- key properties of molecules include (calculated)Molecular Weight number of H bond acceptors and donors (measured) kinetic solubility pKa lipophilicity (logD logP)
Chemical tool -a compound with good potency and selectivity for a specified molecular target but fails to meet all criteria for safety PK or potency needed to become a clinical candidate Suitable for preclinical testing of hypothesis and proof of principal studies but not for lsquopreclinical developmentrsquo
Active molecule describes an individual chemical entity with measurable dose-dependent activity in a biological screening assay
Hit molecule refers to a molecule plus its related structural analogs for which there is an understanding of the structure-properties and structure-activity relationships (SPR and SAR) for a specific biological context Additionally preliminary drug disposition data (both in vitro and in vivo) provide an assessment of pharmacokinetic properties The available data provide a basis for further optimization of the hit series
Lead molecule refers to a molecule plus its related structural analogs that demonstrate o Sufficient exposure at pharmacologically relevant doses by the intended route of administration to explore
intended pharmacology in a relevant in vivo disease or pharmacodynamic model o Proof-of-principle or efficacy in a in vivo model that will be used to establish a margin of safety
Clinical candidate an optimized individual chemical entity derived from a lead series that demonstrates o a dose-response relationship via intended route and schedule of administration in relevant disease model o an exposure-based margin of safety in toxicology studies o In summary a clinical candidate is a molecule that is deemed competent for testing the primary disease
intervention hypothesis in humans
A laboratory notebook is a vital record of events leading to a patentable invention Therecorded information can establish dates of conception and reduction to practice of atechnology as well as the inventorship of a patent claiming the technology Below arefourteen rules you should follow when keeping lab notebooks
1 mdash Do use bound booksInventors should use permanently bound notebooks eg notebooks with spiral or glue bindings If loose-leaf sheets are used they should be consecutively numbered and eachpage should be dated signed and witnessed
2 mdash Do sign and date Each notebook should be signed and dated on the inside front cover to indicate the firstday the recipient started using the notebook Each entry should be dated and signed orinitialed
An independent witness ie someone who understands the technology but will not benamed as a co-inventor of the invention should sign and date each entry after the state-ment ldquoRead and understood by rdquo (The witness should preferably sign theentries on a contemporaneous or fairly contemporaneous basis but entries can also bereviewed signed and dated on a periodic eg weekly or monthly basis)
3 mdash Do use inkNotebook entries should be made in ink and in chronological order Entries should not beerased or ldquowhited outrdquo If an entry contains an error a line should be drawn through theerror and new text should continue in the next available space
4 mdash Donrsquot leave blank spacesBlank gaps between entries should be avoided If a blank space is left on a page a line orcross should be drawn through the blank space and the page dated to prevent subsequententries
5 mdash Donrsquot modifyPrior entries should not be modified at a later date If data were omitted the new datacan be entered under a new date and cross-referenced to the previous entry Record exper-iments when they are performed
6 mdash Do use past tenseUse the past tense (eg ldquowas heatedrdquo) to describe the experiments that were actually performed
Fish amp Richardson pc
Dorsquos and Don rsquo ts forKeeping Lab Notebooks
Boston
Dallas
Delaware
New York
San Diego
Silicon Valley
Twin Cities
Washington dc
FR
7 mdash Do explain abbreviations and special termsExplain all abbreviations and terms that are nonstandard Explain in context in a table ofabbreviations or in a glossary
8 mdash Do staple attachmentsAttachments such as graphs or computer printouts should be permanently attached to pagesin the notebook (eg by stapling) and both the attachment and the notebook page signedand dated If the attachment cannot be stapled it should be placed in an envelope and theenvelope stapled to the notebook page The envelope and page should then be signed andwitnessed making reference to the attachment being placed in the envelope
9 mdash Donrsquot remove originalsNo original pages should be removed from the notebook
10 mdash Do outline new experimentsWhen a new project or experiment is started the objective and rationale should be brieflyoutlined (eg in a short paragraph or by providing a flowchart)
11 mdash Do record lab meeting discussionsRelevant discussions from lab meetings should be recorded as should ideas or suggestionsmade by others The names of the people making the ideas and suggestions should be care-fully documented This information may be important in establishing inventorship
12 mdash Do provide detailRecord test descriptions including preferred operating conditions control conditionsoperable and preferred ranges of conditions and alternate specific materials Also recordtest results and an explanation of the results as well as photos or sketches of the resultsandor the test device Any conclusions should be short and supported by the factual dataOpinions or speculation about the invention should be avoided
13 mdash Do track notebooksIdeally each lab should maintain a catalog of notebooks in which each notebook is assigneda number and the name of the author of each notebook is recorded In addition the datethe author received the notebook as well as the date the notebook was completed andreturned should be recorded Upon leaving the lab the author should return all notebookschecked out by or to him
14 mdash Do save completed notebooksAll completed notebooks should be indexed (eg by number by author andor by subjectarea) and kept safely in a central repository together with corresponding patent applica-tions or patents Lab notebooks that relate to inventions on which patents have been grant-ed should be kept for the life of the patent plus six years
By J Peter Fasse
Fish amp Richardson pcIntellectual property complex litigation technology law800 818-5070wwwfrcominfofrcom
P ER SP EC T I V E
PHARMACOK INET I CS
Data gaps limit the translational potentialof preclinical researchRobin J Kleiman1 and Michael D Ehlers2
The absence of mouse pharmacokinetic reference data hinders translation An analysis ofrecent literature highlights a systematic lack of discussion regarding rationale for the selec-tion of dosing paradigms in preclinical studies and in particular for neuroscience studies inwhich the lack of brain penetration can limit target-organ exposure We propose solutionsto improve study design
on January 6 2016httpstm
sciencemagorg
Dow
nloaded from
Despite widespread use of pharmacologicalagents in mouse models of human diseasethe literature lacks comprehensive pharmaco-kinetic profiles for such studies Coupled witha paucity of suitable data are shortcomingsin the training of experimental biologists inthe application of pharmacometric principlesto experimental study design Many authorssimply cite previously published studies tosupport the selection of a particular dose evenwhen the cited paper lacks drug exposuredata There is an assumption on the part ofresearchers that if a referenced study demon-strates a biological effectmdashthat is any measur-able physiological or behavioral effectmdashin arodent at a given dose then that same dosewill also effectively perturb disease-relevantmechanistic biology in a different study Thedanger occurs when the observed therapeuticeffects are not linked to drug-induced mecha-nistic alterations at the level of the target organLack of a drug exposurendashresponse relationshipin a target organ casts doubt on mechanisticinterpretations In addition any changes inthe route of drug administration vehicle prep-aration species used (rat versus mouse versusprimate) age or strain of animal transgenicmodification time points under investigationduration of dosing or organ targeted for inter-vention (for example brain versus a periph-eral tumor) can alter the relation between doseexposure and measured response In suchcases assumptions regarding the mechanisticbasis for observed therapeutic effects may nothold true
Preclinical pharmacological experimentsthat do not measure drug concentrations in
1Translational Neuroscience Center Kirby NeurobiologyCenter Department of Neurology Boston ChildrenrsquosHospital Harvard Medical School Boston MA 02115USA 2Neuroscience amp Pain Research Unit BioTherapeu-tics Worldwide Research and Development Pfizer IncCambridge MA 02139 USACorresponding author E-mail robinkleimanchildrensharvardedu (RJK) michaelehlerspfizercom (MDE)
the target organ run the risk of producing ex-posures that are too low or too high to inter-pret a mechanistic hypothesis Most drugs arenot selective over a large exposure range for asingle molecular target Confident evaluationof a therapeutic hypothesis requires an under-standing of the drugrsquos penetration and kineticswithin the target tissue as well as its potencyand selectivity for specific molecular targetsFurther investigators must consider the con-centration of the unbound fraction of drugthat is available to interact with the targetPublished reports often overlook the fact thatmany small molecules are more than 90bound to plasma or tissue proteins whichgreatly decreases the fraction of drug availableto bind to the intended target Thus in casesin which drug binding has a slow off-rate anorganismrsquos total drug exposure is not a predic-tor of drug available to interact with its target(1) The failure of some academic scientists toobtain relevant pharmacokinetic data impairsthe interpretation of preclinical research resultsand likely contributes to the acknowledgeddifficulties in replicating some academic liter-ature as reported by industry scientists (2 3)
Drug discovery teams in industry settingsroutinely collect pharmacokinetic data to aidin the mechanistic interpretation of in vivopreclinical data and to project optimal dosingparadigms for efficacy and toxicology studiesData required to evaluate brain penetrationare not typically collected by industry-baseddrug-discovery teams for compounds origi-nally developed for therapeutic indicationsthat do not obviously implicate the centralnervous system making this information es-pecially hard to find for many otherwise well-described drugs In addition because mousedata are not required for preclinical toxicologystudies (the more common small animal spe-cies for preclinical toxicology being rats)industry scientists do not often obtain pharma-cokinetic data from mouse experiments These
wwwScienceTranslationalMedicineo
issues are especially relevant for older drugsthat are potentially suitable for repurposingMany older drugs were discovered and char-acterized before routine pharmacokinetic-pharmacodynamic (PK-PD) modeling ofpreclinical drug exposure and its applicationto predicting human dosing became standardpractice Last pharmacokinetic data are notconsidered innovative and these studies gen-erally do not achieve publication in peer-reviewed journals even when the data havebeen generated When such data are pub-lished it is often relegated to the unsearchableblack hole of supplementary materials Thusmouse neuroPK profiles are not readily avail-able for many drugs that are frequently usedin conjunction with mouse models of humanbrain disorders
DOCUMENTING DOSING STRATEGIES
To evaluate the potential impact of insufficientpharmacokinetic data on dose selection in asample of recent published neuroscience liter-ature we conducted an analysis of papersidentified by means of a PubMed search usingthe search terms ldquodrugrdquo and ldquobrainrdquo for the pub-lication year 2014 from eight journals (Table 1)This list was culled to include only primaryresearch reports that included systemic adminis-tration of a pharmacological agent a pharma-cological therapeutic or a biological therapeuticas part of the study design The search yielded100 articles published between 1 January and30 December 2014 that used systemic drug de-livery with the intended goal of targeting thebrain of rodents (table S1) Each publicationwas examined for the stated rationale behindthe dose selection of study drugs (Table 1)
The reported rationale for dosing strategiesfell into several broad categories including(from lowest confidence to highest) (i) dose se-lected rationale not discussed (ii) literaturecitations of another study in which reportsranged from citation of exposure in the samespecies exposure in a different strain or spe-cies a dose conversion from the human liter-ature to rodent or reports of effects on rodentbehavior in another study (iii) demonstrationof an effect on rodent behavior or function inthe current study (iv) demonstration of adose-responsive biological effect in the currentstudy (v) measurement of drug levels in bloodor plasma in the current study and (vi) mea-surement of drug levels in the target organ(that is the brain) in the current study In onlytwo instances were publications identifiedthat considered the impact of drug binding
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to plasma or brain proteins on the free expo-sure of drug available to interact with the tar-get This is a critical flaw in most publishedstudies that use small molecules for functionaleffects in the brain because many centralnervous system (CNS) drugs that penetratethe blood-brain barrier exhibit high proteinbinding leaving a small fraction of the totaldrug measured in plasma or brain unbound
and free to interact with the molecular targetFurthermore most studies used evidence of abiological activity to justify dose selection with-out consideration for how exposure of theagent relates to the potency of the compoundat known molecular targets which would berequired to test a mechanistic hypothesis
The lack of pharmacokinetic considera-tion does not imply that every study used an
wwwScienceTranslationalMedicineo
inappropriate dose of drug to test their hypoth-esis It does illustrate that a clear rationale wasnot provided for dose selection in most pub-lications Furthermore all 11 of the 100 publi-cations that measured total brain exposureincluded an author from the pharmaceutical in-dustry (n=5) an academic drug screening group(n = 3) or a pharmacologyndashpharmaceuticalsciences department (n = 3) This observationlikely reflects the limited presence of pharma-cology and pharmacometrics departmentswithinmost academic institutions and limitedaccess to the mass spectrometry and otheranalytical resources needed to measure druglevels in study samples Outsourcing the bio-analysis of samples collected from study ani-mals is feasible but the use of contract researchorganizations to support such studies is oftentoo costly for most academic grant budgets toaccommodate
DATABASES AND REPURPOSINGRecent years have seen increasing efforts toinvestigate approved or clinically tested drugsfor new indications (4ndash8) Such repurposinghas been touted as a means to accelerate ther-apeutic development (4) For example a stra-tegic pillar of the US National Institutes ofHealthrsquos (NIHrsquos) translational roadmap callsfor the academic community to actively par-ticipate in the repurposing of drugs approvedby the US Food and Drug Administration(FDA) or investigational drugs that havepassed safety hurdles but failed in clinicaltrials because of lack of efficacy (9ndash11) To havea meaningful impact in neurological and psy-chiatric disorders such drug repurposingefforts will require access to neuropharma-cokinetic (neuroPK) data sets in mice to guidethe testing of new therapeutic hypotheses ingenetically engineered disease models A re-cently published consensus evaluation of drugrepositioning opportunities for Alzheimerrsquosdisease identified 15 potential drug candidatesThese were further prioritized for testing onthe basis of available evidence to produce ashortlist of seven compounds reviewed by in-dustry experts to provide insight into the via-bility of these candidates The most commonshortcoming identified for the compoundsconsidered were issues related to insufficientbrain penetration or the lack of informationabout optimal dosing strategies (11)
The repurposing of statins illustrateshow the neuroPK knowledge gap limits progressStatins were developed as 3-hydroxy-3-methylglutarylndashcoenzyme A (HMG-CoA) reduc-tase inhibitors to lower cholesterol and reduce
Table 1 Preclinical dosing strategies The rationale for drug-dosing strategies was extractedfrom the literature through the analysis of 100 peer-reviewed studies published in2014 from eight journals that cover research on mechanisms of brain function disease andtherapeutic approaches to CNS disorders (Cell Neuron Nature Nature Neuroscience NatureMedicine Neurobiology of Disease Neuropsychopharmacology and Science TranslationalMedicine) (table S1) Forty-four of the 100 publications selected were studies of potentialtherapeutic approaches to disease whereas the remaining were studies of basic neurobiology ormechanisms of disease Each publication was examined to discern how authors selected thedosage of pharmacological tools or therapeutic compounds used in the design of studies toprobe brain function A relatively small number of studies considered what the concentrationof drug available in the brain after administration would be in the context of theirexperimental studies The most common method for selecting a dose of drug was tocite a previous study that demonstrated a biological effect of the drug on someaspect of rodent behavior
Rationale for studyrsquos drug-dose selection
Therapeutic
studies
Number of papers from the100 published studies
analyzed
bull No exposure or rationale for dose selection provided
5
22
bull Rodent dose extrapolated from human studies
0
1
bull Doses are similar to what was used previously toproduce a biological effect
8
23
bull Literature reports cited for multiple functionaleffects of drug at selected dose
4
5
bull Brain penetration evaluated but exposure notmeasured
2
2
bull Literature report of mismatched drug exposure
0
1
bull Observation of a biological effect at a single dosein current study
3
6
bull Observation of dose-responsive biological effectin current study
5
16
bull Brain exposure to drug was measured with routeof administration that differed from the oneused in the efficacy study
1
1
bull Plasma drug concentrations measured literaturereport of brain exposure cited and target-organpharmacodynamic effect observed in the currentstudy
1
1
bull Plasma drug concentrations measured
4
7
bull Brain pharmacodynamic effect of drug observed
2
4
bull Brain drug concentrations measured (totalconcentration)
6
7
bull Unbound brain drug concentrations measured
1
2
bull Brain drug concentrations measured and brainpharmacodynamic effect of drug observed
2
2
Total
44
100
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risk of cardiovascular disease (12) FDA hasapproved at least nine different statins andmost are commonly prescribed nearly one-third of Americans ages 55 to 64 took a pre-scription cholesterol-lowering drug between2009 and 2012 (wwwcdcgovnchsdatahushus14pdf) The widespread availability andsafety profile of statins has lured researchersinto evaluating their potential for repurpos-ing (13) Statins have been profiled extensive-ly in preclinical research to test for potentialtherapeutic benefit in Alzheimerrsquos disease(14ndash19) Fragile X syndrome (20) Rett syn-drome (21 22) epilepsy (23) Huntingtonrsquos dis-ease (24) Parkinsonrsquos disease (25 26) stroke(27) and brain injury (28 29)
A search of the literature reveals no sys-tematic neuroPK studies in any mouse strainthat would enable direct comparisons of CNSexposure across the various statins In silicopredictions based on the drugsrsquo molecularproperties suggest that the nine most widelyprescribed statins each have a different poten-tial to penetrate the blood-brain barrier differ-ent potencies against the HMG-CoA reductaseenzyme and different ldquooff-targetrdquo activity pro-files (30) On the basis of available data thereis reason to believe that simvastatin has thebest overall profile for inhibiting HMG-CoAreductase in the brain (30) A recent study re-ported that lovastatin is able to reverse a rangeof phenotypes in a mouse model of Fragile Xsyndrome (20) However the design of an op-timal clinical trial will require the collection ofmouse pharmacokinetic data to understandhow much CNS drug exposure is required toproduce efficacy in the disease model Thereare at least two possible scenarios Giventhat simvastatin is more potent at inhibitingHMG-CoA reductase than are other statinsand likely to be more brain penetrant inboth mice and humans one would expectthat simvastatin will be more potent than lo-vastatin in ameliorating symptoms in bothmice and humans if the observed efficacy stemsfrom inhibition of HMG-CoA reductase activ-ity in the brain by lovastatin The advantage ofthis outcome would be that better brain pen-etration and potency would lead to a loweroverall dose requirement to achieve efficacyand thus likely a better safety profile
A second scenario could be that lovastatin ismore potent than simvastatin in the mousemodel of Fragile X syndrome because of anadditional biological activity inherent to thelovastatinmolecule whichmaynot yet be doc-umented in the literature In either case un-derstanding the CNS exposure of lovastatin
required to produce efficacy in themouse willdetermine whether there is a safe therapeuticindex for achieving the required concentra-tion in patients Previous attempts to discernuseful neuroPK parameters from the litera-ture for the use of statins in rodent modelshave highlighted the lack of critical data asthe looming roadblock to progress in the field(31 32) Until these data exist the transla-tional potential of preclinical research maybe limited And this is but one example ofone drug class
The creation of a centralized database isneeded for the entire translational researchcommunity and would establish a new mech-anism for academia funding agencies founda-tions and industry to pool resources If studiesare donewell the first time and documented inan open-access resource it will reduce redun-dant efforts and improve the quality of decisionmaking by scientists considering innovativesolutions to our biggest health problems
FILL THE GAPSManuscript submission practices for severalhigh-impact journals now include require-ments that authors include detailed informa-tion regarding study design and statisticalanalysis with each submission A reasonableextension of this checklist should includethe stated rationale for doses selected for studydrugs Information should include a discus-sion of data highlighted in Table 2 Authorsshould be expected to reference a relevant
wwwScienceTranslationalMedicineo
data set from a high-quality database or pub-lication or provide the data in the current study(Table 3)
Industry biologists learn basic principlesof medicinal chemistry pharmacokineticsand drug disposition while working on drugdiscovery project teams Academic groupsare playing an increasing role in transla-tional therapeutics and in particular drugrepurposing Academic programs need toaugment training in pharmacokinetics andpharmacodynamics so as to increase the rigor ofpreclinical work and to ensure that investigator-initiated clinical studies are testing hypotheseseffectively Institutions without a departmentof pharmacology or pharmacometrics mightlack the organizational knowledge needed toconduct drug studies and must identify re-sources or collaborators to patch these defi-cits Formal coursework and Web-basedresources and tutorials are needed to train andsupport translational researchers Manuscriptand grant reviewers need to demand higherstandards for preclinical studies with respect toreporting on drug exposure associated withbiological effects Ethics committees responsi-ble for review of animal protocols should re-quire investigators to provide rationale fordose selections in proposed studies Similarlyscientific review boards at academic medicalcenters need to include clinical pharmacologistswho are able to review investigator-initiatedclinical studies to ensure that proposed dosingstrategies will test a meaningful hypothesis
Table 2 Recommendations for use of pharmacokinetic data The first column includes a listof recommended data sets to aid reviewers of submitted articles in the interpretation ofpreclinical findings The second column includes a list of useful reference data that wouldsupport improved preclinical study design in mice if available in a public database
Literature reports that evaluate studydrugs should include
Compound-specific data that shouldbe included in a rodent
pharmacokinetic database
bull Expected or measured plasma exposure of thestudy drug in the preclinical species during thestudy
bull Elimination half-life (T12)bull Systemic clearance (CL)bull Fraction of drug that is protein bound (fb)
bull Expected or measured target organ exposureof the study drugs in the preclinical speciesduring the study
Maximum plasma concentration after drug admin-istration (Cmax) and time to reach maximum plas-ma concentration (Tmax) for a standardized doseand route of administration
bull Expected or measured free fraction (unboundby protein) of the study drugs in the targetorgan of the preclinical species during thestudy
bull The ratio of drug in brain to that in plasma (BP)bull The ratio of drug found free in brain (Cub) to thatfound free in the plasma (Cup) defined as CubCupbull Any potential impact of drug transporters (foundon the rodent blood-brain barrier) in limiting brainexposure
bull Expected or measured potency of the studydrug against the hypothesized activity in vitro
Expected ormeasured potency of molecule at knownbiological targets
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A central repository that contains brainpenetration protein binding and pharmaco-kinetic profiles of drugs and pharmacologicaltools in rodents is needed to effectively sup-port translational research This databaseshould also provide basic tutorials that de-fine primary pharmacokinetic parameterswith examples to illustrate how data are usedto predict optimal dosing strategies The min-imum data set needed for each compoundin a useful rodent database is highlighted inTable 2 Access to this information and sup-porting materials will have an immediateimpact on the quality of translational drug re-purposing efforts across brain disorders andwill support the development of new thera-peutic approaches to neurological disordersand mental illness Existing databases man-aged by NIH or precompetitive consortia couldbe reinforced with donated pharmacokineticdata sets and tutorials
Industry and government scientists shouldwork precompetitively to collect and curatepharmacokinetic data sets in conjunction withsupporting educational materials Mouse phar-macokinetic data exist inside pharmaceuti-cal companies for a wide range of publicallydisclosed molecules and literature standardsRelease of these data into a public databasewould provide several benefits to companiesincluding (i) increased scientific rigor in theliterature with a higher probability of repro-ducibility (ii) increased appreciation by theacademic biology community for the diffi-culty inherent in generating molecules withpotency and pharmacokinetic profiles suit-able for in vivo work opening the door forin-kind collaboration with academic groups
and (iii) direct comparison of data collectedin-house to that collected at other compa-nies or institutions to enable better internalquality control Comprehensive pharmaco-kinetic data sets will benefit all therapeuticareas regardless of whether the brain is thetarget organ because peripheral and cen-tral exposure data can be generated fromthe same experiments Moreover the prin-ciples described above for the CNS apply toother target tissues in which vascular bar-riers metabolic processes or active transportalter the distribution of systemically admin-istered drugs
Key to ensuring that preclinical mousestudies test the hypotheses they aim to eval-uate is an understanding of the unboundfraction of drug present in the target organat an appropriate time point under studyGrant and journal reviewers need to care-fully consider whether authors of propos-als and manuscripts are providing adequaterationale for their choices of preclinical dos-ing paradigms Importantly the collectionand centralization of rodent pharmacoki-netic datasets will promote efficient genera-tion of future data reduce the collection ofredundant data and improve the return oninvestment for research funds that are de-voted to preclinical studies aimed towardclinical translation
SUPPLEMENTARY MATERIALS
wwwsciencetranslationalmedicineorgcgicontentfull8320320ps1DC1Table S1 One hundred publications that used systemic drugdelivery with the goal of targeting rodent brains
wwwScienceTranslationalMedicineo
REFERENCES AND NOTES1 A Reichel Addressing central nervous system (CNS) penetra-
tion in drug discovery Basics and implications of the evolv-ing new concept Chem Biodivers 6 2030ndash2049 (2009)
2 F Prinz T Schlange K Asadullah Believe it or not Howmuch can we rely on published data on potential drugtargets Nat Rev Drug Discov 10 712 (2011)
3 C G Begley L M Ellis Drug development Raisestandards for preclinical cancer research Nature 483531ndash533 (2012)
4 P Nair Second act Drug repurposing gets a boost asacademic researchers join the search for novel uses ofexisting drugs Proc Natl Acad Sci USA 110 2430ndash2432(2013)
5 T I Oprea J Mestres Drug repurposing Far beyond newtargets for old drugs AAPS J 14 759ndash763 (2012)
6 S M Strittmatter Overcoming drug development bot-tlenecks with repurposing Old drugs learn new tricksNat Med 20 590ndash591 (2014)
7 K Xu T R Coteacute Database identifies FDA-approved drugswith potential to be repurposed for treatment of orphandiseases Brief Bioinform 12 341ndash345 (2011)
8 X Bosch European researchers drug companies joinforces against rare diseases JAMA 294 2014ndash2015 (2005)
9 F S Collins Mining for therapeutic gold Nat Rev DrugDiscov 10 397 (2011)
10 P Vallance P Williams C Dollery The future is much closercollaboration between the pharmaceutical industry andacademic medical centers Clin Pharmacol Ther 87525ndash527 (2010)
11 A Corbett J Pickett A Burns J Corcoran S B DunnettP Edison J J Hagan C Holmes E Jones C KatonaI Kearns P Kehoe A Mudher A Passmore N ShepherdF Walsh C Ballard Drug repositioning for Alzheimerrsquosdisease Nat Rev Drug Discov 11 833ndash846 (2012)
12 J L Goldstein M S Brown A century of cholesterol andcoronaries From plaques to genes to statins Cell 161161ndash172 (2015)
13 A M Malfitano G Marasco M C Proto C Laezza P GazzerroM Bifulco Statins in neurological disorders An overviewand update Pharmacol Res 88 74ndash83 (2014)
14 T Kurata K Miyazaki M Kozuki N Morimoto Y OhtaY Ikeda K Abe Progressive neurovascular disturbances inthe cerebral cortex of Alzheimerrsquos disease-model miceProtection by atorvastatin and pitavastatin Neuroscience197 358ndash368 (2011)
15 H Kurinami N Sato M Shinohara D Takeuchi S TakedaM Shimamura T Ogihara R Morishita Prevention ofamyloid beta-induced memory impairment by fluvastatinassociated with the decrease in amyloid beta accumulationand oxidative stress in amyloid beta injection mousemodel Int J Mol Med 21 531ndash537 (2008)
16 M Shinohara N Sato H Kurinami D Takeuchi S TakedaM Shimamura T Yamashita Y Uchiyama H RakugiR Morishita Reduction of brain beta-amyloid (Abeta)by fluvastatin a hydroxymethylglutaryl-CoA reductaseinhibitor through increase in degradation of amyloidprecursor protein C-terminal fragments (APP-CTFs) andAbeta clearance J Biol Chem 285 22091ndash22102 (2010)
17 G J Siegel N B Chauhan D L Feinstein G Li E B LarsonJ C Breitner T J Montine Statin therapy is associated withreduced neuropathologic changes of Alzheimer diseaseNeurology 71 383 author reply 383 (2008)
18 X-K Tong C Lecrux P Rosa-Neto E Hamel Age-dependentrescue by simvastatin of Alzheimerrsquos disease cerebrovascularand memory deficits J Neurosci 32 4705ndash4715 (2012)
19 X K Tong N Nicolakakis P Fernandes B Ongali J BrouilletteR Quirion E Hamel Simvastatin improves cerebrovascularfunction and counters soluble amyloid-beta inflammationand oxidative stress in aged APP mice Neurobiol Dis35 406ndash414 (2009)
Table 3 Recommendations to improve translation through the use of preclinicalpharmacokinetic data
Journalsbull Require authors to provide explicit rationale for dosing strategies usedbull Rationale should include consideration of the unbound drug exposure in target organas best practices
Educationbull Include basic pharmacology and pharmacokinetic principles in formal coursework requiredfor basic preclinical and clinical research scientists
bull Develop tutorials and on-line calculators for rodent dose projections to support appropriateuse of published pharmacological tools
Databasesbull Reinforce public chemical databases with mouse pharmacokinetic data that includes brainexposure
Precompetitive consortiabull Create precompetitive consortia to solicit mouse pharmacokinetic data sets from industry andfoundation partners for database expansion
bull Targeted data collection for compounds already in the public domain
rg 6 January 2016 Vol 8 Issue 320 320ps1 4
P ER SP EC T I V E
20 E K Osterweil S C Chuang A A Chubykin M SidorovR Bianchi R K Wong M F Bear Lovastatin corrects ex-cess protein synthesis and prevents epileptogenesis in amouse model of fragile X syndrome Neuron 77 243ndash250(2013)
21 C M Buchovecky S D Turley H M Brown S M KyleJ G McDonald B Liu A A Pieper W Huang D M KatzD W Russell J Shendure M J Justice A suppressorscreen in Mecp2 mutant mice implicates cholesterol me-tabolism in Rett syndrome Nat Genet 45 1013ndash1020(2013)
22 M J Justice C M Buchovecky S M Kyle A Djukic A rolefor metabolism in Rett syndrome pathogenesis Newclinical findings and potential treatment targets RareDis 1 e27265 (2013)
23 F Scicchitano A Constanti R Citraro G De Sarro E RussoStatins and epilepsy Preclinical studies clinical trials andstatin-anticonvulsant drug interactions Curr Drug Targets16 747ndash756 (2015)
24 M L Ferlazzo L Sonzogni A Granzotto L Bodgi O LartinC Devic G Vogin S Pereira N Foray Mutations of theHuntingtonrsquos disease protein impact on the ATM-dependentsignaling and repair pathways of the radiation-inducedDNA double-strand breaks Corrective effect of statins andbisphosphonates Mol Neurobiol 49 1200ndash1211 (2014)
25 E K Tan L C Tan Holding on to statins in Parkinsondisease Neurology 81 406ndash407 (2013)
26 B Friedman A Lahad Y Dresner S Vinker Long-termstatin use and the risk of Parkinsonrsquos disease Am J ManagCare 19 626ndash632 (2013)
27 M S Elkind Stroke A step closer to statin therapy forstroke Nat Rev Neurol 9 242ndash244 (2013)
28 E E Abrahamson M D Ikonomovic C E Dixon S T DeKoskySimvastatin therapy prevents brain trauma-inducedincreases in beta-amyloid peptide levels Ann Neurol66 407ndash414 (2009)
29 E F Wible D T Laskowitz Statins in traumatic brain injuryNeurotherapeutics 7 62ndash73 (2010)
wwwScienceTranslationalMedicineo
30 S Sierra M C Ramos P Molina C Esteo J A VaacutezquezJ S Burgos Statins as neuroprotectants A comparativein vitro study of lipophilicity blood-brain-barrier penetra-tion lowering of brain cholesterol and decrease of neuroncell death J Alzheimers Dis 23 307ndash318 (2011)
31 W G Wood G P Eckert U Igbavboa W E Muumlller Statinsand neuroprotection A prescription to move the fieldforward Ann N Y Acad Sci 1199 69ndash76 (2010)
32 W G Wood W E Muumlller G P Eckert Statins and neuro-protection Basic pharmacology needed Mol Neurobiol50 214ndash220 (2014)
101126scitranslmedaac9888
Citation R J Kleiman M D Ehlers Data gaps limit thetranslational potential of preclinical research Sci Transl Med8 320ps1 (2016)
D
rg 6 January 2016 Vol 8 Issue 320 320ps1 5
on January 6 2016httpstm
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ownloaded from
101126scitranslmedaac9888] (320) 320ps1 [doi8Science Translational Medicine
Robin J Kleiman and Michael D Ehlers (January 6 2016) Data gaps limit the translational potential of preclinical research
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s sitesScienceThe editors suggest related resources on
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is a registered trademark of AAASMedicineScience TranslationalAssociation for the Advancement of Science all rights reserved The title
Science 1200 New York Avenue NW Washington DC 20005 Copyright 2016 by the Americanweekly except the last week in December by the American Association for the Advancement of
(print ISSN 1946-6234 online ISSN 1946-6242) is publishedScience Translational Medicine
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nloaded from
Boston Childrenrsquos Hospital ndash Broad Institute Collaboration Grants
Background Meeting the challenges of biomedicine requires bringing together creative scientists exceptional technological resources and world-class expertise across many disciplines that rarely exist within a single institution This guiding principle is the basis for a funding opportunity to support Boston Childrenrsquos Hospital investigators performing research in collaboration with Broad scientists
Goals The fundamental goal of this new award is to spark new collaborations between Boston Childrenrsquos Hospital and the Broad Institute The grants will be awarded to address a very wide range of scientific questions but are specifically designated for projects with the following characteristics
middot Projects where engagement with the Broad would benefit Childrenrsquos Hospital investigators projects that can uniquely benefit from being done at the Broad Institute
middot Projects that create new scientific collaborations and bring together diverse scientific backgrounds projects that spark new scientific directions or technologies and are not currently being pursued at Childrenrsquos Hospital
middot Projects that pilot new approaches that researchers at Childrenrsquos the Broad and the greater scientific community can benefit from in the future the purpose of these awards is not to provide gap or extension funding of existing projects but to initiate new projects
Eligibility Individuals with Principal Investigator status at Boston Childrenrsquos Hospital are eligible Applicants need not be Associate Members of the Broad Institute
Broad Platforms and Scientists Broadrsquos Platforms (Genomics Imaging Metabolite Profiling Proteomics Genomic Perturbation and the Broad Technology Labs) are collaborative organizations that provide scientific leadership and cutting edge technologies in support of project goals Collaborations can also be established with other groups at the Broad including the Klarman Cell Observatory the Stanley Center for Psychiatric Research or the Center for the Development of Therapeutics
Budgets Grants will provide $60000 direct support for 1 year plus philanthropic overhead It is expected that most grants will fund work performed at the Broad Institute either through interaction with Broadrsquos Platforms or via collaboration with a Broad scientist however the work may also occur at Boston Childrenrsquos if it is important to meet the scientific goals of the collaboration
Deadline and Review process Final proposals are due by September 1 2015 Funding decisions are expected to be reached by October 1 2015 Proposals will be reviewed by a joint Childrenrsquos HospitalndashBroad Institute committee Additional submission dates are expected for 2016
Submission Applicants are strongly encouraged to discuss potential applications in advance with the office of the Chief Scientific Officer at the Broad Questions should be directed to Alex Burgin ( 617-714-7124)
Proteomics Genomic Perturbation and the Broad Technology Labs) are collaborative
organizations that provide scientific leadership and cutting edge technologie
s in support of
project goals Collaborations can also be established with other groups at the Broad including
the Klarman Cell Observatory the Stanley Center for Psychiatric Research or the Center for the
Development of Therapeutics
Budgets
Grants wi
ll provide $60000 direct support for 1 year plus philanthropic overhead It
is expected that most grants will fund work performed at the Broad Institute either through
interaction with Broadrsquos Platforms or via collaboration with a Broad scientist howev
er the
work may also occur at Boston Childrenrsquos if it is important to meet the scientific goals of the
collaboration
Deadline and Review process
Final proposals are due by September 1 2015 Funding
decisions are expected to be reached by October 1 201
5 Proposals will be reviewed by a joint
Childrenrsquos Hospital
ndash
Broad Institute committee Additional submission dates are expected for
2016
Submission
Applicants are
strongly encouraged to discuss potential applications in
advance
with the office of the Chief Sc
ientific Officer at the Broad
Questions should be
directed to Alex Burgin (
aburginbroadinstituteorg
617
-
714
-
7124
)
Boston Childrenrsquos Hospital ndash Broad Institute Collaboration Grants
Background Meeting the challenges of biomedicine requires bringing together creative
scientists exceptional technological resources and world-class expertise across many
disciplines that rarely exist within a single institution This guiding principle is the basis for a
funding opportunity to support Boston Childrenrsquos Hospital investigators performing research
in collaboration with Broad scientists
Goals The fundamental goal of this new award is to spark new collaborations between Boston
Childrenrsquos Hospital and the Broad Institute The grants will be awarded to address a very wide
range of scientific questions but are specifically designated for projects with the following
characteristics
Projects where engagement with the Broad would benefit Childrenrsquos Hospital
investigators projects that can uniquely benefit from being done at the Broad Institute
Projects that create new scientific collaborations and bring together diverse scientific
backgrounds projects that spark new scientific directions or technologies and are not
currently being pursued at Childrenrsquos Hospital
Projects that pilot new approaches that researchers at Childrenrsquos the Broad and the
greater scientific community can benefit from in the future the purpose of these awards
is not to provide gap or extension funding of existing projects but to initiate new
projects
Eligibility Individuals with Principal Investigator status at Boston Childrenrsquos Hospital are
eligible Applicants need not be Associate Members of the Broad Institute
Broad Platforms and Scientists Broadrsquos Platforms (Genomics Imaging Metabolite Profiling
Proteomics Genomic Perturbation and the Broad Technology Labs) are collaborative
organizations that provide scientific leadership and cutting edge technologies in support of
project goals Collaborations can also be established with other groups at the Broad including
the Klarman Cell Observatory the Stanley Center for Psychiatric Research or the Center for the
Development of Therapeutics
Budgets Grants will provide $60000 direct support for 1 year plus philanthropic overhead It
is expected that most grants will fund work performed at the Broad Institute either through
interaction with Broadrsquos Platforms or via collaboration with a Broad scientist however the
work may also occur at Boston Childrenrsquos if it is important to meet the scientific goals of the
collaboration
Deadline and Review process Final proposals are due by September 1 2015 Funding
decisions are expected to be reached by October 1 2015 Proposals will be reviewed by a joint
Childrenrsquos HospitalndashBroad Institute committee Additional submission dates are expected for
2016
Submission Applicants are strongly encouraged to discuss potential applications in
advance with the office of the Chief Scientific Officer at the Broad Questions should be
directed to Alex Burgin (aburginbroadinstituteorg 617-714-7124)
Clinical Trials Glossary
ADME an acronym for absorption distribution metabolism and elimination ADME
studies determine how a drug is absorbed by the body the chemical changes that it may
undergo and how it is eliminated from the body
Adverse event (AE) a bothersome event that occurs in a study participant AEs may be
related to the treatment being tested or may be due another cause (eg another treatment
another medical condition an accident or a surgery)
Arm a specific type of treatment to which a group of clinical trial participants is
assigned Some clinical trials have one arm and some have two arms while others have
three or more arms For example a clinical trial comparing two different doses of an
investigational drug versus a placebo would have three arms participants receiving a
higher dose of the investigational drug participants receiving a lower dose of the
investigational drug and participants receiving the placebo
Baseline a point in time at the beginning of a clinical trial before the study participants
receive any treatment At the baseline participants usually have certain types of tests
During and after treatment the same tests may be performed and the results compared
with the baseline results to see if the drug has caused changes
Bias a factor ndash such as a preconceived idea about the effects of the benefits and risks of a
treatment or a lack of balance in selection of patients for a study ndash that reduces the
likelihood that the study results are true Methods such as blinding and randomization
are used to limit the potential for bias
Bioavailability the portion of the dose of a drug that reaches the bloodstream For
example if the drug is administered intravenously its bioavailability is 100 percent
however if the drug is administered in any other way such as orally topically or
through intramuscular injection its bioavailability will decrease due to incomplete
absorption
Bioequivalence study a test performed to compare the portion of a drug in the
bloodstream when administered in different dosage forms
Biologic product any substance that can be used in prevention treatment or cure of
disease Some examples include vaccines blood virus toxin antitoxin and therapeutic
serum
Biopsy the removal of cells or tissue from a patient for examination which is usually
done under a microscope A tissue sample might be taken for genetic studies Sometimes
there is a difference between the blood genotype and the skin or other tissue genotype
This term can also refer to the tissue sample that has been obtained by such a procedure
2
Blinding a process used to prevent the participants the researchers or both from
knowing what specific treatment is being given to participants in a clinical trial The
process of blinding helps to reduce bias because study participants and researchers are
less likely to be unconsciously influenced by the knowledge of what the study participant
is actually receiving If only the participants are blinded the study is called a single-
blind study If both participants and researchers are blinded the study is called a double-
blind study
Carcinogenicity studies long-term studies conducted in animal models to determine a
drugrsquos likelihood of causing cancer
Clinical efficacy a compoundrsquos ability to produce the desired effect
Clinical pharmacology a science that studies properties of drugs in relation to their
therapeutic value in humans
Clinical study or Clinical trial a medical experiment in human beings that helps to
determine how a disease drug or medical device affects study participants Clinical
studies are necessary to answer specific questions about how to better diagnose prevent
or treat a disease or condition
Cohort a group of study participants who have certain characteristics in common such
as female sex a defined age range or particular severity of disease Dividing study
participants into cohorts is often done as part of the analyses of study data
Contraindication a factor that makes the use of a particular drug inadvisable For
example a person who has had an allergic reaction to penicillin in the past is considered
to have a contraindication to using penicillin in the future
Control group a group of participants not receiving the investigational drug but instead
receiving a standard treatment for their disease or receiving a placebo The results
observed in the group of patients receiving the investigational drug are compared with the
results observed in the control group
Crossover study a study design with two or more arms where participants receive one
treatment for a period of time and then switch over to a second treatment for a period of
time Such a study design allows the effects of the two treatments to be compared in the
same patient
Data Monitoring Committee (DMC) or Data Safety and Monitoring Board (DSMB)
A committee of experts that periodically reviews the accumulating data from an ongoing
multicenter clinical trial Members of a DMCDSMB must be independent ie they
cannot be participating as investigators in the clinical trial Based on their review the
DMCDSMB experts advise the sponsor regarding whether it is safe and acceptable to
continue with the study or whether the data suggest that the study should be modified or
stopped A DMCDSMB may recommend that a trial be stopped if there are safety
concerns or if the trial objectives have been achieved
3
Dose-ranging study a clinical trial in which two or more doses of an investigational
drug are tested to determine which dose is likely to offer the best combination of safety
and efficacy in later clinical trials or in medical care
Efficacy or effectiveness the ability of a drug to prevent cure or slow a disease process or to alleviate the symptoms of a disease or condition
Eligibility a determination made during the screening period for a clinical study of
whether a personrsquos participation in the trial is likely to be safe and can contribute data
that will help achieve the study goals
Endpoint occurrence of a disease symptom sign or test result that constitutes one of the
target outcomes of a clinical trial
Inclusionexclusion criteria the factors defined in the protocol of a study that determine
whether a personrsquos participation in a clinical trial is likely to be safe and can contribute
data that will help achieve the study goals Study candidates undergo evaluation during
the study screening period to determine if they meet all of the inclusion criteria and do
not meet any of the exclusion criteria as defined in the protocol These criteria usually
consider such factors as age sex type of disease stage of disease previous treatment
history and other medical conditions in determining eligibility for the study
Informed consent (assent) a process by which medical researchers provide necessary
information to a person about a clinical study and the person voluntarily confirms his or
her willingness to participate in the study Children who are considered old enough to
have a basic understanding of the study may need to provide assent to be involved in the
study a parent or legal guardian must also give informed consent for such a child to
participate
Informed consent (assent) form a document that describes a clinical study to the
participants (or their parentsguardians) The informed consent (assent) form includes
information about the goals of the study the study design and duration the types of tests
to be performed the potential risks and inconveniences the potential benefits the
possible costs or payments associated with study participation the available alternative
therapies the rights and responsibilities of the participant and the people to contact if the
participant has questions The informed consent (assent) form must be reviewed and
signed before the participant has any study tests or treatment including the tests
performed during the screening period at the beginning of the study Participants are
given a copy of the informed consent (assent) form to take home
Institutional Review Board (IRB) or Independent Ethics Committee (IEC) a board
of physicians statisticians researchers community advocates and others who are
responsible for ensuring the protection of the rights safety and well-being of participants
in a clinical trial at a study center This board is called an IRB in the United States and is
often called an IEC in other countries IRBIECs review and approve important study
documents (eg protocols informed consent forms study advertisements and patient
4
brochures) before the start of the study and periodically review the progress of the study
while it is ongoing
Investigational Drug a drug that is being tested as a potential treatment for a disease or
condition but has not yet been proven safe and effective for that use
Investigator a physician or other health care worker who carries out a clinical trial by enrolling treating and monitoring participants and recording the results
In vitro testing testing conducted in test tubes or other artificial environments
In vivo testing testing conducted in living animals or humans
Longitudinal study a clinical study that involves observations of the same items over
long periods often many decades Because longitudinal studies track the same people
they are often used to study trends across the life span to uncover predictors of certain
diseases or to track the effects of a particular treatment on a patientrsquos condition over
time
Multicenter study a study conducted at more than one location Multicenter clinical
studies are generally performed when each individual clinical trial site does not have
enough study candidates to complete a large trial
Natural history study a study of the natural development of a disease or condition over
a period of time Natural history studies are usually longitudinal studies
New Drug Application (NDA) the registration document through which a
pharmaceutical company formally proposes that the FDA approve a new drug for
manufacturing and sale The application includes detailed reports of pharmacology
toxicology manufacturing and chemistry as well as data from clinical trials
Open-label study a study in which the participants and the investigators know which
treatment is being given In an open-label study there is no blinding and none of the participants receives a placebo
Orphan disease a disease or condition that affects a relatively small number of people
In the US this defined as fewer than 200000 people In Europe this is defined as fewer
than five in 110000 people
Orphan drug a drug intended to treat an orphan disease
Participant or subject a patient or healthy volunteer who participates in a clinical trial
Phase 1 the initial phase of testing of an investigational drug in humans Usually a
Phase 1 clinical study is conducted in a small number of healthy volunteers or patients
with a disease for which the drug may be useful Generally the study is designed to
determine the side effects of the drug and its pharmacokinetics Some information
5
regarding drug efficacy may be collected if patients with a disease participate A phase
frequently encompasses more than one clinical trial Phase 1 sometimes is sub-divided
into Phases 1a and 1b for example when the first set of Phase 1 trials (Phase 1a) is
performed in healthy volunteers and a second set of Phase 1 trials (Phase 1b) is
performed in patients with a disease
Phase 2 the intermediate phase of testing of an investigational drug in humans Usually
a Phase 2 clinical study conducted in patients with a disease for which the drug may be
useful Generally the study is designed to evaluate dosing to obtain preliminary data on
the effectiveness of the drug and to acquire more safety information Phase 2 sometimes
is sub-divided into Phases 2a and 2b Phase 2a studies typically are smaller and shorter
in duration and evaluate different drug doses to see how they affect certain tests that can
indicate whether the drug is working as expected Phase 2b studies typically enroll more
patients are of longer duration and evaluate whether the drug is offering clinical benefits to patients Phase 2b studies sometimes are considered pivotal or registration-directed
Phase 3 the final phase of testing an investigational drug in humans before regulatory
approval Phase 3 studies are usually conducted in a large population of patients and are
generally designed to confirm the effectiveness of the drug and to evaluate the overall
risk-benefit ratio Phase 3 studies usually test the investigational drug in comparison with
a standard treatment for the disease or a placebo
Phase 4 testing of a drug in humans after it has already been approved by regulatory
authorities and can be used in medical practice Phase 4 studies may be conducted to
compare the drug to a similar type of drug to explore whether it may help patients with
other diseases to further study the long-term safety of the drug or for other reasons
Pivotal study a study that is designed to generate the data required by regulatory
authorities to decide whether to approve an investigational drug A pivotal study is
usually a large randomized Phase 2b or Phase 3 study and often is blinded and uses a
placebo as a control Sometimes a pivotal study is described as a registration-directed
study
Placebo an inactive version of an investigational drug A placebo has a similar
appearance to the investigational drug but is expected to have no therapeutic value A
placebo is used as a comparison treatment to reduce bias in randomized studies
Preapproval access program an umbrella term for programs that allow seriously ill
patients to receive an investigational drug when they are unable to participate in clinical
trials and there is no alternative treatment This is sometimes referred to as
compassionate use Types of pre-approval access programs include expanded access
parallel-track named patient program single-patient exemption and treatment IND The
timing for starting an expanded access program usually depends upon what is known
about the risk-benefit of the drug and whether the drug can be provided in a manner that
is fair to patients with the disease
6
Preclinical (nonclinical) testing testing of a drug in test tubes or in animals A drug
undergoes preclinical testing before being tested in humans to make sure that it shows
evidence of desired effects and is sufficiently safe for study in people Preclinical testing
sometimes also helps to determine the doses of the drug that should be evaluated in
humans Preclinical testing is sometimes called nonclinical testing
Protocol a document describing what types of people may participate in a clinical study
and the objectives treatments measurements statistical methods timing and
organization of a clinical trial The protocol must be prepared in advance of the study
and must be reviewed and approved by review committees and regulatory authorities
before the study is started Investigators must follow the protocol to carry out the study
Randomization assignment of participants to treatment arms based on chance This is
usually done by a computer program in a way that does not allow either the participants
or the investigators to choose who is assigned to which arm Randomization is used to
reduce bias in clinical trials
Risk-benefit ratio the balance of the risk of side effects expected with use of a drug
versus the potential for benefit with the use of that drug A drug with a good risk-benefit
ratio has few side effects and is very effective
Serious adverse event (SAE) an adverse event that is life-threatening requires inpatient
hospitalization or lengthens a hospital stay leads to substantial disability leads to a birth
defect or results in death
Side effect any effect of a drug other than the desired effect Side effects are often
unwanted and may be bothersome Other names for a bothersome side effect are adverse
drug reaction (ADR) or drug toxicity
Screening period a period at the beginning of a clinical trial when candidates for the
study are evaluated to determine if their participation is likely to be safe and can
contribute data that will help achieve the study goals
Significant or statistically significant an outcome in a clinical trial is likely to result
from a real difference (eg due to an effect of a treatment) and is unlikely to be due to
chance alone The level of statistical significance is often expressed in terms of a p-
value which indicates the probability that a difference is not due to chance alone
Usually a p-value smaller 005 is considered statistically significant
Sponsor the organization responsible for financing and coordinating a clinical trial
Most often this is a pharmaceutical or biotechnology company
Standard treatment a treatment currently in wide use often approved by regulatory
agencies and generally considered effective in the treatment of a specific disease or
condition
7
Toxicity a side effect produced by a drug that is bothersome to the person taking the
drug
Toxicology the study of the adverse effects of chemicals conducted in animal models to
predict potential adverse effects in humans Some studies are conducted during clinical
development to evaluate dosing regimens
Boston Childrenrsquos Hospital Clinical Research Map 1 Mouse over for additional info Bold = hyperlink
CLINICAL RESEARCH MAP
Boston Childrenrsquos Hospital Clinical Research Map 2 Mouse over for additional info Bold = hyperlink
ObjectiveThis clinical research map is designed to serve as a guide for investigators study coordinators and research nurses at Boston Childrenrsquos Hospital The research map outlines the key steps in preparing to launch a research study and provides embedded links to institutional resources tools and documents
An investigator need not follow the steps on the Clinical Research Map in any particular order There is flexibility and the steps followed will in part de-pend on the type of research study
For new as well as more experienced investigators the Clinical Research Map can be used as a checklist or an inves-tigator can use the steps on the map as points for consideration as they are developing a protocol and launching a study
This tool is not intended to substitute for the important collaboration be-tween a junior investigator and a senior investigatormentor A senior investiga-tor plays a pivotal role in coaching and advising a junior investigator regarding the many subtleties and variations that apply to designing and implementing a protocol
This process map cannot be inclusive of every possible task or step but is intended as a general guide for investi-gators and their study teams
ResourcesThere are many institutional resources at Boston Childrenrsquos Hospital designed to support investigators and their clini-cal research teams In addition to links to resources tools and documents that are embedded in the steps of the clini-cal research map the last page of this document contains website addresses that will take you to additional helpful institutional resources
Acknowledgements Cindy Williams DNP RN PNP NE-BC Nursing Director CTSU Clinical Research Nursing
Ellen McGrath MSN RN CPNP Nurse Practitioner Department of Surgery
Grace Yoon MSN RN CNNP Research Nurse Department of Ophthalmology
Laura Feloney BA Lab Technician
ContentsOverview Four stages 3
1st Stage Protocol development 4
1st Stage Protocol development contrsquod 5
2nd Stage Implementation planning 6
3rd stage Study launch7
4th stage Statistical analysis reporting and dissemination 8
Discarded specimens Additional steps 9
Chart review Steps if you are completing a chart review 10
Appendix A Resources for researchers 11
Boston Childrenrsquos Hospital Clinical Research Map 3 Mouse over for additional info Bold = hyperlink
Overview Four stages
Protocol development
Implementation planning
Study launch
Statistical analysis reporting and dissemination
1
2
3
4
Boston Childrenrsquos Hospital Clinical Research Map 4 Mouse over for additional info Bold = hyperlink
1st Stage Protocol development
Explore resources
CRIT
CRC
EQuIP
CTSU
Harvard Catalyst
Complete training
CITI training
EQUiP
Consult research pharmacistResearch Pharmacy
Rocco Anzaldi
Consult statistician
CRC
Draft a protocol
Protocol guidelines
Study personnel
FDA Guidance for Investigators
Consult Clinical Research Center
CRC
Bio Bank
Start IRB application
TransLab
Consider applying for grants
securing funding
Office of Sponsored Programs
If INDIDE application to FDA
Does my study need an INDIDE
Regulatory resources
Arrange a consultation with
CRIT
ConsultationTasks for investigators and study teams
Boston Childrenrsquos Hospital Clinical Research Map 5 Mouse over for additional info Bold = hyperlink
Respond to IRB questionsrequests
for clarification
1st Stage Protocol development contrsquod
Departmental Scientific Review
Organize DSMB design DSMP
DSMPDSMB
Templates for Research Study
Documents and Tools
Study Templates and Tools
Investigators who sponsor an FDA regulated trial
ClinicalTrialsgov
Create regulatory binder
Regulatory Binder Template
Submit the grant application to OSP
OSP
TIDO
CTBO
Consult Office Intellectual Property
Technology and Innovation
Development Office
TIDO
IRB approval
Consider blood volume for research
Research blood volume policy
Confidentiality plan
Confidentiality guidelines
Boston Childrenrsquos Hospital Clinical Research Map 6 Mouse over for additional info Bold = hyperlink
Develop Case Report Forms
(CRFs)
CRF guidelines
Establish electronic shared
folder or study binder for study
documents
CRIT
Set date for trial launch
Develop fast fact sheet for bedside staff
Consult programmer re database
CRIT
Research study resource manual
for the clinical unit
Confirm study drug
in pharmacy
Rocco Anzaldi
Clarify system for screening
and enrolling patients
Recruitment guideline
Updated protocol to
nurse manager
Consult MDsNPs on unitclinic
2nd Stage Implementation planning
Tasks for investigators and study teams
Study logistics Documentation logistics
Data storage
Confidentiality plan
Confidentiality guidelines
Create study orderset
Consider blood volume for research
Research blood volume policy
Create Manual of Operations
MOO Guide
Study implementation
meeting
Develop study logstools
EQUIP
Finalize tracking sheet
Research Administration
Fernando Valles
Boston Childrenrsquos Hospital Clinical Research Map 7 Mouse over for additional info Bold = hyperlink
3 Document informed consent
Informed Consent
Consent library
Schedule weekly study team meeting
Communicate to department faculty
and multidisciplinary
team announcing trial launch
Steps before trial launch
3rd stage Study launch
Patient flow
1 Seek permission
to approach potential subjects
2 Screenenroll
patients
EQUIP
5 Send Study
Tracking Sheet (STS)
6 Collection of
patient data and assessing for
adverse events
7 Study
documents and data handling
4 Datetime study tests
Create a checklist outlining study action items for each subject
Boston Childrenrsquos Hospital Clinical Research Map 8 Mouse over for additional info Bold = hyperlink
Annual IRB Report
Annual Progress ReportStaff Report
raquo Maintain Interest of Staff
raquo Important to See Study Progress
Write Abstract
Dissemination of Research Results
raquo Conference raquo Internal Presentation for Colleagues
raquo Publication
Plan DSMB MeetingInterim
Analysis
4th stage Statistical analysis reporting and dissemination
Data Entry
When Enrollment Complete Data
Cleaning
Monitor Subjects to Identify
Adverse Events (CCI sponsor
DSMB)
Report Adverse Events
Update MOO Based on Experience
with First Several Patients Enrolled
Weekly Study Team Meeting
Report study findings to
subjects and stakeholders
Data management Trial management
Reporting Dissemination
Regular Review of Data
to Identify Deviations
and Workflow Improvements
Consult Statistician When Approaching Target Enrollment
Discarded specimens Additional steps
Boston Childrenrsquos Hospital Clinical Research Map 9 Mouse over for additional info Bold = hyperlink
Send IRB Approval to lab manager
Maureen Samson
Educate staff in areasunits about sample collection
Locate the discarded samples
Locate the accession number in PowerChart
Retrieve specimen
Mark Kellogg
Follow Shipping Rules and Procedures
IATAShipping with dry ice instructions
Communicate with laboratory staff
Contact Dr Mark Kellogg to discuss specimen retrieval
Consult with Biorepository
Biorepository
Chart review Steps if you are completing a chart review
Boston Childrenrsquos Hospital Clinical Research Map 10 Mouse over for additional info Bold = hyperlink
7 8
4321
Databaserecord review guidelines
5 6
Consult programmer re database
CRC Request
Respond to IRB questions
requests for clarification
Departmental Scientific Review
Complete training
CITI Training
Draft a protocol
Protocol Guidelines
Prepare IRB Application
Information about the CCI
IRB Application
Develop Case Report Forms (CRFs)
CRF Guidelines
IRB Review
Boston Childrenrsquos Hospital Clinical Research Map 11 Mouse over for additional info Bold = hyperlink
Clinical Research Center (CRC) x84720
Committee on Clinical Investigation (CCI IRB) x57052
Research Pharmacist x52014
Clinical and Translational Science Unit (CTSU) x57541
Education and Quality Improvement Program (EQUIP) x57052
Clinical Trials Office Central Budgeting x4-2714
Office of Sponsored Programs x4-2723
Technology and Innovation Development Office 617-919-3079
Research Finance x8-3517
Harvard Catalyst 617-432-7810
Regulatory Affairs x4-2777
Appendix A Resources for researchers
RES_4446_ClinicalResearchMap-FINAL FOR LINKS 1
RES_4446_ClinicalResearchMap-FINAL FOR LINKS 10
Overview Four stages
1st Stage Protocol development
1st Stage Protocol development contrsquod
2nd Stage Implementation planning
3rd stage Study launch
4th stage Statistical analysis reporting and dissemination
Discarded specimens Additional steps
Chart reviewSteps if you are completing a chart review
Appendix A Resources for researchers
RES_4446_ClinicalResearchMap-FINAL FOR LINKS 11
RES_4446_ClinicalResearchMap-FINAL FOR LINKS 2
RES_4446_ClinicalResearchMap-FINAL FOR LINKS 3
RES_4446_ClinicalResearchMap-FINAL FOR LINKS 4
RES_4446_ClinicalResearchMap-FINAL FOR LINKS 5
RES_4446_ClinicalResearchMap-FINAL FOR LINKS 6
RES_4446_ClinicalResearchMap-FINAL FOR LINKS 7
RES_4446_ClinicalResearchMap-FINAL FOR LINKS 8
RES_4446_ClinicalResearchMap-FINAL FOR LINKS 9
RES_4446_ClinicalResearchMap-PAGE 5pdf
Overview Four stages
1st Stage Protocol development
1st Stage Protocol development contrsquod
2nd Stage Implementation planning
3rd stage Study launch
4th stage Statistical analysis reporting and dissemination
Discarded specimens Additional steps
Chart reviewSteps if you are completing a chart review
Appendix A Resources for researchers
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MOUSE OVER
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COVER BUTTON
Previous Page
Page 118
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Page 1
Button 91
Button 92
Button 94
IRB review
Button 102
Develop Case Report Forms
Button 136
Consult clinical research center
INDIDE 1
Explore resources
Button 1016
Bio Bank p
4
Consult statistician
Consult research pharmacist
Study personnel
Complete training
Consider grantsfunding
Draft a Protocal 2
Arrange a consutlations with CRIT
Next Page 1
Previous Page 1
TransLab
Start IRB application 3
Develop study logs
Updatedd protocol
Confirm study drug
Establish electronic shared
COnsult programmer
Clarify system
Research study resrouce manual
Develop case report forms
MOO
Set date for trial launch
Button 44
Study implementation meeting
Finalize tracking sheet
Data storage
Confidentiality
Blood volume 3
Develop fast fact
Consult MDs
Schedule weekly
Communicate early
Button 71
Screenenroll patients
Document informed consent
Datetime tests
Send study tracking sheets
Collection patient data
Button 77
Dissemination
Button 87
Button 124
Button 125
Communicate with lab staff
Button 106
Button 109
Button 1010
Shipping page 9
Button 1012
Button 99
Button 133
Button 134
Button 135
Biorepository
Locate assession number
Retrieve specimen
Button 30
Consult office
Negotiate Contract
Organizing DSMB
Submit Grant
Respond to IRB questions
Button 66
Create regulatory binder
Templates for research stufy
Clinical Trials Business Office
Blood volume 2
Confidentiality plan
Investigators who sponsor
clinicaltrials
gov
BPN Project
Drug Discovery amp Development Testing Funnel
Tier 1 2 3
Tier 6 7 8
Tier 5
Tier 4
Example Drug Discovery amp Development Testing Funnel
Cytotoxicity
Grant
Project
Example Drug Discovery amp Development Testing Funnel
TIER 1A ndash Primary Screen
Chemical purity and identity of active compounds
Primary bioactivity screen
Cell viability (When Appropriate)
ScaffoldsMoiety Chemical liabilities (for example Michael acceptor GSH reactive)
Calculated properties CLogP
PSA
Molecular Weight
rotatable bonds
H-bond donors and acceptors
permeability
pKa
Solubility
TIER 1B
Confirm EC50 determinations for actives compounds in primary screen with fresh
compounds from the original stock Confirm EC50 determinations for the lead (most
active) compound in primary screen with a new sample either repurchased purified
and characterized in-house or independently synthesized in-house
Compounds with IC50s (EC50s) less than X advance to Tier 2
TIER 2A ndash Activity Confirmation
Secondary screen
TIER 2B
Repeat EC50 determinations for actives in secondary screen with fresh
compounds from the original stock
Compounds with IC50s (EC50s) less than X advance to Tier 3
Example Drug Discovery amp Development Testing Funnel
TIER 3 ndash Drug-like Properties Specificity
IC50 selectivity in selectivity screen
CYP450 Inhibition competitive and time-dependent if structural alerts exist
(spot check illustrative examples from compound series)
Measured solubility
Measured protein binding (spot check illustrative examples from
compound series)
Test of Permeability in vitro permeability [indicate assay eg Caco2 orand
PAMPA] (spot check illustrative examples from compound series)
hERG
Cytoxicity assays
All compounds with no significant issues (Define Minimum Conditions for
Advancement) to advance to Tier 4
Example Drug Discovery amp Development Testing Funnel
TIER 4 ndash Scale-up Synthesis and Preliminary PK
Scale-up synthesis
Purity determination gt98 with no single impurity gt1
Rodent bioavailability and PK (define target delivery route) Tmax
Cmax
AUC
Bioavailibility
Vss CL T12 MRT
Brain to Plasma ratios
P-glycoprotein transport MDCK-MDR1 and MDCK-mdr1a
Plasma Protein Binding (species)
Microsomal Stability ndash rodent and human
Defineplan Patent Protection Strategy
All compounds with no significant issues (Define
Minimum Conditions for Advancement) advance
in parallel to Tiers 5AampB
Example Drug Discovery amp Development Testing Funnel
TIER 5A ndash In Vivo Bioactivity
Animal efficacy
Validate Biomarker
Target engagement
Advance to Tier 6 if (Define Minimum Conditions for advancement)
TIER 5B ndash Advanced Drug-like Properties
Microsomal stability in multiple
species
Chemical Stability
CYP450 induction
CYP reaction phenotyping
Metabolism ndash human
hepatocytesmicrosomes
Metab ID define major human rat dog and
non-human primates (NHP) metabolites
In vitro Tox Ames
Chromosome Aberration
CNS effects
Example Drug Discovery amp Development Testing Funnel
TIER 6 ndash Liability Assessment
Broad Pharmacological Profile and Toxicology
PK in second species
TIER 7
Non-GLP exposure studies single and multiple dose
Advance to late stage pre-clinical development (Define Minimum
Conditions for advancement)
Example Drug Discovery amp Development Testing Funnel
Principal InvestigatorProgram Director (Last First Middle)
enspenspenspenspensp
DETAILED BUDGET FOR INITIAL BUDGET PERIOD
DIRECT COSTS ONLY
FROM
THROUGH
enspenspenspenspensp
enspenspenspenspensp
PERSONNEL
DOLLAR AMOUNT REQUESTED (omit cents)
NAME
ROLE ONPROJECT
TYPEAPPT (months)
EFFORTONPROJ
INSTBASESALARY
SALARYREQUESTED
FRINGEBENEFITS
TOTAL
enspenspenspenspensp
PrincipalInvestigator
enspenspenspenspensp
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enspenspenspenspensp
SUBTOTALS
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enspenspenspenspensp
enspenspenspenspensp
CONSULTANT COSTS
enspenspenspenspensp
enspenspenspenspensp
EQUIPMENT (Itemize)
enspenspenspenspensp
enspenspenspenspensp
SUPPLIES (Itemize by category)
enspenspenspenspensp
enspenspenspenspensp
TRAVEL
enspenspenspenspensp
enspenspenspenspensp
PATIENT CARE COSTS
INPATIENT
enspenspenspenspensp
enspenspenspenspensp
OUTPATIENT
enspenspenspenspensp
enspenspenspenspensp
ALTERATIONS AND RENOVATIONS (Itemize by category)
enspenspenspenspensp
enspenspenspenspensp
OTHER EXPENSES (Itemize by category)
enspenspenspenspensp
enspenspenspenspensp
SUBTOTAL DIRECT COSTS FOR INITIAL BUDGET PERIOD
$
enspenspenspenspensp
CONSORTIUMCONTRACTUAL COSTS
DIRECT COSTS
enspenspenspenspensp
FACILITIES AND ADMINISTRATIVE COSTS
enspenspenspenspensp
TOTAL DIRECT COSTS FOR INITIAL BUDGET PERIOD
$
enspenspenspenspensp
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
Download a short guide to Acronyms and Terminology associated with Drug Discovery
ACRONYMSampTERMpdf
Download an Introductory Slide Deck on the Drug Discovery Process for Neuroscience
roadmapoverviewkleimanpdf
Download an Introductory slide deck on the Role of the Biology Team in a drug discovery program
drug discovery biologykleimanpdf
Below are listed databases and other resources that can help address questions about rationale distribution of target or its
relationship to other disease genes
RNA expression data sets
GEO- Gene Expression Omnibus data base of all published RNA expression data sets
httpwwwncbinlmnihgovgeo
Allen Brain Atlas- database of brain RNA expression data httpwwwbrain-maporg
Brain Span database-Brain RNA expression data including transcriptome and ISH for human brain
httpwwwbrainspanorg
Human genome resources at NCBI
httpwwwncbinlmnihgovgenomeguidehuman
OMIM- human genes and inherited disorders maintained by Johnrsquos Hopkins
Gene Database- database of genes and associated information
dbSNP- a database of SNP and other nucleotide variations
dbGaP- database of Genotypes and Phenotypes
NextBio Free Harvard enterprise account
Mine transcriptional profiling studies for changes in your target
Search connectivity map for compounds that modulate your target
Correlate human data to animal models and cell lines
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
Compare disease profiles across cohorts and stages of disease
wwwnextbiocom
iHOP--information Hyperlinked Over Proteins
A portal for searching literature by gene or gene Interactions httpwwwihop-netorgUniPubiHOP
Ingenuity Pathway Analysis
Available from research computing Find disease related literature for your target
httpwwwingenuitycomproductsipa
TISSUES database of Expression of targets (RNA and Protein)
TISSUES is a frequently updated web resource that integrates evidence on tissue expression from manually curated
literature proteomics and transcriptomics screens and automatic text mining They map all evidence to common
protein identifiers and Brenda Tissue Ontology terms and further unify it by assigning confidence scores that facilitate
comparison of the different types and sources of evidence Finally these scores are visualized on a schematic human
body to provide a convenient overview
httptissuesjensenlaborgSearch
Refrence Literature related to target identification and validation
Bunnage ME Gilbert AM Jones LH Hett EC Know your target know your molecule Nature chemical biology 2015
11(6)368-372 httpwwwncbinlmnihgovpubmed15718163
Grover MP Ballouz S Mohanasundaram KA George RA Sherman CD Crowley TM Wouters MA Identification of
novel therapeutics for complex diseases from genome-wide association data BMC medical genomics 2014 7 Suppl
1S8 httpwwwncbinlmnihgovpubmed25077696
Plenge RM Scolnick EM Altshuler D Validating therapeutic targets through human genetics Nature reviews Drug
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
main menu
Resources available at BCH Assay Development Screening Funnel development Chemical compound files Assistance
with identification of academic and industry partners for collaborative SAR campaigns
Identification of the correct molecule requires a clearly defined set of laboratory objectives and a well-designed screening
funnel to select the molecule that will meet those objectives Laboratory objectives for a molecule include specific criteria
for the mode of binding to target (eg agonist partial agonist inverse agonist non-competitive inhibitor) the potency
(eg Ki lt30nM) selectivity (eg gt30X selectivity over family member target XY and Z) brain penetration (yesno) dosing
paradigm ( eg oral once daily intravenous once monthly) and duration of expected treatment (eg sub-chronic daily
treatment for 2 weeks chronic treatment for years) Each of these laboratory objectives will have bearing on the design of
the screening funnel required to identify the molecule
The screening funnel requires a robust high-throughput (HTS) biochemical assay capable of testing gt100000 compounds
good sensitivity (Zrsquogt05) and an appropriate orthogonal assay (usually cell based) to confirm functional activity of the
compound at the target which can be used to weed out false positives and primary HTS artifacts Critical features defined
by the laboratory objectives may require additional in vitro absorption and metabolism data from compounds slated to
progress in vivo to ensure that structure activity relationships being developed will support expected dosing profiles and
target organ disposition A collection of critical off target assays to ensure required selectivity of the candidate drug must
be available to test molecules progressing from functional assays Compounds expected to be tested in vivo will require
pharmacokinetic studies to ensure target organ exposure in concentration ranges needed to support hypothesis testing
Link to sample Screening Funnels
httpswwwnimhnihgovresearchprioritiestherapeutics
The types of information needed to Characterize a Lead Compound are summarized here
Download an introductory slide deck on Medicinal Chemistry Structure Activity Relationship (SAR) campaign courtesy Dr
Johnny Bennett Merck
Childrens MedChem 29Jul2015pdf
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
Resources for assay development
The Assay Guidance Manual httpwwwncbinlmnihgovbooksNBK53196
This is a key resource for design and qualification of all types of biochemical and cell based assays It covers many
different modes of assay development and optimization as well as troubleshooting guides Do not run a screen
without consulting the manual first
The Assay Development Screening Facility (ADSF) at BCH Hourly access to equipment and technical assistance
consultations compound libraries- live cell medium throughput screening For more information contact Dr Lee Barrett
The ICCB at Longwood Project based access to equipment and expertise for design and execution of high-throughput
screens access to wide collection of chemical and genomic libraries For more information contact Dr Caroline Shamu
caroline_shamuhmsharvardedu
Website httpiccbmedharvardedu
Databases and references with information about activity and properties of small molecule compounds
PubChem provides information on the biological activities of small molecules PubChem is organized as three linked
databases within the NCBIs Entrez information retrieval system These are PubChem Substance PubChem Compound and
PubChem BioAssay Links from PubChems chemical structure records to other Entrez databases provide information on
biological properties These include links to PubMed scientific literature and NCBIs protein 3D structure resource Links to
PubChems bioassay database present the results of biological screening Links to depositor web sites provide further
information A PubChem FTP site Download Facility Power User Gateway(PUG) Standardization Service Score Matrix
Service Structure Clustering and Deposition Gateway are also available Home page is here
httpspubchemncbinlmnihgov
httpspubchemncbinlmnihgovsearch
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
DrugBank The DrugBank database is a unique bioinformatics and cheminformatics resource that combines detailed drug
(ie chemical pharmacological and pharmaceutical) data with comprehensive drug target (ie sequence structure and
pathway) information The database contains 7759 drug entries including 1602 FDA-approved small molecule drugs 161
FDA-approved biotech (proteinpeptide) drugs 89 nutraceuticals and over 6000 experimental drugs Additionally 4300
non-redundant protein (ie drug targetenzymetransportercarrier) sequences are linked to these drug entries Each
DrugCard entry contains more than 200 data fields with half of the information being devoted to drugchemical data and
the other half devoted to drug target or protein data Homepage is here httpwwwdrugbankca
Protein Data Bank archive Targets with protein crystal structures are more attractive targets for structure based drug design
Determine if your target has a known crystal structure by looking it up in the protein database- A Structural View of Biology
This resource is powered by the Protein Data Bank archive-information about the 3D shapes of proteins nucleic acids and
complex assemblies that helps students and researchers understand all aspects of biomedicine and agriculture from
protein synthesis to health and disease Homepage is here httpwwwrcsborgpdbhomehomedo
High Quality Chemical tools are required for testing biological hypothesis Find chemical tools that are fit for purpose by
virtue of target potency and selectivity needed to test hypothesis The dangers of using inadequate chemical tools are
detailed here httpwwwnaturecomnchembiojournalv11n8fullnchembio1867html To support the needs of the
biology community the industrial chemistry research community has joined a pre-competitive effort to provide
characterization data for high quality chemical probes That data is stored here httpwwwchemicalprobesorgprotein-
family
ChemNavigator The National Institutes of Health (NIH) has formed an agreement with ChemNavigator to provide the NIH
with a current and comprehensive database of commercially accessible drug discovery screening compounds to be
made available to all NIH researchers ChemNavigator is pleased to serve NIH affiliated scientific researchers in compound
sample procurement As an NIH researcher you have full access to use the iResearch System All you need to do is take a
few minutes to register in the system Then you will be able to perform chemical structure searches for compound samples
of interest and purchase these samples through this on-line system Link is here httpwwwchemnavigatorcomnihasp
Additional References related to biological activity of compounds
Edwards AM Bountra C Kerr DJ Willson TM Open access chemical and clinical probes to support drug discovery Nature
chemical biology 2009 5(7)436-440
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
Wang Y Suzek T Zhang J Wang J He S Cheng T Shoemaker BA Gindulyte A Bryant SH PubChem BioAssay 2014 update
Nucleic acids research 2014 42(Database issue)D1075-1082
Wang Y Bolton E Dracheva S Karapetyan K Shoemaker BA Suzek TO Wang J Xiao J Zhang J Bryant SH An overview of
the PubChem BioAssay resource Nucleic acids research 2010 38(Database issue)D255-266
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
main menu
Pharmacokinetic tutorial drug exposure measurement services pharmacokinetic data references
Selecting the correct dose to achieve exposure of drug that are adequate to test a hypothesis in preclinical species
requires that you know the potency of the molecule at the desired drug target and the dose of compound required to
achieve target organ exposure that will result in the free (not bound by protein) concentration of drug required to engage
the molecular target within the target organ compartment Estimates of Drug potency can be found in many of the
databases listed under correct molecule The free concentration of a drug is determined in the plasma by multiplying the
concentration of drug in the plasma by the fraction unbound This must be measured for each compound A literature
reference that provides the measured plasma protein binding (PPB) values for many common drugs is provided here
Zhang Xue Shao and Jia (2012) Compilation of 222 drugsrsquo plasma protein binding data and guidance for study designs
Drug Discovery Today Vol 17 Issue 9-10 Pages 476-485 httpwwwncbinlmnihgovpubmed22210121
If your drug target is the brain then you must also understand the kinetics of drug disposition and clearance including blood
brain barrier (BBB) penetration in your test species to select a dose of compound adequate to test your hypothesis
Download a tutorial deck on basic principles of drug disposition and their application in small molecule drug discovery
courtesy of Dr Chris Shaffer Pfizer
150805DMPKTutorial(CLSBCHCourse)pdf
Pharmacometrics Research Core and Pharmacokinetics Service The Pharmacometrics Research Core is directed by Dr Luis
Pereira and provides analytical services for assaying drugsmetabolites in biological matrices (eg plasma serum blood
urine CSF saliva tissues) The Core provides pharmacokinetic and pharmacodynamic analyses for current and future
clinical trials and research projects (including contract services) It conducts stability and potency studies for pediatric
formulations compounded at BCH as per recent demand from FDA and CMS Finally the Core fosters grant applications
and research collaborations both intra and extramural The TNC can additionally provide investigators with consultation in
the identification of resources for pharmacodynamic assay development and contract research organizations able to
provide bioanalysis of preclinical samples needed to support animal clinical trials Contact Dr Luis Pereira for more
information LuisPereirachildrensharvardedu
article on importance of understanding drug exposure in preclinical drug studies here
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
References on Pharmacokinetics and Brain Penetration of Small Molecules
Di L Rong H Feng B Demystifying brain penetration in central nervous system drug discovery Miniperspective Journal of
medicinal chemistry 2013 56(1)2-12
Reichel A Addressing central nervous system (CNS) penetration in drug discovery basics and implications of the evolving
new concept Chemistry amp biodiversity 2009 6(11)2030-2049
Smith DA Di L Kerns EH The effect of plasma protein binding on in vivo efficacy misconceptions in drug discovery Nature
reviews Drug discovery 2010 9(12)929-939
Moda TL Torres LG Carrara AE Andricopulo AD PKDB database for pharmacokinetic properties and predictive in silico
ADME models Bioinformatics 2008 24(19)2270-2271
Law V Knox C Djoumbou Y Jewison T Guo AC Liu Y Maciejewski A Arndt D Wilson M Neveu V et al DrugBank 40
shedding new light on drug metabolism Nucleic acids research 2014 42(Database issue)D1091-1097
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
main menu
Formulations advice and assistance with preclinical drug delivery Neurodevelopmental Behavioral Core
To effectively deliver drug to preclinical species for the duration of a study researchers must choose a dose a formulation
and a route of administration that will support target organ exposure long enough to test a therapeutic hypothesis Since
most drugs developed for humans are optimized for human metabolism parameters many compounds developed for
humans are rapidly metabolized and cleared in rodents requiring alternative formulations and routes of preclinical
administration (see tutorial under Correct Dose)
Proper formulation of drugs and vehicles to ensure appropriate drug exposure is a critical factor in preclinical study design
The Neurodevelopmental Behavioral Core may provide advice on standard formulations Preclinical assistance and
training across many routes of administration including IV cannulation osmotic minipumps oral gavage sc and ip is also
available through the Neurodevelopmental Behavioral Core
Contact is Dr Nick Andrews NickAndrewschildrensharvardedu
Custom formulation used for human studies are supported on a case by case basis by the Pharmacometrics Research Core
or Clinical Research Pharmacy Contact for the Pharmacometrics Core is Dr Luis Pereira LuisPereirachildrensharvardedu
The Clinical Research Pharmacy can provide advice on unusual formulations Contact is Dr Rocco Anzaldi
RoccoAnzaldichildrensharvardedu
idspharmacy-dlchildrensharvardedu
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
main menu
Stratification Biomarker development and resources patient sample repositories requests for collection of new types of
patient samples development of patient specific iPSC lines and neurons Genetic databases RNA expression databases
Humans are diverse Not only do patients come in different sizes ages genders and ethnic backgrounds but the same
disease diagnosis often develops in people as a function of different environmental insults and genetic predispositions
Finding biomarkers that will segregate similarly diagnosed patients into subsets of biologically more homogenous
populations is a critical feature of good clinical trial design A lsquostratification biomarkerrsquo can be a biochemical measure from
patient samples a structural or a functional feature of a human imaging technology or a functional measure of an
electrophysiological readout
The Translational Neuroscience Center can help investigators access advice and assistance for investigators with vendors
experienced in profiling DNA RNA or protein across a range of platforms httpwwwchildrenshospitalorgresearch-and-
Neurophysiology Services can assist investigators with identification of biomarkers to stratify patients based on EEG
signatures Contact Drs Charles Nelson and Jurriaan Peters Co-Directors
CharlesNelsonchildrensharvardedu
JurriaanPeterschildrensharvardedu
MRIRadiology Imaging Core can assist with identification of biomarkers to stratify patients by functional or structural deficits
in brain circuitry Contact Dr Simon Warfield Director SimonWarfieldchildrensharvardedu
Molecular Genetics core can assist investigators with identification of genetic stratification biomarkers or gene expression-
based stratification biomarkers Contact Drs Louis Kunkel and Christopher Walsh Co-Directors
LouisKunkelchildrensharvardedu
ChristopherWalshchildrensharvardedu
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
The Human Neuron Differentiation Service within the Translational Neuroscience Center can help investigators recruit
specific subtypes of patients to be consented for reprogramming of blood or fibroblast cells into iPSC lines that will support
differentiation into human neurons for phenotypic analysis and screening ContactDr Robin Kleiman
RobinKleimanchildrensharvardedu
Translab can assist with routine processes as well as complex laboratory-‐developed tests They place special emphasis on
assay development for use in clinical trials Translab website with contact information can be viewed here
httpwwwtranslabbostonorg
TransLab Flyer 2 2015pdf
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
main menu
Patient sample repositoryBiobank Patient registry
Disease processes are dynamic The molecular underpinnings of disease differ between inception progression and
response of the body to disease Thus each stage of disease may require alternative therapeutic strategies Understanding
which stage of disease is best suited to testing a specific therapeutic approach will require information about disease from
patient samples collected at different stages of disease well as an ability to collect and recruit patients at relevant stages of
disease
To locate human RNA profiling data in the public domain from disease samples and tissues at specific stages of disease
search databases referenced in the Correct Target section of this document
The Translational Neuroscience Center offers multiple services that can assist with identification of the correct patients The
Core Repository for Neurological Disorders stores a wide variety of patient samples from many stages of disease The
biorepository is directed by Dr Mustafa Sahin and these samples and de-identified clinical data can be searched and
requested through the Translational Neuroscience Center
The Biobank Core Lab serves as a core resource that ensures top-level specimen handling and services to the Boston
Childrens Hospital research community It serves as both a service core and a biorepository providing an institutional
perspective on the presence of specimens that may be available for use to foster collaborations and accelerate research
and discovery
The Clinical Research and Regulatory Affairs Service can provide assistance to investigators in identifying patients andor
repository samplesdata Contact Co-Directors Stephanie Brewster and Kira Dies for more information about access to
these resources
StephanieBrewsterchildrensharvardedu
KiraDieschildrensharvardedu
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
main menu
Statistical support clinical trialsgov
Determining the correct sample size to support preclinical and clinical studies requires power calculations that take into
account the variability of the endpoint being measured Statistical support for preclinical studies is available on a
department by department basis Neurology and Neurobiology requests for preclinical biostatistics support can be made
through the CRC website
httpredcap-qiredcap_edcsurveyss=Rma5u83qKC
Clinical statistical support for all departments is also available through the CRC Design and Analysis Core For more
information contact Michael Monuteaux michaelmonuteauxchildrensharvardedu
Clinical datasets that provide data for supporting power calculations can be found by searching through clinical trialsgov
database All studies in the clinical trials data base are required to describe the study design the endpoints under
evaluation and the treatments as well as links to publications of the studies The studies can be searched by topic This can
be a good way to find historical data to help you evaluate variability of endpoint measures in clinical populations This will
be needed to support sample size power calculations httpsclinicaltrialsgov
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
main menu
Understanding RDoC Human Neurobehavioral Core Service IRB assistance with clinical protocols
Different stages of clinical trials have different goals for selecting endpoints Early stage clinical trials are typically in search
of a translatable pharmacodynamic or target engagement endpoint to ensure that the molecule in question will be
competent to test a clinical hypothesis in humans Developing translatable measures of target engagement in preclinical
species and humans is critical to developing data sets that will enable subsequent therapeutic efficacy trials The earliest
trials require endpoints that can be measured in a functionally equivalent manner across species Therefore it is critical for
preclinical researchers to develop dose-responsive data sets in preclinical species using quantitative endpoints such as EEG
visual or auditory evoked potentials PET ligands plasma or CSF based biochemical measures or translatable task based
behaviors Preclinical data must be a developed with an eye towards what the equivalent measure will be in the clinic
Toward that end the NIMH has initiated the Research Domain Criteria (RDoC) that is aimed at characterizing mental health
disorders across many different dimensions across species A big focus of the RDoC initiative is the identification of
translatable endpoints for evaluating pharmacodynamics and efficacy in Neuroscience Drug Discovery Preclinical
Neuroscience researchers should be familiar with the RDoC framework For advice on in vivo characterization of preclinical
endpoints with translational potential for Neuroscience related disorders contact Dr Robin Kleiman at the TNC
robinkleimanchildrensharvardedu
The Human Neurobehavioral Core Service of the Translational Neuroscience Center can provide guidance to investigators
on the appropriate tests that will provide the best translation from animal studies to human studies The Service also offers
human neurobehavioral assessment services Contact-Drs Charles Nelson and Deborah Waber Co-Directors
CharlesNelsonchildrensharvardedu
DeborahWaberchildrensharvardedu
Developing clinical protocols and obtaining IRB approval for human study of translatable endpoints can be supported by
the Translational Neuroscience Center Clinical Research and Regulatory Affairs Service Contact-Kira Dies and Stephanie
Brewster Co-Directors
KiraDieschildrensharvardedu
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
StephanieBrewsterchildrensharvardedu
Background Information on RDoC httpswwwnimhnihgovresearch-prioritiesrdocindexshtml
Casey BJ Oliveri ME Insel T A neurodevelopmental perspective on the research domain criteria (RDoC) framework
Cuthbert BN Insel TR Toward the future of psychiatric diagnosis the seven pillars of RDoC BMC Med 2013 11126
httpwwwncbinlmnihgovpmcarticlesPMC3653747
Insel T Cuthbert B Garvey M Heinssen R Pine DS Quinn K Sanislow C Wang P Research domain criteria (RDoC)
toward a new classification framework for research on mental disorders The American journal of psychiatry 2010
167(7)748-751 httpwwwncbinlmnihgovpubmed20595427
Insel TR The NIMH Research Domain Criteria (RDoC) Project precision medicine for psychiatry The American journal
of psychiatry 2014 171(4)395-397 httpwwwncbinlmnihgovpubmed24687194
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
main menu
Body atlases for expression of mRNA and protein guides to chemical alerts guidance for preclinical toxicology studies for
Investigational New Drug (IND) applications
Discovery scientists must consider the distribution of the proposed drug target across the entire body in human samples in
order to understand potential safety risks to be monitored during preclinical toxicological testing Teams also have to be
aware of differences in distribution of the target and related family members in preclinical species Many of the target
expression databases listed in the Correct Target section of this document are useful in this regard Assays that can be used
to monitor any potential safety risks are critical to the development of a suitable testing funnel needed to advance
compounds
Many chemical classes of compounds that are identified in screens are not suitable for drug development due to the
presence of structural alerts that are known to cause chemical toxicity Databases that house information of structural alerts
can be used to de-prioritize structural series early in the life of a program Some toxicology databases that can help
deprioritize toxic chemotypes include httppubsacsorgdoiabs101021ci300245q
Some web resources for identifying side effects of known compounds httpintsideirbbarcelonaorg
Once a potential clinical candidate molecule is identified GLP-qualified toxicology studies must be carried out with a
qualified vendor to support regulatory filings of an Investigational New Drug (IND) application For a short tutorial on studies
needed to support preclinical toxicology testing and guidance on evaluating contract research organizations that are
qualified to perform this work see attached tutorial courtesy of Dr Joe Brady Pfizer
Brady boston childrens hosp talk aug2015 IND toxpdf
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
main menu
FAQs
Industry partners and collaborators can bring tremendous expertise and complementary resources to bear on research
projects with therapeutic applications These may include medicinal chemistry expertise pharmacology expertise access
to unique and undisclosed chemical probe molecules assay development and high-throughput screening resources
antibody and other reagent development pharmacokinetic analysis pharmacokinetic and pharmacodynamics
modeling formulation expertise post-doctoral training programs and in some cases financial support There is a wide range
of models of interacting with industry in a range of different capacities Some frequently asked questions about types of
relationships and the responsibilities associated with those interactions can be found in the following document
Download Frequently Asked Questions about working with Industry
Translation of basic research into new marketed drugs will require a transition from exploring scientific principles and testing
hypotheses into commercial products Industry partners capable of developing these potential products need to be able
to license the intellectual property required to sell the product in order to justify investment in building programs around new
ideas This requires that scientific researchers protect and patent potential inventions from their work to enable future
commercialization by partners with appropriate expertise To ensure that researchers are appropriately documenting their
work in a manner that will support preservation of intellectual property all investigators are encouraged to consult with TIDO
before any public disclosures of new research Similarly the following documentation provides guidance for documenting
your work according to standards that will support patent applications
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
Download the compliance manual for BCH for Intellectual property policy
cm_021_intellectual_propertydocx
Download a summary of laboratory notebook Dorsquos and Donrsquot
Dosdontsnotebookspdf
Link to TIDO Technology Innovation and Development Office
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
main menu
A phenotypic screen requires a biologically robust assay that represents a significant aspect of disease-relevant human
biology It can be used to identify molecular targets for target validation studies through the use of well-annotated
bioactive molecules or genomic libraries (eg RNAi CRISPER) Alternatively phenotypic screens can be used to identify
novel compounds that must subsequently be lsquoDE convolutedrsquo to identify novel targets using lsquowarheadsrsquo These screens rely
on identification and manipulation of a functional deficit or phenotype using a patient-derived cellular system
The strengths of this approach
Use of human systems can improve translatability
Identified compounds may empirically balance therapeutic activity at multiple required targets
Well-suited to drug repurposing
Phenotypic screens can be used to identify compounds or targets for mechanism based drug discovery programs
Many CNS drugs have been discovered using a phenotypic repurposing screen (Swinney and Anthony 2011)
Drawbacks to this approach
Assays are slow low throughput and more expensive as compared to cell-free assays
Cell-based assays may not predict circuit level or brain phenotypes
Furthermore as a primary screening approach
Precludes leveraging strengths in uHTS SBDD and parallel design
Every molecule must be de-risked independently thus safety can be very hard to predict
Drug Repurposing Drug Repurposing is a strategic pillar of the National Center for Advancing Translational Science (NCATS)
Details on resources and funding opportunities can be found here httpsncatsnihgovntu
Chemogenomic Files from industry partners Many companies have well designed and annotated chemical files that are
designed to cover the druggable genome with small molecule compounds from their proprietary collections Each
company has different criteria and stipulations associated with use of the library It is advisable to consult with TIDO
regarding terms and conditions associated with individual companies
ICCB-LongwoodKirby ADSF The ICCB screening center and the Kirby ADSF have multiple collections of compounds that
include bioactive or FDA approved molecules available for screening
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
Kirby ADSF libraries contact Dr Lee Barrett LeeBarrettchildrensharvardedu
References related to phenotypic screens and Drug Repurposing
Vincent F Loria P Pregel M Stanton R Kitching L Nocka K Doyonnas R Steppan C Gilbert A Schroeter T
and MC Peakman Developing predictive assays The phenotypic screening ldquorule of 3rdquo Sci Transl Med 7 293ps15
(2015)
Langedijk J Mantel-Teeuwisse AK Slijkerman DS Schutjens MH Drug repositioning and repurposing terminology and
definitions in literature Drug Discov Today (2015)
Swinney DC and J Anthony How were new medicines discovered Nature Reviews Drug Discovery 10 507-
519 (July 2011) | doi101038nrd3480
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
main menu
TNC Clinical Research and Regulatory Affairs Service Research Participant Registry CRC
Glossary of Terms
Glossary-of-Clinical-Trials-Termspdf
Clinical Research and Regulatory Affairs Service This Translational Neuroscience Center service facilitates the mission of the
Translational Neuroscience Center providing coordination among studies communications resource development and
implementation of new or ongoing preclinical and clinical studies The service is led by experts in protocol development
and launching of new studies The directors are available to guide TNC researchers in designing human studies including
the preparation of Institutional Review Board (IRB) and FDA submissions Additionally staff of the Clinical Research and
Regulatory Affairs Service will help researchers with recruitment plans budget development supervision of study
coordinators study monitoring and audit preparation For more information contact Co-Directors Kira Dies ScM CGC and
Stephanie Brewster MS CGC
KiraDieschildrensharvardedu
StephanieBrewsterchildrensharvardedu
Clinical Research Center (CRC) Assists investigators at BCH with research project initiation and implementation resources
in the CTSU for the conduct of clinical research visits and ancillary services education on research methods and practices
The CRC has biostatisticians project managers research specialists clinical trials specialists research coordinators and
highly skilled nurses and nurse project managers who work every day to facilitate the many research needs of the BCH
community httpwwwchildrenshospitalorgresearch-and-innovationresearchclinicalclinical-research-center
Clinical and Translational Study Unit (CTSU) The CTSU provides clinical research infrastructure for investigators in the design
initiation conduct and reporting of clinical research with the goal of translating scientific knowledge into new therapies for
pediatric conditions httpweb2tchharvardeductsu
Clinical Research Roadmap This clinical research map is designed to serve as a guide for investigators study coordinators
and research nurses at Boston Childrenrsquos Hospital The research map outlines the key steps in preparing to launch a
research study and provides embedded links to institutional resources tools and documents
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
Clinical Research Mappdf
main menu
Office of Sponsored Programs Research Administration TIDO
Many government and foundation grant opportunities are available for developing Drug Discovery Projects updated lists of
funding options exist on OSP and Research Administration web sites
Some good options for finding relevant requests for proposals
Translational Research Program annual call for proposals
Boston Childrenrsquos Hospital ndash Broad Institute Collaboration Grants Proposals will be reviewed by a joint Childrenrsquos Hospitalndash
Broad Institute committee Additional submission dates are expected for 2016
BCH_Broad collaborative grant 852015docx
Kirby Neurobiology Screening Pilot awards- available to Kirby Neurobiology PIs as funding is available
Translational Neuroscience Center- Pilot awards supported by trust sponsored donations as available Distributed through
TNC e-mail lists
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
ADDF The ADDF Academic Drug Discovery and Development Program seeks to create and support innovative translational
research programs for Alzheimerrsquos disease related dementias and cognitive aging in academic medical centers and
universities Biomarker development studies and innovative proof of concept pilot clinical trials of new approaches to
treatment prevention and early detection are also supported
Department of Defense ALSRP The FY15 Defense Appropriations Act provides $75 million (M) to the Department of Defense
Amyotrophic Lateral Sclerosis Research Program (ALSRP) to support innovative high-impact Amyotrophic Lateral Sclerosis
research As directed by the Office of the Assistant Secretary of Defense for Health Affairs the Defense Health Agency
Research Development and Acquisition (DHA RDA) Directorate manages and executes the Defense Health Program
(DHP) Research Development Test and Evaluation (RDTampE) appropriation The executing agent for the anticipated
Program AnnouncementsFunding Opportunities is the Congressionally Directed Medical Research Programs (CDMRP)
httpcdmrparmymilpubspress201515alsrppreannshtml
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
Michael J Fox Foundation Therapeutic Pipeline Program Supports Parkinsons disease therapeutic development along the
pre-clinical and clinical path (both drug and non-pharmacological therapeutics including gene therapy biological
surgical and non-invasive approaches) The Michael J Fox Foundation seeks applications with potential for fundamentally
altering disease course andor significantly improving treatment of symptoms above and beyond current standards of care
Proposals must have a well-defined plan for moving toward clinical utility for patients The Therapeutic Pipeline Program is
open to industry and academic investigators proposing novel approaches or repositioning approved or clinically safe
therapies from non-PD indications httpswwwmichaeljfoxorgresearchgrant-detailphpid=28
NINDS The Blueprint Neurotherapeutics Network (BPN) Provides the neuroscience community access to a complete and
seamless pipeline for preclinical drug development beginning with chemical optimization and concluding after phase I
clinical trials Participants in the BPN will receive funding to conduct bioactivity and efficacy testing in their own laboratories
as well as access to millions of dollars in NIH-contracted drug development services including medicinal chemistry
pharmacology toxicology and phase 1 clinical trials NIH will also provide drug development consultants who have had
years of experience working at a senior level in industry Because the Blueprint is establishing a network of drug
development service providers that typically cater to biopharmaceutical companies neuroscientists who join the BPN can
readily plug in to all of the drug development expertise that typically resides in industry The projects supported through the
network will be highly collaborative and the researchers who initiate the projects will serve as the principal investigators
(PIs) directing their projects through the development pipeline with the help of industry consultants The PIs and their
institutions will have the opportunity to attain assignment of intellectual property rights from all other network participants
who may have intellectual input into their projects This will allow the PIs to retain control of the intellectual property for drug
candidates developed through the network and eventually pursue licensing and commercialization partnerships
httpneuroscienceblueprintnihgovbpdrugs
NeuroNEXT Will establish a consortium of clinical sites capable of forming disease-specific cadres of investigators in order to
develop and implement trials rapidly in a wide range of neurological disorders that affect adults andor children With a
stable and experienced research staff a central IRB model and master trial agreements NeuroNEXT will streamline the
administrative processes for clinical trials and reduce start-up times NeuroNEXT will also be able to design and implement
evidence-based measures to improve patient recruitment into clinical trials httpswwwneuronextorgresearchers
NIMH Many grant options see overview here httpwwwnimhnihgovresearch-prioritiestherapeuticsindexshtml
Building on High Impact Basic Neurobiology Through Assay Development Advancing Tools for Therapeutic Discovery (R01) -
See more at httpgrantsnihgovgrantsguidepa-filesPAR-15-066htmlsthashs1HMWjWudpuf
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
NCATS many grant options see overview here httpwwwncatsnihgovprograms
Bridging Interventional Development Gaps (BrIDGs) Program Makes available on a competitive basis certain critical
resources needed for the development of new therapeutic agents for both common and rare diseases Investigators do not
receive grant funds through this program Instead successful applicants receive access to NIH experts and contractors who
conduct pre-clinical studies at no cost to the investigator In general synthesis formulation pharmacokinetic and
toxicology services in support of investigator-held IND applications to the Food and Drug Administration (FDA) are available
httpwwwncatsnihgovbridgsworksolicitation
NCATS Discovering New Therapeutic Uses for Existing Molecules (New Therapeutic Uses) A collaborative program designed
to develop partnerships between pharmaceutical companies and the biomedical research community to advance
therapeutics development This innovative program matches researchers with a selection of pharmaceutical industry
assets to test ideas for new therapeutic uses with the ultimate goal of identifying promising new treatments for patients
httpwwwncatsnihgovntu
Pfizer Centers for Therapeutic Innovation (CTI) Suitable for biotherapeutic or small molecule projects with a strong project
rationale (demonstrated association between target biology pathway and disease mechanism) CTIrsquos areas of interest
include inflammation autoimmunity tissue remodeling oncology cancer immunology rare or genetic diseases
cardiovascular and metabolic diseases and neuroscience Selected projects are undertaken by a joint team with BCH
members and Pfizer CTI drug development experts located on the 18th floor of CLS working towards agreed common
goals The Pfizer CTIBCH collaboration program is managed by a Joint Steering Committee with representation from both
Boston Childrenrsquos and CTI httpswwwpfizercticom Calls for proposals come through TIDO three times a year in January
May and September httpwwwchildrensinnovationsorgPagesHighlightsHighlights-83aspx
Shire-BCH Collaborative Program Development The Joint Steering Committee of the Shire Alliance extends a call for ldquoPre-
Proposalsrdquo with defined objectives from time to time generally annually in the late fall or winter That call is publicized
through emails from BCH Research Administration and TIDO Following review by the JSC a full proposal may be requested
Unsolicited proposals may also be considered from time to time
ACRONYMS
HTS- High-throughput Screen run with 96 well 384 well 1536 wells or 3456 well capacity- screen has capacity to run through a library of 1-3Million compounds in total
uHTS- Ultra High-throughput Screen ndash arbitrary cut off to denote capability to measure 100s of thousands of assays per day with automation and high density plate readers
HCS- High Content Screen usually a cell based assay that is able to monitor multiple endpoints reflective of different cellular processes in a single well of cells treated with a compound May be biochemical or image based endpoints
SAR- Structure-Activity Relationship ie relationship of modifications to chemical structure on relevant activity SPR-Structure-Property Relationship ie relationship of modifications of chemical structure on physicochemical
properties
PK- Pharmacokinetic measure of drug levels in a body compartment
PD- Pharmacodynamic a measure of functional activity of a drug
PKPD- PharmacoKinetic PharmacoDynamic relationship- how drug levels relate to drug response in a system
DDI-Drug-Drug Interactions- occurs when one drug affects the activity of another drug when co- administered Often due to changes in ADME properties of one of the co-administered drugs (ie for example induction by one drug of enzymes that will metabolize the second drug )
DMPK- Drug Metabolism and PharmacoKinetics
ADME- Absorption Distribution Metabolism amp Excretion
PDM-pharmacokinetics dynamics and metabolism GLP- Good Laboratory Practice- regulations that govern toxicology studies required by the FDA to support IND
and NDA
POM- Proof of Mechanism clinical studies to demonstrate hit the target and elicited a biological response
POC- Proof of Concept Clinical studies to demonstrate a clinically meaningful outcome measure improved
PoP-Proof of Principal usually preclinical studies that demonstrate that engaging target in a disease model produced efficacy
FIH- First in Human clinical trial to evaluate new molecule in humans for safety and PK- Ph1
FIP-First in Patient first clinical trial to evaluate new molecule in patients hERG (the human Ether-agrave-go-go-Related Gene) is a gene KCNH2 that codes for a subunit of Kv111 and
contributes to the repolarizing current in the heart that coordinates the hearts beating When compromised by application drugs or by rare mutations in some families it can result in a potentially fatal disorder called long QT syndrome A number of clinically successful drugs in the market have had the tendency to inhibit hERG and create a concomitant risk of sudden death as a side-effect which has made hERG inhibition an important anti-target that must be avoided during drug development
IND-Investigational New Drug Application- formal application to FDA to evaluate a NCE in people
NME- New Molecular Entity- a new FDA approved drug
NCE-New Chemical Entity-an investigational drug that is not yet a FDA approved NME NDA- New Drug Application (A lsquoFilingrsquo)- a formal application for approval of a new drug
CAN-(Pfizer-specific shorthand )-Clinical Candidate- a molecule competent to be tested in humans IB- Investigators Brochure- basic information on an investigational drug and its mechanism for clinicans involved
in conducting a clinical trial Provides background information on the hypothesis being tested and the types of patients that should be included excluded and risks and how the drug should be administered It must be updated continually by the sponsor to include all new findings
SOC- Standard of Care- in our context it is the drug treatment that a clinican should prescribe for a particular type of patient used as a benchmark for comparing new entities
MTD- Maximum Tolerated Dose- first identified in GLP safety studies during preclinical development AE- Adverse Event- a side effect that causes safety concerns
TI- Therapeutic Index -ratio of the concentration of drug needed to produce efficacy and the concentration of drug that is safely tolerated ( also called ldquoSafety Marginrdquo)
Questions Contact Robin Kleiman- email RobinKleimanchildrensharvardedu office CLS 13070
Terms that relate to Targets Molecular target- the protein that binds drug to produce efficacy Off-Target- other proteins that bind the drug that do not relate to efficacy and may produce Adverse Events (AEs) Druggable target ndashcomes from a class of proteins that has successfully been targeted with small molecule drugs in
the past Primarily transporters enzymes receptors ion channels (Not protein-protein interactions transcription factors RNA binding proteins etc)
Druggable genome- about 3000 genes encoding all druggable proteins Druggability- the presence of protein folds (quarternary structures) that favor specific interactions with drug-like
molecules Exploratory target- Hypothesis that a modulating a target via a particular mode of action will be beneficial to a
particular patient population Validated target- Hypothesis regarding a target also has in vivo efficacy data for a disease or a disease model- along
with a complete understanding of how the target mechanism relates to disease- (also called lsquoProof of Principlersquo) Phenotypic screen- a screen for compounds that will reverse a phenotype the molecular target may not be known Systems pharmacology target(s)-a precisely defined combination or lsquofingerprintrsquo of molecular targets to be
modulated to correct a phenotype (Poly-pharmacology)
Terms that relate to programs
Biomarker- a physiological pathological or anatomical characteristic that is measured by an automated process or algorithm as an indicator of the normal biological process pathological process or biological response to a therapeutic intervention Many types of Biomarkers target engagement biomarkers stratification biomarkers efficacy biomarkers pharmacodynamic biomarkers etchellip
Laboratory Objectives-Criteria established at the start of the program to define the desired pharmacological properties of the molecule with regard to potency selectivity mode of action frequency and route of administration For antibodies would include minimal criteria for knock down stability etc
Therapeutic Modality- small molecule biologic RNAi stem cell etc
Screening tree Screening funnel- A decision tree for utilizing a panel of assays to identify molecules that meet the laboratory objectives
Terms that relate to molecules
Drug-like molecule- has physicochemical properties in line with known oral medications The molecule will be largely rule of 5 (RO5) compliant therefore small and moderately lipophilic Not related to pharmacological activity
Rule of Five (RO5)=Chris Lipinskirsquos rule of 5 states that a drug like molecule will have the following properties Molecular Weight of less than 500 a clogP lt5 fewer than 5 H-bond donors and the number of H-bond acceptors ( which is the sum of N and O atoms) is less than 10
Physicochemical properties- key properties of molecules include (calculated)Molecular Weight number of H bond acceptors and donors (measured) kinetic solubility pKa lipophilicity (logD logP)
Chemical tool -a compound with good potency and selectivity for a specified molecular target but fails to meet all criteria for safety PK or potency needed to become a clinical candidate Suitable for preclinical testing of hypothesis and proof of principal studies but not for lsquopreclinical developmentrsquo
Active molecule describes an individual chemical entity with measurable dose-dependent activity in a biological screening assay
Hit molecule refers to a molecule plus its related structural analogs for which there is an understanding of the structure-properties and structure-activity relationships (SPR and SAR) for a specific biological context Additionally preliminary drug disposition data (both in vitro and in vivo) provide an assessment of pharmacokinetic properties The available data provide a basis for further optimization of the hit series
Lead molecule refers to a molecule plus its related structural analogs that demonstrate o Sufficient exposure at pharmacologically relevant doses by the intended route of administration to explore
intended pharmacology in a relevant in vivo disease or pharmacodynamic model o Proof-of-principle or efficacy in a in vivo model that will be used to establish a margin of safety
Clinical candidate an optimized individual chemical entity derived from a lead series that demonstrates o a dose-response relationship via intended route and schedule of administration in relevant disease model o an exposure-based margin of safety in toxicology studies o In summary a clinical candidate is a molecule that is deemed competent for testing the primary disease
intervention hypothesis in humans
A laboratory notebook is a vital record of events leading to a patentable invention Therecorded information can establish dates of conception and reduction to practice of atechnology as well as the inventorship of a patent claiming the technology Below arefourteen rules you should follow when keeping lab notebooks
1 mdash Do use bound booksInventors should use permanently bound notebooks eg notebooks with spiral or glue bindings If loose-leaf sheets are used they should be consecutively numbered and eachpage should be dated signed and witnessed
2 mdash Do sign and date Each notebook should be signed and dated on the inside front cover to indicate the firstday the recipient started using the notebook Each entry should be dated and signed orinitialed
An independent witness ie someone who understands the technology but will not benamed as a co-inventor of the invention should sign and date each entry after the state-ment ldquoRead and understood by rdquo (The witness should preferably sign theentries on a contemporaneous or fairly contemporaneous basis but entries can also bereviewed signed and dated on a periodic eg weekly or monthly basis)
3 mdash Do use inkNotebook entries should be made in ink and in chronological order Entries should not beerased or ldquowhited outrdquo If an entry contains an error a line should be drawn through theerror and new text should continue in the next available space
