The promise, current state, and future of personalized medicine
Jeffrey M. Otto, PhD MBA National Director, CHI’s Center for Translational Research
April 17, 2013
Overview
§ Intro to personalized medicine § Short look at the early days, circa
2000-2001 § Review of current state § Discussion of the gap between the initial
promise and the current state § The CTR’s approach § Summary and conclusion
Definitions
§ Personalized medicine: the tailoring of medical treatment to the individual characteristics of each patient in order to classify individuals into subpopulations that differ in their susceptibility to a particular disease or their response to a specific treatment. Preventative or therapeutic interventions can then be concentrated on those who will benefit, sparing expense and side effects for those who will not.
§ Biomarkers: An indicator or pattern in a patient that reflects normal biologic processes, disease processes, or the effect of medical treatment.
§ Translational Research: Translational research transforms scientific discoveries arising from laboratory, clinical, or population studies into clinical applications to reduce disease incidence, morbidity, and mortality.
Personalized Medicine 101
The Promise § Better diagnoses and earlier interventions § More efficient drug development § More effective therapies The Challenges § Intellectual property § Regulatory oversight § Reimbursement Retrieved 03/28/2013 from http://www.personalizedmedicinecoalition.org/about/about-personalized-medicine
The Classic Personalized Medicine Paradigm
Toxic Not Toxic
Effec%ve
Not Effec%ve
The standard approach to medicine does not distinguish between individuals….
…although individuals within a population are often very different.
Biomarkers can be used to stratify patients… …and to select a safer, more efficacious treatment for the individual.
Personalized medicine is akin to shoe manufacturing:
Like shoes at a department store, many different drugs are available. Although several drugs may be available to treat a particular disease, all drugs are not safe or effective for all people.
Similar to sizing for a shoe, molecular diagnostic tests inform the selection of the appropriate drug.
Although the selected drug was not created specifically for you, it is more likely to work for you.
Biomarkers currently used in clinical medicine
§ Electrocardiogram § PET brain image § Bone densitometric
measurement § Serum chemistries
§ Auto-antigens in blood § Pulmonary function test § X-ray § MRI
Examples of -Omic Biomarkers
§ DNA variation q SNPs, rearrangements,
CNVs § DNA methylation § Chromosomal
rearrangements § microRNA § RNA expression § Protein panels
The beginning of “irrational exuberance” in personalized medicine
June 11, 2001 "We strongly believe that pharmacogenomics will shortly transform the way drugs are developed, marketed, and prescribed. I think you're going to see the benefits of this appearing within a five-‐year %meframe,"
Gerald F. Vovis SVP & Chief Technology Officer of Genaissance Pharmaceu%cals
The Challenge of “chasing the tail”
§ Statistically significant results are easier to achieve between populations at the left and right ends of the diagram, but are not necessarily meaningful from a health economics perspective
Treatment efficacy
Freq
uenc
y in
pop
ulat
ion
Genomic medicine milestones
1953: Structure of DNA elucidated by Watson & Crick
1950 1960
1956: 1st discovery of a gene%c basis for selec%ve toxicity (primaquine – an%malarial drug)
1970
1977: DNA sequencing technology developed by Fred Sanger
1977: Discovery of CYP450 metabolic enzymes -‐ varia%on in these enzymes significantly influence the effec%ve dose of a drug
1980
1994: EGFR TKI class discovered
1990
1990: The Human Genome Project is launched
2000 2010
1998: Hercep%n approved by FDA for HER2+ metasta%c breast cancer
1998: 1st CDx developed by Dako – Hercep-‐Test
2003: The Human Genome Project is completed
2004: Targeted therapies approved in colorectal and NSC lung cancer
2007: FDA updated Coumadin label to recommend gene%c tes%ng for dosage administra%on
2011: 1st simultaneous approval for drug (Zelboraf) & CDx for melanoma with BRAF V600E muta%on
2011: Simultaneous approval for Xalkori & CDx for NSCLC with abnormal ALK gene
Milestones Research
Drugs
Diagnos?c
Drug + CDx
Regulatory
Milestones Research
Drugs
Diagnos?c
Drug + CDx
Regulatory
Overview of Targeted Cancer Therapies
Manchana, T., Ittiwut, C., Mutirangura, A., & Kavanagh, J. J. (2010). Targeted therapies for rare gynaecological cancers. Lancet Oncol, 11(7), 685-693. doi: http://dx.doi.org/10.1016/S1470-2045(09)70368-7
Why so few success stories?
