February 2010 / 1 Fast Track Drug Development – The Clinical (Caleidoscopic) Perspective 20 Years AGAH, Annual Meeting, Hamburg 21.-23. February 2010 Fritz R. Bühler, MD ECPM, University of Basel European Innovative Medicine Initiative, PharmaTrain, Coordinator ex Roche Head Global Clinical Research and Development
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February 2010 / 1
Fast Track Drug Development – The Clinical (Caleidoscopic) Perspective
20 Years AGAH, Annual Meeting, Hamburg21.-23. February 2010
Fritz R. Bühler, MDECPM, University of Basel
European Innovative Medicine Initiative, PharmaTrain, Coordinatorex Roche Head Global Clinical Research and Development
February 2010 / 2
PatientPatient
PhysicianPhysician
Health Care ProviderHealth Care Provider
RegulatorRegulator
IndustryIndustry
(Academic) Researcher(Academic) Researcher
Individual,Patient-specificDecision
Drug- andPopulation-
specificDecisions
Stakeholders
February 2010 / 3
February 2010 / 4
Pharma needs to alter the blockbuster approach
Training Platform
• Serendipitous discovery of “one size fits all” drugs is increasingly difficult and costly
• Scientific advances in biology, IT, mobile and networking technologies offer radically new approaches
• Health technology assessment is now part of health care decision making
• Patients and patient groups have growing influence and demand greater access to treatments
• Industry must deliver higher value medicines to patients and demonstrate clear benefits
Because
February 2010 / 5
Significant new Technologies emerged …
Proteinchips
Transgenicanimals
Bio-informatics
Chem-informatics
Functional genomics
Molecularmodelling
Proteomics
In silicoexperiment-
ation
Pharmaco-genomics
Source: Strategic Planning Pharma
February 2010 / 6
From … To …
… which will trigger a paradigm shift in R&D and medicine …
Clinical definition of disease diagnosis
Molecular definition diagnosis andpredisposition
Courtesy of Don Stanski, Novartis
February 2010 / 7
• Understanding of disease at molecular level
• Better drug targets
• Preventive medicine
• Identification of drugs
• Diagnostics
• Knowledge of individual risk profiles
• Drug therapy will become more selective
• Gene therapy partly replacing existing therapies
New Technologies
February 2010 / 8
CCS POCEIM FDP NDA Approval
Market
Exploratoryclinical
research
Simulation – Modeling TechniquesGenome-based subject selection
HTS
Combinatoral chemistry
Targetvalidation
Hit
LeadIdentificationOptimization
CLOP
SAR
GenomicsProteomics
HTS(Cell) Assays• Mech• ADME• Tox• Interactions
Bioinformatics
00 0 I II III IIIB IV
Frontloaded High Throughput Drug Development
February 2010 / 9
• Genomics-based (GB)
• Pathophysio (PP)-logical
• Whole body pharmacokinetic (PK)
• Toxicokinetic (TK) and Pharmacodynamic(PD) model
‘Frontloaded High Throughput Drug Development’
February 2010 / 10
Key Drivers to Transform Development
Modeling and simulation
Rapid compound selection in man
Biomarkers
Innovative clinical trial design
Innovative approaches to initial registration (“provisional approval”)
Integrated safety assessment & risk management
Quality by design manufacturing
1
2
3
4
5
6
7
February 2010 / 11
Modeling and Simulation is fundamental to a new Paradigm of Drug Develoment
Full Release
MonitoredRelease
Full Approval
Confirm the model
ProvisionalApproval
Build themodel
l------------Continuous sharing of data with Health Authority--------l
Biomarkers
Modeling & Simulation
MarketAccess
February 2010 / 12
Biomarkers … A simple conceptual architecture
Disease Biomarkers• Predisposition• Early detection• Prognosis• Monitoring/
Recurrence
Pharmacodiagnostic Biomarkers
• Treatment eligibility
• Response prediction
Pharmacological Biomarkers• Pharmacodynamic
markers• Pharmacokinetic
markers• Mechanism of
action markers
Biomarkers
February 2010 / 13
• Many currently defined “diseases” are clinical syndromes (defined observationally) undoubtedly comprised of a collection of distinct pathogenic states