4 mdash Donrsquot leave blank spacesBlank gaps between entries should be avoided If a blank space is left on a page a line orcross should be drawn through the blank space and the page dated to prevent subsequententries
5 mdash Donrsquot modifyPrior entries should not be modified at a later date If data were omitted the new datacan be entered under a new date and cross-referenced to the previous entry Record exper-iments when they are performed
6 mdash Do use past tenseUse the past tense (eg ldquowas heatedrdquo) to describe the experiments that were actually performed
Fish amp Richardson pc
Dorsquos and Don rsquo ts forKeeping Lab Notebooks
Boston
Dallas
Delaware
New York
San Diego
Silicon Valley
Twin Cities
Washington dc
FR
7 mdash Do explain abbreviations and special termsExplain all abbreviations and terms that are nonstandard Explain in context in a table ofabbreviations or in a glossary
8 mdash Do staple attachmentsAttachments such as graphs or computer printouts should be permanently attached to pagesin the notebook (eg by stapling) and both the attachment and the notebook page signedand dated If the attachment cannot be stapled it should be placed in an envelope and theenvelope stapled to the notebook page The envelope and page should then be signed andwitnessed making reference to the attachment being placed in the envelope
9 mdash Donrsquot remove originalsNo original pages should be removed from the notebook
10 mdash Do outline new experimentsWhen a new project or experiment is started the objective and rationale should be brieflyoutlined (eg in a short paragraph or by providing a flowchart)
11 mdash Do record lab meeting discussionsRelevant discussions from lab meetings should be recorded as should ideas or suggestionsmade by others The names of the people making the ideas and suggestions should be care-fully documented This information may be important in establishing inventorship
12 mdash Do provide detailRecord test descriptions including preferred operating conditions control conditionsoperable and preferred ranges of conditions and alternate specific materials Also recordtest results and an explanation of the results as well as photos or sketches of the resultsandor the test device Any conclusions should be short and supported by the factual dataOpinions or speculation about the invention should be avoided
13 mdash Do track notebooksIdeally each lab should maintain a catalog of notebooks in which each notebook is assigneda number and the name of the author of each notebook is recorded In addition the datethe author received the notebook as well as the date the notebook was completed andreturned should be recorded Upon leaving the lab the author should return all notebookschecked out by or to him
14 mdash Do save completed notebooksAll completed notebooks should be indexed (eg by number by author andor by subjectarea) and kept safely in a central repository together with corresponding patent applica-tions or patents Lab notebooks that relate to inventions on which patents have been grant-ed should be kept for the life of the patent plus six years
By J Peter Fasse
Fish amp Richardson pcIntellectual property complex litigation technology law800 818-5070wwwfrcominfofrcom
P ER SP EC T I V E
PHARMACOK INET I CS
Data gaps limit the translational potentialof preclinical researchRobin J Kleiman1 and Michael D Ehlers2
The absence of mouse pharmacokinetic reference data hinders translation An analysis ofrecent literature highlights a systematic lack of discussion regarding rationale for the selec-tion of dosing paradigms in preclinical studies and in particular for neuroscience studies inwhich the lack of brain penetration can limit target-organ exposure We propose solutionsto improve study design
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Despite widespread use of pharmacologicalagents in mouse models of human diseasethe literature lacks comprehensive pharmaco-kinetic profiles for such studies Coupled witha paucity of suitable data are shortcomingsin the training of experimental biologists inthe application of pharmacometric principlesto experimental study design Many authorssimply cite previously published studies tosupport the selection of a particular dose evenwhen the cited paper lacks drug exposuredata There is an assumption on the part ofresearchers that if a referenced study demon-strates a biological effectmdashthat is any measur-able physiological or behavioral effectmdashin arodent at a given dose then that same dosewill also effectively perturb disease-relevantmechanistic biology in a different study Thedanger occurs when the observed therapeuticeffects are not linked to drug-induced mecha-nistic alterations at the level of the target organLack of a drug exposurendashresponse relationshipin a target organ casts doubt on mechanisticinterpretations In addition any changes inthe route of drug administration vehicle prep-aration species used (rat versus mouse versusprimate) age or strain of animal transgenicmodification time points under investigationduration of dosing or organ targeted for inter-vention (for example brain versus a periph-eral tumor) can alter the relation between doseexposure and measured response In suchcases assumptions regarding the mechanisticbasis for observed therapeutic effects may nothold true
Preclinical pharmacological experimentsthat do not measure drug concentrations in
1Translational Neuroscience Center Kirby NeurobiologyCenter Department of Neurology Boston ChildrenrsquosHospital Harvard Medical School Boston MA 02115USA 2Neuroscience amp Pain Research Unit BioTherapeu-tics Worldwide Research and Development Pfizer IncCambridge MA 02139 USACorresponding author E-mail robinkleimanchildrensharvardedu (RJK) michaelehlerspfizercom (MDE)
the target organ run the risk of producing ex-posures that are too low or too high to inter-pret a mechanistic hypothesis Most drugs arenot selective over a large exposure range for asingle molecular target Confident evaluationof a therapeutic hypothesis requires an under-standing of the drugrsquos penetration and kineticswithin the target tissue as well as its potencyand selectivity for specific molecular targetsFurther investigators must consider the con-centration of the unbound fraction of drugthat is available to interact with the targetPublished reports often overlook the fact thatmany small molecules are more than 90bound to plasma or tissue proteins whichgreatly decreases the fraction of drug availableto bind to the intended target Thus in casesin which drug binding has a slow off-rate anorganismrsquos total drug exposure is not a predic-tor of drug available to interact with its target(1) The failure of some academic scientists toobtain relevant pharmacokinetic data impairsthe interpretation of preclinical research resultsand likely contributes to the acknowledgeddifficulties in replicating some academic liter-ature as reported by industry scientists (2 3)
Drug discovery teams in industry settingsroutinely collect pharmacokinetic data to aidin the mechanistic interpretation of in vivopreclinical data and to project optimal dosingparadigms for efficacy and toxicology studiesData required to evaluate brain penetrationare not typically collected by industry-baseddrug-discovery teams for compounds origi-nally developed for therapeutic indicationsthat do not obviously implicate the centralnervous system making this information es-pecially hard to find for many otherwise well-described drugs In addition because mousedata are not required for preclinical toxicologystudies (the more common small animal spe-cies for preclinical toxicology being rats)industry scientists do not often obtain pharma-cokinetic data from mouse experiments These
wwwScienceTranslationalMedicineo
issues are especially relevant for older drugsthat are potentially suitable for repurposingMany older drugs were discovered and char-acterized before routine pharmacokinetic-pharmacodynamic (PK-PD) modeling ofpreclinical drug exposure and its applicationto predicting human dosing became standardpractice Last pharmacokinetic data are notconsidered innovative and these studies gen-erally do not achieve publication in peer-reviewed journals even when the data havebeen generated When such data are pub-lished it is often relegated to the unsearchableblack hole of supplementary materials Thusmouse neuroPK profiles are not readily avail-able for many drugs that are frequently usedin conjunction with mouse models of humanbrain disorders
DOCUMENTING DOSING STRATEGIES
To evaluate the potential impact of insufficientpharmacokinetic data on dose selection in asample of recent published neuroscience liter-ature we conducted an analysis of papersidentified by means of a PubMed search usingthe search terms ldquodrugrdquo and ldquobrainrdquo for the pub-lication year 2014 from eight journals (Table 1)This list was culled to include only primaryresearch reports that included systemic adminis-tration of a pharmacological agent a pharma-cological therapeutic or a biological therapeuticas part of the study design The search yielded100 articles published between 1 January and30 December 2014 that used systemic drug de-livery with the intended goal of targeting thebrain of rodents (table S1) Each publicationwas examined for the stated rationale behindthe dose selection of study drugs (Table 1)
The reported rationale for dosing strategiesfell into several broad categories including(from lowest confidence to highest) (i) dose se-lected rationale not discussed (ii) literaturecitations of another study in which reportsranged from citation of exposure in the samespecies exposure in a different strain or spe-cies a dose conversion from the human liter-ature to rodent or reports of effects on rodentbehavior in another study (iii) demonstrationof an effect on rodent behavior or function inthe current study (iv) demonstration of adose-responsive biological effect in the currentstudy (v) measurement of drug levels in bloodor plasma in the current study and (vi) mea-surement of drug levels in the target organ(that is the brain) in the current study In onlytwo instances were publications identifiedthat considered the impact of drug binding
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to plasma or brain proteins on the free expo-sure of drug available to interact with the tar-get This is a critical flaw in most publishedstudies that use small molecules for functionaleffects in the brain because many centralnervous system (CNS) drugs that penetratethe blood-brain barrier exhibit high proteinbinding leaving a small fraction of the totaldrug measured in plasma or brain unbound
and free to interact with the molecular targetFurthermore most studies used evidence of abiological activity to justify dose selection with-out consideration for how exposure of theagent relates to the potency of the compoundat known molecular targets which would berequired to test a mechanistic hypothesis
The lack of pharmacokinetic considera-tion does not imply that every study used an
wwwScienceTranslationalMedicineo
inappropriate dose of drug to test their hypoth-esis It does illustrate that a clear rationale wasnot provided for dose selection in most pub-lications Furthermore all 11 of the 100 publi-cations that measured total brain exposureincluded an author from the pharmaceutical in-dustry (n=5) an academic drug screening group(n = 3) or a pharmacologyndashpharmaceuticalsciences department (n = 3) This observationlikely reflects the limited presence of pharma-cology and pharmacometrics departmentswithinmost academic institutions and limitedaccess to the mass spectrometry and otheranalytical resources needed to measure druglevels in study samples Outsourcing the bio-analysis of samples collected from study ani-mals is feasible but the use of contract researchorganizations to support such studies is oftentoo costly for most academic grant budgets toaccommodate
DATABASES AND REPURPOSINGRecent years have seen increasing efforts toinvestigate approved or clinically tested drugsfor new indications (4ndash8) Such repurposinghas been touted as a means to accelerate ther-apeutic development (4) For example a stra-tegic pillar of the US National Institutes ofHealthrsquos (NIHrsquos) translational roadmap callsfor the academic community to actively par-ticipate in the repurposing of drugs approvedby the US Food and Drug Administration(FDA) or investigational drugs that havepassed safety hurdles but failed in clinicaltrials because of lack of efficacy (9ndash11) To havea meaningful impact in neurological and psy-chiatric disorders such drug repurposingefforts will require access to neuropharma-cokinetic (neuroPK) data sets in mice to guidethe testing of new therapeutic hypotheses ingenetically engineered disease models A re-cently published consensus evaluation of drugrepositioning opportunities for Alzheimerrsquosdisease identified 15 potential drug candidatesThese were further prioritized for testing onthe basis of available evidence to produce ashortlist of seven compounds reviewed by in-dustry experts to provide insight into the via-bility of these candidates The most commonshortcoming identified for the compoundsconsidered were issues related to insufficientbrain penetration or the lack of informationabout optimal dosing strategies (11)
The repurposing of statins illustrateshow the neuroPK knowledge gap limits progressStatins were developed as 3-hydroxy-3-methylglutarylndashcoenzyme A (HMG-CoA) reduc-tase inhibitors to lower cholesterol and reduce
Table 1 Preclinical dosing strategies The rationale for drug-dosing strategies was extractedfrom the literature through the analysis of 100 peer-reviewed studies published in2014 from eight journals that cover research on mechanisms of brain function disease andtherapeutic approaches to CNS disorders (Cell Neuron Nature Nature Neuroscience NatureMedicine Neurobiology of Disease Neuropsychopharmacology and Science TranslationalMedicine) (table S1) Forty-four of the 100 publications selected were studies of potentialtherapeutic approaches to disease whereas the remaining were studies of basic neurobiology ormechanisms of disease Each publication was examined to discern how authors selected thedosage of pharmacological tools or therapeutic compounds used in the design of studies toprobe brain function A relatively small number of studies considered what the concentrationof drug available in the brain after administration would be in the context of theirexperimental studies The most common method for selecting a dose of drug was tocite a previous study that demonstrated a biological effect of the drug on someaspect of rodent behavior
Rationale for studyrsquos drug-dose selection
Therapeutic
studies
Number of papers from the100 published studies
analyzed
bull No exposure or rationale for dose selection provided
5
22
bull Rodent dose extrapolated from human studies
0
1
bull Doses are similar to what was used previously toproduce a biological effect
8
23
bull Literature reports cited for multiple functionaleffects of drug at selected dose
4
5
bull Brain penetration evaluated but exposure notmeasured
2
2
bull Literature report of mismatched drug exposure
0
1
bull Observation of a biological effect at a single dosein current study
3
6
bull Observation of dose-responsive biological effectin current study
5
16
bull Brain exposure to drug was measured with routeof administration that differed from the oneused in the efficacy study
1
1
bull Plasma drug concentrations measured literaturereport of brain exposure cited and target-organpharmacodynamic effect observed in the currentstudy
1
1
bull Plasma drug concentrations measured
4
7
bull Brain pharmacodynamic effect of drug observed
2
4
bull Brain drug concentrations measured (totalconcentration)
6
7
bull Unbound brain drug concentrations measured
1
2
bull Brain drug concentrations measured and brainpharmacodynamic effect of drug observed
2
2
Total
44
100
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risk of cardiovascular disease (12) FDA hasapproved at least nine different statins andmost are commonly prescribed nearly one-third of Americans ages 55 to 64 took a pre-scription cholesterol-lowering drug between2009 and 2012 (wwwcdcgovnchsdatahushus14pdf) The widespread availability andsafety profile of statins has lured researchersinto evaluating their potential for repurpos-ing (13) Statins have been profiled extensive-ly in preclinical research to test for potentialtherapeutic benefit in Alzheimerrsquos disease(14ndash19) Fragile X syndrome (20) Rett syn-drome (21 22) epilepsy (23) Huntingtonrsquos dis-ease (24) Parkinsonrsquos disease (25 26) stroke(27) and brain injury (28 29)
A search of the literature reveals no sys-tematic neuroPK studies in any mouse strainthat would enable direct comparisons of CNSexposure across the various statins In silicopredictions based on the drugsrsquo molecularproperties suggest that the nine most widelyprescribed statins each have a different poten-tial to penetrate the blood-brain barrier differ-ent potencies against the HMG-CoA reductaseenzyme and different ldquooff-targetrdquo activity pro-files (30) On the basis of available data thereis reason to believe that simvastatin has thebest overall profile for inhibiting HMG-CoAreductase in the brain (30) A recent study re-ported that lovastatin is able to reverse a rangeof phenotypes in a mouse model of Fragile Xsyndrome (20) However the design of an op-timal clinical trial will require the collection ofmouse pharmacokinetic data to understandhow much CNS drug exposure is required toproduce efficacy in the disease model Thereare at least two possible scenarios Giventhat simvastatin is more potent at inhibitingHMG-CoA reductase than are other statinsand likely to be more brain penetrant inboth mice and humans one would expectthat simvastatin will be more potent than lo-vastatin in ameliorating symptoms in bothmice and humans if the observed efficacy stemsfrom inhibition of HMG-CoA reductase activ-ity in the brain by lovastatin The advantage ofthis outcome would be that better brain pen-etration and potency would lead to a loweroverall dose requirement to achieve efficacyand thus likely a better safety profile
A second scenario could be that lovastatin ismore potent than simvastatin in the mousemodel of Fragile X syndrome because of anadditional biological activity inherent to thelovastatinmolecule whichmaynot yet be doc-umented in the literature In either case un-derstanding the CNS exposure of lovastatin
required to produce efficacy in themouse willdetermine whether there is a safe therapeuticindex for achieving the required concentra-tion in patients Previous attempts to discernuseful neuroPK parameters from the litera-ture for the use of statins in rodent modelshave highlighted the lack of critical data asthe looming roadblock to progress in the field(31 32) Until these data exist the transla-tional potential of preclinical research maybe limited And this is but one example ofone drug class
The creation of a centralized database isneeded for the entire translational researchcommunity and would establish a new mech-anism for academia funding agencies founda-tions and industry to pool resources If studiesare donewell the first time and documented inan open-access resource it will reduce redun-dant efforts and improve the quality of decisionmaking by scientists considering innovativesolutions to our biggest health problems
FILL THE GAPSManuscript submission practices for severalhigh-impact journals now include require-ments that authors include detailed informa-tion regarding study design and statisticalanalysis with each submission A reasonableextension of this checklist should includethe stated rationale for doses selected for studydrugs Information should include a discus-sion of data highlighted in Table 2 Authorsshould be expected to reference a relevant
wwwScienceTranslationalMedicineo
data set from a high-quality database or pub-lication or provide the data in the current study(Table 3)
Industry biologists learn basic principlesof medicinal chemistry pharmacokineticsand drug disposition while working on drugdiscovery project teams Academic groupsare playing an increasing role in transla-tional therapeutics and in particular drugrepurposing Academic programs need toaugment training in pharmacokinetics andpharmacodynamics so as to increase the rigor ofpreclinical work and to ensure that investigator-initiated clinical studies are testing hypotheseseffectively Institutions without a departmentof pharmacology or pharmacometrics mightlack the organizational knowledge needed toconduct drug studies and must identify re-sources or collaborators to patch these defi-cits Formal coursework and Web-basedresources and tutorials are needed to train andsupport translational researchers Manuscriptand grant reviewers need to demand higherstandards for preclinical studies with respect toreporting on drug exposure associated withbiological effects Ethics committees responsi-ble for review of animal protocols should re-quire investigators to provide rationale fordose selections in proposed studies Similarlyscientific review boards at academic medicalcenters need to include clinical pharmacologistswho are able to review investigator-initiatedclinical studies to ensure that proposed dosingstrategies will test a meaningful hypothesis
Table 2 Recommendations for use of pharmacokinetic data The first column includes a listof recommended data sets to aid reviewers of submitted articles in the interpretation ofpreclinical findings The second column includes a list of useful reference data that wouldsupport improved preclinical study design in mice if available in a public database
Literature reports that evaluate studydrugs should include
Compound-specific data that shouldbe included in a rodent
pharmacokinetic database
bull Expected or measured plasma exposure of thestudy drug in the preclinical species during thestudy
bull Elimination half-life (T12)bull Systemic clearance (CL)bull Fraction of drug that is protein bound (fb)
bull Expected or measured target organ exposureof the study drugs in the preclinical speciesduring the study
Maximum plasma concentration after drug admin-istration (Cmax) and time to reach maximum plas-ma concentration (Tmax) for a standardized doseand route of administration
bull Expected or measured free fraction (unboundby protein) of the study drugs in the targetorgan of the preclinical species during thestudy
bull The ratio of drug in brain to that in plasma (BP)bull The ratio of drug found free in brain (Cub) to thatfound free in the plasma (Cup) defined as CubCupbull Any potential impact of drug transporters (foundon the rodent blood-brain barrier) in limiting brainexposure
bull Expected or measured potency of the studydrug against the hypothesized activity in vitro
Expected ormeasured potency of molecule at knownbiological targets
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P ER SP EC T I V E
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A central repository that contains brainpenetration protein binding and pharmaco-kinetic profiles of drugs and pharmacologicaltools in rodents is needed to effectively sup-port translational research This databaseshould also provide basic tutorials that de-fine primary pharmacokinetic parameterswith examples to illustrate how data are usedto predict optimal dosing strategies The min-imum data set needed for each compoundin a useful rodent database is highlighted inTable 2 Access to this information and sup-porting materials will have an immediateimpact on the quality of translational drug re-purposing efforts across brain disorders andwill support the development of new thera-peutic approaches to neurological disordersand mental illness Existing databases man-aged by NIH or precompetitive consortia couldbe reinforced with donated pharmacokineticdata sets and tutorials
Industry and government scientists shouldwork precompetitively to collect and curatepharmacokinetic data sets in conjunction withsupporting educational materials Mouse phar-macokinetic data exist inside pharmaceuti-cal companies for a wide range of publicallydisclosed molecules and literature standardsRelease of these data into a public databasewould provide several benefits to companiesincluding (i) increased scientific rigor in theliterature with a higher probability of repro-ducibility (ii) increased appreciation by theacademic biology community for the diffi-culty inherent in generating molecules withpotency and pharmacokinetic profiles suit-able for in vivo work opening the door forin-kind collaboration with academic groups
and (iii) direct comparison of data collectedin-house to that collected at other compa-nies or institutions to enable better internalquality control Comprehensive pharmaco-kinetic data sets will benefit all therapeuticareas regardless of whether the brain is thetarget organ because peripheral and cen-tral exposure data can be generated fromthe same experiments Moreover the prin-ciples described above for the CNS apply toother target tissues in which vascular bar-riers metabolic processes or active transportalter the distribution of systemically admin-istered drugs
Key to ensuring that preclinical mousestudies test the hypotheses they aim to eval-uate is an understanding of the unboundfraction of drug present in the target organat an appropriate time point under studyGrant and journal reviewers need to care-fully consider whether authors of propos-als and manuscripts are providing adequaterationale for their choices of preclinical dos-ing paradigms Importantly the collectionand centralization of rodent pharmacoki-netic datasets will promote efficient genera-tion of future data reduce the collection ofredundant data and improve the return oninvestment for research funds that are de-voted to preclinical studies aimed towardclinical translation
SUPPLEMENTARY MATERIALS
wwwsciencetranslationalmedicineorgcgicontentfull8320320ps1DC1Table S1 One hundred publications that used systemic drugdelivery with the goal of targeting rodent brains
wwwScienceTranslationalMedicineo
REFERENCES AND NOTES1 A Reichel Addressing central nervous system (CNS) penetra-
tion in drug discovery Basics and implications of the evolv-ing new concept Chem Biodivers 6 2030ndash2049 (2009)
2 F Prinz T Schlange K Asadullah Believe it or not Howmuch can we rely on published data on potential drugtargets Nat Rev Drug Discov 10 712 (2011)
3 C G Begley L M Ellis Drug development Raisestandards for preclinical cancer research Nature 483531ndash533 (2012)
4 P Nair Second act Drug repurposing gets a boost asacademic researchers join the search for novel uses ofexisting drugs Proc Natl Acad Sci USA 110 2430ndash2432(2013)
5 T I Oprea J Mestres Drug repurposing Far beyond newtargets for old drugs AAPS J 14 759ndash763 (2012)
6 S M Strittmatter Overcoming drug development bot-tlenecks with repurposing Old drugs learn new tricksNat Med 20 590ndash591 (2014)
7 K Xu T R Coteacute Database identifies FDA-approved drugswith potential to be repurposed for treatment of orphandiseases Brief Bioinform 12 341ndash345 (2011)
8 X Bosch European researchers drug companies joinforces against rare diseases JAMA 294 2014ndash2015 (2005)
9 F S Collins Mining for therapeutic gold Nat Rev DrugDiscov 10 397 (2011)
10 P Vallance P Williams C Dollery The future is much closercollaboration between the pharmaceutical industry andacademic medical centers Clin Pharmacol Ther 87525ndash527 (2010)
11 A Corbett J Pickett A Burns J Corcoran S B DunnettP Edison J J Hagan C Holmes E Jones C KatonaI Kearns P Kehoe A Mudher A Passmore N ShepherdF Walsh C Ballard Drug repositioning for Alzheimerrsquosdisease Nat Rev Drug Discov 11 833ndash846 (2012)
12 J L Goldstein M S Brown A century of cholesterol andcoronaries From plaques to genes to statins Cell 161161ndash172 (2015)
13 A M Malfitano G Marasco M C Proto C Laezza P GazzerroM Bifulco Statins in neurological disorders An overviewand update Pharmacol Res 88 74ndash83 (2014)
14 T Kurata K Miyazaki M Kozuki N Morimoto Y OhtaY Ikeda K Abe Progressive neurovascular disturbances inthe cerebral cortex of Alzheimerrsquos disease-model miceProtection by atorvastatin and pitavastatin Neuroscience197 358ndash368 (2011)
15 H Kurinami N Sato M Shinohara D Takeuchi S TakedaM Shimamura T Ogihara R Morishita Prevention ofamyloid beta-induced memory impairment by fluvastatinassociated with the decrease in amyloid beta accumulationand oxidative stress in amyloid beta injection mousemodel Int J Mol Med 21 531ndash537 (2008)
16 M Shinohara N Sato H Kurinami D Takeuchi S TakedaM Shimamura T Yamashita Y Uchiyama H RakugiR Morishita Reduction of brain beta-amyloid (Abeta)by fluvastatin a hydroxymethylglutaryl-CoA reductaseinhibitor through increase in degradation of amyloidprecursor protein C-terminal fragments (APP-CTFs) andAbeta clearance J Biol Chem 285 22091ndash22102 (2010)
17 G J Siegel N B Chauhan D L Feinstein G Li E B LarsonJ C Breitner T J Montine Statin therapy is associated withreduced neuropathologic changes of Alzheimer diseaseNeurology 71 383 author reply 383 (2008)
18 X-K Tong C Lecrux P Rosa-Neto E Hamel Age-dependentrescue by simvastatin of Alzheimerrsquos disease cerebrovascularand memory deficits J Neurosci 32 4705ndash4715 (2012)
19 X K Tong N Nicolakakis P Fernandes B Ongali J BrouilletteR Quirion E Hamel Simvastatin improves cerebrovascularfunction and counters soluble amyloid-beta inflammationand oxidative stress in aged APP mice Neurobiol Dis35 406ndash414 (2009)
Table 3 Recommendations to improve translation through the use of preclinicalpharmacokinetic data
Journalsbull Require authors to provide explicit rationale for dosing strategies usedbull Rationale should include consideration of the unbound drug exposure in target organas best practices
Educationbull Include basic pharmacology and pharmacokinetic principles in formal coursework requiredfor basic preclinical and clinical research scientists
bull Develop tutorials and on-line calculators for rodent dose projections to support appropriateuse of published pharmacological tools
Databasesbull Reinforce public chemical databases with mouse pharmacokinetic data that includes brainexposure
Precompetitive consortiabull Create precompetitive consortia to solicit mouse pharmacokinetic data sets from industry andfoundation partners for database expansion
bull Targeted data collection for compounds already in the public domain
rg 6 January 2016 Vol 8 Issue 320 320ps1 4
P ER SP EC T I V E
20 E K Osterweil S C Chuang A A Chubykin M SidorovR Bianchi R K Wong M F Bear Lovastatin corrects ex-cess protein synthesis and prevents epileptogenesis in amouse model of fragile X syndrome Neuron 77 243ndash250(2013)
21 C M Buchovecky S D Turley H M Brown S M KyleJ G McDonald B Liu A A Pieper W Huang D M KatzD W Russell J Shendure M J Justice A suppressorscreen in Mecp2 mutant mice implicates cholesterol me-tabolism in Rett syndrome Nat Genet 45 1013ndash1020(2013)
22 M J Justice C M Buchovecky S M Kyle A Djukic A rolefor metabolism in Rett syndrome pathogenesis Newclinical findings and potential treatment targets RareDis 1 e27265 (2013)
23 F Scicchitano A Constanti R Citraro G De Sarro E RussoStatins and epilepsy Preclinical studies clinical trials andstatin-anticonvulsant drug interactions Curr Drug Targets16 747ndash756 (2015)
24 M L Ferlazzo L Sonzogni A Granzotto L Bodgi O LartinC Devic G Vogin S Pereira N Foray Mutations of theHuntingtonrsquos disease protein impact on the ATM-dependentsignaling and repair pathways of the radiation-inducedDNA double-strand breaks Corrective effect of statins andbisphosphonates Mol Neurobiol 49 1200ndash1211 (2014)
25 E K Tan L C Tan Holding on to statins in Parkinsondisease Neurology 81 406ndash407 (2013)
26 B Friedman A Lahad Y Dresner S Vinker Long-termstatin use and the risk of Parkinsonrsquos disease Am J ManagCare 19 626ndash632 (2013)
27 M S Elkind Stroke A step closer to statin therapy forstroke Nat Rev Neurol 9 242ndash244 (2013)
28 E E Abrahamson M D Ikonomovic C E Dixon S T DeKoskySimvastatin therapy prevents brain trauma-inducedincreases in beta-amyloid peptide levels Ann Neurol66 407ndash414 (2009)
29 E F Wible D T Laskowitz Statins in traumatic brain injuryNeurotherapeutics 7 62ndash73 (2010)
wwwScienceTranslationalMedicineo
30 S Sierra M C Ramos P Molina C Esteo J A VaacutezquezJ S Burgos Statins as neuroprotectants A comparativein vitro study of lipophilicity blood-brain-barrier penetra-tion lowering of brain cholesterol and decrease of neuroncell death J Alzheimers Dis 23 307ndash318 (2011)
31 W G Wood G P Eckert U Igbavboa W E Muumlller Statinsand neuroprotection A prescription to move the fieldforward Ann N Y Acad Sci 1199 69ndash76 (2010)
32 W G Wood W E Muumlller G P Eckert Statins and neuro-protection Basic pharmacology needed Mol Neurobiol50 214ndash220 (2014)
101126scitranslmedaac9888
Citation R J Kleiman M D Ehlers Data gaps limit thetranslational potential of preclinical research Sci Transl Med8 320ps1 (2016)
D
rg 6 January 2016 Vol 8 Issue 320 320ps1 5
on January 6 2016httpstm
sciencemagorg
ownloaded from
101126scitranslmedaac9888] (320) 320ps1 [doi8Science Translational Medicine
Robin J Kleiman and Michael D Ehlers (January 6 2016) Data gaps limit the translational potential of preclinical research
Editors Summary
This information is current as of January 6 2016 The following resources related to this article are available online at httpstmsciencemagorg
Article Tools
httpstmsciencemagorgcontent8320320ps1article tools Visit the online version of this article to access the personalization and
s sitesScienceThe editors suggest related resources on
PermissionshttpwwwsciencemagorgaboutpermissionsdtlObtain information about reproducing this article
is a registered trademark of AAASMedicineScience TranslationalAssociation for the Advancement of Science all rights reserved The title
Science 1200 New York Avenue NW Washington DC 20005 Copyright 2016 by the Americanweekly except the last week in December by the American Association for the Advancement of
(print ISSN 1946-6234 online ISSN 1946-6242) is publishedScience Translational Medicine
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Dow
nloaded from
Boston Childrenrsquos Hospital ndash Broad Institute Collaboration Grants
Background Meeting the challenges of biomedicine requires bringing together creative scientists exceptional technological resources and world-class expertise across many disciplines that rarely exist within a single institution This guiding principle is the basis for a funding opportunity to support Boston Childrenrsquos Hospital investigators performing research in collaboration with Broad scientists
Goals The fundamental goal of this new award is to spark new collaborations between Boston Childrenrsquos Hospital and the Broad Institute The grants will be awarded to address a very wide range of scientific questions but are specifically designated for projects with the following characteristics
middot Projects where engagement with the Broad would benefit Childrenrsquos Hospital investigators projects that can uniquely benefit from being done at the Broad Institute
middot Projects that create new scientific collaborations and bring together diverse scientific backgrounds projects that spark new scientific directions or technologies and are not currently being pursued at Childrenrsquos Hospital
middot Projects that pilot new approaches that researchers at Childrenrsquos the Broad and the greater scientific community can benefit from in the future the purpose of these awards is not to provide gap or extension funding of existing projects but to initiate new projects
Eligibility Individuals with Principal Investigator status at Boston Childrenrsquos Hospital are eligible Applicants need not be Associate Members of the Broad Institute
Broad Platforms and Scientists Broadrsquos Platforms (Genomics Imaging Metabolite Profiling Proteomics Genomic Perturbation and the Broad Technology Labs) are collaborative organizations that provide scientific leadership and cutting edge technologies in support of project goals Collaborations can also be established with other groups at the Broad including the Klarman Cell Observatory the Stanley Center for Psychiatric Research or the Center for the Development of Therapeutics
Budgets Grants will provide $60000 direct support for 1 year plus philanthropic overhead It is expected that most grants will fund work performed at the Broad Institute either through interaction with Broadrsquos Platforms or via collaboration with a Broad scientist however the work may also occur at Boston Childrenrsquos if it is important to meet the scientific goals of the collaboration
Deadline and Review process Final proposals are due by September 1 2015 Funding decisions are expected to be reached by October 1 2015 Proposals will be reviewed by a joint Childrenrsquos HospitalndashBroad Institute committee Additional submission dates are expected for 2016
Submission Applicants are strongly encouraged to discuss potential applications in advance with the office of the Chief Scientific Officer at the Broad Questions should be directed to Alex Burgin ( 617-714-7124)
Proteomics Genomic Perturbation and the Broad Technology Labs) are collaborative
organizations that provide scientific leadership and cutting edge technologie
s in support of
project goals Collaborations can also be established with other groups at the Broad including
the Klarman Cell Observatory the Stanley Center for Psychiatric Research or the Center for the
Development of Therapeutics
Budgets
Grants wi
ll provide $60000 direct support for 1 year plus philanthropic overhead It
is expected that most grants will fund work performed at the Broad Institute either through
interaction with Broadrsquos Platforms or via collaboration with a Broad scientist howev
er the
work may also occur at Boston Childrenrsquos if it is important to meet the scientific goals of the
collaboration
Deadline and Review process
Final proposals are due by September 1 2015 Funding
decisions are expected to be reached by October 1 201
5 Proposals will be reviewed by a joint
Childrenrsquos Hospital
ndash
Broad Institute committee Additional submission dates are expected for
2016
Submission
Applicants are
strongly encouraged to discuss potential applications in
advance
with the office of the Chief Sc
ientific Officer at the Broad
Questions should be
directed to Alex Burgin (
aburginbroadinstituteorg
617
-
714
-
7124
)
Boston Childrenrsquos Hospital ndash Broad Institute Collaboration Grants
Background Meeting the challenges of biomedicine requires bringing together creative
scientists exceptional technological resources and world-class expertise across many
disciplines that rarely exist within a single institution This guiding principle is the basis for a
funding opportunity to support Boston Childrenrsquos Hospital investigators performing research
in collaboration with Broad scientists
Goals The fundamental goal of this new award is to spark new collaborations between Boston
Childrenrsquos Hospital and the Broad Institute The grants will be awarded to address a very wide
range of scientific questions but are specifically designated for projects with the following
characteristics
Projects where engagement with the Broad would benefit Childrenrsquos Hospital
investigators projects that can uniquely benefit from being done at the Broad Institute
Projects that create new scientific collaborations and bring together diverse scientific
backgrounds projects that spark new scientific directions or technologies and are not
currently being pursued at Childrenrsquos Hospital
Projects that pilot new approaches that researchers at Childrenrsquos the Broad and the
greater scientific community can benefit from in the future the purpose of these awards
is not to provide gap or extension funding of existing projects but to initiate new
projects
Eligibility Individuals with Principal Investigator status at Boston Childrenrsquos Hospital are
eligible Applicants need not be Associate Members of the Broad Institute
Broad Platforms and Scientists Broadrsquos Platforms (Genomics Imaging Metabolite Profiling
Proteomics Genomic Perturbation and the Broad Technology Labs) are collaborative
organizations that provide scientific leadership and cutting edge technologies in support of
project goals Collaborations can also be established with other groups at the Broad including
the Klarman Cell Observatory the Stanley Center for Psychiatric Research or the Center for the
Development of Therapeutics
Budgets Grants will provide $60000 direct support for 1 year plus philanthropic overhead It
is expected that most grants will fund work performed at the Broad Institute either through
interaction with Broadrsquos Platforms or via collaboration with a Broad scientist however the
work may also occur at Boston Childrenrsquos if it is important to meet the scientific goals of the
collaboration
Deadline and Review process Final proposals are due by September 1 2015 Funding
decisions are expected to be reached by October 1 2015 Proposals will be reviewed by a joint
Childrenrsquos HospitalndashBroad Institute committee Additional submission dates are expected for
2016
Submission Applicants are strongly encouraged to discuss potential applications in
advance with the office of the Chief Scientific Officer at the Broad Questions should be
directed to Alex Burgin (aburginbroadinstituteorg 617-714-7124)
Clinical Trials Glossary
ADME an acronym for absorption distribution metabolism and elimination ADME
studies determine how a drug is absorbed by the body the chemical changes that it may
undergo and how it is eliminated from the body
Adverse event (AE) a bothersome event that occurs in a study participant AEs may be
related to the treatment being tested or may be due another cause (eg another treatment
another medical condition an accident or a surgery)
Arm a specific type of treatment to which a group of clinical trial participants is
assigned Some clinical trials have one arm and some have two arms while others have
three or more arms For example a clinical trial comparing two different doses of an
investigational drug versus a placebo would have three arms participants receiving a
higher dose of the investigational drug participants receiving a lower dose of the
investigational drug and participants receiving the placebo
Baseline a point in time at the beginning of a clinical trial before the study participants
receive any treatment At the baseline participants usually have certain types of tests
During and after treatment the same tests may be performed and the results compared
with the baseline results to see if the drug has caused changes
Bias a factor ndash such as a preconceived idea about the effects of the benefits and risks of a
treatment or a lack of balance in selection of patients for a study ndash that reduces the
likelihood that the study results are true Methods such as blinding and randomization
are used to limit the potential for bias
Bioavailability the portion of the dose of a drug that reaches the bloodstream For
example if the drug is administered intravenously its bioavailability is 100 percent
however if the drug is administered in any other way such as orally topically or
through intramuscular injection its bioavailability will decrease due to incomplete
absorption
Bioequivalence study a test performed to compare the portion of a drug in the
bloodstream when administered in different dosage forms
Biologic product any substance that can be used in prevention treatment or cure of
disease Some examples include vaccines blood virus toxin antitoxin and therapeutic
serum
Biopsy the removal of cells or tissue from a patient for examination which is usually
done under a microscope A tissue sample might be taken for genetic studies Sometimes
there is a difference between the blood genotype and the skin or other tissue genotype
This term can also refer to the tissue sample that has been obtained by such a procedure
2
Blinding a process used to prevent the participants the researchers or both from
knowing what specific treatment is being given to participants in a clinical trial The
process of blinding helps to reduce bias because study participants and researchers are
less likely to be unconsciously influenced by the knowledge of what the study participant
is actually receiving If only the participants are blinded the study is called a single-
blind study If both participants and researchers are blinded the study is called a double-
blind study
Carcinogenicity studies long-term studies conducted in animal models to determine a
drugrsquos likelihood of causing cancer
Clinical efficacy a compoundrsquos ability to produce the desired effect
Clinical pharmacology a science that studies properties of drugs in relation to their
therapeutic value in humans
Clinical study or Clinical trial a medical experiment in human beings that helps to
determine how a disease drug or medical device affects study participants Clinical
studies are necessary to answer specific questions about how to better diagnose prevent
or treat a disease or condition
Cohort a group of study participants who have certain characteristics in common such
as female sex a defined age range or particular severity of disease Dividing study
participants into cohorts is often done as part of the analyses of study data
Contraindication a factor that makes the use of a particular drug inadvisable For
example a person who has had an allergic reaction to penicillin in the past is considered
to have a contraindication to using penicillin in the future
Control group a group of participants not receiving the investigational drug but instead
receiving a standard treatment for their disease or receiving a placebo The results
observed in the group of patients receiving the investigational drug are compared with the
results observed in the control group
Crossover study a study design with two or more arms where participants receive one
treatment for a period of time and then switch over to a second treatment for a period of
time Such a study design allows the effects of the two treatments to be compared in the
same patient
Data Monitoring Committee (DMC) or Data Safety and Monitoring Board (DSMB)
A committee of experts that periodically reviews the accumulating data from an ongoing
multicenter clinical trial Members of a DMCDSMB must be independent ie they
cannot be participating as investigators in the clinical trial Based on their review the
DMCDSMB experts advise the sponsor regarding whether it is safe and acceptable to
continue with the study or whether the data suggest that the study should be modified or
stopped A DMCDSMB may recommend that a trial be stopped if there are safety
concerns or if the trial objectives have been achieved
3
Dose-ranging study a clinical trial in which two or more doses of an investigational
drug are tested to determine which dose is likely to offer the best combination of safety
and efficacy in later clinical trials or in medical care
Efficacy or effectiveness the ability of a drug to prevent cure or slow a disease process or to alleviate the symptoms of a disease or condition
Eligibility a determination made during the screening period for a clinical study of
whether a personrsquos participation in the trial is likely to be safe and can contribute data
that will help achieve the study goals
Endpoint occurrence of a disease symptom sign or test result that constitutes one of the
target outcomes of a clinical trial
Inclusionexclusion criteria the factors defined in the protocol of a study that determine
whether a personrsquos participation in a clinical trial is likely to be safe and can contribute
data that will help achieve the study goals Study candidates undergo evaluation during
the study screening period to determine if they meet all of the inclusion criteria and do
not meet any of the exclusion criteria as defined in the protocol These criteria usually
consider such factors as age sex type of disease stage of disease previous treatment
history and other medical conditions in determining eligibility for the study
Informed consent (assent) a process by which medical researchers provide necessary
information to a person about a clinical study and the person voluntarily confirms his or
her willingness to participate in the study Children who are considered old enough to
have a basic understanding of the study may need to provide assent to be involved in the
study a parent or legal guardian must also give informed consent for such a child to
participate
Informed consent (assent) form a document that describes a clinical study to the
participants (or their parentsguardians) The informed consent (assent) form includes
information about the goals of the study the study design and duration the types of tests
to be performed the potential risks and inconveniences the potential benefits the
possible costs or payments associated with study participation the available alternative
therapies the rights and responsibilities of the participant and the people to contact if the
participant has questions The informed consent (assent) form must be reviewed and
signed before the participant has any study tests or treatment including the tests
performed during the screening period at the beginning of the study Participants are
given a copy of the informed consent (assent) form to take home
Institutional Review Board (IRB) or Independent Ethics Committee (IEC) a board
of physicians statisticians researchers community advocates and others who are
responsible for ensuring the protection of the rights safety and well-being of participants
in a clinical trial at a study center This board is called an IRB in the United States and is
often called an IEC in other countries IRBIECs review and approve important study
documents (eg protocols informed consent forms study advertisements and patient
4
brochures) before the start of the study and periodically review the progress of the study
while it is ongoing
Investigational Drug a drug that is being tested as a potential treatment for a disease or
condition but has not yet been proven safe and effective for that use
Investigator a physician or other health care worker who carries out a clinical trial by enrolling treating and monitoring participants and recording the results
In vitro testing testing conducted in test tubes or other artificial environments
In vivo testing testing conducted in living animals or humans
Longitudinal study a clinical study that involves observations of the same items over
long periods often many decades Because longitudinal studies track the same people
they are often used to study trends across the life span to uncover predictors of certain
diseases or to track the effects of a particular treatment on a patientrsquos condition over
time
Multicenter study a study conducted at more than one location Multicenter clinical
studies are generally performed when each individual clinical trial site does not have
enough study candidates to complete a large trial
Natural history study a study of the natural development of a disease or condition over
a period of time Natural history studies are usually longitudinal studies
New Drug Application (NDA) the registration document through which a
pharmaceutical company formally proposes that the FDA approve a new drug for
manufacturing and sale The application includes detailed reports of pharmacology
toxicology manufacturing and chemistry as well as data from clinical trials
Open-label study a study in which the participants and the investigators know which
treatment is being given In an open-label study there is no blinding and none of the participants receives a placebo
Orphan disease a disease or condition that affects a relatively small number of people
In the US this defined as fewer than 200000 people In Europe this is defined as fewer
than five in 110000 people
Orphan drug a drug intended to treat an orphan disease
Participant or subject a patient or healthy volunteer who participates in a clinical trial
Phase 1 the initial phase of testing of an investigational drug in humans Usually a
Phase 1 clinical study is conducted in a small number of healthy volunteers or patients
with a disease for which the drug may be useful Generally the study is designed to
determine the side effects of the drug and its pharmacokinetics Some information
5
regarding drug efficacy may be collected if patients with a disease participate A phase
frequently encompasses more than one clinical trial Phase 1 sometimes is sub-divided
into Phases 1a and 1b for example when the first set of Phase 1 trials (Phase 1a) is
performed in healthy volunteers and a second set of Phase 1 trials (Phase 1b) is
performed in patients with a disease
Phase 2 the intermediate phase of testing of an investigational drug in humans Usually
a Phase 2 clinical study conducted in patients with a disease for which the drug may be
useful Generally the study is designed to evaluate dosing to obtain preliminary data on
the effectiveness of the drug and to acquire more safety information Phase 2 sometimes
is sub-divided into Phases 2a and 2b Phase 2a studies typically are smaller and shorter
in duration and evaluate different drug doses to see how they affect certain tests that can
indicate whether the drug is working as expected Phase 2b studies typically enroll more
patients are of longer duration and evaluate whether the drug is offering clinical benefits to patients Phase 2b studies sometimes are considered pivotal or registration-directed
Phase 3 the final phase of testing an investigational drug in humans before regulatory
approval Phase 3 studies are usually conducted in a large population of patients and are
generally designed to confirm the effectiveness of the drug and to evaluate the overall
risk-benefit ratio Phase 3 studies usually test the investigational drug in comparison with
a standard treatment for the disease or a placebo
Phase 4 testing of a drug in humans after it has already been approved by regulatory
authorities and can be used in medical practice Phase 4 studies may be conducted to
compare the drug to a similar type of drug to explore whether it may help patients with
other diseases to further study the long-term safety of the drug or for other reasons
Pivotal study a study that is designed to generate the data required by regulatory
authorities to decide whether to approve an investigational drug A pivotal study is
usually a large randomized Phase 2b or Phase 3 study and often is blinded and uses a
placebo as a control Sometimes a pivotal study is described as a registration-directed
study
Placebo an inactive version of an investigational drug A placebo has a similar
appearance to the investigational drug but is expected to have no therapeutic value A
placebo is used as a comparison treatment to reduce bias in randomized studies
Preapproval access program an umbrella term for programs that allow seriously ill
patients to receive an investigational drug when they are unable to participate in clinical
trials and there is no alternative treatment This is sometimes referred to as
compassionate use Types of pre-approval access programs include expanded access
parallel-track named patient program single-patient exemption and treatment IND The
timing for starting an expanded access program usually depends upon what is known
about the risk-benefit of the drug and whether the drug can be provided in a manner that
is fair to patients with the disease
6
Preclinical (nonclinical) testing testing of a drug in test tubes or in animals A drug
undergoes preclinical testing before being tested in humans to make sure that it shows
evidence of desired effects and is sufficiently safe for study in people Preclinical testing
sometimes also helps to determine the doses of the drug that should be evaluated in
humans Preclinical testing is sometimes called nonclinical testing
Protocol a document describing what types of people may participate in a clinical study
and the objectives treatments measurements statistical methods timing and
organization of a clinical trial The protocol must be prepared in advance of the study
and must be reviewed and approved by review committees and regulatory authorities
before the study is started Investigators must follow the protocol to carry out the study
Randomization assignment of participants to treatment arms based on chance This is
usually done by a computer program in a way that does not allow either the participants
or the investigators to choose who is assigned to which arm Randomization is used to
reduce bias in clinical trials
Risk-benefit ratio the balance of the risk of side effects expected with use of a drug
versus the potential for benefit with the use of that drug A drug with a good risk-benefit
ratio has few side effects and is very effective
Serious adverse event (SAE) an adverse event that is life-threatening requires inpatient
hospitalization or lengthens a hospital stay leads to substantial disability leads to a birth
defect or results in death
Side effect any effect of a drug other than the desired effect Side effects are often
unwanted and may be bothersome Other names for a bothersome side effect are adverse
drug reaction (ADR) or drug toxicity
Screening period a period at the beginning of a clinical trial when candidates for the
study are evaluated to determine if their participation is likely to be safe and can
contribute data that will help achieve the study goals
Significant or statistically significant an outcome in a clinical trial is likely to result
from a real difference (eg due to an effect of a treatment) and is unlikely to be due to
chance alone The level of statistical significance is often expressed in terms of a p-
value which indicates the probability that a difference is not due to chance alone
Usually a p-value smaller 005 is considered statistically significant
Sponsor the organization responsible for financing and coordinating a clinical trial
Most often this is a pharmaceutical or biotechnology company
Standard treatment a treatment currently in wide use often approved by regulatory
agencies and generally considered effective in the treatment of a specific disease or
condition
7
Toxicity a side effect produced by a drug that is bothersome to the person taking the
drug
Toxicology the study of the adverse effects of chemicals conducted in animal models to
predict potential adverse effects in humans Some studies are conducted during clinical
development to evaluate dosing regimens
Boston Childrenrsquos Hospital Clinical Research Map 1 Mouse over for additional info Bold = hyperlink
CLINICAL RESEARCH MAP
Boston Childrenrsquos Hospital Clinical Research Map 2 Mouse over for additional info Bold = hyperlink
ObjectiveThis clinical research map is designed to serve as a guide for investigators study coordinators and research nurses at Boston Childrenrsquos Hospital The research map outlines the key steps in preparing to launch a research study and provides embedded links to institutional resources tools and documents
An investigator need not follow the steps on the Clinical Research Map in any particular order There is flexibility and the steps followed will in part de-pend on the type of research study
For new as well as more experienced investigators the Clinical Research Map can be used as a checklist or an inves-tigator can use the steps on the map as points for consideration as they are developing a protocol and launching a study
This tool is not intended to substitute for the important collaboration be-tween a junior investigator and a senior investigatormentor A senior investiga-tor plays a pivotal role in coaching and advising a junior investigator regarding the many subtleties and variations that apply to designing and implementing a protocol
This process map cannot be inclusive of every possible task or step but is intended as a general guide for investi-gators and their study teams
ResourcesThere are many institutional resources at Boston Childrenrsquos Hospital designed to support investigators and their clini-cal research teams In addition to links to resources tools and documents that are embedded in the steps of the clini-cal research map the last page of this document contains website addresses that will take you to additional helpful institutional resources
Acknowledgements Cindy Williams DNP RN PNP NE-BC Nursing Director CTSU Clinical Research Nursing
Ellen McGrath MSN RN CPNP Nurse Practitioner Department of Surgery
Grace Yoon MSN RN CNNP Research Nurse Department of Ophthalmology
Laura Feloney BA Lab Technician
ContentsOverview Four stages 3
1st Stage Protocol development 4
1st Stage Protocol development contrsquod 5
2nd Stage Implementation planning 6
3rd stage Study launch7
4th stage Statistical analysis reporting and dissemination 8
Discarded specimens Additional steps 9
Chart review Steps if you are completing a chart review 10
Appendix A Resources for researchers 11
Boston Childrenrsquos Hospital Clinical Research Map 3 Mouse over for additional info Bold = hyperlink
Overview Four stages
Protocol development
Implementation planning
Study launch
Statistical analysis reporting and dissemination
1
2
3
4
Boston Childrenrsquos Hospital Clinical Research Map 4 Mouse over for additional info Bold = hyperlink
1st Stage Protocol development
Explore resources
CRIT
CRC
EQuIP
CTSU
Harvard Catalyst
Complete training
CITI training
EQUiP
Consult research pharmacistResearch Pharmacy
Rocco Anzaldi
Consult statistician
CRC
Draft a protocol
Protocol guidelines
Study personnel
FDA Guidance for Investigators
Consult Clinical Research Center
CRC
Bio Bank
Start IRB application
TransLab
Consider applying for grants
securing funding
Office of Sponsored Programs
If INDIDE application to FDA
Does my study need an INDIDE
Regulatory resources
Arrange a consultation with
CRIT
ConsultationTasks for investigators and study teams
Boston Childrenrsquos Hospital Clinical Research Map 5 Mouse over for additional info Bold = hyperlink
Respond to IRB questionsrequests
for clarification
1st Stage Protocol development contrsquod
Departmental Scientific Review
Organize DSMB design DSMP
DSMPDSMB
Templates for Research Study
Documents and Tools
Study Templates and Tools
Investigators who sponsor an FDA regulated trial
ClinicalTrialsgov
Create regulatory binder
Regulatory Binder Template
Submit the grant application to OSP
OSP
TIDO
CTBO
Consult Office Intellectual Property
Technology and Innovation
Development Office
TIDO
IRB approval
Consider blood volume for research
Research blood volume policy
Confidentiality plan
Confidentiality guidelines
Boston Childrenrsquos Hospital Clinical Research Map 6 Mouse over for additional info Bold = hyperlink
Develop Case Report Forms
(CRFs)
CRF guidelines
Establish electronic shared
folder or study binder for study
documents
CRIT
Set date for trial launch
Develop fast fact sheet for bedside staff
Consult programmer re database
CRIT
Research study resource manual
for the clinical unit
Confirm study drug
in pharmacy
Rocco Anzaldi
Clarify system for screening
and enrolling patients
Recruitment guideline
Updated protocol to
nurse manager
Consult MDsNPs on unitclinic
2nd Stage Implementation planning
Tasks for investigators and study teams
Study logistics Documentation logistics
Data storage
Confidentiality plan
Confidentiality guidelines
Create study orderset
Consider blood volume for research
Research blood volume policy
Create Manual of Operations
MOO Guide
Study implementation
meeting
Develop study logstools
EQUIP
Finalize tracking sheet
Research Administration
Fernando Valles
Boston Childrenrsquos Hospital Clinical Research Map 7 Mouse over for additional info Bold = hyperlink
3 Document informed consent
Informed Consent
Consent library
Schedule weekly study team meeting
Communicate to department faculty
and multidisciplinary
team announcing trial launch
Steps before trial launch
3rd stage Study launch
Patient flow
1 Seek permission
to approach potential subjects
2 Screenenroll
patients
EQUIP
5 Send Study
Tracking Sheet (STS)
6 Collection of
patient data and assessing for
adverse events
7 Study
documents and data handling
4 Datetime study tests
Create a checklist outlining study action items for each subject
Boston Childrenrsquos Hospital Clinical Research Map 8 Mouse over for additional info Bold = hyperlink
Annual IRB Report
Annual Progress ReportStaff Report
raquo Maintain Interest of Staff
raquo Important to See Study Progress
Write Abstract
Dissemination of Research Results
raquo Conference raquo Internal Presentation for Colleagues
raquo Publication
Plan DSMB MeetingInterim
Analysis
4th stage Statistical analysis reporting and dissemination
Data Entry
When Enrollment Complete Data
Cleaning
Monitor Subjects to Identify
Adverse Events (CCI sponsor
DSMB)
Report Adverse Events
Update MOO Based on Experience
with First Several Patients Enrolled
Weekly Study Team Meeting
Report study findings to
subjects and stakeholders
Data management Trial management
Reporting Dissemination
Regular Review of Data
to Identify Deviations
and Workflow Improvements
Consult Statistician When Approaching Target Enrollment
Discarded specimens Additional steps
Boston Childrenrsquos Hospital Clinical Research Map 9 Mouse over for additional info Bold = hyperlink
Send IRB Approval to lab manager
Maureen Samson
Educate staff in areasunits about sample collection
Locate the discarded samples
Locate the accession number in PowerChart
Retrieve specimen
Mark Kellogg
Follow Shipping Rules and Procedures
IATAShipping with dry ice instructions
Communicate with laboratory staff
Contact Dr Mark Kellogg to discuss specimen retrieval
Consult with Biorepository
Biorepository
Chart review Steps if you are completing a chart review
Boston Childrenrsquos Hospital Clinical Research Map 10 Mouse over for additional info Bold = hyperlink
7 8
4321
Databaserecord review guidelines
5 6
Consult programmer re database
CRC Request
Respond to IRB questions
requests for clarification
Departmental Scientific Review
Complete training
CITI Training
Draft a protocol
Protocol Guidelines
Prepare IRB Application
Information about the CCI
IRB Application
Develop Case Report Forms (CRFs)
CRF Guidelines
IRB Review
Boston Childrenrsquos Hospital Clinical Research Map 11 Mouse over for additional info Bold = hyperlink
Clinical Research Center (CRC) x84720
Committee on Clinical Investigation (CCI IRB) x57052
Research Pharmacist x52014
Clinical and Translational Science Unit (CTSU) x57541
Education and Quality Improvement Program (EQUIP) x57052
Clinical Trials Office Central Budgeting x4-2714
Office of Sponsored Programs x4-2723
Technology and Innovation Development Office 617-919-3079
Research Finance x8-3517
Harvard Catalyst 617-432-7810
Regulatory Affairs x4-2777
Appendix A Resources for researchers
RES_4446_ClinicalResearchMap-FINAL FOR LINKS 1
RES_4446_ClinicalResearchMap-FINAL FOR LINKS 10
Overview Four stages
1st Stage Protocol development
1st Stage Protocol development contrsquod
2nd Stage Implementation planning
3rd stage Study launch
4th stage Statistical analysis reporting and dissemination
Discarded specimens Additional steps
Chart reviewSteps if you are completing a chart review
Appendix A Resources for researchers
RES_4446_ClinicalResearchMap-FINAL FOR LINKS 11
RES_4446_ClinicalResearchMap-FINAL FOR LINKS 2
RES_4446_ClinicalResearchMap-FINAL FOR LINKS 3
RES_4446_ClinicalResearchMap-FINAL FOR LINKS 4
RES_4446_ClinicalResearchMap-FINAL FOR LINKS 5
RES_4446_ClinicalResearchMap-FINAL FOR LINKS 6
RES_4446_ClinicalResearchMap-FINAL FOR LINKS 7
RES_4446_ClinicalResearchMap-FINAL FOR LINKS 8
RES_4446_ClinicalResearchMap-FINAL FOR LINKS 9
RES_4446_ClinicalResearchMap-PAGE 5pdf
Overview Four stages
1st Stage Protocol development
1st Stage Protocol development contrsquod
2nd Stage Implementation planning
3rd stage Study launch
4th stage Statistical analysis reporting and dissemination
Discarded specimens Additional steps
Chart reviewSteps if you are completing a chart review
Appendix A Resources for researchers
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Button 111
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MOUSE OVER
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Page 98
COVER BUTTON
Previous Page
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Page 96
Page 1
Button 91
Button 92
Button 94
IRB review
Button 102
Develop Case Report Forms
Button 136
Consult clinical research center
INDIDE 1
Explore resources
Button 1016
Bio Bank p
4
Consult statistician
Consult research pharmacist
Study personnel
Complete training
Consider grantsfunding
Draft a Protocal 2
Arrange a consutlations with CRIT
Next Page 1
Previous Page 1
TransLab
Start IRB application 3
Develop study logs
Updatedd protocol
Confirm study drug
Establish electronic shared
COnsult programmer
Clarify system
Research study resrouce manual
Develop case report forms
MOO
Set date for trial launch
Button 44
Study implementation meeting
Finalize tracking sheet
Data storage
Confidentiality
Blood volume 3
Develop fast fact
Consult MDs
Schedule weekly
Communicate early
Button 71
Screenenroll patients
Document informed consent
Datetime tests
Send study tracking sheets
Collection patient data
Button 77
Dissemination
Button 87
Button 124
Button 125
Communicate with lab staff
Button 106
Button 109
Button 1010
Shipping page 9
Button 1012
Button 99
Button 133
Button 134
Button 135
Biorepository
Locate assession number
Retrieve specimen
Button 30
Consult office
Negotiate Contract
Organizing DSMB
Submit Grant
Respond to IRB questions
Button 66
Create regulatory binder
Templates for research stufy
Clinical Trials Business Office
Blood volume 2
Confidentiality plan
Investigators who sponsor
clinicaltrials
gov
BPN Project
Drug Discovery amp Development Testing Funnel
Tier 1 2 3
Tier 6 7 8
Tier 5
Tier 4
Example Drug Discovery amp Development Testing Funnel
Cytotoxicity
Grant
Project
Example Drug Discovery amp Development Testing Funnel
TIER 1A ndash Primary Screen
Chemical purity and identity of active compounds
Primary bioactivity screen
Cell viability (When Appropriate)
ScaffoldsMoiety Chemical liabilities (for example Michael acceptor GSH reactive)
Calculated properties CLogP
PSA
Molecular Weight
rotatable bonds
H-bond donors and acceptors
permeability
pKa
Solubility
TIER 1B
Confirm EC50 determinations for actives compounds in primary screen with fresh
compounds from the original stock Confirm EC50 determinations for the lead (most
active) compound in primary screen with a new sample either repurchased purified
and characterized in-house or independently synthesized in-house
Compounds with IC50s (EC50s) less than X advance to Tier 2
TIER 2A ndash Activity Confirmation
Secondary screen
TIER 2B
Repeat EC50 determinations for actives in secondary screen with fresh
compounds from the original stock
Compounds with IC50s (EC50s) less than X advance to Tier 3
Example Drug Discovery amp Development Testing Funnel
TIER 3 ndash Drug-like Properties Specificity
IC50 selectivity in selectivity screen
CYP450 Inhibition competitive and time-dependent if structural alerts exist
(spot check illustrative examples from compound series)
Measured solubility
Measured protein binding (spot check illustrative examples from
compound series)
Test of Permeability in vitro permeability [indicate assay eg Caco2 orand
PAMPA] (spot check illustrative examples from compound series)
hERG
Cytoxicity assays
All compounds with no significant issues (Define Minimum Conditions for
Advancement) to advance to Tier 4
Example Drug Discovery amp Development Testing Funnel
TIER 4 ndash Scale-up Synthesis and Preliminary PK
Scale-up synthesis
Purity determination gt98 with no single impurity gt1
Rodent bioavailability and PK (define target delivery route) Tmax
Cmax
AUC
Bioavailibility
Vss CL T12 MRT
Brain to Plasma ratios
P-glycoprotein transport MDCK-MDR1 and MDCK-mdr1a
Plasma Protein Binding (species)
Microsomal Stability ndash rodent and human
Defineplan Patent Protection Strategy
All compounds with no significant issues (Define
Minimum Conditions for Advancement) advance
in parallel to Tiers 5AampB
Example Drug Discovery amp Development Testing Funnel
TIER 5A ndash In Vivo Bioactivity
Animal efficacy
Validate Biomarker
Target engagement
Advance to Tier 6 if (Define Minimum Conditions for advancement)
TIER 5B ndash Advanced Drug-like Properties
Microsomal stability in multiple
species
Chemical Stability
CYP450 induction
CYP reaction phenotyping
Metabolism ndash human
hepatocytesmicrosomes
Metab ID define major human rat dog and
non-human primates (NHP) metabolites
In vitro Tox Ames
Chromosome Aberration
CNS effects
Example Drug Discovery amp Development Testing Funnel
TIER 6 ndash Liability Assessment
Broad Pharmacological Profile and Toxicology
PK in second species
TIER 7
Non-GLP exposure studies single and multiple dose
Advance to late stage pre-clinical development (Define Minimum
Conditions for advancement)
Example Drug Discovery amp Development Testing Funnel
Principal InvestigatorProgram Director (Last First Middle)
enspenspenspenspensp
DETAILED BUDGET FOR INITIAL BUDGET PERIOD
DIRECT COSTS ONLY
FROM
THROUGH
enspenspenspenspensp
enspenspenspenspensp
PERSONNEL
DOLLAR AMOUNT REQUESTED (omit cents)
NAME
ROLE ONPROJECT
TYPEAPPT (months)
EFFORTONPROJ
INSTBASESALARY
SALARYREQUESTED
FRINGEBENEFITS
TOTAL
enspenspenspenspensp
PrincipalInvestigator
enspenspenspenspensp
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enspenspenspenspensp
SUBTOTALS
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
CONSULTANT COSTS
enspenspenspenspensp
enspenspenspenspensp
EQUIPMENT (Itemize)
enspenspenspenspensp
enspenspenspenspensp
SUPPLIES (Itemize by category)
enspenspenspenspensp
enspenspenspenspensp
TRAVEL
enspenspenspenspensp
enspenspenspenspensp
PATIENT CARE COSTS
INPATIENT
enspenspenspenspensp
enspenspenspenspensp
OUTPATIENT
enspenspenspenspensp
enspenspenspenspensp
ALTERATIONS AND RENOVATIONS (Itemize by category)
enspenspenspenspensp
enspenspenspenspensp
OTHER EXPENSES (Itemize by category)
enspenspenspenspensp
enspenspenspenspensp
SUBTOTAL DIRECT COSTS FOR INITIAL BUDGET PERIOD
$
enspenspenspenspensp
CONSORTIUMCONTRACTUAL COSTS
DIRECT COSTS
enspenspenspenspensp
FACILITIES AND ADMINISTRATIVE COSTS
enspenspenspenspensp
TOTAL DIRECT COSTS FOR INITIAL BUDGET PERIOD
$
enspenspenspenspensp
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
Compare disease profiles across cohorts and stages of disease
wwwnextbiocom
iHOP--information Hyperlinked Over Proteins
A portal for searching literature by gene or gene Interactions httpwwwihop-netorgUniPubiHOP
Ingenuity Pathway Analysis
Available from research computing Find disease related literature for your target
httpwwwingenuitycomproductsipa
TISSUES database of Expression of targets (RNA and Protein)
TISSUES is a frequently updated web resource that integrates evidence on tissue expression from manually curated
literature proteomics and transcriptomics screens and automatic text mining They map all evidence to common
protein identifiers and Brenda Tissue Ontology terms and further unify it by assigning confidence scores that facilitate
comparison of the different types and sources of evidence Finally these scores are visualized on a schematic human
body to provide a convenient overview
httptissuesjensenlaborgSearch
Refrence Literature related to target identification and validation
Bunnage ME Gilbert AM Jones LH Hett EC Know your target know your molecule Nature chemical biology 2015
11(6)368-372 httpwwwncbinlmnihgovpubmed15718163
Grover MP Ballouz S Mohanasundaram KA George RA Sherman CD Crowley TM Wouters MA Identification of
novel therapeutics for complex diseases from genome-wide association data BMC medical genomics 2014 7 Suppl
1S8 httpwwwncbinlmnihgovpubmed25077696
Plenge RM Scolnick EM Altshuler D Validating therapeutic targets through human genetics Nature reviews Drug
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
main menu
Resources available at BCH Assay Development Screening Funnel development Chemical compound files Assistance
with identification of academic and industry partners for collaborative SAR campaigns
Identification of the correct molecule requires a clearly defined set of laboratory objectives and a well-designed screening
funnel to select the molecule that will meet those objectives Laboratory objectives for a molecule include specific criteria
for the mode of binding to target (eg agonist partial agonist inverse agonist non-competitive inhibitor) the potency
(eg Ki lt30nM) selectivity (eg gt30X selectivity over family member target XY and Z) brain penetration (yesno) dosing
paradigm ( eg oral once daily intravenous once monthly) and duration of expected treatment (eg sub-chronic daily
treatment for 2 weeks chronic treatment for years) Each of these laboratory objectives will have bearing on the design of
the screening funnel required to identify the molecule
The screening funnel requires a robust high-throughput (HTS) biochemical assay capable of testing gt100000 compounds
good sensitivity (Zrsquogt05) and an appropriate orthogonal assay (usually cell based) to confirm functional activity of the
compound at the target which can be used to weed out false positives and primary HTS artifacts Critical features defined
by the laboratory objectives may require additional in vitro absorption and metabolism data from compounds slated to
progress in vivo to ensure that structure activity relationships being developed will support expected dosing profiles and
target organ disposition A collection of critical off target assays to ensure required selectivity of the candidate drug must
be available to test molecules progressing from functional assays Compounds expected to be tested in vivo will require
pharmacokinetic studies to ensure target organ exposure in concentration ranges needed to support hypothesis testing
Link to sample Screening Funnels
httpswwwnimhnihgovresearchprioritiestherapeutics
The types of information needed to Characterize a Lead Compound are summarized here
Download an introductory slide deck on Medicinal Chemistry Structure Activity Relationship (SAR) campaign courtesy Dr
Johnny Bennett Merck
Childrens MedChem 29Jul2015pdf
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
Resources for assay development
The Assay Guidance Manual httpwwwncbinlmnihgovbooksNBK53196
This is a key resource for design and qualification of all types of biochemical and cell based assays It covers many
different modes of assay development and optimization as well as troubleshooting guides Do not run a screen
without consulting the manual first
The Assay Development Screening Facility (ADSF) at BCH Hourly access to equipment and technical assistance
consultations compound libraries- live cell medium throughput screening For more information contact Dr Lee Barrett
The ICCB at Longwood Project based access to equipment and expertise for design and execution of high-throughput
screens access to wide collection of chemical and genomic libraries For more information contact Dr Caroline Shamu
caroline_shamuhmsharvardedu
Website httpiccbmedharvardedu
Databases and references with information about activity and properties of small molecule compounds
PubChem provides information on the biological activities of small molecules PubChem is organized as three linked
databases within the NCBIs Entrez information retrieval system These are PubChem Substance PubChem Compound and
PubChem BioAssay Links from PubChems chemical structure records to other Entrez databases provide information on
biological properties These include links to PubMed scientific literature and NCBIs protein 3D structure resource Links to
PubChems bioassay database present the results of biological screening Links to depositor web sites provide further
information A PubChem FTP site Download Facility Power User Gateway(PUG) Standardization Service Score Matrix
Service Structure Clustering and Deposition Gateway are also available Home page is here
httpspubchemncbinlmnihgov
httpspubchemncbinlmnihgovsearch
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
DrugBank The DrugBank database is a unique bioinformatics and cheminformatics resource that combines detailed drug
(ie chemical pharmacological and pharmaceutical) data with comprehensive drug target (ie sequence structure and
pathway) information The database contains 7759 drug entries including 1602 FDA-approved small molecule drugs 161
FDA-approved biotech (proteinpeptide) drugs 89 nutraceuticals and over 6000 experimental drugs Additionally 4300
non-redundant protein (ie drug targetenzymetransportercarrier) sequences are linked to these drug entries Each
DrugCard entry contains more than 200 data fields with half of the information being devoted to drugchemical data and
the other half devoted to drug target or protein data Homepage is here httpwwwdrugbankca
Protein Data Bank archive Targets with protein crystal structures are more attractive targets for structure based drug design
Determine if your target has a known crystal structure by looking it up in the protein database- A Structural View of Biology
This resource is powered by the Protein Data Bank archive-information about the 3D shapes of proteins nucleic acids and
complex assemblies that helps students and researchers understand all aspects of biomedicine and agriculture from
protein synthesis to health and disease Homepage is here httpwwwrcsborgpdbhomehomedo
High Quality Chemical tools are required for testing biological hypothesis Find chemical tools that are fit for purpose by
virtue of target potency and selectivity needed to test hypothesis The dangers of using inadequate chemical tools are
detailed here httpwwwnaturecomnchembiojournalv11n8fullnchembio1867html To support the needs of the
biology community the industrial chemistry research community has joined a pre-competitive effort to provide
characterization data for high quality chemical probes That data is stored here httpwwwchemicalprobesorgprotein-
family
ChemNavigator The National Institutes of Health (NIH) has formed an agreement with ChemNavigator to provide the NIH
with a current and comprehensive database of commercially accessible drug discovery screening compounds to be
made available to all NIH researchers ChemNavigator is pleased to serve NIH affiliated scientific researchers in compound
sample procurement As an NIH researcher you have full access to use the iResearch System All you need to do is take a
few minutes to register in the system Then you will be able to perform chemical structure searches for compound samples
of interest and purchase these samples through this on-line system Link is here httpwwwchemnavigatorcomnihasp
Additional References related to biological activity of compounds
Edwards AM Bountra C Kerr DJ Willson TM Open access chemical and clinical probes to support drug discovery Nature
chemical biology 2009 5(7)436-440
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
Wang Y Suzek T Zhang J Wang J He S Cheng T Shoemaker BA Gindulyte A Bryant SH PubChem BioAssay 2014 update
Nucleic acids research 2014 42(Database issue)D1075-1082
Wang Y Bolton E Dracheva S Karapetyan K Shoemaker BA Suzek TO Wang J Xiao J Zhang J Bryant SH An overview of
the PubChem BioAssay resource Nucleic acids research 2010 38(Database issue)D255-266
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
main menu
Pharmacokinetic tutorial drug exposure measurement services pharmacokinetic data references
Selecting the correct dose to achieve exposure of drug that are adequate to test a hypothesis in preclinical species
requires that you know the potency of the molecule at the desired drug target and the dose of compound required to
achieve target organ exposure that will result in the free (not bound by protein) concentration of drug required to engage
the molecular target within the target organ compartment Estimates of Drug potency can be found in many of the
databases listed under correct molecule The free concentration of a drug is determined in the plasma by multiplying the
concentration of drug in the plasma by the fraction unbound This must be measured for each compound A literature
reference that provides the measured plasma protein binding (PPB) values for many common drugs is provided here
Zhang Xue Shao and Jia (2012) Compilation of 222 drugsrsquo plasma protein binding data and guidance for study designs
Drug Discovery Today Vol 17 Issue 9-10 Pages 476-485 httpwwwncbinlmnihgovpubmed22210121
If your drug target is the brain then you must also understand the kinetics of drug disposition and clearance including blood
brain barrier (BBB) penetration in your test species to select a dose of compound adequate to test your hypothesis
Download a tutorial deck on basic principles of drug disposition and their application in small molecule drug discovery
courtesy of Dr Chris Shaffer Pfizer
150805DMPKTutorial(CLSBCHCourse)pdf
Pharmacometrics Research Core and Pharmacokinetics Service The Pharmacometrics Research Core is directed by Dr Luis
Pereira and provides analytical services for assaying drugsmetabolites in biological matrices (eg plasma serum blood
urine CSF saliva tissues) The Core provides pharmacokinetic and pharmacodynamic analyses for current and future
clinical trials and research projects (including contract services) It conducts stability and potency studies for pediatric
formulations compounded at BCH as per recent demand from FDA and CMS Finally the Core fosters grant applications
and research collaborations both intra and extramural The TNC can additionally provide investigators with consultation in
the identification of resources for pharmacodynamic assay development and contract research organizations able to
provide bioanalysis of preclinical samples needed to support animal clinical trials Contact Dr Luis Pereira for more
information LuisPereirachildrensharvardedu
article on importance of understanding drug exposure in preclinical drug studies here
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
References on Pharmacokinetics and Brain Penetration of Small Molecules
Di L Rong H Feng B Demystifying brain penetration in central nervous system drug discovery Miniperspective Journal of
medicinal chemistry 2013 56(1)2-12
Reichel A Addressing central nervous system (CNS) penetration in drug discovery basics and implications of the evolving
new concept Chemistry amp biodiversity 2009 6(11)2030-2049
Smith DA Di L Kerns EH The effect of plasma protein binding on in vivo efficacy misconceptions in drug discovery Nature
reviews Drug discovery 2010 9(12)929-939
Moda TL Torres LG Carrara AE Andricopulo AD PKDB database for pharmacokinetic properties and predictive in silico
ADME models Bioinformatics 2008 24(19)2270-2271
Law V Knox C Djoumbou Y Jewison T Guo AC Liu Y Maciejewski A Arndt D Wilson M Neveu V et al DrugBank 40
shedding new light on drug metabolism Nucleic acids research 2014 42(Database issue)D1091-1097
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
main menu
Formulations advice and assistance with preclinical drug delivery Neurodevelopmental Behavioral Core
To effectively deliver drug to preclinical species for the duration of a study researchers must choose a dose a formulation
and a route of administration that will support target organ exposure long enough to test a therapeutic hypothesis Since
most drugs developed for humans are optimized for human metabolism parameters many compounds developed for
humans are rapidly metabolized and cleared in rodents requiring alternative formulations and routes of preclinical
administration (see tutorial under Correct Dose)
Proper formulation of drugs and vehicles to ensure appropriate drug exposure is a critical factor in preclinical study design
The Neurodevelopmental Behavioral Core may provide advice on standard formulations Preclinical assistance and
training across many routes of administration including IV cannulation osmotic minipumps oral gavage sc and ip is also
available through the Neurodevelopmental Behavioral Core
Contact is Dr Nick Andrews NickAndrewschildrensharvardedu
Custom formulation used for human studies are supported on a case by case basis by the Pharmacometrics Research Core
or Clinical Research Pharmacy Contact for the Pharmacometrics Core is Dr Luis Pereira LuisPereirachildrensharvardedu
The Clinical Research Pharmacy can provide advice on unusual formulations Contact is Dr Rocco Anzaldi
RoccoAnzaldichildrensharvardedu
idspharmacy-dlchildrensharvardedu
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
main menu
Stratification Biomarker development and resources patient sample repositories requests for collection of new types of
patient samples development of patient specific iPSC lines and neurons Genetic databases RNA expression databases
Humans are diverse Not only do patients come in different sizes ages genders and ethnic backgrounds but the same
disease diagnosis often develops in people as a function of different environmental insults and genetic predispositions
Finding biomarkers that will segregate similarly diagnosed patients into subsets of biologically more homogenous
populations is a critical feature of good clinical trial design A lsquostratification biomarkerrsquo can be a biochemical measure from
patient samples a structural or a functional feature of a human imaging technology or a functional measure of an
electrophysiological readout
The Translational Neuroscience Center can help investigators access advice and assistance for investigators with vendors
experienced in profiling DNA RNA or protein across a range of platforms httpwwwchildrenshospitalorgresearch-and-
Neurophysiology Services can assist investigators with identification of biomarkers to stratify patients based on EEG
signatures Contact Drs Charles Nelson and Jurriaan Peters Co-Directors
CharlesNelsonchildrensharvardedu
JurriaanPeterschildrensharvardedu
MRIRadiology Imaging Core can assist with identification of biomarkers to stratify patients by functional or structural deficits
in brain circuitry Contact Dr Simon Warfield Director SimonWarfieldchildrensharvardedu
Molecular Genetics core can assist investigators with identification of genetic stratification biomarkers or gene expression-
based stratification biomarkers Contact Drs Louis Kunkel and Christopher Walsh Co-Directors
LouisKunkelchildrensharvardedu
ChristopherWalshchildrensharvardedu
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
The Human Neuron Differentiation Service within the Translational Neuroscience Center can help investigators recruit
specific subtypes of patients to be consented for reprogramming of blood or fibroblast cells into iPSC lines that will support
differentiation into human neurons for phenotypic analysis and screening ContactDr Robin Kleiman
RobinKleimanchildrensharvardedu
Translab can assist with routine processes as well as complex laboratory-‐developed tests They place special emphasis on
assay development for use in clinical trials Translab website with contact information can be viewed here
httpwwwtranslabbostonorg
TransLab Flyer 2 2015pdf
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
main menu
Patient sample repositoryBiobank Patient registry
Disease processes are dynamic The molecular underpinnings of disease differ between inception progression and
response of the body to disease Thus each stage of disease may require alternative therapeutic strategies Understanding
which stage of disease is best suited to testing a specific therapeutic approach will require information about disease from
patient samples collected at different stages of disease well as an ability to collect and recruit patients at relevant stages of
disease
To locate human RNA profiling data in the public domain from disease samples and tissues at specific stages of disease
search databases referenced in the Correct Target section of this document
The Translational Neuroscience Center offers multiple services that can assist with identification of the correct patients The
Core Repository for Neurological Disorders stores a wide variety of patient samples from many stages of disease The
biorepository is directed by Dr Mustafa Sahin and these samples and de-identified clinical data can be searched and
requested through the Translational Neuroscience Center
The Biobank Core Lab serves as a core resource that ensures top-level specimen handling and services to the Boston
Childrens Hospital research community It serves as both a service core and a biorepository providing an institutional
perspective on the presence of specimens that may be available for use to foster collaborations and accelerate research
and discovery
The Clinical Research and Regulatory Affairs Service can provide assistance to investigators in identifying patients andor
repository samplesdata Contact Co-Directors Stephanie Brewster and Kira Dies for more information about access to
these resources
StephanieBrewsterchildrensharvardedu
KiraDieschildrensharvardedu
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
main menu
Statistical support clinical trialsgov
Determining the correct sample size to support preclinical and clinical studies requires power calculations that take into
account the variability of the endpoint being measured Statistical support for preclinical studies is available on a
department by department basis Neurology and Neurobiology requests for preclinical biostatistics support can be made
through the CRC website
httpredcap-qiredcap_edcsurveyss=Rma5u83qKC
Clinical statistical support for all departments is also available through the CRC Design and Analysis Core For more
information contact Michael Monuteaux michaelmonuteauxchildrensharvardedu
Clinical datasets that provide data for supporting power calculations can be found by searching through clinical trialsgov
database All studies in the clinical trials data base are required to describe the study design the endpoints under
evaluation and the treatments as well as links to publications of the studies The studies can be searched by topic This can
be a good way to find historical data to help you evaluate variability of endpoint measures in clinical populations This will
be needed to support sample size power calculations httpsclinicaltrialsgov
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
main menu
Understanding RDoC Human Neurobehavioral Core Service IRB assistance with clinical protocols
Different stages of clinical trials have different goals for selecting endpoints Early stage clinical trials are typically in search
of a translatable pharmacodynamic or target engagement endpoint to ensure that the molecule in question will be
competent to test a clinical hypothesis in humans Developing translatable measures of target engagement in preclinical
species and humans is critical to developing data sets that will enable subsequent therapeutic efficacy trials The earliest
trials require endpoints that can be measured in a functionally equivalent manner across species Therefore it is critical for
preclinical researchers to develop dose-responsive data sets in preclinical species using quantitative endpoints such as EEG
visual or auditory evoked potentials PET ligands plasma or CSF based biochemical measures or translatable task based
behaviors Preclinical data must be a developed with an eye towards what the equivalent measure will be in the clinic
Toward that end the NIMH has initiated the Research Domain Criteria (RDoC) that is aimed at characterizing mental health
disorders across many different dimensions across species A big focus of the RDoC initiative is the identification of
translatable endpoints for evaluating pharmacodynamics and efficacy in Neuroscience Drug Discovery Preclinical
Neuroscience researchers should be familiar with the RDoC framework For advice on in vivo characterization of preclinical
endpoints with translational potential for Neuroscience related disorders contact Dr Robin Kleiman at the TNC
robinkleimanchildrensharvardedu
The Human Neurobehavioral Core Service of the Translational Neuroscience Center can provide guidance to investigators
on the appropriate tests that will provide the best translation from animal studies to human studies The Service also offers
human neurobehavioral assessment services Contact-Drs Charles Nelson and Deborah Waber Co-Directors
CharlesNelsonchildrensharvardedu
DeborahWaberchildrensharvardedu
Developing clinical protocols and obtaining IRB approval for human study of translatable endpoints can be supported by
the Translational Neuroscience Center Clinical Research and Regulatory Affairs Service Contact-Kira Dies and Stephanie
Brewster Co-Directors
KiraDieschildrensharvardedu
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
StephanieBrewsterchildrensharvardedu
Background Information on RDoC httpswwwnimhnihgovresearch-prioritiesrdocindexshtml
Casey BJ Oliveri ME Insel T A neurodevelopmental perspective on the research domain criteria (RDoC) framework
Cuthbert BN Insel TR Toward the future of psychiatric diagnosis the seven pillars of RDoC BMC Med 2013 11126
httpwwwncbinlmnihgovpmcarticlesPMC3653747
Insel T Cuthbert B Garvey M Heinssen R Pine DS Quinn K Sanislow C Wang P Research domain criteria (RDoC)
toward a new classification framework for research on mental disorders The American journal of psychiatry 2010
167(7)748-751 httpwwwncbinlmnihgovpubmed20595427
Insel TR The NIMH Research Domain Criteria (RDoC) Project precision medicine for psychiatry The American journal
of psychiatry 2014 171(4)395-397 httpwwwncbinlmnihgovpubmed24687194
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
main menu
Body atlases for expression of mRNA and protein guides to chemical alerts guidance for preclinical toxicology studies for
Investigational New Drug (IND) applications
Discovery scientists must consider the distribution of the proposed drug target across the entire body in human samples in
order to understand potential safety risks to be monitored during preclinical toxicological testing Teams also have to be
aware of differences in distribution of the target and related family members in preclinical species Many of the target
expression databases listed in the Correct Target section of this document are useful in this regard Assays that can be used
to monitor any potential safety risks are critical to the development of a suitable testing funnel needed to advance
compounds
Many chemical classes of compounds that are identified in screens are not suitable for drug development due to the
presence of structural alerts that are known to cause chemical toxicity Databases that house information of structural alerts
can be used to de-prioritize structural series early in the life of a program Some toxicology databases that can help
deprioritize toxic chemotypes include httppubsacsorgdoiabs101021ci300245q
Some web resources for identifying side effects of known compounds httpintsideirbbarcelonaorg
Once a potential clinical candidate molecule is identified GLP-qualified toxicology studies must be carried out with a
qualified vendor to support regulatory filings of an Investigational New Drug (IND) application For a short tutorial on studies
needed to support preclinical toxicology testing and guidance on evaluating contract research organizations that are
qualified to perform this work see attached tutorial courtesy of Dr Joe Brady Pfizer
Brady boston childrens hosp talk aug2015 IND toxpdf
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
main menu
FAQs
Industry partners and collaborators can bring tremendous expertise and complementary resources to bear on research
projects with therapeutic applications These may include medicinal chemistry expertise pharmacology expertise access
to unique and undisclosed chemical probe molecules assay development and high-throughput screening resources
antibody and other reagent development pharmacokinetic analysis pharmacokinetic and pharmacodynamics
modeling formulation expertise post-doctoral training programs and in some cases financial support There is a wide range
of models of interacting with industry in a range of different capacities Some frequently asked questions about types of
relationships and the responsibilities associated with those interactions can be found in the following document
Download Frequently Asked Questions about working with Industry
Translation of basic research into new marketed drugs will require a transition from exploring scientific principles and testing
hypotheses into commercial products Industry partners capable of developing these potential products need to be able
to license the intellectual property required to sell the product in order to justify investment in building programs around new
ideas This requires that scientific researchers protect and patent potential inventions from their work to enable future
commercialization by partners with appropriate expertise To ensure that researchers are appropriately documenting their
work in a manner that will support preservation of intellectual property all investigators are encouraged to consult with TIDO
before any public disclosures of new research Similarly the following documentation provides guidance for documenting
your work according to standards that will support patent applications
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
Download the compliance manual for BCH for Intellectual property policy
cm_021_intellectual_propertydocx
Download a summary of laboratory notebook Dorsquos and Donrsquot
Dosdontsnotebookspdf
Link to TIDO Technology Innovation and Development Office
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
main menu
A phenotypic screen requires a biologically robust assay that represents a significant aspect of disease-relevant human
biology It can be used to identify molecular targets for target validation studies through the use of well-annotated
bioactive molecules or genomic libraries (eg RNAi CRISPER) Alternatively phenotypic screens can be used to identify
novel compounds that must subsequently be lsquoDE convolutedrsquo to identify novel targets using lsquowarheadsrsquo These screens rely
on identification and manipulation of a functional deficit or phenotype using a patient-derived cellular system
The strengths of this approach
Use of human systems can improve translatability
Identified compounds may empirically balance therapeutic activity at multiple required targets
Well-suited to drug repurposing
Phenotypic screens can be used to identify compounds or targets for mechanism based drug discovery programs
Many CNS drugs have been discovered using a phenotypic repurposing screen (Swinney and Anthony 2011)
Drawbacks to this approach
Assays are slow low throughput and more expensive as compared to cell-free assays
Cell-based assays may not predict circuit level or brain phenotypes
Furthermore as a primary screening approach
Precludes leveraging strengths in uHTS SBDD and parallel design
Every molecule must be de-risked independently thus safety can be very hard to predict
Drug Repurposing Drug Repurposing is a strategic pillar of the National Center for Advancing Translational Science (NCATS)
Details on resources and funding opportunities can be found here httpsncatsnihgovntu
Chemogenomic Files from industry partners Many companies have well designed and annotated chemical files that are
designed to cover the druggable genome with small molecule compounds from their proprietary collections Each
company has different criteria and stipulations associated with use of the library It is advisable to consult with TIDO
regarding terms and conditions associated with individual companies
ICCB-LongwoodKirby ADSF The ICCB screening center and the Kirby ADSF have multiple collections of compounds that
include bioactive or FDA approved molecules available for screening
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
Kirby ADSF libraries contact Dr Lee Barrett LeeBarrettchildrensharvardedu
References related to phenotypic screens and Drug Repurposing
Vincent F Loria P Pregel M Stanton R Kitching L Nocka K Doyonnas R Steppan C Gilbert A Schroeter T
and MC Peakman Developing predictive assays The phenotypic screening ldquorule of 3rdquo Sci Transl Med 7 293ps15
(2015)
Langedijk J Mantel-Teeuwisse AK Slijkerman DS Schutjens MH Drug repositioning and repurposing terminology and
definitions in literature Drug Discov Today (2015)
Swinney DC and J Anthony How were new medicines discovered Nature Reviews Drug Discovery 10 507-
519 (July 2011) | doi101038nrd3480
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
main menu
TNC Clinical Research and Regulatory Affairs Service Research Participant Registry CRC
Glossary of Terms
Glossary-of-Clinical-Trials-Termspdf
Clinical Research and Regulatory Affairs Service This Translational Neuroscience Center service facilitates the mission of the
Translational Neuroscience Center providing coordination among studies communications resource development and
implementation of new or ongoing preclinical and clinical studies The service is led by experts in protocol development
and launching of new studies The directors are available to guide TNC researchers in designing human studies including
the preparation of Institutional Review Board (IRB) and FDA submissions Additionally staff of the Clinical Research and
Regulatory Affairs Service will help researchers with recruitment plans budget development supervision of study
coordinators study monitoring and audit preparation For more information contact Co-Directors Kira Dies ScM CGC and
Stephanie Brewster MS CGC
KiraDieschildrensharvardedu
StephanieBrewsterchildrensharvardedu
Clinical Research Center (CRC) Assists investigators at BCH with research project initiation and implementation resources
in the CTSU for the conduct of clinical research visits and ancillary services education on research methods and practices
The CRC has biostatisticians project managers research specialists clinical trials specialists research coordinators and
highly skilled nurses and nurse project managers who work every day to facilitate the many research needs of the BCH
community httpwwwchildrenshospitalorgresearch-and-innovationresearchclinicalclinical-research-center
Clinical and Translational Study Unit (CTSU) The CTSU provides clinical research infrastructure for investigators in the design
initiation conduct and reporting of clinical research with the goal of translating scientific knowledge into new therapies for
pediatric conditions httpweb2tchharvardeductsu
Clinical Research Roadmap This clinical research map is designed to serve as a guide for investigators study coordinators
and research nurses at Boston Childrenrsquos Hospital The research map outlines the key steps in preparing to launch a
research study and provides embedded links to institutional resources tools and documents
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
Clinical Research Mappdf
main menu
Office of Sponsored Programs Research Administration TIDO
Many government and foundation grant opportunities are available for developing Drug Discovery Projects updated lists of
funding options exist on OSP and Research Administration web sites
Some good options for finding relevant requests for proposals
Translational Research Program annual call for proposals
Boston Childrenrsquos Hospital ndash Broad Institute Collaboration Grants Proposals will be reviewed by a joint Childrenrsquos Hospitalndash
Broad Institute committee Additional submission dates are expected for 2016
BCH_Broad collaborative grant 852015docx
Kirby Neurobiology Screening Pilot awards- available to Kirby Neurobiology PIs as funding is available
Translational Neuroscience Center- Pilot awards supported by trust sponsored donations as available Distributed through
TNC e-mail lists
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
ADDF The ADDF Academic Drug Discovery and Development Program seeks to create and support innovative translational
research programs for Alzheimerrsquos disease related dementias and cognitive aging in academic medical centers and
universities Biomarker development studies and innovative proof of concept pilot clinical trials of new approaches to
treatment prevention and early detection are also supported
Department of Defense ALSRP The FY15 Defense Appropriations Act provides $75 million (M) to the Department of Defense
Amyotrophic Lateral Sclerosis Research Program (ALSRP) to support innovative high-impact Amyotrophic Lateral Sclerosis
research As directed by the Office of the Assistant Secretary of Defense for Health Affairs the Defense Health Agency
Research Development and Acquisition (DHA RDA) Directorate manages and executes the Defense Health Program
(DHP) Research Development Test and Evaluation (RDTampE) appropriation The executing agent for the anticipated
Program AnnouncementsFunding Opportunities is the Congressionally Directed Medical Research Programs (CDMRP)
httpcdmrparmymilpubspress201515alsrppreannshtml
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
Michael J Fox Foundation Therapeutic Pipeline Program Supports Parkinsons disease therapeutic development along the
pre-clinical and clinical path (both drug and non-pharmacological therapeutics including gene therapy biological
surgical and non-invasive approaches) The Michael J Fox Foundation seeks applications with potential for fundamentally
altering disease course andor significantly improving treatment of symptoms above and beyond current standards of care
Proposals must have a well-defined plan for moving toward clinical utility for patients The Therapeutic Pipeline Program is
open to industry and academic investigators proposing novel approaches or repositioning approved or clinically safe
therapies from non-PD indications httpswwwmichaeljfoxorgresearchgrant-detailphpid=28
NINDS The Blueprint Neurotherapeutics Network (BPN) Provides the neuroscience community access to a complete and
seamless pipeline for preclinical drug development beginning with chemical optimization and concluding after phase I
clinical trials Participants in the BPN will receive funding to conduct bioactivity and efficacy testing in their own laboratories
as well as access to millions of dollars in NIH-contracted drug development services including medicinal chemistry
pharmacology toxicology and phase 1 clinical trials NIH will also provide drug development consultants who have had
years of experience working at a senior level in industry Because the Blueprint is establishing a network of drug
development service providers that typically cater to biopharmaceutical companies neuroscientists who join the BPN can
readily plug in to all of the drug development expertise that typically resides in industry The projects supported through the
network will be highly collaborative and the researchers who initiate the projects will serve as the principal investigators
(PIs) directing their projects through the development pipeline with the help of industry consultants The PIs and their
institutions will have the opportunity to attain assignment of intellectual property rights from all other network participants
who may have intellectual input into their projects This will allow the PIs to retain control of the intellectual property for drug
candidates developed through the network and eventually pursue licensing and commercialization partnerships
httpneuroscienceblueprintnihgovbpdrugs
NeuroNEXT Will establish a consortium of clinical sites capable of forming disease-specific cadres of investigators in order to
develop and implement trials rapidly in a wide range of neurological disorders that affect adults andor children With a
stable and experienced research staff a central IRB model and master trial agreements NeuroNEXT will streamline the
administrative processes for clinical trials and reduce start-up times NeuroNEXT will also be able to design and implement
evidence-based measures to improve patient recruitment into clinical trials httpswwwneuronextorgresearchers
NIMH Many grant options see overview here httpwwwnimhnihgovresearch-prioritiestherapeuticsindexshtml
Building on High Impact Basic Neurobiology Through Assay Development Advancing Tools for Therapeutic Discovery (R01) -
See more at httpgrantsnihgovgrantsguidepa-filesPAR-15-066htmlsthashs1HMWjWudpuf
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
NCATS many grant options see overview here httpwwwncatsnihgovprograms
Bridging Interventional Development Gaps (BrIDGs) Program Makes available on a competitive basis certain critical
resources needed for the development of new therapeutic agents for both common and rare diseases Investigators do not
receive grant funds through this program Instead successful applicants receive access to NIH experts and contractors who
conduct pre-clinical studies at no cost to the investigator In general synthesis formulation pharmacokinetic and
toxicology services in support of investigator-held IND applications to the Food and Drug Administration (FDA) are available
httpwwwncatsnihgovbridgsworksolicitation
NCATS Discovering New Therapeutic Uses for Existing Molecules (New Therapeutic Uses) A collaborative program designed
to develop partnerships between pharmaceutical companies and the biomedical research community to advance
therapeutics development This innovative program matches researchers with a selection of pharmaceutical industry
assets to test ideas for new therapeutic uses with the ultimate goal of identifying promising new treatments for patients
httpwwwncatsnihgovntu
Pfizer Centers for Therapeutic Innovation (CTI) Suitable for biotherapeutic or small molecule projects with a strong project
rationale (demonstrated association between target biology pathway and disease mechanism) CTIrsquos areas of interest
include inflammation autoimmunity tissue remodeling oncology cancer immunology rare or genetic diseases
cardiovascular and metabolic diseases and neuroscience Selected projects are undertaken by a joint team with BCH
members and Pfizer CTI drug development experts located on the 18th floor of CLS working towards agreed common
goals The Pfizer CTIBCH collaboration program is managed by a Joint Steering Committee with representation from both
Boston Childrenrsquos and CTI httpswwwpfizercticom Calls for proposals come through TIDO three times a year in January
May and September httpwwwchildrensinnovationsorgPagesHighlightsHighlights-83aspx
Shire-BCH Collaborative Program Development The Joint Steering Committee of the Shire Alliance extends a call for ldquoPre-
Proposalsrdquo with defined objectives from time to time generally annually in the late fall or winter That call is publicized
through emails from BCH Research Administration and TIDO Following review by the JSC a full proposal may be requested
Unsolicited proposals may also be considered from time to time
ACRONYMS
HTS- High-throughput Screen run with 96 well 384 well 1536 wells or 3456 well capacity- screen has capacity to run through a library of 1-3Million compounds in total
uHTS- Ultra High-throughput Screen ndash arbitrary cut off to denote capability to measure 100s of thousands of assays per day with automation and high density plate readers
HCS- High Content Screen usually a cell based assay that is able to monitor multiple endpoints reflective of different cellular processes in a single well of cells treated with a compound May be biochemical or image based endpoints
SAR- Structure-Activity Relationship ie relationship of modifications to chemical structure on relevant activity SPR-Structure-Property Relationship ie relationship of modifications of chemical structure on physicochemical
properties
PK- Pharmacokinetic measure of drug levels in a body compartment
PD- Pharmacodynamic a measure of functional activity of a drug
PKPD- PharmacoKinetic PharmacoDynamic relationship- how drug levels relate to drug response in a system
DDI-Drug-Drug Interactions- occurs when one drug affects the activity of another drug when co- administered Often due to changes in ADME properties of one of the co-administered drugs (ie for example induction by one drug of enzymes that will metabolize the second drug )
DMPK- Drug Metabolism and PharmacoKinetics
ADME- Absorption Distribution Metabolism amp Excretion
PDM-pharmacokinetics dynamics and metabolism GLP- Good Laboratory Practice- regulations that govern toxicology studies required by the FDA to support IND
and NDA
POM- Proof of Mechanism clinical studies to demonstrate hit the target and elicited a biological response
POC- Proof of Concept Clinical studies to demonstrate a clinically meaningful outcome measure improved
PoP-Proof of Principal usually preclinical studies that demonstrate that engaging target in a disease model produced efficacy
FIH- First in Human clinical trial to evaluate new molecule in humans for safety and PK- Ph1
FIP-First in Patient first clinical trial to evaluate new molecule in patients hERG (the human Ether-agrave-go-go-Related Gene) is a gene KCNH2 that codes for a subunit of Kv111 and
contributes to the repolarizing current in the heart that coordinates the hearts beating When compromised by application drugs or by rare mutations in some families it can result in a potentially fatal disorder called long QT syndrome A number of clinically successful drugs in the market have had the tendency to inhibit hERG and create a concomitant risk of sudden death as a side-effect which has made hERG inhibition an important anti-target that must be avoided during drug development
IND-Investigational New Drug Application- formal application to FDA to evaluate a NCE in people
NME- New Molecular Entity- a new FDA approved drug
NCE-New Chemical Entity-an investigational drug that is not yet a FDA approved NME NDA- New Drug Application (A lsquoFilingrsquo)- a formal application for approval of a new drug
CAN-(Pfizer-specific shorthand )-Clinical Candidate- a molecule competent to be tested in humans IB- Investigators Brochure- basic information on an investigational drug and its mechanism for clinicans involved
in conducting a clinical trial Provides background information on the hypothesis being tested and the types of patients that should be included excluded and risks and how the drug should be administered It must be updated continually by the sponsor to include all new findings
SOC- Standard of Care- in our context it is the drug treatment that a clinican should prescribe for a particular type of patient used as a benchmark for comparing new entities
MTD- Maximum Tolerated Dose- first identified in GLP safety studies during preclinical development AE- Adverse Event- a side effect that causes safety concerns
TI- Therapeutic Index -ratio of the concentration of drug needed to produce efficacy and the concentration of drug that is safely tolerated ( also called ldquoSafety Marginrdquo)
Questions Contact Robin Kleiman- email RobinKleimanchildrensharvardedu office CLS 13070
Terms that relate to Targets Molecular target- the protein that binds drug to produce efficacy Off-Target- other proteins that bind the drug that do not relate to efficacy and may produce Adverse Events (AEs) Druggable target ndashcomes from a class of proteins that has successfully been targeted with small molecule drugs in
the past Primarily transporters enzymes receptors ion channels (Not protein-protein interactions transcription factors RNA binding proteins etc)
Druggable genome- about 3000 genes encoding all druggable proteins Druggability- the presence of protein folds (quarternary structures) that favor specific interactions with drug-like
molecules Exploratory target- Hypothesis that a modulating a target via a particular mode of action will be beneficial to a
particular patient population Validated target- Hypothesis regarding a target also has in vivo efficacy data for a disease or a disease model- along
with a complete understanding of how the target mechanism relates to disease- (also called lsquoProof of Principlersquo) Phenotypic screen- a screen for compounds that will reverse a phenotype the molecular target may not be known Systems pharmacology target(s)-a precisely defined combination or lsquofingerprintrsquo of molecular targets to be
modulated to correct a phenotype (Poly-pharmacology)
Terms that relate to programs
Biomarker- a physiological pathological or anatomical characteristic that is measured by an automated process or algorithm as an indicator of the normal biological process pathological process or biological response to a therapeutic intervention Many types of Biomarkers target engagement biomarkers stratification biomarkers efficacy biomarkers pharmacodynamic biomarkers etchellip
Laboratory Objectives-Criteria established at the start of the program to define the desired pharmacological properties of the molecule with regard to potency selectivity mode of action frequency and route of administration For antibodies would include minimal criteria for knock down stability etc
Therapeutic Modality- small molecule biologic RNAi stem cell etc
Screening tree Screening funnel- A decision tree for utilizing a panel of assays to identify molecules that meet the laboratory objectives
Terms that relate to molecules
Drug-like molecule- has physicochemical properties in line with known oral medications The molecule will be largely rule of 5 (RO5) compliant therefore small and moderately lipophilic Not related to pharmacological activity
Rule of Five (RO5)=Chris Lipinskirsquos rule of 5 states that a drug like molecule will have the following properties Molecular Weight of less than 500 a clogP lt5 fewer than 5 H-bond donors and the number of H-bond acceptors ( which is the sum of N and O atoms) is less than 10
Physicochemical properties- key properties of molecules include (calculated)Molecular Weight number of H bond acceptors and donors (measured) kinetic solubility pKa lipophilicity (logD logP)
Chemical tool -a compound with good potency and selectivity for a specified molecular target but fails to meet all criteria for safety PK or potency needed to become a clinical candidate Suitable for preclinical testing of hypothesis and proof of principal studies but not for lsquopreclinical developmentrsquo
Active molecule describes an individual chemical entity with measurable dose-dependent activity in a biological screening assay
Hit molecule refers to a molecule plus its related structural analogs for which there is an understanding of the structure-properties and structure-activity relationships (SPR and SAR) for a specific biological context Additionally preliminary drug disposition data (both in vitro and in vivo) provide an assessment of pharmacokinetic properties The available data provide a basis for further optimization of the hit series
Lead molecule refers to a molecule plus its related structural analogs that demonstrate o Sufficient exposure at pharmacologically relevant doses by the intended route of administration to explore
intended pharmacology in a relevant in vivo disease or pharmacodynamic model o Proof-of-principle or efficacy in a in vivo model that will be used to establish a margin of safety
Clinical candidate an optimized individual chemical entity derived from a lead series that demonstrates o a dose-response relationship via intended route and schedule of administration in relevant disease model o an exposure-based margin of safety in toxicology studies o In summary a clinical candidate is a molecule that is deemed competent for testing the primary disease
intervention hypothesis in humans
A laboratory notebook is a vital record of events leading to a patentable invention Therecorded information can establish dates of conception and reduction to practice of atechnology as well as the inventorship of a patent claiming the technology Below arefourteen rules you should follow when keeping lab notebooks
1 mdash Do use bound booksInventors should use permanently bound notebooks eg notebooks with spiral or glue bindings If loose-leaf sheets are used they should be consecutively numbered and eachpage should be dated signed and witnessed
2 mdash Do sign and date Each notebook should be signed and dated on the inside front cover to indicate the firstday the recipient started using the notebook Each entry should be dated and signed orinitialed
An independent witness ie someone who understands the technology but will not benamed as a co-inventor of the invention should sign and date each entry after the state-ment ldquoRead and understood by rdquo (The witness should preferably sign theentries on a contemporaneous or fairly contemporaneous basis but entries can also bereviewed signed and dated on a periodic eg weekly or monthly basis)
3 mdash Do use inkNotebook entries should be made in ink and in chronological order Entries should not beerased or ldquowhited outrdquo If an entry contains an error a line should be drawn through theerror and new text should continue in the next available space
4 mdash Donrsquot leave blank spacesBlank gaps between entries should be avoided If a blank space is left on a page a line orcross should be drawn through the blank space and the page dated to prevent subsequententries
5 mdash Donrsquot modifyPrior entries should not be modified at a later date If data were omitted the new datacan be entered under a new date and cross-referenced to the previous entry Record exper-iments when they are performed
6 mdash Do use past tenseUse the past tense (eg ldquowas heatedrdquo) to describe the experiments that were actually performed
Fish amp Richardson pc
Dorsquos and Don rsquo ts forKeeping Lab Notebooks
Boston
Dallas
Delaware
New York
San Diego
Silicon Valley
Twin Cities
Washington dc
FR
7 mdash Do explain abbreviations and special termsExplain all abbreviations and terms that are nonstandard Explain in context in a table ofabbreviations or in a glossary
8 mdash Do staple attachmentsAttachments such as graphs or computer printouts should be permanently attached to pagesin the notebook (eg by stapling) and both the attachment and the notebook page signedand dated If the attachment cannot be stapled it should be placed in an envelope and theenvelope stapled to the notebook page The envelope and page should then be signed andwitnessed making reference to the attachment being placed in the envelope
9 mdash Donrsquot remove originalsNo original pages should be removed from the notebook
10 mdash Do outline new experimentsWhen a new project or experiment is started the objective and rationale should be brieflyoutlined (eg in a short paragraph or by providing a flowchart)
11 mdash Do record lab meeting discussionsRelevant discussions from lab meetings should be recorded as should ideas or suggestionsmade by others The names of the people making the ideas and suggestions should be care-fully documented This information may be important in establishing inventorship
12 mdash Do provide detailRecord test descriptions including preferred operating conditions control conditionsoperable and preferred ranges of conditions and alternate specific materials Also recordtest results and an explanation of the results as well as photos or sketches of the resultsandor the test device Any conclusions should be short and supported by the factual dataOpinions or speculation about the invention should be avoided
13 mdash Do track notebooksIdeally each lab should maintain a catalog of notebooks in which each notebook is assigneda number and the name of the author of each notebook is recorded In addition the datethe author received the notebook as well as the date the notebook was completed andreturned should be recorded Upon leaving the lab the author should return all notebookschecked out by or to him
14 mdash Do save completed notebooksAll completed notebooks should be indexed (eg by number by author andor by subjectarea) and kept safely in a central repository together with corresponding patent applica-tions or patents Lab notebooks that relate to inventions on which patents have been grant-ed should be kept for the life of the patent plus six years
By J Peter Fasse
Fish amp Richardson pcIntellectual property complex litigation technology law800 818-5070wwwfrcominfofrcom
P ER SP EC T I V E
PHARMACOK INET I CS
Data gaps limit the translational potentialof preclinical researchRobin J Kleiman1 and Michael D Ehlers2
The absence of mouse pharmacokinetic reference data hinders translation An analysis ofrecent literature highlights a systematic lack of discussion regarding rationale for the selec-tion of dosing paradigms in preclinical studies and in particular for neuroscience studies inwhich the lack of brain penetration can limit target-organ exposure We propose solutionsto improve study design