§ Genomic era of medicine is less than 15 yrs old
§ Technology is not sufficient on its own
§ Biomarkers are not necessarily “fit for purpose”
§ Test needs to work within the existing healthcare workflow
§ Stakeholder alignment § Is the patient the customer?
Cartoon: Agres, Ted. (2009) The hunt for personalization. Retrieved 03/08/2013 from http://www.dddmag.com/articles/2009/06/hunt-personalization
Catholic Health Initiatives & The Center for Translational Research
CHI: 5th Largest Hospital Network in US
Strength in Numbers § 5th largest US network § 81 acute care hospitals in 17 states § 40 LTC facilities § 86,000 employees § 2,900 physicians and midlevel providers § Diverse markets with 90% ranked #1 or #2 § $15B in assets, $9.8B in annual revenue § FY 2012 – provided $715M+ in charity care
16
CIRI Overview
Center for Transla%onal Research (CTR) • Discovery Research Network na%onal biospecimen collec%on & repository with EHR connec%vity
• Biomarker discovery, molecular diagnos%c development & valida%on
Center for Clinical Research (CCR) • Ownership and management of • Research/clinical trial opera%ons: single site, mul%-‐site, mul%-‐therapeu%c
• Research data warehouse connected to EHR and de-‐iden%fied pa%ent data/outcomes
Center for Healthcare Innova%on (CHCI) • Design and test innova%ons in care delivery
• Co-‐develop new technology and methods to manage popula%on health
17
Personalized Medicine
Clinical Opera%ons + EHR Research Environment
Popula%on Health Management
Executive Summary: The CHI/CIRI Research “Onion”
18
CCR
CTR
CHCI
CIRI Hospitals
Government
Academia
Industry Lab
Pharmacy
Radiology
Tumor Registry
Pathology
Cloud-based Informatics: Network Strength
Research Datamart
CCR CTR
Research Data
Analysis
19
Cloud-based informatics: Patient Data & Sample Annotation
Hospita
l Network
Digital Slide Images (QC) Staging – pTNM, cTNM
Images Radiology Reports
Genomic Data Blood Report
Demographics Clinical History Epidemiology
Drugs Interac%ons/Adverse Events
Consent & IRB Approval
Pre-‐Sampling Ischemic dura%on Chain of Custody
Anesthesia
outcomes
Lab
Radiology
ADT*
Tumor Registry
Pharmacy
Pathology
Post-‐Sampling Time to freeze samples
Type and %me of fixa%ve Tissue QC
ELECTRONIC HEALTH RECORD BIOREPOSITORY NETWORK
Drug and Biomarker Discovery
Protocol
De-Identified Data Warehouse
Biospecimen Variables
Tissue Report
Anesthesia Ischemic Time Time to Freeze
Tumor Staging Diagnosis % Tumor
% Necrosis
Image Data Demographics
MRI PET/CT Scan Image Report
Age Race
Gene Expression Profiling
Genotype/ Sequence Data
Affy Human Genome Expression Array
EGFR KRAS
Follow Up Data Treatment
Treatment Outcome Recurrence
Disease Status
Drugs Radiation Response
Pre-‐Acquisi%on Variables
Post-‐Acquisi%on Variables
*Admission/Discharge/Transfer
TRANSLATIONAL INFORMATICS
Bench to Bedside Translational Research
CTR
CCR
Benefits to CHI Hospitals
Clinical Trials
Personalized Medicine
Benefits to Pa%ents
Bener Drugs
Bener Diagnos%cs
Research Ques?ons
Hypothesis Generated
Hypothesis Tested
Results: IP &
Publica?ons Generated
Benefits
Research Data
21
Key Opinion Leaders
Physicians
Academic Researchers
CIRI Staff
Others
21
Study Design: An Integrated Approach
FFPE Sample
EHR data
Biosta%s%cal Analysis
Predic%ve Signature
Gene%c
Epigene%c
Environmental
22
Thank You