• New genomic, proteomic, imaging, etc. biomarkers may provide better discrimination by providing more information on underlying pathologic pro-cesses (without necessarily providing full mecha-nistic, explanatory data)
Disease Subset Definition
February 2010 / 14
Lewis B. Sheiner, M.D., Ph.D.Physician and Scientist1940 – 2004
Learning ‐‐mechanistic (causal) understanding of product‐exposure‐response relationships
Confirming – demonstrating evidence of mechanism, therapeutic concept, safety & effectiveness
LEARNING CONFIRMING
Learn-Confirm ParadigmFramework for Optimal Drug Development
February 2010 / 15
CCS POCEIM FDP NDA Approval
Market
Exploratoryclinical
research
Simulation – Modeling TechniquesGenome-based subject selection
HTS
Combinatoral chemistry
Targetvalidation
Hit
LeadIdentificationOptimization
CLOP
SAR
GenomicsProteomics
HTS(Cell) Assays• Mech• ADME• Tox• Interactions
Bioinformatics
00 0 I II III IIIB IV
Frontloaded High Throughput Drug Development
February 2010 / 16
Developingleads
Discovery&
screening
Today – Intensive all-or-nothing regulation
2020 – Collaborative, evolving, automated regulation
Pre-clinicalevaluation Phase I Phase II Phase III Submission
MAA / NDAPhaseIIIb / IV
Scientific advice / pre-IND
Submission of CTA / IND CIM CIS Launch
CIM
Discussion and agreed plan
of action with Regulators Limited launch
with Living Licence
Instant automated approvals
Development loop for extended indications
and regulatory activities
PathoPhysiology
MoleculeDevelopment
In-lifelicensing
trials
Automatedsubmission/approvals
CIS
CIM = Confidence in mechanismCIS = Confidence in safetyIND = Investigative New DrugCTA = Clinical Trial ApplicationMAA = Marketing Authorisation
Application
Developingleads
Discovery&
screening
Today – Intensive all-or-nothing regulation
2020 – Collaborative, evolving, automated regulation
Pre-clinicalevaluation Phase I Phase II Phase III Submission
MAA / NDAPhaseIIIb / IV
Scientific advice / pre-IND
Submission of CTA / IND CIM CIS Launch
CIM
Discussion and agreed plan
of action with Regulators Limited launch
with Living Licence
Instant automated approvals
Development loop for extended indications
and regulatory activities
PathoPhysiology
MoleculeDevelopment
In-lifelicensing
trials
Automatedsubmission/approvals
CIS
CIM = Confidence in mechanismCIS = Confidence in safetyIND = Investigative New DrugCTA = Clinical Trial ApplicationMAA = Marketing Authorisation
Application
How will the R&D process look in 2020?
Courtesy of Steven Arlington, PWC
February 2010 / 17
How will the R&D process look in 2020?
Development loop for extended indications
and regulatory activities
CIM = Confidence in mechanismCIS = Confidence in safetyIND = Investigative New DrugCTA = Clinical Trial ApplicationMAA = Marketing Authorisation
Application
Development loop for extended indications
and regulatory activities
CIM = Confidence in mechanismCIS = Confidence in safetyIND = Investigative New DrugCTA = Clinical Trial ApplicationMAA = Marketing Authorisation
Application
PathoPhysiology
CIM
Discussion and agreed plan
of action with Regulators Limited launch
with Living Licence
Instant automated approvals
MoleculeDevelopment
In-lifelicensing
trials
Automatedsubmission/
approvals
CIS
CIM
Discussion and agreed plan
of action with Regulators Limited launch
with Living Licence
Instant automated approvals
MoleculeDevelopment
In-lifelicensing
trials
Automatedsubmission/
approvals
CIS
Disease knowledge
ContextualPathophysiology
Testable hypotheses
Early humanStudies (POC)
Public domain knowledge
• Biology• Epidemiology• ‘omics• Etc.
Internal understanding
• Disease sub-type
• Mechanisms• Targets• Biomarkers• Safety• Incidence• Economics• Differentiation
• Targets• Molecular entities• Patient sub-type• Disease specific biomarkers• Efficacy biomarkers• Safety biomarkers• Differentiation
Disease knowledge
ContextualPathophysiology
Testable hypotheses
Early humanStudies (POC)
Public domain knowledge
• Biology• Epidemiology• ‘omics• Etc.