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Despite widespread use of pharmacologicalagents in mouse models of human diseasethe literature lacks comprehensive pharmaco-kinetic profiles for such studies Coupled witha paucity of suitable data are shortcomingsin the training of experimental biologists inthe application of pharmacometric principlesto experimental study design Many authorssimply cite previously published studies tosupport the selection of a particular dose evenwhen the cited paper lacks drug exposuredata There is an assumption on the part ofresearchers that if a referenced study demon-strates a biological effectmdashthat is any measur-able physiological or behavioral effectmdashin arodent at a given dose then that same dosewill also effectively perturb disease-relevantmechanistic biology in a different study Thedanger occurs when the observed therapeuticeffects are not linked to drug-induced mecha-nistic alterations at the level of the target organLack of a drug exposurendashresponse relationshipin a target organ casts doubt on mechanisticinterpretations In addition any changes inthe route of drug administration vehicle prep-aration species used (rat versus mouse versusprimate) age or strain of animal transgenicmodification time points under investigationduration of dosing or organ targeted for inter-vention (for example brain versus a periph-eral tumor) can alter the relation between doseexposure and measured response In suchcases assumptions regarding the mechanisticbasis for observed therapeutic effects may nothold true
Preclinical pharmacological experimentsthat do not measure drug concentrations in
1Translational Neuroscience Center Kirby NeurobiologyCenter Department of Neurology Boston ChildrenrsquosHospital Harvard Medical School Boston MA 02115USA 2Neuroscience amp Pain Research Unit BioTherapeu-tics Worldwide Research and Development Pfizer IncCambridge MA 02139 USACorresponding author E-mail robinkleimanchildrensharvardedu (RJK) michaelehlerspfizercom (MDE)
the target organ run the risk of producing ex-posures that are too low or too high to inter-pret a mechanistic hypothesis Most drugs arenot selective over a large exposure range for asingle molecular target Confident evaluationof a therapeutic hypothesis requires an under-standing of the drugrsquos penetration and kineticswithin the target tissue as well as its potencyand selectivity for specific molecular targetsFurther investigators must consider the con-centration of the unbound fraction of drugthat is available to interact with the targetPublished reports often overlook the fact thatmany small molecules are more than 90bound to plasma or tissue proteins whichgreatly decreases the fraction of drug availableto bind to the intended target Thus in casesin which drug binding has a slow off-rate anorganismrsquos total drug exposure is not a predic-tor of drug available to interact with its target(1) The failure of some academic scientists toobtain relevant pharmacokinetic data impairsthe interpretation of preclinical research resultsand likely contributes to the acknowledgeddifficulties in replicating some academic liter-ature as reported by industry scientists (2 3)
Drug discovery teams in industry settingsroutinely collect pharmacokinetic data to aidin the mechanistic interpretation of in vivopreclinical data and to project optimal dosingparadigms for efficacy and toxicology studiesData required to evaluate brain penetrationare not typically collected by industry-baseddrug-discovery teams for compounds origi-nally developed for therapeutic indicationsthat do not obviously implicate the centralnervous system making this information es-pecially hard to find for many otherwise well-described drugs In addition because mousedata are not required for preclinical toxicologystudies (the more common small animal spe-cies for preclinical toxicology being rats)industry scientists do not often obtain pharma-cokinetic data from mouse experiments These
wwwScienceTranslationalMedicineo
issues are especially relevant for older drugsthat are potentially suitable for repurposingMany older drugs were discovered and char-acterized before routine pharmacokinetic-pharmacodynamic (PK-PD) modeling ofpreclinical drug exposure and its applicationto predicting human dosing became standardpractice Last pharmacokinetic data are notconsidered innovative and these studies gen-erally do not achieve publication in peer-reviewed journals even when the data havebeen generated When such data are pub-lished it is often relegated to the unsearchableblack hole of supplementary materials Thusmouse neuroPK profiles are not readily avail-able for many drugs that are frequently usedin conjunction with mouse models of humanbrain disorders
DOCUMENTING DOSING STRATEGIES
To evaluate the potential impact of insufficientpharmacokinetic data on dose selection in asample of recent published neuroscience liter-ature we conducted an analysis of papersidentified by means of a PubMed search usingthe search terms ldquodrugrdquo and ldquobrainrdquo for the pub-lication year 2014 from eight journals (Table 1)This list was culled to include only primaryresearch reports that included systemic adminis-tration of a pharmacological agent a pharma-cological therapeutic or a biological therapeuticas part of the study design The search yielded100 articles published between 1 January and30 December 2014 that used systemic drug de-livery with the intended goal of targeting thebrain of rodents (table S1) Each publicationwas examined for the stated rationale behindthe dose selection of study drugs (Table 1)
The reported rationale for dosing strategiesfell into several broad categories including(from lowest confidence to highest) (i) dose se-lected rationale not discussed (ii) literaturecitations of another study in which reportsranged from citation of exposure in the samespecies exposure in a different strain or spe-cies a dose conversion from the human liter-ature to rodent or reports of effects on rodentbehavior in another study (iii) demonstrationof an effect on rodent behavior or function inthe current study (iv) demonstration of adose-responsive biological effect in the currentstudy (v) measurement of drug levels in bloodor plasma in the current study and (vi) mea-surement of drug levels in the target organ(that is the brain) in the current study In onlytwo instances were publications identifiedthat considered the impact of drug binding
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to plasma or brain proteins on the free expo-sure of drug available to interact with the tar-get This is a critical flaw in most publishedstudies that use small molecules for functionaleffects in the brain because many centralnervous system (CNS) drugs that penetratethe blood-brain barrier exhibit high proteinbinding leaving a small fraction of the totaldrug measured in plasma or brain unbound
and free to interact with the molecular targetFurthermore most studies used evidence of abiological activity to justify dose selection with-out consideration for how exposure of theagent relates to the potency of the compoundat known molecular targets which would berequired to test a mechanistic hypothesis
The lack of pharmacokinetic considera-tion does not imply that every study used an
wwwScienceTranslationalMedicineo
inappropriate dose of drug to test their hypoth-esis It does illustrate that a clear rationale wasnot provided for dose selection in most pub-lications Furthermore all 11 of the 100 publi-cations that measured total brain exposureincluded an author from the pharmaceutical in-dustry (n=5) an academic drug screening group(n = 3) or a pharmacologyndashpharmaceuticalsciences department (n = 3) This observationlikely reflects the limited presence of pharma-cology and pharmacometrics departmentswithinmost academic institutions and limitedaccess to the mass spectrometry and otheranalytical resources needed to measure druglevels in study samples Outsourcing the bio-analysis of samples collected from study ani-mals is feasible but the use of contract researchorganizations to support such studies is oftentoo costly for most academic grant budgets toaccommodate
DATABASES AND REPURPOSINGRecent years have seen increasing efforts toinvestigate approved or clinically tested drugsfor new indications (4ndash8) Such repurposinghas been touted as a means to accelerate ther-apeutic development (4) For example a stra-tegic pillar of the US National Institutes ofHealthrsquos (NIHrsquos) translational roadmap callsfor the academic community to actively par-ticipate in the repurposing of drugs approvedby the US Food and Drug Administration(FDA) or investigational drugs that havepassed safety hurdles but failed in clinicaltrials because of lack of efficacy (9ndash11) To havea meaningful impact in neurological and psy-chiatric disorders such drug repurposingefforts will require access to neuropharma-cokinetic (neuroPK) data sets in mice to guidethe testing of new therapeutic hypotheses ingenetically engineered disease models A re-cently published consensus evaluation of drugrepositioning opportunities for Alzheimerrsquosdisease identified 15 potential drug candidatesThese were further prioritized for testing onthe basis of available evidence to produce ashortlist of seven compounds reviewed by in-dustry experts to provide insight into the via-bility of these candidates The most commonshortcoming identified for the compoundsconsidered were issues related to insufficientbrain penetration or the lack of informationabout optimal dosing strategies (11)
The repurposing of statins illustrateshow the neuroPK knowledge gap limits progressStatins were developed as 3-hydroxy-3-methylglutarylndashcoenzyme A (HMG-CoA) reduc-tase inhibitors to lower cholesterol and reduce
Table 1 Preclinical dosing strategies The rationale for drug-dosing strategies was extractedfrom the literature through the analysis of 100 peer-reviewed studies published in2014 from eight journals that cover research on mechanisms of brain function disease andtherapeutic approaches to CNS disorders (Cell Neuron Nature Nature Neuroscience NatureMedicine Neurobiology of Disease Neuropsychopharmacology and Science TranslationalMedicine) (table S1) Forty-four of the 100 publications selected were studies of potentialtherapeutic approaches to disease whereas the remaining were studies of basic neurobiology ormechanisms of disease Each publication was examined to discern how authors selected thedosage of pharmacological tools or therapeutic compounds used in the design of studies toprobe brain function A relatively small number of studies considered what the concentrationof drug available in the brain after administration would be in the context of theirexperimental studies The most common method for selecting a dose of drug was tocite a previous study that demonstrated a biological effect of the drug on someaspect of rodent behavior
Rationale for studyrsquos drug-dose selection
Therapeutic
studies
Number of papers from the100 published studies
analyzed
bull No exposure or rationale for dose selection provided
5
22
bull Rodent dose extrapolated from human studies
0
1
bull Doses are similar to what was used previously toproduce a biological effect
8
23
bull Literature reports cited for multiple functionaleffects of drug at selected dose
4
5
bull Brain penetration evaluated but exposure notmeasured
2
2
bull Literature report of mismatched drug exposure
0
1
bull Observation of a biological effect at a single dosein current study
3
6
bull Observation of dose-responsive biological effectin current study
5
16
bull Brain exposure to drug was measured with routeof administration that differed from the oneused in the efficacy study
1
1
bull Plasma drug concentrations measured literaturereport of brain exposure cited and target-organpharmacodynamic effect observed in the currentstudy
1
1
bull Plasma drug concentrations measured
4
7
bull Brain pharmacodynamic effect of drug observed
2
4
bull Brain drug concentrations measured (totalconcentration)
6
7
bull Unbound brain drug concentrations measured
1
2
bull Brain drug concentrations measured and brainpharmacodynamic effect of drug observed
2
2
Total
44
100
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risk of cardiovascular disease (12) FDA hasapproved at least nine different statins andmost are commonly prescribed nearly one-third of Americans ages 55 to 64 took a pre-scription cholesterol-lowering drug between2009 and 2012 (wwwcdcgovnchsdatahushus14pdf) The widespread availability andsafety profile of statins has lured researchersinto evaluating their potential for repurpos-ing (13) Statins have been profiled extensive-ly in preclinical research to test for potentialtherapeutic benefit in Alzheimerrsquos disease(14ndash19) Fragile X syndrome (20) Rett syn-drome (21 22) epilepsy (23) Huntingtonrsquos dis-ease (24) Parkinsonrsquos disease (25 26) stroke(27) and brain injury (28 29)
A search of the literature reveals no sys-tematic neuroPK studies in any mouse strainthat would enable direct comparisons of CNSexposure across the various statins In silicopredictions based on the drugsrsquo molecularproperties suggest that the nine most widelyprescribed statins each have a different poten-tial to penetrate the blood-brain barrier differ-ent potencies against the HMG-CoA reductaseenzyme and different ldquooff-targetrdquo activity pro-files (30) On the basis of available data thereis reason to believe that simvastatin has thebest overall profile for inhibiting HMG-CoAreductase in the brain (30) A recent study re-ported that lovastatin is able to reverse a rangeof phenotypes in a mouse model of Fragile Xsyndrome (20) However the design of an op-timal clinical trial will require the collection ofmouse pharmacokinetic data to understandhow much CNS drug exposure is required toproduce efficacy in the disease model Thereare at least two possible scenarios Giventhat simvastatin is more potent at inhibitingHMG-CoA reductase than are other statinsand likely to be more brain penetrant inboth mice and humans one would expectthat simvastatin will be more potent than lo-vastatin in ameliorating symptoms in bothmice and humans if the observed efficacy stemsfrom inhibition of HMG-CoA reductase activ-ity in the brain by lovastatin The advantage ofthis outcome would be that better brain pen-etration and potency would lead to a loweroverall dose requirement to achieve efficacyand thus likely a better safety profile
A second scenario could be that lovastatin ismore potent than simvastatin in the mousemodel of Fragile X syndrome because of anadditional biological activity inherent to thelovastatinmolecule whichmaynot yet be doc-umented in the literature In either case un-derstanding the CNS exposure of lovastatin
required to produce efficacy in themouse willdetermine whether there is a safe therapeuticindex for achieving the required concentra-tion in patients Previous attempts to discernuseful neuroPK parameters from the litera-ture for the use of statins in rodent modelshave highlighted the lack of critical data asthe looming roadblock to progress in the field(31 32) Until these data exist the transla-tional potential of preclinical research maybe limited And this is but one example ofone drug class
The creation of a centralized database isneeded for the entire translational researchcommunity and would establish a new mech-anism for academia funding agencies founda-tions and industry to pool resources If studiesare donewell the first time and documented inan open-access resource it will reduce redun-dant efforts and improve the quality of decisionmaking by scientists considering innovativesolutions to our biggest health problems
FILL THE GAPSManuscript submission practices for severalhigh-impact journals now include require-ments that authors include detailed informa-tion regarding study design and statisticalanalysis with each submission A reasonableextension of this checklist should includethe stated rationale for doses selected for studydrugs Information should include a discus-sion of data highlighted in Table 2 Authorsshould be expected to reference a relevant
wwwScienceTranslationalMedicineo
data set from a high-quality database or pub-lication or provide the data in the current study(Table 3)
Industry biologists learn basic principlesof medicinal chemistry pharmacokineticsand drug disposition while working on drugdiscovery project teams Academic groupsare playing an increasing role in transla-tional therapeutics and in particular drugrepurposing Academic programs need toaugment training in pharmacokinetics andpharmacodynamics so as to increase the rigor ofpreclinical work and to ensure that investigator-initiated clinical studies are testing hypotheseseffectively Institutions without a departmentof pharmacology or pharmacometrics mightlack the organizational knowledge needed toconduct drug studies and must identify re-sources or collaborators to patch these defi-cits Formal coursework and Web-basedresources and tutorials are needed to train andsupport translational researchers Manuscriptand grant reviewers need to demand higherstandards for preclinical studies with respect toreporting on drug exposure associated withbiological effects Ethics committees responsi-ble for review of animal protocols should re-quire investigators to provide rationale fordose selections in proposed studies Similarlyscientific review boards at academic medicalcenters need to include clinical pharmacologistswho are able to review investigator-initiatedclinical studies to ensure that proposed dosingstrategies will test a meaningful hypothesis
Table 2 Recommendations for use of pharmacokinetic data The first column includes a listof recommended data sets to aid reviewers of submitted articles in the interpretation ofpreclinical findings The second column includes a list of useful reference data that wouldsupport improved preclinical study design in mice if available in a public database
Literature reports that evaluate studydrugs should include
Compound-specific data that shouldbe included in a rodent
pharmacokinetic database
bull Expected or measured plasma exposure of thestudy drug in the preclinical species during thestudy
bull Elimination half-life (T12)bull Systemic clearance (CL)bull Fraction of drug that is protein bound (fb)
bull Expected or measured target organ exposureof the study drugs in the preclinical speciesduring the study
Maximum plasma concentration after drug admin-istration (Cmax) and time to reach maximum plas-ma concentration (Tmax) for a standardized doseand route of administration
bull Expected or measured free fraction (unboundby protein) of the study drugs in the targetorgan of the preclinical species during thestudy
bull The ratio of drug in brain to that in plasma (BP)bull The ratio of drug found free in brain (Cub) to thatfound free in the plasma (Cup) defined as CubCupbull Any potential impact of drug transporters (foundon the rodent blood-brain barrier) in limiting brainexposure
bull Expected or measured potency of the studydrug against the hypothesized activity in vitro
Expected ormeasured potency of molecule at knownbiological targets
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A central repository that contains brainpenetration protein binding and pharmaco-kinetic profiles of drugs and pharmacologicaltools in rodents is needed to effectively sup-port translational research This databaseshould also provide basic tutorials that de-fine primary pharmacokinetic parameterswith examples to illustrate how data are usedto predict optimal dosing strategies The min-imum data set needed for each compoundin a useful rodent database is highlighted inTable 2 Access to this information and sup-porting materials will have an immediateimpact on the quality of translational drug re-purposing efforts across brain disorders andwill support the development of new thera-peutic approaches to neurological disordersand mental illness Existing databases man-aged by NIH or precompetitive consortia couldbe reinforced with donated pharmacokineticdata sets and tutorials
Industry and government scientists shouldwork precompetitively to collect and curatepharmacokinetic data sets in conjunction withsupporting educational materials Mouse phar-macokinetic data exist inside pharmaceuti-cal companies for a wide range of publicallydisclosed molecules and literature standardsRelease of these data into a public databasewould provide several benefits to companiesincluding (i) increased scientific rigor in theliterature with a higher probability of repro-ducibility (ii) increased appreciation by theacademic biology community for the diffi-culty inherent in generating molecules withpotency and pharmacokinetic profiles suit-able for in vivo work opening the door forin-kind collaboration with academic groups
and (iii) direct comparison of data collectedin-house to that collected at other compa-nies or institutions to enable better internalquality control Comprehensive pharmaco-kinetic data sets will benefit all therapeuticareas regardless of whether the brain is thetarget organ because peripheral and cen-tral exposure data can be generated fromthe same experiments Moreover the prin-ciples described above for the CNS apply toother target tissues in which vascular bar-riers metabolic processes or active transportalter the distribution of systemically admin-istered drugs
Key to ensuring that preclinical mousestudies test the hypotheses they aim to eval-uate is an understanding of the unboundfraction of drug present in the target organat an appropriate time point under studyGrant and journal reviewers need to care-fully consider whether authors of propos-als and manuscripts are providing adequaterationale for their choices of preclinical dos-ing paradigms Importantly the collectionand centralization of rodent pharmacoki-netic datasets will promote efficient genera-tion of future data reduce the collection ofredundant data and improve the return oninvestment for research funds that are de-voted to preclinical studies aimed towardclinical translation
SUPPLEMENTARY MATERIALS
wwwsciencetranslationalmedicineorgcgicontentfull8320320ps1DC1Table S1 One hundred publications that used systemic drugdelivery with the goal of targeting rodent brains
wwwScienceTranslationalMedicineo
REFERENCES AND NOTES1 A Reichel Addressing central nervous system (CNS) penetra-
tion in drug discovery Basics and implications of the evolv-ing new concept Chem Biodivers 6 2030ndash2049 (2009)
2 F Prinz T Schlange K Asadullah Believe it or not Howmuch can we rely on published data on potential drugtargets Nat Rev Drug Discov 10 712 (2011)
3 C G Begley L M Ellis Drug development Raisestandards for preclinical cancer research Nature 483531ndash533 (2012)
4 P Nair Second act Drug repurposing gets a boost asacademic researchers join the search for novel uses ofexisting drugs Proc Natl Acad Sci USA 110 2430ndash2432(2013)
5 T I Oprea J Mestres Drug repurposing Far beyond newtargets for old drugs AAPS J 14 759ndash763 (2012)
6 S M Strittmatter Overcoming drug development bot-tlenecks with repurposing Old drugs learn new tricksNat Med 20 590ndash591 (2014)
7 K Xu T R Coteacute Database identifies FDA-approved drugswith potential to be repurposed for treatment of orphandiseases Brief Bioinform 12 341ndash345 (2011)
8 X Bosch European researchers drug companies joinforces against rare diseases JAMA 294 2014ndash2015 (2005)
9 F S Collins Mining for therapeutic gold Nat Rev DrugDiscov 10 397 (2011)
10 P Vallance P Williams C Dollery The future is much closercollaboration between the pharmaceutical industry andacademic medical centers Clin Pharmacol Ther 87525ndash527 (2010)
11 A Corbett J Pickett A Burns J Corcoran S B DunnettP Edison J J Hagan C Holmes E Jones C KatonaI Kearns P Kehoe A Mudher A Passmore N ShepherdF Walsh C Ballard Drug repositioning for Alzheimerrsquosdisease Nat Rev Drug Discov 11 833ndash846 (2012)
12 J L Goldstein M S Brown A century of cholesterol andcoronaries From plaques to genes to statins Cell 161161ndash172 (2015)
13 A M Malfitano G Marasco M C Proto C Laezza P GazzerroM Bifulco Statins in neurological disorders An overviewand update Pharmacol Res 88 74ndash83 (2014)
14 T Kurata K Miyazaki M Kozuki N Morimoto Y OhtaY Ikeda K Abe Progressive neurovascular disturbances inthe cerebral cortex of Alzheimerrsquos disease-model miceProtection by atorvastatin and pitavastatin Neuroscience197 358ndash368 (2011)
15 H Kurinami N Sato M Shinohara D Takeuchi S TakedaM Shimamura T Ogihara R Morishita Prevention ofamyloid beta-induced memory impairment by fluvastatinassociated with the decrease in amyloid beta accumulationand oxidative stress in amyloid beta injection mousemodel Int J Mol Med 21 531ndash537 (2008)
16 M Shinohara N Sato H Kurinami D Takeuchi S TakedaM Shimamura T Yamashita Y Uchiyama H RakugiR Morishita Reduction of brain beta-amyloid (Abeta)by fluvastatin a hydroxymethylglutaryl-CoA reductaseinhibitor through increase in degradation of amyloidprecursor protein C-terminal fragments (APP-CTFs) andAbeta clearance J Biol Chem 285 22091ndash22102 (2010)
17 G J Siegel N B Chauhan D L Feinstein G Li E B LarsonJ C Breitner T J Montine Statin therapy is associated withreduced neuropathologic changes of Alzheimer diseaseNeurology 71 383 author reply 383 (2008)
18 X-K Tong C Lecrux P Rosa-Neto E Hamel Age-dependentrescue by simvastatin of Alzheimerrsquos disease cerebrovascularand memory deficits J Neurosci 32 4705ndash4715 (2012)
19 X K Tong N Nicolakakis P Fernandes B Ongali J BrouilletteR Quirion E Hamel Simvastatin improves cerebrovascularfunction and counters soluble amyloid-beta inflammationand oxidative stress in aged APP mice Neurobiol Dis35 406ndash414 (2009)
Table 3 Recommendations to improve translation through the use of preclinicalpharmacokinetic data
Journalsbull Require authors to provide explicit rationale for dosing strategies usedbull Rationale should include consideration of the unbound drug exposure in target organas best practices
Educationbull Include basic pharmacology and pharmacokinetic principles in formal coursework requiredfor basic preclinical and clinical research scientists
bull Develop tutorials and on-line calculators for rodent dose projections to support appropriateuse of published pharmacological tools
Databasesbull Reinforce public chemical databases with mouse pharmacokinetic data that includes brainexposure
Precompetitive consortiabull Create precompetitive consortia to solicit mouse pharmacokinetic data sets from industry andfoundation partners for database expansion
bull Targeted data collection for compounds already in the public domain
rg 6 January 2016 Vol 8 Issue 320 320ps1 4
P ER SP EC T I V E
20 E K Osterweil S C Chuang A A Chubykin M SidorovR Bianchi R K Wong M F Bear Lovastatin corrects ex-cess protein synthesis and prevents epileptogenesis in amouse model of fragile X syndrome Neuron 77 243ndash250(2013)
21 C M Buchovecky S D Turley H M Brown S M KyleJ G McDonald B Liu A A Pieper W Huang D M KatzD W Russell J Shendure M J Justice A suppressorscreen in Mecp2 mutant mice implicates cholesterol me-tabolism in Rett syndrome Nat Genet 45 1013ndash1020(2013)
22 M J Justice C M Buchovecky S M Kyle A Djukic A rolefor metabolism in Rett syndrome pathogenesis Newclinical findings and potential treatment targets RareDis 1 e27265 (2013)
23 F Scicchitano A Constanti R Citraro G De Sarro E RussoStatins and epilepsy Preclinical studies clinical trials andstatin-anticonvulsant drug interactions Curr Drug Targets16 747ndash756 (2015)
24 M L Ferlazzo L Sonzogni A Granzotto L Bodgi O LartinC Devic G Vogin S Pereira N Foray Mutations of theHuntingtonrsquos disease protein impact on the ATM-dependentsignaling and repair pathways of the radiation-inducedDNA double-strand breaks Corrective effect of statins andbisphosphonates Mol Neurobiol 49 1200ndash1211 (2014)
25 E K Tan L C Tan Holding on to statins in Parkinsondisease Neurology 81 406ndash407 (2013)
26 B Friedman A Lahad Y Dresner S Vinker Long-termstatin use and the risk of Parkinsonrsquos disease Am J ManagCare 19 626ndash632 (2013)
27 M S Elkind Stroke A step closer to statin therapy forstroke Nat Rev Neurol 9 242ndash244 (2013)
28 E E Abrahamson M D Ikonomovic C E Dixon S T DeKoskySimvastatin therapy prevents brain trauma-inducedincreases in beta-amyloid peptide levels Ann Neurol66 407ndash414 (2009)
29 E F Wible D T Laskowitz Statins in traumatic brain injuryNeurotherapeutics 7 62ndash73 (2010)
wwwScienceTranslationalMedicineo
30 S Sierra M C Ramos P Molina C Esteo J A VaacutezquezJ S Burgos Statins as neuroprotectants A comparativein vitro study of lipophilicity blood-brain-barrier penetra-tion lowering of brain cholesterol and decrease of neuroncell death J Alzheimers Dis 23 307ndash318 (2011)
31 W G Wood G P Eckert U Igbavboa W E Muumlller Statinsand neuroprotection A prescription to move the fieldforward Ann N Y Acad Sci 1199 69ndash76 (2010)
32 W G Wood W E Muumlller G P Eckert Statins and neuro-protection Basic pharmacology needed Mol Neurobiol50 214ndash220 (2014)
101126scitranslmedaac9888
Citation R J Kleiman M D Ehlers Data gaps limit thetranslational potential of preclinical research Sci Transl Med8 320ps1 (2016)
D
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ownloaded from
101126scitranslmedaac9888] (320) 320ps1 [doi8Science Translational Medicine
Robin J Kleiman and Michael D Ehlers (January 6 2016) Data gaps limit the translational potential of preclinical research
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Boston Childrenrsquos Hospital ndash Broad Institute Collaboration Grants
Background Meeting the challenges of biomedicine requires bringing together creative scientists exceptional technological resources and world-class expertise across many disciplines that rarely exist within a single institution This guiding principle is the basis for a funding opportunity to support Boston Childrenrsquos Hospital investigators performing research in collaboration with Broad scientists
Goals The fundamental goal of this new award is to spark new collaborations between Boston Childrenrsquos Hospital and the Broad Institute The grants will be awarded to address a very wide range of scientific questions but are specifically designated for projects with the following characteristics
middot Projects where engagement with the Broad would benefit Childrenrsquos Hospital investigators projects that can uniquely benefit from being done at the Broad Institute
middot Projects that create new scientific collaborations and bring together diverse scientific backgrounds projects that spark new scientific directions or technologies and are not currently being pursued at Childrenrsquos Hospital
middot Projects that pilot new approaches that researchers at Childrenrsquos the Broad and the greater scientific community can benefit from in the future the purpose of these awards is not to provide gap or extension funding of existing projects but to initiate new projects
Eligibility Individuals with Principal Investigator status at Boston Childrenrsquos Hospital are eligible Applicants need not be Associate Members of the Broad Institute
Broad Platforms and Scientists Broadrsquos Platforms (Genomics Imaging Metabolite Profiling Proteomics Genomic Perturbation and the Broad Technology Labs) are collaborative organizations that provide scientific leadership and cutting edge technologies in support of project goals Collaborations can also be established with other groups at the Broad including the Klarman Cell Observatory the Stanley Center for Psychiatric Research or the Center for the Development of Therapeutics
Budgets Grants will provide $60000 direct support for 1 year plus philanthropic overhead It is expected that most grants will fund work performed at the Broad Institute either through interaction with Broadrsquos Platforms or via collaboration with a Broad scientist however the work may also occur at Boston Childrenrsquos if it is important to meet the scientific goals of the collaboration
Deadline and Review process Final proposals are due by September 1 2015 Funding decisions are expected to be reached by October 1 2015 Proposals will be reviewed by a joint Childrenrsquos HospitalndashBroad Institute committee Additional submission dates are expected for 2016
Submission Applicants are strongly encouraged to discuss potential applications in advance with the office of the Chief Scientific Officer at the Broad Questions should be directed to Alex Burgin ( 617-714-7124)
Proteomics Genomic Perturbation and the Broad Technology Labs) are collaborative
organizations that provide scientific leadership and cutting edge technologie
s in support of
project goals Collaborations can also be established with other groups at the Broad including
the Klarman Cell Observatory the Stanley Center for Psychiatric Research or the Center for the
Development of Therapeutics
Budgets
Grants wi
ll provide $60000 direct support for 1 year plus philanthropic overhead It
is expected that most grants will fund work performed at the Broad Institute either through
interaction with Broadrsquos Platforms or via collaboration with a Broad scientist howev
er the
work may also occur at Boston Childrenrsquos if it is important to meet the scientific goals of the
collaboration
Deadline and Review process
Final proposals are due by September 1 2015 Funding
decisions are expected to be reached by October 1 201
5 Proposals will be reviewed by a joint
Childrenrsquos Hospital
ndash
Broad Institute committee Additional submission dates are expected for
2016
Submission
Applicants are
strongly encouraged to discuss potential applications in
advance
with the office of the Chief Sc
ientific Officer at the Broad
Questions should be
directed to Alex Burgin (
aburginbroadinstituteorg
617
-
714
-
7124
)
Boston Childrenrsquos Hospital ndash Broad Institute Collaboration Grants
Background Meeting the challenges of biomedicine requires bringing together creative
scientists exceptional technological resources and world-class expertise across many
disciplines that rarely exist within a single institution This guiding principle is the basis for a
funding opportunity to support Boston Childrenrsquos Hospital investigators performing research
in collaboration with Broad scientists
Goals The fundamental goal of this new award is to spark new collaborations between Boston
Childrenrsquos Hospital and the Broad Institute The grants will be awarded to address a very wide
range of scientific questions but are specifically designated for projects with the following
characteristics
Projects where engagement with the Broad would benefit Childrenrsquos Hospital
investigators projects that can uniquely benefit from being done at the Broad Institute
Projects that create new scientific collaborations and bring together diverse scientific
backgrounds projects that spark new scientific directions or technologies and are not
currently being pursued at Childrenrsquos Hospital
Projects that pilot new approaches that researchers at Childrenrsquos the Broad and the
greater scientific community can benefit from in the future the purpose of these awards
is not to provide gap or extension funding of existing projects but to initiate new
projects
Eligibility Individuals with Principal Investigator status at Boston Childrenrsquos Hospital are
eligible Applicants need not be Associate Members of the Broad Institute
Broad Platforms and Scientists Broadrsquos Platforms (Genomics Imaging Metabolite Profiling
Proteomics Genomic Perturbation and the Broad Technology Labs) are collaborative
organizations that provide scientific leadership and cutting edge technologies in support of
project goals Collaborations can also be established with other groups at the Broad including
the Klarman Cell Observatory the Stanley Center for Psychiatric Research or the Center for the
Development of Therapeutics
Budgets Grants will provide $60000 direct support for 1 year plus philanthropic overhead It
is expected that most grants will fund work performed at the Broad Institute either through
interaction with Broadrsquos Platforms or via collaboration with a Broad scientist however the
work may also occur at Boston Childrenrsquos if it is important to meet the scientific goals of the
collaboration
Deadline and Review process Final proposals are due by September 1 2015 Funding
decisions are expected to be reached by October 1 2015 Proposals will be reviewed by a joint
Childrenrsquos HospitalndashBroad Institute committee Additional submission dates are expected for
2016
Submission Applicants are strongly encouraged to discuss potential applications in
advance with the office of the Chief Scientific Officer at the Broad Questions should be
directed to Alex Burgin (aburginbroadinstituteorg 617-714-7124)
Clinical Trials Glossary
ADME an acronym for absorption distribution metabolism and elimination ADME
studies determine how a drug is absorbed by the body the chemical changes that it may
undergo and how it is eliminated from the body
Adverse event (AE) a bothersome event that occurs in a study participant AEs may be
related to the treatment being tested or may be due another cause (eg another treatment
another medical condition an accident or a surgery)
Arm a specific type of treatment to which a group of clinical trial participants is
assigned Some clinical trials have one arm and some have two arms while others have
three or more arms For example a clinical trial comparing two different doses of an
investigational drug versus a placebo would have three arms participants receiving a
higher dose of the investigational drug participants receiving a lower dose of the
investigational drug and participants receiving the placebo
Baseline a point in time at the beginning of a clinical trial before the study participants
receive any treatment At the baseline participants usually have certain types of tests
During and after treatment the same tests may be performed and the results compared
with the baseline results to see if the drug has caused changes
Bias a factor ndash such as a preconceived idea about the effects of the benefits and risks of a
treatment or a lack of balance in selection of patients for a study ndash that reduces the
likelihood that the study results are true Methods such as blinding and randomization
are used to limit the potential for bias
Bioavailability the portion of the dose of a drug that reaches the bloodstream For
example if the drug is administered intravenously its bioavailability is 100 percent
however if the drug is administered in any other way such as orally topically or
through intramuscular injection its bioavailability will decrease due to incomplete
absorption
Bioequivalence study a test performed to compare the portion of a drug in the
bloodstream when administered in different dosage forms
Biologic product any substance that can be used in prevention treatment or cure of
disease Some examples include vaccines blood virus toxin antitoxin and therapeutic
serum
Biopsy the removal of cells or tissue from a patient for examination which is usually
done under a microscope A tissue sample might be taken for genetic studies Sometimes
there is a difference between the blood genotype and the skin or other tissue genotype
This term can also refer to the tissue sample that has been obtained by such a procedure
2
Blinding a process used to prevent the participants the researchers or both from
knowing what specific treatment is being given to participants in a clinical trial The
process of blinding helps to reduce bias because study participants and researchers are
less likely to be unconsciously influenced by the knowledge of what the study participant
is actually receiving If only the participants are blinded the study is called a single-
blind study If both participants and researchers are blinded the study is called a double-
blind study
Carcinogenicity studies long-term studies conducted in animal models to determine a
drugrsquos likelihood of causing cancer
Clinical efficacy a compoundrsquos ability to produce the desired effect
Clinical pharmacology a science that studies properties of drugs in relation to their
therapeutic value in humans
Clinical study or Clinical trial a medical experiment in human beings that helps to
determine how a disease drug or medical device affects study participants Clinical
studies are necessary to answer specific questions about how to better diagnose prevent
or treat a disease or condition
Cohort a group of study participants who have certain characteristics in common such
as female sex a defined age range or particular severity of disease Dividing study
participants into cohorts is often done as part of the analyses of study data
Contraindication a factor that makes the use of a particular drug inadvisable For
example a person who has had an allergic reaction to penicillin in the past is considered
to have a contraindication to using penicillin in the future
Control group a group of participants not receiving the investigational drug but instead
receiving a standard treatment for their disease or receiving a placebo The results
observed in the group of patients receiving the investigational drug are compared with the
results observed in the control group
Crossover study a study design with two or more arms where participants receive one
treatment for a period of time and then switch over to a second treatment for a period of
time Such a study design allows the effects of the two treatments to be compared in the
same patient
Data Monitoring Committee (DMC) or Data Safety and Monitoring Board (DSMB)
A committee of experts that periodically reviews the accumulating data from an ongoing
multicenter clinical trial Members of a DMCDSMB must be independent ie they
cannot be participating as investigators in the clinical trial Based on their review the
DMCDSMB experts advise the sponsor regarding whether it is safe and acceptable to
continue with the study or whether the data suggest that the study should be modified or
stopped A DMCDSMB may recommend that a trial be stopped if there are safety
concerns or if the trial objectives have been achieved
3
Dose-ranging study a clinical trial in which two or more doses of an investigational
drug are tested to determine which dose is likely to offer the best combination of safety
and efficacy in later clinical trials or in medical care
Efficacy or effectiveness the ability of a drug to prevent cure or slow a disease process or to alleviate the symptoms of a disease or condition
Eligibility a determination made during the screening period for a clinical study of
whether a personrsquos participation in the trial is likely to be safe and can contribute data
that will help achieve the study goals
Endpoint occurrence of a disease symptom sign or test result that constitutes one of the
target outcomes of a clinical trial
Inclusionexclusion criteria the factors defined in the protocol of a study that determine
whether a personrsquos participation in a clinical trial is likely to be safe and can contribute
data that will help achieve the study goals Study candidates undergo evaluation during
the study screening period to determine if they meet all of the inclusion criteria and do
not meet any of the exclusion criteria as defined in the protocol These criteria usually
consider such factors as age sex type of disease stage of disease previous treatment
history and other medical conditions in determining eligibility for the study
Informed consent (assent) a process by which medical researchers provide necessary
information to a person about a clinical study and the person voluntarily confirms his or
her willingness to participate in the study Children who are considered old enough to
have a basic understanding of the study may need to provide assent to be involved in the
study a parent or legal guardian must also give informed consent for such a child to
participate
Informed consent (assent) form a document that describes a clinical study to the
participants (or their parentsguardians) The informed consent (assent) form includes
information about the goals of the study the study design and duration the types of tests
to be performed the potential risks and inconveniences the potential benefits the
possible costs or payments associated with study participation the available alternative
therapies the rights and responsibilities of the participant and the people to contact if the
participant has questions The informed consent (assent) form must be reviewed and
signed before the participant has any study tests or treatment including the tests
performed during the screening period at the beginning of the study Participants are
given a copy of the informed consent (assent) form to take home
Institutional Review Board (IRB) or Independent Ethics Committee (IEC) a board
of physicians statisticians researchers community advocates and others who are
responsible for ensuring the protection of the rights safety and well-being of participants
in a clinical trial at a study center This board is called an IRB in the United States and is
often called an IEC in other countries IRBIECs review and approve important study
documents (eg protocols informed consent forms study advertisements and patient
4
brochures) before the start of the study and periodically review the progress of the study
while it is ongoing
Investigational Drug a drug that is being tested as a potential treatment for a disease or
condition but has not yet been proven safe and effective for that use
Investigator a physician or other health care worker who carries out a clinical trial by enrolling treating and monitoring participants and recording the results
In vitro testing testing conducted in test tubes or other artificial environments
In vivo testing testing conducted in living animals or humans
Longitudinal study a clinical study that involves observations of the same items over
long periods often many decades Because longitudinal studies track the same people
they are often used to study trends across the life span to uncover predictors of certain
diseases or to track the effects of a particular treatment on a patientrsquos condition over
time
Multicenter study a study conducted at more than one location Multicenter clinical
studies are generally performed when each individual clinical trial site does not have
enough study candidates to complete a large trial
Natural history study a study of the natural development of a disease or condition over
a period of time Natural history studies are usually longitudinal studies
New Drug Application (NDA) the registration document through which a
pharmaceutical company formally proposes that the FDA approve a new drug for
manufacturing and sale The application includes detailed reports of pharmacology
toxicology manufacturing and chemistry as well as data from clinical trials
Open-label study a study in which the participants and the investigators know which
treatment is being given In an open-label study there is no blinding and none of the participants receives a placebo
Orphan disease a disease or condition that affects a relatively small number of people
In the US this defined as fewer than 200000 people In Europe this is defined as fewer
than five in 110000 people
Orphan drug a drug intended to treat an orphan disease
Participant or subject a patient or healthy volunteer who participates in a clinical trial
Phase 1 the initial phase of testing of an investigational drug in humans Usually a
Phase 1 clinical study is conducted in a small number of healthy volunteers or patients
with a disease for which the drug may be useful Generally the study is designed to
determine the side effects of the drug and its pharmacokinetics Some information
5
regarding drug efficacy may be collected if patients with a disease participate A phase
frequently encompasses more than one clinical trial Phase 1 sometimes is sub-divided
into Phases 1a and 1b for example when the first set of Phase 1 trials (Phase 1a) is
performed in healthy volunteers and a second set of Phase 1 trials (Phase 1b) is
performed in patients with a disease
Phase 2 the intermediate phase of testing of an investigational drug in humans Usually
a Phase 2 clinical study conducted in patients with a disease for which the drug may be
useful Generally the study is designed to evaluate dosing to obtain preliminary data on
the effectiveness of the drug and to acquire more safety information Phase 2 sometimes
is sub-divided into Phases 2a and 2b Phase 2a studies typically are smaller and shorter
in duration and evaluate different drug doses to see how they affect certain tests that can
indicate whether the drug is working as expected Phase 2b studies typically enroll more
patients are of longer duration and evaluate whether the drug is offering clinical benefits to patients Phase 2b studies sometimes are considered pivotal or registration-directed
Phase 3 the final phase of testing an investigational drug in humans before regulatory
approval Phase 3 studies are usually conducted in a large population of patients and are
generally designed to confirm the effectiveness of the drug and to evaluate the overall
risk-benefit ratio Phase 3 studies usually test the investigational drug in comparison with
a standard treatment for the disease or a placebo
Phase 4 testing of a drug in humans after it has already been approved by regulatory
authorities and can be used in medical practice Phase 4 studies may be conducted to
compare the drug to a similar type of drug to explore whether it may help patients with
other diseases to further study the long-term safety of the drug or for other reasons
Pivotal study a study that is designed to generate the data required by regulatory
authorities to decide whether to approve an investigational drug A pivotal study is
usually a large randomized Phase 2b or Phase 3 study and often is blinded and uses a
placebo as a control Sometimes a pivotal study is described as a registration-directed
study
Placebo an inactive version of an investigational drug A placebo has a similar
appearance to the investigational drug but is expected to have no therapeutic value A
placebo is used as a comparison treatment to reduce bias in randomized studies
Preapproval access program an umbrella term for programs that allow seriously ill
patients to receive an investigational drug when they are unable to participate in clinical
trials and there is no alternative treatment This is sometimes referred to as
compassionate use Types of pre-approval access programs include expanded access
parallel-track named patient program single-patient exemption and treatment IND The
timing for starting an expanded access program usually depends upon what is known
about the risk-benefit of the drug and whether the drug can be provided in a manner that
is fair to patients with the disease
6
Preclinical (nonclinical) testing testing of a drug in test tubes or in animals A drug
undergoes preclinical testing before being tested in humans to make sure that it shows
evidence of desired effects and is sufficiently safe for study in people Preclinical testing
sometimes also helps to determine the doses of the drug that should be evaluated in
humans Preclinical testing is sometimes called nonclinical testing
Protocol a document describing what types of people may participate in a clinical study
and the objectives treatments measurements statistical methods timing and
organization of a clinical trial The protocol must be prepared in advance of the study
and must be reviewed and approved by review committees and regulatory authorities
before the study is started Investigators must follow the protocol to carry out the study
Randomization assignment of participants to treatment arms based on chance This is
usually done by a computer program in a way that does not allow either the participants
or the investigators to choose who is assigned to which arm Randomization is used to
reduce bias in clinical trials
Risk-benefit ratio the balance of the risk of side effects expected with use of a drug
versus the potential for benefit with the use of that drug A drug with a good risk-benefit
ratio has few side effects and is very effective
Serious adverse event (SAE) an adverse event that is life-threatening requires inpatient
hospitalization or lengthens a hospital stay leads to substantial disability leads to a birth
defect or results in death
Side effect any effect of a drug other than the desired effect Side effects are often
unwanted and may be bothersome Other names for a bothersome side effect are adverse
drug reaction (ADR) or drug toxicity
Screening period a period at the beginning of a clinical trial when candidates for the
study are evaluated to determine if their participation is likely to be safe and can
contribute data that will help achieve the study goals
Significant or statistically significant an outcome in a clinical trial is likely to result
from a real difference (eg due to an effect of a treatment) and is unlikely to be due to
chance alone The level of statistical significance is often expressed in terms of a p-
value which indicates the probability that a difference is not due to chance alone
Usually a p-value smaller 005 is considered statistically significant
Sponsor the organization responsible for financing and coordinating a clinical trial
Most often this is a pharmaceutical or biotechnology company
Standard treatment a treatment currently in wide use often approved by regulatory
agencies and generally considered effective in the treatment of a specific disease or
condition
7
Toxicity a side effect produced by a drug that is bothersome to the person taking the
drug
Toxicology the study of the adverse effects of chemicals conducted in animal models to
predict potential adverse effects in humans Some studies are conducted during clinical
development to evaluate dosing regimens
Boston Childrenrsquos Hospital Clinical Research Map 1 Mouse over for additional info Bold = hyperlink
CLINICAL RESEARCH MAP
Boston Childrenrsquos Hospital Clinical Research Map 2 Mouse over for additional info Bold = hyperlink
ObjectiveThis clinical research map is designed to serve as a guide for investigators study coordinators and research nurses at Boston Childrenrsquos Hospital The research map outlines the key steps in preparing to launch a research study and provides embedded links to institutional resources tools and documents
An investigator need not follow the steps on the Clinical Research Map in any particular order There is flexibility and the steps followed will in part de-pend on the type of research study
For new as well as more experienced investigators the Clinical Research Map can be used as a checklist or an inves-tigator can use the steps on the map as points for consideration as they are developing a protocol and launching a study
This tool is not intended to substitute for the important collaboration be-tween a junior investigator and a senior investigatormentor A senior investiga-tor plays a pivotal role in coaching and advising a junior investigator regarding the many subtleties and variations that apply to designing and implementing a protocol
This process map cannot be inclusive of every possible task or step but is intended as a general guide for investi-gators and their study teams
ResourcesThere are many institutional resources at Boston Childrenrsquos Hospital designed to support investigators and their clini-cal research teams In addition to links to resources tools and documents that are embedded in the steps of the clini-cal research map the last page of this document contains website addresses that will take you to additional helpful institutional resources
Acknowledgements Cindy Williams DNP RN PNP NE-BC Nursing Director CTSU Clinical Research Nursing
Ellen McGrath MSN RN CPNP Nurse Practitioner Department of Surgery
Grace Yoon MSN RN CNNP Research Nurse Department of Ophthalmology
Laura Feloney BA Lab Technician
ContentsOverview Four stages 3
1st Stage Protocol development 4
1st Stage Protocol development contrsquod 5
2nd Stage Implementation planning 6
3rd stage Study launch7
4th stage Statistical analysis reporting and dissemination 8
Discarded specimens Additional steps 9
Chart review Steps if you are completing a chart review 10
Appendix A Resources for researchers 11
Boston Childrenrsquos Hospital Clinical Research Map 3 Mouse over for additional info Bold = hyperlink
Overview Four stages
Protocol development
Implementation planning
Study launch
Statistical analysis reporting and dissemination
1
2
3
4
Boston Childrenrsquos Hospital Clinical Research Map 4 Mouse over for additional info Bold = hyperlink
1st Stage Protocol development
Explore resources
CRIT
CRC
EQuIP
CTSU
Harvard Catalyst
Complete training
CITI training
EQUiP
Consult research pharmacistResearch Pharmacy
Rocco Anzaldi
Consult statistician
CRC
Draft a protocol
Protocol guidelines
Study personnel
FDA Guidance for Investigators
Consult Clinical Research Center
CRC
Bio Bank
Start IRB application
TransLab
Consider applying for grants
securing funding
Office of Sponsored Programs
If INDIDE application to FDA
Does my study need an INDIDE
Regulatory resources
Arrange a consultation with
CRIT
ConsultationTasks for investigators and study teams
Boston Childrenrsquos Hospital Clinical Research Map 5 Mouse over for additional info Bold = hyperlink
Respond to IRB questionsrequests
for clarification
1st Stage Protocol development contrsquod
Departmental Scientific Review
Organize DSMB design DSMP
DSMPDSMB
Templates for Research Study
Documents and Tools
Study Templates and Tools
Investigators who sponsor an FDA regulated trial
ClinicalTrialsgov
Create regulatory binder
Regulatory Binder Template
Submit the grant application to OSP
OSP
TIDO
CTBO
Consult Office Intellectual Property
Technology and Innovation
Development Office
TIDO
IRB approval
Consider blood volume for research
Research blood volume policy
Confidentiality plan
Confidentiality guidelines
Boston Childrenrsquos Hospital Clinical Research Map 6 Mouse over for additional info Bold = hyperlink
Develop Case Report Forms
(CRFs)
CRF guidelines
Establish electronic shared
folder or study binder for study
documents
CRIT
Set date for trial launch
Develop fast fact sheet for bedside staff
Consult programmer re database
CRIT
Research study resource manual
for the clinical unit
Confirm study drug
in pharmacy
Rocco Anzaldi
Clarify system for screening
and enrolling patients
Recruitment guideline
Updated protocol to
nurse manager
Consult MDsNPs on unitclinic
2nd Stage Implementation planning
Tasks for investigators and study teams
Study logistics Documentation logistics
Data storage
Confidentiality plan
Confidentiality guidelines
Create study orderset
Consider blood volume for research
Research blood volume policy
Create Manual of Operations
MOO Guide
Study implementation
meeting
Develop study logstools
EQUIP
Finalize tracking sheet
Research Administration
Fernando Valles
Boston Childrenrsquos Hospital Clinical Research Map 7 Mouse over for additional info Bold = hyperlink
3 Document informed consent
Informed Consent
Consent library
Schedule weekly study team meeting
Communicate to department faculty
and multidisciplinary
team announcing trial launch
Steps before trial launch
3rd stage Study launch
Patient flow
1 Seek permission
to approach potential subjects
2 Screenenroll
patients
EQUIP
5 Send Study
Tracking Sheet (STS)
6 Collection of
patient data and assessing for
adverse events
7 Study
documents and data handling
4 Datetime study tests
Create a checklist outlining study action items for each subject
Boston Childrenrsquos Hospital Clinical Research Map 8 Mouse over for additional info Bold = hyperlink
Annual IRB Report
Annual Progress ReportStaff Report
raquo Maintain Interest of Staff
raquo Important to See Study Progress
Write Abstract
Dissemination of Research Results
raquo Conference raquo Internal Presentation for Colleagues
raquo Publication
Plan DSMB MeetingInterim
Analysis
4th stage Statistical analysis reporting and dissemination
Data Entry
When Enrollment Complete Data
Cleaning
Monitor Subjects to Identify
Adverse Events (CCI sponsor
DSMB)
Report Adverse Events
Update MOO Based on Experience
with First Several Patients Enrolled
Weekly Study Team Meeting
Report study findings to
subjects and stakeholders
Data management Trial management
Reporting Dissemination
Regular Review of Data
to Identify Deviations
and Workflow Improvements
Consult Statistician When Approaching Target Enrollment
Discarded specimens Additional steps
Boston Childrenrsquos Hospital Clinical Research Map 9 Mouse over for additional info Bold = hyperlink
Send IRB Approval to lab manager
Maureen Samson
Educate staff in areasunits about sample collection
Locate the discarded samples
Locate the accession number in PowerChart
Retrieve specimen
Mark Kellogg
Follow Shipping Rules and Procedures
IATAShipping with dry ice instructions
Communicate with laboratory staff
Contact Dr Mark Kellogg to discuss specimen retrieval
Consult with Biorepository
Biorepository
Chart review Steps if you are completing a chart review
Boston Childrenrsquos Hospital Clinical Research Map 10 Mouse over for additional info Bold = hyperlink
7 8
4321
Databaserecord review guidelines
5 6
Consult programmer re database
CRC Request
Respond to IRB questions
requests for clarification
Departmental Scientific Review
Complete training
CITI Training
Draft a protocol
Protocol Guidelines
Prepare IRB Application
Information about the CCI
IRB Application
Develop Case Report Forms (CRFs)
CRF Guidelines
IRB Review
Boston Childrenrsquos Hospital Clinical Research Map 11 Mouse over for additional info Bold = hyperlink
Clinical Research Center (CRC) x84720
Committee on Clinical Investigation (CCI IRB) x57052
Research Pharmacist x52014
Clinical and Translational Science Unit (CTSU) x57541
Education and Quality Improvement Program (EQUIP) x57052
Clinical Trials Office Central Budgeting x4-2714
Office of Sponsored Programs x4-2723
Technology and Innovation Development Office 617-919-3079
Research Finance x8-3517
Harvard Catalyst 617-432-7810
Regulatory Affairs x4-2777
Appendix A Resources for researchers
RES_4446_ClinicalResearchMap-FINAL FOR LINKS 1
RES_4446_ClinicalResearchMap-FINAL FOR LINKS 10
Overview Four stages
1st Stage Protocol development
1st Stage Protocol development contrsquod
2nd Stage Implementation planning
3rd stage Study launch
4th stage Statistical analysis reporting and dissemination
Discarded specimens Additional steps
Chart reviewSteps if you are completing a chart review
Appendix A Resources for researchers
RES_4446_ClinicalResearchMap-FINAL FOR LINKS 11
RES_4446_ClinicalResearchMap-FINAL FOR LINKS 2
RES_4446_ClinicalResearchMap-FINAL FOR LINKS 3
RES_4446_ClinicalResearchMap-FINAL FOR LINKS 4
RES_4446_ClinicalResearchMap-FINAL FOR LINKS 5
RES_4446_ClinicalResearchMap-FINAL FOR LINKS 6
RES_4446_ClinicalResearchMap-FINAL FOR LINKS 7
RES_4446_ClinicalResearchMap-FINAL FOR LINKS 8
RES_4446_ClinicalResearchMap-FINAL FOR LINKS 9
RES_4446_ClinicalResearchMap-PAGE 5pdf
Overview Four stages
1st Stage Protocol development
1st Stage Protocol development contrsquod
2nd Stage Implementation planning
3rd stage Study launch
4th stage Statistical analysis reporting and dissemination
Discarded specimens Additional steps
Chart reviewSteps if you are completing a chart review
Appendix A Resources for researchers
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MOUSE OVER
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COVER BUTTON
Previous Page
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Button 91
Button 92
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IRB review
Button 102
Develop Case Report Forms
Button 136
Consult clinical research center
INDIDE 1
Explore resources
Button 1016
Bio Bank p
4
Consult statistician
Consult research pharmacist
Study personnel
Complete training
Consider grantsfunding
Draft a Protocal 2
Arrange a consutlations with CRIT
Next Page 1
Previous Page 1
TransLab
Start IRB application 3
Develop study logs
Updatedd protocol
Confirm study drug
Establish electronic shared
COnsult programmer
Clarify system
Research study resrouce manual
Develop case report forms
MOO
Set date for trial launch
Button 44
Study implementation meeting
Finalize tracking sheet
Data storage
Confidentiality
Blood volume 3
Develop fast fact
Consult MDs
Schedule weekly
Communicate early
Button 71
Screenenroll patients
Document informed consent
Datetime tests
Send study tracking sheets
Collection patient data
Button 77
Dissemination
Button 87
Button 124
Button 125
Communicate with lab staff
Button 106
Button 109
Button 1010
Shipping page 9
Button 1012
Button 99
Button 133
Button 134
Button 135
Biorepository
Locate assession number
Retrieve specimen
Button 30
Consult office
Negotiate Contract
Organizing DSMB
Submit Grant
Respond to IRB questions
Button 66
Create regulatory binder
Templates for research stufy
Clinical Trials Business Office
Blood volume 2
Confidentiality plan
Investigators who sponsor
clinicaltrials
gov
BPN Project
Drug Discovery amp Development Testing Funnel
Tier 1 2 3
Tier 6 7 8
Tier 5
Tier 4
Example Drug Discovery amp Development Testing Funnel
Cytotoxicity
Grant
Project
Example Drug Discovery amp Development Testing Funnel
TIER 1A ndash Primary Screen
Chemical purity and identity of active compounds
Primary bioactivity screen
Cell viability (When Appropriate)
ScaffoldsMoiety Chemical liabilities (for example Michael acceptor GSH reactive)
Calculated properties CLogP
PSA
Molecular Weight
rotatable bonds
H-bond donors and acceptors
permeability
pKa
Solubility
TIER 1B
Confirm EC50 determinations for actives compounds in primary screen with fresh
compounds from the original stock Confirm EC50 determinations for the lead (most
active) compound in primary screen with a new sample either repurchased purified
and characterized in-house or independently synthesized in-house
Compounds with IC50s (EC50s) less than X advance to Tier 2
TIER 2A ndash Activity Confirmation
Secondary screen
TIER 2B
Repeat EC50 determinations for actives in secondary screen with fresh
compounds from the original stock
Compounds with IC50s (EC50s) less than X advance to Tier 3
Example Drug Discovery amp Development Testing Funnel
TIER 3 ndash Drug-like Properties Specificity
IC50 selectivity in selectivity screen
CYP450 Inhibition competitive and time-dependent if structural alerts exist
(spot check illustrative examples from compound series)
Measured solubility
Measured protein binding (spot check illustrative examples from
compound series)
Test of Permeability in vitro permeability [indicate assay eg Caco2 orand
PAMPA] (spot check illustrative examples from compound series)
hERG
Cytoxicity assays
All compounds with no significant issues (Define Minimum Conditions for
Advancement) to advance to Tier 4
Example Drug Discovery amp Development Testing Funnel
TIER 4 ndash Scale-up Synthesis and Preliminary PK
Scale-up synthesis
Purity determination gt98 with no single impurity gt1
Rodent bioavailability and PK (define target delivery route) Tmax
Cmax
AUC
Bioavailibility
Vss CL T12 MRT
Brain to Plasma ratios
P-glycoprotein transport MDCK-MDR1 and MDCK-mdr1a
Plasma Protein Binding (species)
Microsomal Stability ndash rodent and human
Defineplan Patent Protection Strategy
All compounds with no significant issues (Define
Minimum Conditions for Advancement) advance
in parallel to Tiers 5AampB
Example Drug Discovery amp Development Testing Funnel
TIER 5A ndash In Vivo Bioactivity
Animal efficacy
Validate Biomarker
Target engagement
Advance to Tier 6 if (Define Minimum Conditions for advancement)
TIER 5B ndash Advanced Drug-like Properties
Microsomal stability in multiple
species
Chemical Stability
CYP450 induction
CYP reaction phenotyping
Metabolism ndash human
hepatocytesmicrosomes
Metab ID define major human rat dog and
non-human primates (NHP) metabolites
In vitro Tox Ames
Chromosome Aberration
CNS effects
Example Drug Discovery amp Development Testing Funnel
TIER 6 ndash Liability Assessment
Broad Pharmacological Profile and Toxicology
PK in second species
TIER 7
Non-GLP exposure studies single and multiple dose
Advance to late stage pre-clinical development (Define Minimum
Conditions for advancement)
Example Drug Discovery amp Development Testing Funnel
Principal InvestigatorProgram Director (Last First Middle)
enspenspenspenspensp
DETAILED BUDGET FOR INITIAL BUDGET PERIOD
DIRECT COSTS ONLY
FROM
THROUGH
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DOLLAR AMOUNT REQUESTED (omit cents)
NAME
ROLE ONPROJECT
TYPEAPPT (months)
EFFORTONPROJ
INSTBASESALARY
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FRINGEBENEFITS
TOTAL
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PrincipalInvestigator
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CONSULTANT COSTS
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SUPPLIES (Itemize by category)
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INPATIENT
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SUBTOTAL DIRECT COSTS FOR INITIAL BUDGET PERIOD
$
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CONSORTIUMCONTRACTUAL COSTS
DIRECT COSTS
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FACILITIES AND ADMINISTRATIVE COSTS
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TOTAL DIRECT COSTS FOR INITIAL BUDGET PERIOD
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copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
main menu
Resources available at BCH Assay Development Screening Funnel development Chemical compound files Assistance
with identification of academic and industry partners for collaborative SAR campaigns
Identification of the correct molecule requires a clearly defined set of laboratory objectives and a well-designed screening
funnel to select the molecule that will meet those objectives Laboratory objectives for a molecule include specific criteria
for the mode of binding to target (eg agonist partial agonist inverse agonist non-competitive inhibitor) the potency
(eg Ki lt30nM) selectivity (eg gt30X selectivity over family member target XY and Z) brain penetration (yesno) dosing
paradigm ( eg oral once daily intravenous once monthly) and duration of expected treatment (eg sub-chronic daily
treatment for 2 weeks chronic treatment for years) Each of these laboratory objectives will have bearing on the design of
the screening funnel required to identify the molecule
The screening funnel requires a robust high-throughput (HTS) biochemical assay capable of testing gt100000 compounds
good sensitivity (Zrsquogt05) and an appropriate orthogonal assay (usually cell based) to confirm functional activity of the
compound at the target which can be used to weed out false positives and primary HTS artifacts Critical features defined
by the laboratory objectives may require additional in vitro absorption and metabolism data from compounds slated to
progress in vivo to ensure that structure activity relationships being developed will support expected dosing profiles and
target organ disposition A collection of critical off target assays to ensure required selectivity of the candidate drug must
be available to test molecules progressing from functional assays Compounds expected to be tested in vivo will require
pharmacokinetic studies to ensure target organ exposure in concentration ranges needed to support hypothesis testing
Link to sample Screening Funnels
httpswwwnimhnihgovresearchprioritiestherapeutics
The types of information needed to Characterize a Lead Compound are summarized here
Download an introductory slide deck on Medicinal Chemistry Structure Activity Relationship (SAR) campaign courtesy Dr
Johnny Bennett Merck
Childrens MedChem 29Jul2015pdf
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
Resources for assay development
The Assay Guidance Manual httpwwwncbinlmnihgovbooksNBK53196
This is a key resource for design and qualification of all types of biochemical and cell based assays It covers many
different modes of assay development and optimization as well as troubleshooting guides Do not run a screen
without consulting the manual first
The Assay Development Screening Facility (ADSF) at BCH Hourly access to equipment and technical assistance
consultations compound libraries- live cell medium throughput screening For more information contact Dr Lee Barrett
The ICCB at Longwood Project based access to equipment and expertise for design and execution of high-throughput
screens access to wide collection of chemical and genomic libraries For more information contact Dr Caroline Shamu
caroline_shamuhmsharvardedu
Website httpiccbmedharvardedu
Databases and references with information about activity and properties of small molecule compounds
PubChem provides information on the biological activities of small molecules PubChem is organized as three linked
databases within the NCBIs Entrez information retrieval system These are PubChem Substance PubChem Compound and
PubChem BioAssay Links from PubChems chemical structure records to other Entrez databases provide information on
biological properties These include links to PubMed scientific literature and NCBIs protein 3D structure resource Links to
PubChems bioassay database present the results of biological screening Links to depositor web sites provide further
information A PubChem FTP site Download Facility Power User Gateway(PUG) Standardization Service Score Matrix
Service Structure Clustering and Deposition Gateway are also available Home page is here
httpspubchemncbinlmnihgov
httpspubchemncbinlmnihgovsearch
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
DrugBank The DrugBank database is a unique bioinformatics and cheminformatics resource that combines detailed drug
(ie chemical pharmacological and pharmaceutical) data with comprehensive drug target (ie sequence structure and
pathway) information The database contains 7759 drug entries including 1602 FDA-approved small molecule drugs 161
FDA-approved biotech (proteinpeptide) drugs 89 nutraceuticals and over 6000 experimental drugs Additionally 4300
non-redundant protein (ie drug targetenzymetransportercarrier) sequences are linked to these drug entries Each
DrugCard entry contains more than 200 data fields with half of the information being devoted to drugchemical data and
the other half devoted to drug target or protein data Homepage is here httpwwwdrugbankca
Protein Data Bank archive Targets with protein crystal structures are more attractive targets for structure based drug design
Determine if your target has a known crystal structure by looking it up in the protein database- A Structural View of Biology
This resource is powered by the Protein Data Bank archive-information about the 3D shapes of proteins nucleic acids and
complex assemblies that helps students and researchers understand all aspects of biomedicine and agriculture from
protein synthesis to health and disease Homepage is here httpwwwrcsborgpdbhomehomedo
High Quality Chemical tools are required for testing biological hypothesis Find chemical tools that are fit for purpose by
virtue of target potency and selectivity needed to test hypothesis The dangers of using inadequate chemical tools are
detailed here httpwwwnaturecomnchembiojournalv11n8fullnchembio1867html To support the needs of the
biology community the industrial chemistry research community has joined a pre-competitive effort to provide
characterization data for high quality chemical probes That data is stored here httpwwwchemicalprobesorgprotein-
family
ChemNavigator The National Institutes of Health (NIH) has formed an agreement with ChemNavigator to provide the NIH
with a current and comprehensive database of commercially accessible drug discovery screening compounds to be
made available to all NIH researchers ChemNavigator is pleased to serve NIH affiliated scientific researchers in compound
sample procurement As an NIH researcher you have full access to use the iResearch System All you need to do is take a
few minutes to register in the system Then you will be able to perform chemical structure searches for compound samples
of interest and purchase these samples through this on-line system Link is here httpwwwchemnavigatorcomnihasp
Additional References related to biological activity of compounds
Edwards AM Bountra C Kerr DJ Willson TM Open access chemical and clinical probes to support drug discovery Nature
chemical biology 2009 5(7)436-440
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
Wang Y Suzek T Zhang J Wang J He S Cheng T Shoemaker BA Gindulyte A Bryant SH PubChem BioAssay 2014 update
Nucleic acids research 2014 42(Database issue)D1075-1082
Wang Y Bolton E Dracheva S Karapetyan K Shoemaker BA Suzek TO Wang J Xiao J Zhang J Bryant SH An overview of
the PubChem BioAssay resource Nucleic acids research 2010 38(Database issue)D255-266
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
main menu
Pharmacokinetic tutorial drug exposure measurement services pharmacokinetic data references
Selecting the correct dose to achieve exposure of drug that are adequate to test a hypothesis in preclinical species
requires that you know the potency of the molecule at the desired drug target and the dose of compound required to
achieve target organ exposure that will result in the free (not bound by protein) concentration of drug required to engage
the molecular target within the target organ compartment Estimates of Drug potency can be found in many of the
databases listed under correct molecule The free concentration of a drug is determined in the plasma by multiplying the
concentration of drug in the plasma by the fraction unbound This must be measured for each compound A literature
reference that provides the measured plasma protein binding (PPB) values for many common drugs is provided here
Zhang Xue Shao and Jia (2012) Compilation of 222 drugsrsquo plasma protein binding data and guidance for study designs
Drug Discovery Today Vol 17 Issue 9-10 Pages 476-485 httpwwwncbinlmnihgovpubmed22210121
If your drug target is the brain then you must also understand the kinetics of drug disposition and clearance including blood
brain barrier (BBB) penetration in your test species to select a dose of compound adequate to test your hypothesis
Download a tutorial deck on basic principles of drug disposition and their application in small molecule drug discovery
courtesy of Dr Chris Shaffer Pfizer
150805DMPKTutorial(CLSBCHCourse)pdf
Pharmacometrics Research Core and Pharmacokinetics Service The Pharmacometrics Research Core is directed by Dr Luis
Pereira and provides analytical services for assaying drugsmetabolites in biological matrices (eg plasma serum blood
urine CSF saliva tissues) The Core provides pharmacokinetic and pharmacodynamic analyses for current and future
clinical trials and research projects (including contract services) It conducts stability and potency studies for pediatric
formulations compounded at BCH as per recent demand from FDA and CMS Finally the Core fosters grant applications
and research collaborations both intra and extramural The TNC can additionally provide investigators with consultation in
the identification of resources for pharmacodynamic assay development and contract research organizations able to
provide bioanalysis of preclinical samples needed to support animal clinical trials Contact Dr Luis Pereira for more
information LuisPereirachildrensharvardedu
article on importance of understanding drug exposure in preclinical drug studies here
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
References on Pharmacokinetics and Brain Penetration of Small Molecules
Di L Rong H Feng B Demystifying brain penetration in central nervous system drug discovery Miniperspective Journal of
medicinal chemistry 2013 56(1)2-12
Reichel A Addressing central nervous system (CNS) penetration in drug discovery basics and implications of the evolving
new concept Chemistry amp biodiversity 2009 6(11)2030-2049
Smith DA Di L Kerns EH The effect of plasma protein binding on in vivo efficacy misconceptions in drug discovery Nature
reviews Drug discovery 2010 9(12)929-939
Moda TL Torres LG Carrara AE Andricopulo AD PKDB database for pharmacokinetic properties and predictive in silico
ADME models Bioinformatics 2008 24(19)2270-2271
Law V Knox C Djoumbou Y Jewison T Guo AC Liu Y Maciejewski A Arndt D Wilson M Neveu V et al DrugBank 40
shedding new light on drug metabolism Nucleic acids research 2014 42(Database issue)D1091-1097
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
main menu
Formulations advice and assistance with preclinical drug delivery Neurodevelopmental Behavioral Core
To effectively deliver drug to preclinical species for the duration of a study researchers must choose a dose a formulation
and a route of administration that will support target organ exposure long enough to test a therapeutic hypothesis Since
most drugs developed for humans are optimized for human metabolism parameters many compounds developed for
humans are rapidly metabolized and cleared in rodents requiring alternative formulations and routes of preclinical
administration (see tutorial under Correct Dose)
Proper formulation of drugs and vehicles to ensure appropriate drug exposure is a critical factor in preclinical study design
The Neurodevelopmental Behavioral Core may provide advice on standard formulations Preclinical assistance and
training across many routes of administration including IV cannulation osmotic minipumps oral gavage sc and ip is also
available through the Neurodevelopmental Behavioral Core
Contact is Dr Nick Andrews NickAndrewschildrensharvardedu
Custom formulation used for human studies are supported on a case by case basis by the Pharmacometrics Research Core
or Clinical Research Pharmacy Contact for the Pharmacometrics Core is Dr Luis Pereira LuisPereirachildrensharvardedu
The Clinical Research Pharmacy can provide advice on unusual formulations Contact is Dr Rocco Anzaldi
RoccoAnzaldichildrensharvardedu
idspharmacy-dlchildrensharvardedu
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
main menu
Stratification Biomarker development and resources patient sample repositories requests for collection of new types of
patient samples development of patient specific iPSC lines and neurons Genetic databases RNA expression databases
Humans are diverse Not only do patients come in different sizes ages genders and ethnic backgrounds but the same
disease diagnosis often develops in people as a function of different environmental insults and genetic predispositions
Finding biomarkers that will segregate similarly diagnosed patients into subsets of biologically more homogenous
populations is a critical feature of good clinical trial design A lsquostratification biomarkerrsquo can be a biochemical measure from
patient samples a structural or a functional feature of a human imaging technology or a functional measure of an
electrophysiological readout
The Translational Neuroscience Center can help investigators access advice and assistance for investigators with vendors
experienced in profiling DNA RNA or protein across a range of platforms httpwwwchildrenshospitalorgresearch-and-
Neurophysiology Services can assist investigators with identification of biomarkers to stratify patients based on EEG
signatures Contact Drs Charles Nelson and Jurriaan Peters Co-Directors
CharlesNelsonchildrensharvardedu
JurriaanPeterschildrensharvardedu
MRIRadiology Imaging Core can assist with identification of biomarkers to stratify patients by functional or structural deficits
in brain circuitry Contact Dr Simon Warfield Director SimonWarfieldchildrensharvardedu
Molecular Genetics core can assist investigators with identification of genetic stratification biomarkers or gene expression-
based stratification biomarkers Contact Drs Louis Kunkel and Christopher Walsh Co-Directors
LouisKunkelchildrensharvardedu
ChristopherWalshchildrensharvardedu
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
The Human Neuron Differentiation Service within the Translational Neuroscience Center can help investigators recruit
specific subtypes of patients to be consented for reprogramming of blood or fibroblast cells into iPSC lines that will support
differentiation into human neurons for phenotypic analysis and screening ContactDr Robin Kleiman
RobinKleimanchildrensharvardedu
Translab can assist with routine processes as well as complex laboratory-‐developed tests They place special emphasis on
assay development for use in clinical trials Translab website with contact information can be viewed here
httpwwwtranslabbostonorg
TransLab Flyer 2 2015pdf
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
main menu
Patient sample repositoryBiobank Patient registry
Disease processes are dynamic The molecular underpinnings of disease differ between inception progression and
response of the body to disease Thus each stage of disease may require alternative therapeutic strategies Understanding
which stage of disease is best suited to testing a specific therapeutic approach will require information about disease from
patient samples collected at different stages of disease well as an ability to collect and recruit patients at relevant stages of
disease
To locate human RNA profiling data in the public domain from disease samples and tissues at specific stages of disease
search databases referenced in the Correct Target section of this document
The Translational Neuroscience Center offers multiple services that can assist with identification of the correct patients The
Core Repository for Neurological Disorders stores a wide variety of patient samples from many stages of disease The
biorepository is directed by Dr Mustafa Sahin and these samples and de-identified clinical data can be searched and
requested through the Translational Neuroscience Center
The Biobank Core Lab serves as a core resource that ensures top-level specimen handling and services to the Boston
Childrens Hospital research community It serves as both a service core and a biorepository providing an institutional
perspective on the presence of specimens that may be available for use to foster collaborations and accelerate research
and discovery
The Clinical Research and Regulatory Affairs Service can provide assistance to investigators in identifying patients andor
repository samplesdata Contact Co-Directors Stephanie Brewster and Kira Dies for more information about access to
these resources
StephanieBrewsterchildrensharvardedu
KiraDieschildrensharvardedu
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
main menu
Statistical support clinical trialsgov
Determining the correct sample size to support preclinical and clinical studies requires power calculations that take into
account the variability of the endpoint being measured Statistical support for preclinical studies is available on a
department by department basis Neurology and Neurobiology requests for preclinical biostatistics support can be made
through the CRC website
httpredcap-qiredcap_edcsurveyss=Rma5u83qKC
Clinical statistical support for all departments is also available through the CRC Design and Analysis Core For more
information contact Michael Monuteaux michaelmonuteauxchildrensharvardedu
Clinical datasets that provide data for supporting power calculations can be found by searching through clinical trialsgov
database All studies in the clinical trials data base are required to describe the study design the endpoints under
evaluation and the treatments as well as links to publications of the studies The studies can be searched by topic This can
be a good way to find historical data to help you evaluate variability of endpoint measures in clinical populations This will
be needed to support sample size power calculations httpsclinicaltrialsgov
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
main menu
Understanding RDoC Human Neurobehavioral Core Service IRB assistance with clinical protocols
Different stages of clinical trials have different goals for selecting endpoints Early stage clinical trials are typically in search
of a translatable pharmacodynamic or target engagement endpoint to ensure that the molecule in question will be
competent to test a clinical hypothesis in humans Developing translatable measures of target engagement in preclinical
species and humans is critical to developing data sets that will enable subsequent therapeutic efficacy trials The earliest
trials require endpoints that can be measured in a functionally equivalent manner across species Therefore it is critical for
preclinical researchers to develop dose-responsive data sets in preclinical species using quantitative endpoints such as EEG
visual or auditory evoked potentials PET ligands plasma or CSF based biochemical measures or translatable task based
behaviors Preclinical data must be a developed with an eye towards what the equivalent measure will be in the clinic
Toward that end the NIMH has initiated the Research Domain Criteria (RDoC) that is aimed at characterizing mental health
disorders across many different dimensions across species A big focus of the RDoC initiative is the identification of
translatable endpoints for evaluating pharmacodynamics and efficacy in Neuroscience Drug Discovery Preclinical
Neuroscience researchers should be familiar with the RDoC framework For advice on in vivo characterization of preclinical
endpoints with translational potential for Neuroscience related disorders contact Dr Robin Kleiman at the TNC
robinkleimanchildrensharvardedu
The Human Neurobehavioral Core Service of the Translational Neuroscience Center can provide guidance to investigators
on the appropriate tests that will provide the best translation from animal studies to human studies The Service also offers
human neurobehavioral assessment services Contact-Drs Charles Nelson and Deborah Waber Co-Directors
CharlesNelsonchildrensharvardedu
DeborahWaberchildrensharvardedu
Developing clinical protocols and obtaining IRB approval for human study of translatable endpoints can be supported by
the Translational Neuroscience Center Clinical Research and Regulatory Affairs Service Contact-Kira Dies and Stephanie
Brewster Co-Directors
KiraDieschildrensharvardedu
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
StephanieBrewsterchildrensharvardedu
Background Information on RDoC httpswwwnimhnihgovresearch-prioritiesrdocindexshtml
Casey BJ Oliveri ME Insel T A neurodevelopmental perspective on the research domain criteria (RDoC) framework
Cuthbert BN Insel TR Toward the future of psychiatric diagnosis the seven pillars of RDoC BMC Med 2013 11126
httpwwwncbinlmnihgovpmcarticlesPMC3653747
Insel T Cuthbert B Garvey M Heinssen R Pine DS Quinn K Sanislow C Wang P Research domain criteria (RDoC)
toward a new classification framework for research on mental disorders The American journal of psychiatry 2010
167(7)748-751 httpwwwncbinlmnihgovpubmed20595427
Insel TR The NIMH Research Domain Criteria (RDoC) Project precision medicine for psychiatry The American journal
of psychiatry 2014 171(4)395-397 httpwwwncbinlmnihgovpubmed24687194
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
main menu
Body atlases for expression of mRNA and protein guides to chemical alerts guidance for preclinical toxicology studies for
Investigational New Drug (IND) applications
Discovery scientists must consider the distribution of the proposed drug target across the entire body in human samples in
order to understand potential safety risks to be monitored during preclinical toxicological testing Teams also have to be
aware of differences in distribution of the target and related family members in preclinical species Many of the target
expression databases listed in the Correct Target section of this document are useful in this regard Assays that can be used
to monitor any potential safety risks are critical to the development of a suitable testing funnel needed to advance
compounds
Many chemical classes of compounds that are identified in screens are not suitable for drug development due to the
presence of structural alerts that are known to cause chemical toxicity Databases that house information of structural alerts
can be used to de-prioritize structural series early in the life of a program Some toxicology databases that can help
deprioritize toxic chemotypes include httppubsacsorgdoiabs101021ci300245q
Some web resources for identifying side effects of known compounds httpintsideirbbarcelonaorg
Once a potential clinical candidate molecule is identified GLP-qualified toxicology studies must be carried out with a
qualified vendor to support regulatory filings of an Investigational New Drug (IND) application For a short tutorial on studies
needed to support preclinical toxicology testing and guidance on evaluating contract research organizations that are
qualified to perform this work see attached tutorial courtesy of Dr Joe Brady Pfizer
Brady boston childrens hosp talk aug2015 IND toxpdf
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
main menu
FAQs
Industry partners and collaborators can bring tremendous expertise and complementary resources to bear on research
projects with therapeutic applications These may include medicinal chemistry expertise pharmacology expertise access
to unique and undisclosed chemical probe molecules assay development and high-throughput screening resources
antibody and other reagent development pharmacokinetic analysis pharmacokinetic and pharmacodynamics
modeling formulation expertise post-doctoral training programs and in some cases financial support There is a wide range
of models of interacting with industry in a range of different capacities Some frequently asked questions about types of
relationships and the responsibilities associated with those interactions can be found in the following document
Download Frequently Asked Questions about working with Industry
Translation of basic research into new marketed drugs will require a transition from exploring scientific principles and testing
hypotheses into commercial products Industry partners capable of developing these potential products need to be able
to license the intellectual property required to sell the product in order to justify investment in building programs around new
ideas This requires that scientific researchers protect and patent potential inventions from their work to enable future
commercialization by partners with appropriate expertise To ensure that researchers are appropriately documenting their
work in a manner that will support preservation of intellectual property all investigators are encouraged to consult with TIDO
before any public disclosures of new research Similarly the following documentation provides guidance for documenting
your work according to standards that will support patent applications
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
Download the compliance manual for BCH for Intellectual property policy
cm_021_intellectual_propertydocx
Download a summary of laboratory notebook Dorsquos and Donrsquot
Dosdontsnotebookspdf
Link to TIDO Technology Innovation and Development Office
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
main menu
A phenotypic screen requires a biologically robust assay that represents a significant aspect of disease-relevant human
biology It can be used to identify molecular targets for target validation studies through the use of well-annotated
bioactive molecules or genomic libraries (eg RNAi CRISPER) Alternatively phenotypic screens can be used to identify
novel compounds that must subsequently be lsquoDE convolutedrsquo to identify novel targets using lsquowarheadsrsquo These screens rely
on identification and manipulation of a functional deficit or phenotype using a patient-derived cellular system
The strengths of this approach
Use of human systems can improve translatability
Identified compounds may empirically balance therapeutic activity at multiple required targets
Well-suited to drug repurposing
Phenotypic screens can be used to identify compounds or targets for mechanism based drug discovery programs
Many CNS drugs have been discovered using a phenotypic repurposing screen (Swinney and Anthony 2011)
Drawbacks to this approach
Assays are slow low throughput and more expensive as compared to cell-free assays
Cell-based assays may not predict circuit level or brain phenotypes
Furthermore as a primary screening approach
Precludes leveraging strengths in uHTS SBDD and parallel design
Every molecule must be de-risked independently thus safety can be very hard to predict
Drug Repurposing Drug Repurposing is a strategic pillar of the National Center for Advancing Translational Science (NCATS)
Details on resources and funding opportunities can be found here httpsncatsnihgovntu
Chemogenomic Files from industry partners Many companies have well designed and annotated chemical files that are
designed to cover the druggable genome with small molecule compounds from their proprietary collections Each
company has different criteria and stipulations associated with use of the library It is advisable to consult with TIDO
regarding terms and conditions associated with individual companies
ICCB-LongwoodKirby ADSF The ICCB screening center and the Kirby ADSF have multiple collections of compounds that
include bioactive or FDA approved molecules available for screening
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
Kirby ADSF libraries contact Dr Lee Barrett LeeBarrettchildrensharvardedu
References related to phenotypic screens and Drug Repurposing
Vincent F Loria P Pregel M Stanton R Kitching L Nocka K Doyonnas R Steppan C Gilbert A Schroeter T
and MC Peakman Developing predictive assays The phenotypic screening ldquorule of 3rdquo Sci Transl Med 7 293ps15
(2015)
Langedijk J Mantel-Teeuwisse AK Slijkerman DS Schutjens MH Drug repositioning and repurposing terminology and
definitions in literature Drug Discov Today (2015)
Swinney DC and J Anthony How were new medicines discovered Nature Reviews Drug Discovery 10 507-
519 (July 2011) | doi101038nrd3480
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
main menu
TNC Clinical Research and Regulatory Affairs Service Research Participant Registry CRC
Glossary of Terms
Glossary-of-Clinical-Trials-Termspdf
Clinical Research and Regulatory Affairs Service This Translational Neuroscience Center service facilitates the mission of the
Translational Neuroscience Center providing coordination among studies communications resource development and
implementation of new or ongoing preclinical and clinical studies The service is led by experts in protocol development
and launching of new studies The directors are available to guide TNC researchers in designing human studies including
the preparation of Institutional Review Board (IRB) and FDA submissions Additionally staff of the Clinical Research and
Regulatory Affairs Service will help researchers with recruitment plans budget development supervision of study
coordinators study monitoring and audit preparation For more information contact Co-Directors Kira Dies ScM CGC and
Stephanie Brewster MS CGC
KiraDieschildrensharvardedu
StephanieBrewsterchildrensharvardedu
Clinical Research Center (CRC) Assists investigators at BCH with research project initiation and implementation resources
in the CTSU for the conduct of clinical research visits and ancillary services education on research methods and practices
The CRC has biostatisticians project managers research specialists clinical trials specialists research coordinators and
highly skilled nurses and nurse project managers who work every day to facilitate the many research needs of the BCH
community httpwwwchildrenshospitalorgresearch-and-innovationresearchclinicalclinical-research-center
Clinical and Translational Study Unit (CTSU) The CTSU provides clinical research infrastructure for investigators in the design
initiation conduct and reporting of clinical research with the goal of translating scientific knowledge into new therapies for
pediatric conditions httpweb2tchharvardeductsu
Clinical Research Roadmap This clinical research map is designed to serve as a guide for investigators study coordinators
and research nurses at Boston Childrenrsquos Hospital The research map outlines the key steps in preparing to launch a
research study and provides embedded links to institutional resources tools and documents
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
Clinical Research Mappdf
main menu
Office of Sponsored Programs Research Administration TIDO
Many government and foundation grant opportunities are available for developing Drug Discovery Projects updated lists of
funding options exist on OSP and Research Administration web sites
Some good options for finding relevant requests for proposals
Translational Research Program annual call for proposals
Boston Childrenrsquos Hospital ndash Broad Institute Collaboration Grants Proposals will be reviewed by a joint Childrenrsquos Hospitalndash
Broad Institute committee Additional submission dates are expected for 2016
BCH_Broad collaborative grant 852015docx
Kirby Neurobiology Screening Pilot awards- available to Kirby Neurobiology PIs as funding is available
Translational Neuroscience Center- Pilot awards supported by trust sponsored donations as available Distributed through
TNC e-mail lists
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
ADDF The ADDF Academic Drug Discovery and Development Program seeks to create and support innovative translational
research programs for Alzheimerrsquos disease related dementias and cognitive aging in academic medical centers and
universities Biomarker development studies and innovative proof of concept pilot clinical trials of new approaches to
treatment prevention and early detection are also supported
Department of Defense ALSRP The FY15 Defense Appropriations Act provides $75 million (M) to the Department of Defense
Amyotrophic Lateral Sclerosis Research Program (ALSRP) to support innovative high-impact Amyotrophic Lateral Sclerosis
research As directed by the Office of the Assistant Secretary of Defense for Health Affairs the Defense Health Agency
Research Development and Acquisition (DHA RDA) Directorate manages and executes the Defense Health Program
(DHP) Research Development Test and Evaluation (RDTampE) appropriation The executing agent for the anticipated
Program AnnouncementsFunding Opportunities is the Congressionally Directed Medical Research Programs (CDMRP)
httpcdmrparmymilpubspress201515alsrppreannshtml
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
Michael J Fox Foundation Therapeutic Pipeline Program Supports Parkinsons disease therapeutic development along the
pre-clinical and clinical path (both drug and non-pharmacological therapeutics including gene therapy biological
surgical and non-invasive approaches) The Michael J Fox Foundation seeks applications with potential for fundamentally
altering disease course andor significantly improving treatment of symptoms above and beyond current standards of care
Proposals must have a well-defined plan for moving toward clinical utility for patients The Therapeutic Pipeline Program is
open to industry and academic investigators proposing novel approaches or repositioning approved or clinically safe
therapies from non-PD indications httpswwwmichaeljfoxorgresearchgrant-detailphpid=28
NINDS The Blueprint Neurotherapeutics Network (BPN) Provides the neuroscience community access to a complete and
seamless pipeline for preclinical drug development beginning with chemical optimization and concluding after phase I
clinical trials Participants in the BPN will receive funding to conduct bioactivity and efficacy testing in their own laboratories
as well as access to millions of dollars in NIH-contracted drug development services including medicinal chemistry
pharmacology toxicology and phase 1 clinical trials NIH will also provide drug development consultants who have had
years of experience working at a senior level in industry Because the Blueprint is establishing a network of drug
development service providers that typically cater to biopharmaceutical companies neuroscientists who join the BPN can
readily plug in to all of the drug development expertise that typically resides in industry The projects supported through the
network will be highly collaborative and the researchers who initiate the projects will serve as the principal investigators
(PIs) directing their projects through the development pipeline with the help of industry consultants The PIs and their
institutions will have the opportunity to attain assignment of intellectual property rights from all other network participants
who may have intellectual input into their projects This will allow the PIs to retain control of the intellectual property for drug
candidates developed through the network and eventually pursue licensing and commercialization partnerships
httpneuroscienceblueprintnihgovbpdrugs
NeuroNEXT Will establish a consortium of clinical sites capable of forming disease-specific cadres of investigators in order to
develop and implement trials rapidly in a wide range of neurological disorders that affect adults andor children With a
stable and experienced research staff a central IRB model and master trial agreements NeuroNEXT will streamline the
administrative processes for clinical trials and reduce start-up times NeuroNEXT will also be able to design and implement
evidence-based measures to improve patient recruitment into clinical trials httpswwwneuronextorgresearchers
NIMH Many grant options see overview here httpwwwnimhnihgovresearch-prioritiestherapeuticsindexshtml
Building on High Impact Basic Neurobiology Through Assay Development Advancing Tools for Therapeutic Discovery (R01) -
See more at httpgrantsnihgovgrantsguidepa-filesPAR-15-066htmlsthashs1HMWjWudpuf
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
NCATS many grant options see overview here httpwwwncatsnihgovprograms
Bridging Interventional Development Gaps (BrIDGs) Program Makes available on a competitive basis certain critical
resources needed for the development of new therapeutic agents for both common and rare diseases Investigators do not
receive grant funds through this program Instead successful applicants receive access to NIH experts and contractors who
conduct pre-clinical studies at no cost to the investigator In general synthesis formulation pharmacokinetic and
toxicology services in support of investigator-held IND applications to the Food and Drug Administration (FDA) are available
httpwwwncatsnihgovbridgsworksolicitation
NCATS Discovering New Therapeutic Uses for Existing Molecules (New Therapeutic Uses) A collaborative program designed
to develop partnerships between pharmaceutical companies and the biomedical research community to advance
therapeutics development This innovative program matches researchers with a selection of pharmaceutical industry
assets to test ideas for new therapeutic uses with the ultimate goal of identifying promising new treatments for patients
httpwwwncatsnihgovntu
Pfizer Centers for Therapeutic Innovation (CTI) Suitable for biotherapeutic or small molecule projects with a strong project
rationale (demonstrated association between target biology pathway and disease mechanism) CTIrsquos areas of interest
include inflammation autoimmunity tissue remodeling oncology cancer immunology rare or genetic diseases
cardiovascular and metabolic diseases and neuroscience Selected projects are undertaken by a joint team with BCH
members and Pfizer CTI drug development experts located on the 18th floor of CLS working towards agreed common
goals The Pfizer CTIBCH collaboration program is managed by a Joint Steering Committee with representation from both
Boston Childrenrsquos and CTI httpswwwpfizercticom Calls for proposals come through TIDO three times a year in January
May and September httpwwwchildrensinnovationsorgPagesHighlightsHighlights-83aspx
Shire-BCH Collaborative Program Development The Joint Steering Committee of the Shire Alliance extends a call for ldquoPre-
Proposalsrdquo with defined objectives from time to time generally annually in the late fall or winter That call is publicized
through emails from BCH Research Administration and TIDO Following review by the JSC a full proposal may be requested
Unsolicited proposals may also be considered from time to time
ACRONYMS
HTS- High-throughput Screen run with 96 well 384 well 1536 wells or 3456 well capacity- screen has capacity to run through a library of 1-3Million compounds in total
uHTS- Ultra High-throughput Screen ndash arbitrary cut off to denote capability to measure 100s of thousands of assays per day with automation and high density plate readers
HCS- High Content Screen usually a cell based assay that is able to monitor multiple endpoints reflective of different cellular processes in a single well of cells treated with a compound May be biochemical or image based endpoints
SAR- Structure-Activity Relationship ie relationship of modifications to chemical structure on relevant activity SPR-Structure-Property Relationship ie relationship of modifications of chemical structure on physicochemical
properties
PK- Pharmacokinetic measure of drug levels in a body compartment
PD- Pharmacodynamic a measure of functional activity of a drug
PKPD- PharmacoKinetic PharmacoDynamic relationship- how drug levels relate to drug response in a system
DDI-Drug-Drug Interactions- occurs when one drug affects the activity of another drug when co- administered Often due to changes in ADME properties of one of the co-administered drugs (ie for example induction by one drug of enzymes that will metabolize the second drug )
DMPK- Drug Metabolism and PharmacoKinetics
ADME- Absorption Distribution Metabolism amp Excretion
PDM-pharmacokinetics dynamics and metabolism GLP- Good Laboratory Practice- regulations that govern toxicology studies required by the FDA to support IND
and NDA
POM- Proof of Mechanism clinical studies to demonstrate hit the target and elicited a biological response
POC- Proof of Concept Clinical studies to demonstrate a clinically meaningful outcome measure improved
PoP-Proof of Principal usually preclinical studies that demonstrate that engaging target in a disease model produced efficacy
FIH- First in Human clinical trial to evaluate new molecule in humans for safety and PK- Ph1
FIP-First in Patient first clinical trial to evaluate new molecule in patients hERG (the human Ether-agrave-go-go-Related Gene) is a gene KCNH2 that codes for a subunit of Kv111 and
contributes to the repolarizing current in the heart that coordinates the hearts beating When compromised by application drugs or by rare mutations in some families it can result in a potentially fatal disorder called long QT syndrome A number of clinically successful drugs in the market have had the tendency to inhibit hERG and create a concomitant risk of sudden death as a side-effect which has made hERG inhibition an important anti-target that must be avoided during drug development
IND-Investigational New Drug Application- formal application to FDA to evaluate a NCE in people
NME- New Molecular Entity- a new FDA approved drug
NCE-New Chemical Entity-an investigational drug that is not yet a FDA approved NME NDA- New Drug Application (A lsquoFilingrsquo)- a formal application for approval of a new drug
CAN-(Pfizer-specific shorthand )-Clinical Candidate- a molecule competent to be tested in humans IB- Investigators Brochure- basic information on an investigational drug and its mechanism for clinicans involved
in conducting a clinical trial Provides background information on the hypothesis being tested and the types of patients that should be included excluded and risks and how the drug should be administered It must be updated continually by the sponsor to include all new findings
SOC- Standard of Care- in our context it is the drug treatment that a clinican should prescribe for a particular type of patient used as a benchmark for comparing new entities
MTD- Maximum Tolerated Dose- first identified in GLP safety studies during preclinical development AE- Adverse Event- a side effect that causes safety concerns
TI- Therapeutic Index -ratio of the concentration of drug needed to produce efficacy and the concentration of drug that is safely tolerated ( also called ldquoSafety Marginrdquo)
Questions Contact Robin Kleiman- email RobinKleimanchildrensharvardedu office CLS 13070
Terms that relate to Targets Molecular target- the protein that binds drug to produce efficacy Off-Target- other proteins that bind the drug that do not relate to efficacy and may produce Adverse Events (AEs) Druggable target ndashcomes from a class of proteins that has successfully been targeted with small molecule drugs in
the past Primarily transporters enzymes receptors ion channels (Not protein-protein interactions transcription factors RNA binding proteins etc)
Druggable genome- about 3000 genes encoding all druggable proteins Druggability- the presence of protein folds (quarternary structures) that favor specific interactions with drug-like
molecules Exploratory target- Hypothesis that a modulating a target via a particular mode of action will be beneficial to a
particular patient population Validated target- Hypothesis regarding a target also has in vivo efficacy data for a disease or a disease model- along
with a complete understanding of how the target mechanism relates to disease- (also called lsquoProof of Principlersquo) Phenotypic screen- a screen for compounds that will reverse a phenotype the molecular target may not be known Systems pharmacology target(s)-a precisely defined combination or lsquofingerprintrsquo of molecular targets to be
modulated to correct a phenotype (Poly-pharmacology)
Terms that relate to programs
Biomarker- a physiological pathological or anatomical characteristic that is measured by an automated process or algorithm as an indicator of the normal biological process pathological process or biological response to a therapeutic intervention Many types of Biomarkers target engagement biomarkers stratification biomarkers efficacy biomarkers pharmacodynamic biomarkers etchellip
Laboratory Objectives-Criteria established at the start of the program to define the desired pharmacological properties of the molecule with regard to potency selectivity mode of action frequency and route of administration For antibodies would include minimal criteria for knock down stability etc
Therapeutic Modality- small molecule biologic RNAi stem cell etc
Screening tree Screening funnel- A decision tree for utilizing a panel of assays to identify molecules that meet the laboratory objectives
Terms that relate to molecules
Drug-like molecule- has physicochemical properties in line with known oral medications The molecule will be largely rule of 5 (RO5) compliant therefore small and moderately lipophilic Not related to pharmacological activity
Rule of Five (RO5)=Chris Lipinskirsquos rule of 5 states that a drug like molecule will have the following properties Molecular Weight of less than 500 a clogP lt5 fewer than 5 H-bond donors and the number of H-bond acceptors ( which is the sum of N and O atoms) is less than 10
Physicochemical properties- key properties of molecules include (calculated)Molecular Weight number of H bond acceptors and donors (measured) kinetic solubility pKa lipophilicity (logD logP)
Chemical tool -a compound with good potency and selectivity for a specified molecular target but fails to meet all criteria for safety PK or potency needed to become a clinical candidate Suitable for preclinical testing of hypothesis and proof of principal studies but not for lsquopreclinical developmentrsquo
Active molecule describes an individual chemical entity with measurable dose-dependent activity in a biological screening assay
Hit molecule refers to a molecule plus its related structural analogs for which there is an understanding of the structure-properties and structure-activity relationships (SPR and SAR) for a specific biological context Additionally preliminary drug disposition data (both in vitro and in vivo) provide an assessment of pharmacokinetic properties The available data provide a basis for further optimization of the hit series
Lead molecule refers to a molecule plus its related structural analogs that demonstrate o Sufficient exposure at pharmacologically relevant doses by the intended route of administration to explore
intended pharmacology in a relevant in vivo disease or pharmacodynamic model o Proof-of-principle or efficacy in a in vivo model that will be used to establish a margin of safety
Clinical candidate an optimized individual chemical entity derived from a lead series that demonstrates o a dose-response relationship via intended route and schedule of administration in relevant disease model o an exposure-based margin of safety in toxicology studies o In summary a clinical candidate is a molecule that is deemed competent for testing the primary disease
intervention hypothesis in humans
A laboratory notebook is a vital record of events leading to a patentable invention Therecorded information can establish dates of conception and reduction to practice of atechnology as well as the inventorship of a patent claiming the technology Below arefourteen rules you should follow when keeping lab notebooks
1 mdash Do use bound booksInventors should use permanently bound notebooks eg notebooks with spiral or glue bindings If loose-leaf sheets are used they should be consecutively numbered and eachpage should be dated signed and witnessed
2 mdash Do sign and date Each notebook should be signed and dated on the inside front cover to indicate the firstday the recipient started using the notebook Each entry should be dated and signed orinitialed
An independent witness ie someone who understands the technology but will not benamed as a co-inventor of the invention should sign and date each entry after the state-ment ldquoRead and understood by rdquo (The witness should preferably sign theentries on a contemporaneous or fairly contemporaneous basis but entries can also bereviewed signed and dated on a periodic eg weekly or monthly basis)
3 mdash Do use inkNotebook entries should be made in ink and in chronological order Entries should not beerased or ldquowhited outrdquo If an entry contains an error a line should be drawn through theerror and new text should continue in the next available space
4 mdash Donrsquot leave blank spacesBlank gaps between entries should be avoided If a blank space is left on a page a line orcross should be drawn through the blank space and the page dated to prevent subsequententries
5 mdash Donrsquot modifyPrior entries should not be modified at a later date If data were omitted the new datacan be entered under a new date and cross-referenced to the previous entry Record exper-iments when they are performed
6 mdash Do use past tenseUse the past tense (eg ldquowas heatedrdquo) to describe the experiments that were actually performed
Fish amp Richardson pc
Dorsquos and Don rsquo ts forKeeping Lab Notebooks
Boston
Dallas
Delaware
New York
San Diego
Silicon Valley
Twin Cities
Washington dc
FR
7 mdash Do explain abbreviations and special termsExplain all abbreviations and terms that are nonstandard Explain in context in a table ofabbreviations or in a glossary
8 mdash Do staple attachmentsAttachments such as graphs or computer printouts should be permanently attached to pagesin the notebook (eg by stapling) and both the attachment and the notebook page signedand dated If the attachment cannot be stapled it should be placed in an envelope and theenvelope stapled to the notebook page The envelope and page should then be signed andwitnessed making reference to the attachment being placed in the envelope
9 mdash Donrsquot remove originalsNo original pages should be removed from the notebook
10 mdash Do outline new experimentsWhen a new project or experiment is started the objective and rationale should be brieflyoutlined (eg in a short paragraph or by providing a flowchart)
11 mdash Do record lab meeting discussionsRelevant discussions from lab meetings should be recorded as should ideas or suggestionsmade by others The names of the people making the ideas and suggestions should be care-fully documented This information may be important in establishing inventorship
12 mdash Do provide detailRecord test descriptions including preferred operating conditions control conditionsoperable and preferred ranges of conditions and alternate specific materials Also recordtest results and an explanation of the results as well as photos or sketches of the resultsandor the test device Any conclusions should be short and supported by the factual dataOpinions or speculation about the invention should be avoided
13 mdash Do track notebooksIdeally each lab should maintain a catalog of notebooks in which each notebook is assigneda number and the name of the author of each notebook is recorded In addition the datethe author received the notebook as well as the date the notebook was completed andreturned should be recorded Upon leaving the lab the author should return all notebookschecked out by or to him
14 mdash Do save completed notebooksAll completed notebooks should be indexed (eg by number by author andor by subjectarea) and kept safely in a central repository together with corresponding patent applica-tions or patents Lab notebooks that relate to inventions on which patents have been grant-ed should be kept for the life of the patent plus six years
By J Peter Fasse
Fish amp Richardson pcIntellectual property complex litigation technology law800 818-5070wwwfrcominfofrcom
P ER SP EC T I V E
PHARMACOK INET I CS
Data gaps limit the translational potentialof preclinical researchRobin J Kleiman1 and Michael D Ehlers2
The absence of mouse pharmacokinetic reference data hinders translation An analysis ofrecent literature highlights a systematic lack of discussion regarding rationale for the selec-tion of dosing paradigms in preclinical studies and in particular for neuroscience studies inwhich the lack of brain penetration can limit target-organ exposure We propose solutionsto improve study design
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nloaded from
Despite widespread use of pharmacologicalagents in mouse models of human diseasethe literature lacks comprehensive pharmaco-kinetic profiles for such studies Coupled witha paucity of suitable data are shortcomingsin the training of experimental biologists inthe application of pharmacometric principlesto experimental study design Many authorssimply cite previously published studies tosupport the selection of a particular dose evenwhen the cited paper lacks drug exposuredata There is an assumption on the part ofresearchers that if a referenced study demon-strates a biological effectmdashthat is any measur-able physiological or behavioral effectmdashin arodent at a given dose then that same dosewill also effectively perturb disease-relevantmechanistic biology in a different study Thedanger occurs when the observed therapeuticeffects are not linked to drug-induced mecha-nistic alterations at the level of the target organLack of a drug exposurendashresponse relationshipin a target organ casts doubt on mechanisticinterpretations In addition any changes inthe route of drug administration vehicle prep-aration species used (rat versus mouse versusprimate) age or strain of animal transgenicmodification time points under investigationduration of dosing or organ targeted for inter-vention (for example brain versus a periph-eral tumor) can alter the relation between doseexposure and measured response In suchcases assumptions regarding the mechanisticbasis for observed therapeutic effects may nothold true
Preclinical pharmacological experimentsthat do not measure drug concentrations in
1Translational Neuroscience Center Kirby NeurobiologyCenter Department of Neurology Boston ChildrenrsquosHospital Harvard Medical School Boston MA 02115USA 2Neuroscience amp Pain Research Unit BioTherapeu-tics Worldwide Research and Development Pfizer IncCambridge MA 02139 USACorresponding author E-mail robinkleimanchildrensharvardedu (RJK) michaelehlerspfizercom (MDE)
the target organ run the risk of producing ex-posures that are too low or too high to inter-pret a mechanistic hypothesis Most drugs arenot selective over a large exposure range for asingle molecular target Confident evaluationof a therapeutic hypothesis requires an under-standing of the drugrsquos penetration and kineticswithin the target tissue as well as its potencyand selectivity for specific molecular targetsFurther investigators must consider the con-centration of the unbound fraction of drugthat is available to interact with the targetPublished reports often overlook the fact thatmany small molecules are more than 90bound to plasma or tissue proteins whichgreatly decreases the fraction of drug availableto bind to the intended target Thus in casesin which drug binding has a slow off-rate anorganismrsquos total drug exposure is not a predic-tor of drug available to interact with its target(1) The failure of some academic scientists toobtain relevant pharmacokinetic data impairsthe interpretation of preclinical research resultsand likely contributes to the acknowledgeddifficulties in replicating some academic liter-ature as reported by industry scientists (2 3)
Drug discovery teams in industry settingsroutinely collect pharmacokinetic data to aidin the mechanistic interpretation of in vivopreclinical data and to project optimal dosingparadigms for efficacy and toxicology studiesData required to evaluate brain penetrationare not typically collected by industry-baseddrug-discovery teams for compounds origi-nally developed for therapeutic indicationsthat do not obviously implicate the centralnervous system making this information es-pecially hard to find for many otherwise well-described drugs In addition because mousedata are not required for preclinical toxicologystudies (the more common small animal spe-cies for preclinical toxicology being rats)industry scientists do not often obtain pharma-cokinetic data from mouse experiments These
wwwScienceTranslationalMedicineo
issues are especially relevant for older drugsthat are potentially suitable for repurposingMany older drugs were discovered and char-acterized before routine pharmacokinetic-pharmacodynamic (PK-PD) modeling ofpreclinical drug exposure and its applicationto predicting human dosing became standardpractice Last pharmacokinetic data are notconsidered innovative and these studies gen-erally do not achieve publication in peer-reviewed journals even when the data havebeen generated When such data are pub-lished it is often relegated to the unsearchableblack hole of supplementary materials Thusmouse neuroPK profiles are not readily avail-able for many drugs that are frequently usedin conjunction with mouse models of humanbrain disorders
DOCUMENTING DOSING STRATEGIES
To evaluate the potential impact of insufficientpharmacokinetic data on dose selection in asample of recent published neuroscience liter-ature we conducted an analysis of papersidentified by means of a PubMed search usingthe search terms ldquodrugrdquo and ldquobrainrdquo for the pub-lication year 2014 from eight journals (Table 1)This list was culled to include only primaryresearch reports that included systemic adminis-tration of a pharmacological agent a pharma-cological therapeutic or a biological therapeuticas part of the study design The search yielded100 articles published between 1 January and30 December 2014 that used systemic drug de-livery with the intended goal of targeting thebrain of rodents (table S1) Each publicationwas examined for the stated rationale behindthe dose selection of study drugs (Table 1)
The reported rationale for dosing strategiesfell into several broad categories including(from lowest confidence to highest) (i) dose se-lected rationale not discussed (ii) literaturecitations of another study in which reportsranged from citation of exposure in the samespecies exposure in a different strain or spe-cies a dose conversion from the human liter-ature to rodent or reports of effects on rodentbehavior in another study (iii) demonstrationof an effect on rodent behavior or function inthe current study (iv) demonstration of adose-responsive biological effect in the currentstudy (v) measurement of drug levels in bloodor plasma in the current study and (vi) mea-surement of drug levels in the target organ(that is the brain) in the current study In onlytwo instances were publications identifiedthat considered the impact of drug binding
rg 6 January 2016 Vol 8 Issue 320 320ps1 1
P ER SP EC T I V E
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to plasma or brain proteins on the free expo-sure of drug available to interact with the tar-get This is a critical flaw in most publishedstudies that use small molecules for functionaleffects in the brain because many centralnervous system (CNS) drugs that penetratethe blood-brain barrier exhibit high proteinbinding leaving a small fraction of the totaldrug measured in plasma or brain unbound
and free to interact with the molecular targetFurthermore most studies used evidence of abiological activity to justify dose selection with-out consideration for how exposure of theagent relates to the potency of the compoundat known molecular targets which would berequired to test a mechanistic hypothesis
The lack of pharmacokinetic considera-tion does not imply that every study used an
wwwScienceTranslationalMedicineo