Internal understanding
• Disease sub-type
• Mechanisms• Targets• Biomarkers• Safety• Incidence• Economics• Differentiation
• Targets• Molecular entities• Patient sub-type• Disease specific biomarkers• Efficacy biomarkers• Safety biomarkers• Differentiation
Disease knowledge
ContextualPathophysiology
Testable hypotheses
Early humanStudies (POC)
Public domain knowledge
• Biology• Epidemiology• ‘omics• Etc.
Internal understanding
• Disease sub-type
• Mechanisms• Targets• Biomarkers• Safety• Incidence• Economics• Differentiation
• Targets• Molecular entities• Patient sub-type• Disease specific biomarkers• Efficacy biomarkers• Safety biomarkers• Differentiation
February 2010 / 18
How will the R&D process look in 2020?
Development loop for extended indications and
regulatory activities
CIM
Discussion and agreed plan
of action with Regulators Limited launch
with Living Licence
Instant automated approvals
PathoPhysiology
MoleculeDevelopment
In-lifelicensing
trials
Automatedsubmission/approvals
CIS
CIM
Discussion and agreed plan
of action with Regulators Limited launch
with Living Licence
Instant automated approvals
PathoPhysiology
MoleculeDevelopment
In-lifelicensing
trials
Automatedsubmission/approvals
CIS CIM = Confidence in mechanismCIS = Confidence in safetyIND = Investigative New DrugCTA = Clinical Trial ApplicationMAA = Marketing Authorisation
Application
External understanding
Pharm Sci,
Regulatory Toxicology
Efficacy & Safety Clinical trials
Submission PreparationBiomarker, Device, live licence
Biomarkers
DevicesExternal understanding
Pharm Sci,
Regulatory Toxicology
Efficacy & Safety Clinical trials
Submission PreparationBiomarker, Device, live licence
Biomarkers
Devices
February 2010 / 19 PharmaTrainPharmaTrain
February 2010 / 20
Four Education and Training Excellence Programmes:
• European Medicines Research Training Network – EMTrain
• European Modular Education and Training Progarmme in Safety Sciences for Medicine – Safe SciMET
• Pharmaceutical Medicine Training Programme – PharmaTrain
• European progarmme of Pahrmacovigilance and Pharmacoepidemiology – Eu2P
PharmaTrainPharmaTrain
February 2010 / 21
Postgraduate Three Tier Modular Process: “Good Bologna Practice, GBP”
Diploma Exam MDDS/MSc
Learning Paths• mono-centric, 20% e-blended• multi-centric, 50% e-blended• distant, 80% e-blended
30 ECTSKnowledge
60 ECTSExpertise
90 ECTSCompetence
Concept• Syllabus-based• Learning outcomes• Base Course / Master extension• Modularity• ECTS/modul (1+3+1)• Mobility
CPDLifelonglearning
Work-Project• Thesis (10 ECTS)• Electives• (Research) Project
ExtensionModules
Base-Courses
Workload60 ECTS à 30 hrs= 1800 hrs= 1 academic year
February 2010 / 22
Master Thesis
Global Drug Development and Pharmaceutical
Business Environment
From PreclinicalTesting to Proof
of Concept in Humans
Learning and Confirming Trials:
Finding and Confir-rming the Right
Dose
Integrated ProductDevelopment, Port-folio Management
and Marketing
ConfirmingTrials:
Methodologyand Biostatistics
The Global Registration and Market Approval
Process
PharmacologyADME, PK/PD
Disease-Biology-Based Pharmacology
Drug Safety /Surveillance
Pharmaco-epidemiology
Practice of ClinicalTrials & Regulation
Ethical Issues in BiomedicalResearch
CMC/GMP
PharmaceuticalTechnologies
Medicinal Chemistry
European Coursefor Life Sciences Exe.Leadership
Principles of MarketingManagement
European Coursefor Biobusiness
Development
MDDS-Example- Base Course Modules (circle)- MDDS mandatory
Extension Modules (elipse)- Elective Modules (stippled)
Few examples of thePharmaTrain (IMI E+T?) Electives Platform
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