inappropriate dose of drug to test their hypoth-esis It does illustrate that a clear rationale wasnot provided for dose selection in most pub-lications Furthermore all 11 of the 100 publi-cations that measured total brain exposureincluded an author from the pharmaceutical in-dustry (n=5) an academic drug screening group(n = 3) or a pharmacologyndashpharmaceuticalsciences department (n = 3) This observationlikely reflects the limited presence of pharma-cology and pharmacometrics departmentswithinmost academic institutions and limitedaccess to the mass spectrometry and otheranalytical resources needed to measure druglevels in study samples Outsourcing the bio-analysis of samples collected from study ani-mals is feasible but the use of contract researchorganizations to support such studies is oftentoo costly for most academic grant budgets toaccommodate
DATABASES AND REPURPOSINGRecent years have seen increasing efforts toinvestigate approved or clinically tested drugsfor new indications (4ndash8) Such repurposinghas been touted as a means to accelerate ther-apeutic development (4) For example a stra-tegic pillar of the US National Institutes ofHealthrsquos (NIHrsquos) translational roadmap callsfor the academic community to actively par-ticipate in the repurposing of drugs approvedby the US Food and Drug Administration(FDA) or investigational drugs that havepassed safety hurdles but failed in clinicaltrials because of lack of efficacy (9ndash11) To havea meaningful impact in neurological and psy-chiatric disorders such drug repurposingefforts will require access to neuropharma-cokinetic (neuroPK) data sets in mice to guidethe testing of new therapeutic hypotheses ingenetically engineered disease models A re-cently published consensus evaluation of drugrepositioning opportunities for Alzheimerrsquosdisease identified 15 potential drug candidatesThese were further prioritized for testing onthe basis of available evidence to produce ashortlist of seven compounds reviewed by in-dustry experts to provide insight into the via-bility of these candidates The most commonshortcoming identified for the compoundsconsidered were issues related to insufficientbrain penetration or the lack of informationabout optimal dosing strategies (11)
The repurposing of statins illustrateshow the neuroPK knowledge gap limits progressStatins were developed as 3-hydroxy-3-methylglutarylndashcoenzyme A (HMG-CoA) reduc-tase inhibitors to lower cholesterol and reduce
Table 1 Preclinical dosing strategies The rationale for drug-dosing strategies was extractedfrom the literature through the analysis of 100 peer-reviewed studies published in2014 from eight journals that cover research on mechanisms of brain function disease andtherapeutic approaches to CNS disorders (Cell Neuron Nature Nature Neuroscience NatureMedicine Neurobiology of Disease Neuropsychopharmacology and Science TranslationalMedicine) (table S1) Forty-four of the 100 publications selected were studies of potentialtherapeutic approaches to disease whereas the remaining were studies of basic neurobiology ormechanisms of disease Each publication was examined to discern how authors selected thedosage of pharmacological tools or therapeutic compounds used in the design of studies toprobe brain function A relatively small number of studies considered what the concentrationof drug available in the brain after administration would be in the context of theirexperimental studies The most common method for selecting a dose of drug was tocite a previous study that demonstrated a biological effect of the drug on someaspect of rodent behavior
Rationale for studyrsquos drug-dose selection
Therapeutic
studies
Number of papers from the100 published studies
analyzed
bull No exposure or rationale for dose selection provided
5
22
bull Rodent dose extrapolated from human studies
0
1
bull Doses are similar to what was used previously toproduce a biological effect
8
23
bull Literature reports cited for multiple functionaleffects of drug at selected dose
4
5
bull Brain penetration evaluated but exposure notmeasured
2
2
bull Literature report of mismatched drug exposure
0
1
bull Observation of a biological effect at a single dosein current study
3
6
bull Observation of dose-responsive biological effectin current study
5
16
bull Brain exposure to drug was measured with routeof administration that differed from the oneused in the efficacy study
1
1
bull Plasma drug concentrations measured literaturereport of brain exposure cited and target-organpharmacodynamic effect observed in the currentstudy
1
1
bull Plasma drug concentrations measured
4
7
bull Brain pharmacodynamic effect of drug observed
2
4
bull Brain drug concentrations measured (totalconcentration)
6
7
bull Unbound brain drug concentrations measured
1
2
bull Brain drug concentrations measured and brainpharmacodynamic effect of drug observed
2
2
Total
44
100
rg 6 January 2016 Vol 8 Issue 320 320ps1 2
P ER SP EC T I V E
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risk of cardiovascular disease (12) FDA hasapproved at least nine different statins andmost are commonly prescribed nearly one-third of Americans ages 55 to 64 took a pre-scription cholesterol-lowering drug between2009 and 2012 (wwwcdcgovnchsdatahushus14pdf) The widespread availability andsafety profile of statins has lured researchersinto evaluating their potential for repurpos-ing (13) Statins have been profiled extensive-ly in preclinical research to test for potentialtherapeutic benefit in Alzheimerrsquos disease(14ndash19) Fragile X syndrome (20) Rett syn-drome (21 22) epilepsy (23) Huntingtonrsquos dis-ease (24) Parkinsonrsquos disease (25 26) stroke(27) and brain injury (28 29)
A search of the literature reveals no sys-tematic neuroPK studies in any mouse strainthat would enable direct comparisons of CNSexposure across the various statins In silicopredictions based on the drugsrsquo molecularproperties suggest that the nine most widelyprescribed statins each have a different poten-tial to penetrate the blood-brain barrier differ-ent potencies against the HMG-CoA reductaseenzyme and different ldquooff-targetrdquo activity pro-files (30) On the basis of available data thereis reason to believe that simvastatin has thebest overall profile for inhibiting HMG-CoAreductase in the brain (30) A recent study re-ported that lovastatin is able to reverse a rangeof phenotypes in a mouse model of Fragile Xsyndrome (20) However the design of an op-timal clinical trial will require the collection ofmouse pharmacokinetic data to understandhow much CNS drug exposure is required toproduce efficacy in the disease model Thereare at least two possible scenarios Giventhat simvastatin is more potent at inhibitingHMG-CoA reductase than are other statinsand likely to be more brain penetrant inboth mice and humans one would expectthat simvastatin will be more potent than lo-vastatin in ameliorating symptoms in bothmice and humans if the observed efficacy stemsfrom inhibition of HMG-CoA reductase activ-ity in the brain by lovastatin The advantage ofthis outcome would be that better brain pen-etration and potency would lead to a loweroverall dose requirement to achieve efficacyand thus likely a better safety profile
A second scenario could be that lovastatin ismore potent than simvastatin in the mousemodel of Fragile X syndrome because of anadditional biological activity inherent to thelovastatinmolecule whichmaynot yet be doc-umented in the literature In either case un-derstanding the CNS exposure of lovastatin
required to produce efficacy in themouse willdetermine whether there is a safe therapeuticindex for achieving the required concentra-tion in patients Previous attempts to discernuseful neuroPK parameters from the litera-ture for the use of statins in rodent modelshave highlighted the lack of critical data asthe looming roadblock to progress in the field(31 32) Until these data exist the transla-tional potential of preclinical research maybe limited And this is but one example ofone drug class
The creation of a centralized database isneeded for the entire translational researchcommunity and would establish a new mech-anism for academia funding agencies founda-tions and industry to pool resources If studiesare donewell the first time and documented inan open-access resource it will reduce redun-dant efforts and improve the quality of decisionmaking by scientists considering innovativesolutions to our biggest health problems
FILL THE GAPSManuscript submission practices for severalhigh-impact journals now include require-ments that authors include detailed informa-tion regarding study design and statisticalanalysis with each submission A reasonableextension of this checklist should includethe stated rationale for doses selected for studydrugs Information should include a discus-sion of data highlighted in Table 2 Authorsshould be expected to reference a relevant
wwwScienceTranslationalMedicineo
data set from a high-quality database or pub-lication or provide the data in the current study(Table 3)
Industry biologists learn basic principlesof medicinal chemistry pharmacokineticsand drug disposition while working on drugdiscovery project teams Academic groupsare playing an increasing role in transla-tional therapeutics and in particular drugrepurposing Academic programs need toaugment training in pharmacokinetics andpharmacodynamics so as to increase the rigor ofpreclinical work and to ensure that investigator-initiated clinical studies are testing hypotheseseffectively Institutions without a departmentof pharmacology or pharmacometrics mightlack the organizational knowledge needed toconduct drug studies and must identify re-sources or collaborators to patch these defi-cits Formal coursework and Web-basedresources and tutorials are needed to train andsupport translational researchers Manuscriptand grant reviewers need to demand higherstandards for preclinical studies with respect toreporting on drug exposure associated withbiological effects Ethics committees responsi-ble for review of animal protocols should re-quire investigators to provide rationale fordose selections in proposed studies Similarlyscientific review boards at academic medicalcenters need to include clinical pharmacologistswho are able to review investigator-initiatedclinical studies to ensure that proposed dosingstrategies will test a meaningful hypothesis
Table 2 Recommendations for use of pharmacokinetic data The first column includes a listof recommended data sets to aid reviewers of submitted articles in the interpretation ofpreclinical findings The second column includes a list of useful reference data that wouldsupport improved preclinical study design in mice if available in a public database
Literature reports that evaluate studydrugs should include
Compound-specific data that shouldbe included in a rodent
pharmacokinetic database
bull Expected or measured plasma exposure of thestudy drug in the preclinical species during thestudy
bull Elimination half-life (T12)bull Systemic clearance (CL)bull Fraction of drug that is protein bound (fb)
bull Expected or measured target organ exposureof the study drugs in the preclinical speciesduring the study
Maximum plasma concentration after drug admin-istration (Cmax) and time to reach maximum plas-ma concentration (Tmax) for a standardized doseand route of administration
bull Expected or measured free fraction (unboundby protein) of the study drugs in the targetorgan of the preclinical species during thestudy
bull The ratio of drug in brain to that in plasma (BP)bull The ratio of drug found free in brain (Cub) to thatfound free in the plasma (Cup) defined as CubCupbull Any potential impact of drug transporters (foundon the rodent blood-brain barrier) in limiting brainexposure
bull Expected or measured potency of the studydrug against the hypothesized activity in vitro
Expected ormeasured potency of molecule at knownbiological targets
rg 6 January 2016 Vol 8 Issue 320 320ps1 3
P ER SP EC T I V E
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A central repository that contains brainpenetration protein binding and pharmaco-kinetic profiles of drugs and pharmacologicaltools in rodents is needed to effectively sup-port translational research This databaseshould also provide basic tutorials that de-fine primary pharmacokinetic parameterswith examples to illustrate how data are usedto predict optimal dosing strategies The min-imum data set needed for each compoundin a useful rodent database is highlighted inTable 2 Access to this information and sup-porting materials will have an immediateimpact on the quality of translational drug re-purposing efforts across brain disorders andwill support the development of new thera-peutic approaches to neurological disordersand mental illness Existing databases man-aged by NIH or precompetitive consortia couldbe reinforced with donated pharmacokineticdata sets and tutorials
Industry and government scientists shouldwork precompetitively to collect and curatepharmacokinetic data sets in conjunction withsupporting educational materials Mouse phar-macokinetic data exist inside pharmaceuti-cal companies for a wide range of publicallydisclosed molecules and literature standardsRelease of these data into a public databasewould provide several benefits to companiesincluding (i) increased scientific rigor in theliterature with a higher probability of repro-ducibility (ii) increased appreciation by theacademic biology community for the diffi-culty inherent in generating molecules withpotency and pharmacokinetic profiles suit-able for in vivo work opening the door forin-kind collaboration with academic groups
and (iii) direct comparison of data collectedin-house to that collected at other compa-nies or institutions to enable better internalquality control Comprehensive pharmaco-kinetic data sets will benefit all therapeuticareas regardless of whether the brain is thetarget organ because peripheral and cen-tral exposure data can be generated fromthe same experiments Moreover the prin-ciples described above for the CNS apply toother target tissues in which vascular bar-riers metabolic processes or active transportalter the distribution of systemically admin-istered drugs
Key to ensuring that preclinical mousestudies test the hypotheses they aim to eval-uate is an understanding of the unboundfraction of drug present in the target organat an appropriate time point under studyGrant and journal reviewers need to care-fully consider whether authors of propos-als and manuscripts are providing adequaterationale for their choices of preclinical dos-ing paradigms Importantly the collectionand centralization of rodent pharmacoki-netic datasets will promote efficient genera-tion of future data reduce the collection ofredundant data and improve the return oninvestment for research funds that are de-voted to preclinical studies aimed towardclinical translation
SUPPLEMENTARY MATERIALS
wwwsciencetranslationalmedicineorgcgicontentfull8320320ps1DC1Table S1 One hundred publications that used systemic drugdelivery with the goal of targeting rodent brains
wwwScienceTranslationalMedicineo
REFERENCES AND NOTES1 A Reichel Addressing central nervous system (CNS) penetra-
tion in drug discovery Basics and implications of the evolv-ing new concept Chem Biodivers 6 2030ndash2049 (2009)
2 F Prinz T Schlange K Asadullah Believe it or not Howmuch can we rely on published data on potential drugtargets Nat Rev Drug Discov 10 712 (2011)
3 C G Begley L M Ellis Drug development Raisestandards for preclinical cancer research Nature 483531ndash533 (2012)
4 P Nair Second act Drug repurposing gets a boost asacademic researchers join the search for novel uses ofexisting drugs Proc Natl Acad Sci USA 110 2430ndash2432(2013)
5 T I Oprea J Mestres Drug repurposing Far beyond newtargets for old drugs AAPS J 14 759ndash763 (2012)
6 S M Strittmatter Overcoming drug development bot-tlenecks with repurposing Old drugs learn new tricksNat Med 20 590ndash591 (2014)
7 K Xu T R Coteacute Database identifies FDA-approved drugswith potential to be repurposed for treatment of orphandiseases Brief Bioinform 12 341ndash345 (2011)
8 X Bosch European researchers drug companies joinforces against rare diseases JAMA 294 2014ndash2015 (2005)
9 F S Collins Mining for therapeutic gold Nat Rev DrugDiscov 10 397 (2011)
10 P Vallance P Williams C Dollery The future is much closercollaboration between the pharmaceutical industry andacademic medical centers Clin Pharmacol Ther 87525ndash527 (2010)
11 A Corbett J Pickett A Burns J Corcoran S B DunnettP Edison J J Hagan C Holmes E Jones C KatonaI Kearns P Kehoe A Mudher A Passmore N ShepherdF Walsh C Ballard Drug repositioning for Alzheimerrsquosdisease Nat Rev Drug Discov 11 833ndash846 (2012)
12 J L Goldstein M S Brown A century of cholesterol andcoronaries From plaques to genes to statins Cell 161161ndash172 (2015)
13 A M Malfitano G Marasco M C Proto C Laezza P GazzerroM Bifulco Statins in neurological disorders An overviewand update Pharmacol Res 88 74ndash83 (2014)
14 T Kurata K Miyazaki M Kozuki N Morimoto Y OhtaY Ikeda K Abe Progressive neurovascular disturbances inthe cerebral cortex of Alzheimerrsquos disease-model miceProtection by atorvastatin and pitavastatin Neuroscience197 358ndash368 (2011)
15 H Kurinami N Sato M Shinohara D Takeuchi S TakedaM Shimamura T Ogihara R Morishita Prevention ofamyloid beta-induced memory impairment by fluvastatinassociated with the decrease in amyloid beta accumulationand oxidative stress in amyloid beta injection mousemodel Int J Mol Med 21 531ndash537 (2008)
16 M Shinohara N Sato H Kurinami D Takeuchi S TakedaM Shimamura T Yamashita Y Uchiyama H RakugiR Morishita Reduction of brain beta-amyloid (Abeta)by fluvastatin a hydroxymethylglutaryl-CoA reductaseinhibitor through increase in degradation of amyloidprecursor protein C-terminal fragments (APP-CTFs) andAbeta clearance J Biol Chem 285 22091ndash22102 (2010)
17 G J Siegel N B Chauhan D L Feinstein G Li E B LarsonJ C Breitner T J Montine Statin therapy is associated withreduced neuropathologic changes of Alzheimer diseaseNeurology 71 383 author reply 383 (2008)
18 X-K Tong C Lecrux P Rosa-Neto E Hamel Age-dependentrescue by simvastatin of Alzheimerrsquos disease cerebrovascularand memory deficits J Neurosci 32 4705ndash4715 (2012)
19 X K Tong N Nicolakakis P Fernandes B Ongali J BrouilletteR Quirion E Hamel Simvastatin improves cerebrovascularfunction and counters soluble amyloid-beta inflammationand oxidative stress in aged APP mice Neurobiol Dis35 406ndash414 (2009)
Table 3 Recommendations to improve translation through the use of preclinicalpharmacokinetic data
Journalsbull Require authors to provide explicit rationale for dosing strategies usedbull Rationale should include consideration of the unbound drug exposure in target organas best practices
Educationbull Include basic pharmacology and pharmacokinetic principles in formal coursework requiredfor basic preclinical and clinical research scientists
bull Develop tutorials and on-line calculators for rodent dose projections to support appropriateuse of published pharmacological tools
Databasesbull Reinforce public chemical databases with mouse pharmacokinetic data that includes brainexposure
Precompetitive consortiabull Create precompetitive consortia to solicit mouse pharmacokinetic data sets from industry andfoundation partners for database expansion
bull Targeted data collection for compounds already in the public domain
rg 6 January 2016 Vol 8 Issue 320 320ps1 4
P ER SP EC T I V E
20 E K Osterweil S C Chuang A A Chubykin M SidorovR Bianchi R K Wong M F Bear Lovastatin corrects ex-cess protein synthesis and prevents epileptogenesis in amouse model of fragile X syndrome Neuron 77 243ndash250(2013)
21 C M Buchovecky S D Turley H M Brown S M KyleJ G McDonald B Liu A A Pieper W Huang D M KatzD W Russell J Shendure M J Justice A suppressorscreen in Mecp2 mutant mice implicates cholesterol me-tabolism in Rett syndrome Nat Genet 45 1013ndash1020(2013)
22 M J Justice C M Buchovecky S M Kyle A Djukic A rolefor metabolism in Rett syndrome pathogenesis Newclinical findings and potential treatment targets RareDis 1 e27265 (2013)
23 F Scicchitano A Constanti R Citraro G De Sarro E RussoStatins and epilepsy Preclinical studies clinical trials andstatin-anticonvulsant drug interactions Curr Drug Targets16 747ndash756 (2015)
24 M L Ferlazzo L Sonzogni A Granzotto L Bodgi O LartinC Devic G Vogin S Pereira N Foray Mutations of theHuntingtonrsquos disease protein impact on the ATM-dependentsignaling and repair pathways of the radiation-inducedDNA double-strand breaks Corrective effect of statins andbisphosphonates Mol Neurobiol 49 1200ndash1211 (2014)
25 E K Tan L C Tan Holding on to statins in Parkinsondisease Neurology 81 406ndash407 (2013)
26 B Friedman A Lahad Y Dresner S Vinker Long-termstatin use and the risk of Parkinsonrsquos disease Am J ManagCare 19 626ndash632 (2013)
27 M S Elkind Stroke A step closer to statin therapy forstroke Nat Rev Neurol 9 242ndash244 (2013)
28 E E Abrahamson M D Ikonomovic C E Dixon S T DeKoskySimvastatin therapy prevents brain trauma-inducedincreases in beta-amyloid peptide levels Ann Neurol66 407ndash414 (2009)
29 E F Wible D T Laskowitz Statins in traumatic brain injuryNeurotherapeutics 7 62ndash73 (2010)
wwwScienceTranslationalMedicineo
30 S Sierra M C Ramos P Molina C Esteo J A VaacutezquezJ S Burgos Statins as neuroprotectants A comparativein vitro study of lipophilicity blood-brain-barrier penetra-tion lowering of brain cholesterol and decrease of neuroncell death J Alzheimers Dis 23 307ndash318 (2011)
31 W G Wood G P Eckert U Igbavboa W E Muumlller Statinsand neuroprotection A prescription to move the fieldforward Ann N Y Acad Sci 1199 69ndash76 (2010)
32 W G Wood W E Muumlller G P Eckert Statins and neuro-protection Basic pharmacology needed Mol Neurobiol50 214ndash220 (2014)
101126scitranslmedaac9888
Citation R J Kleiman M D Ehlers Data gaps limit thetranslational potential of preclinical research Sci Transl Med8 320ps1 (2016)
D
rg 6 January 2016 Vol 8 Issue 320 320ps1 5
on January 6 2016httpstm
sciencemagorg
ownloaded from
101126scitranslmedaac9888] (320) 320ps1 [doi8Science Translational Medicine
Robin J Kleiman and Michael D Ehlers (January 6 2016) Data gaps limit the translational potential of preclinical research
Editors Summary
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is a registered trademark of AAASMedicineScience TranslationalAssociation for the Advancement of Science all rights reserved The title
Science 1200 New York Avenue NW Washington DC 20005 Copyright 2016 by the Americanweekly except the last week in December by the American Association for the Advancement of
(print ISSN 1946-6234 online ISSN 1946-6242) is publishedScience Translational Medicine
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Dow
nloaded from
Boston Childrenrsquos Hospital ndash Broad Institute Collaboration Grants
Background Meeting the challenges of biomedicine requires bringing together creative scientists exceptional technological resources and world-class expertise across many disciplines that rarely exist within a single institution This guiding principle is the basis for a funding opportunity to support Boston Childrenrsquos Hospital investigators performing research in collaboration with Broad scientists
Goals The fundamental goal of this new award is to spark new collaborations between Boston Childrenrsquos Hospital and the Broad Institute The grants will be awarded to address a very wide range of scientific questions but are specifically designated for projects with the following characteristics
middot Projects where engagement with the Broad would benefit Childrenrsquos Hospital investigators projects that can uniquely benefit from being done at the Broad Institute
middot Projects that create new scientific collaborations and bring together diverse scientific backgrounds projects that spark new scientific directions or technologies and are not currently being pursued at Childrenrsquos Hospital
middot Projects that pilot new approaches that researchers at Childrenrsquos the Broad and the greater scientific community can benefit from in the future the purpose of these awards is not to provide gap or extension funding of existing projects but to initiate new projects
Eligibility Individuals with Principal Investigator status at Boston Childrenrsquos Hospital are eligible Applicants need not be Associate Members of the Broad Institute
Broad Platforms and Scientists Broadrsquos Platforms (Genomics Imaging Metabolite Profiling Proteomics Genomic Perturbation and the Broad Technology Labs) are collaborative organizations that provide scientific leadership and cutting edge technologies in support of project goals Collaborations can also be established with other groups at the Broad including the Klarman Cell Observatory the Stanley Center for Psychiatric Research or the Center for the Development of Therapeutics
Budgets Grants will provide $60000 direct support for 1 year plus philanthropic overhead It is expected that most grants will fund work performed at the Broad Institute either through interaction with Broadrsquos Platforms or via collaboration with a Broad scientist however the work may also occur at Boston Childrenrsquos if it is important to meet the scientific goals of the collaboration
Deadline and Review process Final proposals are due by September 1 2015 Funding decisions are expected to be reached by October 1 2015 Proposals will be reviewed by a joint Childrenrsquos HospitalndashBroad Institute committee Additional submission dates are expected for 2016
Submission Applicants are strongly encouraged to discuss potential applications in advance with the office of the Chief Scientific Officer at the Broad Questions should be directed to Alex Burgin ( 617-714-7124)
Proteomics Genomic Perturbation and the Broad Technology Labs) are collaborative
organizations that provide scientific leadership and cutting edge technologie
s in support of
project goals Collaborations can also be established with other groups at the Broad including
the Klarman Cell Observatory the Stanley Center for Psychiatric Research or the Center for the
Development of Therapeutics
Budgets
Grants wi
ll provide $60000 direct support for 1 year plus philanthropic overhead It
is expected that most grants will fund work performed at the Broad Institute either through
interaction with Broadrsquos Platforms or via collaboration with a Broad scientist howev
er the
work may also occur at Boston Childrenrsquos if it is important to meet the scientific goals of the
collaboration
Deadline and Review process
Final proposals are due by September 1 2015 Funding
decisions are expected to be reached by October 1 201
5 Proposals will be reviewed by a joint
Childrenrsquos Hospital
ndash
Broad Institute committee Additional submission dates are expected for
2016
Submission
Applicants are
strongly encouraged to discuss potential applications in
advance
with the office of the Chief Sc
ientific Officer at the Broad
Questions should be
directed to Alex Burgin (
aburginbroadinstituteorg
617
-
714
-
7124
)
Boston Childrenrsquos Hospital ndash Broad Institute Collaboration Grants
Background Meeting the challenges of biomedicine requires bringing together creative
scientists exceptional technological resources and world-class expertise across many
disciplines that rarely exist within a single institution This guiding principle is the basis for a
funding opportunity to support Boston Childrenrsquos Hospital investigators performing research
in collaboration with Broad scientists
Goals The fundamental goal of this new award is to spark new collaborations between Boston
Childrenrsquos Hospital and the Broad Institute The grants will be awarded to address a very wide
range of scientific questions but are specifically designated for projects with the following
characteristics
Projects where engagement with the Broad would benefit Childrenrsquos Hospital
investigators projects that can uniquely benefit from being done at the Broad Institute
Projects that create new scientific collaborations and bring together diverse scientific
backgrounds projects that spark new scientific directions or technologies and are not
currently being pursued at Childrenrsquos Hospital
Projects that pilot new approaches that researchers at Childrenrsquos the Broad and the
greater scientific community can benefit from in the future the purpose of these awards
is not to provide gap or extension funding of existing projects but to initiate new
projects
Eligibility Individuals with Principal Investigator status at Boston Childrenrsquos Hospital are
eligible Applicants need not be Associate Members of the Broad Institute
Broad Platforms and Scientists Broadrsquos Platforms (Genomics Imaging Metabolite Profiling
Proteomics Genomic Perturbation and the Broad Technology Labs) are collaborative
organizations that provide scientific leadership and cutting edge technologies in support of
project goals Collaborations can also be established with other groups at the Broad including
the Klarman Cell Observatory the Stanley Center for Psychiatric Research or the Center for the
Development of Therapeutics
Budgets Grants will provide $60000 direct support for 1 year plus philanthropic overhead It
is expected that most grants will fund work performed at the Broad Institute either through
interaction with Broadrsquos Platforms or via collaboration with a Broad scientist however the
work may also occur at Boston Childrenrsquos if it is important to meet the scientific goals of the
collaboration
Deadline and Review process Final proposals are due by September 1 2015 Funding
decisions are expected to be reached by October 1 2015 Proposals will be reviewed by a joint
Childrenrsquos HospitalndashBroad Institute committee Additional submission dates are expected for
2016
Submission Applicants are strongly encouraged to discuss potential applications in
advance with the office of the Chief Scientific Officer at the Broad Questions should be
directed to Alex Burgin (aburginbroadinstituteorg 617-714-7124)
Clinical Trials Glossary
ADME an acronym for absorption distribution metabolism and elimination ADME
studies determine how a drug is absorbed by the body the chemical changes that it may
undergo and how it is eliminated from the body
Adverse event (AE) a bothersome event that occurs in a study participant AEs may be
related to the treatment being tested or may be due another cause (eg another treatment
another medical condition an accident or a surgery)
Arm a specific type of treatment to which a group of clinical trial participants is
assigned Some clinical trials have one arm and some have two arms while others have
three or more arms For example a clinical trial comparing two different doses of an
investigational drug versus a placebo would have three arms participants receiving a
higher dose of the investigational drug participants receiving a lower dose of the
investigational drug and participants receiving the placebo
Baseline a point in time at the beginning of a clinical trial before the study participants
receive any treatment At the baseline participants usually have certain types of tests
During and after treatment the same tests may be performed and the results compared
with the baseline results to see if the drug has caused changes
Bias a factor ndash such as a preconceived idea about the effects of the benefits and risks of a
treatment or a lack of balance in selection of patients for a study ndash that reduces the
likelihood that the study results are true Methods such as blinding and randomization
are used to limit the potential for bias
Bioavailability the portion of the dose of a drug that reaches the bloodstream For
example if the drug is administered intravenously its bioavailability is 100 percent
however if the drug is administered in any other way such as orally topically or
through intramuscular injection its bioavailability will decrease due to incomplete
absorption
Bioequivalence study a test performed to compare the portion of a drug in the
bloodstream when administered in different dosage forms
Biologic product any substance that can be used in prevention treatment or cure of
disease Some examples include vaccines blood virus toxin antitoxin and therapeutic
serum
Biopsy the removal of cells or tissue from a patient for examination which is usually
done under a microscope A tissue sample might be taken for genetic studies Sometimes
there is a difference between the blood genotype and the skin or other tissue genotype
This term can also refer to the tissue sample that has been obtained by such a procedure
2
Blinding a process used to prevent the participants the researchers or both from
knowing what specific treatment is being given to participants in a clinical trial The
process of blinding helps to reduce bias because study participants and researchers are
less likely to be unconsciously influenced by the knowledge of what the study participant
is actually receiving If only the participants are blinded the study is called a single-
blind study If both participants and researchers are blinded the study is called a double-
blind study
Carcinogenicity studies long-term studies conducted in animal models to determine a
drugrsquos likelihood of causing cancer
Clinical efficacy a compoundrsquos ability to produce the desired effect
Clinical pharmacology a science that studies properties of drugs in relation to their
therapeutic value in humans
Clinical study or Clinical trial a medical experiment in human beings that helps to
determine how a disease drug or medical device affects study participants Clinical
studies are necessary to answer specific questions about how to better diagnose prevent
or treat a disease or condition
Cohort a group of study participants who have certain characteristics in common such
as female sex a defined age range or particular severity of disease Dividing study
participants into cohorts is often done as part of the analyses of study data
Contraindication a factor that makes the use of a particular drug inadvisable For
example a person who has had an allergic reaction to penicillin in the past is considered
to have a contraindication to using penicillin in the future
Control group a group of participants not receiving the investigational drug but instead
receiving a standard treatment for their disease or receiving a placebo The results
observed in the group of patients receiving the investigational drug are compared with the
results observed in the control group
Crossover study a study design with two or more arms where participants receive one
treatment for a period of time and then switch over to a second treatment for a period of
time Such a study design allows the effects of the two treatments to be compared in the
same patient
Data Monitoring Committee (DMC) or Data Safety and Monitoring Board (DSMB)
A committee of experts that periodically reviews the accumulating data from an ongoing
multicenter clinical trial Members of a DMCDSMB must be independent ie they
cannot be participating as investigators in the clinical trial Based on their review the
DMCDSMB experts advise the sponsor regarding whether it is safe and acceptable to
continue with the study or whether the data suggest that the study should be modified or
stopped A DMCDSMB may recommend that a trial be stopped if there are safety
concerns or if the trial objectives have been achieved
3
Dose-ranging study a clinical trial in which two or more doses of an investigational
drug are tested to determine which dose is likely to offer the best combination of safety
and efficacy in later clinical trials or in medical care
Efficacy or effectiveness the ability of a drug to prevent cure or slow a disease process or to alleviate the symptoms of a disease or condition
Eligibility a determination made during the screening period for a clinical study of
whether a personrsquos participation in the trial is likely to be safe and can contribute data
that will help achieve the study goals
Endpoint occurrence of a disease symptom sign or test result that constitutes one of the
target outcomes of a clinical trial
Inclusionexclusion criteria the factors defined in the protocol of a study that determine
whether a personrsquos participation in a clinical trial is likely to be safe and can contribute
data that will help achieve the study goals Study candidates undergo evaluation during
the study screening period to determine if they meet all of the inclusion criteria and do
not meet any of the exclusion criteria as defined in the protocol These criteria usually
consider such factors as age sex type of disease stage of disease previous treatment
history and other medical conditions in determining eligibility for the study
Informed consent (assent) a process by which medical researchers provide necessary
information to a person about a clinical study and the person voluntarily confirms his or
her willingness to participate in the study Children who are considered old enough to
have a basic understanding of the study may need to provide assent to be involved in the
study a parent or legal guardian must also give informed consent for such a child to
participate
Informed consent (assent) form a document that describes a clinical study to the
participants (or their parentsguardians) The informed consent (assent) form includes
information about the goals of the study the study design and duration the types of tests
to be performed the potential risks and inconveniences the potential benefits the
possible costs or payments associated with study participation the available alternative
therapies the rights and responsibilities of the participant and the people to contact if the
participant has questions The informed consent (assent) form must be reviewed and
signed before the participant has any study tests or treatment including the tests
performed during the screening period at the beginning of the study Participants are
given a copy of the informed consent (assent) form to take home
Institutional Review Board (IRB) or Independent Ethics Committee (IEC) a board
of physicians statisticians researchers community advocates and others who are
responsible for ensuring the protection of the rights safety and well-being of participants
in a clinical trial at a study center This board is called an IRB in the United States and is
often called an IEC in other countries IRBIECs review and approve important study
documents (eg protocols informed consent forms study advertisements and patient
4
brochures) before the start of the study and periodically review the progress of the study
while it is ongoing
Investigational Drug a drug that is being tested as a potential treatment for a disease or
condition but has not yet been proven safe and effective for that use
Investigator a physician or other health care worker who carries out a clinical trial by enrolling treating and monitoring participants and recording the results
In vitro testing testing conducted in test tubes or other artificial environments
In vivo testing testing conducted in living animals or humans
Longitudinal study a clinical study that involves observations of the same items over
long periods often many decades Because longitudinal studies track the same people
they are often used to study trends across the life span to uncover predictors of certain
diseases or to track the effects of a particular treatment on a patientrsquos condition over
time
Multicenter study a study conducted at more than one location Multicenter clinical
studies are generally performed when each individual clinical trial site does not have
enough study candidates to complete a large trial
Natural history study a study of the natural development of a disease or condition over
a period of time Natural history studies are usually longitudinal studies
New Drug Application (NDA) the registration document through which a
pharmaceutical company formally proposes that the FDA approve a new drug for
manufacturing and sale The application includes detailed reports of pharmacology
toxicology manufacturing and chemistry as well as data from clinical trials
Open-label study a study in which the participants and the investigators know which
treatment is being given In an open-label study there is no blinding and none of the participants receives a placebo
Orphan disease a disease or condition that affects a relatively small number of people
In the US this defined as fewer than 200000 people In Europe this is defined as fewer
than five in 110000 people
Orphan drug a drug intended to treat an orphan disease
Participant or subject a patient or healthy volunteer who participates in a clinical trial
Phase 1 the initial phase of testing of an investigational drug in humans Usually a
Phase 1 clinical study is conducted in a small number of healthy volunteers or patients
with a disease for which the drug may be useful Generally the study is designed to
determine the side effects of the drug and its pharmacokinetics Some information
5
regarding drug efficacy may be collected if patients with a disease participate A phase
frequently encompasses more than one clinical trial Phase 1 sometimes is sub-divided
into Phases 1a and 1b for example when the first set of Phase 1 trials (Phase 1a) is
performed in healthy volunteers and a second set of Phase 1 trials (Phase 1b) is
performed in patients with a disease
Phase 2 the intermediate phase of testing of an investigational drug in humans Usually
a Phase 2 clinical study conducted in patients with a disease for which the drug may be
useful Generally the study is designed to evaluate dosing to obtain preliminary data on
the effectiveness of the drug and to acquire more safety information Phase 2 sometimes
is sub-divided into Phases 2a and 2b Phase 2a studies typically are smaller and shorter
in duration and evaluate different drug doses to see how they affect certain tests that can
indicate whether the drug is working as expected Phase 2b studies typically enroll more
patients are of longer duration and evaluate whether the drug is offering clinical benefits to patients Phase 2b studies sometimes are considered pivotal or registration-directed
Phase 3 the final phase of testing an investigational drug in humans before regulatory
approval Phase 3 studies are usually conducted in a large population of patients and are
generally designed to confirm the effectiveness of the drug and to evaluate the overall
risk-benefit ratio Phase 3 studies usually test the investigational drug in comparison with
a standard treatment for the disease or a placebo
Phase 4 testing of a drug in humans after it has already been approved by regulatory
authorities and can be used in medical practice Phase 4 studies may be conducted to
compare the drug to a similar type of drug to explore whether it may help patients with
other diseases to further study the long-term safety of the drug or for other reasons
Pivotal study a study that is designed to generate the data required by regulatory
authorities to decide whether to approve an investigational drug A pivotal study is
usually a large randomized Phase 2b or Phase 3 study and often is blinded and uses a
placebo as a control Sometimes a pivotal study is described as a registration-directed
study
Placebo an inactive version of an investigational drug A placebo has a similar
appearance to the investigational drug but is expected to have no therapeutic value A
placebo is used as a comparison treatment to reduce bias in randomized studies
Preapproval access program an umbrella term for programs that allow seriously ill
patients to receive an investigational drug when they are unable to participate in clinical
trials and there is no alternative treatment This is sometimes referred to as
compassionate use Types of pre-approval access programs include expanded access
parallel-track named patient program single-patient exemption and treatment IND The
timing for starting an expanded access program usually depends upon what is known
about the risk-benefit of the drug and whether the drug can be provided in a manner that
is fair to patients with the disease
6
Preclinical (nonclinical) testing testing of a drug in test tubes or in animals A drug
undergoes preclinical testing before being tested in humans to make sure that it shows
evidence of desired effects and is sufficiently safe for study in people Preclinical testing
sometimes also helps to determine the doses of the drug that should be evaluated in
humans Preclinical testing is sometimes called nonclinical testing
Protocol a document describing what types of people may participate in a clinical study
and the objectives treatments measurements statistical methods timing and
organization of a clinical trial The protocol must be prepared in advance of the study
and must be reviewed and approved by review committees and regulatory authorities
before the study is started Investigators must follow the protocol to carry out the study
Randomization assignment of participants to treatment arms based on chance This is
usually done by a computer program in a way that does not allow either the participants
or the investigators to choose who is assigned to which arm Randomization is used to
reduce bias in clinical trials
Risk-benefit ratio the balance of the risk of side effects expected with use of a drug
versus the potential for benefit with the use of that drug A drug with a good risk-benefit
ratio has few side effects and is very effective
Serious adverse event (SAE) an adverse event that is life-threatening requires inpatient
hospitalization or lengthens a hospital stay leads to substantial disability leads to a birth
defect or results in death
Side effect any effect of a drug other than the desired effect Side effects are often
unwanted and may be bothersome Other names for a bothersome side effect are adverse
drug reaction (ADR) or drug toxicity
Screening period a period at the beginning of a clinical trial when candidates for the
study are evaluated to determine if their participation is likely to be safe and can
contribute data that will help achieve the study goals
Significant or statistically significant an outcome in a clinical trial is likely to result
from a real difference (eg due to an effect of a treatment) and is unlikely to be due to
chance alone The level of statistical significance is often expressed in terms of a p-
value which indicates the probability that a difference is not due to chance alone
Usually a p-value smaller 005 is considered statistically significant
Sponsor the organization responsible for financing and coordinating a clinical trial
Most often this is a pharmaceutical or biotechnology company
Standard treatment a treatment currently in wide use often approved by regulatory
agencies and generally considered effective in the treatment of a specific disease or
condition
7
Toxicity a side effect produced by a drug that is bothersome to the person taking the
drug
Toxicology the study of the adverse effects of chemicals conducted in animal models to
predict potential adverse effects in humans Some studies are conducted during clinical
development to evaluate dosing regimens
Boston Childrenrsquos Hospital Clinical Research Map 1 Mouse over for additional info Bold = hyperlink
CLINICAL RESEARCH MAP
Boston Childrenrsquos Hospital Clinical Research Map 2 Mouse over for additional info Bold = hyperlink
ObjectiveThis clinical research map is designed to serve as a guide for investigators study coordinators and research nurses at Boston Childrenrsquos Hospital The research map outlines the key steps in preparing to launch a research study and provides embedded links to institutional resources tools and documents
An investigator need not follow the steps on the Clinical Research Map in any particular order There is flexibility and the steps followed will in part de-pend on the type of research study
For new as well as more experienced investigators the Clinical Research Map can be used as a checklist or an inves-tigator can use the steps on the map as points for consideration as they are developing a protocol and launching a study
This tool is not intended to substitute for the important collaboration be-tween a junior investigator and a senior investigatormentor A senior investiga-tor plays a pivotal role in coaching and advising a junior investigator regarding the many subtleties and variations that apply to designing and implementing a protocol
This process map cannot be inclusive of every possible task or step but is intended as a general guide for investi-gators and their study teams
ResourcesThere are many institutional resources at Boston Childrenrsquos Hospital designed to support investigators and their clini-cal research teams In addition to links to resources tools and documents that are embedded in the steps of the clini-cal research map the last page of this document contains website addresses that will take you to additional helpful institutional resources
Acknowledgements Cindy Williams DNP RN PNP NE-BC Nursing Director CTSU Clinical Research Nursing
Ellen McGrath MSN RN CPNP Nurse Practitioner Department of Surgery
Grace Yoon MSN RN CNNP Research Nurse Department of Ophthalmology
Laura Feloney BA Lab Technician
ContentsOverview Four stages 3
1st Stage Protocol development 4
1st Stage Protocol development contrsquod 5
2nd Stage Implementation planning 6
3rd stage Study launch7
4th stage Statistical analysis reporting and dissemination 8
Discarded specimens Additional steps 9
Chart review Steps if you are completing a chart review 10
Appendix A Resources for researchers 11
Boston Childrenrsquos Hospital Clinical Research Map 3 Mouse over for additional info Bold = hyperlink
Overview Four stages
Protocol development
Implementation planning
Study launch
Statistical analysis reporting and dissemination
1
2
3
4
Boston Childrenrsquos Hospital Clinical Research Map 4 Mouse over for additional info Bold = hyperlink
1st Stage Protocol development
Explore resources
CRIT
CRC
EQuIP
CTSU
Harvard Catalyst
Complete training
CITI training
EQUiP
Consult research pharmacistResearch Pharmacy
Rocco Anzaldi
Consult statistician
CRC
Draft a protocol
Protocol guidelines
Study personnel
FDA Guidance for Investigators
Consult Clinical Research Center
CRC
Bio Bank
Start IRB application
TransLab
Consider applying for grants
securing funding
Office of Sponsored Programs
If INDIDE application to FDA
Does my study need an INDIDE
Regulatory resources
Arrange a consultation with
CRIT
ConsultationTasks for investigators and study teams
Boston Childrenrsquos Hospital Clinical Research Map 5 Mouse over for additional info Bold = hyperlink
Respond to IRB questionsrequests
for clarification
1st Stage Protocol development contrsquod
Departmental Scientific Review
Organize DSMB design DSMP
DSMPDSMB
Templates for Research Study
Documents and Tools
Study Templates and Tools
Investigators who sponsor an FDA regulated trial
ClinicalTrialsgov
Create regulatory binder
Regulatory Binder Template
Submit the grant application to OSP
OSP
TIDO
CTBO
Consult Office Intellectual Property
Technology and Innovation
Development Office
TIDO
IRB approval
Consider blood volume for research
Research blood volume policy
Confidentiality plan
Confidentiality guidelines
Boston Childrenrsquos Hospital Clinical Research Map 6 Mouse over for additional info Bold = hyperlink
Develop Case Report Forms
(CRFs)
CRF guidelines
Establish electronic shared
folder or study binder for study
documents
CRIT
Set date for trial launch
Develop fast fact sheet for bedside staff
Consult programmer re database
CRIT
Research study resource manual
for the clinical unit
Confirm study drug
in pharmacy
Rocco Anzaldi
Clarify system for screening
and enrolling patients
Recruitment guideline
Updated protocol to
nurse manager
Consult MDsNPs on unitclinic
2nd Stage Implementation planning
Tasks for investigators and study teams
Study logistics Documentation logistics
Data storage
Confidentiality plan
Confidentiality guidelines
Create study orderset
Consider blood volume for research
Research blood volume policy
Create Manual of Operations
MOO Guide
Study implementation
meeting
Develop study logstools
EQUIP
Finalize tracking sheet
Research Administration
Fernando Valles
Boston Childrenrsquos Hospital Clinical Research Map 7 Mouse over for additional info Bold = hyperlink
3 Document informed consent
Informed Consent
Consent library
Schedule weekly study team meeting
Communicate to department faculty
and multidisciplinary
team announcing trial launch
Steps before trial launch
3rd stage Study launch
Patient flow
1 Seek permission
to approach potential subjects
2 Screenenroll
patients
EQUIP
5 Send Study
Tracking Sheet (STS)
6 Collection of
patient data and assessing for
adverse events
7 Study
documents and data handling
4 Datetime study tests
Create a checklist outlining study action items for each subject
Boston Childrenrsquos Hospital Clinical Research Map 8 Mouse over for additional info Bold = hyperlink
Annual IRB Report
Annual Progress ReportStaff Report
raquo Maintain Interest of Staff
raquo Important to See Study Progress
Write Abstract
Dissemination of Research Results
raquo Conference raquo Internal Presentation for Colleagues
raquo Publication
Plan DSMB MeetingInterim
Analysis
4th stage Statistical analysis reporting and dissemination
Data Entry
When Enrollment Complete Data
Cleaning
Monitor Subjects to Identify
Adverse Events (CCI sponsor
DSMB)
Report Adverse Events
Update MOO Based on Experience
with First Several Patients Enrolled
Weekly Study Team Meeting
Report study findings to
subjects and stakeholders
Data management Trial management
Reporting Dissemination
Regular Review of Data
to Identify Deviations
and Workflow Improvements
Consult Statistician When Approaching Target Enrollment
Discarded specimens Additional steps
Boston Childrenrsquos Hospital Clinical Research Map 9 Mouse over for additional info Bold = hyperlink
Send IRB Approval to lab manager
Maureen Samson
Educate staff in areasunits about sample collection
Locate the discarded samples
Locate the accession number in PowerChart
Retrieve specimen
Mark Kellogg
Follow Shipping Rules and Procedures
IATAShipping with dry ice instructions
Communicate with laboratory staff
Contact Dr Mark Kellogg to discuss specimen retrieval
Consult with Biorepository
Biorepository
Chart review Steps if you are completing a chart review
Boston Childrenrsquos Hospital Clinical Research Map 10 Mouse over for additional info Bold = hyperlink
7 8
4321
Databaserecord review guidelines
5 6
Consult programmer re database
CRC Request
Respond to IRB questions
requests for clarification
Departmental Scientific Review
Complete training
CITI Training
Draft a protocol
Protocol Guidelines
Prepare IRB Application
Information about the CCI
IRB Application
Develop Case Report Forms (CRFs)
CRF Guidelines
IRB Review
Boston Childrenrsquos Hospital Clinical Research Map 11 Mouse over for additional info Bold = hyperlink
Clinical Research Center (CRC) x84720
Committee on Clinical Investigation (CCI IRB) x57052
Research Pharmacist x52014
Clinical and Translational Science Unit (CTSU) x57541
Education and Quality Improvement Program (EQUIP) x57052
Clinical Trials Office Central Budgeting x4-2714
Office of Sponsored Programs x4-2723
Technology and Innovation Development Office 617-919-3079
Research Finance x8-3517
Harvard Catalyst 617-432-7810
Regulatory Affairs x4-2777
Appendix A Resources for researchers
RES_4446_ClinicalResearchMap-FINAL FOR LINKS 1
RES_4446_ClinicalResearchMap-FINAL FOR LINKS 10
Overview Four stages
1st Stage Protocol development
1st Stage Protocol development contrsquod
2nd Stage Implementation planning
3rd stage Study launch
4th stage Statistical analysis reporting and dissemination
Discarded specimens Additional steps
Chart reviewSteps if you are completing a chart review
Appendix A Resources for researchers
RES_4446_ClinicalResearchMap-FINAL FOR LINKS 11
RES_4446_ClinicalResearchMap-FINAL FOR LINKS 2
RES_4446_ClinicalResearchMap-FINAL FOR LINKS 3
RES_4446_ClinicalResearchMap-FINAL FOR LINKS 4
RES_4446_ClinicalResearchMap-FINAL FOR LINKS 5
RES_4446_ClinicalResearchMap-FINAL FOR LINKS 6
RES_4446_ClinicalResearchMap-FINAL FOR LINKS 7
RES_4446_ClinicalResearchMap-FINAL FOR LINKS 8
RES_4446_ClinicalResearchMap-FINAL FOR LINKS 9
RES_4446_ClinicalResearchMap-PAGE 5pdf
Overview Four stages
1st Stage Protocol development
1st Stage Protocol development contrsquod
2nd Stage Implementation planning
3rd stage Study launch
4th stage Statistical analysis reporting and dissemination
Discarded specimens Additional steps
Chart reviewSteps if you are completing a chart review
Appendix A Resources for researchers
Next Page
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Button 110
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Button 111
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Page 98
MOUSE OVER
Page 1
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Page 98
COVER BUTTON
Previous Page
Page 118
Page 2
Page 31
Page 63
Page 74
Page 85
Page 96
Page 1
Button 91
Button 92
Button 94
IRB review
Button 102
Develop Case Report Forms
Button 136
Consult clinical research center
INDIDE 1
Explore resources
Button 1016
Bio Bank p
4
Consult statistician
Consult research pharmacist
Study personnel
Complete training
Consider grantsfunding
Draft a Protocal 2
Arrange a consutlations with CRIT
Next Page 1
Previous Page 1
TransLab
Start IRB application 3
Develop study logs
Updatedd protocol
Confirm study drug
Establish electronic shared
COnsult programmer
Clarify system
Research study resrouce manual
Develop case report forms
MOO
Set date for trial launch
Button 44
Study implementation meeting
Finalize tracking sheet
Data storage
Confidentiality
Blood volume 3
Develop fast fact
Consult MDs
Schedule weekly
Communicate early
Button 71
Screenenroll patients
Document informed consent
Datetime tests
Send study tracking sheets
Collection patient data
Button 77
Dissemination
Button 87
Button 124
Button 125
Communicate with lab staff
Button 106
Button 109
Button 1010
Shipping page 9
Button 1012
Button 99
Button 133
Button 134
Button 135
Biorepository
Locate assession number
Retrieve specimen
Button 30
Consult office
Negotiate Contract
Organizing DSMB
Submit Grant
Respond to IRB questions
Button 66
Create regulatory binder
Templates for research stufy
Clinical Trials Business Office
Blood volume 2
Confidentiality plan
Investigators who sponsor
clinicaltrials
gov
BPN Project
Drug Discovery amp Development Testing Funnel
Tier 1 2 3
Tier 6 7 8
Tier 5
Tier 4
Example Drug Discovery amp Development Testing Funnel
Cytotoxicity
Grant
Project
Example Drug Discovery amp Development Testing Funnel
TIER 1A ndash Primary Screen
Chemical purity and identity of active compounds
Primary bioactivity screen
Cell viability (When Appropriate)
ScaffoldsMoiety Chemical liabilities (for example Michael acceptor GSH reactive)
Calculated properties CLogP
PSA
Molecular Weight
rotatable bonds
H-bond donors and acceptors
permeability
pKa
Solubility
TIER 1B
Confirm EC50 determinations for actives compounds in primary screen with fresh
compounds from the original stock Confirm EC50 determinations for the lead (most
active) compound in primary screen with a new sample either repurchased purified
and characterized in-house or independently synthesized in-house
Compounds with IC50s (EC50s) less than X advance to Tier 2
TIER 2A ndash Activity Confirmation
Secondary screen
TIER 2B
Repeat EC50 determinations for actives in secondary screen with fresh
compounds from the original stock
Compounds with IC50s (EC50s) less than X advance to Tier 3
Example Drug Discovery amp Development Testing Funnel
TIER 3 ndash Drug-like Properties Specificity
IC50 selectivity in selectivity screen
CYP450 Inhibition competitive and time-dependent if structural alerts exist
(spot check illustrative examples from compound series)
Measured solubility
Measured protein binding (spot check illustrative examples from
compound series)
Test of Permeability in vitro permeability [indicate assay eg Caco2 orand
PAMPA] (spot check illustrative examples from compound series)
hERG
Cytoxicity assays
All compounds with no significant issues (Define Minimum Conditions for
Advancement) to advance to Tier 4
Example Drug Discovery amp Development Testing Funnel
TIER 4 ndash Scale-up Synthesis and Preliminary PK
Scale-up synthesis
Purity determination gt98 with no single impurity gt1
Rodent bioavailability and PK (define target delivery route) Tmax
Cmax
AUC
Bioavailibility
Vss CL T12 MRT
Brain to Plasma ratios
P-glycoprotein transport MDCK-MDR1 and MDCK-mdr1a
Plasma Protein Binding (species)
Microsomal Stability ndash rodent and human
Defineplan Patent Protection Strategy
All compounds with no significant issues (Define
Minimum Conditions for Advancement) advance
in parallel to Tiers 5AampB
Example Drug Discovery amp Development Testing Funnel
TIER 5A ndash In Vivo Bioactivity
Animal efficacy
Validate Biomarker
Target engagement
Advance to Tier 6 if (Define Minimum Conditions for advancement)
TIER 5B ndash Advanced Drug-like Properties
Microsomal stability in multiple
species
Chemical Stability
CYP450 induction
CYP reaction phenotyping
Metabolism ndash human
hepatocytesmicrosomes
Metab ID define major human rat dog and
non-human primates (NHP) metabolites
In vitro Tox Ames
Chromosome Aberration
CNS effects
Example Drug Discovery amp Development Testing Funnel
TIER 6 ndash Liability Assessment
Broad Pharmacological Profile and Toxicology
PK in second species
TIER 7
Non-GLP exposure studies single and multiple dose
Advance to late stage pre-clinical development (Define Minimum
Conditions for advancement)
Example Drug Discovery amp Development Testing Funnel
Principal InvestigatorProgram Director (Last First Middle)
enspenspenspenspensp
DETAILED BUDGET FOR INITIAL BUDGET PERIOD
DIRECT COSTS ONLY
FROM
THROUGH
enspenspenspenspensp
enspenspenspenspensp
PERSONNEL
DOLLAR AMOUNT REQUESTED (omit cents)
NAME
ROLE ONPROJECT
TYPEAPPT (months)
EFFORTONPROJ
INSTBASESALARY
SALARYREQUESTED
FRINGEBENEFITS
TOTAL
enspenspenspenspensp
PrincipalInvestigator
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
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enspenspenspenspensp
enspenspenspenspensp
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enspenspenspenspensp
enspenspenspenspensp
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enspenspenspenspensp
enspenspenspenspensp
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enspenspenspenspensp
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enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
SUBTOTALS
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
CONSULTANT COSTS
enspenspenspenspensp
enspenspenspenspensp
EQUIPMENT (Itemize)
enspenspenspenspensp
enspenspenspenspensp
SUPPLIES (Itemize by category)
enspenspenspenspensp
enspenspenspenspensp
TRAVEL
enspenspenspenspensp
enspenspenspenspensp
PATIENT CARE COSTS
INPATIENT
enspenspenspenspensp
enspenspenspenspensp
OUTPATIENT
enspenspenspenspensp
enspenspenspenspensp
ALTERATIONS AND RENOVATIONS (Itemize by category)
enspenspenspenspensp
enspenspenspenspensp
OTHER EXPENSES (Itemize by category)
enspenspenspenspensp
enspenspenspenspensp
SUBTOTAL DIRECT COSTS FOR INITIAL BUDGET PERIOD
$
enspenspenspenspensp
CONSORTIUMCONTRACTUAL COSTS
DIRECT COSTS
enspenspenspenspensp
FACILITIES AND ADMINISTRATIVE COSTS
enspenspenspenspensp
TOTAL DIRECT COSTS FOR INITIAL BUDGET PERIOD
$
enspenspenspenspensp
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
Resources for assay development
The Assay Guidance Manual httpwwwncbinlmnihgovbooksNBK53196
This is a key resource for design and qualification of all types of biochemical and cell based assays It covers many
different modes of assay development and optimization as well as troubleshooting guides Do not run a screen
without consulting the manual first
The Assay Development Screening Facility (ADSF) at BCH Hourly access to equipment and technical assistance
consultations compound libraries- live cell medium throughput screening For more information contact Dr Lee Barrett
The ICCB at Longwood Project based access to equipment and expertise for design and execution of high-throughput
screens access to wide collection of chemical and genomic libraries For more information contact Dr Caroline Shamu
caroline_shamuhmsharvardedu
Website httpiccbmedharvardedu
Databases and references with information about activity and properties of small molecule compounds
PubChem provides information on the biological activities of small molecules PubChem is organized as three linked
databases within the NCBIs Entrez information retrieval system These are PubChem Substance PubChem Compound and
PubChem BioAssay Links from PubChems chemical structure records to other Entrez databases provide information on
biological properties These include links to PubMed scientific literature and NCBIs protein 3D structure resource Links to
PubChems bioassay database present the results of biological screening Links to depositor web sites provide further
information A PubChem FTP site Download Facility Power User Gateway(PUG) Standardization Service Score Matrix
Service Structure Clustering and Deposition Gateway are also available Home page is here
httpspubchemncbinlmnihgov
httpspubchemncbinlmnihgovsearch
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
DrugBank The DrugBank database is a unique bioinformatics and cheminformatics resource that combines detailed drug
(ie chemical pharmacological and pharmaceutical) data with comprehensive drug target (ie sequence structure and
pathway) information The database contains 7759 drug entries including 1602 FDA-approved small molecule drugs 161
FDA-approved biotech (proteinpeptide) drugs 89 nutraceuticals and over 6000 experimental drugs Additionally 4300
non-redundant protein (ie drug targetenzymetransportercarrier) sequences are linked to these drug entries Each
DrugCard entry contains more than 200 data fields with half of the information being devoted to drugchemical data and
the other half devoted to drug target or protein data Homepage is here httpwwwdrugbankca
Protein Data Bank archive Targets with protein crystal structures are more attractive targets for structure based drug design
Determine if your target has a known crystal structure by looking it up in the protein database- A Structural View of Biology
This resource is powered by the Protein Data Bank archive-information about the 3D shapes of proteins nucleic acids and
complex assemblies that helps students and researchers understand all aspects of biomedicine and agriculture from
protein synthesis to health and disease Homepage is here httpwwwrcsborgpdbhomehomedo
High Quality Chemical tools are required for testing biological hypothesis Find chemical tools that are fit for purpose by
virtue of target potency and selectivity needed to test hypothesis The dangers of using inadequate chemical tools are
detailed here httpwwwnaturecomnchembiojournalv11n8fullnchembio1867html To support the needs of the
biology community the industrial chemistry research community has joined a pre-competitive effort to provide
characterization data for high quality chemical probes That data is stored here httpwwwchemicalprobesorgprotein-
family
ChemNavigator The National Institutes of Health (NIH) has formed an agreement with ChemNavigator to provide the NIH
with a current and comprehensive database of commercially accessible drug discovery screening compounds to be
made available to all NIH researchers ChemNavigator is pleased to serve NIH affiliated scientific researchers in compound
sample procurement As an NIH researcher you have full access to use the iResearch System All you need to do is take a
few minutes to register in the system Then you will be able to perform chemical structure searches for compound samples
of interest and purchase these samples through this on-line system Link is here httpwwwchemnavigatorcomnihasp
Additional References related to biological activity of compounds
Edwards AM Bountra C Kerr DJ Willson TM Open access chemical and clinical probes to support drug discovery Nature
chemical biology 2009 5(7)436-440
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
Wang Y Suzek T Zhang J Wang J He S Cheng T Shoemaker BA Gindulyte A Bryant SH PubChem BioAssay 2014 update
Nucleic acids research 2014 42(Database issue)D1075-1082
Wang Y Bolton E Dracheva S Karapetyan K Shoemaker BA Suzek TO Wang J Xiao J Zhang J Bryant SH An overview of
the PubChem BioAssay resource Nucleic acids research 2010 38(Database issue)D255-266
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
main menu
Pharmacokinetic tutorial drug exposure measurement services pharmacokinetic data references
Selecting the correct dose to achieve exposure of drug that are adequate to test a hypothesis in preclinical species
requires that you know the potency of the molecule at the desired drug target and the dose of compound required to
achieve target organ exposure that will result in the free (not bound by protein) concentration of drug required to engage
the molecular target within the target organ compartment Estimates of Drug potency can be found in many of the
databases listed under correct molecule The free concentration of a drug is determined in the plasma by multiplying the
concentration of drug in the plasma by the fraction unbound This must be measured for each compound A literature
reference that provides the measured plasma protein binding (PPB) values for many common drugs is provided here
Zhang Xue Shao and Jia (2012) Compilation of 222 drugsrsquo plasma protein binding data and guidance for study designs
Drug Discovery Today Vol 17 Issue 9-10 Pages 476-485 httpwwwncbinlmnihgovpubmed22210121
If your drug target is the brain then you must also understand the kinetics of drug disposition and clearance including blood
brain barrier (BBB) penetration in your test species to select a dose of compound adequate to test your hypothesis
Download a tutorial deck on basic principles of drug disposition and their application in small molecule drug discovery
courtesy of Dr Chris Shaffer Pfizer
150805DMPKTutorial(CLSBCHCourse)pdf
Pharmacometrics Research Core and Pharmacokinetics Service The Pharmacometrics Research Core is directed by Dr Luis
Pereira and provides analytical services for assaying drugsmetabolites in biological matrices (eg plasma serum blood
urine CSF saliva tissues) The Core provides pharmacokinetic and pharmacodynamic analyses for current and future
clinical trials and research projects (including contract services) It conducts stability and potency studies for pediatric
formulations compounded at BCH as per recent demand from FDA and CMS Finally the Core fosters grant applications
and research collaborations both intra and extramural The TNC can additionally provide investigators with consultation in
the identification of resources for pharmacodynamic assay development and contract research organizations able to
provide bioanalysis of preclinical samples needed to support animal clinical trials Contact Dr Luis Pereira for more
information LuisPereirachildrensharvardedu
article on importance of understanding drug exposure in preclinical drug studies here
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
References on Pharmacokinetics and Brain Penetration of Small Molecules
Di L Rong H Feng B Demystifying brain penetration in central nervous system drug discovery Miniperspective Journal of
medicinal chemistry 2013 56(1)2-12
Reichel A Addressing central nervous system (CNS) penetration in drug discovery basics and implications of the evolving
new concept Chemistry amp biodiversity 2009 6(11)2030-2049
Smith DA Di L Kerns EH The effect of plasma protein binding on in vivo efficacy misconceptions in drug discovery Nature
reviews Drug discovery 2010 9(12)929-939
Moda TL Torres LG Carrara AE Andricopulo AD PKDB database for pharmacokinetic properties and predictive in silico
ADME models Bioinformatics 2008 24(19)2270-2271
Law V Knox C Djoumbou Y Jewison T Guo AC Liu Y Maciejewski A Arndt D Wilson M Neveu V et al DrugBank 40
shedding new light on drug metabolism Nucleic acids research 2014 42(Database issue)D1091-1097
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
main menu
Formulations advice and assistance with preclinical drug delivery Neurodevelopmental Behavioral Core
To effectively deliver drug to preclinical species for the duration of a study researchers must choose a dose a formulation
and a route of administration that will support target organ exposure long enough to test a therapeutic hypothesis Since
most drugs developed for humans are optimized for human metabolism parameters many compounds developed for
humans are rapidly metabolized and cleared in rodents requiring alternative formulations and routes of preclinical
administration (see tutorial under Correct Dose)
Proper formulation of drugs and vehicles to ensure appropriate drug exposure is a critical factor in preclinical study design
The Neurodevelopmental Behavioral Core may provide advice on standard formulations Preclinical assistance and
training across many routes of administration including IV cannulation osmotic minipumps oral gavage sc and ip is also
available through the Neurodevelopmental Behavioral Core
Contact is Dr Nick Andrews NickAndrewschildrensharvardedu
Custom formulation used for human studies are supported on a case by case basis by the Pharmacometrics Research Core
or Clinical Research Pharmacy Contact for the Pharmacometrics Core is Dr Luis Pereira LuisPereirachildrensharvardedu
The Clinical Research Pharmacy can provide advice on unusual formulations Contact is Dr Rocco Anzaldi
RoccoAnzaldichildrensharvardedu
idspharmacy-dlchildrensharvardedu
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
main menu
Stratification Biomarker development and resources patient sample repositories requests for collection of new types of
patient samples development of patient specific iPSC lines and neurons Genetic databases RNA expression databases
Humans are diverse Not only do patients come in different sizes ages genders and ethnic backgrounds but the same
disease diagnosis often develops in people as a function of different environmental insults and genetic predispositions
Finding biomarkers that will segregate similarly diagnosed patients into subsets of biologically more homogenous
populations is a critical feature of good clinical trial design A lsquostratification biomarkerrsquo can be a biochemical measure from
patient samples a structural or a functional feature of a human imaging technology or a functional measure of an
electrophysiological readout
The Translational Neuroscience Center can help investigators access advice and assistance for investigators with vendors
experienced in profiling DNA RNA or protein across a range of platforms httpwwwchildrenshospitalorgresearch-and-
Neurophysiology Services can assist investigators with identification of biomarkers to stratify patients based on EEG
signatures Contact Drs Charles Nelson and Jurriaan Peters Co-Directors
CharlesNelsonchildrensharvardedu
JurriaanPeterschildrensharvardedu
MRIRadiology Imaging Core can assist with identification of biomarkers to stratify patients by functional or structural deficits
in brain circuitry Contact Dr Simon Warfield Director SimonWarfieldchildrensharvardedu
Molecular Genetics core can assist investigators with identification of genetic stratification biomarkers or gene expression-
based stratification biomarkers Contact Drs Louis Kunkel and Christopher Walsh Co-Directors
LouisKunkelchildrensharvardedu
ChristopherWalshchildrensharvardedu
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
The Human Neuron Differentiation Service within the Translational Neuroscience Center can help investigators recruit
specific subtypes of patients to be consented for reprogramming of blood or fibroblast cells into iPSC lines that will support
differentiation into human neurons for phenotypic analysis and screening ContactDr Robin Kleiman
RobinKleimanchildrensharvardedu
Translab can assist with routine processes as well as complex laboratory-‐developed tests They place special emphasis on
assay development for use in clinical trials Translab website with contact information can be viewed here
httpwwwtranslabbostonorg
TransLab Flyer 2 2015pdf
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
main menu
Patient sample repositoryBiobank Patient registry
Disease processes are dynamic The molecular underpinnings of disease differ between inception progression and
response of the body to disease Thus each stage of disease may require alternative therapeutic strategies Understanding
which stage of disease is best suited to testing a specific therapeutic approach will require information about disease from
patient samples collected at different stages of disease well as an ability to collect and recruit patients at relevant stages of
disease
To locate human RNA profiling data in the public domain from disease samples and tissues at specific stages of disease
search databases referenced in the Correct Target section of this document
The Translational Neuroscience Center offers multiple services that can assist with identification of the correct patients The
Core Repository for Neurological Disorders stores a wide variety of patient samples from many stages of disease The
biorepository is directed by Dr Mustafa Sahin and these samples and de-identified clinical data can be searched and
requested through the Translational Neuroscience Center
The Biobank Core Lab serves as a core resource that ensures top-level specimen handling and services to the Boston
Childrens Hospital research community It serves as both a service core and a biorepository providing an institutional
perspective on the presence of specimens that may be available for use to foster collaborations and accelerate research
and discovery
The Clinical Research and Regulatory Affairs Service can provide assistance to investigators in identifying patients andor
repository samplesdata Contact Co-Directors Stephanie Brewster and Kira Dies for more information about access to
these resources
StephanieBrewsterchildrensharvardedu
KiraDieschildrensharvardedu
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
main menu
Statistical support clinical trialsgov
Determining the correct sample size to support preclinical and clinical studies requires power calculations that take into
account the variability of the endpoint being measured Statistical support for preclinical studies is available on a
department by department basis Neurology and Neurobiology requests for preclinical biostatistics support can be made
through the CRC website
httpredcap-qiredcap_edcsurveyss=Rma5u83qKC
Clinical statistical support for all departments is also available through the CRC Design and Analysis Core For more
information contact Michael Monuteaux michaelmonuteauxchildrensharvardedu
Clinical datasets that provide data for supporting power calculations can be found by searching through clinical trialsgov
database All studies in the clinical trials data base are required to describe the study design the endpoints under
evaluation and the treatments as well as links to publications of the studies The studies can be searched by topic This can
be a good way to find historical data to help you evaluate variability of endpoint measures in clinical populations This will
be needed to support sample size power calculations httpsclinicaltrialsgov
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
main menu
Understanding RDoC Human Neurobehavioral Core Service IRB assistance with clinical protocols
Different stages of clinical trials have different goals for selecting endpoints Early stage clinical trials are typically in search
of a translatable pharmacodynamic or target engagement endpoint to ensure that the molecule in question will be
competent to test a clinical hypothesis in humans Developing translatable measures of target engagement in preclinical
species and humans is critical to developing data sets that will enable subsequent therapeutic efficacy trials The earliest
trials require endpoints that can be measured in a functionally equivalent manner across species Therefore it is critical for
preclinical researchers to develop dose-responsive data sets in preclinical species using quantitative endpoints such as EEG
visual or auditory evoked potentials PET ligands plasma or CSF based biochemical measures or translatable task based
behaviors Preclinical data must be a developed with an eye towards what the equivalent measure will be in the clinic
Toward that end the NIMH has initiated the Research Domain Criteria (RDoC) that is aimed at characterizing mental health
disorders across many different dimensions across species A big focus of the RDoC initiative is the identification of
translatable endpoints for evaluating pharmacodynamics and efficacy in Neuroscience Drug Discovery Preclinical
Neuroscience researchers should be familiar with the RDoC framework For advice on in vivo characterization of preclinical
endpoints with translational potential for Neuroscience related disorders contact Dr Robin Kleiman at the TNC
robinkleimanchildrensharvardedu
The Human Neurobehavioral Core Service of the Translational Neuroscience Center can provide guidance to investigators
on the appropriate tests that will provide the best translation from animal studies to human studies The Service also offers
human neurobehavioral assessment services Contact-Drs Charles Nelson and Deborah Waber Co-Directors
CharlesNelsonchildrensharvardedu
DeborahWaberchildrensharvardedu
Developing clinical protocols and obtaining IRB approval for human study of translatable endpoints can be supported by
the Translational Neuroscience Center Clinical Research and Regulatory Affairs Service Contact-Kira Dies and Stephanie
Brewster Co-Directors
KiraDieschildrensharvardedu
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
StephanieBrewsterchildrensharvardedu
Background Information on RDoC httpswwwnimhnihgovresearch-prioritiesrdocindexshtml
Casey BJ Oliveri ME Insel T A neurodevelopmental perspective on the research domain criteria (RDoC) framework
Cuthbert BN Insel TR Toward the future of psychiatric diagnosis the seven pillars of RDoC BMC Med 2013 11126
httpwwwncbinlmnihgovpmcarticlesPMC3653747
Insel T Cuthbert B Garvey M Heinssen R Pine DS Quinn K Sanislow C Wang P Research domain criteria (RDoC)
toward a new classification framework for research on mental disorders The American journal of psychiatry 2010
167(7)748-751 httpwwwncbinlmnihgovpubmed20595427
Insel TR The NIMH Research Domain Criteria (RDoC) Project precision medicine for psychiatry The American journal
of psychiatry 2014 171(4)395-397 httpwwwncbinlmnihgovpubmed24687194
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
main menu
Body atlases for expression of mRNA and protein guides to chemical alerts guidance for preclinical toxicology studies for
Investigational New Drug (IND) applications
Discovery scientists must consider the distribution of the proposed drug target across the entire body in human samples in
order to understand potential safety risks to be monitored during preclinical toxicological testing Teams also have to be
aware of differences in distribution of the target and related family members in preclinical species Many of the target
expression databases listed in the Correct Target section of this document are useful in this regard Assays that can be used
to monitor any potential safety risks are critical to the development of a suitable testing funnel needed to advance
compounds
Many chemical classes of compounds that are identified in screens are not suitable for drug development due to the
presence of structural alerts that are known to cause chemical toxicity Databases that house information of structural alerts
can be used to de-prioritize structural series early in the life of a program Some toxicology databases that can help
deprioritize toxic chemotypes include httppubsacsorgdoiabs101021ci300245q
Some web resources for identifying side effects of known compounds httpintsideirbbarcelonaorg
Once a potential clinical candidate molecule is identified GLP-qualified toxicology studies must be carried out with a
qualified vendor to support regulatory filings of an Investigational New Drug (IND) application For a short tutorial on studies
needed to support preclinical toxicology testing and guidance on evaluating contract research organizations that are
qualified to perform this work see attached tutorial courtesy of Dr Joe Brady Pfizer
Brady boston childrens hosp talk aug2015 IND toxpdf
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
main menu
FAQs
Industry partners and collaborators can bring tremendous expertise and complementary resources to bear on research
projects with therapeutic applications These may include medicinal chemistry expertise pharmacology expertise access
to unique and undisclosed chemical probe molecules assay development and high-throughput screening resources
antibody and other reagent development pharmacokinetic analysis pharmacokinetic and pharmacodynamics
modeling formulation expertise post-doctoral training programs and in some cases financial support There is a wide range
of models of interacting with industry in a range of different capacities Some frequently asked questions about types of
relationships and the responsibilities associated with those interactions can be found in the following document
Download Frequently Asked Questions about working with Industry
Translation of basic research into new marketed drugs will require a transition from exploring scientific principles and testing
hypotheses into commercial products Industry partners capable of developing these potential products need to be able
to license the intellectual property required to sell the product in order to justify investment in building programs around new
ideas This requires that scientific researchers protect and patent potential inventions from their work to enable future
commercialization by partners with appropriate expertise To ensure that researchers are appropriately documenting their
work in a manner that will support preservation of intellectual property all investigators are encouraged to consult with TIDO
before any public disclosures of new research Similarly the following documentation provides guidance for documenting
your work according to standards that will support patent applications
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
Download the compliance manual for BCH for Intellectual property policy
cm_021_intellectual_propertydocx
Download a summary of laboratory notebook Dorsquos and Donrsquot
Dosdontsnotebookspdf
Link to TIDO Technology Innovation and Development Office
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
main menu
A phenotypic screen requires a biologically robust assay that represents a significant aspect of disease-relevant human
biology It can be used to identify molecular targets for target validation studies through the use of well-annotated
bioactive molecules or genomic libraries (eg RNAi CRISPER) Alternatively phenotypic screens can be used to identify
novel compounds that must subsequently be lsquoDE convolutedrsquo to identify novel targets using lsquowarheadsrsquo These screens rely
on identification and manipulation of a functional deficit or phenotype using a patient-derived cellular system
The strengths of this approach
Use of human systems can improve translatability
Identified compounds may empirically balance therapeutic activity at multiple required targets
Well-suited to drug repurposing
Phenotypic screens can be used to identify compounds or targets for mechanism based drug discovery programs
Many CNS drugs have been discovered using a phenotypic repurposing screen (Swinney and Anthony 2011)
Drawbacks to this approach
Assays are slow low throughput and more expensive as compared to cell-free assays
Cell-based assays may not predict circuit level or brain phenotypes
Furthermore as a primary screening approach
Precludes leveraging strengths in uHTS SBDD and parallel design
Every molecule must be de-risked independently thus safety can be very hard to predict
Drug Repurposing Drug Repurposing is a strategic pillar of the National Center for Advancing Translational Science (NCATS)
Details on resources and funding opportunities can be found here httpsncatsnihgovntu
Chemogenomic Files from industry partners Many companies have well designed and annotated chemical files that are
designed to cover the druggable genome with small molecule compounds from their proprietary collections Each
company has different criteria and stipulations associated with use of the library It is advisable to consult with TIDO
regarding terms and conditions associated with individual companies
ICCB-LongwoodKirby ADSF The ICCB screening center and the Kirby ADSF have multiple collections of compounds that
include bioactive or FDA approved molecules available for screening
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
Kirby ADSF libraries contact Dr Lee Barrett LeeBarrettchildrensharvardedu
References related to phenotypic screens and Drug Repurposing
Vincent F Loria P Pregel M Stanton R Kitching L Nocka K Doyonnas R Steppan C Gilbert A Schroeter T
and MC Peakman Developing predictive assays The phenotypic screening ldquorule of 3rdquo Sci Transl Med 7 293ps15
(2015)
Langedijk J Mantel-Teeuwisse AK Slijkerman DS Schutjens MH Drug repositioning and repurposing terminology and
definitions in literature Drug Discov Today (2015)
Swinney DC and J Anthony How were new medicines discovered Nature Reviews Drug Discovery 10 507-
519 (July 2011) | doi101038nrd3480
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
main menu
TNC Clinical Research and Regulatory Affairs Service Research Participant Registry CRC
Glossary of Terms
Glossary-of-Clinical-Trials-Termspdf
Clinical Research and Regulatory Affairs Service This Translational Neuroscience Center service facilitates the mission of the
Translational Neuroscience Center providing coordination among studies communications resource development and
implementation of new or ongoing preclinical and clinical studies The service is led by experts in protocol development
and launching of new studies The directors are available to guide TNC researchers in designing human studies including
the preparation of Institutional Review Board (IRB) and FDA submissions Additionally staff of the Clinical Research and
Regulatory Affairs Service will help researchers with recruitment plans budget development supervision of study
coordinators study monitoring and audit preparation For more information contact Co-Directors Kira Dies ScM CGC and
Stephanie Brewster MS CGC
KiraDieschildrensharvardedu
StephanieBrewsterchildrensharvardedu
Clinical Research Center (CRC) Assists investigators at BCH with research project initiation and implementation resources
in the CTSU for the conduct of clinical research visits and ancillary services education on research methods and practices
The CRC has biostatisticians project managers research specialists clinical trials specialists research coordinators and
highly skilled nurses and nurse project managers who work every day to facilitate the many research needs of the BCH
community httpwwwchildrenshospitalorgresearch-and-innovationresearchclinicalclinical-research-center
Clinical and Translational Study Unit (CTSU) The CTSU provides clinical research infrastructure for investigators in the design
initiation conduct and reporting of clinical research with the goal of translating scientific knowledge into new therapies for
pediatric conditions httpweb2tchharvardeductsu
Clinical Research Roadmap This clinical research map is designed to serve as a guide for investigators study coordinators
and research nurses at Boston Childrenrsquos Hospital The research map outlines the key steps in preparing to launch a
research study and provides embedded links to institutional resources tools and documents
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
Clinical Research Mappdf
main menu
Office of Sponsored Programs Research Administration TIDO
Many government and foundation grant opportunities are available for developing Drug Discovery Projects updated lists of
funding options exist on OSP and Research Administration web sites
Some good options for finding relevant requests for proposals
Translational Research Program annual call for proposals
Boston Childrenrsquos Hospital ndash Broad Institute Collaboration Grants Proposals will be reviewed by a joint Childrenrsquos Hospitalndash
Broad Institute committee Additional submission dates are expected for 2016
BCH_Broad collaborative grant 852015docx
Kirby Neurobiology Screening Pilot awards- available to Kirby Neurobiology PIs as funding is available
Translational Neuroscience Center- Pilot awards supported by trust sponsored donations as available Distributed through
TNC e-mail lists
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
ADDF The ADDF Academic Drug Discovery and Development Program seeks to create and support innovative translational
research programs for Alzheimerrsquos disease related dementias and cognitive aging in academic medical centers and
universities Biomarker development studies and innovative proof of concept pilot clinical trials of new approaches to
treatment prevention and early detection are also supported
Department of Defense ALSRP The FY15 Defense Appropriations Act provides $75 million (M) to the Department of Defense
Amyotrophic Lateral Sclerosis Research Program (ALSRP) to support innovative high-impact Amyotrophic Lateral Sclerosis
research As directed by the Office of the Assistant Secretary of Defense for Health Affairs the Defense Health Agency
Research Development and Acquisition (DHA RDA) Directorate manages and executes the Defense Health Program
(DHP) Research Development Test and Evaluation (RDTampE) appropriation The executing agent for the anticipated
Program AnnouncementsFunding Opportunities is the Congressionally Directed Medical Research Programs (CDMRP)
httpcdmrparmymilpubspress201515alsrppreannshtml
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
Michael J Fox Foundation Therapeutic Pipeline Program Supports Parkinsons disease therapeutic development along the
pre-clinical and clinical path (both drug and non-pharmacological therapeutics including gene therapy biological
surgical and non-invasive approaches) The Michael J Fox Foundation seeks applications with potential for fundamentally
altering disease course andor significantly improving treatment of symptoms above and beyond current standards of care
Proposals must have a well-defined plan for moving toward clinical utility for patients The Therapeutic Pipeline Program is
open to industry and academic investigators proposing novel approaches or repositioning approved or clinically safe
therapies from non-PD indications httpswwwmichaeljfoxorgresearchgrant-detailphpid=28
NINDS The Blueprint Neurotherapeutics Network (BPN) Provides the neuroscience community access to a complete and
seamless pipeline for preclinical drug development beginning with chemical optimization and concluding after phase I
clinical trials Participants in the BPN will receive funding to conduct bioactivity and efficacy testing in their own laboratories
as well as access to millions of dollars in NIH-contracted drug development services including medicinal chemistry
pharmacology toxicology and phase 1 clinical trials NIH will also provide drug development consultants who have had
years of experience working at a senior level in industry Because the Blueprint is establishing a network of drug
development service providers that typically cater to biopharmaceutical companies neuroscientists who join the BPN can
readily plug in to all of the drug development expertise that typically resides in industry The projects supported through the
network will be highly collaborative and the researchers who initiate the projects will serve as the principal investigators
(PIs) directing their projects through the development pipeline with the help of industry consultants The PIs and their
institutions will have the opportunity to attain assignment of intellectual property rights from all other network participants
who may have intellectual input into their projects This will allow the PIs to retain control of the intellectual property for drug
candidates developed through the network and eventually pursue licensing and commercialization partnerships
httpneuroscienceblueprintnihgovbpdrugs
NeuroNEXT Will establish a consortium of clinical sites capable of forming disease-specific cadres of investigators in order to
develop and implement trials rapidly in a wide range of neurological disorders that affect adults andor children With a
stable and experienced research staff a central IRB model and master trial agreements NeuroNEXT will streamline the
administrative processes for clinical trials and reduce start-up times NeuroNEXT will also be able to design and implement
evidence-based measures to improve patient recruitment into clinical trials httpswwwneuronextorgresearchers
NIMH Many grant options see overview here httpwwwnimhnihgovresearch-prioritiestherapeuticsindexshtml
Building on High Impact Basic Neurobiology Through Assay Development Advancing Tools for Therapeutic Discovery (R01) -
See more at httpgrantsnihgovgrantsguidepa-filesPAR-15-066htmlsthashs1HMWjWudpuf
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
NCATS many grant options see overview here httpwwwncatsnihgovprograms
Bridging Interventional Development Gaps (BrIDGs) Program Makes available on a competitive basis certain critical
resources needed for the development of new therapeutic agents for both common and rare diseases Investigators do not
receive grant funds through this program Instead successful applicants receive access to NIH experts and contractors who
conduct pre-clinical studies at no cost to the investigator In general synthesis formulation pharmacokinetic and
toxicology services in support of investigator-held IND applications to the Food and Drug Administration (FDA) are available
httpwwwncatsnihgovbridgsworksolicitation
NCATS Discovering New Therapeutic Uses for Existing Molecules (New Therapeutic Uses) A collaborative program designed
to develop partnerships between pharmaceutical companies and the biomedical research community to advance
therapeutics development This innovative program matches researchers with a selection of pharmaceutical industry
assets to test ideas for new therapeutic uses with the ultimate goal of identifying promising new treatments for patients
httpwwwncatsnihgovntu
Pfizer Centers for Therapeutic Innovation (CTI) Suitable for biotherapeutic or small molecule projects with a strong project
rationale (demonstrated association between target biology pathway and disease mechanism) CTIrsquos areas of interest
include inflammation autoimmunity tissue remodeling oncology cancer immunology rare or genetic diseases
cardiovascular and metabolic diseases and neuroscience Selected projects are undertaken by a joint team with BCH
members and Pfizer CTI drug development experts located on the 18th floor of CLS working towards agreed common
goals The Pfizer CTIBCH collaboration program is managed by a Joint Steering Committee with representation from both
Boston Childrenrsquos and CTI httpswwwpfizercticom Calls for proposals come through TIDO three times a year in January
May and September httpwwwchildrensinnovationsorgPagesHighlightsHighlights-83aspx
Shire-BCH Collaborative Program Development The Joint Steering Committee of the Shire Alliance extends a call for ldquoPre-
Proposalsrdquo with defined objectives from time to time generally annually in the late fall or winter That call is publicized
through emails from BCH Research Administration and TIDO Following review by the JSC a full proposal may be requested
Unsolicited proposals may also be considered from time to time
ACRONYMS
HTS- High-throughput Screen run with 96 well 384 well 1536 wells or 3456 well capacity- screen has capacity to run through a library of 1-3Million compounds in total
uHTS- Ultra High-throughput Screen ndash arbitrary cut off to denote capability to measure 100s of thousands of assays per day with automation and high density plate readers
HCS- High Content Screen usually a cell based assay that is able to monitor multiple endpoints reflective of different cellular processes in a single well of cells treated with a compound May be biochemical or image based endpoints
SAR- Structure-Activity Relationship ie relationship of modifications to chemical structure on relevant activity SPR-Structure-Property Relationship ie relationship of modifications of chemical structure on physicochemical
properties
PK- Pharmacokinetic measure of drug levels in a body compartment
PD- Pharmacodynamic a measure of functional activity of a drug
PKPD- PharmacoKinetic PharmacoDynamic relationship- how drug levels relate to drug response in a system
DDI-Drug-Drug Interactions- occurs when one drug affects the activity of another drug when co- administered Often due to changes in ADME properties of one of the co-administered drugs (ie for example induction by one drug of enzymes that will metabolize the second drug )
DMPK- Drug Metabolism and PharmacoKinetics
ADME- Absorption Distribution Metabolism amp Excretion
PDM-pharmacokinetics dynamics and metabolism GLP- Good Laboratory Practice- regulations that govern toxicology studies required by the FDA to support IND
and NDA
POM- Proof of Mechanism clinical studies to demonstrate hit the target and elicited a biological response
POC- Proof of Concept Clinical studies to demonstrate a clinically meaningful outcome measure improved
PoP-Proof of Principal usually preclinical studies that demonstrate that engaging target in a disease model produced efficacy
FIH- First in Human clinical trial to evaluate new molecule in humans for safety and PK- Ph1
FIP-First in Patient first clinical trial to evaluate new molecule in patients hERG (the human Ether-agrave-go-go-Related Gene) is a gene KCNH2 that codes for a subunit of Kv111 and
contributes to the repolarizing current in the heart that coordinates the hearts beating When compromised by application drugs or by rare mutations in some families it can result in a potentially fatal disorder called long QT syndrome A number of clinically successful drugs in the market have had the tendency to inhibit hERG and create a concomitant risk of sudden death as a side-effect which has made hERG inhibition an important anti-target that must be avoided during drug development
IND-Investigational New Drug Application- formal application to FDA to evaluate a NCE in people
NME- New Molecular Entity- a new FDA approved drug
NCE-New Chemical Entity-an investigational drug that is not yet a FDA approved NME NDA- New Drug Application (A lsquoFilingrsquo)- a formal application for approval of a new drug
CAN-(Pfizer-specific shorthand )-Clinical Candidate- a molecule competent to be tested in humans IB- Investigators Brochure- basic information on an investigational drug and its mechanism for clinicans involved
in conducting a clinical trial Provides background information on the hypothesis being tested and the types of patients that should be included excluded and risks and how the drug should be administered It must be updated continually by the sponsor to include all new findings
SOC- Standard of Care- in our context it is the drug treatment that a clinican should prescribe for a particular type of patient used as a benchmark for comparing new entities
MTD- Maximum Tolerated Dose- first identified in GLP safety studies during preclinical development AE- Adverse Event- a side effect that causes safety concerns
TI- Therapeutic Index -ratio of the concentration of drug needed to produce efficacy and the concentration of drug that is safely tolerated ( also called ldquoSafety Marginrdquo)
Questions Contact Robin Kleiman- email RobinKleimanchildrensharvardedu office CLS 13070
Terms that relate to Targets Molecular target- the protein that binds drug to produce efficacy Off-Target- other proteins that bind the drug that do not relate to efficacy and may produce Adverse Events (AEs) Druggable target ndashcomes from a class of proteins that has successfully been targeted with small molecule drugs in
the past Primarily transporters enzymes receptors ion channels (Not protein-protein interactions transcription factors RNA binding proteins etc)
Druggable genome- about 3000 genes encoding all druggable proteins Druggability- the presence of protein folds (quarternary structures) that favor specific interactions with drug-like
molecules Exploratory target- Hypothesis that a modulating a target via a particular mode of action will be beneficial to a
particular patient population Validated target- Hypothesis regarding a target also has in vivo efficacy data for a disease or a disease model- along
with a complete understanding of how the target mechanism relates to disease- (also called lsquoProof of Principlersquo) Phenotypic screen- a screen for compounds that will reverse a phenotype the molecular target may not be known Systems pharmacology target(s)-a precisely defined combination or lsquofingerprintrsquo of molecular targets to be
modulated to correct a phenotype (Poly-pharmacology)
Terms that relate to programs
Biomarker- a physiological pathological or anatomical characteristic that is measured by an automated process or algorithm as an indicator of the normal biological process pathological process or biological response to a therapeutic intervention Many types of Biomarkers target engagement biomarkers stratification biomarkers efficacy biomarkers pharmacodynamic biomarkers etchellip
Laboratory Objectives-Criteria established at the start of the program to define the desired pharmacological properties of the molecule with regard to potency selectivity mode of action frequency and route of administration For antibodies would include minimal criteria for knock down stability etc
Therapeutic Modality- small molecule biologic RNAi stem cell etc
Screening tree Screening funnel- A decision tree for utilizing a panel of assays to identify molecules that meet the laboratory objectives
Terms that relate to molecules
Drug-like molecule- has physicochemical properties in line with known oral medications The molecule will be largely rule of 5 (RO5) compliant therefore small and moderately lipophilic Not related to pharmacological activity
Rule of Five (RO5)=Chris Lipinskirsquos rule of 5 states that a drug like molecule will have the following properties Molecular Weight of less than 500 a clogP lt5 fewer than 5 H-bond donors and the number of H-bond acceptors ( which is the sum of N and O atoms) is less than 10
Physicochemical properties- key properties of molecules include (calculated)Molecular Weight number of H bond acceptors and donors (measured) kinetic solubility pKa lipophilicity (logD logP)
Chemical tool -a compound with good potency and selectivity for a specified molecular target but fails to meet all criteria for safety PK or potency needed to become a clinical candidate Suitable for preclinical testing of hypothesis and proof of principal studies but not for lsquopreclinical developmentrsquo
Active molecule describes an individual chemical entity with measurable dose-dependent activity in a biological screening assay
Hit molecule refers to a molecule plus its related structural analogs for which there is an understanding of the structure-properties and structure-activity relationships (SPR and SAR) for a specific biological context Additionally preliminary drug disposition data (both in vitro and in vivo) provide an assessment of pharmacokinetic properties The available data provide a basis for further optimization of the hit series
Lead molecule refers to a molecule plus its related structural analogs that demonstrate o Sufficient exposure at pharmacologically relevant doses by the intended route of administration to explore
intended pharmacology in a relevant in vivo disease or pharmacodynamic model o Proof-of-principle or efficacy in a in vivo model that will be used to establish a margin of safety
Clinical candidate an optimized individual chemical entity derived from a lead series that demonstrates o a dose-response relationship via intended route and schedule of administration in relevant disease model o an exposure-based margin of safety in toxicology studies o In summary a clinical candidate is a molecule that is deemed competent for testing the primary disease
intervention hypothesis in humans
A laboratory notebook is a vital record of events leading to a patentable invention Therecorded information can establish dates of conception and reduction to practice of atechnology as well as the inventorship of a patent claiming the technology Below arefourteen rules you should follow when keeping lab notebooks
1 mdash Do use bound booksInventors should use permanently bound notebooks eg notebooks with spiral or glue bindings If loose-leaf sheets are used they should be consecutively numbered and eachpage should be dated signed and witnessed
2 mdash Do sign and date Each notebook should be signed and dated on the inside front cover to indicate the firstday the recipient started using the notebook Each entry should be dated and signed orinitialed
An independent witness ie someone who understands the technology but will not benamed as a co-inventor of the invention should sign and date each entry after the state-ment ldquoRead and understood by rdquo (The witness should preferably sign theentries on a contemporaneous or fairly contemporaneous basis but entries can also bereviewed signed and dated on a periodic eg weekly or monthly basis)
3 mdash Do use inkNotebook entries should be made in ink and in chronological order Entries should not beerased or ldquowhited outrdquo If an entry contains an error a line should be drawn through theerror and new text should continue in the next available space
4 mdash Donrsquot leave blank spacesBlank gaps between entries should be avoided If a blank space is left on a page a line orcross should be drawn through the blank space and the page dated to prevent subsequententries
5 mdash Donrsquot modifyPrior entries should not be modified at a later date If data were omitted the new datacan be entered under a new date and cross-referenced to the previous entry Record exper-iments when they are performed
6 mdash Do use past tenseUse the past tense (eg ldquowas heatedrdquo) to describe the experiments that were actually performed
Fish amp Richardson pc
Dorsquos and Don rsquo ts forKeeping Lab Notebooks
Boston
Dallas
Delaware
New York
San Diego
Silicon Valley
Twin Cities
Washington dc
FR
7 mdash Do explain abbreviations and special termsExplain all abbreviations and terms that are nonstandard Explain in context in a table ofabbreviations or in a glossary
8 mdash Do staple attachmentsAttachments such as graphs or computer printouts should be permanently attached to pagesin the notebook (eg by stapling) and both the attachment and the notebook page signedand dated If the attachment cannot be stapled it should be placed in an envelope and theenvelope stapled to the notebook page The envelope and page should then be signed andwitnessed making reference to the attachment being placed in the envelope
9 mdash Donrsquot remove originalsNo original pages should be removed from the notebook
10 mdash Do outline new experimentsWhen a new project or experiment is started the objective and rationale should be brieflyoutlined (eg in a short paragraph or by providing a flowchart)
11 mdash Do record lab meeting discussionsRelevant discussions from lab meetings should be recorded as should ideas or suggestionsmade by others The names of the people making the ideas and suggestions should be care-fully documented This information may be important in establishing inventorship
12 mdash Do provide detailRecord test descriptions including preferred operating conditions control conditionsoperable and preferred ranges of conditions and alternate specific materials Also recordtest results and an explanation of the results as well as photos or sketches of the resultsandor the test device Any conclusions should be short and supported by the factual dataOpinions or speculation about the invention should be avoided
13 mdash Do track notebooksIdeally each lab should maintain a catalog of notebooks in which each notebook is assigneda number and the name of the author of each notebook is recorded In addition the datethe author received the notebook as well as the date the notebook was completed andreturned should be recorded Upon leaving the lab the author should return all notebookschecked out by or to him
14 mdash Do save completed notebooksAll completed notebooks should be indexed (eg by number by author andor by subjectarea) and kept safely in a central repository together with corresponding patent applica-tions or patents Lab notebooks that relate to inventions on which patents have been grant-ed should be kept for the life of the patent plus six years
By J Peter Fasse
Fish amp Richardson pcIntellectual property complex litigation technology law800 818-5070wwwfrcominfofrcom
P ER SP EC T I V E
PHARMACOK INET I CS
Data gaps limit the translational potentialof preclinical researchRobin J Kleiman1 and Michael D Ehlers2
The absence of mouse pharmacokinetic reference data hinders translation An analysis ofrecent literature highlights a systematic lack of discussion regarding rationale for the selec-tion of dosing paradigms in preclinical studies and in particular for neuroscience studies inwhich the lack of brain penetration can limit target-organ exposure We propose solutionsto improve study design
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Despite widespread use of pharmacologicalagents in mouse models of human diseasethe literature lacks comprehensive pharmaco-kinetic profiles for such studies Coupled witha paucity of suitable data are shortcomingsin the training of experimental biologists inthe application of pharmacometric principlesto experimental study design Many authorssimply cite previously published studies tosupport the selection of a particular dose evenwhen the cited paper lacks drug exposuredata There is an assumption on the part ofresearchers that if a referenced study demon-strates a biological effectmdashthat is any measur-able physiological or behavioral effectmdashin arodent at a given dose then that same dosewill also effectively perturb disease-relevantmechanistic biology in a different study Thedanger occurs when the observed therapeuticeffects are not linked to drug-induced mecha-nistic alterations at the level of the target organLack of a drug exposurendashresponse relationshipin a target organ casts doubt on mechanisticinterpretations In addition any changes inthe route of drug administration vehicle prep-aration species used (rat versus mouse versusprimate) age or strain of animal transgenicmodification time points under investigationduration of dosing or organ targeted for inter-vention (for example brain versus a periph-eral tumor) can alter the relation between doseexposure and measured response In suchcases assumptions regarding the mechanisticbasis for observed therapeutic effects may nothold true
Preclinical pharmacological experimentsthat do not measure drug concentrations in
1Translational Neuroscience Center Kirby NeurobiologyCenter Department of Neurology Boston ChildrenrsquosHospital Harvard Medical School Boston MA 02115USA 2Neuroscience amp Pain Research Unit BioTherapeu-tics Worldwide Research and Development Pfizer IncCambridge MA 02139 USACorresponding author E-mail robinkleimanchildrensharvardedu (RJK) michaelehlerspfizercom (MDE)
the target organ run the risk of producing ex-posures that are too low or too high to inter-pret a mechanistic hypothesis Most drugs arenot selective over a large exposure range for asingle molecular target Confident evaluationof a therapeutic hypothesis requires an under-standing of the drugrsquos penetration and kineticswithin the target tissue as well as its potencyand selectivity for specific molecular targetsFurther investigators must consider the con-centration of the unbound fraction of drugthat is available to interact with the targetPublished reports often overlook the fact thatmany small molecules are more than 90bound to plasma or tissue proteins whichgreatly decreases the fraction of drug availableto bind to the intended target Thus in casesin which drug binding has a slow off-rate anorganismrsquos total drug exposure is not a predic-tor of drug available to interact with its target(1) The failure of some academic scientists toobtain relevant pharmacokinetic data impairsthe interpretation of preclinical research resultsand likely contributes to the acknowledgeddifficulties in replicating some academic liter-ature as reported by industry scientists (2 3)
Drug discovery teams in industry settingsroutinely collect pharmacokinetic data to aidin the mechanistic interpretation of in vivopreclinical data and to project optimal dosingparadigms for efficacy and toxicology studiesData required to evaluate brain penetrationare not typically collected by industry-baseddrug-discovery teams for compounds origi-nally developed for therapeutic indicationsthat do not obviously implicate the centralnervous system making this information es-pecially hard to find for many otherwise well-described drugs In addition because mousedata are not required for preclinical toxicologystudies (the more common small animal spe-cies for preclinical toxicology being rats)industry scientists do not often obtain pharma-cokinetic data from mouse experiments These
wwwScienceTranslationalMedicineo
issues are especially relevant for older drugsthat are potentially suitable for repurposingMany older drugs were discovered and char-acterized before routine pharmacokinetic-pharmacodynamic (PK-PD) modeling ofpreclinical drug exposure and its applicationto predicting human dosing became standardpractice Last pharmacokinetic data are notconsidered innovative and these studies gen-erally do not achieve publication in peer-reviewed journals even when the data havebeen generated When such data are pub-lished it is often relegated to the unsearchableblack hole of supplementary materials Thusmouse neuroPK profiles are not readily avail-able for many drugs that are frequently usedin conjunction with mouse models of humanbrain disorders
DOCUMENTING DOSING STRATEGIES
To evaluate the potential impact of insufficientpharmacokinetic data on dose selection in asample of recent published neuroscience liter-ature we conducted an analysis of papersidentified by means of a PubMed search usingthe search terms ldquodrugrdquo and ldquobrainrdquo for the pub-lication year 2014 from eight journals (Table 1)This list was culled to include only primaryresearch reports that included systemic adminis-tration of a pharmacological agent a pharma-cological therapeutic or a biological therapeuticas part of the study design The search yielded100 articles published between 1 January and30 December 2014 that used systemic drug de-livery with the intended goal of targeting thebrain of rodents (table S1) Each publicationwas examined for the stated rationale behindthe dose selection of study drugs (Table 1)
The reported rationale for dosing strategiesfell into several broad categories including(from lowest confidence to highest) (i) dose se-lected rationale not discussed (ii) literaturecitations of another study in which reportsranged from citation of exposure in the samespecies exposure in a different strain or spe-cies a dose conversion from the human liter-ature to rodent or reports of effects on rodentbehavior in another study (iii) demonstrationof an effect on rodent behavior or function inthe current study (iv) demonstration of adose-responsive biological effect in the currentstudy (v) measurement of drug levels in bloodor plasma in the current study and (vi) mea-surement of drug levels in the target organ(that is the brain) in the current study In onlytwo instances were publications identifiedthat considered the impact of drug binding
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to plasma or brain proteins on the free expo-sure of drug available to interact with the tar-get This is a critical flaw in most publishedstudies that use small molecules for functionaleffects in the brain because many centralnervous system (CNS) drugs that penetratethe blood-brain barrier exhibit high proteinbinding leaving a small fraction of the totaldrug measured in plasma or brain unbound
and free to interact with the molecular targetFurthermore most studies used evidence of abiological activity to justify dose selection with-out consideration for how exposure of theagent relates to the potency of the compoundat known molecular targets which would berequired to test a mechanistic hypothesis
The lack of pharmacokinetic considera-tion does not imply that every study used an
wwwScienceTranslationalMedicineo
inappropriate dose of drug to test their hypoth-esis It does illustrate that a clear rationale wasnot provided for dose selection in most pub-lications Furthermore all 11 of the 100 publi-cations that measured total brain exposureincluded an author from the pharmaceutical in-dustry (n=5) an academic drug screening group(n = 3) or a pharmacologyndashpharmaceuticalsciences department (n = 3) This observationlikely reflects the limited presence of pharma-cology and pharmacometrics departmentswithinmost academic institutions and limitedaccess to the mass spectrometry and otheranalytical resources needed to measure druglevels in study samples Outsourcing the bio-analysis of samples collected from study ani-mals is feasible but the use of contract researchorganizations to support such studies is oftentoo costly for most academic grant budgets toaccommodate
DATABASES AND REPURPOSINGRecent years have seen increasing efforts toinvestigate approved or clinically tested drugsfor new indications (4ndash8) Such repurposinghas been touted as a means to accelerate ther-apeutic development (4) For example a stra-tegic pillar of the US National Institutes ofHealthrsquos (NIHrsquos) translational roadmap callsfor the academic community to actively par-ticipate in the repurposing of drugs approvedby the US Food and Drug Administration(FDA) or investigational drugs that havepassed safety hurdles but failed in clinicaltrials because of lack of efficacy (9ndash11) To havea meaningful impact in neurological and psy-chiatric disorders such drug repurposingefforts will require access to neuropharma-cokinetic (neuroPK) data sets in mice to guidethe testing of new therapeutic hypotheses ingenetically engineered disease models A re-cently published consensus evaluation of drugrepositioning opportunities for Alzheimerrsquosdisease identified 15 potential drug candidatesThese were further prioritized for testing onthe basis of available evidence to produce ashortlist of seven compounds reviewed by in-dustry experts to provide insight into the via-bility of these candidates The most commonshortcoming identified for the compoundsconsidered were issues related to insufficientbrain penetration or the lack of informationabout optimal dosing strategies (11)
The repurposing of statins illustrateshow the neuroPK knowledge gap limits progressStatins were developed as 3-hydroxy-3-methylglutarylndashcoenzyme A (HMG-CoA) reduc-tase inhibitors to lower cholesterol and reduce
Table 1 Preclinical dosing strategies The rationale for drug-dosing strategies was extractedfrom the literature through the analysis of 100 peer-reviewed studies published in2014 from eight journals that cover research on mechanisms of brain function disease andtherapeutic approaches to CNS disorders (Cell Neuron Nature Nature Neuroscience NatureMedicine Neurobiology of Disease Neuropsychopharmacology and Science TranslationalMedicine) (table S1) Forty-four of the 100 publications selected were studies of potentialtherapeutic approaches to disease whereas the remaining were studies of basic neurobiology ormechanisms of disease Each publication was examined to discern how authors selected thedosage of pharmacological tools or therapeutic compounds used in the design of studies toprobe brain function A relatively small number of studies considered what the concentrationof drug available in the brain after administration would be in the context of theirexperimental studies The most common method for selecting a dose of drug was tocite a previous study that demonstrated a biological effect of the drug on someaspect of rodent behavior
Rationale for studyrsquos drug-dose selection
Therapeutic
studies
Number of papers from the100 published studies
analyzed
bull No exposure or rationale for dose selection provided
5
22
bull Rodent dose extrapolated from human studies
0
1
bull Doses are similar to what was used previously toproduce a biological effect
8
23
bull Literature reports cited for multiple functionaleffects of drug at selected dose
4
5
bull Brain penetration evaluated but exposure notmeasured
2
2
bull Literature report of mismatched drug exposure
0
1
bull Observation of a biological effect at a single dosein current study
3
6
bull Observation of dose-responsive biological effectin current study
5
16
bull Brain exposure to drug was measured with routeof administration that differed from the oneused in the efficacy study
1
1
bull Plasma drug concentrations measured literaturereport of brain exposure cited and target-organpharmacodynamic effect observed in the currentstudy
1
1
bull Plasma drug concentrations measured
4
7
bull Brain pharmacodynamic effect of drug observed
2
4
bull Brain drug concentrations measured (totalconcentration)
6
7
bull Unbound brain drug concentrations measured
1
2
bull Brain drug concentrations measured and brainpharmacodynamic effect of drug observed
2
2
Total
44
100
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risk of cardiovascular disease (12) FDA hasapproved at least nine different statins andmost are commonly prescribed nearly one-third of Americans ages 55 to 64 took a pre-scription cholesterol-lowering drug between2009 and 2012 (wwwcdcgovnchsdatahushus14pdf) The widespread availability andsafety profile of statins has lured researchersinto evaluating their potential for repurpos-ing (13) Statins have been profiled extensive-ly in preclinical research to test for potentialtherapeutic benefit in Alzheimerrsquos disease(14ndash19) Fragile X syndrome (20) Rett syn-drome (21 22) epilepsy (23) Huntingtonrsquos dis-ease (24) Parkinsonrsquos disease (25 26) stroke(27) and brain injury (28 29)
A search of the literature reveals no sys-tematic neuroPK studies in any mouse strainthat would enable direct comparisons of CNSexposure across the various statins In silicopredictions based on the drugsrsquo molecularproperties suggest that the nine most widelyprescribed statins each have a different poten-tial to penetrate the blood-brain barrier differ-ent potencies against the HMG-CoA reductaseenzyme and different ldquooff-targetrdquo activity pro-files (30) On the basis of available data thereis reason to believe that simvastatin has thebest overall profile for inhibiting HMG-CoAreductase in the brain (30) A recent study re-ported that lovastatin is able to reverse a rangeof phenotypes in a mouse model of Fragile Xsyndrome (20) However the design of an op-timal clinical trial will require the collection ofmouse pharmacokinetic data to understandhow much CNS drug exposure is required toproduce efficacy in the disease model Thereare at least two possible scenarios Giventhat simvastatin is more potent at inhibitingHMG-CoA reductase than are other statinsand likely to be more brain penetrant inboth mice and humans one would expectthat simvastatin will be more potent than lo-vastatin in ameliorating symptoms in bothmice and humans if the observed efficacy stemsfrom inhibition of HMG-CoA reductase activ-ity in the brain by lovastatin The advantage ofthis outcome would be that better brain pen-etration and potency would lead to a loweroverall dose requirement to achieve efficacyand thus likely a better safety profile
A second scenario could be that lovastatin ismore potent than simvastatin in the mousemodel of Fragile X syndrome because of anadditional biological activity inherent to thelovastatinmolecule whichmaynot yet be doc-umented in the literature In either case un-derstanding the CNS exposure of lovastatin
required to produce efficacy in themouse willdetermine whether there is a safe therapeuticindex for achieving the required concentra-tion in patients Previous attempts to discernuseful neuroPK parameters from the litera-ture for the use of statins in rodent modelshave highlighted the lack of critical data asthe looming roadblock to progress in the field(31 32) Until these data exist the transla-tional potential of preclinical research maybe limited And this is but one example ofone drug class
The creation of a centralized database isneeded for the entire translational researchcommunity and would establish a new mech-anism for academia funding agencies founda-tions and industry to pool resources If studiesare donewell the first time and documented inan open-access resource it will reduce redun-dant efforts and improve the quality of decisionmaking by scientists considering innovativesolutions to our biggest health problems
FILL THE GAPSManuscript submission practices for severalhigh-impact journals now include require-ments that authors include detailed informa-tion regarding study design and statisticalanalysis with each submission A reasonableextension of this checklist should includethe stated rationale for doses selected for studydrugs Information should include a discus-sion of data highlighted in Table 2 Authorsshould be expected to reference a relevant
wwwScienceTranslationalMedicineo
data set from a high-quality database or pub-lication or provide the data in the current study(Table 3)
Industry biologists learn basic principlesof medicinal chemistry pharmacokineticsand drug disposition while working on drugdiscovery project teams Academic groupsare playing an increasing role in transla-tional therapeutics and in particular drugrepurposing Academic programs need toaugment training in pharmacokinetics andpharmacodynamics so as to increase the rigor ofpreclinical work and to ensure that investigator-initiated clinical studies are testing hypotheseseffectively Institutions without a departmentof pharmacology or pharmacometrics mightlack the organizational knowledge needed toconduct drug studies and must identify re-sources or collaborators to patch these defi-cits Formal coursework and Web-basedresources and tutorials are needed to train andsupport translational researchers Manuscriptand grant reviewers need to demand higherstandards for preclinical studies with respect toreporting on drug exposure associated withbiological effects Ethics committees responsi-ble for review of animal protocols should re-quire investigators to provide rationale fordose selections in proposed studies Similarlyscientific review boards at academic medicalcenters need to include clinical pharmacologistswho are able to review investigator-initiatedclinical studies to ensure that proposed dosingstrategies will test a meaningful hypothesis
Table 2 Recommendations for use of pharmacokinetic data The first column includes a listof recommended data sets to aid reviewers of submitted articles in the interpretation ofpreclinical findings The second column includes a list of useful reference data that wouldsupport improved preclinical study design in mice if available in a public database
Literature reports that evaluate studydrugs should include
Compound-specific data that shouldbe included in a rodent
pharmacokinetic database
bull Expected or measured plasma exposure of thestudy drug in the preclinical species during thestudy
bull Elimination half-life (T12)bull Systemic clearance (CL)bull Fraction of drug that is protein bound (fb)
bull Expected or measured target organ exposureof the study drugs in the preclinical speciesduring the study
Maximum plasma concentration after drug admin-istration (Cmax) and time to reach maximum plas-ma concentration (Tmax) for a standardized doseand route of administration
bull Expected or measured free fraction (unboundby protein) of the study drugs in the targetorgan of the preclinical species during thestudy
bull The ratio of drug in brain to that in plasma (BP)bull The ratio of drug found free in brain (Cub) to thatfound free in the plasma (Cup) defined as CubCupbull Any potential impact of drug transporters (foundon the rodent blood-brain barrier) in limiting brainexposure
bull Expected or measured potency of the studydrug against the hypothesized activity in vitro
Expected ormeasured potency of molecule at knownbiological targets
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P ER SP EC T I V E
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A central repository that contains brainpenetration protein binding and pharmaco-kinetic profiles of drugs and pharmacologicaltools in rodents is needed to effectively sup-port translational research This databaseshould also provide basic tutorials that de-fine primary pharmacokinetic parameterswith examples to illustrate how data are usedto predict optimal dosing strategies The min-imum data set needed for each compoundin a useful rodent database is highlighted inTable 2 Access to this information and sup-porting materials will have an immediateimpact on the quality of translational drug re-purposing efforts across brain disorders andwill support the development of new thera-peutic approaches to neurological disordersand mental illness Existing databases man-aged by NIH or precompetitive consortia couldbe reinforced with donated pharmacokineticdata sets and tutorials
Industry and government scientists shouldwork precompetitively to collect and curatepharmacokinetic data sets in conjunction withsupporting educational materials Mouse phar-macokinetic data exist inside pharmaceuti-cal companies for a wide range of publicallydisclosed molecules and literature standardsRelease of these data into a public databasewould provide several benefits to companiesincluding (i) increased scientific rigor in theliterature with a higher probability of repro-ducibility (ii) increased appreciation by theacademic biology community for the diffi-culty inherent in generating molecules withpotency and pharmacokinetic profiles suit-able for in vivo work opening the door forin-kind collaboration with academic groups
and (iii) direct comparison of data collectedin-house to that collected at other compa-nies or institutions to enable better internalquality control Comprehensive pharmaco-kinetic data sets will benefit all therapeuticareas regardless of whether the brain is thetarget organ because peripheral and cen-tral exposure data can be generated fromthe same experiments Moreover the prin-ciples described above for the CNS apply toother target tissues in which vascular bar-riers metabolic processes or active transportalter the distribution of systemically admin-istered drugs
Key to ensuring that preclinical mousestudies test the hypotheses they aim to eval-uate is an understanding of the unboundfraction of drug present in the target organat an appropriate time point under studyGrant and journal reviewers need to care-fully consider whether authors of propos-als and manuscripts are providing adequaterationale for their choices of preclinical dos-ing paradigms Importantly the collectionand centralization of rodent pharmacoki-netic datasets will promote efficient genera-tion of future data reduce the collection ofredundant data and improve the return oninvestment for research funds that are de-voted to preclinical studies aimed towardclinical translation
SUPPLEMENTARY MATERIALS
wwwsciencetranslationalmedicineorgcgicontentfull8320320ps1DC1Table S1 One hundred publications that used systemic drugdelivery with the goal of targeting rodent brains
wwwScienceTranslationalMedicineo
REFERENCES AND NOTES1 A Reichel Addressing central nervous system (CNS) penetra-
tion in drug discovery Basics and implications of the evolv-ing new concept Chem Biodivers 6 2030ndash2049 (2009)
2 F Prinz T Schlange K Asadullah Believe it or not Howmuch can we rely on published data on potential drugtargets Nat Rev Drug Discov 10 712 (2011)
3 C G Begley L M Ellis Drug development Raisestandards for preclinical cancer research Nature 483531ndash533 (2012)
4 P Nair Second act Drug repurposing gets a boost asacademic researchers join the search for novel uses ofexisting drugs Proc Natl Acad Sci USA 110 2430ndash2432(2013)
5 T I Oprea J Mestres Drug repurposing Far beyond newtargets for old drugs AAPS J 14 759ndash763 (2012)
6 S M Strittmatter Overcoming drug development bot-tlenecks with repurposing Old drugs learn new tricksNat Med 20 590ndash591 (2014)
7 K Xu T R Coteacute Database identifies FDA-approved drugswith potential to be repurposed for treatment of orphandiseases Brief Bioinform 12 341ndash345 (2011)
8 X Bosch European researchers drug companies joinforces against rare diseases JAMA 294 2014ndash2015 (2005)
9 F S Collins Mining for therapeutic gold Nat Rev DrugDiscov 10 397 (2011)
10 P Vallance P Williams C Dollery The future is much closercollaboration between the pharmaceutical industry andacademic medical centers Clin Pharmacol Ther 87525ndash527 (2010)
11 A Corbett J Pickett A Burns J Corcoran S B DunnettP Edison J J Hagan C Holmes E Jones C KatonaI Kearns P Kehoe A Mudher A Passmore N ShepherdF Walsh C Ballard Drug repositioning for Alzheimerrsquosdisease Nat Rev Drug Discov 11 833ndash846 (2012)
12 J L Goldstein M S Brown A century of cholesterol andcoronaries From plaques to genes to statins Cell 161161ndash172 (2015)
13 A M Malfitano G Marasco M C Proto C Laezza P GazzerroM Bifulco Statins in neurological disorders An overviewand update Pharmacol Res 88 74ndash83 (2014)
14 T Kurata K Miyazaki M Kozuki N Morimoto Y OhtaY Ikeda K Abe Progressive neurovascular disturbances inthe cerebral cortex of Alzheimerrsquos disease-model miceProtection by atorvastatin and pitavastatin Neuroscience197 358ndash368 (2011)
15 H Kurinami N Sato M Shinohara D Takeuchi S TakedaM Shimamura T Ogihara R Morishita Prevention ofamyloid beta-induced memory impairment by fluvastatinassociated with the decrease in amyloid beta accumulationand oxidative stress in amyloid beta injection mousemodel Int J Mol Med 21 531ndash537 (2008)
16 M Shinohara N Sato H Kurinami D Takeuchi S TakedaM Shimamura T Yamashita Y Uchiyama H RakugiR Morishita Reduction of brain beta-amyloid (Abeta)by fluvastatin a hydroxymethylglutaryl-CoA reductaseinhibitor through increase in degradation of amyloidprecursor protein C-terminal fragments (APP-CTFs) andAbeta clearance J Biol Chem 285 22091ndash22102 (2010)
17 G J Siegel N B Chauhan D L Feinstein G Li E B LarsonJ C Breitner T J Montine Statin therapy is associated withreduced neuropathologic changes of Alzheimer diseaseNeurology 71 383 author reply 383 (2008)
18 X-K Tong C Lecrux P Rosa-Neto E Hamel Age-dependentrescue by simvastatin of Alzheimerrsquos disease cerebrovascularand memory deficits J Neurosci 32 4705ndash4715 (2012)
19 X K Tong N Nicolakakis P Fernandes B Ongali J BrouilletteR Quirion E Hamel Simvastatin improves cerebrovascularfunction and counters soluble amyloid-beta inflammationand oxidative stress in aged APP mice Neurobiol Dis35 406ndash414 (2009)
Table 3 Recommendations to improve translation through the use of preclinicalpharmacokinetic data
Journalsbull Require authors to provide explicit rationale for dosing strategies usedbull Rationale should include consideration of the unbound drug exposure in target organas best practices
Educationbull Include basic pharmacology and pharmacokinetic principles in formal coursework requiredfor basic preclinical and clinical research scientists
bull Develop tutorials and on-line calculators for rodent dose projections to support appropriateuse of published pharmacological tools
Databasesbull Reinforce public chemical databases with mouse pharmacokinetic data that includes brainexposure
Precompetitive consortiabull Create precompetitive consortia to solicit mouse pharmacokinetic data sets from industry andfoundation partners for database expansion
bull Targeted data collection for compounds already in the public domain
rg 6 January 2016 Vol 8 Issue 320 320ps1 4
P ER SP EC T I V E
20 E K Osterweil S C Chuang A A Chubykin M SidorovR Bianchi R K Wong M F Bear Lovastatin corrects ex-cess protein synthesis and prevents epileptogenesis in amouse model of fragile X syndrome Neuron 77 243ndash250(2013)
21 C M Buchovecky S D Turley H M Brown S M KyleJ G McDonald B Liu A A Pieper W Huang D M KatzD W Russell J Shendure M J Justice A suppressorscreen in Mecp2 mutant mice implicates cholesterol me-tabolism in Rett syndrome Nat Genet 45 1013ndash1020(2013)
22 M J Justice C M Buchovecky S M Kyle A Djukic A rolefor metabolism in Rett syndrome pathogenesis Newclinical findings and potential treatment targets RareDis 1 e27265 (2013)
23 F Scicchitano A Constanti R Citraro G De Sarro E RussoStatins and epilepsy Preclinical studies clinical trials andstatin-anticonvulsant drug interactions Curr Drug Targets16 747ndash756 (2015)
24 M L Ferlazzo L Sonzogni A Granzotto L Bodgi O LartinC Devic G Vogin S Pereira N Foray Mutations of theHuntingtonrsquos disease protein impact on the ATM-dependentsignaling and repair pathways of the radiation-inducedDNA double-strand breaks Corrective effect of statins andbisphosphonates Mol Neurobiol 49 1200ndash1211 (2014)
25 E K Tan L C Tan Holding on to statins in Parkinsondisease Neurology 81 406ndash407 (2013)
26 B Friedman A Lahad Y Dresner S Vinker Long-termstatin use and the risk of Parkinsonrsquos disease Am J ManagCare 19 626ndash632 (2013)
27 M S Elkind Stroke A step closer to statin therapy forstroke Nat Rev Neurol 9 242ndash244 (2013)
28 E E Abrahamson M D Ikonomovic C E Dixon S T DeKoskySimvastatin therapy prevents brain trauma-inducedincreases in beta-amyloid peptide levels Ann Neurol66 407ndash414 (2009)
29 E F Wible D T Laskowitz Statins in traumatic brain injuryNeurotherapeutics 7 62ndash73 (2010)
wwwScienceTranslationalMedicineo
30 S Sierra M C Ramos P Molina C Esteo J A VaacutezquezJ S Burgos Statins as neuroprotectants A comparativein vitro study of lipophilicity blood-brain-barrier penetra-tion lowering of brain cholesterol and decrease of neuroncell death J Alzheimers Dis 23 307ndash318 (2011)
31 W G Wood G P Eckert U Igbavboa W E Muumlller Statinsand neuroprotection A prescription to move the fieldforward Ann N Y Acad Sci 1199 69ndash76 (2010)
32 W G Wood W E Muumlller G P Eckert Statins and neuro-protection Basic pharmacology needed Mol Neurobiol50 214ndash220 (2014)
101126scitranslmedaac9888
Citation R J Kleiman M D Ehlers Data gaps limit thetranslational potential of preclinical research Sci Transl Med8 320ps1 (2016)
D
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ownloaded from
101126scitranslmedaac9888] (320) 320ps1 [doi8Science Translational Medicine
Robin J Kleiman and Michael D Ehlers (January 6 2016) Data gaps limit the translational potential of preclinical research
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nloaded from
Boston Childrenrsquos Hospital ndash Broad Institute Collaboration Grants
Background Meeting the challenges of biomedicine requires bringing together creative scientists exceptional technological resources and world-class expertise across many disciplines that rarely exist within a single institution This guiding principle is the basis for a funding opportunity to support Boston Childrenrsquos Hospital investigators performing research in collaboration with Broad scientists
Goals The fundamental goal of this new award is to spark new collaborations between Boston Childrenrsquos Hospital and the Broad Institute The grants will be awarded to address a very wide range of scientific questions but are specifically designated for projects with the following characteristics
middot Projects where engagement with the Broad would benefit Childrenrsquos Hospital investigators projects that can uniquely benefit from being done at the Broad Institute
middot Projects that create new scientific collaborations and bring together diverse scientific backgrounds projects that spark new scientific directions or technologies and are not currently being pursued at Childrenrsquos Hospital
middot Projects that pilot new approaches that researchers at Childrenrsquos the Broad and the greater scientific community can benefit from in the future the purpose of these awards is not to provide gap or extension funding of existing projects but to initiate new projects
Eligibility Individuals with Principal Investigator status at Boston Childrenrsquos Hospital are eligible Applicants need not be Associate Members of the Broad Institute
Broad Platforms and Scientists Broadrsquos Platforms (Genomics Imaging Metabolite Profiling Proteomics Genomic Perturbation and the Broad Technology Labs) are collaborative organizations that provide scientific leadership and cutting edge technologies in support of project goals Collaborations can also be established with other groups at the Broad including the Klarman Cell Observatory the Stanley Center for Psychiatric Research or the Center for the Development of Therapeutics
Budgets Grants will provide $60000 direct support for 1 year plus philanthropic overhead It is expected that most grants will fund work performed at the Broad Institute either through interaction with Broadrsquos Platforms or via collaboration with a Broad scientist however the work may also occur at Boston Childrenrsquos if it is important to meet the scientific goals of the collaboration
Deadline and Review process Final proposals are due by September 1 2015 Funding decisions are expected to be reached by October 1 2015 Proposals will be reviewed by a joint Childrenrsquos HospitalndashBroad Institute committee Additional submission dates are expected for 2016
Submission Applicants are strongly encouraged to discuss potential applications in advance with the office of the Chief Scientific Officer at the Broad Questions should be directed to Alex Burgin ( 617-714-7124)
Proteomics Genomic Perturbation and the Broad Technology Labs) are collaborative
organizations that provide scientific leadership and cutting edge technologie
s in support of
project goals Collaborations can also be established with other groups at the Broad including
the Klarman Cell Observatory the Stanley Center for Psychiatric Research or the Center for the
Development of Therapeutics
Budgets
Grants wi
ll provide $60000 direct support for 1 year plus philanthropic overhead It
is expected that most grants will fund work performed at the Broad Institute either through
interaction with Broadrsquos Platforms or via collaboration with a Broad scientist howev
er the
work may also occur at Boston Childrenrsquos if it is important to meet the scientific goals of the
collaboration
Deadline and Review process
Final proposals are due by September 1 2015 Funding
decisions are expected to be reached by October 1 201
5 Proposals will be reviewed by a joint
Childrenrsquos Hospital
ndash
Broad Institute committee Additional submission dates are expected for
2016
Submission
Applicants are
strongly encouraged to discuss potential applications in
advance
with the office of the Chief Sc
ientific Officer at the Broad
Questions should be
directed to Alex Burgin (
aburginbroadinstituteorg
617
-
714
-
7124
)
Boston Childrenrsquos Hospital ndash Broad Institute Collaboration Grants
Background Meeting the challenges of biomedicine requires bringing together creative
scientists exceptional technological resources and world-class expertise across many
disciplines that rarely exist within a single institution This guiding principle is the basis for a
funding opportunity to support Boston Childrenrsquos Hospital investigators performing research
in collaboration with Broad scientists
Goals The fundamental goal of this new award is to spark new collaborations between Boston
Childrenrsquos Hospital and the Broad Institute The grants will be awarded to address a very wide
range of scientific questions but are specifically designated for projects with the following
characteristics
Projects where engagement with the Broad would benefit Childrenrsquos Hospital
investigators projects that can uniquely benefit from being done at the Broad Institute
Projects that create new scientific collaborations and bring together diverse scientific
backgrounds projects that spark new scientific directions or technologies and are not
currently being pursued at Childrenrsquos Hospital
Projects that pilot new approaches that researchers at Childrenrsquos the Broad and the
greater scientific community can benefit from in the future the purpose of these awards
is not to provide gap or extension funding of existing projects but to initiate new
projects
Eligibility Individuals with Principal Investigator status at Boston Childrenrsquos Hospital are
eligible Applicants need not be Associate Members of the Broad Institute
Broad Platforms and Scientists Broadrsquos Platforms (Genomics Imaging Metabolite Profiling
Proteomics Genomic Perturbation and the Broad Technology Labs) are collaborative
organizations that provide scientific leadership and cutting edge technologies in support of
project goals Collaborations can also be established with other groups at the Broad including
the Klarman Cell Observatory the Stanley Center for Psychiatric Research or the Center for the
Development of Therapeutics
Budgets Grants will provide $60000 direct support for 1 year plus philanthropic overhead It
is expected that most grants will fund work performed at the Broad Institute either through
interaction with Broadrsquos Platforms or via collaboration with a Broad scientist however the
work may also occur at Boston Childrenrsquos if it is important to meet the scientific goals of the
collaboration
Deadline and Review process Final proposals are due by September 1 2015 Funding
decisions are expected to be reached by October 1 2015 Proposals will be reviewed by a joint
Childrenrsquos HospitalndashBroad Institute committee Additional submission dates are expected for
2016
Submission Applicants are strongly encouraged to discuss potential applications in
advance with the office of the Chief Scientific Officer at the Broad Questions should be
directed to Alex Burgin (aburginbroadinstituteorg 617-714-7124)
Clinical Trials Glossary
ADME an acronym for absorption distribution metabolism and elimination ADME
studies determine how a drug is absorbed by the body the chemical changes that it may
undergo and how it is eliminated from the body
Adverse event (AE) a bothersome event that occurs in a study participant AEs may be
related to the treatment being tested or may be due another cause (eg another treatment
another medical condition an accident or a surgery)
Arm a specific type of treatment to which a group of clinical trial participants is
assigned Some clinical trials have one arm and some have two arms while others have
three or more arms For example a clinical trial comparing two different doses of an
investigational drug versus a placebo would have three arms participants receiving a
higher dose of the investigational drug participants receiving a lower dose of the
investigational drug and participants receiving the placebo
Baseline a point in time at the beginning of a clinical trial before the study participants
receive any treatment At the baseline participants usually have certain types of tests
During and after treatment the same tests may be performed and the results compared
with the baseline results to see if the drug has caused changes
Bias a factor ndash such as a preconceived idea about the effects of the benefits and risks of a
treatment or a lack of balance in selection of patients for a study ndash that reduces the
likelihood that the study results are true Methods such as blinding and randomization
are used to limit the potential for bias
Bioavailability the portion of the dose of a drug that reaches the bloodstream For
example if the drug is administered intravenously its bioavailability is 100 percent
however if the drug is administered in any other way such as orally topically or
through intramuscular injection its bioavailability will decrease due to incomplete
absorption
Bioequivalence study a test performed to compare the portion of a drug in the
bloodstream when administered in different dosage forms
Biologic product any substance that can be used in prevention treatment or cure of
disease Some examples include vaccines blood virus toxin antitoxin and therapeutic
serum
Biopsy the removal of cells or tissue from a patient for examination which is usually
done under a microscope A tissue sample might be taken for genetic studies Sometimes
there is a difference between the blood genotype and the skin or other tissue genotype
This term can also refer to the tissue sample that has been obtained by such a procedure
2
Blinding a process used to prevent the participants the researchers or both from
knowing what specific treatment is being given to participants in a clinical trial The
process of blinding helps to reduce bias because study participants and researchers are
less likely to be unconsciously influenced by the knowledge of what the study participant
is actually receiving If only the participants are blinded the study is called a single-
blind study If both participants and researchers are blinded the study is called a double-
blind study
Carcinogenicity studies long-term studies conducted in animal models to determine a
drugrsquos likelihood of causing cancer
Clinical efficacy a compoundrsquos ability to produce the desired effect
Clinical pharmacology a science that studies properties of drugs in relation to their
therapeutic value in humans
Clinical study or Clinical trial a medical experiment in human beings that helps to
determine how a disease drug or medical device affects study participants Clinical
studies are necessary to answer specific questions about how to better diagnose prevent
or treat a disease or condition
Cohort a group of study participants who have certain characteristics in common such
as female sex a defined age range or particular severity of disease Dividing study
participants into cohorts is often done as part of the analyses of study data
Contraindication a factor that makes the use of a particular drug inadvisable For
example a person who has had an allergic reaction to penicillin in the past is considered
to have a contraindication to using penicillin in the future
Control group a group of participants not receiving the investigational drug but instead
receiving a standard treatment for their disease or receiving a placebo The results
observed in the group of patients receiving the investigational drug are compared with the
results observed in the control group
Crossover study a study design with two or more arms where participants receive one
treatment for a period of time and then switch over to a second treatment for a period of
time Such a study design allows the effects of the two treatments to be compared in the
same patient
Data Monitoring Committee (DMC) or Data Safety and Monitoring Board (DSMB)
A committee of experts that periodically reviews the accumulating data from an ongoing
multicenter clinical trial Members of a DMCDSMB must be independent ie they
cannot be participating as investigators in the clinical trial Based on their review the
DMCDSMB experts advise the sponsor regarding whether it is safe and acceptable to
continue with the study or whether the data suggest that the study should be modified or
stopped A DMCDSMB may recommend that a trial be stopped if there are safety
concerns or if the trial objectives have been achieved
3
Dose-ranging study a clinical trial in which two or more doses of an investigational
drug are tested to determine which dose is likely to offer the best combination of safety
and efficacy in later clinical trials or in medical care
Efficacy or effectiveness the ability of a drug to prevent cure or slow a disease process or to alleviate the symptoms of a disease or condition
Eligibility a determination made during the screening period for a clinical study of
whether a personrsquos participation in the trial is likely to be safe and can contribute data
that will help achieve the study goals
Endpoint occurrence of a disease symptom sign or test result that constitutes one of the
target outcomes of a clinical trial
Inclusionexclusion criteria the factors defined in the protocol of a study that determine
whether a personrsquos participation in a clinical trial is likely to be safe and can contribute
data that will help achieve the study goals Study candidates undergo evaluation during
the study screening period to determine if they meet all of the inclusion criteria and do
not meet any of the exclusion criteria as defined in the protocol These criteria usually
consider such factors as age sex type of disease stage of disease previous treatment
history and other medical conditions in determining eligibility for the study
Informed consent (assent) a process by which medical researchers provide necessary
information to a person about a clinical study and the person voluntarily confirms his or
her willingness to participate in the study Children who are considered old enough to
have a basic understanding of the study may need to provide assent to be involved in the
study a parent or legal guardian must also give informed consent for such a child to
participate
Informed consent (assent) form a document that describes a clinical study to the
participants (or their parentsguardians) The informed consent (assent) form includes
information about the goals of the study the study design and duration the types of tests
to be performed the potential risks and inconveniences the potential benefits the
possible costs or payments associated with study participation the available alternative
therapies the rights and responsibilities of the participant and the people to contact if the
participant has questions The informed consent (assent) form must be reviewed and
signed before the participant has any study tests or treatment including the tests
performed during the screening period at the beginning of the study Participants are
given a copy of the informed consent (assent) form to take home
Institutional Review Board (IRB) or Independent Ethics Committee (IEC) a board
of physicians statisticians researchers community advocates and others who are
responsible for ensuring the protection of the rights safety and well-being of participants
in a clinical trial at a study center This board is called an IRB in the United States and is
often called an IEC in other countries IRBIECs review and approve important study
documents (eg protocols informed consent forms study advertisements and patient
4
brochures) before the start of the study and periodically review the progress of the study
while it is ongoing
Investigational Drug a drug that is being tested as a potential treatment for a disease or
condition but has not yet been proven safe and effective for that use
Investigator a physician or other health care worker who carries out a clinical trial by enrolling treating and monitoring participants and recording the results
In vitro testing testing conducted in test tubes or other artificial environments
In vivo testing testing conducted in living animals or humans
Longitudinal study a clinical study that involves observations of the same items over
long periods often many decades Because longitudinal studies track the same people
they are often used to study trends across the life span to uncover predictors of certain
diseases or to track the effects of a particular treatment on a patientrsquos condition over
time
Multicenter study a study conducted at more than one location Multicenter clinical
studies are generally performed when each individual clinical trial site does not have
enough study candidates to complete a large trial
Natural history study a study of the natural development of a disease or condition over
a period of time Natural history studies are usually longitudinal studies
New Drug Application (NDA) the registration document through which a
pharmaceutical company formally proposes that the FDA approve a new drug for
manufacturing and sale The application includes detailed reports of pharmacology
toxicology manufacturing and chemistry as well as data from clinical trials
Open-label study a study in which the participants and the investigators know which
treatment is being given In an open-label study there is no blinding and none of the participants receives a placebo
Orphan disease a disease or condition that affects a relatively small number of people
In the US this defined as fewer than 200000 people In Europe this is defined as fewer
than five in 110000 people
Orphan drug a drug intended to treat an orphan disease
Participant or subject a patient or healthy volunteer who participates in a clinical trial
Phase 1 the initial phase of testing of an investigational drug in humans Usually a
Phase 1 clinical study is conducted in a small number of healthy volunteers or patients
with a disease for which the drug may be useful Generally the study is designed to
determine the side effects of the drug and its pharmacokinetics Some information
5
regarding drug efficacy may be collected if patients with a disease participate A phase
frequently encompasses more than one clinical trial Phase 1 sometimes is sub-divided
into Phases 1a and 1b for example when the first set of Phase 1 trials (Phase 1a) is
performed in healthy volunteers and a second set of Phase 1 trials (Phase 1b) is
performed in patients with a disease
Phase 2 the intermediate phase of testing of an investigational drug in humans Usually
a Phase 2 clinical study conducted in patients with a disease for which the drug may be
useful Generally the study is designed to evaluate dosing to obtain preliminary data on
the effectiveness of the drug and to acquire more safety information Phase 2 sometimes
is sub-divided into Phases 2a and 2b Phase 2a studies typically are smaller and shorter
in duration and evaluate different drug doses to see how they affect certain tests that can
indicate whether the drug is working as expected Phase 2b studies typically enroll more
patients are of longer duration and evaluate whether the drug is offering clinical benefits to patients Phase 2b studies sometimes are considered pivotal or registration-directed
Phase 3 the final phase of testing an investigational drug in humans before regulatory
approval Phase 3 studies are usually conducted in a large population of patients and are
generally designed to confirm the effectiveness of the drug and to evaluate the overall
risk-benefit ratio Phase 3 studies usually test the investigational drug in comparison with
a standard treatment for the disease or a placebo
Phase 4 testing of a drug in humans after it has already been approved by regulatory
authorities and can be used in medical practice Phase 4 studies may be conducted to
compare the drug to a similar type of drug to explore whether it may help patients with
other diseases to further study the long-term safety of the drug or for other reasons
Pivotal study a study that is designed to generate the data required by regulatory
authorities to decide whether to approve an investigational drug A pivotal study is
usually a large randomized Phase 2b or Phase 3 study and often is blinded and uses a
placebo as a control Sometimes a pivotal study is described as a registration-directed
study
Placebo an inactive version of an investigational drug A placebo has a similar
appearance to the investigational drug but is expected to have no therapeutic value A
placebo is used as a comparison treatment to reduce bias in randomized studies
Preapproval access program an umbrella term for programs that allow seriously ill
patients to receive an investigational drug when they are unable to participate in clinical
trials and there is no alternative treatment This is sometimes referred to as
compassionate use Types of pre-approval access programs include expanded access
parallel-track named patient program single-patient exemption and treatment IND The
timing for starting an expanded access program usually depends upon what is known
about the risk-benefit of the drug and whether the drug can be provided in a manner that
is fair to patients with the disease
6
Preclinical (nonclinical) testing testing of a drug in test tubes or in animals A drug
undergoes preclinical testing before being tested in humans to make sure that it shows
evidence of desired effects and is sufficiently safe for study in people Preclinical testing
sometimes also helps to determine the doses of the drug that should be evaluated in
humans Preclinical testing is sometimes called nonclinical testing
Protocol a document describing what types of people may participate in a clinical study
and the objectives treatments measurements statistical methods timing and
organization of a clinical trial The protocol must be prepared in advance of the study
and must be reviewed and approved by review committees and regulatory authorities
before the study is started Investigators must follow the protocol to carry out the study
Randomization assignment of participants to treatment arms based on chance This is
usually done by a computer program in a way that does not allow either the participants
or the investigators to choose who is assigned to which arm Randomization is used to
reduce bias in clinical trials
Risk-benefit ratio the balance of the risk of side effects expected with use of a drug
versus the potential for benefit with the use of that drug A drug with a good risk-benefit
ratio has few side effects and is very effective
Serious adverse event (SAE) an adverse event that is life-threatening requires inpatient
hospitalization or lengthens a hospital stay leads to substantial disability leads to a birth
defect or results in death
Side effect any effect of a drug other than the desired effect Side effects are often
unwanted and may be bothersome Other names for a bothersome side effect are adverse
drug reaction (ADR) or drug toxicity
Screening period a period at the beginning of a clinical trial when candidates for the
study are evaluated to determine if their participation is likely to be safe and can
contribute data that will help achieve the study goals
Significant or statistically significant an outcome in a clinical trial is likely to result
from a real difference (eg due to an effect of a treatment) and is unlikely to be due to
chance alone The level of statistical significance is often expressed in terms of a p-
value which indicates the probability that a difference is not due to chance alone
Usually a p-value smaller 005 is considered statistically significant
Sponsor the organization responsible for financing and coordinating a clinical trial
Most often this is a pharmaceutical or biotechnology company
Standard treatment a treatment currently in wide use often approved by regulatory
agencies and generally considered effective in the treatment of a specific disease or
condition
7
Toxicity a side effect produced by a drug that is bothersome to the person taking the
drug
Toxicology the study of the adverse effects of chemicals conducted in animal models to
predict potential adverse effects in humans Some studies are conducted during clinical
development to evaluate dosing regimens
Boston Childrenrsquos Hospital Clinical Research Map 1 Mouse over for additional info Bold = hyperlink
CLINICAL RESEARCH MAP
Boston Childrenrsquos Hospital Clinical Research Map 2 Mouse over for additional info Bold = hyperlink
ObjectiveThis clinical research map is designed to serve as a guide for investigators study coordinators and research nurses at Boston Childrenrsquos Hospital The research map outlines the key steps in preparing to launch a research study and provides embedded links to institutional resources tools and documents
An investigator need not follow the steps on the Clinical Research Map in any particular order There is flexibility and the steps followed will in part de-pend on the type of research study
For new as well as more experienced investigators the Clinical Research Map can be used as a checklist or an inves-tigator can use the steps on the map as points for consideration as they are developing a protocol and launching a study
This tool is not intended to substitute for the important collaboration be-tween a junior investigator and a senior investigatormentor A senior investiga-tor plays a pivotal role in coaching and advising a junior investigator regarding the many subtleties and variations that apply to designing and implementing a protocol
This process map cannot be inclusive of every possible task or step but is intended as a general guide for investi-gators and their study teams
ResourcesThere are many institutional resources at Boston Childrenrsquos Hospital designed to support investigators and their clini-cal research teams In addition to links to resources tools and documents that are embedded in the steps of the clini-cal research map the last page of this document contains website addresses that will take you to additional helpful institutional resources
Acknowledgements Cindy Williams DNP RN PNP NE-BC Nursing Director CTSU Clinical Research Nursing
Ellen McGrath MSN RN CPNP Nurse Practitioner Department of Surgery
Grace Yoon MSN RN CNNP Research Nurse Department of Ophthalmology
Laura Feloney BA Lab Technician
ContentsOverview Four stages 3
1st Stage Protocol development 4
1st Stage Protocol development contrsquod 5
2nd Stage Implementation planning 6
3rd stage Study launch7
4th stage Statistical analysis reporting and dissemination 8
Discarded specimens Additional steps 9
Chart review Steps if you are completing a chart review 10
Appendix A Resources for researchers 11
Boston Childrenrsquos Hospital Clinical Research Map 3 Mouse over for additional info Bold = hyperlink
Overview Four stages
Protocol development
Implementation planning
Study launch
Statistical analysis reporting and dissemination
1
2
3
4
Boston Childrenrsquos Hospital Clinical Research Map 4 Mouse over for additional info Bold = hyperlink
1st Stage Protocol development
Explore resources
CRIT
CRC
EQuIP
CTSU
Harvard Catalyst
Complete training
CITI training
EQUiP
Consult research pharmacistResearch Pharmacy
Rocco Anzaldi
Consult statistician
CRC
Draft a protocol
Protocol guidelines
Study personnel
FDA Guidance for Investigators
Consult Clinical Research Center
CRC
Bio Bank
Start IRB application
TransLab
Consider applying for grants
securing funding
Office of Sponsored Programs
If INDIDE application to FDA
Does my study need an INDIDE
Regulatory resources
Arrange a consultation with
CRIT
ConsultationTasks for investigators and study teams
Boston Childrenrsquos Hospital Clinical Research Map 5 Mouse over for additional info Bold = hyperlink
Respond to IRB questionsrequests
for clarification
1st Stage Protocol development contrsquod
Departmental Scientific Review
Organize DSMB design DSMP
DSMPDSMB
Templates for Research Study
Documents and Tools
Study Templates and Tools
Investigators who sponsor an FDA regulated trial
ClinicalTrialsgov
Create regulatory binder
Regulatory Binder Template
Submit the grant application to OSP
OSP
TIDO
CTBO
Consult Office Intellectual Property
Technology and Innovation
Development Office
TIDO
IRB approval
Consider blood volume for research
Research blood volume policy
Confidentiality plan
Confidentiality guidelines
Boston Childrenrsquos Hospital Clinical Research Map 6 Mouse over for additional info Bold = hyperlink
Develop Case Report Forms
(CRFs)
CRF guidelines
Establish electronic shared
folder or study binder for study
documents
CRIT
Set date for trial launch
Develop fast fact sheet for bedside staff
Consult programmer re database
CRIT
Research study resource manual
for the clinical unit
Confirm study drug
in pharmacy
Rocco Anzaldi
Clarify system for screening
and enrolling patients
Recruitment guideline
Updated protocol to
nurse manager
Consult MDsNPs on unitclinic
2nd Stage Implementation planning
Tasks for investigators and study teams
Study logistics Documentation logistics
Data storage
Confidentiality plan
Confidentiality guidelines
Create study orderset
Consider blood volume for research
Research blood volume policy
Create Manual of Operations
MOO Guide
Study implementation
meeting
Develop study logstools
EQUIP
Finalize tracking sheet
Research Administration
Fernando Valles
Boston Childrenrsquos Hospital Clinical Research Map 7 Mouse over for additional info Bold = hyperlink
3 Document informed consent
Informed Consent
Consent library
Schedule weekly study team meeting
Communicate to department faculty
and multidisciplinary
team announcing trial launch
Steps before trial launch
3rd stage Study launch
Patient flow
1 Seek permission
to approach potential subjects
2 Screenenroll
patients
EQUIP
5 Send Study
Tracking Sheet (STS)
6 Collection of
patient data and assessing for
adverse events
7 Study
documents and data handling
4 Datetime study tests
Create a checklist outlining study action items for each subject
Boston Childrenrsquos Hospital Clinical Research Map 8 Mouse over for additional info Bold = hyperlink
Annual IRB Report
Annual Progress ReportStaff Report
raquo Maintain Interest of Staff
raquo Important to See Study Progress
Write Abstract
Dissemination of Research Results
raquo Conference raquo Internal Presentation for Colleagues
raquo Publication
Plan DSMB MeetingInterim
Analysis
4th stage Statistical analysis reporting and dissemination
Data Entry
When Enrollment Complete Data
Cleaning
Monitor Subjects to Identify
Adverse Events (CCI sponsor
DSMB)
Report Adverse Events
Update MOO Based on Experience
with First Several Patients Enrolled
Weekly Study Team Meeting
Report study findings to
subjects and stakeholders
Data management Trial management
Reporting Dissemination
Regular Review of Data
to Identify Deviations
and Workflow Improvements
Consult Statistician When Approaching Target Enrollment
Discarded specimens Additional steps
Boston Childrenrsquos Hospital Clinical Research Map 9 Mouse over for additional info Bold = hyperlink
Send IRB Approval to lab manager
Maureen Samson
Educate staff in areasunits about sample collection
Locate the discarded samples
Locate the accession number in PowerChart
Retrieve specimen
Mark Kellogg
Follow Shipping Rules and Procedures
IATAShipping with dry ice instructions
Communicate with laboratory staff
Contact Dr Mark Kellogg to discuss specimen retrieval
Consult with Biorepository
Biorepository
Chart review Steps if you are completing a chart review
Boston Childrenrsquos Hospital Clinical Research Map 10 Mouse over for additional info Bold = hyperlink
7 8
4321
Databaserecord review guidelines
5 6
Consult programmer re database
CRC Request
Respond to IRB questions
requests for clarification
Departmental Scientific Review
Complete training
CITI Training
Draft a protocol
Protocol Guidelines
Prepare IRB Application
Information about the CCI
IRB Application
Develop Case Report Forms (CRFs)
CRF Guidelines
IRB Review
Boston Childrenrsquos Hospital Clinical Research Map 11 Mouse over for additional info Bold = hyperlink
Clinical Research Center (CRC) x84720
Committee on Clinical Investigation (CCI IRB) x57052
Research Pharmacist x52014
Clinical and Translational Science Unit (CTSU) x57541
Education and Quality Improvement Program (EQUIP) x57052
Clinical Trials Office Central Budgeting x4-2714
Office of Sponsored Programs x4-2723
Technology and Innovation Development Office 617-919-3079
Research Finance x8-3517
Harvard Catalyst 617-432-7810
Regulatory Affairs x4-2777
Appendix A Resources for researchers
RES_4446_ClinicalResearchMap-FINAL FOR LINKS 1
RES_4446_ClinicalResearchMap-FINAL FOR LINKS 10
Overview Four stages
1st Stage Protocol development
1st Stage Protocol development contrsquod
2nd Stage Implementation planning
3rd stage Study launch
4th stage Statistical analysis reporting and dissemination
Discarded specimens Additional steps
Chart reviewSteps if you are completing a chart review
Appendix A Resources for researchers
RES_4446_ClinicalResearchMap-FINAL FOR LINKS 11
RES_4446_ClinicalResearchMap-FINAL FOR LINKS 2
RES_4446_ClinicalResearchMap-FINAL FOR LINKS 3
RES_4446_ClinicalResearchMap-FINAL FOR LINKS 4
RES_4446_ClinicalResearchMap-FINAL FOR LINKS 5
RES_4446_ClinicalResearchMap-FINAL FOR LINKS 6
RES_4446_ClinicalResearchMap-FINAL FOR LINKS 7
RES_4446_ClinicalResearchMap-FINAL FOR LINKS 8
RES_4446_ClinicalResearchMap-FINAL FOR LINKS 9
RES_4446_ClinicalResearchMap-PAGE 5pdf
Overview Four stages
1st Stage Protocol development
1st Stage Protocol development contrsquod
2nd Stage Implementation planning
3rd stage Study launch
4th stage Statistical analysis reporting and dissemination
Discarded specimens Additional steps
Chart reviewSteps if you are completing a chart review
Appendix A Resources for researchers
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MOUSE OVER
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COVER BUTTON
Previous Page
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Button 91
Button 92
Button 94
IRB review
Button 102
Develop Case Report Forms
Button 136
Consult clinical research center
INDIDE 1
Explore resources
Button 1016
Bio Bank p
4
Consult statistician
Consult research pharmacist
Study personnel
Complete training
Consider grantsfunding
Draft a Protocal 2
Arrange a consutlations with CRIT
Next Page 1
Previous Page 1
TransLab
Start IRB application 3
Develop study logs
Updatedd protocol
Confirm study drug
Establish electronic shared
COnsult programmer
Clarify system
Research study resrouce manual
Develop case report forms
MOO
Set date for trial launch
Button 44
Study implementation meeting
Finalize tracking sheet
Data storage
Confidentiality
Blood volume 3
Develop fast fact
Consult MDs
Schedule weekly
Communicate early
Button 71
Screenenroll patients
Document informed consent
Datetime tests
Send study tracking sheets
Collection patient data
Button 77
Dissemination
Button 87
Button 124
Button 125
Communicate with lab staff
Button 106
Button 109
Button 1010
Shipping page 9
Button 1012
Button 99
Button 133
Button 134
Button 135
Biorepository
Locate assession number
Retrieve specimen
Button 30
Consult office
Negotiate Contract
Organizing DSMB
Submit Grant
Respond to IRB questions
Button 66
Create regulatory binder
Templates for research stufy
Clinical Trials Business Office
Blood volume 2
Confidentiality plan
Investigators who sponsor
clinicaltrials
gov
BPN Project
Drug Discovery amp Development Testing Funnel
Tier 1 2 3
Tier 6 7 8
Tier 5
Tier 4
Example Drug Discovery amp Development Testing Funnel
Cytotoxicity
Grant
Project
Example Drug Discovery amp Development Testing Funnel
TIER 1A ndash Primary Screen
Chemical purity and identity of active compounds
Primary bioactivity screen
Cell viability (When Appropriate)
ScaffoldsMoiety Chemical liabilities (for example Michael acceptor GSH reactive)
Calculated properties CLogP
PSA
Molecular Weight
rotatable bonds
H-bond donors and acceptors
permeability
pKa
Solubility
TIER 1B
Confirm EC50 determinations for actives compounds in primary screen with fresh
compounds from the original stock Confirm EC50 determinations for the lead (most
active) compound in primary screen with a new sample either repurchased purified
and characterized in-house or independently synthesized in-house
Compounds with IC50s (EC50s) less than X advance to Tier 2
TIER 2A ndash Activity Confirmation
Secondary screen
TIER 2B
Repeat EC50 determinations for actives in secondary screen with fresh
compounds from the original stock
Compounds with IC50s (EC50s) less than X advance to Tier 3
Example Drug Discovery amp Development Testing Funnel
TIER 3 ndash Drug-like Properties Specificity
IC50 selectivity in selectivity screen
CYP450 Inhibition competitive and time-dependent if structural alerts exist
(spot check illustrative examples from compound series)
Measured solubility
Measured protein binding (spot check illustrative examples from
compound series)
Test of Permeability in vitro permeability [indicate assay eg Caco2 orand
PAMPA] (spot check illustrative examples from compound series)
hERG
Cytoxicity assays
All compounds with no significant issues (Define Minimum Conditions for
Advancement) to advance to Tier 4
Example Drug Discovery amp Development Testing Funnel
TIER 4 ndash Scale-up Synthesis and Preliminary PK
Scale-up synthesis
Purity determination gt98 with no single impurity gt1
Rodent bioavailability and PK (define target delivery route) Tmax
Cmax
AUC
Bioavailibility
Vss CL T12 MRT
Brain to Plasma ratios
P-glycoprotein transport MDCK-MDR1 and MDCK-mdr1a
Plasma Protein Binding (species)
Microsomal Stability ndash rodent and human
Defineplan Patent Protection Strategy
All compounds with no significant issues (Define
Minimum Conditions for Advancement) advance
in parallel to Tiers 5AampB
Example Drug Discovery amp Development Testing Funnel
TIER 5A ndash In Vivo Bioactivity
Animal efficacy
Validate Biomarker
Target engagement
Advance to Tier 6 if (Define Minimum Conditions for advancement)
TIER 5B ndash Advanced Drug-like Properties
Microsomal stability in multiple
species
Chemical Stability
CYP450 induction
CYP reaction phenotyping
Metabolism ndash human
hepatocytesmicrosomes
Metab ID define major human rat dog and
non-human primates (NHP) metabolites
In vitro Tox Ames
Chromosome Aberration
CNS effects
Example Drug Discovery amp Development Testing Funnel
TIER 6 ndash Liability Assessment
Broad Pharmacological Profile and Toxicology
PK in second species
TIER 7
Non-GLP exposure studies single and multiple dose
Advance to late stage pre-clinical development (Define Minimum
Conditions for advancement)
Example Drug Discovery amp Development Testing Funnel
Principal InvestigatorProgram Director (Last First Middle)
enspenspenspenspensp
DETAILED BUDGET FOR INITIAL BUDGET PERIOD
DIRECT COSTS ONLY
FROM
THROUGH
enspenspenspenspensp
enspenspenspenspensp
PERSONNEL
DOLLAR AMOUNT REQUESTED (omit cents)
NAME
ROLE ONPROJECT
TYPEAPPT (months)
EFFORTONPROJ
INSTBASESALARY
SALARYREQUESTED
FRINGEBENEFITS
TOTAL
enspenspenspenspensp
PrincipalInvestigator
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
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SUBTOTALS
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CONSULTANT COSTS
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EQUIPMENT (Itemize)
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SUPPLIES (Itemize by category)
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TRAVEL
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PATIENT CARE COSTS
INPATIENT
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OUTPATIENT
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ALTERATIONS AND RENOVATIONS (Itemize by category)
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OTHER EXPENSES (Itemize by category)
enspenspenspenspensp
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SUBTOTAL DIRECT COSTS FOR INITIAL BUDGET PERIOD
$
enspenspenspenspensp
CONSORTIUMCONTRACTUAL COSTS
DIRECT COSTS
enspenspenspenspensp
FACILITIES AND ADMINISTRATIVE COSTS
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TOTAL DIRECT COSTS FOR INITIAL BUDGET PERIOD
$
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copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
DrugBank The DrugBank database is a unique bioinformatics and cheminformatics resource that combines detailed drug
(ie chemical pharmacological and pharmaceutical) data with comprehensive drug target (ie sequence structure and
pathway) information The database contains 7759 drug entries including 1602 FDA-approved small molecule drugs 161
FDA-approved biotech (proteinpeptide) drugs 89 nutraceuticals and over 6000 experimental drugs Additionally 4300
non-redundant protein (ie drug targetenzymetransportercarrier) sequences are linked to these drug entries Each
DrugCard entry contains more than 200 data fields with half of the information being devoted to drugchemical data and
the other half devoted to drug target or protein data Homepage is here httpwwwdrugbankca
Protein Data Bank archive Targets with protein crystal structures are more attractive targets for structure based drug design
Determine if your target has a known crystal structure by looking it up in the protein database- A Structural View of Biology
This resource is powered by the Protein Data Bank archive-information about the 3D shapes of proteins nucleic acids and
complex assemblies that helps students and researchers understand all aspects of biomedicine and agriculture from
protein synthesis to health and disease Homepage is here httpwwwrcsborgpdbhomehomedo
High Quality Chemical tools are required for testing biological hypothesis Find chemical tools that are fit for purpose by
virtue of target potency and selectivity needed to test hypothesis The dangers of using inadequate chemical tools are
detailed here httpwwwnaturecomnchembiojournalv11n8fullnchembio1867html To support the needs of the
biology community the industrial chemistry research community has joined a pre-competitive effort to provide
characterization data for high quality chemical probes That data is stored here httpwwwchemicalprobesorgprotein-
family
ChemNavigator The National Institutes of Health (NIH) has formed an agreement with ChemNavigator to provide the NIH
with a current and comprehensive database of commercially accessible drug discovery screening compounds to be
made available to all NIH researchers ChemNavigator is pleased to serve NIH affiliated scientific researchers in compound
sample procurement As an NIH researcher you have full access to use the iResearch System All you need to do is take a
few minutes to register in the system Then you will be able to perform chemical structure searches for compound samples
of interest and purchase these samples through this on-line system Link is here httpwwwchemnavigatorcomnihasp
Additional References related to biological activity of compounds
Edwards AM Bountra C Kerr DJ Willson TM Open access chemical and clinical probes to support drug discovery Nature
chemical biology 2009 5(7)436-440
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
Wang Y Suzek T Zhang J Wang J He S Cheng T Shoemaker BA Gindulyte A Bryant SH PubChem BioAssay 2014 update
Nucleic acids research 2014 42(Database issue)D1075-1082
Wang Y Bolton E Dracheva S Karapetyan K Shoemaker BA Suzek TO Wang J Xiao J Zhang J Bryant SH An overview of
the PubChem BioAssay resource Nucleic acids research 2010 38(Database issue)D255-266
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
main menu
Pharmacokinetic tutorial drug exposure measurement services pharmacokinetic data references
Selecting the correct dose to achieve exposure of drug that are adequate to test a hypothesis in preclinical species
requires that you know the potency of the molecule at the desired drug target and the dose of compound required to
achieve target organ exposure that will result in the free (not bound by protein) concentration of drug required to engage
the molecular target within the target organ compartment Estimates of Drug potency can be found in many of the
databases listed under correct molecule The free concentration of a drug is determined in the plasma by multiplying the
concentration of drug in the plasma by the fraction unbound This must be measured for each compound A literature
reference that provides the measured plasma protein binding (PPB) values for many common drugs is provided here
Zhang Xue Shao and Jia (2012) Compilation of 222 drugsrsquo plasma protein binding data and guidance for study designs
Drug Discovery Today Vol 17 Issue 9-10 Pages 476-485 httpwwwncbinlmnihgovpubmed22210121
If your drug target is the brain then you must also understand the kinetics of drug disposition and clearance including blood
brain barrier (BBB) penetration in your test species to select a dose of compound adequate to test your hypothesis
Download a tutorial deck on basic principles of drug disposition and their application in small molecule drug discovery
courtesy of Dr Chris Shaffer Pfizer
150805DMPKTutorial(CLSBCHCourse)pdf
Pharmacometrics Research Core and Pharmacokinetics Service The Pharmacometrics Research Core is directed by Dr Luis
Pereira and provides analytical services for assaying drugsmetabolites in biological matrices (eg plasma serum blood
urine CSF saliva tissues) The Core provides pharmacokinetic and pharmacodynamic analyses for current and future
clinical trials and research projects (including contract services) It conducts stability and potency studies for pediatric
formulations compounded at BCH as per recent demand from FDA and CMS Finally the Core fosters grant applications
and research collaborations both intra and extramural The TNC can additionally provide investigators with consultation in
the identification of resources for pharmacodynamic assay development and contract research organizations able to
provide bioanalysis of preclinical samples needed to support animal clinical trials Contact Dr Luis Pereira for more
information LuisPereirachildrensharvardedu
article on importance of understanding drug exposure in preclinical drug studies here
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
References on Pharmacokinetics and Brain Penetration of Small Molecules
Di L Rong H Feng B Demystifying brain penetration in central nervous system drug discovery Miniperspective Journal of
medicinal chemistry 2013 56(1)2-12
Reichel A Addressing central nervous system (CNS) penetration in drug discovery basics and implications of the evolving
new concept Chemistry amp biodiversity 2009 6(11)2030-2049
Smith DA Di L Kerns EH The effect of plasma protein binding on in vivo efficacy misconceptions in drug discovery Nature
reviews Drug discovery 2010 9(12)929-939
Moda TL Torres LG Carrara AE Andricopulo AD PKDB database for pharmacokinetic properties and predictive in silico
ADME models Bioinformatics 2008 24(19)2270-2271
Law V Knox C Djoumbou Y Jewison T Guo AC Liu Y Maciejewski A Arndt D Wilson M Neveu V et al DrugBank 40
shedding new light on drug metabolism Nucleic acids research 2014 42(Database issue)D1091-1097
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
main menu
Formulations advice and assistance with preclinical drug delivery Neurodevelopmental Behavioral Core
To effectively deliver drug to preclinical species for the duration of a study researchers must choose a dose a formulation
and a route of administration that will support target organ exposure long enough to test a therapeutic hypothesis Since
most drugs developed for humans are optimized for human metabolism parameters many compounds developed for
humans are rapidly metabolized and cleared in rodents requiring alternative formulations and routes of preclinical
administration (see tutorial under Correct Dose)
Proper formulation of drugs and vehicles to ensure appropriate drug exposure is a critical factor in preclinical study design
The Neurodevelopmental Behavioral Core may provide advice on standard formulations Preclinical assistance and
training across many routes of administration including IV cannulation osmotic minipumps oral gavage sc and ip is also
available through the Neurodevelopmental Behavioral Core
Contact is Dr Nick Andrews NickAndrewschildrensharvardedu
Custom formulation used for human studies are supported on a case by case basis by the Pharmacometrics Research Core
or Clinical Research Pharmacy Contact for the Pharmacometrics Core is Dr Luis Pereira LuisPereirachildrensharvardedu
The Clinical Research Pharmacy can provide advice on unusual formulations Contact is Dr Rocco Anzaldi
RoccoAnzaldichildrensharvardedu
idspharmacy-dlchildrensharvardedu
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
main menu
Stratification Biomarker development and resources patient sample repositories requests for collection of new types of
patient samples development of patient specific iPSC lines and neurons Genetic databases RNA expression databases
Humans are diverse Not only do patients come in different sizes ages genders and ethnic backgrounds but the same
disease diagnosis often develops in people as a function of different environmental insults and genetic predispositions
Finding biomarkers that will segregate similarly diagnosed patients into subsets of biologically more homogenous
populations is a critical feature of good clinical trial design A lsquostratification biomarkerrsquo can be a biochemical measure from
patient samples a structural or a functional feature of a human imaging technology or a functional measure of an
electrophysiological readout
The Translational Neuroscience Center can help investigators access advice and assistance for investigators with vendors
experienced in profiling DNA RNA or protein across a range of platforms httpwwwchildrenshospitalorgresearch-and-
Neurophysiology Services can assist investigators with identification of biomarkers to stratify patients based on EEG
signatures Contact Drs Charles Nelson and Jurriaan Peters Co-Directors
CharlesNelsonchildrensharvardedu
JurriaanPeterschildrensharvardedu
MRIRadiology Imaging Core can assist with identification of biomarkers to stratify patients by functional or structural deficits
in brain circuitry Contact Dr Simon Warfield Director SimonWarfieldchildrensharvardedu
Molecular Genetics core can assist investigators with identification of genetic stratification biomarkers or gene expression-
based stratification biomarkers Contact Drs Louis Kunkel and Christopher Walsh Co-Directors
LouisKunkelchildrensharvardedu
ChristopherWalshchildrensharvardedu
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
The Human Neuron Differentiation Service within the Translational Neuroscience Center can help investigators recruit
specific subtypes of patients to be consented for reprogramming of blood or fibroblast cells into iPSC lines that will support
differentiation into human neurons for phenotypic analysis and screening ContactDr Robin Kleiman
RobinKleimanchildrensharvardedu
Translab can assist with routine processes as well as complex laboratory-‐developed tests They place special emphasis on
assay development for use in clinical trials Translab website with contact information can be viewed here
httpwwwtranslabbostonorg
TransLab Flyer 2 2015pdf
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
main menu
Patient sample repositoryBiobank Patient registry
Disease processes are dynamic The molecular underpinnings of disease differ between inception progression and
response of the body to disease Thus each stage of disease may require alternative therapeutic strategies Understanding
which stage of disease is best suited to testing a specific therapeutic approach will require information about disease from
patient samples collected at different stages of disease well as an ability to collect and recruit patients at relevant stages of
disease
To locate human RNA profiling data in the public domain from disease samples and tissues at specific stages of disease
search databases referenced in the Correct Target section of this document
The Translational Neuroscience Center offers multiple services that can assist with identification of the correct patients The
Core Repository for Neurological Disorders stores a wide variety of patient samples from many stages of disease The
biorepository is directed by Dr Mustafa Sahin and these samples and de-identified clinical data can be searched and
requested through the Translational Neuroscience Center
The Biobank Core Lab serves as a core resource that ensures top-level specimen handling and services to the Boston
Childrens Hospital research community It serves as both a service core and a biorepository providing an institutional
perspective on the presence of specimens that may be available for use to foster collaborations and accelerate research
and discovery
The Clinical Research and Regulatory Affairs Service can provide assistance to investigators in identifying patients andor
repository samplesdata Contact Co-Directors Stephanie Brewster and Kira Dies for more information about access to
these resources
StephanieBrewsterchildrensharvardedu
KiraDieschildrensharvardedu
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
main menu
Statistical support clinical trialsgov
Determining the correct sample size to support preclinical and clinical studies requires power calculations that take into
account the variability of the endpoint being measured Statistical support for preclinical studies is available on a
department by department basis Neurology and Neurobiology requests for preclinical biostatistics support can be made
through the CRC website
httpredcap-qiredcap_edcsurveyss=Rma5u83qKC
Clinical statistical support for all departments is also available through the CRC Design and Analysis Core For more
information contact Michael Monuteaux michaelmonuteauxchildrensharvardedu
Clinical datasets that provide data for supporting power calculations can be found by searching through clinical trialsgov
database All studies in the clinical trials data base are required to describe the study design the endpoints under
evaluation and the treatments as well as links to publications of the studies The studies can be searched by topic This can
be a good way to find historical data to help you evaluate variability of endpoint measures in clinical populations This will
be needed to support sample size power calculations httpsclinicaltrialsgov
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
main menu
Understanding RDoC Human Neurobehavioral Core Service IRB assistance with clinical protocols
Different stages of clinical trials have different goals for selecting endpoints Early stage clinical trials are typically in search
of a translatable pharmacodynamic or target engagement endpoint to ensure that the molecule in question will be
competent to test a clinical hypothesis in humans Developing translatable measures of target engagement in preclinical
species and humans is critical to developing data sets that will enable subsequent therapeutic efficacy trials The earliest
trials require endpoints that can be measured in a functionally equivalent manner across species Therefore it is critical for
preclinical researchers to develop dose-responsive data sets in preclinical species using quantitative endpoints such as EEG
visual or auditory evoked potentials PET ligands plasma or CSF based biochemical measures or translatable task based
behaviors Preclinical data must be a developed with an eye towards what the equivalent measure will be in the clinic
Toward that end the NIMH has initiated the Research Domain Criteria (RDoC) that is aimed at characterizing mental health
disorders across many different dimensions across species A big focus of the RDoC initiative is the identification of
translatable endpoints for evaluating pharmacodynamics and efficacy in Neuroscience Drug Discovery Preclinical
Neuroscience researchers should be familiar with the RDoC framework For advice on in vivo characterization of preclinical
endpoints with translational potential for Neuroscience related disorders contact Dr Robin Kleiman at the TNC
robinkleimanchildrensharvardedu
The Human Neurobehavioral Core Service of the Translational Neuroscience Center can provide guidance to investigators
on the appropriate tests that will provide the best translation from animal studies to human studies The Service also offers
human neurobehavioral assessment services Contact-Drs Charles Nelson and Deborah Waber Co-Directors
CharlesNelsonchildrensharvardedu
DeborahWaberchildrensharvardedu
Developing clinical protocols and obtaining IRB approval for human study of translatable endpoints can be supported by
the Translational Neuroscience Center Clinical Research and Regulatory Affairs Service Contact-Kira Dies and Stephanie
Brewster Co-Directors
KiraDieschildrensharvardedu
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
StephanieBrewsterchildrensharvardedu
Background Information on RDoC httpswwwnimhnihgovresearch-prioritiesrdocindexshtml
Casey BJ Oliveri ME Insel T A neurodevelopmental perspective on the research domain criteria (RDoC) framework
Cuthbert BN Insel TR Toward the future of psychiatric diagnosis the seven pillars of RDoC BMC Med 2013 11126
httpwwwncbinlmnihgovpmcarticlesPMC3653747
Insel T Cuthbert B Garvey M Heinssen R Pine DS Quinn K Sanislow C Wang P Research domain criteria (RDoC)
toward a new classification framework for research on mental disorders The American journal of psychiatry 2010
167(7)748-751 httpwwwncbinlmnihgovpubmed20595427
Insel TR The NIMH Research Domain Criteria (RDoC) Project precision medicine for psychiatry The American journal
of psychiatry 2014 171(4)395-397 httpwwwncbinlmnihgovpubmed24687194
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
main menu
Body atlases for expression of mRNA and protein guides to chemical alerts guidance for preclinical toxicology studies for
Investigational New Drug (IND) applications
Discovery scientists must consider the distribution of the proposed drug target across the entire body in human samples in
order to understand potential safety risks to be monitored during preclinical toxicological testing Teams also have to be
aware of differences in distribution of the target and related family members in preclinical species Many of the target
expression databases listed in the Correct Target section of this document are useful in this regard Assays that can be used
to monitor any potential safety risks are critical to the development of a suitable testing funnel needed to advance
compounds
Many chemical classes of compounds that are identified in screens are not suitable for drug development due to the
presence of structural alerts that are known to cause chemical toxicity Databases that house information of structural alerts
can be used to de-prioritize structural series early in the life of a program Some toxicology databases that can help
deprioritize toxic chemotypes include httppubsacsorgdoiabs101021ci300245q
Some web resources for identifying side effects of known compounds httpintsideirbbarcelonaorg
Once a potential clinical candidate molecule is identified GLP-qualified toxicology studies must be carried out with a
qualified vendor to support regulatory filings of an Investigational New Drug (IND) application For a short tutorial on studies
needed to support preclinical toxicology testing and guidance on evaluating contract research organizations that are
qualified to perform this work see attached tutorial courtesy of Dr Joe Brady Pfizer
Brady boston childrens hosp talk aug2015 IND toxpdf
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
main menu
FAQs
Industry partners and collaborators can bring tremendous expertise and complementary resources to bear on research
projects with therapeutic applications These may include medicinal chemistry expertise pharmacology expertise access
to unique and undisclosed chemical probe molecules assay development and high-throughput screening resources
antibody and other reagent development pharmacokinetic analysis pharmacokinetic and pharmacodynamics
modeling formulation expertise post-doctoral training programs and in some cases financial support There is a wide range
of models of interacting with industry in a range of different capacities Some frequently asked questions about types of
relationships and the responsibilities associated with those interactions can be found in the following document
Download Frequently Asked Questions about working with Industry
Translation of basic research into new marketed drugs will require a transition from exploring scientific principles and testing
hypotheses into commercial products Industry partners capable of developing these potential products need to be able
to license the intellectual property required to sell the product in order to justify investment in building programs around new
ideas This requires that scientific researchers protect and patent potential inventions from their work to enable future
commercialization by partners with appropriate expertise To ensure that researchers are appropriately documenting their
work in a manner that will support preservation of intellectual property all investigators are encouraged to consult with TIDO
before any public disclosures of new research Similarly the following documentation provides guidance for documenting
your work according to standards that will support patent applications
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
Download the compliance manual for BCH for Intellectual property policy
cm_021_intellectual_propertydocx
Download a summary of laboratory notebook Dorsquos and Donrsquot
Dosdontsnotebookspdf
Link to TIDO Technology Innovation and Development Office
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
main menu
A phenotypic screen requires a biologically robust assay that represents a significant aspect of disease-relevant human
biology It can be used to identify molecular targets for target validation studies through the use of well-annotated
bioactive molecules or genomic libraries (eg RNAi CRISPER) Alternatively phenotypic screens can be used to identify
novel compounds that must subsequently be lsquoDE convolutedrsquo to identify novel targets using lsquowarheadsrsquo These screens rely
on identification and manipulation of a functional deficit or phenotype using a patient-derived cellular system
The strengths of this approach
Use of human systems can improve translatability
Identified compounds may empirically balance therapeutic activity at multiple required targets
Well-suited to drug repurposing
Phenotypic screens can be used to identify compounds or targets for mechanism based drug discovery programs
Many CNS drugs have been discovered using a phenotypic repurposing screen (Swinney and Anthony 2011)
Drawbacks to this approach
Assays are slow low throughput and more expensive as compared to cell-free assays
Cell-based assays may not predict circuit level or brain phenotypes
Furthermore as a primary screening approach
Precludes leveraging strengths in uHTS SBDD and parallel design
Every molecule must be de-risked independently thus safety can be very hard to predict
Drug Repurposing Drug Repurposing is a strategic pillar of the National Center for Advancing Translational Science (NCATS)
Details on resources and funding opportunities can be found here httpsncatsnihgovntu
Chemogenomic Files from industry partners Many companies have well designed and annotated chemical files that are
designed to cover the druggable genome with small molecule compounds from their proprietary collections Each
company has different criteria and stipulations associated with use of the library It is advisable to consult with TIDO
regarding terms and conditions associated with individual companies
ICCB-LongwoodKirby ADSF The ICCB screening center and the Kirby ADSF have multiple collections of compounds that
include bioactive or FDA approved molecules available for screening
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
Kirby ADSF libraries contact Dr Lee Barrett LeeBarrettchildrensharvardedu
References related to phenotypic screens and Drug Repurposing
Vincent F Loria P Pregel M Stanton R Kitching L Nocka K Doyonnas R Steppan C Gilbert A Schroeter T
and MC Peakman Developing predictive assays The phenotypic screening ldquorule of 3rdquo Sci Transl Med 7 293ps15
(2015)
Langedijk J Mantel-Teeuwisse AK Slijkerman DS Schutjens MH Drug repositioning and repurposing terminology and
definitions in literature Drug Discov Today (2015)
Swinney DC and J Anthony How were new medicines discovered Nature Reviews Drug Discovery 10 507-
519 (July 2011) | doi101038nrd3480
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
main menu
TNC Clinical Research and Regulatory Affairs Service Research Participant Registry CRC
Glossary of Terms
Glossary-of-Clinical-Trials-Termspdf
Clinical Research and Regulatory Affairs Service This Translational Neuroscience Center service facilitates the mission of the
Translational Neuroscience Center providing coordination among studies communications resource development and
implementation of new or ongoing preclinical and clinical studies The service is led by experts in protocol development
and launching of new studies The directors are available to guide TNC researchers in designing human studies including
the preparation of Institutional Review Board (IRB) and FDA submissions Additionally staff of the Clinical Research and
Regulatory Affairs Service will help researchers with recruitment plans budget development supervision of study
coordinators study monitoring and audit preparation For more information contact Co-Directors Kira Dies ScM CGC and
Stephanie Brewster MS CGC
KiraDieschildrensharvardedu
StephanieBrewsterchildrensharvardedu
Clinical Research Center (CRC) Assists investigators at BCH with research project initiation and implementation resources
in the CTSU for the conduct of clinical research visits and ancillary services education on research methods and practices
The CRC has biostatisticians project managers research specialists clinical trials specialists research coordinators and
highly skilled nurses and nurse project managers who work every day to facilitate the many research needs of the BCH
community httpwwwchildrenshospitalorgresearch-and-innovationresearchclinicalclinical-research-center
Clinical and Translational Study Unit (CTSU) The CTSU provides clinical research infrastructure for investigators in the design
initiation conduct and reporting of clinical research with the goal of translating scientific knowledge into new therapies for
pediatric conditions httpweb2tchharvardeductsu
Clinical Research Roadmap This clinical research map is designed to serve as a guide for investigators study coordinators
and research nurses at Boston Childrenrsquos Hospital The research map outlines the key steps in preparing to launch a
research study and provides embedded links to institutional resources tools and documents
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
Clinical Research Mappdf
main menu
Office of Sponsored Programs Research Administration TIDO
Many government and foundation grant opportunities are available for developing Drug Discovery Projects updated lists of
funding options exist on OSP and Research Administration web sites
Some good options for finding relevant requests for proposals
Translational Research Program annual call for proposals
Boston Childrenrsquos Hospital ndash Broad Institute Collaboration Grants Proposals will be reviewed by a joint Childrenrsquos Hospitalndash
Broad Institute committee Additional submission dates are expected for 2016
BCH_Broad collaborative grant 852015docx
Kirby Neurobiology Screening Pilot awards- available to Kirby Neurobiology PIs as funding is available
Translational Neuroscience Center- Pilot awards supported by trust sponsored donations as available Distributed through
TNC e-mail lists
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
ADDF The ADDF Academic Drug Discovery and Development Program seeks to create and support innovative translational
research programs for Alzheimerrsquos disease related dementias and cognitive aging in academic medical centers and
universities Biomarker development studies and innovative proof of concept pilot clinical trials of new approaches to
treatment prevention and early detection are also supported
Department of Defense ALSRP The FY15 Defense Appropriations Act provides $75 million (M) to the Department of Defense
Amyotrophic Lateral Sclerosis Research Program (ALSRP) to support innovative high-impact Amyotrophic Lateral Sclerosis
research As directed by the Office of the Assistant Secretary of Defense for Health Affairs the Defense Health Agency
Research Development and Acquisition (DHA RDA) Directorate manages and executes the Defense Health Program
(DHP) Research Development Test and Evaluation (RDTampE) appropriation The executing agent for the anticipated
Program AnnouncementsFunding Opportunities is the Congressionally Directed Medical Research Programs (CDMRP)
httpcdmrparmymilpubspress201515alsrppreannshtml
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
Michael J Fox Foundation Therapeutic Pipeline Program Supports Parkinsons disease therapeutic development along the
pre-clinical and clinical path (both drug and non-pharmacological therapeutics including gene therapy biological
surgical and non-invasive approaches) The Michael J Fox Foundation seeks applications with potential for fundamentally
altering disease course andor significantly improving treatment of symptoms above and beyond current standards of care
Proposals must have a well-defined plan for moving toward clinical utility for patients The Therapeutic Pipeline Program is
open to industry and academic investigators proposing novel approaches or repositioning approved or clinically safe
therapies from non-PD indications httpswwwmichaeljfoxorgresearchgrant-detailphpid=28
NINDS The Blueprint Neurotherapeutics Network (BPN) Provides the neuroscience community access to a complete and
seamless pipeline for preclinical drug development beginning with chemical optimization and concluding after phase I
clinical trials Participants in the BPN will receive funding to conduct bioactivity and efficacy testing in their own laboratories
as well as access to millions of dollars in NIH-contracted drug development services including medicinal chemistry
pharmacology toxicology and phase 1 clinical trials NIH will also provide drug development consultants who have had
years of experience working at a senior level in industry Because the Blueprint is establishing a network of drug
development service providers that typically cater to biopharmaceutical companies neuroscientists who join the BPN can
readily plug in to all of the drug development expertise that typically resides in industry The projects supported through the
network will be highly collaborative and the researchers who initiate the projects will serve as the principal investigators
(PIs) directing their projects through the development pipeline with the help of industry consultants The PIs and their
institutions will have the opportunity to attain assignment of intellectual property rights from all other network participants
who may have intellectual input into their projects This will allow the PIs to retain control of the intellectual property for drug
candidates developed through the network and eventually pursue licensing and commercialization partnerships
httpneuroscienceblueprintnihgovbpdrugs
NeuroNEXT Will establish a consortium of clinical sites capable of forming disease-specific cadres of investigators in order to
develop and implement trials rapidly in a wide range of neurological disorders that affect adults andor children With a
stable and experienced research staff a central IRB model and master trial agreements NeuroNEXT will streamline the
administrative processes for clinical trials and reduce start-up times NeuroNEXT will also be able to design and implement
evidence-based measures to improve patient recruitment into clinical trials httpswwwneuronextorgresearchers
NIMH Many grant options see overview here httpwwwnimhnihgovresearch-prioritiestherapeuticsindexshtml
Building on High Impact Basic Neurobiology Through Assay Development Advancing Tools for Therapeutic Discovery (R01) -
See more at httpgrantsnihgovgrantsguidepa-filesPAR-15-066htmlsthashs1HMWjWudpuf
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
NCATS many grant options see overview here httpwwwncatsnihgovprograms
Bridging Interventional Development Gaps (BrIDGs) Program Makes available on a competitive basis certain critical
resources needed for the development of new therapeutic agents for both common and rare diseases Investigators do not
receive grant funds through this program Instead successful applicants receive access to NIH experts and contractors who
conduct pre-clinical studies at no cost to the investigator In general synthesis formulation pharmacokinetic and
toxicology services in support of investigator-held IND applications to the Food and Drug Administration (FDA) are available
httpwwwncatsnihgovbridgsworksolicitation
NCATS Discovering New Therapeutic Uses for Existing Molecules (New Therapeutic Uses) A collaborative program designed
to develop partnerships between pharmaceutical companies and the biomedical research community to advance
therapeutics development This innovative program matches researchers with a selection of pharmaceutical industry
assets to test ideas for new therapeutic uses with the ultimate goal of identifying promising new treatments for patients
httpwwwncatsnihgovntu
Pfizer Centers for Therapeutic Innovation (CTI) Suitable for biotherapeutic or small molecule projects with a strong project
rationale (demonstrated association between target biology pathway and disease mechanism) CTIrsquos areas of interest
include inflammation autoimmunity tissue remodeling oncology cancer immunology rare or genetic diseases
cardiovascular and metabolic diseases and neuroscience Selected projects are undertaken by a joint team with BCH
members and Pfizer CTI drug development experts located on the 18th floor of CLS working towards agreed common
goals The Pfizer CTIBCH collaboration program is managed by a Joint Steering Committee with representation from both
Boston Childrenrsquos and CTI httpswwwpfizercticom Calls for proposals come through TIDO three times a year in January
May and September httpwwwchildrensinnovationsorgPagesHighlightsHighlights-83aspx
Shire-BCH Collaborative Program Development The Joint Steering Committee of the Shire Alliance extends a call for ldquoPre-
Proposalsrdquo with defined objectives from time to time generally annually in the late fall or winter That call is publicized
through emails from BCH Research Administration and TIDO Following review by the JSC a full proposal may be requested
Unsolicited proposals may also be considered from time to time
ACRONYMS
HTS- High-throughput Screen run with 96 well 384 well 1536 wells or 3456 well capacity- screen has capacity to run through a library of 1-3Million compounds in total
uHTS- Ultra High-throughput Screen ndash arbitrary cut off to denote capability to measure 100s of thousands of assays per day with automation and high density plate readers
HCS- High Content Screen usually a cell based assay that is able to monitor multiple endpoints reflective of different cellular processes in a single well of cells treated with a compound May be biochemical or image based endpoints
SAR- Structure-Activity Relationship ie relationship of modifications to chemical structure on relevant activity SPR-Structure-Property Relationship ie relationship of modifications of chemical structure on physicochemical
properties
PK- Pharmacokinetic measure of drug levels in a body compartment
PD- Pharmacodynamic a measure of functional activity of a drug
PKPD- PharmacoKinetic PharmacoDynamic relationship- how drug levels relate to drug response in a system
DDI-Drug-Drug Interactions- occurs when one drug affects the activity of another drug when co- administered Often due to changes in ADME properties of one of the co-administered drugs (ie for example induction by one drug of enzymes that will metabolize the second drug )
DMPK- Drug Metabolism and PharmacoKinetics
ADME- Absorption Distribution Metabolism amp Excretion
PDM-pharmacokinetics dynamics and metabolism GLP- Good Laboratory Practice- regulations that govern toxicology studies required by the FDA to support IND
and NDA
POM- Proof of Mechanism clinical studies to demonstrate hit the target and elicited a biological response
POC- Proof of Concept Clinical studies to demonstrate a clinically meaningful outcome measure improved
PoP-Proof of Principal usually preclinical studies that demonstrate that engaging target in a disease model produced efficacy
FIH- First in Human clinical trial to evaluate new molecule in humans for safety and PK- Ph1
FIP-First in Patient first clinical trial to evaluate new molecule in patients hERG (the human Ether-agrave-go-go-Related Gene) is a gene KCNH2 that codes for a subunit of Kv111 and
contributes to the repolarizing current in the heart that coordinates the hearts beating When compromised by application drugs or by rare mutations in some families it can result in a potentially fatal disorder called long QT syndrome A number of clinically successful drugs in the market have had the tendency to inhibit hERG and create a concomitant risk of sudden death as a side-effect which has made hERG inhibition an important anti-target that must be avoided during drug development
IND-Investigational New Drug Application- formal application to FDA to evaluate a NCE in people
NME- New Molecular Entity- a new FDA approved drug
NCE-New Chemical Entity-an investigational drug that is not yet a FDA approved NME NDA- New Drug Application (A lsquoFilingrsquo)- a formal application for approval of a new drug
CAN-(Pfizer-specific shorthand )-Clinical Candidate- a molecule competent to be tested in humans IB- Investigators Brochure- basic information on an investigational drug and its mechanism for clinicans involved
in conducting a clinical trial Provides background information on the hypothesis being tested and the types of patients that should be included excluded and risks and how the drug should be administered It must be updated continually by the sponsor to include all new findings
SOC- Standard of Care- in our context it is the drug treatment that a clinican should prescribe for a particular type of patient used as a benchmark for comparing new entities
MTD- Maximum Tolerated Dose- first identified in GLP safety studies during preclinical development AE- Adverse Event- a side effect that causes safety concerns
TI- Therapeutic Index -ratio of the concentration of drug needed to produce efficacy and the concentration of drug that is safely tolerated ( also called ldquoSafety Marginrdquo)
Questions Contact Robin Kleiman- email RobinKleimanchildrensharvardedu office CLS 13070
Terms that relate to Targets Molecular target- the protein that binds drug to produce efficacy Off-Target- other proteins that bind the drug that do not relate to efficacy and may produce Adverse Events (AEs) Druggable target ndashcomes from a class of proteins that has successfully been targeted with small molecule drugs in
the past Primarily transporters enzymes receptors ion channels (Not protein-protein interactions transcription factors RNA binding proteins etc)
Druggable genome- about 3000 genes encoding all druggable proteins Druggability- the presence of protein folds (quarternary structures) that favor specific interactions with drug-like
molecules Exploratory target- Hypothesis that a modulating a target via a particular mode of action will be beneficial to a
particular patient population Validated target- Hypothesis regarding a target also has in vivo efficacy data for a disease or a disease model- along
with a complete understanding of how the target mechanism relates to disease- (also called lsquoProof of Principlersquo) Phenotypic screen- a screen for compounds that will reverse a phenotype the molecular target may not be known Systems pharmacology target(s)-a precisely defined combination or lsquofingerprintrsquo of molecular targets to be
modulated to correct a phenotype (Poly-pharmacology)
Terms that relate to programs
Biomarker- a physiological pathological or anatomical characteristic that is measured by an automated process or algorithm as an indicator of the normal biological process pathological process or biological response to a therapeutic intervention Many types of Biomarkers target engagement biomarkers stratification biomarkers efficacy biomarkers pharmacodynamic biomarkers etchellip
Laboratory Objectives-Criteria established at the start of the program to define the desired pharmacological properties of the molecule with regard to potency selectivity mode of action frequency and route of administration For antibodies would include minimal criteria for knock down stability etc
Therapeutic Modality- small molecule biologic RNAi stem cell etc
Screening tree Screening funnel- A decision tree for utilizing a panel of assays to identify molecules that meet the laboratory objectives
Terms that relate to molecules
Drug-like molecule- has physicochemical properties in line with known oral medications The molecule will be largely rule of 5 (RO5) compliant therefore small and moderately lipophilic Not related to pharmacological activity
Rule of Five (RO5)=Chris Lipinskirsquos rule of 5 states that a drug like molecule will have the following properties Molecular Weight of less than 500 a clogP lt5 fewer than 5 H-bond donors and the number of H-bond acceptors ( which is the sum of N and O atoms) is less than 10
Physicochemical properties- key properties of molecules include (calculated)Molecular Weight number of H bond acceptors and donors (measured) kinetic solubility pKa lipophilicity (logD logP)
Chemical tool -a compound with good potency and selectivity for a specified molecular target but fails to meet all criteria for safety PK or potency needed to become a clinical candidate Suitable for preclinical testing of hypothesis and proof of principal studies but not for lsquopreclinical developmentrsquo
Active molecule describes an individual chemical entity with measurable dose-dependent activity in a biological screening assay
Hit molecule refers to a molecule plus its related structural analogs for which there is an understanding of the structure-properties and structure-activity relationships (SPR and SAR) for a specific biological context Additionally preliminary drug disposition data (both in vitro and in vivo) provide an assessment of pharmacokinetic properties The available data provide a basis for further optimization of the hit series
Lead molecule refers to a molecule plus its related structural analogs that demonstrate o Sufficient exposure at pharmacologically relevant doses by the intended route of administration to explore
intended pharmacology in a relevant in vivo disease or pharmacodynamic model o Proof-of-principle or efficacy in a in vivo model that will be used to establish a margin of safety
Clinical candidate an optimized individual chemical entity derived from a lead series that demonstrates o a dose-response relationship via intended route and schedule of administration in relevant disease model o an exposure-based margin of safety in toxicology studies o In summary a clinical candidate is a molecule that is deemed competent for testing the primary disease
intervention hypothesis in humans
A laboratory notebook is a vital record of events leading to a patentable invention Therecorded information can establish dates of conception and reduction to practice of atechnology as well as the inventorship of a patent claiming the technology Below arefourteen rules you should follow when keeping lab notebooks
1 mdash Do use bound booksInventors should use permanently bound notebooks eg notebooks with spiral or glue bindings If loose-leaf sheets are used they should be consecutively numbered and eachpage should be dated signed and witnessed
2 mdash Do sign and date Each notebook should be signed and dated on the inside front cover to indicate the firstday the recipient started using the notebook Each entry should be dated and signed orinitialed
An independent witness ie someone who understands the technology but will not benamed as a co-inventor of the invention should sign and date each entry after the state-ment ldquoRead and understood by rdquo (The witness should preferably sign theentries on a contemporaneous or fairly contemporaneous basis but entries can also bereviewed signed and dated on a periodic eg weekly or monthly basis)
3 mdash Do use inkNotebook entries should be made in ink and in chronological order Entries should not beerased or ldquowhited outrdquo If an entry contains an error a line should be drawn through theerror and new text should continue in the next available space
4 mdash Donrsquot leave blank spacesBlank gaps between entries should be avoided If a blank space is left on a page a line orcross should be drawn through the blank space and the page dated to prevent subsequententries
5 mdash Donrsquot modifyPrior entries should not be modified at a later date If data were omitted the new datacan be entered under a new date and cross-referenced to the previous entry Record exper-iments when they are performed
6 mdash Do use past tenseUse the past tense (eg ldquowas heatedrdquo) to describe the experiments that were actually performed
Fish amp Richardson pc
Dorsquos and Don rsquo ts forKeeping Lab Notebooks
Boston
Dallas
Delaware
New York
San Diego
Silicon Valley
Twin Cities
Washington dc
FR
7 mdash Do explain abbreviations and special termsExplain all abbreviations and terms that are nonstandard Explain in context in a table ofabbreviations or in a glossary
8 mdash Do staple attachmentsAttachments such as graphs or computer printouts should be permanently attached to pagesin the notebook (eg by stapling) and both the attachment and the notebook page signedand dated If the attachment cannot be stapled it should be placed in an envelope and theenvelope stapled to the notebook page The envelope and page should then be signed andwitnessed making reference to the attachment being placed in the envelope
9 mdash Donrsquot remove originalsNo original pages should be removed from the notebook
10 mdash Do outline new experimentsWhen a new project or experiment is started the objective and rationale should be brieflyoutlined (eg in a short paragraph or by providing a flowchart)
11 mdash Do record lab meeting discussionsRelevant discussions from lab meetings should be recorded as should ideas or suggestionsmade by others The names of the people making the ideas and suggestions should be care-fully documented This information may be important in establishing inventorship
12 mdash Do provide detailRecord test descriptions including preferred operating conditions control conditionsoperable and preferred ranges of conditions and alternate specific materials Also recordtest results and an explanation of the results as well as photos or sketches of the resultsandor the test device Any conclusions should be short and supported by the factual dataOpinions or speculation about the invention should be avoided
13 mdash Do track notebooksIdeally each lab should maintain a catalog of notebooks in which each notebook is assigneda number and the name of the author of each notebook is recorded In addition the datethe author received the notebook as well as the date the notebook was completed andreturned should be recorded Upon leaving the lab the author should return all notebookschecked out by or to him
14 mdash Do save completed notebooksAll completed notebooks should be indexed (eg by number by author andor by subjectarea) and kept safely in a central repository together with corresponding patent applica-tions or patents Lab notebooks that relate to inventions on which patents have been grant-ed should be kept for the life of the patent plus six years
By J Peter Fasse
Fish amp Richardson pcIntellectual property complex litigation technology law800 818-5070wwwfrcominfofrcom
P ER SP EC T I V E
PHARMACOK INET I CS
Data gaps limit the translational potentialof preclinical researchRobin J Kleiman1 and Michael D Ehlers2
The absence of mouse pharmacokinetic reference data hinders translation An analysis ofrecent literature highlights a systematic lack of discussion regarding rationale for the selec-tion of dosing paradigms in preclinical studies and in particular for neuroscience studies inwhich the lack of brain penetration can limit target-organ exposure We propose solutionsto improve study design
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Despite widespread use of pharmacologicalagents in mouse models of human diseasethe literature lacks comprehensive pharmaco-kinetic profiles for such studies Coupled witha paucity of suitable data are shortcomingsin the training of experimental biologists inthe application of pharmacometric principlesto experimental study design Many authorssimply cite previously published studies tosupport the selection of a particular dose evenwhen the cited paper lacks drug exposuredata There is an assumption on the part ofresearchers that if a referenced study demon-strates a biological effectmdashthat is any measur-able physiological or behavioral effectmdashin arodent at a given dose then that same dosewill also effectively perturb disease-relevantmechanistic biology in a different study Thedanger occurs when the observed therapeuticeffects are not linked to drug-induced mecha-nistic alterations at the level of the target organLack of a drug exposurendashresponse relationshipin a target organ casts doubt on mechanisticinterpretations In addition any changes inthe route of drug administration vehicle prep-aration species used (rat versus mouse versusprimate) age or strain of animal transgenicmodification time points under investigationduration of dosing or organ targeted for inter-vention (for example brain versus a periph-eral tumor) can alter the relation between doseexposure and measured response In suchcases assumptions regarding the mechanisticbasis for observed therapeutic effects may nothold true
Preclinical pharmacological experimentsthat do not measure drug concentrations in
1Translational Neuroscience Center Kirby NeurobiologyCenter Department of Neurology Boston ChildrenrsquosHospital Harvard Medical School Boston MA 02115USA 2Neuroscience amp Pain Research Unit BioTherapeu-tics Worldwide Research and Development Pfizer IncCambridge MA 02139 USACorresponding author E-mail robinkleimanchildrensharvardedu (RJK) michaelehlerspfizercom (MDE)
the target organ run the risk of producing ex-posures that are too low or too high to inter-pret a mechanistic hypothesis Most drugs arenot selective over a large exposure range for asingle molecular target Confident evaluationof a therapeutic hypothesis requires an under-standing of the drugrsquos penetration and kineticswithin the target tissue as well as its potencyand selectivity for specific molecular targetsFurther investigators must consider the con-centration of the unbound fraction of drugthat is available to interact with the targetPublished reports often overlook the fact thatmany small molecules are more than 90bound to plasma or tissue proteins whichgreatly decreases the fraction of drug availableto bind to the intended target Thus in casesin which drug binding has a slow off-rate anorganismrsquos total drug exposure is not a predic-tor of drug available to interact with its target(1) The failure of some academic scientists toobtain relevant pharmacokinetic data impairsthe interpretation of preclinical research resultsand likely contributes to the acknowledgeddifficulties in replicating some academic liter-ature as reported by industry scientists (2 3)
Drug discovery teams in industry settingsroutinely collect pharmacokinetic data to aidin the mechanistic interpretation of in vivopreclinical data and to project optimal dosingparadigms for efficacy and toxicology studiesData required to evaluate brain penetrationare not typically collected by industry-baseddrug-discovery teams for compounds origi-nally developed for therapeutic indicationsthat do not obviously implicate the centralnervous system making this information es-pecially hard to find for many otherwise well-described drugs In addition because mousedata are not required for preclinical toxicologystudies (the more common small animal spe-cies for preclinical toxicology being rats)industry scientists do not often obtain pharma-cokinetic data from mouse experiments These
wwwScienceTranslationalMedicineo
issues are especially relevant for older drugsthat are potentially suitable for repurposingMany older drugs were discovered and char-acterized before routine pharmacokinetic-pharmacodynamic (PK-PD) modeling ofpreclinical drug exposure and its applicationto predicting human dosing became standardpractice Last pharmacokinetic data are notconsidered innovative and these studies gen-erally do not achieve publication in peer-reviewed journals even when the data havebeen generated When such data are pub-lished it is often relegated to the unsearchableblack hole of supplementary materials Thusmouse neuroPK profiles are not readily avail-able for many drugs that are frequently usedin conjunction with mouse models of humanbrain disorders
DOCUMENTING DOSING STRATEGIES
To evaluate the potential impact of insufficientpharmacokinetic data on dose selection in asample of recent published neuroscience liter-ature we conducted an analysis of papersidentified by means of a PubMed search usingthe search terms ldquodrugrdquo and ldquobrainrdquo for the pub-lication year 2014 from eight journals (Table 1)This list was culled to include only primaryresearch reports that included systemic adminis-tration of a pharmacological agent a pharma-cological therapeutic or a biological therapeuticas part of the study design The search yielded100 articles published between 1 January and30 December 2014 that used systemic drug de-livery with the intended goal of targeting thebrain of rodents (table S1) Each publicationwas examined for the stated rationale behindthe dose selection of study drugs (Table 1)
The reported rationale for dosing strategiesfell into several broad categories including(from lowest confidence to highest) (i) dose se-lected rationale not discussed (ii) literaturecitations of another study in which reportsranged from citation of exposure in the samespecies exposure in a different strain or spe-cies a dose conversion from the human liter-ature to rodent or reports of effects on rodentbehavior in another study (iii) demonstrationof an effect on rodent behavior or function inthe current study (iv) demonstration of adose-responsive biological effect in the currentstudy (v) measurement of drug levels in bloodor plasma in the current study and (vi) mea-surement of drug levels in the target organ(that is the brain) in the current study In onlytwo instances were publications identifiedthat considered the impact of drug binding
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to plasma or brain proteins on the free expo-sure of drug available to interact with the tar-get This is a critical flaw in most publishedstudies that use small molecules for functionaleffects in the brain because many centralnervous system (CNS) drugs that penetratethe blood-brain barrier exhibit high proteinbinding leaving a small fraction of the totaldrug measured in plasma or brain unbound
and free to interact with the molecular targetFurthermore most studies used evidence of abiological activity to justify dose selection with-out consideration for how exposure of theagent relates to the potency of the compoundat known molecular targets which would berequired to test a mechanistic hypothesis
The lack of pharmacokinetic considera-tion does not imply that every study used an
wwwScienceTranslationalMedicineo
inappropriate dose of drug to test their hypoth-esis It does illustrate that a clear rationale wasnot provided for dose selection in most pub-lications Furthermore all 11 of the 100 publi-cations that measured total brain exposureincluded an author from the pharmaceutical in-dustry (n=5) an academic drug screening group(n = 3) or a pharmacologyndashpharmaceuticalsciences department (n = 3) This observationlikely reflects the limited presence of pharma-cology and pharmacometrics departmentswithinmost academic institutions and limitedaccess to the mass spectrometry and otheranalytical resources needed to measure druglevels in study samples Outsourcing the bio-analysis of samples collected from study ani-mals is feasible but the use of contract researchorganizations to support such studies is oftentoo costly for most academic grant budgets toaccommodate
DATABASES AND REPURPOSINGRecent years have seen increasing efforts toinvestigate approved or clinically tested drugsfor new indications (4ndash8) Such repurposinghas been touted as a means to accelerate ther-apeutic development (4) For example a stra-tegic pillar of the US National Institutes ofHealthrsquos (NIHrsquos) translational roadmap callsfor the academic community to actively par-ticipate in the repurposing of drugs approvedby the US Food and Drug Administration(FDA) or investigational drugs that havepassed safety hurdles but failed in clinicaltrials because of lack of efficacy (9ndash11) To havea meaningful impact in neurological and psy-chiatric disorders such drug repurposingefforts will require access to neuropharma-cokinetic (neuroPK) data sets in mice to guidethe testing of new therapeutic hypotheses ingenetically engineered disease models A re-cently published consensus evaluation of drugrepositioning opportunities for Alzheimerrsquosdisease identified 15 potential drug candidatesThese were further prioritized for testing onthe basis of available evidence to produce ashortlist of seven compounds reviewed by in-dustry experts to provide insight into the via-bility of these candidates The most commonshortcoming identified for the compoundsconsidered were issues related to insufficientbrain penetration or the lack of informationabout optimal dosing strategies (11)
The repurposing of statins illustrateshow the neuroPK knowledge gap limits progressStatins were developed as 3-hydroxy-3-methylglutarylndashcoenzyme A (HMG-CoA) reduc-tase inhibitors to lower cholesterol and reduce
Table 1 Preclinical dosing strategies The rationale for drug-dosing strategies was extractedfrom the literature through the analysis of 100 peer-reviewed studies published in2014 from eight journals that cover research on mechanisms of brain function disease andtherapeutic approaches to CNS disorders (Cell Neuron Nature Nature Neuroscience NatureMedicine Neurobiology of Disease Neuropsychopharmacology and Science TranslationalMedicine) (table S1) Forty-four of the 100 publications selected were studies of potentialtherapeutic approaches to disease whereas the remaining were studies of basic neurobiology ormechanisms of disease Each publication was examined to discern how authors selected thedosage of pharmacological tools or therapeutic compounds used in the design of studies toprobe brain function A relatively small number of studies considered what the concentrationof drug available in the brain after administration would be in the context of theirexperimental studies The most common method for selecting a dose of drug was tocite a previous study that demonstrated a biological effect of the drug on someaspect of rodent behavior
Rationale for studyrsquos drug-dose selection
Therapeutic
studies
Number of papers from the100 published studies
analyzed
bull No exposure or rationale for dose selection provided
5
22
bull Rodent dose extrapolated from human studies
0
1
bull Doses are similar to what was used previously toproduce a biological effect
8
23
bull Literature reports cited for multiple functionaleffects of drug at selected dose
4
5
bull Brain penetration evaluated but exposure notmeasured
2
2
bull Literature report of mismatched drug exposure
0
1
bull Observation of a biological effect at a single dosein current study
3
6
bull Observation of dose-responsive biological effectin current study
5
16
bull Brain exposure to drug was measured with routeof administration that differed from the oneused in the efficacy study
1
1
bull Plasma drug concentrations measured literaturereport of brain exposure cited and target-organpharmacodynamic effect observed in the currentstudy
1
1
bull Plasma drug concentrations measured
4
7
bull Brain pharmacodynamic effect of drug observed
2
4
bull Brain drug concentrations measured (totalconcentration)
6
7
bull Unbound brain drug concentrations measured
1
2
bull Brain drug concentrations measured and brainpharmacodynamic effect of drug observed
2
2
Total
44
100
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risk of cardiovascular disease (12) FDA hasapproved at least nine different statins andmost are commonly prescribed nearly one-third of Americans ages 55 to 64 took a pre-scription cholesterol-lowering drug between2009 and 2012 (wwwcdcgovnchsdatahushus14pdf) The widespread availability andsafety profile of statins has lured researchersinto evaluating their potential for repurpos-ing (13) Statins have been profiled extensive-ly in preclinical research to test for potentialtherapeutic benefit in Alzheimerrsquos disease(14ndash19) Fragile X syndrome (20) Rett syn-drome (21 22) epilepsy (23) Huntingtonrsquos dis-ease (24) Parkinsonrsquos disease (25 26) stroke(27) and brain injury (28 29)
A search of the literature reveals no sys-tematic neuroPK studies in any mouse strainthat would enable direct comparisons of CNSexposure across the various statins In silicopredictions based on the drugsrsquo molecularproperties suggest that the nine most widelyprescribed statins each have a different poten-tial to penetrate the blood-brain barrier differ-ent potencies against the HMG-CoA reductaseenzyme and different ldquooff-targetrdquo activity pro-files (30) On the basis of available data thereis reason to believe that simvastatin has thebest overall profile for inhibiting HMG-CoAreductase in the brain (30) A recent study re-ported that lovastatin is able to reverse a rangeof phenotypes in a mouse model of Fragile Xsyndrome (20) However the design of an op-timal clinical trial will require the collection ofmouse pharmacokinetic data to understandhow much CNS drug exposure is required toproduce efficacy in the disease model Thereare at least two possible scenarios Giventhat simvastatin is more potent at inhibitingHMG-CoA reductase than are other statinsand likely to be more brain penetrant inboth mice and humans one would expectthat simvastatin will be more potent than lo-vastatin in ameliorating symptoms in bothmice and humans if the observed efficacy stemsfrom inhibition of HMG-CoA reductase activ-ity in the brain by lovastatin The advantage ofthis outcome would be that better brain pen-etration and potency would lead to a loweroverall dose requirement to achieve efficacyand thus likely a better safety profile
A second scenario could be that lovastatin ismore potent than simvastatin in the mousemodel of Fragile X syndrome because of anadditional biological activity inherent to thelovastatinmolecule whichmaynot yet be doc-umented in the literature In either case un-derstanding the CNS exposure of lovastatin
required to produce efficacy in themouse willdetermine whether there is a safe therapeuticindex for achieving the required concentra-tion in patients Previous attempts to discernuseful neuroPK parameters from the litera-ture for the use of statins in rodent modelshave highlighted the lack of critical data asthe looming roadblock to progress in the field(31 32) Until these data exist the transla-tional potential of preclinical research maybe limited And this is but one example ofone drug class
The creation of a centralized database isneeded for the entire translational researchcommunity and would establish a new mech-anism for academia funding agencies founda-tions and industry to pool resources If studiesare donewell the first time and documented inan open-access resource it will reduce redun-dant efforts and improve the quality of decisionmaking by scientists considering innovativesolutions to our biggest health problems
FILL THE GAPSManuscript submission practices for severalhigh-impact journals now include require-ments that authors include detailed informa-tion regarding study design and statisticalanalysis with each submission A reasonableextension of this checklist should includethe stated rationale for doses selected for studydrugs Information should include a discus-sion of data highlighted in Table 2 Authorsshould be expected to reference a relevant
wwwScienceTranslationalMedicineo
data set from a high-quality database or pub-lication or provide the data in the current study(Table 3)
Industry biologists learn basic principlesof medicinal chemistry pharmacokineticsand drug disposition while working on drugdiscovery project teams Academic groupsare playing an increasing role in transla-tional therapeutics and in particular drugrepurposing Academic programs need toaugment training in pharmacokinetics andpharmacodynamics so as to increase the rigor ofpreclinical work and to ensure that investigator-initiated clinical studies are testing hypotheseseffectively Institutions without a departmentof pharmacology or pharmacometrics mightlack the organizational knowledge needed toconduct drug studies and must identify re-sources or collaborators to patch these defi-cits Formal coursework and Web-basedresources and tutorials are needed to train andsupport translational researchers Manuscriptand grant reviewers need to demand higherstandards for preclinical studies with respect toreporting on drug exposure associated withbiological effects Ethics committees responsi-ble for review of animal protocols should re-quire investigators to provide rationale fordose selections in proposed studies Similarlyscientific review boards at academic medicalcenters need to include clinical pharmacologistswho are able to review investigator-initiatedclinical studies to ensure that proposed dosingstrategies will test a meaningful hypothesis
Table 2 Recommendations for use of pharmacokinetic data The first column includes a listof recommended data sets to aid reviewers of submitted articles in the interpretation ofpreclinical findings The second column includes a list of useful reference data that wouldsupport improved preclinical study design in mice if available in a public database
Literature reports that evaluate studydrugs should include
Compound-specific data that shouldbe included in a rodent
pharmacokinetic database
bull Expected or measured plasma exposure of thestudy drug in the preclinical species during thestudy
bull Elimination half-life (T12)bull Systemic clearance (CL)bull Fraction of drug that is protein bound (fb)
bull Expected or measured target organ exposureof the study drugs in the preclinical speciesduring the study
Maximum plasma concentration after drug admin-istration (Cmax) and time to reach maximum plas-ma concentration (Tmax) for a standardized doseand route of administration
bull Expected or measured free fraction (unboundby protein) of the study drugs in the targetorgan of the preclinical species during thestudy
bull The ratio of drug in brain to that in plasma (BP)bull The ratio of drug found free in brain (Cub) to thatfound free in the plasma (Cup) defined as CubCupbull Any potential impact of drug transporters (foundon the rodent blood-brain barrier) in limiting brainexposure
bull Expected or measured potency of the studydrug against the hypothesized activity in vitro
Expected ormeasured potency of molecule at knownbiological targets
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A central repository that contains brainpenetration protein binding and pharmaco-kinetic profiles of drugs and pharmacologicaltools in rodents is needed to effectively sup-port translational research This databaseshould also provide basic tutorials that de-fine primary pharmacokinetic parameterswith examples to illustrate how data are usedto predict optimal dosing strategies The min-imum data set needed for each compoundin a useful rodent database is highlighted inTable 2 Access to this information and sup-porting materials will have an immediateimpact on the quality of translational drug re-purposing efforts across brain disorders andwill support the development of new thera-peutic approaches to neurological disordersand mental illness Existing databases man-aged by NIH or precompetitive consortia couldbe reinforced with donated pharmacokineticdata sets and tutorials
Industry and government scientists shouldwork precompetitively to collect and curatepharmacokinetic data sets in conjunction withsupporting educational materials Mouse phar-macokinetic data exist inside pharmaceuti-cal companies for a wide range of publicallydisclosed molecules and literature standardsRelease of these data into a public databasewould provide several benefits to companiesincluding (i) increased scientific rigor in theliterature with a higher probability of repro-ducibility (ii) increased appreciation by theacademic biology community for the diffi-culty inherent in generating molecules withpotency and pharmacokinetic profiles suit-able for in vivo work opening the door forin-kind collaboration with academic groups
and (iii) direct comparison of data collectedin-house to that collected at other compa-nies or institutions to enable better internalquality control Comprehensive pharmaco-kinetic data sets will benefit all therapeuticareas regardless of whether the brain is thetarget organ because peripheral and cen-tral exposure data can be generated fromthe same experiments Moreover the prin-ciples described above for the CNS apply toother target tissues in which vascular bar-riers metabolic processes or active transportalter the distribution of systemically admin-istered drugs
Key to ensuring that preclinical mousestudies test the hypotheses they aim to eval-uate is an understanding of the unboundfraction of drug present in the target organat an appropriate time point under studyGrant and journal reviewers need to care-fully consider whether authors of propos-als and manuscripts are providing adequaterationale for their choices of preclinical dos-ing paradigms Importantly the collectionand centralization of rodent pharmacoki-netic datasets will promote efficient genera-tion of future data reduce the collection ofredundant data and improve the return oninvestment for research funds that are de-voted to preclinical studies aimed towardclinical translation
SUPPLEMENTARY MATERIALS
wwwsciencetranslationalmedicineorgcgicontentfull8320320ps1DC1Table S1 One hundred publications that used systemic drugdelivery with the goal of targeting rodent brains
wwwScienceTranslationalMedicineo
REFERENCES AND NOTES1 A Reichel Addressing central nervous system (CNS) penetra-
tion in drug discovery Basics and implications of the evolv-ing new concept Chem Biodivers 6 2030ndash2049 (2009)
2 F Prinz T Schlange K Asadullah Believe it or not Howmuch can we rely on published data on potential drugtargets Nat Rev Drug Discov 10 712 (2011)
3 C G Begley L M Ellis Drug development Raisestandards for preclinical cancer research Nature 483531ndash533 (2012)
4 P Nair Second act Drug repurposing gets a boost asacademic researchers join the search for novel uses ofexisting drugs Proc Natl Acad Sci USA 110 2430ndash2432(2013)
5 T I Oprea J Mestres Drug repurposing Far beyond newtargets for old drugs AAPS J 14 759ndash763 (2012)
6 S M Strittmatter Overcoming drug development bot-tlenecks with repurposing Old drugs learn new tricksNat Med 20 590ndash591 (2014)
7 K Xu T R Coteacute Database identifies FDA-approved drugswith potential to be repurposed for treatment of orphandiseases Brief Bioinform 12 341ndash345 (2011)
8 X Bosch European researchers drug companies joinforces against rare diseases JAMA 294 2014ndash2015 (2005)
9 F S Collins Mining for therapeutic gold Nat Rev DrugDiscov 10 397 (2011)
10 P Vallance P Williams C Dollery The future is much closercollaboration between the pharmaceutical industry andacademic medical centers Clin Pharmacol Ther 87525ndash527 (2010)
11 A Corbett J Pickett A Burns J Corcoran S B DunnettP Edison J J Hagan C Holmes E Jones C KatonaI Kearns P Kehoe A Mudher A Passmore N ShepherdF Walsh C Ballard Drug repositioning for Alzheimerrsquosdisease Nat Rev Drug Discov 11 833ndash846 (2012)
12 J L Goldstein M S Brown A century of cholesterol andcoronaries From plaques to genes to statins Cell 161161ndash172 (2015)
13 A M Malfitano G Marasco M C Proto C Laezza P GazzerroM Bifulco Statins in neurological disorders An overviewand update Pharmacol Res 88 74ndash83 (2014)
14 T Kurata K Miyazaki M Kozuki N Morimoto Y OhtaY Ikeda K Abe Progressive neurovascular disturbances inthe cerebral cortex of Alzheimerrsquos disease-model miceProtection by atorvastatin and pitavastatin Neuroscience197 358ndash368 (2011)
15 H Kurinami N Sato M Shinohara D Takeuchi S TakedaM Shimamura T Ogihara R Morishita Prevention ofamyloid beta-induced memory impairment by fluvastatinassociated with the decrease in amyloid beta accumulationand oxidative stress in amyloid beta injection mousemodel Int J Mol Med 21 531ndash537 (2008)
16 M Shinohara N Sato H Kurinami D Takeuchi S TakedaM Shimamura T Yamashita Y Uchiyama H RakugiR Morishita Reduction of brain beta-amyloid (Abeta)by fluvastatin a hydroxymethylglutaryl-CoA reductaseinhibitor through increase in degradation of amyloidprecursor protein C-terminal fragments (APP-CTFs) andAbeta clearance J Biol Chem 285 22091ndash22102 (2010)
17 G J Siegel N B Chauhan D L Feinstein G Li E B LarsonJ C Breitner T J Montine Statin therapy is associated withreduced neuropathologic changes of Alzheimer diseaseNeurology 71 383 author reply 383 (2008)
18 X-K Tong C Lecrux P Rosa-Neto E Hamel Age-dependentrescue by simvastatin of Alzheimerrsquos disease cerebrovascularand memory deficits J Neurosci 32 4705ndash4715 (2012)
19 X K Tong N Nicolakakis P Fernandes B Ongali J BrouilletteR Quirion E Hamel Simvastatin improves cerebrovascularfunction and counters soluble amyloid-beta inflammationand oxidative stress in aged APP mice Neurobiol Dis35 406ndash414 (2009)
Table 3 Recommendations to improve translation through the use of preclinicalpharmacokinetic data
Journalsbull Require authors to provide explicit rationale for dosing strategies usedbull Rationale should include consideration of the unbound drug exposure in target organas best practices
Educationbull Include basic pharmacology and pharmacokinetic principles in formal coursework requiredfor basic preclinical and clinical research scientists
bull Develop tutorials and on-line calculators for rodent dose projections to support appropriateuse of published pharmacological tools
Databasesbull Reinforce public chemical databases with mouse pharmacokinetic data that includes brainexposure
Precompetitive consortiabull Create precompetitive consortia to solicit mouse pharmacokinetic data sets from industry andfoundation partners for database expansion
bull Targeted data collection for compounds already in the public domain
rg 6 January 2016 Vol 8 Issue 320 320ps1 4
P ER SP EC T I V E
20 E K Osterweil S C Chuang A A Chubykin M SidorovR Bianchi R K Wong M F Bear Lovastatin corrects ex-cess protein synthesis and prevents epileptogenesis in amouse model of fragile X syndrome Neuron 77 243ndash250(2013)
21 C M Buchovecky S D Turley H M Brown S M KyleJ G McDonald B Liu A A Pieper W Huang D M KatzD W Russell J Shendure M J Justice A suppressorscreen in Mecp2 mutant mice implicates cholesterol me-tabolism in Rett syndrome Nat Genet 45 1013ndash1020(2013)
22 M J Justice C M Buchovecky S M Kyle A Djukic A rolefor metabolism in Rett syndrome pathogenesis Newclinical findings and potential treatment targets RareDis 1 e27265 (2013)
23 F Scicchitano A Constanti R Citraro G De Sarro E RussoStatins and epilepsy Preclinical studies clinical trials andstatin-anticonvulsant drug interactions Curr Drug Targets16 747ndash756 (2015)
24 M L Ferlazzo L Sonzogni A Granzotto L Bodgi O LartinC Devic G Vogin S Pereira N Foray Mutations of theHuntingtonrsquos disease protein impact on the ATM-dependentsignaling and repair pathways of the radiation-inducedDNA double-strand breaks Corrective effect of statins andbisphosphonates Mol Neurobiol 49 1200ndash1211 (2014)
25 E K Tan L C Tan Holding on to statins in Parkinsondisease Neurology 81 406ndash407 (2013)
26 B Friedman A Lahad Y Dresner S Vinker Long-termstatin use and the risk of Parkinsonrsquos disease Am J ManagCare 19 626ndash632 (2013)
27 M S Elkind Stroke A step closer to statin therapy forstroke Nat Rev Neurol 9 242ndash244 (2013)
28 E E Abrahamson M D Ikonomovic C E Dixon S T DeKoskySimvastatin therapy prevents brain trauma-inducedincreases in beta-amyloid peptide levels Ann Neurol66 407ndash414 (2009)
29 E F Wible D T Laskowitz Statins in traumatic brain injuryNeurotherapeutics 7 62ndash73 (2010)
wwwScienceTranslationalMedicineo
30 S Sierra M C Ramos P Molina C Esteo J A VaacutezquezJ S Burgos Statins as neuroprotectants A comparativein vitro study of lipophilicity blood-brain-barrier penetra-tion lowering of brain cholesterol and decrease of neuroncell death J Alzheimers Dis 23 307ndash318 (2011)
31 W G Wood G P Eckert U Igbavboa W E Muumlller Statinsand neuroprotection A prescription to move the fieldforward Ann N Y Acad Sci 1199 69ndash76 (2010)
32 W G Wood W E Muumlller G P Eckert Statins and neuro-protection Basic pharmacology needed Mol Neurobiol50 214ndash220 (2014)
101126scitranslmedaac9888
Citation R J Kleiman M D Ehlers Data gaps limit thetranslational potential of preclinical research Sci Transl Med8 320ps1 (2016)
D
rg 6 January 2016 Vol 8 Issue 320 320ps1 5
on January 6 2016httpstm
sciencemagorg
ownloaded from
101126scitranslmedaac9888] (320) 320ps1 [doi8Science Translational Medicine
Robin J Kleiman and Michael D Ehlers (January 6 2016) Data gaps limit the translational potential of preclinical research
Editors Summary
This information is current as of January 6 2016 The following resources related to this article are available online at httpstmsciencemagorg
Article Tools
httpstmsciencemagorgcontent8320320ps1article tools Visit the online version of this article to access the personalization and
s sitesScienceThe editors suggest related resources on
PermissionshttpwwwsciencemagorgaboutpermissionsdtlObtain information about reproducing this article
is a registered trademark of AAASMedicineScience TranslationalAssociation for the Advancement of Science all rights reserved The title
Science 1200 New York Avenue NW Washington DC 20005 Copyright 2016 by the Americanweekly except the last week in December by the American Association for the Advancement of
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nloaded from
Boston Childrenrsquos Hospital ndash Broad Institute Collaboration Grants
Background Meeting the challenges of biomedicine requires bringing together creative scientists exceptional technological resources and world-class expertise across many disciplines that rarely exist within a single institution This guiding principle is the basis for a funding opportunity to support Boston Childrenrsquos Hospital investigators performing research in collaboration with Broad scientists
Goals The fundamental goal of this new award is to spark new collaborations between Boston Childrenrsquos Hospital and the Broad Institute The grants will be awarded to address a very wide range of scientific questions but are specifically designated for projects with the following characteristics
middot Projects where engagement with the Broad would benefit Childrenrsquos Hospital investigators projects that can uniquely benefit from being done at the Broad Institute
middot Projects that create new scientific collaborations and bring together diverse scientific backgrounds projects that spark new scientific directions or technologies and are not currently being pursued at Childrenrsquos Hospital
middot Projects that pilot new approaches that researchers at Childrenrsquos the Broad and the greater scientific community can benefit from in the future the purpose of these awards is not to provide gap or extension funding of existing projects but to initiate new projects
Eligibility Individuals with Principal Investigator status at Boston Childrenrsquos Hospital are eligible Applicants need not be Associate Members of the Broad Institute
Broad Platforms and Scientists Broadrsquos Platforms (Genomics Imaging Metabolite Profiling Proteomics Genomic Perturbation and the Broad Technology Labs) are collaborative organizations that provide scientific leadership and cutting edge technologies in support of project goals Collaborations can also be established with other groups at the Broad including the Klarman Cell Observatory the Stanley Center for Psychiatric Research or the Center for the Development of Therapeutics
Budgets Grants will provide $60000 direct support for 1 year plus philanthropic overhead It is expected that most grants will fund work performed at the Broad Institute either through interaction with Broadrsquos Platforms or via collaboration with a Broad scientist however the work may also occur at Boston Childrenrsquos if it is important to meet the scientific goals of the collaboration
Deadline and Review process Final proposals are due by September 1 2015 Funding decisions are expected to be reached by October 1 2015 Proposals will be reviewed by a joint Childrenrsquos HospitalndashBroad Institute committee Additional submission dates are expected for 2016
Submission Applicants are strongly encouraged to discuss potential applications in advance with the office of the Chief Scientific Officer at the Broad Questions should be directed to Alex Burgin ( 617-714-7124)
Proteomics Genomic Perturbation and the Broad Technology Labs) are collaborative
organizations that provide scientific leadership and cutting edge technologie
s in support of
project goals Collaborations can also be established with other groups at the Broad including
the Klarman Cell Observatory the Stanley Center for Psychiatric Research or the Center for the
Development of Therapeutics
Budgets
Grants wi
ll provide $60000 direct support for 1 year plus philanthropic overhead It
is expected that most grants will fund work performed at the Broad Institute either through
interaction with Broadrsquos Platforms or via collaboration with a Broad scientist howev
er the
work may also occur at Boston Childrenrsquos if it is important to meet the scientific goals of the
collaboration
Deadline and Review process
Final proposals are due by September 1 2015 Funding
decisions are expected to be reached by October 1 201
5 Proposals will be reviewed by a joint
Childrenrsquos Hospital
ndash
Broad Institute committee Additional submission dates are expected for
2016
Submission
Applicants are
strongly encouraged to discuss potential applications in
advance
with the office of the Chief Sc
ientific Officer at the Broad
Questions should be
directed to Alex Burgin (
aburginbroadinstituteorg
617
-
714
-
7124
)
Boston Childrenrsquos Hospital ndash Broad Institute Collaboration Grants
Background Meeting the challenges of biomedicine requires bringing together creative
scientists exceptional technological resources and world-class expertise across many
disciplines that rarely exist within a single institution This guiding principle is the basis for a
funding opportunity to support Boston Childrenrsquos Hospital investigators performing research
in collaboration with Broad scientists
Goals The fundamental goal of this new award is to spark new collaborations between Boston
Childrenrsquos Hospital and the Broad Institute The grants will be awarded to address a very wide
range of scientific questions but are specifically designated for projects with the following
characteristics
Projects where engagement with the Broad would benefit Childrenrsquos Hospital
investigators projects that can uniquely benefit from being done at the Broad Institute
Projects that create new scientific collaborations and bring together diverse scientific
backgrounds projects that spark new scientific directions or technologies and are not
currently being pursued at Childrenrsquos Hospital
Projects that pilot new approaches that researchers at Childrenrsquos the Broad and the
greater scientific community can benefit from in the future the purpose of these awards
is not to provide gap or extension funding of existing projects but to initiate new
projects
Eligibility Individuals with Principal Investigator status at Boston Childrenrsquos Hospital are
eligible Applicants need not be Associate Members of the Broad Institute
Broad Platforms and Scientists Broadrsquos Platforms (Genomics Imaging Metabolite Profiling
Proteomics Genomic Perturbation and the Broad Technology Labs) are collaborative
organizations that provide scientific leadership and cutting edge technologies in support of
project goals Collaborations can also be established with other groups at the Broad including
the Klarman Cell Observatory the Stanley Center for Psychiatric Research or the Center for the
Development of Therapeutics
Budgets Grants will provide $60000 direct support for 1 year plus philanthropic overhead It
is expected that most grants will fund work performed at the Broad Institute either through
interaction with Broadrsquos Platforms or via collaboration with a Broad scientist however the
work may also occur at Boston Childrenrsquos if it is important to meet the scientific goals of the
collaboration
Deadline and Review process Final proposals are due by September 1 2015 Funding
decisions are expected to be reached by October 1 2015 Proposals will be reviewed by a joint
Childrenrsquos HospitalndashBroad Institute committee Additional submission dates are expected for
2016
Submission Applicants are strongly encouraged to discuss potential applications in
advance with the office of the Chief Scientific Officer at the Broad Questions should be
directed to Alex Burgin (aburginbroadinstituteorg 617-714-7124)
Clinical Trials Glossary
ADME an acronym for absorption distribution metabolism and elimination ADME
studies determine how a drug is absorbed by the body the chemical changes that it may
undergo and how it is eliminated from the body
Adverse event (AE) a bothersome event that occurs in a study participant AEs may be
related to the treatment being tested or may be due another cause (eg another treatment
another medical condition an accident or a surgery)
Arm a specific type of treatment to which a group of clinical trial participants is
assigned Some clinical trials have one arm and some have two arms while others have
three or more arms For example a clinical trial comparing two different doses of an
investigational drug versus a placebo would have three arms participants receiving a
higher dose of the investigational drug participants receiving a lower dose of the
investigational drug and participants receiving the placebo
Baseline a point in time at the beginning of a clinical trial before the study participants
receive any treatment At the baseline participants usually have certain types of tests
During and after treatment the same tests may be performed and the results compared
with the baseline results to see if the drug has caused changes
Bias a factor ndash such as a preconceived idea about the effects of the benefits and risks of a
treatment or a lack of balance in selection of patients for a study ndash that reduces the
likelihood that the study results are true Methods such as blinding and randomization
are used to limit the potential for bias
Bioavailability the portion of the dose of a drug that reaches the bloodstream For
example if the drug is administered intravenously its bioavailability is 100 percent
however if the drug is administered in any other way such as orally topically or
through intramuscular injection its bioavailability will decrease due to incomplete
absorption
Bioequivalence study a test performed to compare the portion of a drug in the
bloodstream when administered in different dosage forms
Biologic product any substance that can be used in prevention treatment or cure of
disease Some examples include vaccines blood virus toxin antitoxin and therapeutic
serum
Biopsy the removal of cells or tissue from a patient for examination which is usually
done under a microscope A tissue sample might be taken for genetic studies Sometimes
there is a difference between the blood genotype and the skin or other tissue genotype
This term can also refer to the tissue sample that has been obtained by such a procedure
2
Blinding a process used to prevent the participants the researchers or both from
knowing what specific treatment is being given to participants in a clinical trial The
process of blinding helps to reduce bias because study participants and researchers are
less likely to be unconsciously influenced by the knowledge of what the study participant
is actually receiving If only the participants are blinded the study is called a single-
blind study If both participants and researchers are blinded the study is called a double-
blind study
Carcinogenicity studies long-term studies conducted in animal models to determine a
drugrsquos likelihood of causing cancer
Clinical efficacy a compoundrsquos ability to produce the desired effect
Clinical pharmacology a science that studies properties of drugs in relation to their
therapeutic value in humans
Clinical study or Clinical trial a medical experiment in human beings that helps to
determine how a disease drug or medical device affects study participants Clinical
studies are necessary to answer specific questions about how to better diagnose prevent
or treat a disease or condition
Cohort a group of study participants who have certain characteristics in common such
as female sex a defined age range or particular severity of disease Dividing study
participants into cohorts is often done as part of the analyses of study data
Contraindication a factor that makes the use of a particular drug inadvisable For
example a person who has had an allergic reaction to penicillin in the past is considered
to have a contraindication to using penicillin in the future
Control group a group of participants not receiving the investigational drug but instead
receiving a standard treatment for their disease or receiving a placebo The results
observed in the group of patients receiving the investigational drug are compared with the
results observed in the control group
Crossover study a study design with two or more arms where participants receive one
treatment for a period of time and then switch over to a second treatment for a period of
time Such a study design allows the effects of the two treatments to be compared in the
same patient
Data Monitoring Committee (DMC) or Data Safety and Monitoring Board (DSMB)
A committee of experts that periodically reviews the accumulating data from an ongoing
multicenter clinical trial Members of a DMCDSMB must be independent ie they
cannot be participating as investigators in the clinical trial Based on their review the
DMCDSMB experts advise the sponsor regarding whether it is safe and acceptable to
continue with the study or whether the data suggest that the study should be modified or
stopped A DMCDSMB may recommend that a trial be stopped if there are safety
concerns or if the trial objectives have been achieved
3
Dose-ranging study a clinical trial in which two or more doses of an investigational
drug are tested to determine which dose is likely to offer the best combination of safety
and efficacy in later clinical trials or in medical care
Efficacy or effectiveness the ability of a drug to prevent cure or slow a disease process or to alleviate the symptoms of a disease or condition
Eligibility a determination made during the screening period for a clinical study of
whether a personrsquos participation in the trial is likely to be safe and can contribute data
that will help achieve the study goals
Endpoint occurrence of a disease symptom sign or test result that constitutes one of the
target outcomes of a clinical trial
Inclusionexclusion criteria the factors defined in the protocol of a study that determine
whether a personrsquos participation in a clinical trial is likely to be safe and can contribute
data that will help achieve the study goals Study candidates undergo evaluation during
the study screening period to determine if they meet all of the inclusion criteria and do
not meet any of the exclusion criteria as defined in the protocol These criteria usually
consider such factors as age sex type of disease stage of disease previous treatment
history and other medical conditions in determining eligibility for the study
Informed consent (assent) a process by which medical researchers provide necessary
information to a person about a clinical study and the person voluntarily confirms his or
her willingness to participate in the study Children who are considered old enough to
have a basic understanding of the study may need to provide assent to be involved in the
study a parent or legal guardian must also give informed consent for such a child to
participate
Informed consent (assent) form a document that describes a clinical study to the
participants (or their parentsguardians) The informed consent (assent) form includes
information about the goals of the study the study design and duration the types of tests
to be performed the potential risks and inconveniences the potential benefits the
possible costs or payments associated with study participation the available alternative
therapies the rights and responsibilities of the participant and the people to contact if the
participant has questions The informed consent (assent) form must be reviewed and
signed before the participant has any study tests or treatment including the tests
performed during the screening period at the beginning of the study Participants are
given a copy of the informed consent (assent) form to take home
Institutional Review Board (IRB) or Independent Ethics Committee (IEC) a board
of physicians statisticians researchers community advocates and others who are
responsible for ensuring the protection of the rights safety and well-being of participants
in a clinical trial at a study center This board is called an IRB in the United States and is
often called an IEC in other countries IRBIECs review and approve important study
documents (eg protocols informed consent forms study advertisements and patient
4
brochures) before the start of the study and periodically review the progress of the study
while it is ongoing
Investigational Drug a drug that is being tested as a potential treatment for a disease or
condition but has not yet been proven safe and effective for that use
Investigator a physician or other health care worker who carries out a clinical trial by enrolling treating and monitoring participants and recording the results
In vitro testing testing conducted in test tubes or other artificial environments
In vivo testing testing conducted in living animals or humans
Longitudinal study a clinical study that involves observations of the same items over
long periods often many decades Because longitudinal studies track the same people
they are often used to study trends across the life span to uncover predictors of certain
diseases or to track the effects of a particular treatment on a patientrsquos condition over
time
Multicenter study a study conducted at more than one location Multicenter clinical
studies are generally performed when each individual clinical trial site does not have
enough study candidates to complete a large trial
Natural history study a study of the natural development of a disease or condition over
a period of time Natural history studies are usually longitudinal studies
New Drug Application (NDA) the registration document through which a
pharmaceutical company formally proposes that the FDA approve a new drug for
manufacturing and sale The application includes detailed reports of pharmacology
toxicology manufacturing and chemistry as well as data from clinical trials
Open-label study a study in which the participants and the investigators know which
treatment is being given In an open-label study there is no blinding and none of the participants receives a placebo
Orphan disease a disease or condition that affects a relatively small number of people
In the US this defined as fewer than 200000 people In Europe this is defined as fewer
than five in 110000 people
Orphan drug a drug intended to treat an orphan disease
Participant or subject a patient or healthy volunteer who participates in a clinical trial
Phase 1 the initial phase of testing of an investigational drug in humans Usually a
Phase 1 clinical study is conducted in a small number of healthy volunteers or patients
with a disease for which the drug may be useful Generally the study is designed to
determine the side effects of the drug and its pharmacokinetics Some information
5
regarding drug efficacy may be collected if patients with a disease participate A phase
frequently encompasses more than one clinical trial Phase 1 sometimes is sub-divided
into Phases 1a and 1b for example when the first set of Phase 1 trials (Phase 1a) is
performed in healthy volunteers and a second set of Phase 1 trials (Phase 1b) is
performed in patients with a disease
Phase 2 the intermediate phase of testing of an investigational drug in humans Usually
a Phase 2 clinical study conducted in patients with a disease for which the drug may be
useful Generally the study is designed to evaluate dosing to obtain preliminary data on
the effectiveness of the drug and to acquire more safety information Phase 2 sometimes
is sub-divided into Phases 2a and 2b Phase 2a studies typically are smaller and shorter
in duration and evaluate different drug doses to see how they affect certain tests that can
indicate whether the drug is working as expected Phase 2b studies typically enroll more
patients are of longer duration and evaluate whether the drug is offering clinical benefits to patients Phase 2b studies sometimes are considered pivotal or registration-directed
Phase 3 the final phase of testing an investigational drug in humans before regulatory
approval Phase 3 studies are usually conducted in a large population of patients and are
generally designed to confirm the effectiveness of the drug and to evaluate the overall
risk-benefit ratio Phase 3 studies usually test the investigational drug in comparison with
a standard treatment for the disease or a placebo
Phase 4 testing of a drug in humans after it has already been approved by regulatory
authorities and can be used in medical practice Phase 4 studies may be conducted to
compare the drug to a similar type of drug to explore whether it may help patients with
other diseases to further study the long-term safety of the drug or for other reasons
Pivotal study a study that is designed to generate the data required by regulatory
authorities to decide whether to approve an investigational drug A pivotal study is
usually a large randomized Phase 2b or Phase 3 study and often is blinded and uses a
placebo as a control Sometimes a pivotal study is described as a registration-directed
study
Placebo an inactive version of an investigational drug A placebo has a similar
appearance to the investigational drug but is expected to have no therapeutic value A
placebo is used as a comparison treatment to reduce bias in randomized studies
Preapproval access program an umbrella term for programs that allow seriously ill
patients to receive an investigational drug when they are unable to participate in clinical
trials and there is no alternative treatment This is sometimes referred to as
compassionate use Types of pre-approval access programs include expanded access
parallel-track named patient program single-patient exemption and treatment IND The
timing for starting an expanded access program usually depends upon what is known
about the risk-benefit of the drug and whether the drug can be provided in a manner that
is fair to patients with the disease
6
Preclinical (nonclinical) testing testing of a drug in test tubes or in animals A drug
undergoes preclinical testing before being tested in humans to make sure that it shows
evidence of desired effects and is sufficiently safe for study in people Preclinical testing
sometimes also helps to determine the doses of the drug that should be evaluated in
humans Preclinical testing is sometimes called nonclinical testing
Protocol a document describing what types of people may participate in a clinical study
and the objectives treatments measurements statistical methods timing and
organization of a clinical trial The protocol must be prepared in advance of the study
and must be reviewed and approved by review committees and regulatory authorities
before the study is started Investigators must follow the protocol to carry out the study
Randomization assignment of participants to treatment arms based on chance This is
usually done by a computer program in a way that does not allow either the participants
or the investigators to choose who is assigned to which arm Randomization is used to
reduce bias in clinical trials
Risk-benefit ratio the balance of the risk of side effects expected with use of a drug
versus the potential for benefit with the use of that drug A drug with a good risk-benefit
ratio has few side effects and is very effective
Serious adverse event (SAE) an adverse event that is life-threatening requires inpatient
hospitalization or lengthens a hospital stay leads to substantial disability leads to a birth
defect or results in death
Side effect any effect of a drug other than the desired effect Side effects are often
unwanted and may be bothersome Other names for a bothersome side effect are adverse
drug reaction (ADR) or drug toxicity
Screening period a period at the beginning of a clinical trial when candidates for the
study are evaluated to determine if their participation is likely to be safe and can
contribute data that will help achieve the study goals
Significant or statistically significant an outcome in a clinical trial is likely to result
from a real difference (eg due to an effect of a treatment) and is unlikely to be due to
chance alone The level of statistical significance is often expressed in terms of a p-
value which indicates the probability that a difference is not due to chance alone
Usually a p-value smaller 005 is considered statistically significant
Sponsor the organization responsible for financing and coordinating a clinical trial
Most often this is a pharmaceutical or biotechnology company
Standard treatment a treatment currently in wide use often approved by regulatory
agencies and generally considered effective in the treatment of a specific disease or
condition
7
Toxicity a side effect produced by a drug that is bothersome to the person taking the
drug
Toxicology the study of the adverse effects of chemicals conducted in animal models to
predict potential adverse effects in humans Some studies are conducted during clinical
development to evaluate dosing regimens
Boston Childrenrsquos Hospital Clinical Research Map 1 Mouse over for additional info Bold = hyperlink
CLINICAL RESEARCH MAP
Boston Childrenrsquos Hospital Clinical Research Map 2 Mouse over for additional info Bold = hyperlink
ObjectiveThis clinical research map is designed to serve as a guide for investigators study coordinators and research nurses at Boston Childrenrsquos Hospital The research map outlines the key steps in preparing to launch a research study and provides embedded links to institutional resources tools and documents
An investigator need not follow the steps on the Clinical Research Map in any particular order There is flexibility and the steps followed will in part de-pend on the type of research study
For new as well as more experienced investigators the Clinical Research Map can be used as a checklist or an inves-tigator can use the steps on the map as points for consideration as they are developing a protocol and launching a study
This tool is not intended to substitute for the important collaboration be-tween a junior investigator and a senior investigatormentor A senior investiga-tor plays a pivotal role in coaching and advising a junior investigator regarding the many subtleties and variations that apply to designing and implementing a protocol
This process map cannot be inclusive of every possible task or step but is intended as a general guide for investi-gators and their study teams
ResourcesThere are many institutional resources at Boston Childrenrsquos Hospital designed to support investigators and their clini-cal research teams In addition to links to resources tools and documents that are embedded in the steps of the clini-cal research map the last page of this document contains website addresses that will take you to additional helpful institutional resources
Acknowledgements Cindy Williams DNP RN PNP NE-BC Nursing Director CTSU Clinical Research Nursing
Ellen McGrath MSN RN CPNP Nurse Practitioner Department of Surgery
Grace Yoon MSN RN CNNP Research Nurse Department of Ophthalmology
Laura Feloney BA Lab Technician
ContentsOverview Four stages 3
1st Stage Protocol development 4
1st Stage Protocol development contrsquod 5
2nd Stage Implementation planning 6
3rd stage Study launch7
4th stage Statistical analysis reporting and dissemination 8
Discarded specimens Additional steps 9
Chart review Steps if you are completing a chart review 10
Appendix A Resources for researchers 11
Boston Childrenrsquos Hospital Clinical Research Map 3 Mouse over for additional info Bold = hyperlink
Overview Four stages
Protocol development
Implementation planning
Study launch
Statistical analysis reporting and dissemination
1
2
3
4
Boston Childrenrsquos Hospital Clinical Research Map 4 Mouse over for additional info Bold = hyperlink
1st Stage Protocol development
Explore resources
CRIT
CRC
EQuIP
CTSU
Harvard Catalyst
Complete training
CITI training
EQUiP
Consult research pharmacistResearch Pharmacy
Rocco Anzaldi
Consult statistician
CRC
Draft a protocol
Protocol guidelines
Study personnel
FDA Guidance for Investigators
Consult Clinical Research Center
CRC
Bio Bank
Start IRB application
TransLab
Consider applying for grants
securing funding
Office of Sponsored Programs
If INDIDE application to FDA
Does my study need an INDIDE
Regulatory resources
Arrange a consultation with
CRIT
ConsultationTasks for investigators and study teams
Boston Childrenrsquos Hospital Clinical Research Map 5 Mouse over for additional info Bold = hyperlink
Respond to IRB questionsrequests
for clarification
1st Stage Protocol development contrsquod
Departmental Scientific Review
Organize DSMB design DSMP
DSMPDSMB
Templates for Research Study
Documents and Tools
Study Templates and Tools
Investigators who sponsor an FDA regulated trial
ClinicalTrialsgov
Create regulatory binder
Regulatory Binder Template
Submit the grant application to OSP
OSP
TIDO
CTBO
Consult Office Intellectual Property
Technology and Innovation
Development Office
TIDO
IRB approval
Consider blood volume for research
Research blood volume policy
Confidentiality plan
Confidentiality guidelines
Boston Childrenrsquos Hospital Clinical Research Map 6 Mouse over for additional info Bold = hyperlink
Develop Case Report Forms
(CRFs)
CRF guidelines
Establish electronic shared
folder or study binder for study
documents
CRIT
Set date for trial launch
Develop fast fact sheet for bedside staff
Consult programmer re database
CRIT
Research study resource manual
for the clinical unit
Confirm study drug
in pharmacy
Rocco Anzaldi
Clarify system for screening
and enrolling patients
Recruitment guideline
Updated protocol to
nurse manager
Consult MDsNPs on unitclinic
2nd Stage Implementation planning
Tasks for investigators and study teams
Study logistics Documentation logistics
Data storage
Confidentiality plan
Confidentiality guidelines
Create study orderset
Consider blood volume for research
Research blood volume policy
Create Manual of Operations
MOO Guide
Study implementation
meeting
Develop study logstools
EQUIP
Finalize tracking sheet
Research Administration
Fernando Valles
Boston Childrenrsquos Hospital Clinical Research Map 7 Mouse over for additional info Bold = hyperlink
3 Document informed consent
Informed Consent
Consent library
Schedule weekly study team meeting
Communicate to department faculty
and multidisciplinary
team announcing trial launch
Steps before trial launch
3rd stage Study launch
Patient flow
1 Seek permission
to approach potential subjects
2 Screenenroll
patients
EQUIP
5 Send Study
Tracking Sheet (STS)
6 Collection of
patient data and assessing for
adverse events
7 Study
documents and data handling
4 Datetime study tests
Create a checklist outlining study action items for each subject
Boston Childrenrsquos Hospital Clinical Research Map 8 Mouse over for additional info Bold = hyperlink
Annual IRB Report
Annual Progress ReportStaff Report
raquo Maintain Interest of Staff
raquo Important to See Study Progress
Write Abstract
Dissemination of Research Results
raquo Conference raquo Internal Presentation for Colleagues
raquo Publication
Plan DSMB MeetingInterim
Analysis
4th stage Statistical analysis reporting and dissemination
Data Entry
When Enrollment Complete Data
Cleaning
Monitor Subjects to Identify
Adverse Events (CCI sponsor
DSMB)
Report Adverse Events
Update MOO Based on Experience
with First Several Patients Enrolled
Weekly Study Team Meeting
Report study findings to
subjects and stakeholders
Data management Trial management
Reporting Dissemination
Regular Review of Data
to Identify Deviations
and Workflow Improvements
Consult Statistician When Approaching Target Enrollment
Discarded specimens Additional steps
Boston Childrenrsquos Hospital Clinical Research Map 9 Mouse over for additional info Bold = hyperlink
Send IRB Approval to lab manager
Maureen Samson
Educate staff in areasunits about sample collection
Locate the discarded samples
Locate the accession number in PowerChart
Retrieve specimen
Mark Kellogg
Follow Shipping Rules and Procedures
IATAShipping with dry ice instructions
Communicate with laboratory staff
Contact Dr Mark Kellogg to discuss specimen retrieval
Consult with Biorepository
Biorepository
Chart review Steps if you are completing a chart review
Boston Childrenrsquos Hospital Clinical Research Map 10 Mouse over for additional info Bold = hyperlink
7 8
4321
Databaserecord review guidelines
5 6
Consult programmer re database
CRC Request
Respond to IRB questions
requests for clarification
Departmental Scientific Review
Complete training
CITI Training
Draft a protocol
Protocol Guidelines
Prepare IRB Application
Information about the CCI
IRB Application
Develop Case Report Forms (CRFs)
CRF Guidelines
IRB Review
Boston Childrenrsquos Hospital Clinical Research Map 11 Mouse over for additional info Bold = hyperlink
Clinical Research Center (CRC) x84720
Committee on Clinical Investigation (CCI IRB) x57052
Research Pharmacist x52014
Clinical and Translational Science Unit (CTSU) x57541
Education and Quality Improvement Program (EQUIP) x57052
Clinical Trials Office Central Budgeting x4-2714
Office of Sponsored Programs x4-2723
Technology and Innovation Development Office 617-919-3079
Research Finance x8-3517
Harvard Catalyst 617-432-7810
Regulatory Affairs x4-2777
Appendix A Resources for researchers
RES_4446_ClinicalResearchMap-FINAL FOR LINKS 1
RES_4446_ClinicalResearchMap-FINAL FOR LINKS 10
Overview Four stages
1st Stage Protocol development
1st Stage Protocol development contrsquod
2nd Stage Implementation planning
3rd stage Study launch
4th stage Statistical analysis reporting and dissemination
Discarded specimens Additional steps
Chart reviewSteps if you are completing a chart review
Appendix A Resources for researchers
RES_4446_ClinicalResearchMap-FINAL FOR LINKS 11
RES_4446_ClinicalResearchMap-FINAL FOR LINKS 2
RES_4446_ClinicalResearchMap-FINAL FOR LINKS 3
RES_4446_ClinicalResearchMap-FINAL FOR LINKS 4
RES_4446_ClinicalResearchMap-FINAL FOR LINKS 5
RES_4446_ClinicalResearchMap-FINAL FOR LINKS 6
RES_4446_ClinicalResearchMap-FINAL FOR LINKS 7
RES_4446_ClinicalResearchMap-FINAL FOR LINKS 8
RES_4446_ClinicalResearchMap-FINAL FOR LINKS 9
RES_4446_ClinicalResearchMap-PAGE 5pdf
Overview Four stages
1st Stage Protocol development
1st Stage Protocol development contrsquod
2nd Stage Implementation planning
3rd stage Study launch
4th stage Statistical analysis reporting and dissemination
Discarded specimens Additional steps
Chart reviewSteps if you are completing a chart review
Appendix A Resources for researchers
Next Page
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Button 111
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MOUSE OVER
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Page 98
COVER BUTTON
Previous Page
Page 118
Page 2
Page 31
Page 63
Page 74
Page 85
Page 96
Page 1
Button 91
Button 92
Button 94
IRB review
Button 102
Develop Case Report Forms
Button 136
Consult clinical research center
INDIDE 1
Explore resources
Button 1016
Bio Bank p
4
Consult statistician
Consult research pharmacist
Study personnel
Complete training
Consider grantsfunding
Draft a Protocal 2
Arrange a consutlations with CRIT
Next Page 1
Previous Page 1
TransLab
Start IRB application 3
Develop study logs
Updatedd protocol
Confirm study drug
Establish electronic shared
COnsult programmer
Clarify system
Research study resrouce manual
Develop case report forms
MOO
Set date for trial launch
Button 44
Study implementation meeting
Finalize tracking sheet
Data storage
Confidentiality
Blood volume 3
Develop fast fact
Consult MDs
Schedule weekly
Communicate early
Button 71
Screenenroll patients
Document informed consent
Datetime tests
Send study tracking sheets
Collection patient data
Button 77
Dissemination
Button 87
Button 124
Button 125
Communicate with lab staff
Button 106
Button 109
Button 1010
Shipping page 9
Button 1012
Button 99
Button 133
Button 134
Button 135
Biorepository
Locate assession number
Retrieve specimen
Button 30
Consult office
Negotiate Contract
Organizing DSMB
Submit Grant
Respond to IRB questions
Button 66
Create regulatory binder
Templates for research stufy
Clinical Trials Business Office
Blood volume 2
Confidentiality plan
Investigators who sponsor
clinicaltrials
gov
BPN Project
Drug Discovery amp Development Testing Funnel
Tier 1 2 3
Tier 6 7 8
Tier 5
Tier 4
Example Drug Discovery amp Development Testing Funnel
Cytotoxicity
Grant
Project
Example Drug Discovery amp Development Testing Funnel
TIER 1A ndash Primary Screen
Chemical purity and identity of active compounds
Primary bioactivity screen
Cell viability (When Appropriate)
ScaffoldsMoiety Chemical liabilities (for example Michael acceptor GSH reactive)
Calculated properties CLogP
PSA
Molecular Weight
rotatable bonds
H-bond donors and acceptors
permeability
pKa
Solubility
TIER 1B
Confirm EC50 determinations for actives compounds in primary screen with fresh
compounds from the original stock Confirm EC50 determinations for the lead (most
active) compound in primary screen with a new sample either repurchased purified
and characterized in-house or independently synthesized in-house
Compounds with IC50s (EC50s) less than X advance to Tier 2
TIER 2A ndash Activity Confirmation
Secondary screen
TIER 2B
Repeat EC50 determinations for actives in secondary screen with fresh
compounds from the original stock
Compounds with IC50s (EC50s) less than X advance to Tier 3
Example Drug Discovery amp Development Testing Funnel
TIER 3 ndash Drug-like Properties Specificity
IC50 selectivity in selectivity screen
CYP450 Inhibition competitive and time-dependent if structural alerts exist
(spot check illustrative examples from compound series)
Measured solubility
Measured protein binding (spot check illustrative examples from
compound series)
Test of Permeability in vitro permeability [indicate assay eg Caco2 orand
PAMPA] (spot check illustrative examples from compound series)
hERG
Cytoxicity assays
All compounds with no significant issues (Define Minimum Conditions for
Advancement) to advance to Tier 4
Example Drug Discovery amp Development Testing Funnel
TIER 4 ndash Scale-up Synthesis and Preliminary PK
Scale-up synthesis
Purity determination gt98 with no single impurity gt1
Rodent bioavailability and PK (define target delivery route) Tmax
Cmax
AUC
Bioavailibility
Vss CL T12 MRT
Brain to Plasma ratios
P-glycoprotein transport MDCK-MDR1 and MDCK-mdr1a
Plasma Protein Binding (species)
Microsomal Stability ndash rodent and human
Defineplan Patent Protection Strategy
All compounds with no significant issues (Define
Minimum Conditions for Advancement) advance
in parallel to Tiers 5AampB
Example Drug Discovery amp Development Testing Funnel
TIER 5A ndash In Vivo Bioactivity
Animal efficacy
Validate Biomarker
Target engagement
Advance to Tier 6 if (Define Minimum Conditions for advancement)
TIER 5B ndash Advanced Drug-like Properties
Microsomal stability in multiple
species
Chemical Stability
CYP450 induction
CYP reaction phenotyping
Metabolism ndash human
hepatocytesmicrosomes
Metab ID define major human rat dog and
non-human primates (NHP) metabolites
In vitro Tox Ames
Chromosome Aberration
CNS effects
Example Drug Discovery amp Development Testing Funnel
TIER 6 ndash Liability Assessment
Broad Pharmacological Profile and Toxicology
PK in second species
TIER 7
Non-GLP exposure studies single and multiple dose
Advance to late stage pre-clinical development (Define Minimum
Conditions for advancement)
Example Drug Discovery amp Development Testing Funnel
Principal InvestigatorProgram Director (Last First Middle)
enspenspenspenspensp
DETAILED BUDGET FOR INITIAL BUDGET PERIOD
DIRECT COSTS ONLY
FROM
THROUGH
enspenspenspenspensp
enspenspenspenspensp
PERSONNEL
DOLLAR AMOUNT REQUESTED (omit cents)
NAME
ROLE ONPROJECT
TYPEAPPT (months)
EFFORTONPROJ
INSTBASESALARY
SALARYREQUESTED
FRINGEBENEFITS
TOTAL
enspenspenspenspensp
PrincipalInvestigator
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
SUBTOTALS
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
CONSULTANT COSTS
enspenspenspenspensp
enspenspenspenspensp
EQUIPMENT (Itemize)
enspenspenspenspensp
enspenspenspenspensp
SUPPLIES (Itemize by category)
enspenspenspenspensp
enspenspenspenspensp
TRAVEL
enspenspenspenspensp
enspenspenspenspensp
PATIENT CARE COSTS
INPATIENT
enspenspenspenspensp
enspenspenspenspensp
OUTPATIENT
enspenspenspenspensp
enspenspenspenspensp
ALTERATIONS AND RENOVATIONS (Itemize by category)
enspenspenspenspensp
enspenspenspenspensp
OTHER EXPENSES (Itemize by category)
enspenspenspenspensp
enspenspenspenspensp
SUBTOTAL DIRECT COSTS FOR INITIAL BUDGET PERIOD
$
enspenspenspenspensp
CONSORTIUMCONTRACTUAL COSTS
DIRECT COSTS
enspenspenspenspensp
FACILITIES AND ADMINISTRATIVE COSTS
enspenspenspenspensp
TOTAL DIRECT COSTS FOR INITIAL BUDGET PERIOD
$
enspenspenspenspensp
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
Wang Y Suzek T Zhang J Wang J He S Cheng T Shoemaker BA Gindulyte A Bryant SH PubChem BioAssay 2014 update
Nucleic acids research 2014 42(Database issue)D1075-1082
Wang Y Bolton E Dracheva S Karapetyan K Shoemaker BA Suzek TO Wang J Xiao J Zhang J Bryant SH An overview of
the PubChem BioAssay resource Nucleic acids research 2010 38(Database issue)D255-266
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
main menu
Pharmacokinetic tutorial drug exposure measurement services pharmacokinetic data references
Selecting the correct dose to achieve exposure of drug that are adequate to test a hypothesis in preclinical species
requires that you know the potency of the molecule at the desired drug target and the dose of compound required to
achieve target organ exposure that will result in the free (not bound by protein) concentration of drug required to engage
the molecular target within the target organ compartment Estimates of Drug potency can be found in many of the
databases listed under correct molecule The free concentration of a drug is determined in the plasma by multiplying the
concentration of drug in the plasma by the fraction unbound This must be measured for each compound A literature
reference that provides the measured plasma protein binding (PPB) values for many common drugs is provided here
Zhang Xue Shao and Jia (2012) Compilation of 222 drugsrsquo plasma protein binding data and guidance for study designs
Drug Discovery Today Vol 17 Issue 9-10 Pages 476-485 httpwwwncbinlmnihgovpubmed22210121
If your drug target is the brain then you must also understand the kinetics of drug disposition and clearance including blood
brain barrier (BBB) penetration in your test species to select a dose of compound adequate to test your hypothesis
Download a tutorial deck on basic principles of drug disposition and their application in small molecule drug discovery
courtesy of Dr Chris Shaffer Pfizer
150805DMPKTutorial(CLSBCHCourse)pdf
Pharmacometrics Research Core and Pharmacokinetics Service The Pharmacometrics Research Core is directed by Dr Luis
Pereira and provides analytical services for assaying drugsmetabolites in biological matrices (eg plasma serum blood
urine CSF saliva tissues) The Core provides pharmacokinetic and pharmacodynamic analyses for current and future
clinical trials and research projects (including contract services) It conducts stability and potency studies for pediatric
formulations compounded at BCH as per recent demand from FDA and CMS Finally the Core fosters grant applications
and research collaborations both intra and extramural The TNC can additionally provide investigators with consultation in
the identification of resources for pharmacodynamic assay development and contract research organizations able to
provide bioanalysis of preclinical samples needed to support animal clinical trials Contact Dr Luis Pereira for more
information LuisPereirachildrensharvardedu
article on importance of understanding drug exposure in preclinical drug studies here
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
References on Pharmacokinetics and Brain Penetration of Small Molecules
Di L Rong H Feng B Demystifying brain penetration in central nervous system drug discovery Miniperspective Journal of
medicinal chemistry 2013 56(1)2-12
Reichel A Addressing central nervous system (CNS) penetration in drug discovery basics and implications of the evolving
new concept Chemistry amp biodiversity 2009 6(11)2030-2049
Smith DA Di L Kerns EH The effect of plasma protein binding on in vivo efficacy misconceptions in drug discovery Nature
reviews Drug discovery 2010 9(12)929-939
Moda TL Torres LG Carrara AE Andricopulo AD PKDB database for pharmacokinetic properties and predictive in silico
ADME models Bioinformatics 2008 24(19)2270-2271
Law V Knox C Djoumbou Y Jewison T Guo AC Liu Y Maciejewski A Arndt D Wilson M Neveu V et al DrugBank 40
shedding new light on drug metabolism Nucleic acids research 2014 42(Database issue)D1091-1097
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
main menu
Formulations advice and assistance with preclinical drug delivery Neurodevelopmental Behavioral Core
To effectively deliver drug to preclinical species for the duration of a study researchers must choose a dose a formulation
and a route of administration that will support target organ exposure long enough to test a therapeutic hypothesis Since
most drugs developed for humans are optimized for human metabolism parameters many compounds developed for
humans are rapidly metabolized and cleared in rodents requiring alternative formulations and routes of preclinical
administration (see tutorial under Correct Dose)
Proper formulation of drugs and vehicles to ensure appropriate drug exposure is a critical factor in preclinical study design
The Neurodevelopmental Behavioral Core may provide advice on standard formulations Preclinical assistance and
training across many routes of administration including IV cannulation osmotic minipumps oral gavage sc and ip is also
available through the Neurodevelopmental Behavioral Core
Contact is Dr Nick Andrews NickAndrewschildrensharvardedu
Custom formulation used for human studies are supported on a case by case basis by the Pharmacometrics Research Core
or Clinical Research Pharmacy Contact for the Pharmacometrics Core is Dr Luis Pereira LuisPereirachildrensharvardedu
The Clinical Research Pharmacy can provide advice on unusual formulations Contact is Dr Rocco Anzaldi
RoccoAnzaldichildrensharvardedu
idspharmacy-dlchildrensharvardedu
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
main menu
Stratification Biomarker development and resources patient sample repositories requests for collection of new types of
patient samples development of patient specific iPSC lines and neurons Genetic databases RNA expression databases
Humans are diverse Not only do patients come in different sizes ages genders and ethnic backgrounds but the same
disease diagnosis often develops in people as a function of different environmental insults and genetic predispositions
Finding biomarkers that will segregate similarly diagnosed patients into subsets of biologically more homogenous
populations is a critical feature of good clinical trial design A lsquostratification biomarkerrsquo can be a biochemical measure from
patient samples a structural or a functional feature of a human imaging technology or a functional measure of an
electrophysiological readout
The Translational Neuroscience Center can help investigators access advice and assistance for investigators with vendors
experienced in profiling DNA RNA or protein across a range of platforms httpwwwchildrenshospitalorgresearch-and-
Neurophysiology Services can assist investigators with identification of biomarkers to stratify patients based on EEG
signatures Contact Drs Charles Nelson and Jurriaan Peters Co-Directors
CharlesNelsonchildrensharvardedu
JurriaanPeterschildrensharvardedu
MRIRadiology Imaging Core can assist with identification of biomarkers to stratify patients by functional or structural deficits
in brain circuitry Contact Dr Simon Warfield Director SimonWarfieldchildrensharvardedu
Molecular Genetics core can assist investigators with identification of genetic stratification biomarkers or gene expression-
based stratification biomarkers Contact Drs Louis Kunkel and Christopher Walsh Co-Directors
LouisKunkelchildrensharvardedu
ChristopherWalshchildrensharvardedu
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
The Human Neuron Differentiation Service within the Translational Neuroscience Center can help investigators recruit
specific subtypes of patients to be consented for reprogramming of blood or fibroblast cells into iPSC lines that will support
differentiation into human neurons for phenotypic analysis and screening ContactDr Robin Kleiman
RobinKleimanchildrensharvardedu
Translab can assist with routine processes as well as complex laboratory-‐developed tests They place special emphasis on
assay development for use in clinical trials Translab website with contact information can be viewed here
httpwwwtranslabbostonorg
TransLab Flyer 2 2015pdf
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
main menu
Patient sample repositoryBiobank Patient registry
Disease processes are dynamic The molecular underpinnings of disease differ between inception progression and
response of the body to disease Thus each stage of disease may require alternative therapeutic strategies Understanding
which stage of disease is best suited to testing a specific therapeutic approach will require information about disease from
patient samples collected at different stages of disease well as an ability to collect and recruit patients at relevant stages of
disease
To locate human RNA profiling data in the public domain from disease samples and tissues at specific stages of disease
search databases referenced in the Correct Target section of this document
The Translational Neuroscience Center offers multiple services that can assist with identification of the correct patients The
Core Repository for Neurological Disorders stores a wide variety of patient samples from many stages of disease The
biorepository is directed by Dr Mustafa Sahin and these samples and de-identified clinical data can be searched and
requested through the Translational Neuroscience Center
The Biobank Core Lab serves as a core resource that ensures top-level specimen handling and services to the Boston
Childrens Hospital research community It serves as both a service core and a biorepository providing an institutional
perspective on the presence of specimens that may be available for use to foster collaborations and accelerate research
and discovery
The Clinical Research and Regulatory Affairs Service can provide assistance to investigators in identifying patients andor
repository samplesdata Contact Co-Directors Stephanie Brewster and Kira Dies for more information about access to
these resources
StephanieBrewsterchildrensharvardedu
KiraDieschildrensharvardedu
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
main menu
Statistical support clinical trialsgov
Determining the correct sample size to support preclinical and clinical studies requires power calculations that take into
account the variability of the endpoint being measured Statistical support for preclinical studies is available on a
department by department basis Neurology and Neurobiology requests for preclinical biostatistics support can be made
through the CRC website
httpredcap-qiredcap_edcsurveyss=Rma5u83qKC
Clinical statistical support for all departments is also available through the CRC Design and Analysis Core For more
information contact Michael Monuteaux michaelmonuteauxchildrensharvardedu
Clinical datasets that provide data for supporting power calculations can be found by searching through clinical trialsgov
database All studies in the clinical trials data base are required to describe the study design the endpoints under
evaluation and the treatments as well as links to publications of the studies The studies can be searched by topic This can
be a good way to find historical data to help you evaluate variability of endpoint measures in clinical populations This will
be needed to support sample size power calculations httpsclinicaltrialsgov
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
main menu
Understanding RDoC Human Neurobehavioral Core Service IRB assistance with clinical protocols
Different stages of clinical trials have different goals for selecting endpoints Early stage clinical trials are typically in search
of a translatable pharmacodynamic or target engagement endpoint to ensure that the molecule in question will be
competent to test a clinical hypothesis in humans Developing translatable measures of target engagement in preclinical
species and humans is critical to developing data sets that will enable subsequent therapeutic efficacy trials The earliest
trials require endpoints that can be measured in a functionally equivalent manner across species Therefore it is critical for
preclinical researchers to develop dose-responsive data sets in preclinical species using quantitative endpoints such as EEG
visual or auditory evoked potentials PET ligands plasma or CSF based biochemical measures or translatable task based
behaviors Preclinical data must be a developed with an eye towards what the equivalent measure will be in the clinic
Toward that end the NIMH has initiated the Research Domain Criteria (RDoC) that is aimed at characterizing mental health
disorders across many different dimensions across species A big focus of the RDoC initiative is the identification of
translatable endpoints for evaluating pharmacodynamics and efficacy in Neuroscience Drug Discovery Preclinical
Neuroscience researchers should be familiar with the RDoC framework For advice on in vivo characterization of preclinical
endpoints with translational potential for Neuroscience related disorders contact Dr Robin Kleiman at the TNC
robinkleimanchildrensharvardedu
The Human Neurobehavioral Core Service of the Translational Neuroscience Center can provide guidance to investigators
on the appropriate tests that will provide the best translation from animal studies to human studies The Service also offers
human neurobehavioral assessment services Contact-Drs Charles Nelson and Deborah Waber Co-Directors
CharlesNelsonchildrensharvardedu
DeborahWaberchildrensharvardedu
Developing clinical protocols and obtaining IRB approval for human study of translatable endpoints can be supported by
the Translational Neuroscience Center Clinical Research and Regulatory Affairs Service Contact-Kira Dies and Stephanie
Brewster Co-Directors
KiraDieschildrensharvardedu
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
StephanieBrewsterchildrensharvardedu
Background Information on RDoC httpswwwnimhnihgovresearch-prioritiesrdocindexshtml
Casey BJ Oliveri ME Insel T A neurodevelopmental perspective on the research domain criteria (RDoC) framework
Cuthbert BN Insel TR Toward the future of psychiatric diagnosis the seven pillars of RDoC BMC Med 2013 11126
httpwwwncbinlmnihgovpmcarticlesPMC3653747
Insel T Cuthbert B Garvey M Heinssen R Pine DS Quinn K Sanislow C Wang P Research domain criteria (RDoC)
toward a new classification framework for research on mental disorders The American journal of psychiatry 2010
167(7)748-751 httpwwwncbinlmnihgovpubmed20595427
Insel TR The NIMH Research Domain Criteria (RDoC) Project precision medicine for psychiatry The American journal
of psychiatry 2014 171(4)395-397 httpwwwncbinlmnihgovpubmed24687194
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
main menu
Body atlases for expression of mRNA and protein guides to chemical alerts guidance for preclinical toxicology studies for
Investigational New Drug (IND) applications
Discovery scientists must consider the distribution of the proposed drug target across the entire body in human samples in
order to understand potential safety risks to be monitored during preclinical toxicological testing Teams also have to be
aware of differences in distribution of the target and related family members in preclinical species Many of the target
expression databases listed in the Correct Target section of this document are useful in this regard Assays that can be used
to monitor any potential safety risks are critical to the development of a suitable testing funnel needed to advance
compounds
Many chemical classes of compounds that are identified in screens are not suitable for drug development due to the
presence of structural alerts that are known to cause chemical toxicity Databases that house information of structural alerts
can be used to de-prioritize structural series early in the life of a program Some toxicology databases that can help
deprioritize toxic chemotypes include httppubsacsorgdoiabs101021ci300245q
Some web resources for identifying side effects of known compounds httpintsideirbbarcelonaorg
Once a potential clinical candidate molecule is identified GLP-qualified toxicology studies must be carried out with a
qualified vendor to support regulatory filings of an Investigational New Drug (IND) application For a short tutorial on studies
needed to support preclinical toxicology testing and guidance on evaluating contract research organizations that are
qualified to perform this work see attached tutorial courtesy of Dr Joe Brady Pfizer
Brady boston childrens hosp talk aug2015 IND toxpdf
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
main menu
FAQs
Industry partners and collaborators can bring tremendous expertise and complementary resources to bear on research
projects with therapeutic applications These may include medicinal chemistry expertise pharmacology expertise access
to unique and undisclosed chemical probe molecules assay development and high-throughput screening resources
antibody and other reagent development pharmacokinetic analysis pharmacokinetic and pharmacodynamics
modeling formulation expertise post-doctoral training programs and in some cases financial support There is a wide range
of models of interacting with industry in a range of different capacities Some frequently asked questions about types of
relationships and the responsibilities associated with those interactions can be found in the following document
Download Frequently Asked Questions about working with Industry
Translation of basic research into new marketed drugs will require a transition from exploring scientific principles and testing
hypotheses into commercial products Industry partners capable of developing these potential products need to be able
to license the intellectual property required to sell the product in order to justify investment in building programs around new
ideas This requires that scientific researchers protect and patent potential inventions from their work to enable future
commercialization by partners with appropriate expertise To ensure that researchers are appropriately documenting their
work in a manner that will support preservation of intellectual property all investigators are encouraged to consult with TIDO
before any public disclosures of new research Similarly the following documentation provides guidance for documenting
your work according to standards that will support patent applications
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
Download the compliance manual for BCH for Intellectual property policy
cm_021_intellectual_propertydocx
Download a summary of laboratory notebook Dorsquos and Donrsquot
Dosdontsnotebookspdf
Link to TIDO Technology Innovation and Development Office
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
main menu
A phenotypic screen requires a biologically robust assay that represents a significant aspect of disease-relevant human
biology It can be used to identify molecular targets for target validation studies through the use of well-annotated
bioactive molecules or genomic libraries (eg RNAi CRISPER) Alternatively phenotypic screens can be used to identify
novel compounds that must subsequently be lsquoDE convolutedrsquo to identify novel targets using lsquowarheadsrsquo These screens rely
on identification and manipulation of a functional deficit or phenotype using a patient-derived cellular system
The strengths of this approach
Use of human systems can improve translatability
Identified compounds may empirically balance therapeutic activity at multiple required targets
Well-suited to drug repurposing
Phenotypic screens can be used to identify compounds or targets for mechanism based drug discovery programs
Many CNS drugs have been discovered using a phenotypic repurposing screen (Swinney and Anthony 2011)
Drawbacks to this approach
Assays are slow low throughput and more expensive as compared to cell-free assays
Cell-based assays may not predict circuit level or brain phenotypes
Furthermore as a primary screening approach
Precludes leveraging strengths in uHTS SBDD and parallel design
Every molecule must be de-risked independently thus safety can be very hard to predict
Drug Repurposing Drug Repurposing is a strategic pillar of the National Center for Advancing Translational Science (NCATS)
Details on resources and funding opportunities can be found here httpsncatsnihgovntu
Chemogenomic Files from industry partners Many companies have well designed and annotated chemical files that are
designed to cover the druggable genome with small molecule compounds from their proprietary collections Each
company has different criteria and stipulations associated with use of the library It is advisable to consult with TIDO
regarding terms and conditions associated with individual companies
ICCB-LongwoodKirby ADSF The ICCB screening center and the Kirby ADSF have multiple collections of compounds that
include bioactive or FDA approved molecules available for screening
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
Kirby ADSF libraries contact Dr Lee Barrett LeeBarrettchildrensharvardedu
References related to phenotypic screens and Drug Repurposing
Vincent F Loria P Pregel M Stanton R Kitching L Nocka K Doyonnas R Steppan C Gilbert A Schroeter T
and MC Peakman Developing predictive assays The phenotypic screening ldquorule of 3rdquo Sci Transl Med 7 293ps15
(2015)
Langedijk J Mantel-Teeuwisse AK Slijkerman DS Schutjens MH Drug repositioning and repurposing terminology and
definitions in literature Drug Discov Today (2015)
Swinney DC and J Anthony How were new medicines discovered Nature Reviews Drug Discovery 10 507-
519 (July 2011) | doi101038nrd3480
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
main menu
TNC Clinical Research and Regulatory Affairs Service Research Participant Registry CRC
Glossary of Terms
Glossary-of-Clinical-Trials-Termspdf
Clinical Research and Regulatory Affairs Service This Translational Neuroscience Center service facilitates the mission of the
Translational Neuroscience Center providing coordination among studies communications resource development and
implementation of new or ongoing preclinical and clinical studies The service is led by experts in protocol development
and launching of new studies The directors are available to guide TNC researchers in designing human studies including
the preparation of Institutional Review Board (IRB) and FDA submissions Additionally staff of the Clinical Research and
Regulatory Affairs Service will help researchers with recruitment plans budget development supervision of study
coordinators study monitoring and audit preparation For more information contact Co-Directors Kira Dies ScM CGC and
Stephanie Brewster MS CGC
KiraDieschildrensharvardedu
StephanieBrewsterchildrensharvardedu
Clinical Research Center (CRC) Assists investigators at BCH with research project initiation and implementation resources
in the CTSU for the conduct of clinical research visits and ancillary services education on research methods and practices
The CRC has biostatisticians project managers research specialists clinical trials specialists research coordinators and
highly skilled nurses and nurse project managers who work every day to facilitate the many research needs of the BCH
community httpwwwchildrenshospitalorgresearch-and-innovationresearchclinicalclinical-research-center
Clinical and Translational Study Unit (CTSU) The CTSU provides clinical research infrastructure for investigators in the design
initiation conduct and reporting of clinical research with the goal of translating scientific knowledge into new therapies for
pediatric conditions httpweb2tchharvardeductsu
Clinical Research Roadmap This clinical research map is designed to serve as a guide for investigators study coordinators
and research nurses at Boston Childrenrsquos Hospital The research map outlines the key steps in preparing to launch a
research study and provides embedded links to institutional resources tools and documents
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
Clinical Research Mappdf
main menu
Office of Sponsored Programs Research Administration TIDO
Many government and foundation grant opportunities are available for developing Drug Discovery Projects updated lists of
funding options exist on OSP and Research Administration web sites
Some good options for finding relevant requests for proposals
Translational Research Program annual call for proposals
Boston Childrenrsquos Hospital ndash Broad Institute Collaboration Grants Proposals will be reviewed by a joint Childrenrsquos Hospitalndash
Broad Institute committee Additional submission dates are expected for 2016
BCH_Broad collaborative grant 852015docx
Kirby Neurobiology Screening Pilot awards- available to Kirby Neurobiology PIs as funding is available
Translational Neuroscience Center- Pilot awards supported by trust sponsored donations as available Distributed through
TNC e-mail lists
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
ADDF The ADDF Academic Drug Discovery and Development Program seeks to create and support innovative translational
research programs for Alzheimerrsquos disease related dementias and cognitive aging in academic medical centers and
universities Biomarker development studies and innovative proof of concept pilot clinical trials of new approaches to
treatment prevention and early detection are also supported
Department of Defense ALSRP The FY15 Defense Appropriations Act provides $75 million (M) to the Department of Defense
Amyotrophic Lateral Sclerosis Research Program (ALSRP) to support innovative high-impact Amyotrophic Lateral Sclerosis
research As directed by the Office of the Assistant Secretary of Defense for Health Affairs the Defense Health Agency
Research Development and Acquisition (DHA RDA) Directorate manages and executes the Defense Health Program
(DHP) Research Development Test and Evaluation (RDTampE) appropriation The executing agent for the anticipated
Program AnnouncementsFunding Opportunities is the Congressionally Directed Medical Research Programs (CDMRP)
httpcdmrparmymilpubspress201515alsrppreannshtml
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
Michael J Fox Foundation Therapeutic Pipeline Program Supports Parkinsons disease therapeutic development along the
pre-clinical and clinical path (both drug and non-pharmacological therapeutics including gene therapy biological
surgical and non-invasive approaches) The Michael J Fox Foundation seeks applications with potential for fundamentally
altering disease course andor significantly improving treatment of symptoms above and beyond current standards of care
Proposals must have a well-defined plan for moving toward clinical utility for patients The Therapeutic Pipeline Program is
open to industry and academic investigators proposing novel approaches or repositioning approved or clinically safe
therapies from non-PD indications httpswwwmichaeljfoxorgresearchgrant-detailphpid=28
NINDS The Blueprint Neurotherapeutics Network (BPN) Provides the neuroscience community access to a complete and
seamless pipeline for preclinical drug development beginning with chemical optimization and concluding after phase I
clinical trials Participants in the BPN will receive funding to conduct bioactivity and efficacy testing in their own laboratories
as well as access to millions of dollars in NIH-contracted drug development services including medicinal chemistry
pharmacology toxicology and phase 1 clinical trials NIH will also provide drug development consultants who have had
years of experience working at a senior level in industry Because the Blueprint is establishing a network of drug
development service providers that typically cater to biopharmaceutical companies neuroscientists who join the BPN can
readily plug in to all of the drug development expertise that typically resides in industry The projects supported through the
network will be highly collaborative and the researchers who initiate the projects will serve as the principal investigators
(PIs) directing their projects through the development pipeline with the help of industry consultants The PIs and their
institutions will have the opportunity to attain assignment of intellectual property rights from all other network participants
who may have intellectual input into their projects This will allow the PIs to retain control of the intellectual property for drug
candidates developed through the network and eventually pursue licensing and commercialization partnerships
httpneuroscienceblueprintnihgovbpdrugs
NeuroNEXT Will establish a consortium of clinical sites capable of forming disease-specific cadres of investigators in order to
develop and implement trials rapidly in a wide range of neurological disorders that affect adults andor children With a
stable and experienced research staff a central IRB model and master trial agreements NeuroNEXT will streamline the
administrative processes for clinical trials and reduce start-up times NeuroNEXT will also be able to design and implement
evidence-based measures to improve patient recruitment into clinical trials httpswwwneuronextorgresearchers
NIMH Many grant options see overview here httpwwwnimhnihgovresearch-prioritiestherapeuticsindexshtml
Building on High Impact Basic Neurobiology Through Assay Development Advancing Tools for Therapeutic Discovery (R01) -
See more at httpgrantsnihgovgrantsguidepa-filesPAR-15-066htmlsthashs1HMWjWudpuf
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
NCATS many grant options see overview here httpwwwncatsnihgovprograms
Bridging Interventional Development Gaps (BrIDGs) Program Makes available on a competitive basis certain critical
resources needed for the development of new therapeutic agents for both common and rare diseases Investigators do not
receive grant funds through this program Instead successful applicants receive access to NIH experts and contractors who
conduct pre-clinical studies at no cost to the investigator In general synthesis formulation pharmacokinetic and
toxicology services in support of investigator-held IND applications to the Food and Drug Administration (FDA) are available
httpwwwncatsnihgovbridgsworksolicitation
NCATS Discovering New Therapeutic Uses for Existing Molecules (New Therapeutic Uses) A collaborative program designed
to develop partnerships between pharmaceutical companies and the biomedical research community to advance
therapeutics development This innovative program matches researchers with a selection of pharmaceutical industry
assets to test ideas for new therapeutic uses with the ultimate goal of identifying promising new treatments for patients
httpwwwncatsnihgovntu
Pfizer Centers for Therapeutic Innovation (CTI) Suitable for biotherapeutic or small molecule projects with a strong project
rationale (demonstrated association between target biology pathway and disease mechanism) CTIrsquos areas of interest
include inflammation autoimmunity tissue remodeling oncology cancer immunology rare or genetic diseases
cardiovascular and metabolic diseases and neuroscience Selected projects are undertaken by a joint team with BCH
members and Pfizer CTI drug development experts located on the 18th floor of CLS working towards agreed common
goals The Pfizer CTIBCH collaboration program is managed by a Joint Steering Committee with representation from both
Boston Childrenrsquos and CTI httpswwwpfizercticom Calls for proposals come through TIDO three times a year in January
May and September httpwwwchildrensinnovationsorgPagesHighlightsHighlights-83aspx
Shire-BCH Collaborative Program Development The Joint Steering Committee of the Shire Alliance extends a call for ldquoPre-
Proposalsrdquo with defined objectives from time to time generally annually in the late fall or winter That call is publicized
through emails from BCH Research Administration and TIDO Following review by the JSC a full proposal may be requested
Unsolicited proposals may also be considered from time to time
ACRONYMS
HTS- High-throughput Screen run with 96 well 384 well 1536 wells or 3456 well capacity- screen has capacity to run through a library of 1-3Million compounds in total
uHTS- Ultra High-throughput Screen ndash arbitrary cut off to denote capability to measure 100s of thousands of assays per day with automation and high density plate readers
HCS- High Content Screen usually a cell based assay that is able to monitor multiple endpoints reflective of different cellular processes in a single well of cells treated with a compound May be biochemical or image based endpoints
SAR- Structure-Activity Relationship ie relationship of modifications to chemical structure on relevant activity SPR-Structure-Property Relationship ie relationship of modifications of chemical structure on physicochemical
properties
PK- Pharmacokinetic measure of drug levels in a body compartment
PD- Pharmacodynamic a measure of functional activity of a drug
PKPD- PharmacoKinetic PharmacoDynamic relationship- how drug levels relate to drug response in a system
DDI-Drug-Drug Interactions- occurs when one drug affects the activity of another drug when co- administered Often due to changes in ADME properties of one of the co-administered drugs (ie for example induction by one drug of enzymes that will metabolize the second drug )
DMPK- Drug Metabolism and PharmacoKinetics
ADME- Absorption Distribution Metabolism amp Excretion
PDM-pharmacokinetics dynamics and metabolism GLP- Good Laboratory Practice- regulations that govern toxicology studies required by the FDA to support IND
and NDA
POM- Proof of Mechanism clinical studies to demonstrate hit the target and elicited a biological response
POC- Proof of Concept Clinical studies to demonstrate a clinically meaningful outcome measure improved
PoP-Proof of Principal usually preclinical studies that demonstrate that engaging target in a disease model produced efficacy
FIH- First in Human clinical trial to evaluate new molecule in humans for safety and PK- Ph1
FIP-First in Patient first clinical trial to evaluate new molecule in patients hERG (the human Ether-agrave-go-go-Related Gene) is a gene KCNH2 that codes for a subunit of Kv111 and
contributes to the repolarizing current in the heart that coordinates the hearts beating When compromised by application drugs or by rare mutations in some families it can result in a potentially fatal disorder called long QT syndrome A number of clinically successful drugs in the market have had the tendency to inhibit hERG and create a concomitant risk of sudden death as a side-effect which has made hERG inhibition an important anti-target that must be avoided during drug development
IND-Investigational New Drug Application- formal application to FDA to evaluate a NCE in people
NME- New Molecular Entity- a new FDA approved drug
NCE-New Chemical Entity-an investigational drug that is not yet a FDA approved NME NDA- New Drug Application (A lsquoFilingrsquo)- a formal application for approval of a new drug
CAN-(Pfizer-specific shorthand )-Clinical Candidate- a molecule competent to be tested in humans IB- Investigators Brochure- basic information on an investigational drug and its mechanism for clinicans involved
in conducting a clinical trial Provides background information on the hypothesis being tested and the types of patients that should be included excluded and risks and how the drug should be administered It must be updated continually by the sponsor to include all new findings
SOC- Standard of Care- in our context it is the drug treatment that a clinican should prescribe for a particular type of patient used as a benchmark for comparing new entities
MTD- Maximum Tolerated Dose- first identified in GLP safety studies during preclinical development AE- Adverse Event- a side effect that causes safety concerns
TI- Therapeutic Index -ratio of the concentration of drug needed to produce efficacy and the concentration of drug that is safely tolerated ( also called ldquoSafety Marginrdquo)
Questions Contact Robin Kleiman- email RobinKleimanchildrensharvardedu office CLS 13070
Terms that relate to Targets Molecular target- the protein that binds drug to produce efficacy Off-Target- other proteins that bind the drug that do not relate to efficacy and may produce Adverse Events (AEs) Druggable target ndashcomes from a class of proteins that has successfully been targeted with small molecule drugs in
the past Primarily transporters enzymes receptors ion channels (Not protein-protein interactions transcription factors RNA binding proteins etc)
Druggable genome- about 3000 genes encoding all druggable proteins Druggability- the presence of protein folds (quarternary structures) that favor specific interactions with drug-like
molecules Exploratory target- Hypothesis that a modulating a target via a particular mode of action will be beneficial to a
particular patient population Validated target- Hypothesis regarding a target also has in vivo efficacy data for a disease or a disease model- along
with a complete understanding of how the target mechanism relates to disease- (also called lsquoProof of Principlersquo) Phenotypic screen- a screen for compounds that will reverse a phenotype the molecular target may not be known Systems pharmacology target(s)-a precisely defined combination or lsquofingerprintrsquo of molecular targets to be
modulated to correct a phenotype (Poly-pharmacology)
Terms that relate to programs
Biomarker- a physiological pathological or anatomical characteristic that is measured by an automated process or algorithm as an indicator of the normal biological process pathological process or biological response to a therapeutic intervention Many types of Biomarkers target engagement biomarkers stratification biomarkers efficacy biomarkers pharmacodynamic biomarkers etchellip
Laboratory Objectives-Criteria established at the start of the program to define the desired pharmacological properties of the molecule with regard to potency selectivity mode of action frequency and route of administration For antibodies would include minimal criteria for knock down stability etc
Therapeutic Modality- small molecule biologic RNAi stem cell etc
Screening tree Screening funnel- A decision tree for utilizing a panel of assays to identify molecules that meet the laboratory objectives
Terms that relate to molecules
Drug-like molecule- has physicochemical properties in line with known oral medications The molecule will be largely rule of 5 (RO5) compliant therefore small and moderately lipophilic Not related to pharmacological activity
Rule of Five (RO5)=Chris Lipinskirsquos rule of 5 states that a drug like molecule will have the following properties Molecular Weight of less than 500 a clogP lt5 fewer than 5 H-bond donors and the number of H-bond acceptors ( which is the sum of N and O atoms) is less than 10
Physicochemical properties- key properties of molecules include (calculated)Molecular Weight number of H bond acceptors and donors (measured) kinetic solubility pKa lipophilicity (logD logP)
Chemical tool -a compound with good potency and selectivity for a specified molecular target but fails to meet all criteria for safety PK or potency needed to become a clinical candidate Suitable for preclinical testing of hypothesis and proof of principal studies but not for lsquopreclinical developmentrsquo
Active molecule describes an individual chemical entity with measurable dose-dependent activity in a biological screening assay
Hit molecule refers to a molecule plus its related structural analogs for which there is an understanding of the structure-properties and structure-activity relationships (SPR and SAR) for a specific biological context Additionally preliminary drug disposition data (both in vitro and in vivo) provide an assessment of pharmacokinetic properties The available data provide a basis for further optimization of the hit series
Lead molecule refers to a molecule plus its related structural analogs that demonstrate o Sufficient exposure at pharmacologically relevant doses by the intended route of administration to explore
intended pharmacology in a relevant in vivo disease or pharmacodynamic model o Proof-of-principle or efficacy in a in vivo model that will be used to establish a margin of safety
Clinical candidate an optimized individual chemical entity derived from a lead series that demonstrates o a dose-response relationship via intended route and schedule of administration in relevant disease model o an exposure-based margin of safety in toxicology studies o In summary a clinical candidate is a molecule that is deemed competent for testing the primary disease
intervention hypothesis in humans
A laboratory notebook is a vital record of events leading to a patentable invention Therecorded information can establish dates of conception and reduction to practice of atechnology as well as the inventorship of a patent claiming the technology Below arefourteen rules you should follow when keeping lab notebooks
1 mdash Do use bound booksInventors should use permanently bound notebooks eg notebooks with spiral or glue bindings If loose-leaf sheets are used they should be consecutively numbered and eachpage should be dated signed and witnessed
2 mdash Do sign and date Each notebook should be signed and dated on the inside front cover to indicate the firstday the recipient started using the notebook Each entry should be dated and signed orinitialed
An independent witness ie someone who understands the technology but will not benamed as a co-inventor of the invention should sign and date each entry after the state-ment ldquoRead and understood by rdquo (The witness should preferably sign theentries on a contemporaneous or fairly contemporaneous basis but entries can also bereviewed signed and dated on a periodic eg weekly or monthly basis)
3 mdash Do use inkNotebook entries should be made in ink and in chronological order Entries should not beerased or ldquowhited outrdquo If an entry contains an error a line should be drawn through theerror and new text should continue in the next available space
4 mdash Donrsquot leave blank spacesBlank gaps between entries should be avoided If a blank space is left on a page a line orcross should be drawn through the blank space and the page dated to prevent subsequententries
5 mdash Donrsquot modifyPrior entries should not be modified at a later date If data were omitted the new datacan be entered under a new date and cross-referenced to the previous entry Record exper-iments when they are performed
6 mdash Do use past tenseUse the past tense (eg ldquowas heatedrdquo) to describe the experiments that were actually performed
Fish amp Richardson pc
Dorsquos and Don rsquo ts forKeeping Lab Notebooks
Boston
Dallas
Delaware
New York
San Diego
Silicon Valley
Twin Cities
Washington dc
FR
7 mdash Do explain abbreviations and special termsExplain all abbreviations and terms that are nonstandard Explain in context in a table ofabbreviations or in a glossary
8 mdash Do staple attachmentsAttachments such as graphs or computer printouts should be permanently attached to pagesin the notebook (eg by stapling) and both the attachment and the notebook page signedand dated If the attachment cannot be stapled it should be placed in an envelope and theenvelope stapled to the notebook page The envelope and page should then be signed andwitnessed making reference to the attachment being placed in the envelope
9 mdash Donrsquot remove originalsNo original pages should be removed from the notebook
10 mdash Do outline new experimentsWhen a new project or experiment is started the objective and rationale should be brieflyoutlined (eg in a short paragraph or by providing a flowchart)
11 mdash Do record lab meeting discussionsRelevant discussions from lab meetings should be recorded as should ideas or suggestionsmade by others The names of the people making the ideas and suggestions should be care-fully documented This information may be important in establishing inventorship
12 mdash Do provide detailRecord test descriptions including preferred operating conditions control conditionsoperable and preferred ranges of conditions and alternate specific materials Also recordtest results and an explanation of the results as well as photos or sketches of the resultsandor the test device Any conclusions should be short and supported by the factual dataOpinions or speculation about the invention should be avoided
13 mdash Do track notebooksIdeally each lab should maintain a catalog of notebooks in which each notebook is assigneda number and the name of the author of each notebook is recorded In addition the datethe author received the notebook as well as the date the notebook was completed andreturned should be recorded Upon leaving the lab the author should return all notebookschecked out by or to him
14 mdash Do save completed notebooksAll completed notebooks should be indexed (eg by number by author andor by subjectarea) and kept safely in a central repository together with corresponding patent applica-tions or patents Lab notebooks that relate to inventions on which patents have been grant-ed should be kept for the life of the patent plus six years
By J Peter Fasse
Fish amp Richardson pcIntellectual property complex litigation technology law800 818-5070wwwfrcominfofrcom
P ER SP EC T I V E
PHARMACOK INET I CS
Data gaps limit the translational potentialof preclinical researchRobin J Kleiman1 and Michael D Ehlers2
The absence of mouse pharmacokinetic reference data hinders translation An analysis ofrecent literature highlights a systematic lack of discussion regarding rationale for the selec-tion of dosing paradigms in preclinical studies and in particular for neuroscience studies inwhich the lack of brain penetration can limit target-organ exposure We propose solutionsto improve study design
on January 6 2016httpstm
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nloaded from
Despite widespread use of pharmacologicalagents in mouse models of human diseasethe literature lacks comprehensive pharmaco-kinetic profiles for such studies Coupled witha paucity of suitable data are shortcomingsin the training of experimental biologists inthe application of pharmacometric principlesto experimental study design Many authorssimply cite previously published studies tosupport the selection of a particular dose evenwhen the cited paper lacks drug exposuredata There is an assumption on the part ofresearchers that if a referenced study demon-strates a biological effectmdashthat is any measur-able physiological or behavioral effectmdashin arodent at a given dose then that same dosewill also effectively perturb disease-relevantmechanistic biology in a different study Thedanger occurs when the observed therapeuticeffects are not linked to drug-induced mecha-nistic alterations at the level of the target organLack of a drug exposurendashresponse relationshipin a target organ casts doubt on mechanisticinterpretations In addition any changes inthe route of drug administration vehicle prep-aration species used (rat versus mouse versusprimate) age or strain of animal transgenicmodification time points under investigationduration of dosing or organ targeted for inter-vention (for example brain versus a periph-eral tumor) can alter the relation between doseexposure and measured response In suchcases assumptions regarding the mechanisticbasis for observed therapeutic effects may nothold true
Preclinical pharmacological experimentsthat do not measure drug concentrations in
1Translational Neuroscience Center Kirby NeurobiologyCenter Department of Neurology Boston ChildrenrsquosHospital Harvard Medical School Boston MA 02115USA 2Neuroscience amp Pain Research Unit BioTherapeu-tics Worldwide Research and Development Pfizer IncCambridge MA 02139 USACorresponding author E-mail robinkleimanchildrensharvardedu (RJK) michaelehlerspfizercom (MDE)
the target organ run the risk of producing ex-posures that are too low or too high to inter-pret a mechanistic hypothesis Most drugs arenot selective over a large exposure range for asingle molecular target Confident evaluationof a therapeutic hypothesis requires an under-standing of the drugrsquos penetration and kineticswithin the target tissue as well as its potencyand selectivity for specific molecular targetsFurther investigators must consider the con-centration of the unbound fraction of drugthat is available to interact with the targetPublished reports often overlook the fact thatmany small molecules are more than 90bound to plasma or tissue proteins whichgreatly decreases the fraction of drug availableto bind to the intended target Thus in casesin which drug binding has a slow off-rate anorganismrsquos total drug exposure is not a predic-tor of drug available to interact with its target(1) The failure of some academic scientists toobtain relevant pharmacokinetic data impairsthe interpretation of preclinical research resultsand likely contributes to the acknowledgeddifficulties in replicating some academic liter-ature as reported by industry scientists (2 3)
Drug discovery teams in industry settingsroutinely collect pharmacokinetic data to aidin the mechanistic interpretation of in vivopreclinical data and to project optimal dosingparadigms for efficacy and toxicology studiesData required to evaluate brain penetrationare not typically collected by industry-baseddrug-discovery teams for compounds origi-nally developed for therapeutic indicationsthat do not obviously implicate the centralnervous system making this information es-pecially hard to find for many otherwise well-described drugs In addition because mousedata are not required for preclinical toxicologystudies (the more common small animal spe-cies for preclinical toxicology being rats)industry scientists do not often obtain pharma-cokinetic data from mouse experiments These
wwwScienceTranslationalMedicineo
issues are especially relevant for older drugsthat are potentially suitable for repurposingMany older drugs were discovered and char-acterized before routine pharmacokinetic-pharmacodynamic (PK-PD) modeling ofpreclinical drug exposure and its applicationto predicting human dosing became standardpractice Last pharmacokinetic data are notconsidered innovative and these studies gen-erally do not achieve publication in peer-reviewed journals even when the data havebeen generated When such data are pub-lished it is often relegated to the unsearchableblack hole of supplementary materials Thusmouse neuroPK profiles are not readily avail-able for many drugs that are frequently usedin conjunction with mouse models of humanbrain disorders
DOCUMENTING DOSING STRATEGIES
To evaluate the potential impact of insufficientpharmacokinetic data on dose selection in asample of recent published neuroscience liter-ature we conducted an analysis of papersidentified by means of a PubMed search usingthe search terms ldquodrugrdquo and ldquobrainrdquo for the pub-lication year 2014 from eight journals (Table 1)This list was culled to include only primaryresearch reports that included systemic adminis-tration of a pharmacological agent a pharma-cological therapeutic or a biological therapeuticas part of the study design The search yielded100 articles published between 1 January and30 December 2014 that used systemic drug de-livery with the intended goal of targeting thebrain of rodents (table S1) Each publicationwas examined for the stated rationale behindthe dose selection of study drugs (Table 1)
The reported rationale for dosing strategiesfell into several broad categories including(from lowest confidence to highest) (i) dose se-lected rationale not discussed (ii) literaturecitations of another study in which reportsranged from citation of exposure in the samespecies exposure in a different strain or spe-cies a dose conversion from the human liter-ature to rodent or reports of effects on rodentbehavior in another study (iii) demonstrationof an effect on rodent behavior or function inthe current study (iv) demonstration of adose-responsive biological effect in the currentstudy (v) measurement of drug levels in bloodor plasma in the current study and (vi) mea-surement of drug levels in the target organ(that is the brain) in the current study In onlytwo instances were publications identifiedthat considered the impact of drug binding
rg 6 January 2016 Vol 8 Issue 320 320ps1 1
P ER SP EC T I V E
on January 6 2016httpstm
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nloaded from
to plasma or brain proteins on the free expo-sure of drug available to interact with the tar-get This is a critical flaw in most publishedstudies that use small molecules for functionaleffects in the brain because many centralnervous system (CNS) drugs that penetratethe blood-brain barrier exhibit high proteinbinding leaving a small fraction of the totaldrug measured in plasma or brain unbound
and free to interact with the molecular targetFurthermore most studies used evidence of abiological activity to justify dose selection with-out consideration for how exposure of theagent relates to the potency of the compoundat known molecular targets which would berequired to test a mechanistic hypothesis
The lack of pharmacokinetic considera-tion does not imply that every study used an
wwwScienceTranslationalMedicineo
inappropriate dose of drug to test their hypoth-esis It does illustrate that a clear rationale wasnot provided for dose selection in most pub-lications Furthermore all 11 of the 100 publi-cations that measured total brain exposureincluded an author from the pharmaceutical in-dustry (n=5) an academic drug screening group(n = 3) or a pharmacologyndashpharmaceuticalsciences department (n = 3) This observationlikely reflects the limited presence of pharma-cology and pharmacometrics departmentswithinmost academic institutions and limitedaccess to the mass spectrometry and otheranalytical resources needed to measure druglevels in study samples Outsourcing the bio-analysis of samples collected from study ani-mals is feasible but the use of contract researchorganizations to support such studies is oftentoo costly for most academic grant budgets toaccommodate
DATABASES AND REPURPOSINGRecent years have seen increasing efforts toinvestigate approved or clinically tested drugsfor new indications (4ndash8) Such repurposinghas been touted as a means to accelerate ther-apeutic development (4) For example a stra-tegic pillar of the US National Institutes ofHealthrsquos (NIHrsquos) translational roadmap callsfor the academic community to actively par-ticipate in the repurposing of drugs approvedby the US Food and Drug Administration(FDA) or investigational drugs that havepassed safety hurdles but failed in clinicaltrials because of lack of efficacy (9ndash11) To havea meaningful impact in neurological and psy-chiatric disorders such drug repurposingefforts will require access to neuropharma-cokinetic (neuroPK) data sets in mice to guidethe testing of new therapeutic hypotheses ingenetically engineered disease models A re-cently published consensus evaluation of drugrepositioning opportunities for Alzheimerrsquosdisease identified 15 potential drug candidatesThese were further prioritized for testing onthe basis of available evidence to produce ashortlist of seven compounds reviewed by in-dustry experts to provide insight into the via-bility of these candidates The most commonshortcoming identified for the compoundsconsidered were issues related to insufficientbrain penetration or the lack of informationabout optimal dosing strategies (11)
The repurposing of statins illustrateshow the neuroPK knowledge gap limits progressStatins were developed as 3-hydroxy-3-methylglutarylndashcoenzyme A (HMG-CoA) reduc-tase inhibitors to lower cholesterol and reduce
Table 1 Preclinical dosing strategies The rationale for drug-dosing strategies was extractedfrom the literature through the analysis of 100 peer-reviewed studies published in2014 from eight journals that cover research on mechanisms of brain function disease andtherapeutic approaches to CNS disorders (Cell Neuron Nature Nature Neuroscience NatureMedicine Neurobiology of Disease Neuropsychopharmacology and Science TranslationalMedicine) (table S1) Forty-four of the 100 publications selected were studies of potentialtherapeutic approaches to disease whereas the remaining were studies of basic neurobiology ormechanisms of disease Each publication was examined to discern how authors selected thedosage of pharmacological tools or therapeutic compounds used in the design of studies toprobe brain function A relatively small number of studies considered what the concentrationof drug available in the brain after administration would be in the context of theirexperimental studies The most common method for selecting a dose of drug was tocite a previous study that demonstrated a biological effect of the drug on someaspect of rodent behavior
Rationale for studyrsquos drug-dose selection
Therapeutic
studies
Number of papers from the100 published studies
analyzed
bull No exposure or rationale for dose selection provided
5
22
bull Rodent dose extrapolated from human studies
0
1
bull Doses are similar to what was used previously toproduce a biological effect
8
23
bull Literature reports cited for multiple functionaleffects of drug at selected dose
4
5
bull Brain penetration evaluated but exposure notmeasured
2
2
bull Literature report of mismatched drug exposure
0
1
bull Observation of a biological effect at a single dosein current study
3
6
bull Observation of dose-responsive biological effectin current study
5
16
bull Brain exposure to drug was measured with routeof administration that differed from the oneused in the efficacy study
1
1
bull Plasma drug concentrations measured literaturereport of brain exposure cited and target-organpharmacodynamic effect observed in the currentstudy
1
1
bull Plasma drug concentrations measured
4
7
bull Brain pharmacodynamic effect of drug observed
2
4
bull Brain drug concentrations measured (totalconcentration)
6
7
bull Unbound brain drug concentrations measured
1
2
bull Brain drug concentrations measured and brainpharmacodynamic effect of drug observed
2
2
Total
44
100
rg 6 January 2016 Vol 8 Issue 320 320ps1 2
P ER SP EC T I V E
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risk of cardiovascular disease (12) FDA hasapproved at least nine different statins andmost are commonly prescribed nearly one-third of Americans ages 55 to 64 took a pre-scription cholesterol-lowering drug between2009 and 2012 (wwwcdcgovnchsdatahushus14pdf) The widespread availability andsafety profile of statins has lured researchersinto evaluating their potential for repurpos-ing (13) Statins have been profiled extensive-ly in preclinical research to test for potentialtherapeutic benefit in Alzheimerrsquos disease(14ndash19) Fragile X syndrome (20) Rett syn-drome (21 22) epilepsy (23) Huntingtonrsquos dis-ease (24) Parkinsonrsquos disease (25 26) stroke(27) and brain injury (28 29)
A search of the literature reveals no sys-tematic neuroPK studies in any mouse strainthat would enable direct comparisons of CNSexposure across the various statins In silicopredictions based on the drugsrsquo molecularproperties suggest that the nine most widelyprescribed statins each have a different poten-tial to penetrate the blood-brain barrier differ-ent potencies against the HMG-CoA reductaseenzyme and different ldquooff-targetrdquo activity pro-files (30) On the basis of available data thereis reason to believe that simvastatin has thebest overall profile for inhibiting HMG-CoAreductase in the brain (30) A recent study re-ported that lovastatin is able to reverse a rangeof phenotypes in a mouse model of Fragile Xsyndrome (20) However the design of an op-timal clinical trial will require the collection ofmouse pharmacokinetic data to understandhow much CNS drug exposure is required toproduce efficacy in the disease model Thereare at least two possible scenarios Giventhat simvastatin is more potent at inhibitingHMG-CoA reductase than are other statinsand likely to be more brain penetrant inboth mice and humans one would expectthat simvastatin will be more potent than lo-vastatin in ameliorating symptoms in bothmice and humans if the observed efficacy stemsfrom inhibition of HMG-CoA reductase activ-ity in the brain by lovastatin The advantage ofthis outcome would be that better brain pen-etration and potency would lead to a loweroverall dose requirement to achieve efficacyand thus likely a better safety profile
A second scenario could be that lovastatin ismore potent than simvastatin in the mousemodel of Fragile X syndrome because of anadditional biological activity inherent to thelovastatinmolecule whichmaynot yet be doc-umented in the literature In either case un-derstanding the CNS exposure of lovastatin
required to produce efficacy in themouse willdetermine whether there is a safe therapeuticindex for achieving the required concentra-tion in patients Previous attempts to discernuseful neuroPK parameters from the litera-ture for the use of statins in rodent modelshave highlighted the lack of critical data asthe looming roadblock to progress in the field(31 32) Until these data exist the transla-tional potential of preclinical research maybe limited And this is but one example ofone drug class
The creation of a centralized database isneeded for the entire translational researchcommunity and would establish a new mech-anism for academia funding agencies founda-tions and industry to pool resources If studiesare donewell the first time and documented inan open-access resource it will reduce redun-dant efforts and improve the quality of decisionmaking by scientists considering innovativesolutions to our biggest health problems
FILL THE GAPSManuscript submission practices for severalhigh-impact journals now include require-ments that authors include detailed informa-tion regarding study design and statisticalanalysis with each submission A reasonableextension of this checklist should includethe stated rationale for doses selected for studydrugs Information should include a discus-sion of data highlighted in Table 2 Authorsshould be expected to reference a relevant
wwwScienceTranslationalMedicineo
data set from a high-quality database or pub-lication or provide the data in the current study(Table 3)
Industry biologists learn basic principlesof medicinal chemistry pharmacokineticsand drug disposition while working on drugdiscovery project teams Academic groupsare playing an increasing role in transla-tional therapeutics and in particular drugrepurposing Academic programs need toaugment training in pharmacokinetics andpharmacodynamics so as to increase the rigor ofpreclinical work and to ensure that investigator-initiated clinical studies are testing hypotheseseffectively Institutions without a departmentof pharmacology or pharmacometrics mightlack the organizational knowledge needed toconduct drug studies and must identify re-sources or collaborators to patch these defi-cits Formal coursework and Web-basedresources and tutorials are needed to train andsupport translational researchers Manuscriptand grant reviewers need to demand higherstandards for preclinical studies with respect toreporting on drug exposure associated withbiological effects Ethics committees responsi-ble for review of animal protocols should re-quire investigators to provide rationale fordose selections in proposed studies Similarlyscientific review boards at academic medicalcenters need to include clinical pharmacologistswho are able to review investigator-initiatedclinical studies to ensure that proposed dosingstrategies will test a meaningful hypothesis
Table 2 Recommendations for use of pharmacokinetic data The first column includes a listof recommended data sets to aid reviewers of submitted articles in the interpretation ofpreclinical findings The second column includes a list of useful reference data that wouldsupport improved preclinical study design in mice if available in a public database
Literature reports that evaluate studydrugs should include
Compound-specific data that shouldbe included in a rodent
pharmacokinetic database
bull Expected or measured plasma exposure of thestudy drug in the preclinical species during thestudy
bull Elimination half-life (T12)bull Systemic clearance (CL)bull Fraction of drug that is protein bound (fb)
bull Expected or measured target organ exposureof the study drugs in the preclinical speciesduring the study
Maximum plasma concentration after drug admin-istration (Cmax) and time to reach maximum plas-ma concentration (Tmax) for a standardized doseand route of administration
bull Expected or measured free fraction (unboundby protein) of the study drugs in the targetorgan of the preclinical species during thestudy
bull The ratio of drug in brain to that in plasma (BP)bull The ratio of drug found free in brain (Cub) to thatfound free in the plasma (Cup) defined as CubCupbull Any potential impact of drug transporters (foundon the rodent blood-brain barrier) in limiting brainexposure
bull Expected or measured potency of the studydrug against the hypothesized activity in vitro
Expected ormeasured potency of molecule at knownbiological targets
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A central repository that contains brainpenetration protein binding and pharmaco-kinetic profiles of drugs and pharmacologicaltools in rodents is needed to effectively sup-port translational research This databaseshould also provide basic tutorials that de-fine primary pharmacokinetic parameterswith examples to illustrate how data are usedto predict optimal dosing strategies The min-imum data set needed for each compoundin a useful rodent database is highlighted inTable 2 Access to this information and sup-porting materials will have an immediateimpact on the quality of translational drug re-purposing efforts across brain disorders andwill support the development of new thera-peutic approaches to neurological disordersand mental illness Existing databases man-aged by NIH or precompetitive consortia couldbe reinforced with donated pharmacokineticdata sets and tutorials
Industry and government scientists shouldwork precompetitively to collect and curatepharmacokinetic data sets in conjunction withsupporting educational materials Mouse phar-macokinetic data exist inside pharmaceuti-cal companies for a wide range of publicallydisclosed molecules and literature standardsRelease of these data into a public databasewould provide several benefits to companiesincluding (i) increased scientific rigor in theliterature with a higher probability of repro-ducibility (ii) increased appreciation by theacademic biology community for the diffi-culty inherent in generating molecules withpotency and pharmacokinetic profiles suit-able for in vivo work opening the door forin-kind collaboration with academic groups
and (iii) direct comparison of data collectedin-house to that collected at other compa-nies or institutions to enable better internalquality control Comprehensive pharmaco-kinetic data sets will benefit all therapeuticareas regardless of whether the brain is thetarget organ because peripheral and cen-tral exposure data can be generated fromthe same experiments Moreover the prin-ciples described above for the CNS apply toother target tissues in which vascular bar-riers metabolic processes or active transportalter the distribution of systemically admin-istered drugs
Key to ensuring that preclinical mousestudies test the hypotheses they aim to eval-uate is an understanding of the unboundfraction of drug present in the target organat an appropriate time point under studyGrant and journal reviewers need to care-fully consider whether authors of propos-als and manuscripts are providing adequaterationale for their choices of preclinical dos-ing paradigms Importantly the collectionand centralization of rodent pharmacoki-netic datasets will promote efficient genera-tion of future data reduce the collection ofredundant data and improve the return oninvestment for research funds that are de-voted to preclinical studies aimed towardclinical translation
SUPPLEMENTARY MATERIALS
wwwsciencetranslationalmedicineorgcgicontentfull8320320ps1DC1Table S1 One hundred publications that used systemic drugdelivery with the goal of targeting rodent brains
wwwScienceTranslationalMedicineo
REFERENCES AND NOTES1 A Reichel Addressing central nervous system (CNS) penetra-
tion in drug discovery Basics and implications of the evolv-ing new concept Chem Biodivers 6 2030ndash2049 (2009)
2 F Prinz T Schlange K Asadullah Believe it or not Howmuch can we rely on published data on potential drugtargets Nat Rev Drug Discov 10 712 (2011)
3 C G Begley L M Ellis Drug development Raisestandards for preclinical cancer research Nature 483531ndash533 (2012)
4 P Nair Second act Drug repurposing gets a boost asacademic researchers join the search for novel uses ofexisting drugs Proc Natl Acad Sci USA 110 2430ndash2432(2013)
5 T I Oprea J Mestres Drug repurposing Far beyond newtargets for old drugs AAPS J 14 759ndash763 (2012)
6 S M Strittmatter Overcoming drug development bot-tlenecks with repurposing Old drugs learn new tricksNat Med 20 590ndash591 (2014)
7 K Xu T R Coteacute Database identifies FDA-approved drugswith potential to be repurposed for treatment of orphandiseases Brief Bioinform 12 341ndash345 (2011)
8 X Bosch European researchers drug companies joinforces against rare diseases JAMA 294 2014ndash2015 (2005)
9 F S Collins Mining for therapeutic gold Nat Rev DrugDiscov 10 397 (2011)
10 P Vallance P Williams C Dollery The future is much closercollaboration between the pharmaceutical industry andacademic medical centers Clin Pharmacol Ther 87525ndash527 (2010)
11 A Corbett J Pickett A Burns J Corcoran S B DunnettP Edison J J Hagan C Holmes E Jones C KatonaI Kearns P Kehoe A Mudher A Passmore N ShepherdF Walsh C Ballard Drug repositioning for Alzheimerrsquosdisease Nat Rev Drug Discov 11 833ndash846 (2012)
12 J L Goldstein M S Brown A century of cholesterol andcoronaries From plaques to genes to statins Cell 161161ndash172 (2015)
13 A M Malfitano G Marasco M C Proto C Laezza P GazzerroM Bifulco Statins in neurological disorders An overviewand update Pharmacol Res 88 74ndash83 (2014)
14 T Kurata K Miyazaki M Kozuki N Morimoto Y OhtaY Ikeda K Abe Progressive neurovascular disturbances inthe cerebral cortex of Alzheimerrsquos disease-model miceProtection by atorvastatin and pitavastatin Neuroscience197 358ndash368 (2011)
15 H Kurinami N Sato M Shinohara D Takeuchi S TakedaM Shimamura T Ogihara R Morishita Prevention ofamyloid beta-induced memory impairment by fluvastatinassociated with the decrease in amyloid beta accumulationand oxidative stress in amyloid beta injection mousemodel Int J Mol Med 21 531ndash537 (2008)
16 M Shinohara N Sato H Kurinami D Takeuchi S TakedaM Shimamura T Yamashita Y Uchiyama H RakugiR Morishita Reduction of brain beta-amyloid (Abeta)by fluvastatin a hydroxymethylglutaryl-CoA reductaseinhibitor through increase in degradation of amyloidprecursor protein C-terminal fragments (APP-CTFs) andAbeta clearance J Biol Chem 285 22091ndash22102 (2010)
17 G J Siegel N B Chauhan D L Feinstein G Li E B LarsonJ C Breitner T J Montine Statin therapy is associated withreduced neuropathologic changes of Alzheimer diseaseNeurology 71 383 author reply 383 (2008)
18 X-K Tong C Lecrux P Rosa-Neto E Hamel Age-dependentrescue by simvastatin of Alzheimerrsquos disease cerebrovascularand memory deficits J Neurosci 32 4705ndash4715 (2012)
19 X K Tong N Nicolakakis P Fernandes B Ongali J BrouilletteR Quirion E Hamel Simvastatin improves cerebrovascularfunction and counters soluble amyloid-beta inflammationand oxidative stress in aged APP mice Neurobiol Dis35 406ndash414 (2009)
Table 3 Recommendations to improve translation through the use of preclinicalpharmacokinetic data
Journalsbull Require authors to provide explicit rationale for dosing strategies usedbull Rationale should include consideration of the unbound drug exposure in target organas best practices
Educationbull Include basic pharmacology and pharmacokinetic principles in formal coursework requiredfor basic preclinical and clinical research scientists
bull Develop tutorials and on-line calculators for rodent dose projections to support appropriateuse of published pharmacological tools
Databasesbull Reinforce public chemical databases with mouse pharmacokinetic data that includes brainexposure
Precompetitive consortiabull Create precompetitive consortia to solicit mouse pharmacokinetic data sets from industry andfoundation partners for database expansion
bull Targeted data collection for compounds already in the public domain
rg 6 January 2016 Vol 8 Issue 320 320ps1 4
P ER SP EC T I V E
20 E K Osterweil S C Chuang A A Chubykin M SidorovR Bianchi R K Wong M F Bear Lovastatin corrects ex-cess protein synthesis and prevents epileptogenesis in amouse model of fragile X syndrome Neuron 77 243ndash250(2013)
21 C M Buchovecky S D Turley H M Brown S M KyleJ G McDonald B Liu A A Pieper W Huang D M KatzD W Russell J Shendure M J Justice A suppressorscreen in Mecp2 mutant mice implicates cholesterol me-tabolism in Rett syndrome Nat Genet 45 1013ndash1020(2013)
22 M J Justice C M Buchovecky S M Kyle A Djukic A rolefor metabolism in Rett syndrome pathogenesis Newclinical findings and potential treatment targets RareDis 1 e27265 (2013)
23 F Scicchitano A Constanti R Citraro G De Sarro E RussoStatins and epilepsy Preclinical studies clinical trials andstatin-anticonvulsant drug interactions Curr Drug Targets16 747ndash756 (2015)
24 M L Ferlazzo L Sonzogni A Granzotto L Bodgi O LartinC Devic G Vogin S Pereira N Foray Mutations of theHuntingtonrsquos disease protein impact on the ATM-dependentsignaling and repair pathways of the radiation-inducedDNA double-strand breaks Corrective effect of statins andbisphosphonates Mol Neurobiol 49 1200ndash1211 (2014)
25 E K Tan L C Tan Holding on to statins in Parkinsondisease Neurology 81 406ndash407 (2013)
26 B Friedman A Lahad Y Dresner S Vinker Long-termstatin use and the risk of Parkinsonrsquos disease Am J ManagCare 19 626ndash632 (2013)
27 M S Elkind Stroke A step closer to statin therapy forstroke Nat Rev Neurol 9 242ndash244 (2013)
28 E E Abrahamson M D Ikonomovic C E Dixon S T DeKoskySimvastatin therapy prevents brain trauma-inducedincreases in beta-amyloid peptide levels Ann Neurol66 407ndash414 (2009)
29 E F Wible D T Laskowitz Statins in traumatic brain injuryNeurotherapeutics 7 62ndash73 (2010)
wwwScienceTranslationalMedicineo
30 S Sierra M C Ramos P Molina C Esteo J A VaacutezquezJ S Burgos Statins as neuroprotectants A comparativein vitro study of lipophilicity blood-brain-barrier penetra-tion lowering of brain cholesterol and decrease of neuroncell death J Alzheimers Dis 23 307ndash318 (2011)
31 W G Wood G P Eckert U Igbavboa W E Muumlller Statinsand neuroprotection A prescription to move the fieldforward Ann N Y Acad Sci 1199 69ndash76 (2010)
32 W G Wood W E Muumlller G P Eckert Statins and neuro-protection Basic pharmacology needed Mol Neurobiol50 214ndash220 (2014)
101126scitranslmedaac9888
Citation R J Kleiman M D Ehlers Data gaps limit thetranslational potential of preclinical research Sci Transl Med8 320ps1 (2016)
D
rg 6 January 2016 Vol 8 Issue 320 320ps1 5
on January 6 2016httpstm
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ownloaded from
101126scitranslmedaac9888] (320) 320ps1 [doi8Science Translational Medicine
Robin J Kleiman and Michael D Ehlers (January 6 2016) Data gaps limit the translational potential of preclinical research
Editors Summary
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is a registered trademark of AAASMedicineScience TranslationalAssociation for the Advancement of Science all rights reserved The title
Science 1200 New York Avenue NW Washington DC 20005 Copyright 2016 by the Americanweekly except the last week in December by the American Association for the Advancement of
(print ISSN 1946-6234 online ISSN 1946-6242) is publishedScience Translational Medicine
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nloaded from
Boston Childrenrsquos Hospital ndash Broad Institute Collaboration Grants
Background Meeting the challenges of biomedicine requires bringing together creative scientists exceptional technological resources and world-class expertise across many disciplines that rarely exist within a single institution This guiding principle is the basis for a funding opportunity to support Boston Childrenrsquos Hospital investigators performing research in collaboration with Broad scientists
Goals The fundamental goal of this new award is to spark new collaborations between Boston Childrenrsquos Hospital and the Broad Institute The grants will be awarded to address a very wide range of scientific questions but are specifically designated for projects with the following characteristics
middot Projects where engagement with the Broad would benefit Childrenrsquos Hospital investigators projects that can uniquely benefit from being done at the Broad Institute
middot Projects that create new scientific collaborations and bring together diverse scientific backgrounds projects that spark new scientific directions or technologies and are not currently being pursued at Childrenrsquos Hospital
middot Projects that pilot new approaches that researchers at Childrenrsquos the Broad and the greater scientific community can benefit from in the future the purpose of these awards is not to provide gap or extension funding of existing projects but to initiate new projects
Eligibility Individuals with Principal Investigator status at Boston Childrenrsquos Hospital are eligible Applicants need not be Associate Members of the Broad Institute
Broad Platforms and Scientists Broadrsquos Platforms (Genomics Imaging Metabolite Profiling Proteomics Genomic Perturbation and the Broad Technology Labs) are collaborative organizations that provide scientific leadership and cutting edge technologies in support of project goals Collaborations can also be established with other groups at the Broad including the Klarman Cell Observatory the Stanley Center for Psychiatric Research or the Center for the Development of Therapeutics
Budgets Grants will provide $60000 direct support for 1 year plus philanthropic overhead It is expected that most grants will fund work performed at the Broad Institute either through interaction with Broadrsquos Platforms or via collaboration with a Broad scientist however the work may also occur at Boston Childrenrsquos if it is important to meet the scientific goals of the collaboration
Deadline and Review process Final proposals are due by September 1 2015 Funding decisions are expected to be reached by October 1 2015 Proposals will be reviewed by a joint Childrenrsquos HospitalndashBroad Institute committee Additional submission dates are expected for 2016
Submission Applicants are strongly encouraged to discuss potential applications in advance with the office of the Chief Scientific Officer at the Broad Questions should be directed to Alex Burgin ( 617-714-7124)
Proteomics Genomic Perturbation and the Broad Technology Labs) are collaborative
organizations that provide scientific leadership and cutting edge technologie
s in support of
project goals Collaborations can also be established with other groups at the Broad including
the Klarman Cell Observatory the Stanley Center for Psychiatric Research or the Center for the
Development of Therapeutics
Budgets
Grants wi
ll provide $60000 direct support for 1 year plus philanthropic overhead It
is expected that most grants will fund work performed at the Broad Institute either through
interaction with Broadrsquos Platforms or via collaboration with a Broad scientist howev
er the
work may also occur at Boston Childrenrsquos if it is important to meet the scientific goals of the
collaboration
Deadline and Review process
Final proposals are due by September 1 2015 Funding
decisions are expected to be reached by October 1 201
5 Proposals will be reviewed by a joint
Childrenrsquos Hospital
ndash
Broad Institute committee Additional submission dates are expected for
2016
Submission
Applicants are
strongly encouraged to discuss potential applications in
advance
with the office of the Chief Sc
ientific Officer at the Broad
Questions should be
directed to Alex Burgin (
aburginbroadinstituteorg
617
-
714
-
7124
)
Boston Childrenrsquos Hospital ndash Broad Institute Collaboration Grants
Background Meeting the challenges of biomedicine requires bringing together creative
scientists exceptional technological resources and world-class expertise across many
disciplines that rarely exist within a single institution This guiding principle is the basis for a
funding opportunity to support Boston Childrenrsquos Hospital investigators performing research
in collaboration with Broad scientists
Goals The fundamental goal of this new award is to spark new collaborations between Boston
Childrenrsquos Hospital and the Broad Institute The grants will be awarded to address a very wide
range of scientific questions but are specifically designated for projects with the following
characteristics
Projects where engagement with the Broad would benefit Childrenrsquos Hospital
investigators projects that can uniquely benefit from being done at the Broad Institute
Projects that create new scientific collaborations and bring together diverse scientific
backgrounds projects that spark new scientific directions or technologies and are not
currently being pursued at Childrenrsquos Hospital
Projects that pilot new approaches that researchers at Childrenrsquos the Broad and the
greater scientific community can benefit from in the future the purpose of these awards
is not to provide gap or extension funding of existing projects but to initiate new
projects
Eligibility Individuals with Principal Investigator status at Boston Childrenrsquos Hospital are
eligible Applicants need not be Associate Members of the Broad Institute
Broad Platforms and Scientists Broadrsquos Platforms (Genomics Imaging Metabolite Profiling
Proteomics Genomic Perturbation and the Broad Technology Labs) are collaborative
organizations that provide scientific leadership and cutting edge technologies in support of
project goals Collaborations can also be established with other groups at the Broad including
the Klarman Cell Observatory the Stanley Center for Psychiatric Research or the Center for the
Development of Therapeutics
Budgets Grants will provide $60000 direct support for 1 year plus philanthropic overhead It
is expected that most grants will fund work performed at the Broad Institute either through
interaction with Broadrsquos Platforms or via collaboration with a Broad scientist however the
work may also occur at Boston Childrenrsquos if it is important to meet the scientific goals of the
collaboration
Deadline and Review process Final proposals are due by September 1 2015 Funding
decisions are expected to be reached by October 1 2015 Proposals will be reviewed by a joint
Childrenrsquos HospitalndashBroad Institute committee Additional submission dates are expected for
2016
Submission Applicants are strongly encouraged to discuss potential applications in
advance with the office of the Chief Scientific Officer at the Broad Questions should be
directed to Alex Burgin (aburginbroadinstituteorg 617-714-7124)
Clinical Trials Glossary
ADME an acronym for absorption distribution metabolism and elimination ADME
studies determine how a drug is absorbed by the body the chemical changes that it may
undergo and how it is eliminated from the body
Adverse event (AE) a bothersome event that occurs in a study participant AEs may be
related to the treatment being tested or may be due another cause (eg another treatment
another medical condition an accident or a surgery)
Arm a specific type of treatment to which a group of clinical trial participants is
assigned Some clinical trials have one arm and some have two arms while others have
three or more arms For example a clinical trial comparing two different doses of an
investigational drug versus a placebo would have three arms participants receiving a
higher dose of the investigational drug participants receiving a lower dose of the
investigational drug and participants receiving the placebo
Baseline a point in time at the beginning of a clinical trial before the study participants
receive any treatment At the baseline participants usually have certain types of tests
During and after treatment the same tests may be performed and the results compared
with the baseline results to see if the drug has caused changes
Bias a factor ndash such as a preconceived idea about the effects of the benefits and risks of a
treatment or a lack of balance in selection of patients for a study ndash that reduces the
likelihood that the study results are true Methods such as blinding and randomization
are used to limit the potential for bias
Bioavailability the portion of the dose of a drug that reaches the bloodstream For
example if the drug is administered intravenously its bioavailability is 100 percent
however if the drug is administered in any other way such as orally topically or
through intramuscular injection its bioavailability will decrease due to incomplete
absorption
Bioequivalence study a test performed to compare the portion of a drug in the
bloodstream when administered in different dosage forms
Biologic product any substance that can be used in prevention treatment or cure of
disease Some examples include vaccines blood virus toxin antitoxin and therapeutic
serum
Biopsy the removal of cells or tissue from a patient for examination which is usually
done under a microscope A tissue sample might be taken for genetic studies Sometimes
there is a difference between the blood genotype and the skin or other tissue genotype
This term can also refer to the tissue sample that has been obtained by such a procedure
2
Blinding a process used to prevent the participants the researchers or both from
knowing what specific treatment is being given to participants in a clinical trial The
process of blinding helps to reduce bias because study participants and researchers are
less likely to be unconsciously influenced by the knowledge of what the study participant
is actually receiving If only the participants are blinded the study is called a single-
blind study If both participants and researchers are blinded the study is called a double-
blind study
Carcinogenicity studies long-term studies conducted in animal models to determine a
drugrsquos likelihood of causing cancer
Clinical efficacy a compoundrsquos ability to produce the desired effect
Clinical pharmacology a science that studies properties of drugs in relation to their
therapeutic value in humans
Clinical study or Clinical trial a medical experiment in human beings that helps to
determine how a disease drug or medical device affects study participants Clinical
studies are necessary to answer specific questions about how to better diagnose prevent
or treat a disease or condition
Cohort a group of study participants who have certain characteristics in common such
as female sex a defined age range or particular severity of disease Dividing study
participants into cohorts is often done as part of the analyses of study data
Contraindication a factor that makes the use of a particular drug inadvisable For
example a person who has had an allergic reaction to penicillin in the past is considered
to have a contraindication to using penicillin in the future
Control group a group of participants not receiving the investigational drug but instead
receiving a standard treatment for their disease or receiving a placebo The results
observed in the group of patients receiving the investigational drug are compared with the
results observed in the control group
Crossover study a study design with two or more arms where participants receive one
treatment for a period of time and then switch over to a second treatment for a period of
time Such a study design allows the effects of the two treatments to be compared in the
same patient
Data Monitoring Committee (DMC) or Data Safety and Monitoring Board (DSMB)
A committee of experts that periodically reviews the accumulating data from an ongoing
multicenter clinical trial Members of a DMCDSMB must be independent ie they
cannot be participating as investigators in the clinical trial Based on their review the
DMCDSMB experts advise the sponsor regarding whether it is safe and acceptable to
continue with the study or whether the data suggest that the study should be modified or
stopped A DMCDSMB may recommend that a trial be stopped if there are safety
concerns or if the trial objectives have been achieved
3
Dose-ranging study a clinical trial in which two or more doses of an investigational
drug are tested to determine which dose is likely to offer the best combination of safety
and efficacy in later clinical trials or in medical care
Efficacy or effectiveness the ability of a drug to prevent cure or slow a disease process or to alleviate the symptoms of a disease or condition
Eligibility a determination made during the screening period for a clinical study of
whether a personrsquos participation in the trial is likely to be safe and can contribute data
that will help achieve the study goals
Endpoint occurrence of a disease symptom sign or test result that constitutes one of the
target outcomes of a clinical trial
Inclusionexclusion criteria the factors defined in the protocol of a study that determine
whether a personrsquos participation in a clinical trial is likely to be safe and can contribute
data that will help achieve the study goals Study candidates undergo evaluation during
the study screening period to determine if they meet all of the inclusion criteria and do
not meet any of the exclusion criteria as defined in the protocol These criteria usually
consider such factors as age sex type of disease stage of disease previous treatment
history and other medical conditions in determining eligibility for the study
Informed consent (assent) a process by which medical researchers provide necessary
information to a person about a clinical study and the person voluntarily confirms his or
her willingness to participate in the study Children who are considered old enough to
have a basic understanding of the study may need to provide assent to be involved in the
study a parent or legal guardian must also give informed consent for such a child to
participate
Informed consent (assent) form a document that describes a clinical study to the
participants (or their parentsguardians) The informed consent (assent) form includes
information about the goals of the study the study design and duration the types of tests
to be performed the potential risks and inconveniences the potential benefits the
possible costs or payments associated with study participation the available alternative
therapies the rights and responsibilities of the participant and the people to contact if the
participant has questions The informed consent (assent) form must be reviewed and
signed before the participant has any study tests or treatment including the tests
performed during the screening period at the beginning of the study Participants are
given a copy of the informed consent (assent) form to take home
Institutional Review Board (IRB) or Independent Ethics Committee (IEC) a board
of physicians statisticians researchers community advocates and others who are
responsible for ensuring the protection of the rights safety and well-being of participants
in a clinical trial at a study center This board is called an IRB in the United States and is
often called an IEC in other countries IRBIECs review and approve important study
documents (eg protocols informed consent forms study advertisements and patient
4
brochures) before the start of the study and periodically review the progress of the study
while it is ongoing
Investigational Drug a drug that is being tested as a potential treatment for a disease or
condition but has not yet been proven safe and effective for that use
Investigator a physician or other health care worker who carries out a clinical trial by enrolling treating and monitoring participants and recording the results
In vitro testing testing conducted in test tubes or other artificial environments
In vivo testing testing conducted in living animals or humans
Longitudinal study a clinical study that involves observations of the same items over
long periods often many decades Because longitudinal studies track the same people
they are often used to study trends across the life span to uncover predictors of certain
diseases or to track the effects of a particular treatment on a patientrsquos condition over
time
Multicenter study a study conducted at more than one location Multicenter clinical
studies are generally performed when each individual clinical trial site does not have
enough study candidates to complete a large trial
Natural history study a study of the natural development of a disease or condition over
a period of time Natural history studies are usually longitudinal studies
New Drug Application (NDA) the registration document through which a
pharmaceutical company formally proposes that the FDA approve a new drug for
manufacturing and sale The application includes detailed reports of pharmacology
toxicology manufacturing and chemistry as well as data from clinical trials
Open-label study a study in which the participants and the investigators know which
treatment is being given In an open-label study there is no blinding and none of the participants receives a placebo
Orphan disease a disease or condition that affects a relatively small number of people
In the US this defined as fewer than 200000 people In Europe this is defined as fewer
than five in 110000 people
Orphan drug a drug intended to treat an orphan disease
Participant or subject a patient or healthy volunteer who participates in a clinical trial
Phase 1 the initial phase of testing of an investigational drug in humans Usually a
Phase 1 clinical study is conducted in a small number of healthy volunteers or patients
with a disease for which the drug may be useful Generally the study is designed to
determine the side effects of the drug and its pharmacokinetics Some information
5
regarding drug efficacy may be collected if patients with a disease participate A phase
frequently encompasses more than one clinical trial Phase 1 sometimes is sub-divided
into Phases 1a and 1b for example when the first set of Phase 1 trials (Phase 1a) is
performed in healthy volunteers and a second set of Phase 1 trials (Phase 1b) is
performed in patients with a disease
Phase 2 the intermediate phase of testing of an investigational drug in humans Usually
a Phase 2 clinical study conducted in patients with a disease for which the drug may be
useful Generally the study is designed to evaluate dosing to obtain preliminary data on
the effectiveness of the drug and to acquire more safety information Phase 2 sometimes
is sub-divided into Phases 2a and 2b Phase 2a studies typically are smaller and shorter
in duration and evaluate different drug doses to see how they affect certain tests that can
indicate whether the drug is working as expected Phase 2b studies typically enroll more
patients are of longer duration and evaluate whether the drug is offering clinical benefits to patients Phase 2b studies sometimes are considered pivotal or registration-directed
Phase 3 the final phase of testing an investigational drug in humans before regulatory
approval Phase 3 studies are usually conducted in a large population of patients and are
generally designed to confirm the effectiveness of the drug and to evaluate the overall
risk-benefit ratio Phase 3 studies usually test the investigational drug in comparison with
a standard treatment for the disease or a placebo
Phase 4 testing of a drug in humans after it has already been approved by regulatory
authorities and can be used in medical practice Phase 4 studies may be conducted to
compare the drug to a similar type of drug to explore whether it may help patients with
other diseases to further study the long-term safety of the drug or for other reasons
Pivotal study a study that is designed to generate the data required by regulatory
authorities to decide whether to approve an investigational drug A pivotal study is
usually a large randomized Phase 2b or Phase 3 study and often is blinded and uses a
placebo as a control Sometimes a pivotal study is described as a registration-directed
study
Placebo an inactive version of an investigational drug A placebo has a similar
appearance to the investigational drug but is expected to have no therapeutic value A
placebo is used as a comparison treatment to reduce bias in randomized studies
Preapproval access program an umbrella term for programs that allow seriously ill
patients to receive an investigational drug when they are unable to participate in clinical
trials and there is no alternative treatment This is sometimes referred to as
compassionate use Types of pre-approval access programs include expanded access
parallel-track named patient program single-patient exemption and treatment IND The
timing for starting an expanded access program usually depends upon what is known
about the risk-benefit of the drug and whether the drug can be provided in a manner that
is fair to patients with the disease
6
Preclinical (nonclinical) testing testing of a drug in test tubes or in animals A drug
undergoes preclinical testing before being tested in humans to make sure that it shows
evidence of desired effects and is sufficiently safe for study in people Preclinical testing
sometimes also helps to determine the doses of the drug that should be evaluated in
humans Preclinical testing is sometimes called nonclinical testing
Protocol a document describing what types of people may participate in a clinical study
and the objectives treatments measurements statistical methods timing and
organization of a clinical trial The protocol must be prepared in advance of the study
and must be reviewed and approved by review committees and regulatory authorities
before the study is started Investigators must follow the protocol to carry out the study
Randomization assignment of participants to treatment arms based on chance This is
usually done by a computer program in a way that does not allow either the participants
or the investigators to choose who is assigned to which arm Randomization is used to
reduce bias in clinical trials
Risk-benefit ratio the balance of the risk of side effects expected with use of a drug
versus the potential for benefit with the use of that drug A drug with a good risk-benefit
ratio has few side effects and is very effective
Serious adverse event (SAE) an adverse event that is life-threatening requires inpatient
hospitalization or lengthens a hospital stay leads to substantial disability leads to a birth
defect or results in death
Side effect any effect of a drug other than the desired effect Side effects are often
unwanted and may be bothersome Other names for a bothersome side effect are adverse
drug reaction (ADR) or drug toxicity
Screening period a period at the beginning of a clinical trial when candidates for the
study are evaluated to determine if their participation is likely to be safe and can
contribute data that will help achieve the study goals
Significant or statistically significant an outcome in a clinical trial is likely to result
from a real difference (eg due to an effect of a treatment) and is unlikely to be due to
chance alone The level of statistical significance is often expressed in terms of a p-
value which indicates the probability that a difference is not due to chance alone
Usually a p-value smaller 005 is considered statistically significant
Sponsor the organization responsible for financing and coordinating a clinical trial
Most often this is a pharmaceutical or biotechnology company
Standard treatment a treatment currently in wide use often approved by regulatory
agencies and generally considered effective in the treatment of a specific disease or
condition
7
Toxicity a side effect produced by a drug that is bothersome to the person taking the
drug
Toxicology the study of the adverse effects of chemicals conducted in animal models to
predict potential adverse effects in humans Some studies are conducted during clinical
development to evaluate dosing regimens
Boston Childrenrsquos Hospital Clinical Research Map 1 Mouse over for additional info Bold = hyperlink
CLINICAL RESEARCH MAP
Boston Childrenrsquos Hospital Clinical Research Map 2 Mouse over for additional info Bold = hyperlink
ObjectiveThis clinical research map is designed to serve as a guide for investigators study coordinators and research nurses at Boston Childrenrsquos Hospital The research map outlines the key steps in preparing to launch a research study and provides embedded links to institutional resources tools and documents
An investigator need not follow the steps on the Clinical Research Map in any particular order There is flexibility and the steps followed will in part de-pend on the type of research study
For new as well as more experienced investigators the Clinical Research Map can be used as a checklist or an inves-tigator can use the steps on the map as points for consideration as they are developing a protocol and launching a study
This tool is not intended to substitute for the important collaboration be-tween a junior investigator and a senior investigatormentor A senior investiga-tor plays a pivotal role in coaching and advising a junior investigator regarding the many subtleties and variations that apply to designing and implementing a protocol
This process map cannot be inclusive of every possible task or step but is intended as a general guide for investi-gators and their study teams
ResourcesThere are many institutional resources at Boston Childrenrsquos Hospital designed to support investigators and their clini-cal research teams In addition to links to resources tools and documents that are embedded in the steps of the clini-cal research map the last page of this document contains website addresses that will take you to additional helpful institutional resources
Acknowledgements Cindy Williams DNP RN PNP NE-BC Nursing Director CTSU Clinical Research Nursing
Ellen McGrath MSN RN CPNP Nurse Practitioner Department of Surgery
Grace Yoon MSN RN CNNP Research Nurse Department of Ophthalmology
Laura Feloney BA Lab Technician
ContentsOverview Four stages 3
1st Stage Protocol development 4
1st Stage Protocol development contrsquod 5
2nd Stage Implementation planning 6
3rd stage Study launch7
4th stage Statistical analysis reporting and dissemination 8
Discarded specimens Additional steps 9
Chart review Steps if you are completing a chart review 10
Appendix A Resources for researchers 11
Boston Childrenrsquos Hospital Clinical Research Map 3 Mouse over for additional info Bold = hyperlink
Overview Four stages
Protocol development
Implementation planning
Study launch
Statistical analysis reporting and dissemination
1
2
3
4
Boston Childrenrsquos Hospital Clinical Research Map 4 Mouse over for additional info Bold = hyperlink
1st Stage Protocol development
Explore resources
CRIT
CRC
EQuIP
CTSU
Harvard Catalyst
Complete training
CITI training
EQUiP
Consult research pharmacistResearch Pharmacy
Rocco Anzaldi
Consult statistician
CRC
Draft a protocol
Protocol guidelines
Study personnel
FDA Guidance for Investigators
Consult Clinical Research Center
CRC
Bio Bank
Start IRB application
TransLab
Consider applying for grants
securing funding
Office of Sponsored Programs
If INDIDE application to FDA
Does my study need an INDIDE
Regulatory resources
Arrange a consultation with
CRIT
ConsultationTasks for investigators and study teams
Boston Childrenrsquos Hospital Clinical Research Map 5 Mouse over for additional info Bold = hyperlink
Respond to IRB questionsrequests
for clarification
1st Stage Protocol development contrsquod
Departmental Scientific Review
Organize DSMB design DSMP
DSMPDSMB
Templates for Research Study
Documents and Tools
Study Templates and Tools
Investigators who sponsor an FDA regulated trial
ClinicalTrialsgov
Create regulatory binder
Regulatory Binder Template
Submit the grant application to OSP
OSP
TIDO
CTBO
Consult Office Intellectual Property
Technology and Innovation
Development Office
TIDO
IRB approval
Consider blood volume for research
Research blood volume policy
Confidentiality plan
Confidentiality guidelines
Boston Childrenrsquos Hospital Clinical Research Map 6 Mouse over for additional info Bold = hyperlink
Develop Case Report Forms
(CRFs)
CRF guidelines
Establish electronic shared
folder or study binder for study
documents
CRIT
Set date for trial launch
Develop fast fact sheet for bedside staff
Consult programmer re database
CRIT
Research study resource manual
for the clinical unit
Confirm study drug
in pharmacy
Rocco Anzaldi
Clarify system for screening
and enrolling patients
Recruitment guideline
Updated protocol to
nurse manager
Consult MDsNPs on unitclinic
2nd Stage Implementation planning
Tasks for investigators and study teams
Study logistics Documentation logistics
Data storage
Confidentiality plan
Confidentiality guidelines
Create study orderset
Consider blood volume for research
Research blood volume policy
Create Manual of Operations
MOO Guide
Study implementation
meeting
Develop study logstools
EQUIP
Finalize tracking sheet
Research Administration
Fernando Valles
Boston Childrenrsquos Hospital Clinical Research Map 7 Mouse over for additional info Bold = hyperlink
3 Document informed consent
Informed Consent
Consent library
Schedule weekly study team meeting
Communicate to department faculty
and multidisciplinary
team announcing trial launch
Steps before trial launch
3rd stage Study launch
Patient flow
1 Seek permission
to approach potential subjects
2 Screenenroll
patients
EQUIP
5 Send Study
Tracking Sheet (STS)
6 Collection of
patient data and assessing for
adverse events
7 Study
documents and data handling
4 Datetime study tests
Create a checklist outlining study action items for each subject
Boston Childrenrsquos Hospital Clinical Research Map 8 Mouse over for additional info Bold = hyperlink
Annual IRB Report
Annual Progress ReportStaff Report
raquo Maintain Interest of Staff
raquo Important to See Study Progress
Write Abstract
Dissemination of Research Results
raquo Conference raquo Internal Presentation for Colleagues
raquo Publication
Plan DSMB MeetingInterim
Analysis
4th stage Statistical analysis reporting and dissemination
Data Entry
When Enrollment Complete Data
Cleaning
Monitor Subjects to Identify
Adverse Events (CCI sponsor
DSMB)
Report Adverse Events
Update MOO Based on Experience
with First Several Patients Enrolled
Weekly Study Team Meeting
Report study findings to
subjects and stakeholders
Data management Trial management
Reporting Dissemination
Regular Review of Data
to Identify Deviations
and Workflow Improvements
Consult Statistician When Approaching Target Enrollment
Discarded specimens Additional steps
Boston Childrenrsquos Hospital Clinical Research Map 9 Mouse over for additional info Bold = hyperlink
Send IRB Approval to lab manager
Maureen Samson
Educate staff in areasunits about sample collection
Locate the discarded samples
Locate the accession number in PowerChart
Retrieve specimen
Mark Kellogg
Follow Shipping Rules and Procedures
IATAShipping with dry ice instructions
Communicate with laboratory staff
Contact Dr Mark Kellogg to discuss specimen retrieval
Consult with Biorepository
Biorepository
Chart review Steps if you are completing a chart review
Boston Childrenrsquos Hospital Clinical Research Map 10 Mouse over for additional info Bold = hyperlink
7 8
4321
Databaserecord review guidelines
5 6
Consult programmer re database
CRC Request
Respond to IRB questions
requests for clarification
Departmental Scientific Review
Complete training
CITI Training
Draft a protocol
Protocol Guidelines
Prepare IRB Application
Information about the CCI
IRB Application
Develop Case Report Forms (CRFs)
CRF Guidelines
IRB Review
Boston Childrenrsquos Hospital Clinical Research Map 11 Mouse over for additional info Bold = hyperlink
Clinical Research Center (CRC) x84720
Committee on Clinical Investigation (CCI IRB) x57052
Research Pharmacist x52014
Clinical and Translational Science Unit (CTSU) x57541
Education and Quality Improvement Program (EQUIP) x57052
Clinical Trials Office Central Budgeting x4-2714
Office of Sponsored Programs x4-2723
Technology and Innovation Development Office 617-919-3079
Research Finance x8-3517
Harvard Catalyst 617-432-7810
Regulatory Affairs x4-2777
Appendix A Resources for researchers
RES_4446_ClinicalResearchMap-FINAL FOR LINKS 1
RES_4446_ClinicalResearchMap-FINAL FOR LINKS 10
Overview Four stages
1st Stage Protocol development
1st Stage Protocol development contrsquod
2nd Stage Implementation planning
3rd stage Study launch
4th stage Statistical analysis reporting and dissemination
Discarded specimens Additional steps
Chart reviewSteps if you are completing a chart review
Appendix A Resources for researchers
RES_4446_ClinicalResearchMap-FINAL FOR LINKS 11
RES_4446_ClinicalResearchMap-FINAL FOR LINKS 2
RES_4446_ClinicalResearchMap-FINAL FOR LINKS 3
RES_4446_ClinicalResearchMap-FINAL FOR LINKS 4
RES_4446_ClinicalResearchMap-FINAL FOR LINKS 5
RES_4446_ClinicalResearchMap-FINAL FOR LINKS 6
RES_4446_ClinicalResearchMap-FINAL FOR LINKS 7
RES_4446_ClinicalResearchMap-FINAL FOR LINKS 8
RES_4446_ClinicalResearchMap-FINAL FOR LINKS 9
RES_4446_ClinicalResearchMap-PAGE 5pdf
Overview Four stages
1st Stage Protocol development
1st Stage Protocol development contrsquod
2nd Stage Implementation planning
3rd stage Study launch
4th stage Statistical analysis reporting and dissemination
Discarded specimens Additional steps
Chart reviewSteps if you are completing a chart review
Appendix A Resources for researchers
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MOUSE OVER
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COVER BUTTON
Previous Page
Page 118
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Page 96
Page 1
Button 91
Button 92
Button 94
IRB review
Button 102
Develop Case Report Forms
Button 136
Consult clinical research center
INDIDE 1
Explore resources
Button 1016
Bio Bank p
4
Consult statistician
Consult research pharmacist
Study personnel
Complete training
Consider grantsfunding
Draft a Protocal 2
Arrange a consutlations with CRIT
Next Page 1
Previous Page 1
TransLab
Start IRB application 3
Develop study logs
Updatedd protocol
Confirm study drug
Establish electronic shared
COnsult programmer
Clarify system
Research study resrouce manual
Develop case report forms
MOO
Set date for trial launch
Button 44
Study implementation meeting
Finalize tracking sheet
Data storage
Confidentiality
Blood volume 3
Develop fast fact
Consult MDs
Schedule weekly
Communicate early
Button 71
Screenenroll patients
Document informed consent
Datetime tests
Send study tracking sheets
Collection patient data
Button 77
Dissemination
Button 87
Button 124
Button 125
Communicate with lab staff
Button 106
Button 109
Button 1010
Shipping page 9
Button 1012
Button 99
Button 133
Button 134
Button 135
Biorepository
Locate assession number
Retrieve specimen
Button 30
Consult office
Negotiate Contract
Organizing DSMB
Submit Grant
Respond to IRB questions
Button 66
Create regulatory binder
Templates for research stufy
Clinical Trials Business Office
Blood volume 2
Confidentiality plan
Investigators who sponsor
clinicaltrials
gov
BPN Project
Drug Discovery amp Development Testing Funnel
Tier 1 2 3
Tier 6 7 8
Tier 5
Tier 4
Example Drug Discovery amp Development Testing Funnel
Cytotoxicity
Grant
Project
Example Drug Discovery amp Development Testing Funnel
TIER 1A ndash Primary Screen
Chemical purity and identity of active compounds
Primary bioactivity screen
Cell viability (When Appropriate)
ScaffoldsMoiety Chemical liabilities (for example Michael acceptor GSH reactive)
Calculated properties CLogP
PSA
Molecular Weight
rotatable bonds
H-bond donors and acceptors
permeability
pKa
Solubility
TIER 1B
Confirm EC50 determinations for actives compounds in primary screen with fresh
compounds from the original stock Confirm EC50 determinations for the lead (most
active) compound in primary screen with a new sample either repurchased purified
and characterized in-house or independently synthesized in-house
Compounds with IC50s (EC50s) less than X advance to Tier 2
TIER 2A ndash Activity Confirmation
Secondary screen
TIER 2B
Repeat EC50 determinations for actives in secondary screen with fresh
compounds from the original stock
Compounds with IC50s (EC50s) less than X advance to Tier 3
Example Drug Discovery amp Development Testing Funnel
TIER 3 ndash Drug-like Properties Specificity
IC50 selectivity in selectivity screen
CYP450 Inhibition competitive and time-dependent if structural alerts exist
(spot check illustrative examples from compound series)
Measured solubility
Measured protein binding (spot check illustrative examples from
compound series)
Test of Permeability in vitro permeability [indicate assay eg Caco2 orand
PAMPA] (spot check illustrative examples from compound series)
hERG
Cytoxicity assays
All compounds with no significant issues (Define Minimum Conditions for
Advancement) to advance to Tier 4
Example Drug Discovery amp Development Testing Funnel
TIER 4 ndash Scale-up Synthesis and Preliminary PK
Scale-up synthesis
Purity determination gt98 with no single impurity gt1
Rodent bioavailability and PK (define target delivery route) Tmax
Cmax
AUC
Bioavailibility
Vss CL T12 MRT
Brain to Plasma ratios
P-glycoprotein transport MDCK-MDR1 and MDCK-mdr1a
Plasma Protein Binding (species)
Microsomal Stability ndash rodent and human
Defineplan Patent Protection Strategy
All compounds with no significant issues (Define
Minimum Conditions for Advancement) advance
in parallel to Tiers 5AampB
Example Drug Discovery amp Development Testing Funnel
TIER 5A ndash In Vivo Bioactivity
Animal efficacy
Validate Biomarker
Target engagement
Advance to Tier 6 if (Define Minimum Conditions for advancement)
TIER 5B ndash Advanced Drug-like Properties
Microsomal stability in multiple
species
Chemical Stability
CYP450 induction
CYP reaction phenotyping
Metabolism ndash human
hepatocytesmicrosomes
Metab ID define major human rat dog and
non-human primates (NHP) metabolites
In vitro Tox Ames
Chromosome Aberration
CNS effects
Example Drug Discovery amp Development Testing Funnel
TIER 6 ndash Liability Assessment
Broad Pharmacological Profile and Toxicology
PK in second species
TIER 7
Non-GLP exposure studies single and multiple dose
Advance to late stage pre-clinical development (Define Minimum
Conditions for advancement)
Example Drug Discovery amp Development Testing Funnel
Principal InvestigatorProgram Director (Last First Middle)
enspenspenspenspensp
DETAILED BUDGET FOR INITIAL BUDGET PERIOD
DIRECT COSTS ONLY
FROM
THROUGH
enspenspenspenspensp
enspenspenspenspensp
PERSONNEL
DOLLAR AMOUNT REQUESTED (omit cents)
NAME
ROLE ONPROJECT
TYPEAPPT (months)
EFFORTONPROJ
INSTBASESALARY
SALARYREQUESTED
FRINGEBENEFITS
TOTAL
enspenspenspenspensp
PrincipalInvestigator
enspenspenspenspensp
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SUBTOTALS
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CONSULTANT COSTS
enspenspenspenspensp
enspenspenspenspensp
EQUIPMENT (Itemize)
enspenspenspenspensp
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SUPPLIES (Itemize by category)
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TRAVEL
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PATIENT CARE COSTS
INPATIENT
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OUTPATIENT
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ALTERATIONS AND RENOVATIONS (Itemize by category)
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OTHER EXPENSES (Itemize by category)
enspenspenspenspensp
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SUBTOTAL DIRECT COSTS FOR INITIAL BUDGET PERIOD
$
enspenspenspenspensp
CONSORTIUMCONTRACTUAL COSTS
DIRECT COSTS
enspenspenspenspensp
FACILITIES AND ADMINISTRATIVE COSTS
enspenspenspenspensp
TOTAL DIRECT COSTS FOR INITIAL BUDGET PERIOD
$
enspenspenspenspensp
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
main menu
Pharmacokinetic tutorial drug exposure measurement services pharmacokinetic data references
Selecting the correct dose to achieve exposure of drug that are adequate to test a hypothesis in preclinical species
requires that you know the potency of the molecule at the desired drug target and the dose of compound required to
achieve target organ exposure that will result in the free (not bound by protein) concentration of drug required to engage
the molecular target within the target organ compartment Estimates of Drug potency can be found in many of the
databases listed under correct molecule The free concentration of a drug is determined in the plasma by multiplying the
concentration of drug in the plasma by the fraction unbound This must be measured for each compound A literature
reference that provides the measured plasma protein binding (PPB) values for many common drugs is provided here
Zhang Xue Shao and Jia (2012) Compilation of 222 drugsrsquo plasma protein binding data and guidance for study designs
Drug Discovery Today Vol 17 Issue 9-10 Pages 476-485 httpwwwncbinlmnihgovpubmed22210121
If your drug target is the brain then you must also understand the kinetics of drug disposition and clearance including blood
brain barrier (BBB) penetration in your test species to select a dose of compound adequate to test your hypothesis
Download a tutorial deck on basic principles of drug disposition and their application in small molecule drug discovery
courtesy of Dr Chris Shaffer Pfizer
150805DMPKTutorial(CLSBCHCourse)pdf
Pharmacometrics Research Core and Pharmacokinetics Service The Pharmacometrics Research Core is directed by Dr Luis
Pereira and provides analytical services for assaying drugsmetabolites in biological matrices (eg plasma serum blood
urine CSF saliva tissues) The Core provides pharmacokinetic and pharmacodynamic analyses for current and future
clinical trials and research projects (including contract services) It conducts stability and potency studies for pediatric
formulations compounded at BCH as per recent demand from FDA and CMS Finally the Core fosters grant applications
and research collaborations both intra and extramural The TNC can additionally provide investigators with consultation in
the identification of resources for pharmacodynamic assay development and contract research organizations able to
provide bioanalysis of preclinical samples needed to support animal clinical trials Contact Dr Luis Pereira for more
information LuisPereirachildrensharvardedu
article on importance of understanding drug exposure in preclinical drug studies here
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
References on Pharmacokinetics and Brain Penetration of Small Molecules
Di L Rong H Feng B Demystifying brain penetration in central nervous system drug discovery Miniperspective Journal of
medicinal chemistry 2013 56(1)2-12
Reichel A Addressing central nervous system (CNS) penetration in drug discovery basics and implications of the evolving
new concept Chemistry amp biodiversity 2009 6(11)2030-2049
Smith DA Di L Kerns EH The effect of plasma protein binding on in vivo efficacy misconceptions in drug discovery Nature
reviews Drug discovery 2010 9(12)929-939
Moda TL Torres LG Carrara AE Andricopulo AD PKDB database for pharmacokinetic properties and predictive in silico
ADME models Bioinformatics 2008 24(19)2270-2271
Law V Knox C Djoumbou Y Jewison T Guo AC Liu Y Maciejewski A Arndt D Wilson M Neveu V et al DrugBank 40
shedding new light on drug metabolism Nucleic acids research 2014 42(Database issue)D1091-1097
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
main menu
Formulations advice and assistance with preclinical drug delivery Neurodevelopmental Behavioral Core
To effectively deliver drug to preclinical species for the duration of a study researchers must choose a dose a formulation
and a route of administration that will support target organ exposure long enough to test a therapeutic hypothesis Since
most drugs developed for humans are optimized for human metabolism parameters many compounds developed for
humans are rapidly metabolized and cleared in rodents requiring alternative formulations and routes of preclinical
administration (see tutorial under Correct Dose)
Proper formulation of drugs and vehicles to ensure appropriate drug exposure is a critical factor in preclinical study design
The Neurodevelopmental Behavioral Core may provide advice on standard formulations Preclinical assistance and
training across many routes of administration including IV cannulation osmotic minipumps oral gavage sc and ip is also
available through the Neurodevelopmental Behavioral Core
Contact is Dr Nick Andrews NickAndrewschildrensharvardedu
Custom formulation used for human studies are supported on a case by case basis by the Pharmacometrics Research Core
or Clinical Research Pharmacy Contact for the Pharmacometrics Core is Dr Luis Pereira LuisPereirachildrensharvardedu
The Clinical Research Pharmacy can provide advice on unusual formulations Contact is Dr Rocco Anzaldi
RoccoAnzaldichildrensharvardedu
idspharmacy-dlchildrensharvardedu
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
main menu
Stratification Biomarker development and resources patient sample repositories requests for collection of new types of
patient samples development of patient specific iPSC lines and neurons Genetic databases RNA expression databases
Humans are diverse Not only do patients come in different sizes ages genders and ethnic backgrounds but the same
disease diagnosis often develops in people as a function of different environmental insults and genetic predispositions
Finding biomarkers that will segregate similarly diagnosed patients into subsets of biologically more homogenous
populations is a critical feature of good clinical trial design A lsquostratification biomarkerrsquo can be a biochemical measure from
patient samples a structural or a functional feature of a human imaging technology or a functional measure of an
electrophysiological readout
The Translational Neuroscience Center can help investigators access advice and assistance for investigators with vendors
experienced in profiling DNA RNA or protein across a range of platforms httpwwwchildrenshospitalorgresearch-and-
Neurophysiology Services can assist investigators with identification of biomarkers to stratify patients based on EEG
signatures Contact Drs Charles Nelson and Jurriaan Peters Co-Directors
CharlesNelsonchildrensharvardedu
JurriaanPeterschildrensharvardedu
MRIRadiology Imaging Core can assist with identification of biomarkers to stratify patients by functional or structural deficits
in brain circuitry Contact Dr Simon Warfield Director SimonWarfieldchildrensharvardedu
Molecular Genetics core can assist investigators with identification of genetic stratification biomarkers or gene expression-
based stratification biomarkers Contact Drs Louis Kunkel and Christopher Walsh Co-Directors
LouisKunkelchildrensharvardedu
ChristopherWalshchildrensharvardedu
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
The Human Neuron Differentiation Service within the Translational Neuroscience Center can help investigators recruit
specific subtypes of patients to be consented for reprogramming of blood or fibroblast cells into iPSC lines that will support
differentiation into human neurons for phenotypic analysis and screening ContactDr Robin Kleiman
RobinKleimanchildrensharvardedu
Translab can assist with routine processes as well as complex laboratory-‐developed tests They place special emphasis on
assay development for use in clinical trials Translab website with contact information can be viewed here
httpwwwtranslabbostonorg
TransLab Flyer 2 2015pdf
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
main menu
Patient sample repositoryBiobank Patient registry
Disease processes are dynamic The molecular underpinnings of disease differ between inception progression and
response of the body to disease Thus each stage of disease may require alternative therapeutic strategies Understanding
which stage of disease is best suited to testing a specific therapeutic approach will require information about disease from
patient samples collected at different stages of disease well as an ability to collect and recruit patients at relevant stages of
disease
To locate human RNA profiling data in the public domain from disease samples and tissues at specific stages of disease
search databases referenced in the Correct Target section of this document
The Translational Neuroscience Center offers multiple services that can assist with identification of the correct patients The
Core Repository for Neurological Disorders stores a wide variety of patient samples from many stages of disease The
biorepository is directed by Dr Mustafa Sahin and these samples and de-identified clinical data can be searched and
requested through the Translational Neuroscience Center
The Biobank Core Lab serves as a core resource that ensures top-level specimen handling and services to the Boston
Childrens Hospital research community It serves as both a service core and a biorepository providing an institutional
perspective on the presence of specimens that may be available for use to foster collaborations and accelerate research
and discovery
The Clinical Research and Regulatory Affairs Service can provide assistance to investigators in identifying patients andor
repository samplesdata Contact Co-Directors Stephanie Brewster and Kira Dies for more information about access to
these resources
StephanieBrewsterchildrensharvardedu
KiraDieschildrensharvardedu
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
main menu
Statistical support clinical trialsgov
Determining the correct sample size to support preclinical and clinical studies requires power calculations that take into
account the variability of the endpoint being measured Statistical support for preclinical studies is available on a
department by department basis Neurology and Neurobiology requests for preclinical biostatistics support can be made
through the CRC website
httpredcap-qiredcap_edcsurveyss=Rma5u83qKC
Clinical statistical support for all departments is also available through the CRC Design and Analysis Core For more
information contact Michael Monuteaux michaelmonuteauxchildrensharvardedu
Clinical datasets that provide data for supporting power calculations can be found by searching through clinical trialsgov
database All studies in the clinical trials data base are required to describe the study design the endpoints under
evaluation and the treatments as well as links to publications of the studies The studies can be searched by topic This can
be a good way to find historical data to help you evaluate variability of endpoint measures in clinical populations This will
be needed to support sample size power calculations httpsclinicaltrialsgov
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
main menu
Understanding RDoC Human Neurobehavioral Core Service IRB assistance with clinical protocols
Different stages of clinical trials have different goals for selecting endpoints Early stage clinical trials are typically in search
of a translatable pharmacodynamic or target engagement endpoint to ensure that the molecule in question will be
competent to test a clinical hypothesis in humans Developing translatable measures of target engagement in preclinical
species and humans is critical to developing data sets that will enable subsequent therapeutic efficacy trials The earliest
trials require endpoints that can be measured in a functionally equivalent manner across species Therefore it is critical for
preclinical researchers to develop dose-responsive data sets in preclinical species using quantitative endpoints such as EEG
visual or auditory evoked potentials PET ligands plasma or CSF based biochemical measures or translatable task based
behaviors Preclinical data must be a developed with an eye towards what the equivalent measure will be in the clinic
Toward that end the NIMH has initiated the Research Domain Criteria (RDoC) that is aimed at characterizing mental health
disorders across many different dimensions across species A big focus of the RDoC initiative is the identification of
translatable endpoints for evaluating pharmacodynamics and efficacy in Neuroscience Drug Discovery Preclinical
Neuroscience researchers should be familiar with the RDoC framework For advice on in vivo characterization of preclinical
endpoints with translational potential for Neuroscience related disorders contact Dr Robin Kleiman at the TNC
robinkleimanchildrensharvardedu
The Human Neurobehavioral Core Service of the Translational Neuroscience Center can provide guidance to investigators
on the appropriate tests that will provide the best translation from animal studies to human studies The Service also offers
human neurobehavioral assessment services Contact-Drs Charles Nelson and Deborah Waber Co-Directors
CharlesNelsonchildrensharvardedu
DeborahWaberchildrensharvardedu
Developing clinical protocols and obtaining IRB approval for human study of translatable endpoints can be supported by
the Translational Neuroscience Center Clinical Research and Regulatory Affairs Service Contact-Kira Dies and Stephanie
Brewster Co-Directors
KiraDieschildrensharvardedu
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
StephanieBrewsterchildrensharvardedu
Background Information on RDoC httpswwwnimhnihgovresearch-prioritiesrdocindexshtml
Casey BJ Oliveri ME Insel T A neurodevelopmental perspective on the research domain criteria (RDoC) framework
Cuthbert BN Insel TR Toward the future of psychiatric diagnosis the seven pillars of RDoC BMC Med 2013 11126
httpwwwncbinlmnihgovpmcarticlesPMC3653747
Insel T Cuthbert B Garvey M Heinssen R Pine DS Quinn K Sanislow C Wang P Research domain criteria (RDoC)
toward a new classification framework for research on mental disorders The American journal of psychiatry 2010
167(7)748-751 httpwwwncbinlmnihgovpubmed20595427
Insel TR The NIMH Research Domain Criteria (RDoC) Project precision medicine for psychiatry The American journal
of psychiatry 2014 171(4)395-397 httpwwwncbinlmnihgovpubmed24687194
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
main menu
Body atlases for expression of mRNA and protein guides to chemical alerts guidance for preclinical toxicology studies for
Investigational New Drug (IND) applications
Discovery scientists must consider the distribution of the proposed drug target across the entire body in human samples in
order to understand potential safety risks to be monitored during preclinical toxicological testing Teams also have to be
aware of differences in distribution of the target and related family members in preclinical species Many of the target
expression databases listed in the Correct Target section of this document are useful in this regard Assays that can be used
to monitor any potential safety risks are critical to the development of a suitable testing funnel needed to advance
compounds
Many chemical classes of compounds that are identified in screens are not suitable for drug development due to the
presence of structural alerts that are known to cause chemical toxicity Databases that house information of structural alerts
can be used to de-prioritize structural series early in the life of a program Some toxicology databases that can help
deprioritize toxic chemotypes include httppubsacsorgdoiabs101021ci300245q
Some web resources for identifying side effects of known compounds httpintsideirbbarcelonaorg
Once a potential clinical candidate molecule is identified GLP-qualified toxicology studies must be carried out with a
qualified vendor to support regulatory filings of an Investigational New Drug (IND) application For a short tutorial on studies
needed to support preclinical toxicology testing and guidance on evaluating contract research organizations that are
qualified to perform this work see attached tutorial courtesy of Dr Joe Brady Pfizer
Brady boston childrens hosp talk aug2015 IND toxpdf
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
main menu
FAQs
Industry partners and collaborators can bring tremendous expertise and complementary resources to bear on research
projects with therapeutic applications These may include medicinal chemistry expertise pharmacology expertise access
to unique and undisclosed chemical probe molecules assay development and high-throughput screening resources
antibody and other reagent development pharmacokinetic analysis pharmacokinetic and pharmacodynamics
modeling formulation expertise post-doctoral training programs and in some cases financial support There is a wide range
of models of interacting with industry in a range of different capacities Some frequently asked questions about types of
relationships and the responsibilities associated with those interactions can be found in the following document
Download Frequently Asked Questions about working with Industry
Translation of basic research into new marketed drugs will require a transition from exploring scientific principles and testing
hypotheses into commercial products Industry partners capable of developing these potential products need to be able
to license the intellectual property required to sell the product in order to justify investment in building programs around new
ideas This requires that scientific researchers protect and patent potential inventions from their work to enable future
commercialization by partners with appropriate expertise To ensure that researchers are appropriately documenting their
work in a manner that will support preservation of intellectual property all investigators are encouraged to consult with TIDO
before any public disclosures of new research Similarly the following documentation provides guidance for documenting
your work according to standards that will support patent applications
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
Download the compliance manual for BCH for Intellectual property policy
cm_021_intellectual_propertydocx
Download a summary of laboratory notebook Dorsquos and Donrsquot
Dosdontsnotebookspdf
Link to TIDO Technology Innovation and Development Office
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
main menu
A phenotypic screen requires a biologically robust assay that represents a significant aspect of disease-relevant human
biology It can be used to identify molecular targets for target validation studies through the use of well-annotated
bioactive molecules or genomic libraries (eg RNAi CRISPER) Alternatively phenotypic screens can be used to identify
novel compounds that must subsequently be lsquoDE convolutedrsquo to identify novel targets using lsquowarheadsrsquo These screens rely
on identification and manipulation of a functional deficit or phenotype using a patient-derived cellular system
The strengths of this approach
Use of human systems can improve translatability
Identified compounds may empirically balance therapeutic activity at multiple required targets
Well-suited to drug repurposing
Phenotypic screens can be used to identify compounds or targets for mechanism based drug discovery programs
Many CNS drugs have been discovered using a phenotypic repurposing screen (Swinney and Anthony 2011)
Drawbacks to this approach
Assays are slow low throughput and more expensive as compared to cell-free assays
Cell-based assays may not predict circuit level or brain phenotypes
Furthermore as a primary screening approach
Precludes leveraging strengths in uHTS SBDD and parallel design
Every molecule must be de-risked independently thus safety can be very hard to predict
Drug Repurposing Drug Repurposing is a strategic pillar of the National Center for Advancing Translational Science (NCATS)
Details on resources and funding opportunities can be found here httpsncatsnihgovntu
Chemogenomic Files from industry partners Many companies have well designed and annotated chemical files that are
designed to cover the druggable genome with small molecule compounds from their proprietary collections Each
company has different criteria and stipulations associated with use of the library It is advisable to consult with TIDO
regarding terms and conditions associated with individual companies
ICCB-LongwoodKirby ADSF The ICCB screening center and the Kirby ADSF have multiple collections of compounds that
include bioactive or FDA approved molecules available for screening
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
Kirby ADSF libraries contact Dr Lee Barrett LeeBarrettchildrensharvardedu
References related to phenotypic screens and Drug Repurposing
Vincent F Loria P Pregel M Stanton R Kitching L Nocka K Doyonnas R Steppan C Gilbert A Schroeter T
and MC Peakman Developing predictive assays The phenotypic screening ldquorule of 3rdquo Sci Transl Med 7 293ps15
(2015)
Langedijk J Mantel-Teeuwisse AK Slijkerman DS Schutjens MH Drug repositioning and repurposing terminology and
definitions in literature Drug Discov Today (2015)
Swinney DC and J Anthony How were new medicines discovered Nature Reviews Drug Discovery 10 507-
519 (July 2011) | doi101038nrd3480
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
main menu
TNC Clinical Research and Regulatory Affairs Service Research Participant Registry CRC
Glossary of Terms
Glossary-of-Clinical-Trials-Termspdf
Clinical Research and Regulatory Affairs Service This Translational Neuroscience Center service facilitates the mission of the
Translational Neuroscience Center providing coordination among studies communications resource development and
implementation of new or ongoing preclinical and clinical studies The service is led by experts in protocol development
and launching of new studies The directors are available to guide TNC researchers in designing human studies including
the preparation of Institutional Review Board (IRB) and FDA submissions Additionally staff of the Clinical Research and
Regulatory Affairs Service will help researchers with recruitment plans budget development supervision of study
coordinators study monitoring and audit preparation For more information contact Co-Directors Kira Dies ScM CGC and
Stephanie Brewster MS CGC
KiraDieschildrensharvardedu
StephanieBrewsterchildrensharvardedu
Clinical Research Center (CRC) Assists investigators at BCH with research project initiation and implementation resources
in the CTSU for the conduct of clinical research visits and ancillary services education on research methods and practices
The CRC has biostatisticians project managers research specialists clinical trials specialists research coordinators and
highly skilled nurses and nurse project managers who work every day to facilitate the many research needs of the BCH
community httpwwwchildrenshospitalorgresearch-and-innovationresearchclinicalclinical-research-center
Clinical and Translational Study Unit (CTSU) The CTSU provides clinical research infrastructure for investigators in the design
initiation conduct and reporting of clinical research with the goal of translating scientific knowledge into new therapies for
pediatric conditions httpweb2tchharvardeductsu
Clinical Research Roadmap This clinical research map is designed to serve as a guide for investigators study coordinators
and research nurses at Boston Childrenrsquos Hospital The research map outlines the key steps in preparing to launch a
research study and provides embedded links to institutional resources tools and documents
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
Clinical Research Mappdf
main menu
Office of Sponsored Programs Research Administration TIDO
Many government and foundation grant opportunities are available for developing Drug Discovery Projects updated lists of
funding options exist on OSP and Research Administration web sites
Some good options for finding relevant requests for proposals
Translational Research Program annual call for proposals
Boston Childrenrsquos Hospital ndash Broad Institute Collaboration Grants Proposals will be reviewed by a joint Childrenrsquos Hospitalndash
Broad Institute committee Additional submission dates are expected for 2016
BCH_Broad collaborative grant 852015docx
Kirby Neurobiology Screening Pilot awards- available to Kirby Neurobiology PIs as funding is available
Translational Neuroscience Center- Pilot awards supported by trust sponsored donations as available Distributed through
TNC e-mail lists
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
ADDF The ADDF Academic Drug Discovery and Development Program seeks to create and support innovative translational
research programs for Alzheimerrsquos disease related dementias and cognitive aging in academic medical centers and
universities Biomarker development studies and innovative proof of concept pilot clinical trials of new approaches to
treatment prevention and early detection are also supported
Department of Defense ALSRP The FY15 Defense Appropriations Act provides $75 million (M) to the Department of Defense
Amyotrophic Lateral Sclerosis Research Program (ALSRP) to support innovative high-impact Amyotrophic Lateral Sclerosis
research As directed by the Office of the Assistant Secretary of Defense for Health Affairs the Defense Health Agency
Research Development and Acquisition (DHA RDA) Directorate manages and executes the Defense Health Program
(DHP) Research Development Test and Evaluation (RDTampE) appropriation The executing agent for the anticipated
Program AnnouncementsFunding Opportunities is the Congressionally Directed Medical Research Programs (CDMRP)
httpcdmrparmymilpubspress201515alsrppreannshtml
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
Michael J Fox Foundation Therapeutic Pipeline Program Supports Parkinsons disease therapeutic development along the
pre-clinical and clinical path (both drug and non-pharmacological therapeutics including gene therapy biological
surgical and non-invasive approaches) The Michael J Fox Foundation seeks applications with potential for fundamentally
altering disease course andor significantly improving treatment of symptoms above and beyond current standards of care
Proposals must have a well-defined plan for moving toward clinical utility for patients The Therapeutic Pipeline Program is
open to industry and academic investigators proposing novel approaches or repositioning approved or clinically safe
therapies from non-PD indications httpswwwmichaeljfoxorgresearchgrant-detailphpid=28
NINDS The Blueprint Neurotherapeutics Network (BPN) Provides the neuroscience community access to a complete and
seamless pipeline for preclinical drug development beginning with chemical optimization and concluding after phase I
clinical trials Participants in the BPN will receive funding to conduct bioactivity and efficacy testing in their own laboratories
as well as access to millions of dollars in NIH-contracted drug development services including medicinal chemistry
pharmacology toxicology and phase 1 clinical trials NIH will also provide drug development consultants who have had
years of experience working at a senior level in industry Because the Blueprint is establishing a network of drug
development service providers that typically cater to biopharmaceutical companies neuroscientists who join the BPN can
readily plug in to all of the drug development expertise that typically resides in industry The projects supported through the
network will be highly collaborative and the researchers who initiate the projects will serve as the principal investigators
(PIs) directing their projects through the development pipeline with the help of industry consultants The PIs and their
institutions will have the opportunity to attain assignment of intellectual property rights from all other network participants
who may have intellectual input into their projects This will allow the PIs to retain control of the intellectual property for drug
candidates developed through the network and eventually pursue licensing and commercialization partnerships
httpneuroscienceblueprintnihgovbpdrugs
NeuroNEXT Will establish a consortium of clinical sites capable of forming disease-specific cadres of investigators in order to
develop and implement trials rapidly in a wide range of neurological disorders that affect adults andor children With a
stable and experienced research staff a central IRB model and master trial agreements NeuroNEXT will streamline the
administrative processes for clinical trials and reduce start-up times NeuroNEXT will also be able to design and implement
evidence-based measures to improve patient recruitment into clinical trials httpswwwneuronextorgresearchers
NIMH Many grant options see overview here httpwwwnimhnihgovresearch-prioritiestherapeuticsindexshtml
Building on High Impact Basic Neurobiology Through Assay Development Advancing Tools for Therapeutic Discovery (R01) -
See more at httpgrantsnihgovgrantsguidepa-filesPAR-15-066htmlsthashs1HMWjWudpuf
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
NCATS many grant options see overview here httpwwwncatsnihgovprograms
Bridging Interventional Development Gaps (BrIDGs) Program Makes available on a competitive basis certain critical
resources needed for the development of new therapeutic agents for both common and rare diseases Investigators do not
receive grant funds through this program Instead successful applicants receive access to NIH experts and contractors who
conduct pre-clinical studies at no cost to the investigator In general synthesis formulation pharmacokinetic and
toxicology services in support of investigator-held IND applications to the Food and Drug Administration (FDA) are available
httpwwwncatsnihgovbridgsworksolicitation
NCATS Discovering New Therapeutic Uses for Existing Molecules (New Therapeutic Uses) A collaborative program designed
to develop partnerships between pharmaceutical companies and the biomedical research community to advance
therapeutics development This innovative program matches researchers with a selection of pharmaceutical industry
assets to test ideas for new therapeutic uses with the ultimate goal of identifying promising new treatments for patients
httpwwwncatsnihgovntu
Pfizer Centers for Therapeutic Innovation (CTI) Suitable for biotherapeutic or small molecule projects with a strong project
rationale (demonstrated association between target biology pathway and disease mechanism) CTIrsquos areas of interest
include inflammation autoimmunity tissue remodeling oncology cancer immunology rare or genetic diseases
cardiovascular and metabolic diseases and neuroscience Selected projects are undertaken by a joint team with BCH
members and Pfizer CTI drug development experts located on the 18th floor of CLS working towards agreed common
goals The Pfizer CTIBCH collaboration program is managed by a Joint Steering Committee with representation from both
Boston Childrenrsquos and CTI httpswwwpfizercticom Calls for proposals come through TIDO three times a year in January
May and September httpwwwchildrensinnovationsorgPagesHighlightsHighlights-83aspx
Shire-BCH Collaborative Program Development The Joint Steering Committee of the Shire Alliance extends a call for ldquoPre-
Proposalsrdquo with defined objectives from time to time generally annually in the late fall or winter That call is publicized
through emails from BCH Research Administration and TIDO Following review by the JSC a full proposal may be requested
Unsolicited proposals may also be considered from time to time
ACRONYMS
HTS- High-throughput Screen run with 96 well 384 well 1536 wells or 3456 well capacity- screen has capacity to run through a library of 1-3Million compounds in total
uHTS- Ultra High-throughput Screen ndash arbitrary cut off to denote capability to measure 100s of thousands of assays per day with automation and high density plate readers
HCS- High Content Screen usually a cell based assay that is able to monitor multiple endpoints reflective of different cellular processes in a single well of cells treated with a compound May be biochemical or image based endpoints
SAR- Structure-Activity Relationship ie relationship of modifications to chemical structure on relevant activity SPR-Structure-Property Relationship ie relationship of modifications of chemical structure on physicochemical
properties
PK- Pharmacokinetic measure of drug levels in a body compartment
PD- Pharmacodynamic a measure of functional activity of a drug
PKPD- PharmacoKinetic PharmacoDynamic relationship- how drug levels relate to drug response in a system
DDI-Drug-Drug Interactions- occurs when one drug affects the activity of another drug when co- administered Often due to changes in ADME properties of one of the co-administered drugs (ie for example induction by one drug of enzymes that will metabolize the second drug )
DMPK- Drug Metabolism and PharmacoKinetics
ADME- Absorption Distribution Metabolism amp Excretion
PDM-pharmacokinetics dynamics and metabolism GLP- Good Laboratory Practice- regulations that govern toxicology studies required by the FDA to support IND
and NDA
POM- Proof of Mechanism clinical studies to demonstrate hit the target and elicited a biological response
POC- Proof of Concept Clinical studies to demonstrate a clinically meaningful outcome measure improved
PoP-Proof of Principal usually preclinical studies that demonstrate that engaging target in a disease model produced efficacy
FIH- First in Human clinical trial to evaluate new molecule in humans for safety and PK- Ph1
FIP-First in Patient first clinical trial to evaluate new molecule in patients hERG (the human Ether-agrave-go-go-Related Gene) is a gene KCNH2 that codes for a subunit of Kv111 and
contributes to the repolarizing current in the heart that coordinates the hearts beating When compromised by application drugs or by rare mutations in some families it can result in a potentially fatal disorder called long QT syndrome A number of clinically successful drugs in the market have had the tendency to inhibit hERG and create a concomitant risk of sudden death as a side-effect which has made hERG inhibition an important anti-target that must be avoided during drug development
IND-Investigational New Drug Application- formal application to FDA to evaluate a NCE in people
NME- New Molecular Entity- a new FDA approved drug
NCE-New Chemical Entity-an investigational drug that is not yet a FDA approved NME NDA- New Drug Application (A lsquoFilingrsquo)- a formal application for approval of a new drug
CAN-(Pfizer-specific shorthand )-Clinical Candidate- a molecule competent to be tested in humans IB- Investigators Brochure- basic information on an investigational drug and its mechanism for clinicans involved
in conducting a clinical trial Provides background information on the hypothesis being tested and the types of patients that should be included excluded and risks and how the drug should be administered It must be updated continually by the sponsor to include all new findings
SOC- Standard of Care- in our context it is the drug treatment that a clinican should prescribe for a particular type of patient used as a benchmark for comparing new entities
MTD- Maximum Tolerated Dose- first identified in GLP safety studies during preclinical development AE- Adverse Event- a side effect that causes safety concerns
TI- Therapeutic Index -ratio of the concentration of drug needed to produce efficacy and the concentration of drug that is safely tolerated ( also called ldquoSafety Marginrdquo)
Questions Contact Robin Kleiman- email RobinKleimanchildrensharvardedu office CLS 13070
Terms that relate to Targets Molecular target- the protein that binds drug to produce efficacy Off-Target- other proteins that bind the drug that do not relate to efficacy and may produce Adverse Events (AEs) Druggable target ndashcomes from a class of proteins that has successfully been targeted with small molecule drugs in
the past Primarily transporters enzymes receptors ion channels (Not protein-protein interactions transcription factors RNA binding proteins etc)
Druggable genome- about 3000 genes encoding all druggable proteins Druggability- the presence of protein folds (quarternary structures) that favor specific interactions with drug-like
molecules Exploratory target- Hypothesis that a modulating a target via a particular mode of action will be beneficial to a
particular patient population Validated target- Hypothesis regarding a target also has in vivo efficacy data for a disease or a disease model- along
with a complete understanding of how the target mechanism relates to disease- (also called lsquoProof of Principlersquo) Phenotypic screen- a screen for compounds that will reverse a phenotype the molecular target may not be known Systems pharmacology target(s)-a precisely defined combination or lsquofingerprintrsquo of molecular targets to be
modulated to correct a phenotype (Poly-pharmacology)
Terms that relate to programs
Biomarker- a physiological pathological or anatomical characteristic that is measured by an automated process or algorithm as an indicator of the normal biological process pathological process or biological response to a therapeutic intervention Many types of Biomarkers target engagement biomarkers stratification biomarkers efficacy biomarkers pharmacodynamic biomarkers etchellip
Laboratory Objectives-Criteria established at the start of the program to define the desired pharmacological properties of the molecule with regard to potency selectivity mode of action frequency and route of administration For antibodies would include minimal criteria for knock down stability etc
Therapeutic Modality- small molecule biologic RNAi stem cell etc
Screening tree Screening funnel- A decision tree for utilizing a panel of assays to identify molecules that meet the laboratory objectives
Terms that relate to molecules
Drug-like molecule- has physicochemical properties in line with known oral medications The molecule will be largely rule of 5 (RO5) compliant therefore small and moderately lipophilic Not related to pharmacological activity
Rule of Five (RO5)=Chris Lipinskirsquos rule of 5 states that a drug like molecule will have the following properties Molecular Weight of less than 500 a clogP lt5 fewer than 5 H-bond donors and the number of H-bond acceptors ( which is the sum of N and O atoms) is less than 10
Physicochemical properties- key properties of molecules include (calculated)Molecular Weight number of H bond acceptors and donors (measured) kinetic solubility pKa lipophilicity (logD logP)
Chemical tool -a compound with good potency and selectivity for a specified molecular target but fails to meet all criteria for safety PK or potency needed to become a clinical candidate Suitable for preclinical testing of hypothesis and proof of principal studies but not for lsquopreclinical developmentrsquo
Active molecule describes an individual chemical entity with measurable dose-dependent activity in a biological screening assay
Hit molecule refers to a molecule plus its related structural analogs for which there is an understanding of the structure-properties and structure-activity relationships (SPR and SAR) for a specific biological context Additionally preliminary drug disposition data (both in vitro and in vivo) provide an assessment of pharmacokinetic properties The available data provide a basis for further optimization of the hit series
Lead molecule refers to a molecule plus its related structural analogs that demonstrate o Sufficient exposure at pharmacologically relevant doses by the intended route of administration to explore
intended pharmacology in a relevant in vivo disease or pharmacodynamic model o Proof-of-principle or efficacy in a in vivo model that will be used to establish a margin of safety
Clinical candidate an optimized individual chemical entity derived from a lead series that demonstrates o a dose-response relationship via intended route and schedule of administration in relevant disease model o an exposure-based margin of safety in toxicology studies o In summary a clinical candidate is a molecule that is deemed competent for testing the primary disease
intervention hypothesis in humans
A laboratory notebook is a vital record of events leading to a patentable invention Therecorded information can establish dates of conception and reduction to practice of atechnology as well as the inventorship of a patent claiming the technology Below arefourteen rules you should follow when keeping lab notebooks
1 mdash Do use bound booksInventors should use permanently bound notebooks eg notebooks with spiral or glue bindings If loose-leaf sheets are used they should be consecutively numbered and eachpage should be dated signed and witnessed
2 mdash Do sign and date Each notebook should be signed and dated on the inside front cover to indicate the firstday the recipient started using the notebook Each entry should be dated and signed orinitialed
An independent witness ie someone who understands the technology but will not benamed as a co-inventor of the invention should sign and date each entry after the state-ment ldquoRead and understood by rdquo (The witness should preferably sign theentries on a contemporaneous or fairly contemporaneous basis but entries can also bereviewed signed and dated on a periodic eg weekly or monthly basis)
3 mdash Do use inkNotebook entries should be made in ink and in chronological order Entries should not beerased or ldquowhited outrdquo If an entry contains an error a line should be drawn through theerror and new text should continue in the next available space
4 mdash Donrsquot leave blank spacesBlank gaps between entries should be avoided If a blank space is left on a page a line orcross should be drawn through the blank space and the page dated to prevent subsequententries
5 mdash Donrsquot modifyPrior entries should not be modified at a later date If data were omitted the new datacan be entered under a new date and cross-referenced to the previous entry Record exper-iments when they are performed
6 mdash Do use past tenseUse the past tense (eg ldquowas heatedrdquo) to describe the experiments that were actually performed
Fish amp Richardson pc
Dorsquos and Don rsquo ts forKeeping Lab Notebooks
Boston
Dallas
Delaware
New York
San Diego
Silicon Valley
Twin Cities
Washington dc
FR
7 mdash Do explain abbreviations and special termsExplain all abbreviations and terms that are nonstandard Explain in context in a table ofabbreviations or in a glossary
8 mdash Do staple attachmentsAttachments such as graphs or computer printouts should be permanently attached to pagesin the notebook (eg by stapling) and both the attachment and the notebook page signedand dated If the attachment cannot be stapled it should be placed in an envelope and theenvelope stapled to the notebook page The envelope and page should then be signed andwitnessed making reference to the attachment being placed in the envelope
9 mdash Donrsquot remove originalsNo original pages should be removed from the notebook
10 mdash Do outline new experimentsWhen a new project or experiment is started the objective and rationale should be brieflyoutlined (eg in a short paragraph or by providing a flowchart)
11 mdash Do record lab meeting discussionsRelevant discussions from lab meetings should be recorded as should ideas or suggestionsmade by others The names of the people making the ideas and suggestions should be care-fully documented This information may be important in establishing inventorship
12 mdash Do provide detailRecord test descriptions including preferred operating conditions control conditionsoperable and preferred ranges of conditions and alternate specific materials Also recordtest results and an explanation of the results as well as photos or sketches of the resultsandor the test device Any conclusions should be short and supported by the factual dataOpinions or speculation about the invention should be avoided
13 mdash Do track notebooksIdeally each lab should maintain a catalog of notebooks in which each notebook is assigneda number and the name of the author of each notebook is recorded In addition the datethe author received the notebook as well as the date the notebook was completed andreturned should be recorded Upon leaving the lab the author should return all notebookschecked out by or to him
14 mdash Do save completed notebooksAll completed notebooks should be indexed (eg by number by author andor by subjectarea) and kept safely in a central repository together with corresponding patent applica-tions or patents Lab notebooks that relate to inventions on which patents have been grant-ed should be kept for the life of the patent plus six years
By J Peter Fasse
Fish amp Richardson pcIntellectual property complex litigation technology law800 818-5070wwwfrcominfofrcom
P ER SP EC T I V E
PHARMACOK INET I CS
Data gaps limit the translational potentialof preclinical researchRobin J Kleiman1 and Michael D Ehlers2
The absence of mouse pharmacokinetic reference data hinders translation An analysis ofrecent literature highlights a systematic lack of discussion regarding rationale for the selec-tion of dosing paradigms in preclinical studies and in particular for neuroscience studies inwhich the lack of brain penetration can limit target-organ exposure We propose solutionsto improve study design
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Despite widespread use of pharmacologicalagents in mouse models of human diseasethe literature lacks comprehensive pharmaco-kinetic profiles for such studies Coupled witha paucity of suitable data are shortcomingsin the training of experimental biologists inthe application of pharmacometric principlesto experimental study design Many authorssimply cite previously published studies tosupport the selection of a particular dose evenwhen the cited paper lacks drug exposuredata There is an assumption on the part ofresearchers that if a referenced study demon-strates a biological effectmdashthat is any measur-able physiological or behavioral effectmdashin arodent at a given dose then that same dosewill also effectively perturb disease-relevantmechanistic biology in a different study Thedanger occurs when the observed therapeuticeffects are not linked to drug-induced mecha-nistic alterations at the level of the target organLack of a drug exposurendashresponse relationshipin a target organ casts doubt on mechanisticinterpretations In addition any changes inthe route of drug administration vehicle prep-aration species used (rat versus mouse versusprimate) age or strain of animal transgenicmodification time points under investigationduration of dosing or organ targeted for inter-vention (for example brain versus a periph-eral tumor) can alter the relation between doseexposure and measured response In suchcases assumptions regarding the mechanisticbasis for observed therapeutic effects may nothold true
Preclinical pharmacological experimentsthat do not measure drug concentrations in
1Translational Neuroscience Center Kirby NeurobiologyCenter Department of Neurology Boston ChildrenrsquosHospital Harvard Medical School Boston MA 02115USA 2Neuroscience amp Pain Research Unit BioTherapeu-tics Worldwide Research and Development Pfizer IncCambridge MA 02139 USACorresponding author E-mail robinkleimanchildrensharvardedu (RJK) michaelehlerspfizercom (MDE)
the target organ run the risk of producing ex-posures that are too low or too high to inter-pret a mechanistic hypothesis Most drugs arenot selective over a large exposure range for asingle molecular target Confident evaluationof a therapeutic hypothesis requires an under-standing of the drugrsquos penetration and kineticswithin the target tissue as well as its potencyand selectivity for specific molecular targetsFurther investigators must consider the con-centration of the unbound fraction of drugthat is available to interact with the targetPublished reports often overlook the fact thatmany small molecules are more than 90bound to plasma or tissue proteins whichgreatly decreases the fraction of drug availableto bind to the intended target Thus in casesin which drug binding has a slow off-rate anorganismrsquos total drug exposure is not a predic-tor of drug available to interact with its target(1) The failure of some academic scientists toobtain relevant pharmacokinetic data impairsthe interpretation of preclinical research resultsand likely contributes to the acknowledgeddifficulties in replicating some academic liter-ature as reported by industry scientists (2 3)
Drug discovery teams in industry settingsroutinely collect pharmacokinetic data to aidin the mechanistic interpretation of in vivopreclinical data and to project optimal dosingparadigms for efficacy and toxicology studiesData required to evaluate brain penetrationare not typically collected by industry-baseddrug-discovery teams for compounds origi-nally developed for therapeutic indicationsthat do not obviously implicate the centralnervous system making this information es-pecially hard to find for many otherwise well-described drugs In addition because mousedata are not required for preclinical toxicologystudies (the more common small animal spe-cies for preclinical toxicology being rats)industry scientists do not often obtain pharma-cokinetic data from mouse experiments These
wwwScienceTranslationalMedicineo
issues are especially relevant for older drugsthat are potentially suitable for repurposingMany older drugs were discovered and char-acterized before routine pharmacokinetic-pharmacodynamic (PK-PD) modeling ofpreclinical drug exposure and its applicationto predicting human dosing became standardpractice Last pharmacokinetic data are notconsidered innovative and these studies gen-erally do not achieve publication in peer-reviewed journals even when the data havebeen generated When such data are pub-lished it is often relegated to the unsearchableblack hole of supplementary materials Thusmouse neuroPK profiles are not readily avail-able for many drugs that are frequently usedin conjunction with mouse models of humanbrain disorders
DOCUMENTING DOSING STRATEGIES
To evaluate the potential impact of insufficientpharmacokinetic data on dose selection in asample of recent published neuroscience liter-ature we conducted an analysis of papersidentified by means of a PubMed search usingthe search terms ldquodrugrdquo and ldquobrainrdquo for the pub-lication year 2014 from eight journals (Table 1)This list was culled to include only primaryresearch reports that included systemic adminis-tration of a pharmacological agent a pharma-cological therapeutic or a biological therapeuticas part of the study design The search yielded100 articles published between 1 January and30 December 2014 that used systemic drug de-livery with the intended goal of targeting thebrain of rodents (table S1) Each publicationwas examined for the stated rationale behindthe dose selection of study drugs (Table 1)
The reported rationale for dosing strategiesfell into several broad categories including(from lowest confidence to highest) (i) dose se-lected rationale not discussed (ii) literaturecitations of another study in which reportsranged from citation of exposure in the samespecies exposure in a different strain or spe-cies a dose conversion from the human liter-ature to rodent or reports of effects on rodentbehavior in another study (iii) demonstrationof an effect on rodent behavior or function inthe current study (iv) demonstration of adose-responsive biological effect in the currentstudy (v) measurement of drug levels in bloodor plasma in the current study and (vi) mea-surement of drug levels in the target organ(that is the brain) in the current study In onlytwo instances were publications identifiedthat considered the impact of drug binding
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to plasma or brain proteins on the free expo-sure of drug available to interact with the tar-get This is a critical flaw in most publishedstudies that use small molecules for functionaleffects in the brain because many centralnervous system (CNS) drugs that penetratethe blood-brain barrier exhibit high proteinbinding leaving a small fraction of the totaldrug measured in plasma or brain unbound
and free to interact with the molecular targetFurthermore most studies used evidence of abiological activity to justify dose selection with-out consideration for how exposure of theagent relates to the potency of the compoundat known molecular targets which would berequired to test a mechanistic hypothesis
The lack of pharmacokinetic considera-tion does not imply that every study used an
wwwScienceTranslationalMedicineo
inappropriate dose of drug to test their hypoth-esis It does illustrate that a clear rationale wasnot provided for dose selection in most pub-lications Furthermore all 11 of the 100 publi-cations that measured total brain exposureincluded an author from the pharmaceutical in-dustry (n=5) an academic drug screening group(n = 3) or a pharmacologyndashpharmaceuticalsciences department (n = 3) This observationlikely reflects the limited presence of pharma-cology and pharmacometrics departmentswithinmost academic institutions and limitedaccess to the mass spectrometry and otheranalytical resources needed to measure druglevels in study samples Outsourcing the bio-analysis of samples collected from study ani-mals is feasible but the use of contract researchorganizations to support such studies is oftentoo costly for most academic grant budgets toaccommodate
DATABASES AND REPURPOSINGRecent years have seen increasing efforts toinvestigate approved or clinically tested drugsfor new indications (4ndash8) Such repurposinghas been touted as a means to accelerate ther-apeutic development (4) For example a stra-tegic pillar of the US National Institutes ofHealthrsquos (NIHrsquos) translational roadmap callsfor the academic community to actively par-ticipate in the repurposing of drugs approvedby the US Food and Drug Administration(FDA) or investigational drugs that havepassed safety hurdles but failed in clinicaltrials because of lack of efficacy (9ndash11) To havea meaningful impact in neurological and psy-chiatric disorders such drug repurposingefforts will require access to neuropharma-cokinetic (neuroPK) data sets in mice to guidethe testing of new therapeutic hypotheses ingenetically engineered disease models A re-cently published consensus evaluation of drugrepositioning opportunities for Alzheimerrsquosdisease identified 15 potential drug candidatesThese were further prioritized for testing onthe basis of available evidence to produce ashortlist of seven compounds reviewed by in-dustry experts to provide insight into the via-bility of these candidates The most commonshortcoming identified for the compoundsconsidered were issues related to insufficientbrain penetration or the lack of informationabout optimal dosing strategies (11)
The repurposing of statins illustrateshow the neuroPK knowledge gap limits progressStatins were developed as 3-hydroxy-3-methylglutarylndashcoenzyme A (HMG-CoA) reduc-tase inhibitors to lower cholesterol and reduce
Table 1 Preclinical dosing strategies The rationale for drug-dosing strategies was extractedfrom the literature through the analysis of 100 peer-reviewed studies published in2014 from eight journals that cover research on mechanisms of brain function disease andtherapeutic approaches to CNS disorders (Cell Neuron Nature Nature Neuroscience NatureMedicine Neurobiology of Disease Neuropsychopharmacology and Science TranslationalMedicine) (table S1) Forty-four of the 100 publications selected were studies of potentialtherapeutic approaches to disease whereas the remaining were studies of basic neurobiology ormechanisms of disease Each publication was examined to discern how authors selected thedosage of pharmacological tools or therapeutic compounds used in the design of studies toprobe brain function A relatively small number of studies considered what the concentrationof drug available in the brain after administration would be in the context of theirexperimental studies The most common method for selecting a dose of drug was tocite a previous study that demonstrated a biological effect of the drug on someaspect of rodent behavior
Rationale for studyrsquos drug-dose selection
Therapeutic
studies
Number of papers from the100 published studies
analyzed
bull No exposure or rationale for dose selection provided
5
22
bull Rodent dose extrapolated from human studies
0
1
bull Doses are similar to what was used previously toproduce a biological effect
8
23
bull Literature reports cited for multiple functionaleffects of drug at selected dose
4
5
bull Brain penetration evaluated but exposure notmeasured
2
2
bull Literature report of mismatched drug exposure
0
1
bull Observation of a biological effect at a single dosein current study
3
6
bull Observation of dose-responsive biological effectin current study
5
16
bull Brain exposure to drug was measured with routeof administration that differed from the oneused in the efficacy study
1
1
bull Plasma drug concentrations measured literaturereport of brain exposure cited and target-organpharmacodynamic effect observed in the currentstudy
1
1
bull Plasma drug concentrations measured
4
7
bull Brain pharmacodynamic effect of drug observed
2
4
bull Brain drug concentrations measured (totalconcentration)
6
7
bull Unbound brain drug concentrations measured
1
2
bull Brain drug concentrations measured and brainpharmacodynamic effect of drug observed
2
2
Total
44
100
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risk of cardiovascular disease (12) FDA hasapproved at least nine different statins andmost are commonly prescribed nearly one-third of Americans ages 55 to 64 took a pre-scription cholesterol-lowering drug between2009 and 2012 (wwwcdcgovnchsdatahushus14pdf) The widespread availability andsafety profile of statins has lured researchersinto evaluating their potential for repurpos-ing (13) Statins have been profiled extensive-ly in preclinical research to test for potentialtherapeutic benefit in Alzheimerrsquos disease(14ndash19) Fragile X syndrome (20) Rett syn-drome (21 22) epilepsy (23) Huntingtonrsquos dis-ease (24) Parkinsonrsquos disease (25 26) stroke(27) and brain injury (28 29)
A search of the literature reveals no sys-tematic neuroPK studies in any mouse strainthat would enable direct comparisons of CNSexposure across the various statins In silicopredictions based on the drugsrsquo molecularproperties suggest that the nine most widelyprescribed statins each have a different poten-tial to penetrate the blood-brain barrier differ-ent potencies against the HMG-CoA reductaseenzyme and different ldquooff-targetrdquo activity pro-files (30) On the basis of available data thereis reason to believe that simvastatin has thebest overall profile for inhibiting HMG-CoAreductase in the brain (30) A recent study re-ported that lovastatin is able to reverse a rangeof phenotypes in a mouse model of Fragile Xsyndrome (20) However the design of an op-timal clinical trial will require the collection ofmouse pharmacokinetic data to understandhow much CNS drug exposure is required toproduce efficacy in the disease model Thereare at least two possible scenarios Giventhat simvastatin is more potent at inhibitingHMG-CoA reductase than are other statinsand likely to be more brain penetrant inboth mice and humans one would expectthat simvastatin will be more potent than lo-vastatin in ameliorating symptoms in bothmice and humans if the observed efficacy stemsfrom inhibition of HMG-CoA reductase activ-ity in the brain by lovastatin The advantage ofthis outcome would be that better brain pen-etration and potency would lead to a loweroverall dose requirement to achieve efficacyand thus likely a better safety profile
A second scenario could be that lovastatin ismore potent than simvastatin in the mousemodel of Fragile X syndrome because of anadditional biological activity inherent to thelovastatinmolecule whichmaynot yet be doc-umented in the literature In either case un-derstanding the CNS exposure of lovastatin
required to produce efficacy in themouse willdetermine whether there is a safe therapeuticindex for achieving the required concentra-tion in patients Previous attempts to discernuseful neuroPK parameters from the litera-ture for the use of statins in rodent modelshave highlighted the lack of critical data asthe looming roadblock to progress in the field(31 32) Until these data exist the transla-tional potential of preclinical research maybe limited And this is but one example ofone drug class
The creation of a centralized database isneeded for the entire translational researchcommunity and would establish a new mech-anism for academia funding agencies founda-tions and industry to pool resources If studiesare donewell the first time and documented inan open-access resource it will reduce redun-dant efforts and improve the quality of decisionmaking by scientists considering innovativesolutions to our biggest health problems
FILL THE GAPSManuscript submission practices for severalhigh-impact journals now include require-ments that authors include detailed informa-tion regarding study design and statisticalanalysis with each submission A reasonableextension of this checklist should includethe stated rationale for doses selected for studydrugs Information should include a discus-sion of data highlighted in Table 2 Authorsshould be expected to reference a relevant
wwwScienceTranslationalMedicineo
data set from a high-quality database or pub-lication or provide the data in the current study(Table 3)
Industry biologists learn basic principlesof medicinal chemistry pharmacokineticsand drug disposition while working on drugdiscovery project teams Academic groupsare playing an increasing role in transla-tional therapeutics and in particular drugrepurposing Academic programs need toaugment training in pharmacokinetics andpharmacodynamics so as to increase the rigor ofpreclinical work and to ensure that investigator-initiated clinical studies are testing hypotheseseffectively Institutions without a departmentof pharmacology or pharmacometrics mightlack the organizational knowledge needed toconduct drug studies and must identify re-sources or collaborators to patch these defi-cits Formal coursework and Web-basedresources and tutorials are needed to train andsupport translational researchers Manuscriptand grant reviewers need to demand higherstandards for preclinical studies with respect toreporting on drug exposure associated withbiological effects Ethics committees responsi-ble for review of animal protocols should re-quire investigators to provide rationale fordose selections in proposed studies Similarlyscientific review boards at academic medicalcenters need to include clinical pharmacologistswho are able to review investigator-initiatedclinical studies to ensure that proposed dosingstrategies will test a meaningful hypothesis
Table 2 Recommendations for use of pharmacokinetic data The first column includes a listof recommended data sets to aid reviewers of submitted articles in the interpretation ofpreclinical findings The second column includes a list of useful reference data that wouldsupport improved preclinical study design in mice if available in a public database
Literature reports that evaluate studydrugs should include
Compound-specific data that shouldbe included in a rodent
pharmacokinetic database
bull Expected or measured plasma exposure of thestudy drug in the preclinical species during thestudy
bull Elimination half-life (T12)bull Systemic clearance (CL)bull Fraction of drug that is protein bound (fb)
bull Expected or measured target organ exposureof the study drugs in the preclinical speciesduring the study
Maximum plasma concentration after drug admin-istration (Cmax) and time to reach maximum plas-ma concentration (Tmax) for a standardized doseand route of administration
bull Expected or measured free fraction (unboundby protein) of the study drugs in the targetorgan of the preclinical species during thestudy
bull The ratio of drug in brain to that in plasma (BP)bull The ratio of drug found free in brain (Cub) to thatfound free in the plasma (Cup) defined as CubCupbull Any potential impact of drug transporters (foundon the rodent blood-brain barrier) in limiting brainexposure
bull Expected or measured potency of the studydrug against the hypothesized activity in vitro
Expected ormeasured potency of molecule at knownbiological targets
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P ER SP EC T I V E
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A central repository that contains brainpenetration protein binding and pharmaco-kinetic profiles of drugs and pharmacologicaltools in rodents is needed to effectively sup-port translational research This databaseshould also provide basic tutorials that de-fine primary pharmacokinetic parameterswith examples to illustrate how data are usedto predict optimal dosing strategies The min-imum data set needed for each compoundin a useful rodent database is highlighted inTable 2 Access to this information and sup-porting materials will have an immediateimpact on the quality of translational drug re-purposing efforts across brain disorders andwill support the development of new thera-peutic approaches to neurological disordersand mental illness Existing databases man-aged by NIH or precompetitive consortia couldbe reinforced with donated pharmacokineticdata sets and tutorials
Industry and government scientists shouldwork precompetitively to collect and curatepharmacokinetic data sets in conjunction withsupporting educational materials Mouse phar-macokinetic data exist inside pharmaceuti-cal companies for a wide range of publicallydisclosed molecules and literature standardsRelease of these data into a public databasewould provide several benefits to companiesincluding (i) increased scientific rigor in theliterature with a higher probability of repro-ducibility (ii) increased appreciation by theacademic biology community for the diffi-culty inherent in generating molecules withpotency and pharmacokinetic profiles suit-able for in vivo work opening the door forin-kind collaboration with academic groups
and (iii) direct comparison of data collectedin-house to that collected at other compa-nies or institutions to enable better internalquality control Comprehensive pharmaco-kinetic data sets will benefit all therapeuticareas regardless of whether the brain is thetarget organ because peripheral and cen-tral exposure data can be generated fromthe same experiments Moreover the prin-ciples described above for the CNS apply toother target tissues in which vascular bar-riers metabolic processes or active transportalter the distribution of systemically admin-istered drugs
Key to ensuring that preclinical mousestudies test the hypotheses they aim to eval-uate is an understanding of the unboundfraction of drug present in the target organat an appropriate time point under studyGrant and journal reviewers need to care-fully consider whether authors of propos-als and manuscripts are providing adequaterationale for their choices of preclinical dos-ing paradigms Importantly the collectionand centralization of rodent pharmacoki-netic datasets will promote efficient genera-tion of future data reduce the collection ofredundant data and improve the return oninvestment for research funds that are de-voted to preclinical studies aimed towardclinical translation
SUPPLEMENTARY MATERIALS
wwwsciencetranslationalmedicineorgcgicontentfull8320320ps1DC1Table S1 One hundred publications that used systemic drugdelivery with the goal of targeting rodent brains
wwwScienceTranslationalMedicineo
REFERENCES AND NOTES1 A Reichel Addressing central nervous system (CNS) penetra-
tion in drug discovery Basics and implications of the evolv-ing new concept Chem Biodivers 6 2030ndash2049 (2009)
2 F Prinz T Schlange K Asadullah Believe it or not Howmuch can we rely on published data on potential drugtargets Nat Rev Drug Discov 10 712 (2011)
3 C G Begley L M Ellis Drug development Raisestandards for preclinical cancer research Nature 483531ndash533 (2012)
4 P Nair Second act Drug repurposing gets a boost asacademic researchers join the search for novel uses ofexisting drugs Proc Natl Acad Sci USA 110 2430ndash2432(2013)
5 T I Oprea J Mestres Drug repurposing Far beyond newtargets for old drugs AAPS J 14 759ndash763 (2012)
6 S M Strittmatter Overcoming drug development bot-tlenecks with repurposing Old drugs learn new tricksNat Med 20 590ndash591 (2014)
7 K Xu T R Coteacute Database identifies FDA-approved drugswith potential to be repurposed for treatment of orphandiseases Brief Bioinform 12 341ndash345 (2011)
8 X Bosch European researchers drug companies joinforces against rare diseases JAMA 294 2014ndash2015 (2005)
9 F S Collins Mining for therapeutic gold Nat Rev DrugDiscov 10 397 (2011)
10 P Vallance P Williams C Dollery The future is much closercollaboration between the pharmaceutical industry andacademic medical centers Clin Pharmacol Ther 87525ndash527 (2010)
11 A Corbett J Pickett A Burns J Corcoran S B DunnettP Edison J J Hagan C Holmes E Jones C KatonaI Kearns P Kehoe A Mudher A Passmore N ShepherdF Walsh C Ballard Drug repositioning for Alzheimerrsquosdisease Nat Rev Drug Discov 11 833ndash846 (2012)
12 J L Goldstein M S Brown A century of cholesterol andcoronaries From plaques to genes to statins Cell 161161ndash172 (2015)
13 A M Malfitano G Marasco M C Proto C Laezza P GazzerroM Bifulco Statins in neurological disorders An overviewand update Pharmacol Res 88 74ndash83 (2014)
14 T Kurata K Miyazaki M Kozuki N Morimoto Y OhtaY Ikeda K Abe Progressive neurovascular disturbances inthe cerebral cortex of Alzheimerrsquos disease-model miceProtection by atorvastatin and pitavastatin Neuroscience197 358ndash368 (2011)
15 H Kurinami N Sato M Shinohara D Takeuchi S TakedaM Shimamura T Ogihara R Morishita Prevention ofamyloid beta-induced memory impairment by fluvastatinassociated with the decrease in amyloid beta accumulationand oxidative stress in amyloid beta injection mousemodel Int J Mol Med 21 531ndash537 (2008)
16 M Shinohara N Sato H Kurinami D Takeuchi S TakedaM Shimamura T Yamashita Y Uchiyama H RakugiR Morishita Reduction of brain beta-amyloid (Abeta)by fluvastatin a hydroxymethylglutaryl-CoA reductaseinhibitor through increase in degradation of amyloidprecursor protein C-terminal fragments (APP-CTFs) andAbeta clearance J Biol Chem 285 22091ndash22102 (2010)
17 G J Siegel N B Chauhan D L Feinstein G Li E B LarsonJ C Breitner T J Montine Statin therapy is associated withreduced neuropathologic changes of Alzheimer diseaseNeurology 71 383 author reply 383 (2008)
18 X-K Tong C Lecrux P Rosa-Neto E Hamel Age-dependentrescue by simvastatin of Alzheimerrsquos disease cerebrovascularand memory deficits J Neurosci 32 4705ndash4715 (2012)
19 X K Tong N Nicolakakis P Fernandes B Ongali J BrouilletteR Quirion E Hamel Simvastatin improves cerebrovascularfunction and counters soluble amyloid-beta inflammationand oxidative stress in aged APP mice Neurobiol Dis35 406ndash414 (2009)
Table 3 Recommendations to improve translation through the use of preclinicalpharmacokinetic data
Journalsbull Require authors to provide explicit rationale for dosing strategies usedbull Rationale should include consideration of the unbound drug exposure in target organas best practices
Educationbull Include basic pharmacology and pharmacokinetic principles in formal coursework requiredfor basic preclinical and clinical research scientists
bull Develop tutorials and on-line calculators for rodent dose projections to support appropriateuse of published pharmacological tools
Databasesbull Reinforce public chemical databases with mouse pharmacokinetic data that includes brainexposure
Precompetitive consortiabull Create precompetitive consortia to solicit mouse pharmacokinetic data sets from industry andfoundation partners for database expansion
bull Targeted data collection for compounds already in the public domain
rg 6 January 2016 Vol 8 Issue 320 320ps1 4
P ER SP EC T I V E
20 E K Osterweil S C Chuang A A Chubykin M SidorovR Bianchi R K Wong M F Bear Lovastatin corrects ex-cess protein synthesis and prevents epileptogenesis in amouse model of fragile X syndrome Neuron 77 243ndash250(2013)
21 C M Buchovecky S D Turley H M Brown S M KyleJ G McDonald B Liu A A Pieper W Huang D M KatzD W Russell J Shendure M J Justice A suppressorscreen in Mecp2 mutant mice implicates cholesterol me-tabolism in Rett syndrome Nat Genet 45 1013ndash1020(2013)
22 M J Justice C M Buchovecky S M Kyle A Djukic A rolefor metabolism in Rett syndrome pathogenesis Newclinical findings and potential treatment targets RareDis 1 e27265 (2013)
23 F Scicchitano A Constanti R Citraro G De Sarro E RussoStatins and epilepsy Preclinical studies clinical trials andstatin-anticonvulsant drug interactions Curr Drug Targets16 747ndash756 (2015)
24 M L Ferlazzo L Sonzogni A Granzotto L Bodgi O LartinC Devic G Vogin S Pereira N Foray Mutations of theHuntingtonrsquos disease protein impact on the ATM-dependentsignaling and repair pathways of the radiation-inducedDNA double-strand breaks Corrective effect of statins andbisphosphonates Mol Neurobiol 49 1200ndash1211 (2014)
25 E K Tan L C Tan Holding on to statins in Parkinsondisease Neurology 81 406ndash407 (2013)
26 B Friedman A Lahad Y Dresner S Vinker Long-termstatin use and the risk of Parkinsonrsquos disease Am J ManagCare 19 626ndash632 (2013)
27 M S Elkind Stroke A step closer to statin therapy forstroke Nat Rev Neurol 9 242ndash244 (2013)
28 E E Abrahamson M D Ikonomovic C E Dixon S T DeKoskySimvastatin therapy prevents brain trauma-inducedincreases in beta-amyloid peptide levels Ann Neurol66 407ndash414 (2009)
29 E F Wible D T Laskowitz Statins in traumatic brain injuryNeurotherapeutics 7 62ndash73 (2010)
wwwScienceTranslationalMedicineo
30 S Sierra M C Ramos P Molina C Esteo J A VaacutezquezJ S Burgos Statins as neuroprotectants A comparativein vitro study of lipophilicity blood-brain-barrier penetra-tion lowering of brain cholesterol and decrease of neuroncell death J Alzheimers Dis 23 307ndash318 (2011)
31 W G Wood G P Eckert U Igbavboa W E Muumlller Statinsand neuroprotection A prescription to move the fieldforward Ann N Y Acad Sci 1199 69ndash76 (2010)
32 W G Wood W E Muumlller G P Eckert Statins and neuro-protection Basic pharmacology needed Mol Neurobiol50 214ndash220 (2014)
101126scitranslmedaac9888
Citation R J Kleiman M D Ehlers Data gaps limit thetranslational potential of preclinical research Sci Transl Med8 320ps1 (2016)
D
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ownloaded from
101126scitranslmedaac9888] (320) 320ps1 [doi8Science Translational Medicine
Robin J Kleiman and Michael D Ehlers (January 6 2016) Data gaps limit the translational potential of preclinical research
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Boston Childrenrsquos Hospital ndash Broad Institute Collaboration Grants
Background Meeting the challenges of biomedicine requires bringing together creative scientists exceptional technological resources and world-class expertise across many disciplines that rarely exist within a single institution This guiding principle is the basis for a funding opportunity to support Boston Childrenrsquos Hospital investigators performing research in collaboration with Broad scientists
Goals The fundamental goal of this new award is to spark new collaborations between Boston Childrenrsquos Hospital and the Broad Institute The grants will be awarded to address a very wide range of scientific questions but are specifically designated for projects with the following characteristics
middot Projects where engagement with the Broad would benefit Childrenrsquos Hospital investigators projects that can uniquely benefit from being done at the Broad Institute
middot Projects that create new scientific collaborations and bring together diverse scientific backgrounds projects that spark new scientific directions or technologies and are not currently being pursued at Childrenrsquos Hospital
middot Projects that pilot new approaches that researchers at Childrenrsquos the Broad and the greater scientific community can benefit from in the future the purpose of these awards is not to provide gap or extension funding of existing projects but to initiate new projects
Eligibility Individuals with Principal Investigator status at Boston Childrenrsquos Hospital are eligible Applicants need not be Associate Members of the Broad Institute
Broad Platforms and Scientists Broadrsquos Platforms (Genomics Imaging Metabolite Profiling Proteomics Genomic Perturbation and the Broad Technology Labs) are collaborative organizations that provide scientific leadership and cutting edge technologies in support of project goals Collaborations can also be established with other groups at the Broad including the Klarman Cell Observatory the Stanley Center for Psychiatric Research or the Center for the Development of Therapeutics
Budgets Grants will provide $60000 direct support for 1 year plus philanthropic overhead It is expected that most grants will fund work performed at the Broad Institute either through interaction with Broadrsquos Platforms or via collaboration with a Broad scientist however the work may also occur at Boston Childrenrsquos if it is important to meet the scientific goals of the collaboration
Deadline and Review process Final proposals are due by September 1 2015 Funding decisions are expected to be reached by October 1 2015 Proposals will be reviewed by a joint Childrenrsquos HospitalndashBroad Institute committee Additional submission dates are expected for 2016
Submission Applicants are strongly encouraged to discuss potential applications in advance with the office of the Chief Scientific Officer at the Broad Questions should be directed to Alex Burgin ( 617-714-7124)
Proteomics Genomic Perturbation and the Broad Technology Labs) are collaborative
organizations that provide scientific leadership and cutting edge technologie
s in support of
project goals Collaborations can also be established with other groups at the Broad including
the Klarman Cell Observatory the Stanley Center for Psychiatric Research or the Center for the
Development of Therapeutics
Budgets
Grants wi
ll provide $60000 direct support for 1 year plus philanthropic overhead It
is expected that most grants will fund work performed at the Broad Institute either through
interaction with Broadrsquos Platforms or via collaboration with a Broad scientist howev
er the
work may also occur at Boston Childrenrsquos if it is important to meet the scientific goals of the
collaboration
Deadline and Review process
Final proposals are due by September 1 2015 Funding
decisions are expected to be reached by October 1 201
5 Proposals will be reviewed by a joint
Childrenrsquos Hospital
ndash
Broad Institute committee Additional submission dates are expected for
2016
Submission
Applicants are
strongly encouraged to discuss potential applications in
advance
with the office of the Chief Sc
ientific Officer at the Broad
Questions should be
directed to Alex Burgin (
aburginbroadinstituteorg
617
-
714
-
7124
)
Boston Childrenrsquos Hospital ndash Broad Institute Collaboration Grants
Background Meeting the challenges of biomedicine requires bringing together creative
scientists exceptional technological resources and world-class expertise across many
disciplines that rarely exist within a single institution This guiding principle is the basis for a
funding opportunity to support Boston Childrenrsquos Hospital investigators performing research
in collaboration with Broad scientists
Goals The fundamental goal of this new award is to spark new collaborations between Boston
Childrenrsquos Hospital and the Broad Institute The grants will be awarded to address a very wide
range of scientific questions but are specifically designated for projects with the following
characteristics
Projects where engagement with the Broad would benefit Childrenrsquos Hospital
investigators projects that can uniquely benefit from being done at the Broad Institute
Projects that create new scientific collaborations and bring together diverse scientific
backgrounds projects that spark new scientific directions or technologies and are not
currently being pursued at Childrenrsquos Hospital
Projects that pilot new approaches that researchers at Childrenrsquos the Broad and the
greater scientific community can benefit from in the future the purpose of these awards
is not to provide gap or extension funding of existing projects but to initiate new
projects
Eligibility Individuals with Principal Investigator status at Boston Childrenrsquos Hospital are
eligible Applicants need not be Associate Members of the Broad Institute
Broad Platforms and Scientists Broadrsquos Platforms (Genomics Imaging Metabolite Profiling
Proteomics Genomic Perturbation and the Broad Technology Labs) are collaborative
organizations that provide scientific leadership and cutting edge technologies in support of
project goals Collaborations can also be established with other groups at the Broad including
the Klarman Cell Observatory the Stanley Center for Psychiatric Research or the Center for the
Development of Therapeutics
Budgets Grants will provide $60000 direct support for 1 year plus philanthropic overhead It
is expected that most grants will fund work performed at the Broad Institute either through
interaction with Broadrsquos Platforms or via collaboration with a Broad scientist however the
work may also occur at Boston Childrenrsquos if it is important to meet the scientific goals of the
collaboration
Deadline and Review process Final proposals are due by September 1 2015 Funding
decisions are expected to be reached by October 1 2015 Proposals will be reviewed by a joint
Childrenrsquos HospitalndashBroad Institute committee Additional submission dates are expected for
2016
Submission Applicants are strongly encouraged to discuss potential applications in
advance with the office of the Chief Scientific Officer at the Broad Questions should be
directed to Alex Burgin (aburginbroadinstituteorg 617-714-7124)
Clinical Trials Glossary
ADME an acronym for absorption distribution metabolism and elimination ADME
studies determine how a drug is absorbed by the body the chemical changes that it may
undergo and how it is eliminated from the body
Adverse event (AE) a bothersome event that occurs in a study participant AEs may be
related to the treatment being tested or may be due another cause (eg another treatment
another medical condition an accident or a surgery)
Arm a specific type of treatment to which a group of clinical trial participants is
assigned Some clinical trials have one arm and some have two arms while others have
three or more arms For example a clinical trial comparing two different doses of an
investigational drug versus a placebo would have three arms participants receiving a
higher dose of the investigational drug participants receiving a lower dose of the
investigational drug and participants receiving the placebo
Baseline a point in time at the beginning of a clinical trial before the study participants
receive any treatment At the baseline participants usually have certain types of tests
During and after treatment the same tests may be performed and the results compared
with the baseline results to see if the drug has caused changes
Bias a factor ndash such as a preconceived idea about the effects of the benefits and risks of a
treatment or a lack of balance in selection of patients for a study ndash that reduces the
likelihood that the study results are true Methods such as blinding and randomization
are used to limit the potential for bias
Bioavailability the portion of the dose of a drug that reaches the bloodstream For
example if the drug is administered intravenously its bioavailability is 100 percent
however if the drug is administered in any other way such as orally topically or
through intramuscular injection its bioavailability will decrease due to incomplete
absorption
Bioequivalence study a test performed to compare the portion of a drug in the
bloodstream when administered in different dosage forms
Biologic product any substance that can be used in prevention treatment or cure of
disease Some examples include vaccines blood virus toxin antitoxin and therapeutic
serum
Biopsy the removal of cells or tissue from a patient for examination which is usually
done under a microscope A tissue sample might be taken for genetic studies Sometimes
there is a difference between the blood genotype and the skin or other tissue genotype
This term can also refer to the tissue sample that has been obtained by such a procedure
2
Blinding a process used to prevent the participants the researchers or both from
knowing what specific treatment is being given to participants in a clinical trial The
process of blinding helps to reduce bias because study participants and researchers are
less likely to be unconsciously influenced by the knowledge of what the study participant
is actually receiving If only the participants are blinded the study is called a single-
blind study If both participants and researchers are blinded the study is called a double-
blind study
Carcinogenicity studies long-term studies conducted in animal models to determine a
drugrsquos likelihood of causing cancer
Clinical efficacy a compoundrsquos ability to produce the desired effect
Clinical pharmacology a science that studies properties of drugs in relation to their
therapeutic value in humans
Clinical study or Clinical trial a medical experiment in human beings that helps to
determine how a disease drug or medical device affects study participants Clinical
studies are necessary to answer specific questions about how to better diagnose prevent
or treat a disease or condition
Cohort a group of study participants who have certain characteristics in common such
as female sex a defined age range or particular severity of disease Dividing study
participants into cohorts is often done as part of the analyses of study data
Contraindication a factor that makes the use of a particular drug inadvisable For
example a person who has had an allergic reaction to penicillin in the past is considered
to have a contraindication to using penicillin in the future
Control group a group of participants not receiving the investigational drug but instead
receiving a standard treatment for their disease or receiving a placebo The results
observed in the group of patients receiving the investigational drug are compared with the
results observed in the control group
Crossover study a study design with two or more arms where participants receive one
treatment for a period of time and then switch over to a second treatment for a period of
time Such a study design allows the effects of the two treatments to be compared in the
same patient
Data Monitoring Committee (DMC) or Data Safety and Monitoring Board (DSMB)
A committee of experts that periodically reviews the accumulating data from an ongoing
multicenter clinical trial Members of a DMCDSMB must be independent ie they
cannot be participating as investigators in the clinical trial Based on their review the
DMCDSMB experts advise the sponsor regarding whether it is safe and acceptable to
continue with the study or whether the data suggest that the study should be modified or
stopped A DMCDSMB may recommend that a trial be stopped if there are safety
concerns or if the trial objectives have been achieved
3
Dose-ranging study a clinical trial in which two or more doses of an investigational
drug are tested to determine which dose is likely to offer the best combination of safety
and efficacy in later clinical trials or in medical care
Efficacy or effectiveness the ability of a drug to prevent cure or slow a disease process or to alleviate the symptoms of a disease or condition
Eligibility a determination made during the screening period for a clinical study of
whether a personrsquos participation in the trial is likely to be safe and can contribute data
that will help achieve the study goals
Endpoint occurrence of a disease symptom sign or test result that constitutes one of the
target outcomes of a clinical trial
Inclusionexclusion criteria the factors defined in the protocol of a study that determine
whether a personrsquos participation in a clinical trial is likely to be safe and can contribute
data that will help achieve the study goals Study candidates undergo evaluation during
the study screening period to determine if they meet all of the inclusion criteria and do
not meet any of the exclusion criteria as defined in the protocol These criteria usually
consider such factors as age sex type of disease stage of disease previous treatment
history and other medical conditions in determining eligibility for the study
Informed consent (assent) a process by which medical researchers provide necessary
information to a person about a clinical study and the person voluntarily confirms his or
her willingness to participate in the study Children who are considered old enough to
have a basic understanding of the study may need to provide assent to be involved in the
study a parent or legal guardian must also give informed consent for such a child to
participate
Informed consent (assent) form a document that describes a clinical study to the
participants (or their parentsguardians) The informed consent (assent) form includes
information about the goals of the study the study design and duration the types of tests
to be performed the potential risks and inconveniences the potential benefits the
possible costs or payments associated with study participation the available alternative
therapies the rights and responsibilities of the participant and the people to contact if the
participant has questions The informed consent (assent) form must be reviewed and
signed before the participant has any study tests or treatment including the tests
performed during the screening period at the beginning of the study Participants are
given a copy of the informed consent (assent) form to take home
Institutional Review Board (IRB) or Independent Ethics Committee (IEC) a board
of physicians statisticians researchers community advocates and others who are
responsible for ensuring the protection of the rights safety and well-being of participants
in a clinical trial at a study center This board is called an IRB in the United States and is
often called an IEC in other countries IRBIECs review and approve important study
documents (eg protocols informed consent forms study advertisements and patient
4
brochures) before the start of the study and periodically review the progress of the study
while it is ongoing
Investigational Drug a drug that is being tested as a potential treatment for a disease or
condition but has not yet been proven safe and effective for that use
Investigator a physician or other health care worker who carries out a clinical trial by enrolling treating and monitoring participants and recording the results
In vitro testing testing conducted in test tubes or other artificial environments
In vivo testing testing conducted in living animals or humans
Longitudinal study a clinical study that involves observations of the same items over
long periods often many decades Because longitudinal studies track the same people
they are often used to study trends across the life span to uncover predictors of certain
diseases or to track the effects of a particular treatment on a patientrsquos condition over
time
Multicenter study a study conducted at more than one location Multicenter clinical
studies are generally performed when each individual clinical trial site does not have
enough study candidates to complete a large trial
Natural history study a study of the natural development of a disease or condition over
a period of time Natural history studies are usually longitudinal studies
New Drug Application (NDA) the registration document through which a
pharmaceutical company formally proposes that the FDA approve a new drug for
manufacturing and sale The application includes detailed reports of pharmacology
toxicology manufacturing and chemistry as well as data from clinical trials
Open-label study a study in which the participants and the investigators know which
treatment is being given In an open-label study there is no blinding and none of the participants receives a placebo
Orphan disease a disease or condition that affects a relatively small number of people
In the US this defined as fewer than 200000 people In Europe this is defined as fewer
than five in 110000 people
Orphan drug a drug intended to treat an orphan disease
Participant or subject a patient or healthy volunteer who participates in a clinical trial
Phase 1 the initial phase of testing of an investigational drug in humans Usually a
Phase 1 clinical study is conducted in a small number of healthy volunteers or patients
with a disease for which the drug may be useful Generally the study is designed to
determine the side effects of the drug and its pharmacokinetics Some information
5
regarding drug efficacy may be collected if patients with a disease participate A phase
frequently encompasses more than one clinical trial Phase 1 sometimes is sub-divided
into Phases 1a and 1b for example when the first set of Phase 1 trials (Phase 1a) is
performed in healthy volunteers and a second set of Phase 1 trials (Phase 1b) is
performed in patients with a disease
Phase 2 the intermediate phase of testing of an investigational drug in humans Usually
a Phase 2 clinical study conducted in patients with a disease for which the drug may be
useful Generally the study is designed to evaluate dosing to obtain preliminary data on
the effectiveness of the drug and to acquire more safety information Phase 2 sometimes
is sub-divided into Phases 2a and 2b Phase 2a studies typically are smaller and shorter
in duration and evaluate different drug doses to see how they affect certain tests that can
indicate whether the drug is working as expected Phase 2b studies typically enroll more
patients are of longer duration and evaluate whether the drug is offering clinical benefits to patients Phase 2b studies sometimes are considered pivotal or registration-directed
Phase 3 the final phase of testing an investigational drug in humans before regulatory
approval Phase 3 studies are usually conducted in a large population of patients and are
generally designed to confirm the effectiveness of the drug and to evaluate the overall
risk-benefit ratio Phase 3 studies usually test the investigational drug in comparison with
a standard treatment for the disease or a placebo
Phase 4 testing of a drug in humans after it has already been approved by regulatory
authorities and can be used in medical practice Phase 4 studies may be conducted to
compare the drug to a similar type of drug to explore whether it may help patients with
other diseases to further study the long-term safety of the drug or for other reasons
Pivotal study a study that is designed to generate the data required by regulatory
authorities to decide whether to approve an investigational drug A pivotal study is
usually a large randomized Phase 2b or Phase 3 study and often is blinded and uses a
placebo as a control Sometimes a pivotal study is described as a registration-directed
study
Placebo an inactive version of an investigational drug A placebo has a similar
appearance to the investigational drug but is expected to have no therapeutic value A
placebo is used as a comparison treatment to reduce bias in randomized studies
Preapproval access program an umbrella term for programs that allow seriously ill
patients to receive an investigational drug when they are unable to participate in clinical
trials and there is no alternative treatment This is sometimes referred to as
compassionate use Types of pre-approval access programs include expanded access
parallel-track named patient program single-patient exemption and treatment IND The
timing for starting an expanded access program usually depends upon what is known
about the risk-benefit of the drug and whether the drug can be provided in a manner that
is fair to patients with the disease
6
Preclinical (nonclinical) testing testing of a drug in test tubes or in animals A drug
undergoes preclinical testing before being tested in humans to make sure that it shows
evidence of desired effects and is sufficiently safe for study in people Preclinical testing
sometimes also helps to determine the doses of the drug that should be evaluated in
humans Preclinical testing is sometimes called nonclinical testing
Protocol a document describing what types of people may participate in a clinical study
and the objectives treatments measurements statistical methods timing and
organization of a clinical trial The protocol must be prepared in advance of the study
and must be reviewed and approved by review committees and regulatory authorities
before the study is started Investigators must follow the protocol to carry out the study
Randomization assignment of participants to treatment arms based on chance This is
usually done by a computer program in a way that does not allow either the participants
or the investigators to choose who is assigned to which arm Randomization is used to
reduce bias in clinical trials
Risk-benefit ratio the balance of the risk of side effects expected with use of a drug
versus the potential for benefit with the use of that drug A drug with a good risk-benefit
ratio has few side effects and is very effective
Serious adverse event (SAE) an adverse event that is life-threatening requires inpatient
hospitalization or lengthens a hospital stay leads to substantial disability leads to a birth
defect or results in death
Side effect any effect of a drug other than the desired effect Side effects are often
unwanted and may be bothersome Other names for a bothersome side effect are adverse
drug reaction (ADR) or drug toxicity
Screening period a period at the beginning of a clinical trial when candidates for the
study are evaluated to determine if their participation is likely to be safe and can
contribute data that will help achieve the study goals
Significant or statistically significant an outcome in a clinical trial is likely to result
from a real difference (eg due to an effect of a treatment) and is unlikely to be due to
chance alone The level of statistical significance is often expressed in terms of a p-
value which indicates the probability that a difference is not due to chance alone
Usually a p-value smaller 005 is considered statistically significant
Sponsor the organization responsible for financing and coordinating a clinical trial
Most often this is a pharmaceutical or biotechnology company
Standard treatment a treatment currently in wide use often approved by regulatory
agencies and generally considered effective in the treatment of a specific disease or
condition
7
Toxicity a side effect produced by a drug that is bothersome to the person taking the
drug
Toxicology the study of the adverse effects of chemicals conducted in animal models to
predict potential adverse effects in humans Some studies are conducted during clinical
development to evaluate dosing regimens
Boston Childrenrsquos Hospital Clinical Research Map 1 Mouse over for additional info Bold = hyperlink
CLINICAL RESEARCH MAP
Boston Childrenrsquos Hospital Clinical Research Map 2 Mouse over for additional info Bold = hyperlink
ObjectiveThis clinical research map is designed to serve as a guide for investigators study coordinators and research nurses at Boston Childrenrsquos Hospital The research map outlines the key steps in preparing to launch a research study and provides embedded links to institutional resources tools and documents
An investigator need not follow the steps on the Clinical Research Map in any particular order There is flexibility and the steps followed will in part de-pend on the type of research study
For new as well as more experienced investigators the Clinical Research Map can be used as a checklist or an inves-tigator can use the steps on the map as points for consideration as they are developing a protocol and launching a study
This tool is not intended to substitute for the important collaboration be-tween a junior investigator and a senior investigatormentor A senior investiga-tor plays a pivotal role in coaching and advising a junior investigator regarding the many subtleties and variations that apply to designing and implementing a protocol
This process map cannot be inclusive of every possible task or step but is intended as a general guide for investi-gators and their study teams
ResourcesThere are many institutional resources at Boston Childrenrsquos Hospital designed to support investigators and their clini-cal research teams In addition to links to resources tools and documents that are embedded in the steps of the clini-cal research map the last page of this document contains website addresses that will take you to additional helpful institutional resources
Acknowledgements Cindy Williams DNP RN PNP NE-BC Nursing Director CTSU Clinical Research Nursing
Ellen McGrath MSN RN CPNP Nurse Practitioner Department of Surgery
Grace Yoon MSN RN CNNP Research Nurse Department of Ophthalmology
Laura Feloney BA Lab Technician
ContentsOverview Four stages 3
1st Stage Protocol development 4
1st Stage Protocol development contrsquod 5
2nd Stage Implementation planning 6
3rd stage Study launch7
4th stage Statistical analysis reporting and dissemination 8
Discarded specimens Additional steps 9
Chart review Steps if you are completing a chart review 10
Appendix A Resources for researchers 11
Boston Childrenrsquos Hospital Clinical Research Map 3 Mouse over for additional info Bold = hyperlink
Overview Four stages
Protocol development
Implementation planning
Study launch
Statistical analysis reporting and dissemination
1
2
3
4
Boston Childrenrsquos Hospital Clinical Research Map 4 Mouse over for additional info Bold = hyperlink
1st Stage Protocol development
Explore resources
CRIT
CRC
EQuIP
CTSU
Harvard Catalyst
Complete training
CITI training
EQUiP
Consult research pharmacistResearch Pharmacy
Rocco Anzaldi
Consult statistician
CRC
Draft a protocol
Protocol guidelines
Study personnel
FDA Guidance for Investigators
Consult Clinical Research Center
CRC
Bio Bank
Start IRB application
TransLab
Consider applying for grants
securing funding
Office of Sponsored Programs
If INDIDE application to FDA
Does my study need an INDIDE
Regulatory resources
Arrange a consultation with
CRIT
ConsultationTasks for investigators and study teams
Boston Childrenrsquos Hospital Clinical Research Map 5 Mouse over for additional info Bold = hyperlink
Respond to IRB questionsrequests
for clarification
1st Stage Protocol development contrsquod
Departmental Scientific Review
Organize DSMB design DSMP
DSMPDSMB
Templates for Research Study
Documents and Tools
Study Templates and Tools
Investigators who sponsor an FDA regulated trial
ClinicalTrialsgov
Create regulatory binder
Regulatory Binder Template
Submit the grant application to OSP
OSP
TIDO
CTBO
Consult Office Intellectual Property
Technology and Innovation
Development Office
TIDO
IRB approval
Consider blood volume for research
Research blood volume policy
Confidentiality plan
Confidentiality guidelines
Boston Childrenrsquos Hospital Clinical Research Map 6 Mouse over for additional info Bold = hyperlink
Develop Case Report Forms
(CRFs)
CRF guidelines
Establish electronic shared
folder or study binder for study
documents
CRIT
Set date for trial launch
Develop fast fact sheet for bedside staff
Consult programmer re database
CRIT
Research study resource manual
for the clinical unit
Confirm study drug
in pharmacy
Rocco Anzaldi
Clarify system for screening
and enrolling patients
Recruitment guideline
Updated protocol to
nurse manager
Consult MDsNPs on unitclinic
2nd Stage Implementation planning
Tasks for investigators and study teams
Study logistics Documentation logistics
Data storage
Confidentiality plan
Confidentiality guidelines
Create study orderset
Consider blood volume for research
Research blood volume policy
Create Manual of Operations
MOO Guide
Study implementation
meeting
Develop study logstools
EQUIP
Finalize tracking sheet
Research Administration
Fernando Valles
Boston Childrenrsquos Hospital Clinical Research Map 7 Mouse over for additional info Bold = hyperlink
3 Document informed consent
Informed Consent
Consent library
Schedule weekly study team meeting
Communicate to department faculty
and multidisciplinary
team announcing trial launch
Steps before trial launch
3rd stage Study launch
Patient flow
1 Seek permission
to approach potential subjects
2 Screenenroll
patients
EQUIP
5 Send Study
Tracking Sheet (STS)
6 Collection of
patient data and assessing for
adverse events
7 Study
documents and data handling
4 Datetime study tests
Create a checklist outlining study action items for each subject
Boston Childrenrsquos Hospital Clinical Research Map 8 Mouse over for additional info Bold = hyperlink
Annual IRB Report
Annual Progress ReportStaff Report
raquo Maintain Interest of Staff
raquo Important to See Study Progress
Write Abstract
Dissemination of Research Results
raquo Conference raquo Internal Presentation for Colleagues
raquo Publication
Plan DSMB MeetingInterim
Analysis
4th stage Statistical analysis reporting and dissemination
Data Entry
When Enrollment Complete Data
Cleaning
Monitor Subjects to Identify
Adverse Events (CCI sponsor
DSMB)
Report Adverse Events
Update MOO Based on Experience
with First Several Patients Enrolled
Weekly Study Team Meeting
Report study findings to
subjects and stakeholders
Data management Trial management
Reporting Dissemination
Regular Review of Data
to Identify Deviations
and Workflow Improvements
Consult Statistician When Approaching Target Enrollment
Discarded specimens Additional steps
Boston Childrenrsquos Hospital Clinical Research Map 9 Mouse over for additional info Bold = hyperlink
Send IRB Approval to lab manager
Maureen Samson
Educate staff in areasunits about sample collection
Locate the discarded samples
Locate the accession number in PowerChart
Retrieve specimen
Mark Kellogg
Follow Shipping Rules and Procedures
IATAShipping with dry ice instructions
Communicate with laboratory staff
Contact Dr Mark Kellogg to discuss specimen retrieval
Consult with Biorepository
Biorepository
Chart review Steps if you are completing a chart review
Boston Childrenrsquos Hospital Clinical Research Map 10 Mouse over for additional info Bold = hyperlink
7 8
4321
Databaserecord review guidelines
5 6
Consult programmer re database
CRC Request
Respond to IRB questions
requests for clarification
Departmental Scientific Review
Complete training
CITI Training
Draft a protocol
Protocol Guidelines
Prepare IRB Application
Information about the CCI
IRB Application
Develop Case Report Forms (CRFs)
CRF Guidelines
IRB Review
Boston Childrenrsquos Hospital Clinical Research Map 11 Mouse over for additional info Bold = hyperlink
Clinical Research Center (CRC) x84720
Committee on Clinical Investigation (CCI IRB) x57052
Research Pharmacist x52014
Clinical and Translational Science Unit (CTSU) x57541
Education and Quality Improvement Program (EQUIP) x57052
Clinical Trials Office Central Budgeting x4-2714
Office of Sponsored Programs x4-2723
Technology and Innovation Development Office 617-919-3079
Research Finance x8-3517
Harvard Catalyst 617-432-7810
Regulatory Affairs x4-2777
Appendix A Resources for researchers
RES_4446_ClinicalResearchMap-FINAL FOR LINKS 1
RES_4446_ClinicalResearchMap-FINAL FOR LINKS 10
Overview Four stages
1st Stage Protocol development
1st Stage Protocol development contrsquod
2nd Stage Implementation planning
3rd stage Study launch
4th stage Statistical analysis reporting and dissemination
Discarded specimens Additional steps
Chart reviewSteps if you are completing a chart review
Appendix A Resources for researchers
RES_4446_ClinicalResearchMap-FINAL FOR LINKS 11
RES_4446_ClinicalResearchMap-FINAL FOR LINKS 2
RES_4446_ClinicalResearchMap-FINAL FOR LINKS 3
RES_4446_ClinicalResearchMap-FINAL FOR LINKS 4
RES_4446_ClinicalResearchMap-FINAL FOR LINKS 5
RES_4446_ClinicalResearchMap-FINAL FOR LINKS 6
RES_4446_ClinicalResearchMap-FINAL FOR LINKS 7
RES_4446_ClinicalResearchMap-FINAL FOR LINKS 8
RES_4446_ClinicalResearchMap-FINAL FOR LINKS 9
RES_4446_ClinicalResearchMap-PAGE 5pdf
Overview Four stages
1st Stage Protocol development
1st Stage Protocol development contrsquod
2nd Stage Implementation planning
3rd stage Study launch
4th stage Statistical analysis reporting and dissemination
Discarded specimens Additional steps
Chart reviewSteps if you are completing a chart review
Appendix A Resources for researchers
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MOUSE OVER
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COVER BUTTON
Previous Page
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Page 1
Button 91
Button 92
Button 94
IRB review
Button 102
Develop Case Report Forms
Button 136
Consult clinical research center
INDIDE 1
Explore resources
Button 1016
Bio Bank p
4
Consult statistician
Consult research pharmacist
Study personnel
Complete training
Consider grantsfunding
Draft a Protocal 2
Arrange a consutlations with CRIT
Next Page 1
Previous Page 1
TransLab
Start IRB application 3
Develop study logs
Updatedd protocol
Confirm study drug
Establish electronic shared
COnsult programmer
Clarify system
Research study resrouce manual
Develop case report forms
MOO
Set date for trial launch
Button 44
Study implementation meeting
Finalize tracking sheet
Data storage
Confidentiality
Blood volume 3
Develop fast fact
Consult MDs
Schedule weekly
Communicate early
Button 71
Screenenroll patients
Document informed consent
Datetime tests
Send study tracking sheets
Collection patient data
Button 77
Dissemination
Button 87
Button 124
Button 125
Communicate with lab staff
Button 106
Button 109
Button 1010
Shipping page 9
Button 1012
Button 99
Button 133
Button 134
Button 135
Biorepository
Locate assession number
Retrieve specimen
Button 30
Consult office
Negotiate Contract
Organizing DSMB
Submit Grant
Respond to IRB questions
Button 66
Create regulatory binder
Templates for research stufy
Clinical Trials Business Office
Blood volume 2
Confidentiality plan
Investigators who sponsor
clinicaltrials
gov
BPN Project
Drug Discovery amp Development Testing Funnel
Tier 1 2 3
Tier 6 7 8
Tier 5
Tier 4
Example Drug Discovery amp Development Testing Funnel
Cytotoxicity
Grant
Project
Example Drug Discovery amp Development Testing Funnel
TIER 1A ndash Primary Screen
Chemical purity and identity of active compounds
Primary bioactivity screen
Cell viability (When Appropriate)
ScaffoldsMoiety Chemical liabilities (for example Michael acceptor GSH reactive)
Calculated properties CLogP
PSA
Molecular Weight
rotatable bonds
H-bond donors and acceptors
permeability
pKa
Solubility
TIER 1B
Confirm EC50 determinations for actives compounds in primary screen with fresh
compounds from the original stock Confirm EC50 determinations for the lead (most
active) compound in primary screen with a new sample either repurchased purified
and characterized in-house or independently synthesized in-house
Compounds with IC50s (EC50s) less than X advance to Tier 2
TIER 2A ndash Activity Confirmation
Secondary screen
TIER 2B
Repeat EC50 determinations for actives in secondary screen with fresh
compounds from the original stock
Compounds with IC50s (EC50s) less than X advance to Tier 3
Example Drug Discovery amp Development Testing Funnel
TIER 3 ndash Drug-like Properties Specificity
IC50 selectivity in selectivity screen
CYP450 Inhibition competitive and time-dependent if structural alerts exist
(spot check illustrative examples from compound series)
Measured solubility
Measured protein binding (spot check illustrative examples from
compound series)
Test of Permeability in vitro permeability [indicate assay eg Caco2 orand
PAMPA] (spot check illustrative examples from compound series)
hERG
Cytoxicity assays
All compounds with no significant issues (Define Minimum Conditions for
Advancement) to advance to Tier 4
Example Drug Discovery amp Development Testing Funnel
TIER 4 ndash Scale-up Synthesis and Preliminary PK
Scale-up synthesis
Purity determination gt98 with no single impurity gt1
Rodent bioavailability and PK (define target delivery route) Tmax
Cmax
AUC
Bioavailibility
Vss CL T12 MRT
Brain to Plasma ratios
P-glycoprotein transport MDCK-MDR1 and MDCK-mdr1a
Plasma Protein Binding (species)
Microsomal Stability ndash rodent and human
Defineplan Patent Protection Strategy
All compounds with no significant issues (Define
Minimum Conditions for Advancement) advance
in parallel to Tiers 5AampB
Example Drug Discovery amp Development Testing Funnel
TIER 5A ndash In Vivo Bioactivity
Animal efficacy
Validate Biomarker
Target engagement
Advance to Tier 6 if (Define Minimum Conditions for advancement)
TIER 5B ndash Advanced Drug-like Properties
Microsomal stability in multiple
species
Chemical Stability
CYP450 induction
CYP reaction phenotyping
Metabolism ndash human
hepatocytesmicrosomes
Metab ID define major human rat dog and
non-human primates (NHP) metabolites
In vitro Tox Ames
Chromosome Aberration
CNS effects
Example Drug Discovery amp Development Testing Funnel
TIER 6 ndash Liability Assessment
Broad Pharmacological Profile and Toxicology
PK in second species
TIER 7
Non-GLP exposure studies single and multiple dose
Advance to late stage pre-clinical development (Define Minimum
Conditions for advancement)
Example Drug Discovery amp Development Testing Funnel
Principal InvestigatorProgram Director (Last First Middle)
enspenspenspenspensp
DETAILED BUDGET FOR INITIAL BUDGET PERIOD
DIRECT COSTS ONLY
FROM
THROUGH
enspenspenspenspensp
enspenspenspenspensp
PERSONNEL
DOLLAR AMOUNT REQUESTED (omit cents)
NAME
ROLE ONPROJECT
TYPEAPPT (months)
EFFORTONPROJ
INSTBASESALARY
SALARYREQUESTED
FRINGEBENEFITS
TOTAL
enspenspenspenspensp
PrincipalInvestigator
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
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enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
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enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
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enspenspenspenspensp
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enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
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enspenspenspenspensp
SUBTOTALS
enspenspenspenspensp
enspenspenspenspensp
enspenspenspenspensp
CONSULTANT COSTS
enspenspenspenspensp
enspenspenspenspensp
EQUIPMENT (Itemize)
enspenspenspenspensp
enspenspenspenspensp
SUPPLIES (Itemize by category)
enspenspenspenspensp
enspenspenspenspensp
TRAVEL
enspenspenspenspensp
enspenspenspenspensp
PATIENT CARE COSTS
INPATIENT
enspenspenspenspensp
enspenspenspenspensp
OUTPATIENT
enspenspenspenspensp
enspenspenspenspensp
ALTERATIONS AND RENOVATIONS (Itemize by category)
enspenspenspenspensp
enspenspenspenspensp
OTHER EXPENSES (Itemize by category)
enspenspenspenspensp
enspenspenspenspensp
SUBTOTAL DIRECT COSTS FOR INITIAL BUDGET PERIOD
$
enspenspenspenspensp
CONSORTIUMCONTRACTUAL COSTS
DIRECT COSTS
enspenspenspenspensp
FACILITIES AND ADMINISTRATIVE COSTS
enspenspenspenspensp
TOTAL DIRECT COSTS FOR INITIAL BUDGET PERIOD
$
enspenspenspenspensp
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
References on Pharmacokinetics and Brain Penetration of Small Molecules
Di L Rong H Feng B Demystifying brain penetration in central nervous system drug discovery Miniperspective Journal of
medicinal chemistry 2013 56(1)2-12
Reichel A Addressing central nervous system (CNS) penetration in drug discovery basics and implications of the evolving
new concept Chemistry amp biodiversity 2009 6(11)2030-2049
Smith DA Di L Kerns EH The effect of plasma protein binding on in vivo efficacy misconceptions in drug discovery Nature
reviews Drug discovery 2010 9(12)929-939
Moda TL Torres LG Carrara AE Andricopulo AD PKDB database for pharmacokinetic properties and predictive in silico
ADME models Bioinformatics 2008 24(19)2270-2271
Law V Knox C Djoumbou Y Jewison T Guo AC Liu Y Maciejewski A Arndt D Wilson M Neveu V et al DrugBank 40
shedding new light on drug metabolism Nucleic acids research 2014 42(Database issue)D1091-1097
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
main menu
Formulations advice and assistance with preclinical drug delivery Neurodevelopmental Behavioral Core
To effectively deliver drug to preclinical species for the duration of a study researchers must choose a dose a formulation
and a route of administration that will support target organ exposure long enough to test a therapeutic hypothesis Since
most drugs developed for humans are optimized for human metabolism parameters many compounds developed for
humans are rapidly metabolized and cleared in rodents requiring alternative formulations and routes of preclinical
administration (see tutorial under Correct Dose)
Proper formulation of drugs and vehicles to ensure appropriate drug exposure is a critical factor in preclinical study design
The Neurodevelopmental Behavioral Core may provide advice on standard formulations Preclinical assistance and
training across many routes of administration including IV cannulation osmotic minipumps oral gavage sc and ip is also
available through the Neurodevelopmental Behavioral Core
Contact is Dr Nick Andrews NickAndrewschildrensharvardedu
Custom formulation used for human studies are supported on a case by case basis by the Pharmacometrics Research Core
or Clinical Research Pharmacy Contact for the Pharmacometrics Core is Dr Luis Pereira LuisPereirachildrensharvardedu
The Clinical Research Pharmacy can provide advice on unusual formulations Contact is Dr Rocco Anzaldi
RoccoAnzaldichildrensharvardedu
idspharmacy-dlchildrensharvardedu
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
main menu
Stratification Biomarker development and resources patient sample repositories requests for collection of new types of
patient samples development of patient specific iPSC lines and neurons Genetic databases RNA expression databases
Humans are diverse Not only do patients come in different sizes ages genders and ethnic backgrounds but the same
disease diagnosis often develops in people as a function of different environmental insults and genetic predispositions
Finding biomarkers that will segregate similarly diagnosed patients into subsets of biologically more homogenous
populations is a critical feature of good clinical trial design A lsquostratification biomarkerrsquo can be a biochemical measure from
patient samples a structural or a functional feature of a human imaging technology or a functional measure of an
electrophysiological readout
The Translational Neuroscience Center can help investigators access advice and assistance for investigators with vendors
experienced in profiling DNA RNA or protein across a range of platforms httpwwwchildrenshospitalorgresearch-and-
Neurophysiology Services can assist investigators with identification of biomarkers to stratify patients based on EEG
signatures Contact Drs Charles Nelson and Jurriaan Peters Co-Directors
CharlesNelsonchildrensharvardedu
JurriaanPeterschildrensharvardedu
MRIRadiology Imaging Core can assist with identification of biomarkers to stratify patients by functional or structural deficits
in brain circuitry Contact Dr Simon Warfield Director SimonWarfieldchildrensharvardedu
Molecular Genetics core can assist investigators with identification of genetic stratification biomarkers or gene expression-
based stratification biomarkers Contact Drs Louis Kunkel and Christopher Walsh Co-Directors
LouisKunkelchildrensharvardedu
ChristopherWalshchildrensharvardedu
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
The Human Neuron Differentiation Service within the Translational Neuroscience Center can help investigators recruit
specific subtypes of patients to be consented for reprogramming of blood or fibroblast cells into iPSC lines that will support
differentiation into human neurons for phenotypic analysis and screening ContactDr Robin Kleiman
RobinKleimanchildrensharvardedu
Translab can assist with routine processes as well as complex laboratory-‐developed tests They place special emphasis on
assay development for use in clinical trials Translab website with contact information can be viewed here
httpwwwtranslabbostonorg
TransLab Flyer 2 2015pdf
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
main menu
Patient sample repositoryBiobank Patient registry
Disease processes are dynamic The molecular underpinnings of disease differ between inception progression and
response of the body to disease Thus each stage of disease may require alternative therapeutic strategies Understanding
which stage of disease is best suited to testing a specific therapeutic approach will require information about disease from
patient samples collected at different stages of disease well as an ability to collect and recruit patients at relevant stages of
disease
To locate human RNA profiling data in the public domain from disease samples and tissues at specific stages of disease
search databases referenced in the Correct Target section of this document
The Translational Neuroscience Center offers multiple services that can assist with identification of the correct patients The
Core Repository for Neurological Disorders stores a wide variety of patient samples from many stages of disease The
biorepository is directed by Dr Mustafa Sahin and these samples and de-identified clinical data can be searched and
requested through the Translational Neuroscience Center
The Biobank Core Lab serves as a core resource that ensures top-level specimen handling and services to the Boston
Childrens Hospital research community It serves as both a service core and a biorepository providing an institutional
perspective on the presence of specimens that may be available for use to foster collaborations and accelerate research
and discovery
The Clinical Research and Regulatory Affairs Service can provide assistance to investigators in identifying patients andor
repository samplesdata Contact Co-Directors Stephanie Brewster and Kira Dies for more information about access to
these resources
StephanieBrewsterchildrensharvardedu
KiraDieschildrensharvardedu
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
main menu
Statistical support clinical trialsgov
Determining the correct sample size to support preclinical and clinical studies requires power calculations that take into
account the variability of the endpoint being measured Statistical support for preclinical studies is available on a
department by department basis Neurology and Neurobiology requests for preclinical biostatistics support can be made
through the CRC website
httpredcap-qiredcap_edcsurveyss=Rma5u83qKC
Clinical statistical support for all departments is also available through the CRC Design and Analysis Core For more
information contact Michael Monuteaux michaelmonuteauxchildrensharvardedu
Clinical datasets that provide data for supporting power calculations can be found by searching through clinical trialsgov
database All studies in the clinical trials data base are required to describe the study design the endpoints under
evaluation and the treatments as well as links to publications of the studies The studies can be searched by topic This can
be a good way to find historical data to help you evaluate variability of endpoint measures in clinical populations This will
be needed to support sample size power calculations httpsclinicaltrialsgov
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
main menu
Understanding RDoC Human Neurobehavioral Core Service IRB assistance with clinical protocols
Different stages of clinical trials have different goals for selecting endpoints Early stage clinical trials are typically in search
of a translatable pharmacodynamic or target engagement endpoint to ensure that the molecule in question will be
competent to test a clinical hypothesis in humans Developing translatable measures of target engagement in preclinical
species and humans is critical to developing data sets that will enable subsequent therapeutic efficacy trials The earliest
trials require endpoints that can be measured in a functionally equivalent manner across species Therefore it is critical for
preclinical researchers to develop dose-responsive data sets in preclinical species using quantitative endpoints such as EEG
visual or auditory evoked potentials PET ligands plasma or CSF based biochemical measures or translatable task based
behaviors Preclinical data must be a developed with an eye towards what the equivalent measure will be in the clinic
Toward that end the NIMH has initiated the Research Domain Criteria (RDoC) that is aimed at characterizing mental health
disorders across many different dimensions across species A big focus of the RDoC initiative is the identification of
translatable endpoints for evaluating pharmacodynamics and efficacy in Neuroscience Drug Discovery Preclinical
Neuroscience researchers should be familiar with the RDoC framework For advice on in vivo characterization of preclinical
endpoints with translational potential for Neuroscience related disorders contact Dr Robin Kleiman at the TNC
robinkleimanchildrensharvardedu
The Human Neurobehavioral Core Service of the Translational Neuroscience Center can provide guidance to investigators
on the appropriate tests that will provide the best translation from animal studies to human studies The Service also offers
human neurobehavioral assessment services Contact-Drs Charles Nelson and Deborah Waber Co-Directors
CharlesNelsonchildrensharvardedu
DeborahWaberchildrensharvardedu
Developing clinical protocols and obtaining IRB approval for human study of translatable endpoints can be supported by
the Translational Neuroscience Center Clinical Research and Regulatory Affairs Service Contact-Kira Dies and Stephanie
Brewster Co-Directors
KiraDieschildrensharvardedu
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
StephanieBrewsterchildrensharvardedu
Background Information on RDoC httpswwwnimhnihgovresearch-prioritiesrdocindexshtml
Casey BJ Oliveri ME Insel T A neurodevelopmental perspective on the research domain criteria (RDoC) framework
Cuthbert BN Insel TR Toward the future of psychiatric diagnosis the seven pillars of RDoC BMC Med 2013 11126
httpwwwncbinlmnihgovpmcarticlesPMC3653747
Insel T Cuthbert B Garvey M Heinssen R Pine DS Quinn K Sanislow C Wang P Research domain criteria (RDoC)
toward a new classification framework for research on mental disorders The American journal of psychiatry 2010
167(7)748-751 httpwwwncbinlmnihgovpubmed20595427
Insel TR The NIMH Research Domain Criteria (RDoC) Project precision medicine for psychiatry The American journal
of psychiatry 2014 171(4)395-397 httpwwwncbinlmnihgovpubmed24687194
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
main menu
Body atlases for expression of mRNA and protein guides to chemical alerts guidance for preclinical toxicology studies for
Investigational New Drug (IND) applications
Discovery scientists must consider the distribution of the proposed drug target across the entire body in human samples in
order to understand potential safety risks to be monitored during preclinical toxicological testing Teams also have to be
aware of differences in distribution of the target and related family members in preclinical species Many of the target
expression databases listed in the Correct Target section of this document are useful in this regard Assays that can be used
to monitor any potential safety risks are critical to the development of a suitable testing funnel needed to advance
compounds
Many chemical classes of compounds that are identified in screens are not suitable for drug development due to the
presence of structural alerts that are known to cause chemical toxicity Databases that house information of structural alerts
can be used to de-prioritize structural series early in the life of a program Some toxicology databases that can help
deprioritize toxic chemotypes include httppubsacsorgdoiabs101021ci300245q
Some web resources for identifying side effects of known compounds httpintsideirbbarcelonaorg
Once a potential clinical candidate molecule is identified GLP-qualified toxicology studies must be carried out with a
qualified vendor to support regulatory filings of an Investigational New Drug (IND) application For a short tutorial on studies
needed to support preclinical toxicology testing and guidance on evaluating contract research organizations that are
qualified to perform this work see attached tutorial courtesy of Dr Joe Brady Pfizer
Brady boston childrens hosp talk aug2015 IND toxpdf
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
main menu
FAQs
Industry partners and collaborators can bring tremendous expertise and complementary resources to bear on research
projects with therapeutic applications These may include medicinal chemistry expertise pharmacology expertise access
to unique and undisclosed chemical probe molecules assay development and high-throughput screening resources
antibody and other reagent development pharmacokinetic analysis pharmacokinetic and pharmacodynamics
modeling formulation expertise post-doctoral training programs and in some cases financial support There is a wide range
of models of interacting with industry in a range of different capacities Some frequently asked questions about types of
relationships and the responsibilities associated with those interactions can be found in the following document
Download Frequently Asked Questions about working with Industry
Translation of basic research into new marketed drugs will require a transition from exploring scientific principles and testing
hypotheses into commercial products Industry partners capable of developing these potential products need to be able
to license the intellectual property required to sell the product in order to justify investment in building programs around new
ideas This requires that scientific researchers protect and patent potential inventions from their work to enable future
commercialization by partners with appropriate expertise To ensure that researchers are appropriately documenting their
work in a manner that will support preservation of intellectual property all investigators are encouraged to consult with TIDO
before any public disclosures of new research Similarly the following documentation provides guidance for documenting
your work according to standards that will support patent applications
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
Download the compliance manual for BCH for Intellectual property policy
cm_021_intellectual_propertydocx
Download a summary of laboratory notebook Dorsquos and Donrsquot
Dosdontsnotebookspdf
Link to TIDO Technology Innovation and Development Office
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
main menu
A phenotypic screen requires a biologically robust assay that represents a significant aspect of disease-relevant human
biology It can be used to identify molecular targets for target validation studies through the use of well-annotated
bioactive molecules or genomic libraries (eg RNAi CRISPER) Alternatively phenotypic screens can be used to identify
novel compounds that must subsequently be lsquoDE convolutedrsquo to identify novel targets using lsquowarheadsrsquo These screens rely
on identification and manipulation of a functional deficit or phenotype using a patient-derived cellular system
The strengths of this approach
Use of human systems can improve translatability
Identified compounds may empirically balance therapeutic activity at multiple required targets
Well-suited to drug repurposing
Phenotypic screens can be used to identify compounds or targets for mechanism based drug discovery programs
Many CNS drugs have been discovered using a phenotypic repurposing screen (Swinney and Anthony 2011)
Drawbacks to this approach
Assays are slow low throughput and more expensive as compared to cell-free assays
Cell-based assays may not predict circuit level or brain phenotypes
Furthermore as a primary screening approach
Precludes leveraging strengths in uHTS SBDD and parallel design
Every molecule must be de-risked independently thus safety can be very hard to predict
Drug Repurposing Drug Repurposing is a strategic pillar of the National Center for Advancing Translational Science (NCATS)
Details on resources and funding opportunities can be found here httpsncatsnihgovntu
Chemogenomic Files from industry partners Many companies have well designed and annotated chemical files that are
designed to cover the druggable genome with small molecule compounds from their proprietary collections Each
company has different criteria and stipulations associated with use of the library It is advisable to consult with TIDO
regarding terms and conditions associated with individual companies
ICCB-LongwoodKirby ADSF The ICCB screening center and the Kirby ADSF have multiple collections of compounds that
include bioactive or FDA approved molecules available for screening
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
Kirby ADSF libraries contact Dr Lee Barrett LeeBarrettchildrensharvardedu
References related to phenotypic screens and Drug Repurposing
Vincent F Loria P Pregel M Stanton R Kitching L Nocka K Doyonnas R Steppan C Gilbert A Schroeter T
and MC Peakman Developing predictive assays The phenotypic screening ldquorule of 3rdquo Sci Transl Med 7 293ps15
(2015)
Langedijk J Mantel-Teeuwisse AK Slijkerman DS Schutjens MH Drug repositioning and repurposing terminology and
definitions in literature Drug Discov Today (2015)
Swinney DC and J Anthony How were new medicines discovered Nature Reviews Drug Discovery 10 507-
519 (July 2011) | doi101038nrd3480
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
main menu
TNC Clinical Research and Regulatory Affairs Service Research Participant Registry CRC
Glossary of Terms
Glossary-of-Clinical-Trials-Termspdf
Clinical Research and Regulatory Affairs Service This Translational Neuroscience Center service facilitates the mission of the
Translational Neuroscience Center providing coordination among studies communications resource development and
implementation of new or ongoing preclinical and clinical studies The service is led by experts in protocol development
and launching of new studies The directors are available to guide TNC researchers in designing human studies including
the preparation of Institutional Review Board (IRB) and FDA submissions Additionally staff of the Clinical Research and
Regulatory Affairs Service will help researchers with recruitment plans budget development supervision of study
coordinators study monitoring and audit preparation For more information contact Co-Directors Kira Dies ScM CGC and
Stephanie Brewster MS CGC
KiraDieschildrensharvardedu
StephanieBrewsterchildrensharvardedu
Clinical Research Center (CRC) Assists investigators at BCH with research project initiation and implementation resources
in the CTSU for the conduct of clinical research visits and ancillary services education on research methods and practices
The CRC has biostatisticians project managers research specialists clinical trials specialists research coordinators and
highly skilled nurses and nurse project managers who work every day to facilitate the many research needs of the BCH
community httpwwwchildrenshospitalorgresearch-and-innovationresearchclinicalclinical-research-center
Clinical and Translational Study Unit (CTSU) The CTSU provides clinical research infrastructure for investigators in the design
initiation conduct and reporting of clinical research with the goal of translating scientific knowledge into new therapies for
pediatric conditions httpweb2tchharvardeductsu
Clinical Research Roadmap This clinical research map is designed to serve as a guide for investigators study coordinators
and research nurses at Boston Childrenrsquos Hospital The research map outlines the key steps in preparing to launch a
research study and provides embedded links to institutional resources tools and documents
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
Clinical Research Mappdf
main menu
Office of Sponsored Programs Research Administration TIDO
Many government and foundation grant opportunities are available for developing Drug Discovery Projects updated lists of
funding options exist on OSP and Research Administration web sites
Some good options for finding relevant requests for proposals
Translational Research Program annual call for proposals
Boston Childrenrsquos Hospital ndash Broad Institute Collaboration Grants Proposals will be reviewed by a joint Childrenrsquos Hospitalndash
Broad Institute committee Additional submission dates are expected for 2016
BCH_Broad collaborative grant 852015docx
Kirby Neurobiology Screening Pilot awards- available to Kirby Neurobiology PIs as funding is available
Translational Neuroscience Center- Pilot awards supported by trust sponsored donations as available Distributed through
TNC e-mail lists
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
ADDF The ADDF Academic Drug Discovery and Development Program seeks to create and support innovative translational
research programs for Alzheimerrsquos disease related dementias and cognitive aging in academic medical centers and
universities Biomarker development studies and innovative proof of concept pilot clinical trials of new approaches to
treatment prevention and early detection are also supported
Department of Defense ALSRP The FY15 Defense Appropriations Act provides $75 million (M) to the Department of Defense
Amyotrophic Lateral Sclerosis Research Program (ALSRP) to support innovative high-impact Amyotrophic Lateral Sclerosis
research As directed by the Office of the Assistant Secretary of Defense for Health Affairs the Defense Health Agency
Research Development and Acquisition (DHA RDA) Directorate manages and executes the Defense Health Program
(DHP) Research Development Test and Evaluation (RDTampE) appropriation The executing agent for the anticipated
Program AnnouncementsFunding Opportunities is the Congressionally Directed Medical Research Programs (CDMRP)
httpcdmrparmymilpubspress201515alsrppreannshtml
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
Michael J Fox Foundation Therapeutic Pipeline Program Supports Parkinsons disease therapeutic development along the
pre-clinical and clinical path (both drug and non-pharmacological therapeutics including gene therapy biological
surgical and non-invasive approaches) The Michael J Fox Foundation seeks applications with potential for fundamentally
altering disease course andor significantly improving treatment of symptoms above and beyond current standards of care
Proposals must have a well-defined plan for moving toward clinical utility for patients The Therapeutic Pipeline Program is
open to industry and academic investigators proposing novel approaches or repositioning approved or clinically safe
therapies from non-PD indications httpswwwmichaeljfoxorgresearchgrant-detailphpid=28
NINDS The Blueprint Neurotherapeutics Network (BPN) Provides the neuroscience community access to a complete and
seamless pipeline for preclinical drug development beginning with chemical optimization and concluding after phase I
clinical trials Participants in the BPN will receive funding to conduct bioactivity and efficacy testing in their own laboratories
as well as access to millions of dollars in NIH-contracted drug development services including medicinal chemistry
pharmacology toxicology and phase 1 clinical trials NIH will also provide drug development consultants who have had
years of experience working at a senior level in industry Because the Blueprint is establishing a network of drug
development service providers that typically cater to biopharmaceutical companies neuroscientists who join the BPN can
readily plug in to all of the drug development expertise that typically resides in industry The projects supported through the
network will be highly collaborative and the researchers who initiate the projects will serve as the principal investigators
(PIs) directing their projects through the development pipeline with the help of industry consultants The PIs and their
institutions will have the opportunity to attain assignment of intellectual property rights from all other network participants
who may have intellectual input into their projects This will allow the PIs to retain control of the intellectual property for drug
candidates developed through the network and eventually pursue licensing and commercialization partnerships
httpneuroscienceblueprintnihgovbpdrugs
NeuroNEXT Will establish a consortium of clinical sites capable of forming disease-specific cadres of investigators in order to
develop and implement trials rapidly in a wide range of neurological disorders that affect adults andor children With a
stable and experienced research staff a central IRB model and master trial agreements NeuroNEXT will streamline the
administrative processes for clinical trials and reduce start-up times NeuroNEXT will also be able to design and implement
evidence-based measures to improve patient recruitment into clinical trials httpswwwneuronextorgresearchers
NIMH Many grant options see overview here httpwwwnimhnihgovresearch-prioritiestherapeuticsindexshtml
Building on High Impact Basic Neurobiology Through Assay Development Advancing Tools for Therapeutic Discovery (R01) -
See more at httpgrantsnihgovgrantsguidepa-filesPAR-15-066htmlsthashs1HMWjWudpuf
copy2015 Boston Childrens Hospital All Rights Reserved For permissions contact Robin Kleiman Translational Neuroscience Center Boston Childrens Hospital 300 Longwood Ave Boston MA 02115
NCATS many grant options see overview here httpwwwncatsnihgovprograms
Bridging Interventional Development Gaps (BrIDGs) Program Makes available on a competitive basis certain critical
resources needed for the development of new therapeutic agents for both common and rare diseases Investigators do not
receive grant funds through this program Instead successful applicants receive access to NIH experts and contractors who
conduct pre-clinical studies at no cost to the investigator In general synthesis formulation pharmacokinetic and
toxicology services in support of investigator-held IND applications to the Food and Drug Administration (FDA) are available
httpwwwncatsnihgovbridgsworksolicitation
NCATS Discovering New Therapeutic Uses for Existing Molecules (New Therapeutic Uses) A collaborative program designed
to develop partnerships between pharmaceutical companies and the biomedical research community to advance
therapeutics development This innovative program matches researchers with a selection of pharmaceutical industry
assets to test ideas for new therapeutic uses with the ultimate goal of identifying promising new treatments for patients
httpwwwncatsnihgovntu
Pfizer Centers for Therapeutic Innovation (CTI) Suitable for biotherapeutic or small molecule projects with a strong project
rationale (demonstrated association between target biology pathway and disease mechanism) CTIrsquos areas of interest
include inflammation autoimmunity tissue remodeling oncology cancer immunology rare or genetic diseases
cardiovascular and metabolic diseases and neuroscience Selected projects are undertaken by a joint team with BCH
members and Pfizer CTI drug development experts located on the 18th floor of CLS working towards agreed common
goals The Pfizer CTIBCH collaboration program is managed by a Joint Steering Committee with representation from both
Boston Childrenrsquos and CTI httpswwwpfizercticom Calls for proposals come through TIDO three times a year in January
May and September httpwwwchildrensinnovationsorgPagesHighlightsHighlights-83aspx
Shire-BCH Collaborative Program Development The Joint Steering Committee of the Shire Alliance extends a call for ldquoPre-
Proposalsrdquo with defined objectives from time to time generally annually in the late fall or winter That call is publicized
through emails from BCH Research Administration and TIDO Following review by the JSC a full proposal may be requested
Unsolicited proposals may also be considered from time to time
ACRONYMS
HTS- High-throughput Screen run with 96 well 384 well 1536 wells or 3456 well capacity- screen has capacity to run through a library of 1-3Million compounds in total
uHTS- Ultra High-throughput Screen ndash arbitrary cut off to denote capability to measure 100s of thousands of assays per day with automation and high density plate readers
HCS- High Content Screen usually a cell based assay that is able to monitor multiple endpoints reflective of different cellular processes in a single well of cells treated with a compound May be biochemical or image based endpoints
SAR- Structure-Activity Relationship ie relationship of modifications to chemical structure on relevant activity SPR-Structure-Property Relationship ie relationship of modifications of chemical structure on physicochemical
properties
PK- Pharmacokinetic measure of drug levels in a body compartment
PD- Pharmacodynamic a measure of functional activity of a drug
PKPD- PharmacoKinetic PharmacoDynamic relationship- how drug levels relate to drug response in a system
DDI-Drug-Drug Interactions- occurs when one drug affects the activity of another drug when co- administered Often due to changes in ADME properties of one of the co-administered drugs (ie for example induction by one drug of enzymes that will metabolize the second drug )
DMPK- Drug Metabolism and PharmacoKinetics
ADME- Absorption Distribution Metabolism amp Excretion
PDM-pharmacokinetics dynamics and metabolism GLP- Good Laboratory Practice- regulations that govern toxicology studies required by the FDA to support IND
and NDA
POM- Proof of Mechanism clinical studies to demonstrate hit the target and elicited a biological response
POC- Proof of Concept Clinical studies to demonstrate a clinically meaningful outcome measure improved
PoP-Proof of Principal usually preclinical studies that demonstrate that engaging target in a disease model produced efficacy
FIH- First in Human clinical trial to evaluate new molecule in humans for safety and PK- Ph1
FIP-First in Patient first clinical trial to evaluate new molecule in patients hERG (the human Ether-agrave-go-go-Related Gene) is a gene KCNH2 that codes for a subunit of Kv111 and
contributes to the repolarizing current in the heart that coordinates the hearts beating When compromised by application drugs or by rare mutations in some families it can result in a potentially fatal disorder called long QT syndrome A number of clinically successful drugs in the market have had the tendency to inhibit hERG and create a concomitant risk of sudden death as a side-effect which has made hERG inhibition an important anti-target that must be avoided during drug development
IND-Investigational New Drug Application- formal application to FDA to evaluate a NCE in people
NME- New Molecular Entity- a new FDA approved drug
NCE-New Chemical Entity-an investigational drug that is not yet a FDA approved NME NDA- New Drug Application (A lsquoFilingrsquo)- a formal application for approval of a new drug
CAN-(Pfizer-specific shorthand )-Clinical Candidate- a molecule competent to be tested in humans IB- Investigators Brochure- basic information on an investigational drug and its mechanism for clinicans involved
in conducting a clinical trial Provides background information on the hypothesis being tested and the types of patients that should be included excluded and risks and how the drug should be administered It must be updated continually by the sponsor to include all new findings
SOC- Standard of Care- in our context it is the drug treatment that a clinican should prescribe for a particular type of patient used as a benchmark for comparing new entities
MTD- Maximum Tolerated Dose- first identified in GLP safety studies during preclinical development AE- Adverse Event- a side effect that causes safety concerns
TI- Therapeutic Index -ratio of the concentration of drug needed to produce efficacy and the concentration of drug that is safely tolerated ( also called ldquoSafety Marginrdquo)
Questions Contact Robin Kleiman- email RobinKleimanchildrensharvardedu office CLS 13070
Terms that relate to Targets Molecular target- the protein that binds drug to produce efficacy Off-Target- other proteins that bind the drug that do not relate to efficacy and may produce Adverse Events (AEs) Druggable target ndashcomes from a class of proteins that has successfully been targeted with small molecule drugs in
the past Primarily transporters enzymes receptors ion channels (Not protein-protein interactions transcription factors RNA binding proteins etc)
Druggable genome- about 3000 genes encoding all druggable proteins Druggability- the presence of protein folds (quarternary structures) that favor specific interactions with drug-like
molecules Exploratory target- Hypothesis that a modulating a target via a particular mode of action will be beneficial to a
particular patient population Validated target- Hypothesis regarding a target also has in vivo efficacy data for a disease or a disease model- along
with a complete understanding of how the target mechanism relates to disease- (also called lsquoProof of Principlersquo) Phenotypic screen- a screen for compounds that will reverse a phenotype the molecular target may not be known Systems pharmacology target(s)-a precisely defined combination or lsquofingerprintrsquo of molecular targets to be
modulated to correct a phenotype (Poly-pharmacology)
Terms that relate to programs
Biomarker- a physiological pathological or anatomical characteristic that is measured by an automated process or algorithm as an indicator of the normal biological process pathological process or biological response to a therapeutic intervention Many types of Biomarkers target engagement biomarkers stratification biomarkers efficacy biomarkers pharmacodynamic biomarkers etchellip
Laboratory Objectives-Criteria established at the start of the program to define the desired pharmacological properties of the molecule with regard to potency selectivity mode of action frequency and route of administration For antibodies would include minimal criteria for knock down stability etc
Therapeutic Modality- small molecule biologic RNAi stem cell etc
Screening tree Screening funnel- A decision tree for utilizing a panel of assays to identify molecules that meet the laboratory objectives
Terms that relate to molecules
Drug-like molecule- has physicochemical properties in line with known oral medications The molecule will be largely rule of 5 (RO5) compliant therefore small and moderately lipophilic Not related to pharmacological activity
Rule of Five (RO5)=Chris Lipinskirsquos rule of 5 states that a drug like molecule will have the following properties Molecular Weight of less than 500 a clogP lt5 fewer than 5 H-bond donors and the number of H-bond acceptors ( which is the sum of N and O atoms) is less than 10
Physicochemical properties- key properties of molecules include (calculated)Molecular Weight number of H bond acceptors and donors (measured) kinetic solubility pKa lipophilicity (logD logP)
Chemical tool -a compound with good potency and selectivity for a specified molecular target but fails to meet all criteria for safety PK or potency needed to become a clinical candidate Suitable for preclinical testing of hypothesis and proof of principal studies but not for lsquopreclinical developmentrsquo
Active molecule describes an individual chemical entity with measurable dose-dependent activity in a biological screening assay
Hit molecule refers to a molecule plus its related structural analogs for which there is an understanding of the structure-properties and structure-activity relationships (SPR and SAR) for a specific biological context Additionally preliminary drug disposition data (both in vitro and in vivo) provide an assessment of pharmacokinetic properties The available data provide a basis for further optimization of the hit series
Lead molecule refers to a molecule plus its related structural analogs that demonstrate o Sufficient exposure at pharmacologically relevant doses by the intended route of administration to explore
intended pharmacology in a relevant in vivo disease or pharmacodynamic model o Proof-of-principle or efficacy in a in vivo model that will be used to establish a margin of safety
Clinical candidate an optimized individual chemical entity derived from a lead series that demonstrates o a dose-response relationship via intended route and schedule of administration in relevant disease model o an exposure-based margin of safety in toxicology studies o In summary a clinical candidate is a molecule that is deemed competent for testing the primary disease
intervention hypothesis in humans
A laboratory notebook is a vital record of events leading to a patentable invention Therecorded information can establish dates of conception and reduction to practice of atechnology as well as the inventorship of a patent claiming the technology Below arefourteen rules you should follow when keeping lab notebooks
1 mdash Do use bound booksInventors should use permanently bound notebooks eg notebooks with spiral or glue bindings If loose-leaf sheets are used they should be consecutively numbered and eachpage should be dated signed and witnessed
2 mdash Do sign and date Each notebook should be signed and dated on the inside front cover to indicate the firstday the recipient started using the notebook Each entry should be dated and signed orinitialed
An independent witness ie someone who understands the technology but will not benamed as a co-inventor of the invention should sign and date each entry after the state-ment ldquoRead and understood by rdquo (The witness should preferably sign theentries on a contemporaneous or fairly contemporaneous basis but entries can also bereviewed signed and dated on a periodic eg weekly or monthly basis)
3 mdash Do use inkNotebook entries should be made in ink and in chronological order Entries should not beerased or ldquowhited outrdquo If an entry contains an error a line should be drawn through theerror and new text should continue in the next available space
4 mdash Donrsquot leave blank spacesBlank gaps between entries should be avoided If a blank space is left on a page a line orcross should be drawn through the blank space and the page dated to prevent subsequententries
5 mdash Donrsquot modifyPrior entries should not be modified at a later date If data were omitted the new datacan be entered under a new date and cross-referenced to the previous entry Record exper-iments when they are performed
6 mdash Do use past tenseUse the past tense (eg ldquowas heatedrdquo) to describe the experiments that were actually performed
Fish amp Richardson pc
Dorsquos and Don rsquo ts forKeeping Lab Notebooks
Boston
Dallas
Delaware
New York
San Diego
Silicon Valley
Twin Cities
Washington dc
FR
7 mdash Do explain abbreviations and special termsExplain all abbreviations and terms that are nonstandard Explain in context in a table ofabbreviations or in a glossary
8 mdash Do staple attachmentsAttachments such as graphs or computer printouts should be permanently attached to pagesin the notebook (eg by stapling) and both the attachment and the notebook page signedand dated If the attachment cannot be stapled it should be placed in an envelope and theenvelope stapled to the notebook page The envelope and page should then be signed andwitnessed making reference to the attachment being placed in the envelope
9 mdash Donrsquot remove originalsNo original pages should be removed from the notebook
10 mdash Do outline new experimentsWhen a new project or experiment is started the objective and rationale should be brieflyoutlined (eg in a short paragraph or by providing a flowchart)
11 mdash Do record lab meeting discussionsRelevant discussions from lab meetings should be recorded as should ideas or suggestionsmade by others The names of the people making the ideas and suggestions should be care-fully documented This information may be important in establishing inventorship
12 mdash Do provide detailRecord test descriptions including preferred operating conditions control conditionsoperable and preferred ranges of conditions and alternate specific materials Also recordtest results and an explanation of the results as well as photos or sketches of the resultsandor the test device Any conclusions should be short and supported by the factual dataOpinions or speculation about the invention should be avoided
13 mdash Do track notebooksIdeally each lab should maintain a catalog of notebooks in which each notebook is assigneda number and the name of the author of each notebook is recorded In addition the datethe author received the notebook as well as the date the notebook was completed andreturned should be recorded Upon leaving the lab the author should return all notebookschecked out by or to him
14 mdash Do save completed notebooksAll completed notebooks should be indexed (eg by number by author andor by subjectarea) and kept safely in a central repository together with corresponding patent applica-tions or patents Lab notebooks that relate to inventions on which patents have been grant-ed should be kept for the life of the patent plus six years
By J Peter Fasse
Fish amp Richardson pcIntellectual property complex litigation technology law800 818-5070wwwfrcominfofrcom
P ER SP EC T I V E
PHARMACOK INET I CS
Data gaps limit the translational potentialof preclinical researchRobin J Kleiman1 and Michael D Ehlers2
The absence of mouse pharmacokinetic reference data hinders translation An analysis ofrecent literature highlights a systematic lack of discussion regarding rationale for the selec-tion of dosing paradigms in preclinical studies and in particular for neuroscience studies inwhich the lack of brain penetration can limit target-organ exposure We propose solutionsto improve study design
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Despite widespread use of pharmacologicalagents in mouse models of human diseasethe literature lacks comprehensive pharmaco-kinetic profiles for such studies Coupled witha paucity of suitable data are shortcomingsin the training of experimental biologists inthe application of pharmacometric principlesto experimental study design Many authorssimply cite previously published studies tosupport the selection of a particular dose evenwhen the cited paper lacks drug exposuredata There is an assumption on the part ofresearchers that if a referenced study demon-strates a biological effectmdashthat is any measur-able physiological or behavioral effectmdashin arodent at a given dose then that same dosewill also effectively perturb disease-relevantmechanistic biology in a different study Thedanger occurs when the observed therapeuticeffects are not linked to drug-induced mecha-nistic alterations at the level of the target organLack of a drug exposurendashresponse relationshipin a target organ casts doubt on mechanisticinterpretations In addition any changes inthe route of drug administration vehicle prep-aration species used (rat versus mouse versusprimate) age or strain of animal transgenicmodification time points under investigationduration of dosing or organ targeted for inter-vention (for example brain versus a periph-eral tumor) can alter the relation between doseexposure and measured response In suchcases assumptions regarding the mechanisticbasis for observed therapeutic effects may nothold true
Preclinical pharmacological experimentsthat do not measure drug concentrations in
1Translational Neuroscience Center Kirby NeurobiologyCenter Department of Neurology Boston ChildrenrsquosHospital Harvard Medical School Boston MA 02115USA 2Neuroscience amp Pain Research Unit BioTherapeu-tics Worldwide Research and Development Pfizer IncCambridge MA 02139 USACorresponding author E-mail robinkleimanchildrensharvardedu (RJK) michaelehlerspfizercom (MDE)
the target organ run the risk of producing ex-posures that are too low or too high to inter-pret a mechanistic hypothesis Most drugs arenot selective over a large exposure range for asingle molecular target Confident evaluationof a therapeutic hypothesis requires an under-standing of the drugrsquos penetration and kineticswithin the target tissue as well as its potencyand selectivity for specific molecular targetsFurther investigators must consider the con-centration of the unbound fraction of drugthat is available to interact with the targetPublished reports often overlook the fact thatmany small molecules are more than 90bound to plasma or tissue proteins whichgreatly decreases the fraction of drug availableto bind to the intended target Thus in casesin which drug binding has a slow off-rate anorganismrsquos total drug exposure is not a predic-tor of drug available to interact with its target(1) The failure of some academic scientists toobtain relevant pharmacokinetic data impairsthe interpretation of preclinical research resultsand likely contributes to the acknowledgeddifficulties in replicating some academic liter-ature as reported by industry scientists (2 3)
Drug discovery teams in industry settingsroutinely collect pharmacokinetic data to aidin the mechanistic interpretation of in vivopreclinical data and to project optimal dosingparadigms for efficacy and toxicology studiesData required to evaluate brain penetrationare not typically collected by industry-baseddrug-discovery teams for compounds origi-nally developed for therapeutic indicationsthat do not obviously implicate the centralnervous system making this information es-pecially hard to find for many otherwise well-described drugs In addition because mousedata are not required for preclinical toxicologystudies (the more common small animal spe-cies for preclinical toxicology being rats)industry scientists do not often obtain pharma-cokinetic data from mouse experiments These
wwwScienceTranslationalMedicineo
issues are especially relevant for older drugsthat are potentially suitable for repurposingMany older drugs were discovered and char-acterized before routine pharmacokinetic-pharmacodynamic (PK-PD) modeling ofpreclinical drug exposure and its applicationto predicting human dosing became standardpractice Last pharmacokinetic data are notconsidered innovative and these studies gen-erally do not achieve publication in peer-reviewed journals even when the data havebeen generated When such data are pub-lished it is often relegated to the unsearchableblack hole of supplementary materials Thusmouse neuroPK profiles are not readily avail-able for many drugs that are frequently usedin conjunction with mouse models of humanbrain disorders
DOCUMENTING DOSING STRATEGIES
To evaluate the potential impact of insufficientpharmacokinetic data on dose selection in asample of recent published neuroscience liter-ature we conducted an analysis of papersidentified by means of a PubMed search usingthe search terms ldquodrugrdquo and ldquobrainrdquo for the pub-lication year 2014 from eight journals (Table 1)This list was culled to include only primaryresearch reports that included systemic adminis-tration of a pharmacological agent a pharma-cological therapeutic or a biological therapeuticas part of the study design The search yielded100 articles published between 1 January and30 December 2014 that used systemic drug de-livery with the intended goal of targeting thebrain of rodents (table S1) Each publicationwas examined for the stated rationale behindthe dose selection of study drugs (Table 1)
The reported rationale for dosing strategiesfell into several broad categories including(from lowest confidence to highest) (i) dose se-lected rationale not discussed (ii) literaturecitations of another study in which reportsranged from citation of exposure in the samespecies exposure in a different strain or spe-cies a dose conversion from the human liter-ature to rodent or reports of effects on rodentbehavior in another study (iii) demonstrationof an effect on rodent behavior or function inthe current study (iv) demonstration of adose-responsive biological effect in the currentstudy (v) measurement of drug levels in bloodor plasma in the current study and (vi) mea-surement of drug levels in the target organ(that is the brain) in the current study In onlytwo instances were publications identifiedthat considered the impact of drug binding
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to plasma or brain proteins on the free expo-sure of drug available to interact with the tar-get This is a critical flaw in most publishedstudies that use small molecules for functionaleffects in the brain because many centralnervous system (CNS) drugs that penetratethe blood-brain barrier exhibit high proteinbinding leaving a small fraction of the totaldrug measured in plasma or brain unbound
and free to interact with the molecular targetFurthermore most studies used evidence of abiological activity to justify dose selection with-out consideration for how exposure of theagent relates to the potency of the compoundat known molecular targets which would berequired to test a mechanistic hypothesis
The lack of pharmacokinetic considera-tion does not imply that every study used an
wwwScienceTranslationalMedicineo
inappropriate dose of drug to test their hypoth-esis It does illustrate that a clear rationale wasnot provided for dose selection in most pub-lications Furthermore all 11 of the 100 publi-cations that measured total brain exposureincluded an author from the pharmaceutical in-dustry (n=5) an academic drug screening group(n = 3) or a pharmacologyndashpharmaceuticalsciences department (n = 3) This observationlikely reflects the limited presence of pharma-cology and pharmacometrics departmentswithinmost academic institutions and limitedaccess to the mass spectrometry and otheranalytical resources needed to measure druglevels in study samples Outsourcing the bio-analysis of samples collected from study ani-mals is feasible but the use of contract researchorganizations to support such studies is oftentoo costly for most academic grant budgets toaccommodate
DATABASES AND REPURPOSINGRecent years have seen increasing efforts toinvestigate approved or clinically tested drugsfor new indications (4ndash8) Such repurposinghas been touted as a means to accelerate ther-apeutic development (4) For example a stra-tegic pillar of the US National Institutes ofHealthrsquos (NIHrsquos) translational roadmap callsfor the academic community to actively par-ticipate in the repurposing of drugs approvedby the US Food and Drug Administration(FDA) or investigational drugs that havepassed safety hurdles but failed in clinicaltrials because of lack of efficacy (9ndash11) To havea meaningful impact in neurological and psy-chiatric disorders such drug repurposingefforts will require access to neuropharma-cokinetic (neuroPK) data sets in mice to guidethe testing of new therapeutic hypotheses ingenetically engineered disease models A re-cently published consensus evaluation of drugrepositioning opportunities for Alzheimerrsquosdisease identified 15 potential drug candidatesThese were further prioritized for testing onthe basis of available evidence to produce ashortlist of seven compounds reviewed by in-dustry experts to provide insight into the via-bility of these candidates The most commonshortcoming identified for the compoundsconsidered were issues related to insufficientbrain penetration or the lack of informationabout optimal dosing strategies (11)
The repurposing of statins illustrateshow the neuroPK knowledge gap limits progressStatins were developed as 3-hydroxy-3-methylglutarylndashcoenzyme A (HMG-CoA) reduc-tase inhibitors to lower cholesterol and reduce
Table 1 Preclinical dosing strategies The rationale for drug-dosing strategies was extractedfrom the literature through the analysis of 100 peer-reviewed studies published in2014 from eight journals that cover research on mechanisms of brain function disease andtherapeutic approaches to CNS disorders (Cell Neuron Nature Nature Neuroscience NatureMedicine Neurobiology of Disease Neuropsychopharmacology and Science TranslationalMedicine) (table S1) Forty-four of the 100 publications selected were studies of potentialtherapeutic approaches to disease whereas the remaining were studies of basic neurobiology ormechanisms of disease Each publication was examined to discern how authors selected thedosage of pharmacological tools or therapeutic compounds used in the design of studies toprobe brain function A relatively small number of studies considered what the concentrationof drug available in the brain after administration would be in the context of theirexperimental studies The most common method for selecting a dose of drug was tocite a previous study that demonstrated a biological effect of the drug on someaspect of rodent behavior
Rationale for studyrsquos drug-dose selection
Therapeutic
studies
Number of papers from the100 published studies
analyzed
bull No exposure or rationale for dose selection provided
5
22
bull Rodent dose extrapolated from human studies
0
1
bull Doses are similar to what was used previously toproduce a biological effect
8
23
bull Literature reports cited for multiple functionaleffects of drug at selected dose
4
5
bull Brain penetration evaluated but exposure notmeasured
2
2
bull Literature report of mismatched drug exposure
0
1
bull Observation of a biological effect at a single dosein current study
3
6
bull Observation of dose-responsive biological effectin current study
5
16
bull Brain exposure to drug was measured with routeof administration that differed from the oneused in the efficacy study
1
1
bull Plasma drug concentrations measured literaturereport of brain exposure cited and target-organpharmacodynamic effect observed in the currentstudy
1
1
bull Plasma drug concentrations measured
4
7
bull Brain pharmacodynamic effect of drug observed
2
4
bull Brain drug concentrations measured (totalconcentration)
6
7
bull Unbound brain drug concentrations measured
1
2
bull Brain drug concentrations measured and brainpharmacodynamic effect of drug observed
2
2
Total
44
100
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risk of cardiovascular disease (12) FDA hasapproved at least nine different statins andmost are commonly prescribed nearly one-third of Americans ages 55 to 64 took a pre-scription cholesterol-lowering drug between2009 and 2012 (wwwcdcgovnchsdatahushus14pdf) The widespread availability andsafety profile of statins has lured researchersinto evaluating their potential for repurpos-ing (13) Statins have been profiled extensive-ly in preclinical research to test for potentialtherapeutic benefit in Alzheimerrsquos disease(14ndash19) Fragile X syndrome (20) Rett syn-drome (21 22) epilepsy (23) Huntingtonrsquos dis-ease (24) Parkinsonrsquos disease (25 26) stroke(27) and brain injury (28 29)
A search of the literature reveals no sys-tematic neuroPK studies in any mouse strainthat would enable direct comparisons of CNSexposure across the various statins In silicopredictions based on the drugsrsquo molecularproperties suggest that the nine most widelyprescribed statins each have a different poten-tial to penetrate the blood-brain barrier differ-ent potencies against the HMG-CoA reductaseenzyme and different ldquooff-targetrdquo activity pro-files (30) On the basis of available data thereis reason to believe that simvastatin has thebest overall profile for inhibiting HMG-CoAreductase in the brain (30) A recent study re-ported that lovastatin is able to reverse a rangeof phenotypes in a mouse model of Fragile Xsyndrome (20) However the design of an op-timal clinical trial will require the collection ofmouse pharmacokinetic data to understandhow much CNS drug exposure is required toproduce efficacy in the disease model Thereare at least two possible scenarios Giventhat simvastatin is more potent at inhibitingHMG-CoA reductase than are other statinsand likely to be more brain penetrant inboth mice and humans one would expectthat simvastatin will be more potent than lo-vastatin in ameliorating symptoms in bothmice and humans if the observed efficacy stemsfrom inhibition of HMG-CoA reductase activ-ity in the brain by lovastatin The advantage ofthis outcome would be that better brain pen-etration and potency would lead to a loweroverall dose requirement to achieve efficacyand thus likely a better safety profile
A second scenario could be that lovastatin ismore potent than simvastatin in the mousemodel of Fragile X syndrome because of anadditional biological activity inherent to thelovastatinmolecule whichmaynot yet be doc-umented in the literature In either case un-derstanding the CNS exposure of lovastatin
required to produce efficacy in themouse willdetermine whether there is a safe therapeuticindex for achieving the required concentra-tion in patients Previous attempts to discernuseful neuroPK parameters from the litera-ture for the use of statins in rodent modelshave highlighted the lack of critical data asthe looming roadblock to progress in the field(31 32) Until these data exist the transla-tional potential of preclinical research maybe limited And this is but one example ofone drug class
The creation of a centralized database isneeded for the entire translational researchcommunity and would establish a new mech-anism for academia funding agencies founda-tions and industry to pool resources If studiesare donewell the first time and documented inan open-access resource it will reduce redun-dant efforts and improve the quality of decisionmaking by scientists considering innovativesolutions to our biggest health problems
FILL THE GAPSManuscript submission practices for severalhigh-impact journals now include require-ments that authors include detailed informa-tion regarding study design and statisticalanalysis with each submission A reasonableextension of this checklist should includethe stated rationale for doses selected for studydrugs Information should include a discus-sion of data highlighted in Table 2 Authorsshould be expected to reference a relevant
wwwScienceTranslationalMedicineo
data set from a high-quality database or pub-lication or provide the data in the current study(Table 3)
Industry biologists learn basic principlesof medicinal chemistry pharmacokineticsand drug disposition while working on drugdiscovery project teams Academic groupsare playing an increasing role in transla-tional therapeutics and in particular drugrepurposing Academic programs need toaugment training in pharmacokinetics andpharmacodynamics so as to increase the rigor ofpreclinical work and to ensure that investigator-initiated clinical studies are testing hypotheseseffectively Institutions without a departmentof pharmacology or pharmacometrics mightlack the organizational knowledge needed toconduct drug studies and must identify re-sources or collaborators to patch these defi-cits Formal coursework and Web-basedresources and tutorials are needed to train andsupport translational researchers Manuscriptand grant reviewers need to demand higherstandards for preclinical studies with respect toreporting on drug exposure associated withbiological effects Ethics committees responsi-ble for review of animal protocols should re-quire investigators to provide rationale fordose selections in proposed studies Similarlyscientific review boards at academic medicalcenters need to include clinical pharmacologistswho are able to review investigator-initiatedclinical studies to ensure that proposed dosingstrategies will test a meaningful hypothesis
Table 2 Recommendations for use of pharmacokinetic data The first column includes a listof recommended data sets to aid reviewers of submitted articles in the interpretation ofpreclinical findings The second column includes a list of useful reference data that wouldsupport improved preclinical study design in mice if available in a public database
Literature reports that evaluate studydrugs should include
Compound-specific data that shouldbe included in a rodent
pharmacokinetic database
bull Expected or measured plasma exposure of thestudy drug in the preclinical species during thestudy
bull Elimination half-life (T12)bull Systemic clearance (CL)bull Fraction of drug that is protein bound (fb)
bull Expected or measured target organ exposureof the study drugs in the preclinical speciesduring the study
Maximum plasma concentration after drug admin-istration (Cmax) and time to reach maximum plas-ma concentration (Tmax) for a standardized doseand route of administration
bull Expected or measured free fraction (unboundby protein) of the study drugs in the targetorgan of the preclinical species during thestudy
bull The ratio of drug in brain to that in plasma (BP)bull The ratio of drug found free in brain (Cub) to thatfound free in the plasma (Cup) defined as CubCupbull Any potential impact of drug transporters (foundon the rodent blood-brain barrier) in limiting brainexposure
bull Expected or measured potency of the studydrug against the hypothesized activity in vitro
Expected ormeasured potency of molecule at knownbiological targets
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A central repository that contains brainpenetration protein binding and pharmaco-kinetic profiles of drugs and pharmacologicaltools in rodents is needed to effectively sup-port translational research This databaseshould also provide basic tutorials that de-fine primary pharmacokinetic parameterswith examples to illustrate how data are usedto predict optimal dosing strategies The min-imum data set needed for each compoundin a useful rodent database is highlighted inTable 2 Access to this information and sup-porting materials will have an immediateimpact on the quality of translational drug re-purposing efforts across brain disorders andwill support the development of new thera-peutic approaches to neurological disordersand mental illness Existing databases man-aged by NIH or precompetitive consortia couldbe reinforced with donated pharmacokineticdata sets and tutorials
Industry and government scientists shouldwork precompetitively to collect and curatepharmacokinetic data sets in conjunction withsupporting educational materials Mouse phar-macokinetic data exist inside pharmaceuti-cal companies for a wide range of publicallydisclosed molecules and literature standardsRelease of these data into a public databasewould provide several benefits to companiesincluding (i) increased scientific rigor in theliterature with a higher probability of repro-ducibility (ii) increased appreciation by theacademic biology community for the diffi-culty inherent in generating molecules withpotency and pharmacokinetic profiles suit-able for in vivo work opening the door forin-kind collaboration with academic groups
and (iii) direct comparison of data collectedin-house to that collected at other compa-nies or institutions to enable better internalquality control Comprehensive pharmaco-kinetic data sets will benefit all therapeuticareas regardless of whether the brain is thetarget organ because peripheral and cen-tral exposure data can be generated fromthe same experiments Moreover the prin-ciples described above for the CNS apply toother target tissues in which vascular bar-riers metabolic processes or active transportalter the distribution of systemically admin-istered drugs
Key to ensuring that preclinical mousestudies test the hypotheses they aim to eval-uate is an understanding of the unboundfraction of drug present in the target organat an appropriate time point under studyGrant and journal reviewers need to care-fully consider whether authors of propos-als and manuscripts are providing adequaterationale for their choices of preclinical dos-ing paradigms Importantly the collectionand centralization of rodent pharmacoki-netic datasets will promote efficient genera-tion of future data reduce the collection ofredundant data and improve the return oninvestment for research funds that are de-voted to preclinical studies aimed towardclinical translation
SUPPLEMENTARY MATERIALS
wwwsciencetranslationalmedicineorgcgicontentfull8320320ps1DC1Table S1 One hundred publications that used systemic drugdelivery with the goal of targeting rodent brains
wwwScienceTranslationalMedicineo
REFERENCES AND NOTES1 A Reichel Addressing central nervous system (CNS) penetra-
tion in drug discovery Basics and implications of the evolv-ing new concept Chem Biodivers 6 2030ndash2049 (2009)
2 F Prinz T Schlange K Asadullah Believe it or not Howmuch can we rely on published data on potential drugtargets Nat Rev Drug Discov 10 712 (2011)
3 C G Begley L M Ellis Drug development Raisestandards for preclinical cancer research Nature 483531ndash533 (2012)
4 P Nair Second act Drug repurposing gets a boost asacademic researchers join the search for novel uses ofexisting drugs Proc Natl Acad Sci USA 110 2430ndash2432(2013)
5 T I Oprea J Mestres Drug repurposing Far beyond newtargets for old drugs AAPS J 14 759ndash763 (2012)
6 S M Strittmatter Overcoming drug development bot-tlenecks with repurposing Old drugs learn new tricksNat Med 20 590ndash591 (2014)
7 K Xu T R Coteacute Database identifies FDA-approved drugswith potential to be repurposed for treatment of orphandiseases Brief Bioinform 12 341ndash345 (2011)
8 X Bosch European researchers drug companies joinforces against rare diseases JAMA 294 2014ndash2015 (2005)
9 F S Collins Mining for therapeutic gold Nat Rev DrugDiscov 10 397 (2011)
10 P Vallance P Williams C Dollery The future is much closercollaboration between the pharmaceutical industry andacademic medical centers Clin Pharmacol Ther 87525ndash527 (2010)
11 A Corbett J Pickett A Burns J Corcoran S B DunnettP Edison J J Hagan C Holmes E Jones C KatonaI Kearns P Kehoe A Mudher A Passmore N ShepherdF Walsh C Ballard Drug repositioning for Alzheimerrsquosdisease Nat Rev Drug Discov 11 833ndash846 (2012)
12 J L Goldstein M S Brown A century of cholesterol andcoronaries From plaques to genes to statins Cell 161161ndash172 (2015)
13 A M Malfitano G Marasco M C Proto C Laezza P GazzerroM Bifulco Statins in neurological disorders An overviewand update Pharmacol Res 88 74ndash83 (2014)
14 T Kurata K Miyazaki M Kozuki N Morimoto Y OhtaY Ikeda K Abe Progressive neurovascular disturbances inthe cerebral cortex of Alzheimerrsquos disease-model miceProtection by atorvastatin and pitavastatin Neuroscience197 358ndash368 (2011)
15 H Kurinami N Sato M Shinohara D Takeuchi S TakedaM Shimamura T Ogihara R Morishita Prevention ofamyloid beta-induced memory impairment by fluvastatinassociated with the decrease in amyloid beta accumulationand oxidative stress in amyloid beta injection mousemodel Int J Mol Med 21 531ndash537 (2008)
16 M Shinohara N Sato H Kurinami D Takeuchi S TakedaM Shimamura T Yamashita Y Uchiyama H RakugiR Morishita Reduction of brain beta-amyloid (Abeta)by fluvastatin a hydroxymethylglutaryl-CoA reductaseinhibitor through increase in degradation of amyloidprecursor protein C-terminal fragments (APP-CTFs) andAbeta clearance J Biol Chem 285 22091ndash22102 (2010)
17 G J Siegel N B Chauhan D L Feinstein G Li E B LarsonJ C Breitner T J Montine Statin therapy is associated withreduced neuropathologic changes of Alzheimer diseaseNeurology 71 383 author reply 383 (2008)
18 X-K Tong C Lecrux P Rosa-Neto E Hamel Age-dependentrescue by simvastatin of Alzheimerrsquos disease cerebrovascularand memory deficits J Neurosci 32 4705ndash4715 (2012)
19 X K Tong N Nicolakakis P Fernandes B Ongali J BrouilletteR Quirion E Hamel Simvastatin improves cerebrovascularfunction and counters soluble amyloid-beta inflammationand oxidative stress in aged APP mice Neurobiol Dis35 406ndash414 (2009)
Table 3 Recommendations to improve translation through the use of preclinicalpharmacokinetic data
Journalsbull Require authors to provide explicit rationale for dosing strategies usedbull Rationale should include consideration of the unbound drug exposure in target organas best practices
Educationbull Include basic pharmacology and pharmacokinetic principles in formal coursework requiredfor basic preclinical and clinical research scientists
bull Develop tutorials and on-line calculators for rodent dose projections to support appropriateuse of published pharmacological tools
Databasesbull Reinforce public chemical databases with mouse pharmacokinetic data that includes brainexposure
Precompetitive consortiabull Create precompetitive consortia to solicit mouse pharmacokinetic data sets from industry andfoundation partners for database expansion
bull Targeted data collection for compounds already in the public domain
rg 6 January 2016 Vol 8 Issue 320 320ps1 4
P ER SP EC T I V E
20 E K Osterweil S C Chuang A A Chubykin M SidorovR Bianchi R K Wong M F Bear Lovastatin corrects ex-cess protein synthesis and prevents epileptogenesis in amouse model of fragile X syndrome Neuron 77 243ndash250(2013)
21 C M Buchovecky S D Turley H M Brown S M KyleJ G McDonald B Liu A A Pieper W Huang D M KatzD W Russell J Shendure M J Justice A suppressorscreen in Mecp2 mutant mice implicates cholesterol me-tabolism in Rett syndrome Nat Genet 45 1013ndash1020(2013)
22 M J Justice C M Buchovecky S M Kyle A Djukic A rolefor metabolism in Rett syndrome pathogenesis Newclinical findings and potential treatment targets RareDis 1 e27265 (2013)
23 F Scicchitano A Constanti R Citraro G De Sarro E RussoStatins and epilepsy Preclinical studies clinical trials andstatin-anticonvulsant drug interactions Curr Drug Targets16 747ndash756 (2015)
24 M L Ferlazzo L Sonzogni A Granzotto L Bodgi O LartinC Devic G Vogin S Pereira N Foray Mutations of theHuntingtonrsquos disease protein impact on the ATM-dependentsignaling and repair pathways of the radiation-inducedDNA double-strand breaks Corrective effect of statins andbisphosphonates Mol Neurobiol 49 1200ndash1211 (2014)
25 E K Tan L C Tan Holding on to statins in Parkinsondisease Neurology 81 406ndash407 (2013)
26 B Friedman A Lahad Y Dresner S Vinker Long-termstatin use and the risk of Parkinsonrsquos disease Am J ManagCare 19 626ndash632 (2013)
27 M S Elkind Stroke A step closer to statin therapy forstroke Nat Rev Neurol 9 242ndash244 (2013)
28 E E Abrahamson M D Ikonomovic C E Dixon S T DeKoskySimvastatin therapy prevents brain trauma-inducedincreases in beta-amyloid peptide levels Ann Neurol66 407ndash414 (2009)
29 E F Wible D T Laskowitz Statins in traumatic brain injuryNeurotherapeutics 7 62ndash73 (2010)
wwwScienceTranslationalMedicineo
30 S Sierra M C Ramos P Molina C Esteo J A VaacutezquezJ S Burgos Statins as neuroprotectants A comparativein vitro study of lipophilicity blood-brain-barrier penetra-tion lowering of brain cholesterol and decrease of neuroncell death J Alzheimers Dis 23 307ndash318 (2011)
31 W G Wood G P Eckert U Igbavboa W E Muumlller Statinsand neuroprotection A prescription to move the fieldforward Ann N Y Acad Sci 1199 69ndash76 (2010)
32 W G Wood W E Muumlller G P Eckert Statins and neuro-protection Basic pharmacology needed Mol Neurobiol50 214ndash220 (2014)
101126scitranslmedaac9888
Citation R J Kleiman M D Ehlers Data gaps limit thetranslational potential of preclinical research Sci Transl Med8 320ps1 (2016)
D
rg 6 January 2016 Vol 8 Issue 320 320ps1 5
on January 6 2016httpstm
sciencemagorg
ownloaded from
101126scitranslmedaac9888] (320) 320ps1 [doi8Science Translational Medicine
Robin J Kleiman and Michael D Ehlers (January 6 2016) Data gaps limit the translational potential of preclinical research
Editors Summary
This information is current as of January 6 2016 The following resources related to this article are available online at httpstmsciencemagorg
Article Tools
httpstmsciencemagorgcontent8320320ps1article tools Visit the online version of this article to access the personalization and
s sitesScienceThe editors suggest related resources on
PermissionshttpwwwsciencemagorgaboutpermissionsdtlObtain information about reproducing this article
is a registered trademark of AAASMedicineScience TranslationalAssociation for the Advancement of Science all rights reserved The title
Science 1200 New York Avenue NW Washington DC 20005 Copyright 2016 by the Americanweekly except the last week in December by the American Association for the Advancement of
(print ISSN 1946-6234 online ISSN 1946-6242) is publishedScience Translational Medicine
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nloaded from
Boston Childrenrsquos Hospital ndash Broad Institute Collaboration Grants
Background Meeting the challenges of biomedicine requires bringing together creative scientists exceptional technological resources and world-class expertise across many disciplines that rarely exist within a single institution This guiding principle is the basis for a funding opportunity to support Boston Childrenrsquos Hospital investigators performing research in collaboration with Broad scientists
Goals The fundamental goal of this new award is to spark new collaborations between Boston Childrenrsquos Hospital and the Broad Institute The grants will be awarded to address a very wide range of scientific questions but are specifically designated for projects with the following characteristics
middot Projects where engagement with the Broad would benefit Childrenrsquos Hospital investigators projects that can uniquely benefit from being done at the Broad Institute
middot Projects that create new scientific collaborations and bring together diverse scientific backgrounds projects that spark new scientific directions or technologies and are not currently being pursued at Childrenrsquos Hospital
middot Projects that pilot new approaches that researchers at Childrenrsquos the Broad and the greater scientific community can benefit from in the future the purpose of these awards is not to provide gap or extension funding of existing projects but to initiate new projects
Eligibility Individuals with Principal Investigator status at Boston Childrenrsquos Hospital are eligible Applicants need not be Associate Members of the Broad Institute
Broad Platforms and Scientists Broadrsquos Platforms (Genomics Imaging Metabolite Profiling Proteomics Genomic Perturbation and the Broad Technology Labs) are collaborative organizations that provide scientific leadership and cutting edge technologies in support of project goals Collaborations can also be established with other groups at the Broad including the Klarman Cell Observatory the Stanley Center for Psychiatric Research or the Center for the Development of Therapeutics
Budgets Grants will provide $60000 direct support for 1 year plus philanthropic overhead It is expected that most grants will fund work performed at the Broad Institute either through interaction with Broadrsquos Platforms or via collaboration with a Broad scientist however the work may also occur at Boston Childrenrsquos if it is important to meet the scientific goals of the collaboration
Deadline and Review process Final proposals are due by September 1 2015 Funding decisions are expected to be reached by October 1 2015 Proposals will be reviewed by a joint Childrenrsquos HospitalndashBroad Institute committee Additional submission dates are expected for 2016
Submission Applicants are strongly encouraged to discuss potential applications in advance with the office of the Chief Scientific Officer at the Broad Questions should be directed to Alex Burgin ( 617-714-7124)
Proteomics Genomic Perturbation and the Broad Technology Labs) are collaborative
organizations that provide scientific leadership and cutting edge technologie
s in support of
project goals Collaborations can also be established with other groups at the Broad including
the Klarman Cell Observatory the Stanley Center for Psychiatric Research or the Center for the
Development of Therapeutics
Budgets
Grants wi
ll provide $60000 direct support for 1 year plus philanthropic overhead It
is expected that most grants will fund work performed at the Broad Institute either through
interaction with Broadrsquos Platforms or via collaboration with a Broad scientist howev
er the
work may also occur at Boston Childrenrsquos if it is important to meet the scientific goals of the
collaboration
Deadline and Review process
Final proposals are due by September 1 2015 Funding
decisions are expected to be reached by October 1 201
5 Proposals will be reviewed by a joint
Childrenrsquos Hospital
ndash
Broad Institute committee Additional submission dates are expected for
2016
Submission
Applicants are
strongly encouraged to discuss potential applications in
advance
with the office of the Chief Sc
ientific Officer at the Broad
Questions should be
directed to Alex Burgin (
aburginbroadinstituteorg
617
-
714
-
7124
)
Boston Childrenrsquos Hospital ndash Broad Institute Collaboration Grants
Background Meeting the challenges of biomedicine requires bringing together creative
scientists exceptional technological resources and world-class expertise across many
disciplines that rarely exist within a single institution This guiding principle is the basis for a
funding opportunity to support Boston Childrenrsquos Hospital investigators performing research
in collaboration with Broad scientists
Goals The fundamental goal of this new award is to spark new collaborations between Boston
Childrenrsquos Hospital and the Broad Institute The grants will be awarded to address a very wide
range of scientific questions but are specifically designated for projects with the following
characteristics
Projects where engagement with the Broad would benefit Childrenrsquos Hospital
investigators projects that can uniquely benefit from being done at the Broad Institute
Projects that create new scientific collaborations and bring together diverse scientific
backgrounds projects that spark new scientific directions or technologies and are not
currently being pursued at Childrenrsquos Hospital
Projects that pilot new approaches that researchers at Childrenrsquos the Broad and the
greater scientific community can benefit from in the future the purpose of these awards
is not to provide gap or extension funding of existing projects but to initiate new
projects
Eligibility Individuals with Principal Investigator status at Boston Childrenrsquos Hospital are
eligible Applicants need not be Associate Members of the Broad Institute
Broad Platforms and Scientists Broadrsquos Platforms (Genomics Imaging Metabolite Profiling
Proteomics Genomic Perturbation and the Broad Technology Labs) are collaborative
organizations that provide scientific leadership and cutting edge technologies in support of
project goals Collaborations can also be established with other groups at the Broad including
the Klarman Cell Observatory the Stanley Center for Psychiatric Research or the Center for the
Development of Therapeutics
Budgets Grants will provide $60000 direct support for 1 year plus philanthropic overhead It
is expected that most grants will fund work performed at the Broad Institute either through
interaction with Broadrsquos Platforms or via collaboration with a Broad scientist however the
work may also occur at Boston Childrenrsquos if it is important to meet the scientific goals of the
collaboration
Deadline and Review process Final proposals are due by September 1 2015 Funding
decisions are expected to be reached by October 1 2015 Proposals will be reviewed by a joint
Childrenrsquos HospitalndashBroad Institute committee Additional submission dates are expected for
2016
Submission Applicants are strongly encouraged to discuss potential applications in
advance with the office of the Chief Scientific Officer at the Broad Questions should be
directed to Alex Burgin (aburginbroadinstituteorg 617-714-7124)
Clinical Trials Glossary
ADME an acronym for absorption distribution metabolism and elimination ADME
studies determine how a drug is absorbed by the body the chemical changes that it may
undergo and how it is eliminated from the body
Adverse event (AE) a bothersome event that occurs in a study participant AEs may be
related to the treatment being tested or may be due another cause (eg another treatment
another medical condition an accident or a surgery)
Arm a specific type of treatment to which a group of clinical trial participants is
assigned Some clinical trials have one arm and some have two arms while others have
three or more arms For example a clinical trial comparing two different doses of an
investigational drug versus a placebo would have three arms participants receiving a
higher dose of the investigational drug participants receiving a lower dose of the
investigational drug and participants receiving the placebo
Baseline a point in time at the beginning of a clinical trial before the study participants
receive any treatment At the baseline participants usually have certain types of tests
During and after treatment the same tests may be performed and the results compared
with the baseline results to see if the drug has caused changes
Bias a factor ndash such as a preconceived idea about the effects of the benefits and risks of a
treatment or a lack of balance in selection of patients for a study ndash that reduces the
likelihood that the study results are true Methods such as blinding and randomization
are used to limit the potential for bias
Bioavailability the portion of the dose of a drug that reaches the bloodstream For
example if the drug is administered intravenously its bioavailability is 100 percent
however if the drug is administered in any other way such as orally topically or
through intramuscular injection its bioavailability will decrease due to incomplete
absorption
Bioequivalence study a test performed to compare the portion of a drug in the
bloodstream when administered in different dosage forms
Biologic product any substance that can be used in prevention treatment or cure of
disease Some examples include vaccines blood virus toxin antitoxin and therapeutic
serum
Biopsy the removal of cells or tissue from a patient for examination which is usually
done under a microscope A tissue sample might be taken for genetic studies Sometimes
there is a difference between the blood genotype and the skin or other tissue genotype
This term can also refer to the tissue sample that has been obtained by such a procedure
2
Blinding a process used to prevent the participants the researchers or both from
knowing what specific treatment is being given to participants in a clinical trial The
process of blinding helps to reduce bias because study participants and researchers are
less likely to be unconsciously influenced by the knowledge of what the study participant
is actually receiving If only the participants are blinded the study is called a single-
blind study If both participants and researchers are blinded the study is called a double-
blind study
Carcinogenicity studies long-term studies conducted in animal models to determine a
drugrsquos likelihood of causing cancer
Clinical efficacy a compoundrsquos ability to produce the desired effect
Clinical pharmacology a science that studies properties of drugs in relation to their
therapeutic value in humans
Clinical study or Clinical trial a medical experiment in human beings that helps to
determine how a disease drug or medical device affects study participants Clinical
studies are necessary to answer specific questions about how to better diagnose prevent
or treat a disease or condition
Cohort a group of study participants who have certain characteristics in common such
as female sex a defined age range or particular severity of disease Dividing study
participants into cohorts is often done as part of the analyses of study data
Contraindication a factor that makes the use of a particular drug inadvisable For
example a person who has had an allergic reaction to penicillin in the past is considered
to have a contraindication to using penicillin in the future
Control group a group of participants not receiving the investigational drug but instead
receiving a standard treatment for their disease or receiving a placebo The results
observed in the group of patients receiving the investigational drug are compared with the
results observed in the control group
Crossover study a study design with two or more arms where participants receive one
treatment for a period of time and then switch over to a second treatment for a period of
time Such a study design allows the effects of the two treatments to be compared in the
same patient
Data Monitoring Committee (DMC) or Data Safety and Monitoring Board (DSMB)
A committee of experts that periodically reviews the accumulating data from an ongoing
multicenter clinical trial Members of a DMCDSMB must be independent ie they
cannot be participating as investigators in the clinical trial Based on their review the
DMCDSMB experts advise the sponsor regarding whether it is safe and acceptable to
continue with the study or whether the data suggest that the study should be modified or
stopped A DMCDSMB may recommend that a trial be stopped if there are safety
concerns or if the trial objectives have been achieved
3
Dose-ranging study a clinical trial in which two or more doses of an investigational
drug are tested to determine which dose is likely to offer the best combination of safety
and efficacy in later clinical trials or in medical care
Efficacy or effectiveness the ability of a drug to prevent cure or slow a disease process or to alleviate the symptoms of a disease or condition
Eligibility a determination made during the screening period for a clinical study of
whether a personrsquos participation in the trial is likely to be safe and can contribute data
that will help achieve the study goals
Endpoint occurrence of a disease symptom sign or test result that constitutes one of the
target outcomes of a clinical trial
Inclusionexclusion criteria the factors defined in the protocol of a study that determine
whether a personrsquos participation in a clinical trial is likely to be safe and can contribute
data that will help achieve the study goals Study candidates undergo evaluation during
the study screening period to determine if they meet all of the inclusion criteria and do
not meet any of the exclusion criteria as defined in the protocol These criteria usually
consider such factors as age sex type of disease stage of disease previous treatment
history and other medical conditions in determining eligibility for the study
Informed consent (assent) a process by which medical researchers provide necessary
information to a person about a clinical study and the person voluntarily confirms his or
her willingness to participate in the study Children who are considered old enough to
have a basic understanding of the study may need to provide assent to be involved in the
study a parent or legal guardian must also give informed consent for such a child to
participate
Informed consent (assent) form a document that describes a clinical study to the
participants (or their parentsguardians) The informed consent (assent) form includes
information about the goals of the study the study design and duration the types of tests
to be performed the potential risks and inconveniences the potential benefits the
possible costs or payments associated with study participation the available alternative
therapies the rights and responsibilities of the participant and the people to contact if the
participant has questions The informed consent (assent) form must be reviewed and
signed before the participant has any study tests or treatment including the tests
performed during the screening period at the beginning of the study Participants are
given a copy of the informed consent (assent) form to take home
Institutional Review Board (IRB) or Independent Ethics Committee (IEC) a board
of physicians statisticians researchers community advocates and others who are
responsible for ensuring the protection of the rights safety and well-being of participants
in a clinical trial at a study center This board is called an IRB in the United States and is
often called an IEC in other countries IRBIECs review and approve important study
documents (eg protocols informed consent forms study advertisements and patient
4
brochures) before the start of the study and periodically review the progress of the study
while it is ongoing
Investigational Drug a drug that is being tested as a potential treatment for a disease or
condition but has not yet been proven safe and effective for that use
Investigator a physician or other health care worker who carries out a clinical trial by enrolling treating and monitoring participants and recording the results
In vitro testing testing conducted in test tubes or other artificial environments
In vivo testing testing conducted in living animals or humans
Longitudinal study a clinical study that involves observations of the same items over
long periods often many decades Because longitudinal studies track the same people
they are often used to study trends across the life span to uncover predictors of certain
diseases or to track the effects of a particular treatment on a patientrsquos condition over
time
Multicenter study a study conducted at more than one location Multicenter clinical
studies are generally performed when each individual clinical trial site does not have
enough study candidates to complete a large trial
Natural history study a study of the natural development of a disease or condition over
a period of time Natural history studies are usually longitudinal studies
New Drug Application (NDA) the registration document through which a
pharmaceutical company formally proposes that the FDA approve a new drug for
manufacturing and sale The application includes detailed reports of pharmacology
toxicology manufacturing and chemistry as well as data from clinical trials
Open-label study a study in which the participants and the investigators know which
treatment is being given In an open-label study there is no blinding and none of the participants receives a placebo
Orphan disease a disease or condition that affects a relatively small number of people
In the US this defined as fewer than 200000 people In Europe this is defined as fewer
than five in 110000 people
Orphan drug a drug intended to treat an orphan disease
Participant or subject a patient or healthy volunteer who participates in a clinical trial
Phase 1 the initial phase of testing of an investigational drug in humans Usually a
Phase 1 clinical study is conducted in a small number of healthy volunteers or patients
with a disease for which the drug may be useful Generally the study is designed to
determine the side effects of the drug and its pharmacokinetics Some information
5
regarding drug efficacy may be collected if patients with a disease participate A phase
frequently encompasses more than one clinical trial Phase 1 sometimes is sub-divided
into Phases 1a and 1b for example when the first set of Phase 1 trials (Phase 1a) is
performed in healthy volunteers and a second set of Phase 1 trials (Phase 1b) is
performed in patients with a disease
Phase 2 the intermediate phase of testing of an investigational drug in humans Usually
a Phase 2 clinical study conducted in patients with a disease for which the drug may be
useful Generally the study is designed to evaluate dosing to obtain preliminary data on
the effectiveness of the drug and to acquire more safety information Phase 2 sometimes
is sub-divided into Phases 2a and 2b Phase 2a studies typically are smaller and shorter
in duration and evaluate different drug doses to see how they affect certain tests that can
indicate whether the drug is working as expected Phase 2b studies typically enroll more
patients are of longer duration and evaluate whether the drug is offering clinical benefits to patients Phase 2b studies sometimes are considered pivotal or registration-directed
Phase 3 the final phase of testing an investigational drug in humans before regulatory
approval Phase 3 studies are usually conducted in a large population of patients and are
generally designed to confirm the effectiveness of the drug and to evaluate the overall
risk-benefit ratio Phase 3 studies usually test the investigational drug in comparison with
a standard treatment for the disease or a placebo
Phase 4 testing of a drug in humans after it has already been approved by regulatory
authorities and can be used in medical practice Phase 4 studies may be conducted to
compare the drug to a similar type of drug to explore whether it may help patients with
other diseases to further study the long-term safety of the drug or for other reasons
Pivotal study a study that is designed to generate the data required by regulatory
authorities to decide whether to approve an investigational drug A pivotal study is
usually a large randomized Phase 2b or Phase 3 study and often is blinded and uses a
placebo as a control Sometimes a pivotal study is described as a registration-directed
study
Placebo an inactive version of an investigational drug A placebo has a similar
appearance to the investigational drug but is expected to have no therapeutic value A
placebo is used as a comparison treatment to reduce bias in randomized studies
Preapproval access program an umbrella term for programs that allow seriously ill
patients to receive an investigational drug when they are unable to participate in clinical
trials and there is no alternative treatment This is sometimes referred to as
compassionate use Types of pre-approval access programs include expanded access
parallel-track named patient program single-patient exemption and treatment IND The
timing for starting an expanded access program usually depends upon what is known
about the risk-benefit of the drug and whether the drug can be provided in a manner that
is fair to patients with the disease
6
Preclinical (nonclinical) testing testing of a drug in test tubes or in animals A drug
undergoes preclinical testing before being tested in humans to make sure that it shows
evidence of desired effects and is sufficiently safe for study in people Preclinical testing
sometimes also helps to determine the doses of the drug that should be evaluated in
humans Preclinical testing is sometimes called nonclinical testing
Protocol a document describing what types of people may participate in a clinical study
and the objectives treatments measurements statistical methods timing and
organization of a clinical trial The protocol must be prepared in advance of the study
and must be reviewed and approved by review committees and regulatory authorities
before the study is started Investigators must follow the protocol to carry out the study
Randomization assignment of participants to treatment arms based on chance This is
usually done by a computer program in a way that does not allow either the participants
or the investigators to choose who is assigned to which arm Randomization is used to
reduce bias in clinical trials
Risk-benefit ratio the balance of the risk of side effects expected with use of a drug
versus the potential for benefit with the use of that drug A drug with a good risk-benefit
ratio has few side effects and is very effective
Serious adverse event (SAE) an adverse event that is life-threatening requires inpatient
hospitalization or lengthens a hospital stay leads to substantial disability leads to a birth
defect or results in death
Side effect any effect of a drug other than the desired effect Side effects are often
unwanted and may be bothersome Other names for a bothersome side effect are adverse
drug reaction (ADR) or drug toxicity
Screening period a period at the beginning of a clinical trial when candidates for the
study are evaluated to determine if their participation is likely to be safe and can
contribute data that will help achieve the study goals
Significant or statistically significant an outcome in a clinical trial is likely to result
from a real difference (eg due to an effect of a treatment) and is unlikely to be due to
chance alone The level of statistical significance is often expressed in terms of a p-
value which indicates the probability that a difference is not due to chance alone
Usually a p-value smaller 005 is considered statistically significant
Sponsor the organization responsible for financing and coordinating a clinical trial
Most often this is a pharmaceutical or biotechnology company
Standard treatment a treatment currently in wide use often approved by regulatory
agencies and generally considered effective in the treatment of a specific disease or
condition
7
Toxicity a side effect produced by a drug that is bothersome to the person taking the
drug
Toxicology the study of the adverse effects of chemicals conducted in animal models to
predict potential adverse effects in humans Some studies are conducted during clinical
development to evaluate dosing regimens
Boston Childrenrsquos Hospital Clinical Research Map 1 Mouse over for additional info Bold = hyperlink
CLINICAL RESEARCH MAP
Boston Childrenrsquos Hospital Clinical Research Map 2 Mouse over for additional info Bold = hyperlink
ObjectiveThis clinical research map is designed to serve as a guide for investigators study coordinators and research nurses at Boston Childrenrsquos Hospital The research map outlines the key steps in preparing to launch a research study and provides embedded links to institutional resources tools and documents
An investigator need not follow the steps on the Clinical Research Map in any particular order There is flexibility and the steps followed will in part de-pend on the type of research study
For new as well as more experienced investigators the Clinical Research Map can be used as a checklist or an inves-tigator can use the steps on the map as points for consideration as they are developing a protocol and launching a study
This tool is not intended to substitute for the important collaboration be-tween a junior investigator and a senior investigatormentor A senior investiga-tor plays a pivotal role in coaching and advising a junior investigator regarding the many subtleties and variations that apply to designing and implementing a protocol
This process map cannot be inclusive of every possible task or step but is intended as a general guide for investi-gators and their study teams
ResourcesThere are many institutional resources at Boston Childrenrsquos Hospital designed to support investigators and their clini-cal research teams In addition to links to resources tools and documents that are embedded in the steps of the clini-cal research map the last page of this document contains website addresses that will take you to additional helpful institutional resources
Acknowledgements Cindy Williams DNP RN PNP NE-BC Nursing Director CTSU Clinical Research Nursing
Ellen McGrath MSN RN CPNP Nurse Practitioner Department of Surgery
Grace Yoon MSN RN CNNP Research Nurse Department of Ophthalmology
Laura Feloney BA Lab Technician
ContentsOverview Four stages 3
1st Stage Protocol development 4
1st Stage Protocol development contrsquod 5
2nd Stage Implementation planning 6
3rd stage Study launch7
4th stage Statistical analysis reporting and dissemination 8
Discarded specimens Additional steps 9
Chart review Steps if you are completing a chart review 10
Appendix A Resources for researchers 11
Boston Childrenrsquos Hospital Clinical Research Map 3 Mouse over for additional info Bold = hyperlink
Overview Four stages
Protocol development
Implementation planning
Study launch
Statistical analysis reporting and dissemination
1
2
3
4
Boston Childrenrsquos Hospital Clinical Research Map 4 Mouse over for additional info Bold = hyperlink
1st Stage Protocol development
Explore resources
CRIT
CRC
EQuIP
CTSU
Harvard Catalyst
Complete training
CITI training
EQUiP
Consult research pharmacistResearch Pharmacy
Rocco Anzaldi
Consult statistician
CRC
Draft a protocol
Protocol guidelines
Study personnel
FDA Guidance for Investigators
Consult Clinical Research Center
CRC
Bio Bank
Start IRB application
TransLab
Consider applying for grants
securing funding
Office of Sponsored Programs
If INDIDE application to FDA
Does my study need an INDIDE
Regulatory resources
Arrange a consultation with
CRIT
ConsultationTasks for investigators and study teams
Boston Childrenrsquos Hospital Clinical Research Map 5 Mouse over for additional info Bold = hyperlink
Respond to IRB questionsrequests
for clarification
1st Stage Protocol development contrsquod
Departmental Scientific Review
Organize DSMB design DSMP
DSMPDSMB
Templates for Research Study
Documents and Tools
Study Templates and Tools
Investigators who sponsor an FDA regulated trial
ClinicalTrialsgov
Create regulatory binder
Regulatory Binder Template
Submit the grant application to OSP
OSP
TIDO
CTBO
Consult Office Intellectual Property
Technology and Innovation
Development Office
TIDO
IRB approval
Consider blood volume for research
Research blood volume policy
Confidentiality plan
Confidentiality guidelines
Boston Childrenrsquos Hospital Clinical Research Map 6 Mouse over for additional info Bold = hyperlink
Develop Case Report Forms
(CRFs)
CRF guidelines
Establish electronic shared
folder or study binder for study
documents
CRIT
Set date for trial launch
Develop fast fact sheet for bedside staff
Consult programmer re database
CRIT
Research study resource manual
for the clinical unit
Confirm study drug
in pharmacy
Rocco Anzaldi
Clarify system for screening
and enrolling patients
Recruitment guideline
Updated protocol to
nurse manager
Consult MDsNPs on unitclinic
2nd Stage Implementation planning
Tasks for investigators and study teams
Study logistics Documentation logistics
Data storage
Confidentiality plan
Confidentiality guidelines
Create study orderset
Consider blood volume for research
Research blood volume policy
Create Manual of Operations
MOO Guide
Study implementation
meeting
Develop study logstools
EQUIP
Finalize tracking sheet
Research Administration
Fernando Valles
Boston Childrenrsquos Hospital Clinical Research Map 7 Mouse over for additional info Bold = hyperlink
3 Document informed consent
Informed Consent
Consent library
Schedule weekly study team meeting
Communicate to department faculty
and multidisciplinary
team announcing trial launch
Steps before trial launch
3rd stage Study launch
Patient flow
1 Seek permission
to approach potential subjects
2 Screenenroll
patients
EQUIP
5 Send Study
Tracking Sheet (STS)
6 Collection of
patient data and assessing for
adverse events
7 Study
documents and data handling
4 Datetime study tests
Create a checklist outlining study action items for each subject
Boston Childrenrsquos Hospital Clinical Research Map 8 Mouse over for additional info Bold = hyperlink
Annual IRB Report
Annual Progress ReportStaff Report
raquo Maintain Interest of Staff
raquo Important to See Study Progress
Write Abstract
Dissemination of Research Results
raquo Conference raquo Internal Presentation for Colleagues
raquo Publication
Plan DSMB MeetingInterim
Analysis
4th stage Statistical analysis reporting and dissemination
Data Entry
When Enrollment Complete Data
Cleaning
Monitor Subjects to Identify
Adverse Events (CCI sponsor
DSMB)
Report Adverse Events
Update MOO Based on Experience
with First Several Patients Enrolled
Weekly Study Team Meeting
Report study findings to
subjects and stakeholders
Data management Trial management
Reporting Dissemination
Regular Review of Data
to Identify Deviations
and Workflow Improvements
Consult Statistician When Approaching Target Enrollment
Discarded specimens Additional steps
Boston Childrenrsquos Hospital Clinical Research Map 9 Mouse over for additional info Bold = hyperlink
Send IRB Approval to lab manager
Maureen Samson
Educate staff in areasunits about sample collection
Locate the discarded samples
Locate the accession number in PowerChart
Retrieve specimen
Mark Kellogg
Follow Shipping Rules and Procedures
IATAShipping with dry ice instructions
Communicate with laboratory staff
Contact Dr Mark Kellogg to discuss specimen retrieval
Consult with Biorepository
Biorepository
Chart review Steps if you are completing a chart review
Boston Childrenrsquos Hospital Clinical Research Map 10 Mouse over for additional info Bold = hyperlink
7 8
4321
Databaserecord review guidelines
5 6
Consult programmer re database
CRC Request
Respond to IRB questions
requests for clarification
Departmental Scientific Review
Complete training
CITI Training
Draft a protocol
Protocol Guidelines
Prepare IRB Application
Information about the CCI
IRB Application
Develop Case Report Forms (CRFs)
CRF Guidelines
IRB Review
Boston Childrenrsquos Hospital Clinical Research Map 11 Mouse over for additional info Bold = hyperlink
Clinical Research Center (CRC) x84720
Committee on Clinical Investigation (CCI IRB) x57052
Research Pharmacist x52014
Clinical and Translational Science Unit (CTSU) x57541
Education and Quality Improvement Program (EQUIP) x57052
Clinical Trials Office Central Budgeting x4-2714
Office of Sponsored Programs x4-2723
Technology and Innovation Development Office 617-919-3079
Research Finance x8-3517
Harvard Catalyst 617-432-7810
Regulatory Affairs x4-2777
Appendix A Resources for researchers
RES_4446_ClinicalResearchMap-FINAL FOR LINKS 1
RES_4446_ClinicalResearchMap-FINAL FOR LINKS 10
Overview Four stages
1st Stage Protocol development
1st Stage Protocol development contrsquod
2nd Stage Implementation planning
3rd stage Study launch
4th stage Statistical analysis reporting and dissemination
Discarded specimens Additional steps
Chart reviewSteps if you are completing a chart review
Appendix A Resources for researchers
RES_4446_ClinicalResearchMap-FINAL FOR LINKS 11
RES_4446_ClinicalResearchMap-FINAL FOR LINKS 2
RES_4446_ClinicalResearchMap-FINAL FOR LINKS 3
RES_4446_ClinicalResearchMap-FINAL FOR LINKS 4
RES_4446_ClinicalResearchMap-FINAL FOR LINKS 5
RES_4446_ClinicalResearchMap-FINAL FOR LINKS 6
RES_4446_ClinicalResearchMap-FINAL FOR LINKS 7
RES_4446_ClinicalResearchMap-FINAL FOR LINKS 8
RES_4446_ClinicalResearchMap-FINAL FOR LINKS 9
RES_4446_ClinicalResearchMap-PAGE 5pdf
Overview Four stages
1st Stage Protocol development
1st Stage Protocol development contrsquod
2nd Stage Implementation planning
3rd stage Study launch
4th stage Statistical analysis reporting and dissemination
Discarded specimens Additional steps
Chart reviewSteps if you are completing a chart review
Appendix A Resources for researchers
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Button 91
Button 92
Button 94
IRB review
Button 102
Develop Case Report Forms
Button 136
Consult clinical research center
INDIDE 1
Explore resources
Button 1016
Bio Bank p
4
Consult statistician
Consult research pharmacist
Study personnel
Complete training
Consider grantsfunding
Draft a Protocal 2
Arrange a consutlations with CRIT
Next Page 1
Previous Page 1
TransLab
Start IRB application 3
Develop study logs
Updatedd protocol
Confirm study drug
Establish electronic shared
COnsult programmer
Clarify system
Research study resrouce manual
Develop case report forms
MOO
Set date for trial launch
Button 44
Study implementation meeting
Finalize tracking sheet
Data storage
Confidentiality
Blood volume 3
Develop fast fact
Consult MDs
Schedule weekly
Communicate early
Button 71
Screenenroll patients
Document informed consent
Datetime tests
Send study tracking sheets
Collection patient data
Button 77
Dissemination
Button 87
Button 124
Button 125
Communicate with lab staff
Button 106
Button 109
Button 1010
Shipping page 9
Button 1012
Button 99
Button 133
Button 134
Button 135
Biorepository
Locate assession number
Retrieve specimen
Button 30
Consult office
Negotiate Contract
Organizing DSMB
Submit Grant
Respond to IRB questions
Button 66
Create regulatory binder
Templates for research stufy
Clinical Trials Business Office
Blood volume 2
Confidentiality plan
Investigators who sponsor
clinicaltrials
gov
BPN Project
Drug Discovery amp Development Testing Funnel
Tier 1 2 3
Tier 6 7 8
Tier 5
Tier 4
Example Drug Discovery amp Development Testing Funnel
Cytotoxicity
Grant
Project
Example Drug Discovery amp Development Testing Funnel
TIER 1A ndash Primary Screen
Chemical purity and identity of active compounds
Primary bioactivity screen
Cell viability (When Appropriate)
ScaffoldsMoiety Chemical liabilities (for example Michael acceptor GSH reactive)
Calculated properties CLogP
PSA
Molecular Weight
rotatable bonds
H-bond donors and acceptors
permeability
pKa
Solubility
TIER 1B
Confirm EC50 determinations for actives compounds in primary screen with fresh
compounds from the original stock Confirm EC50 determinations for the lead (most
active) compound in primary screen with a new sample either repurchased purified
and characterized in-house or independently synthesized in-house
Compounds with IC50s (EC50s) less than X advance to Tier 2
TIER 2A ndash Activity Confirmation
Secondary screen
TIER 2B
Repeat EC50 determinations for actives in secondary screen with fresh
compounds from the original stock
Compounds with IC50s (EC50s) less than X advance to Tier 3
Example Drug Discovery amp Development Testing Funnel
TIER 3 ndash Drug-like Properties Specificity
IC50 selectivity in selectivity screen
CYP450 Inhibition competitive and time-dependent if structural alerts exist
(spot check illustrative examples from compound series)
Measured solubility
Measured protein binding (spot check illustrative examples from
compound series)
Test of Permeability in vitro permeability [indicate assay eg Caco2 orand
PAMPA] (spot check illustrative examples from compound series)
hERG
Cytoxicity assays
All compounds with no significant issues (Define Minimum Conditions for
Advancement) to advance to Tier 4
Example Drug Discovery amp Development Testing Funnel
TIER 4 ndash Scale-up Synthesis and Preliminary PK
Scale-up synthesis
Purity determination gt98 with no single impurity gt1
Rodent bioavailability and PK (define target delivery route) Tmax
Cmax
AUC
Bioavailibility
Vss CL T12 MRT
Brain to Plasma ratios
P-glycoprotein transport MDCK-MDR1 and MDCK-mdr1a
Plasma Protein Binding (species)
Microsomal Stability ndash rodent and human
Defineplan Patent Protection Strategy
All compounds with no significant issues (Define
Minimum Conditions for Advancement) advance
in parallel to Tiers 5AampB
Example Drug Discovery amp Development Testing Funnel
TIER 5A ndash In Vivo Bioactivity
Animal efficacy
Validate Biomarker
Target engagement
Advance to Tier 6 if (Define Minimum Conditions for advancement)
TIER 5B ndash Advanced Drug-like Properties
Microsomal stability in multiple
species
Chemical Stability
CYP450 induction
CYP reaction phenotyping
Metabolism ndash human
hepatocytesmicrosomes
Metab ID define major human rat dog and
non-human primates (NHP) metabolites
In vitro Tox Ames
Chromosome Aberration
CNS effects
Example Drug Discovery amp Development Testing Funnel
TIER 6 ndash Liability Assessment
Broad Pharmacological Profile and Toxicology
PK in second species
TIER 7
Non-GLP exposure studies single and multiple dose
Advance to late stage pre-clinical development (Define Minimum
Conditions for advancement)
Example Drug Discovery amp Development Testing Funnel
Principal InvestigatorProgram Director (Last First Middle)