Post on 10-Dec-2015
transcript
Taking Research and Development to the Clinic:
Issues for PhysiciansAAAS/FDLI Colloquium I
Diagnostics and DiagnosesPaths to Personalized Medicine
Howard Levy, MD, PhDJohns Hopkins University
June 1, 2009
What is Personalized Medicine?
• Biomarkers and genetic tests
• Customization of medical care to the individual patient
• All aspects of care—not just biomarkers, not just genetics
Challenges & Opportunities
Self-evident truths:
• Physicians want to help patients
• Time & resources are scarce
Can biomarkers improve both?
Using a Biomarker
• Select a test
• Order a test
• Get it paid for
• Get it done
• Receive result
• Understand result
• Archive result
• Access result
(now & future)
• Apply result in clinical care
Clinical UtilityDoes the biomarker improve clinical care?
• Pharmacogenetics
• Predictive testing
• Faster or more precise diagnostics
Clinical UtilityWhat are the costs?
• Financial
• Time/Resources
• Social/Ethical/Legal
• Medical (incorrect conclusions)
• Psychological
Pharmacogenetics
• The right drug
• At the right time
• In the right dose
• ↑ Efficacy• ↓ Adverse events
Warfarin Dosing
• Fixed-dose
• Clinical algorithm (weight, age, sex) This is personalized medicine!
• Pharmacogenetic (VKORC1 & CYP2C9) PGx explains ~40% of dose variability Clinical + PGx explains ~54% of variability
Warfarin PGx Clinical Utility
Likely to achieve therapeutic dose fasterRelatively easy to order & receive resultsOften covered by 3rd partiesAlgorithm freely available
• Improved efficacy & fewer adverse events? Seems likely Still being studied
Warfarin PGx Clinical Utility
Limitations:
• Needs to be done promptly at initiation of therapy
• ~45% of dose variability unexplained
• Environmental factors remain important
Drug Metabolism: CYP450
• >50% of all drugs
• Prodrug Active Drug
• Active Inactive
• Relevant Factors: Other drugs Diet & environment Genetic variants
CYP450 PGx Clinical Utility
• Genetic testing is available
• Is PGx testing better than trial & error?
• Drug choice & dosing recommendations?
• What if there are no alternatives? Psychological distress Relative risk Genetic determinism
Genetic Determinism
Belief that clinical outcomes are inexorably defined by genetic factors
Ignores: Genetic/epigenetic modifiers Environmental modifiers Variable expression Reduced penetrance
Predictive Testing
“It’s tough to make predictions, especially about the future”-Dan Quayle, Casey Stengel, et al.
“The future ain’t what it used to be”-Yogi Berra
Genetic Risk Assessment
• Family History Varies over time
• DNA variants Stable over time Relative risk
GWAS: Genome-Wide Association Studies
• Really BIG case-control study 1000’s of subjects 500,000 to 1,000,000 SNPs
• Power to detect small effect sizes
• Subject to same errors & biases as any other epidemiologic study
CAD Risk Assessment:Gene ↔ Environment
• Smoking, HTN, DM, etc: OR ≈ 10-20
• SNPs: OR ≈ 1.2-2.0 (usually 1.2-1.3)
• Family History: intermediate
Heritability
• Proportion of disease predispositionthat is due to inherited factors SNPs—small amount Other heritable factors
(DNA & Non-DNA variants)
• Current tests assess only a small portion of heritability
Analytical & Clinical Validity
• Is the test accurate?
• Does the biomarker correlate clinically (retrospective vs. prospective study)?
• How are results of multiple tests combined?
• Validity is often assumed when test is offered clinically.
Clinical Utility of Genetic Testing for Common Disease?
• What do the results mean?
• Small effect size
• Environmental factors
• Fallacy of genetic determinism
• Undue anxiety/false reassurance?
Clinical Utility of Genetic Testing for Common Disease?
• Modify therapy to reduce risk?
• Motivation to change behavior? Smoking, exercise & diet campaigns Does the Personalized Medicine
model work?
Clinical Utility of Genetic Testing for Common Disease?
• Cost
• Large amounts of clinical data
• Paucity of tools to integrate data
• Uncertain plan of action
• May be appropriate for some patients
PM Opportunities
• Improved diagnostics
• Improved therapeutics
• Improved health maintenance
• More efficient use of time
• Lower health care costs
• Patient & physician satisfaction
PM Challenges
Clinician Education• Test indications
• Test validity
• Result interpretation
• Clinical utility
• Integration into clinical care
Clinician Education
Learning Preferences
• Clinically relevant
• Just in time (point of care)
• Fast (<2 minutes)
• Increasingly Internet-based
• 2o sources (authority vs. accuracy)
• GeneFacts
PM Challenges
Test Validity• Transparency
Providers lack time & knowledge to evaluate
• Regulation Slows progress, limits access, ↑ cost
• Paternalism vs. Autonomy
PM Challenges
Test Ordering & Payment• Facilitating ordering the correct test
• DTC testing vs. physician gatekeeper
• 3rd party payers
• Paternalism vs. Autonomy
PM Challenges
Receiving, Archiving and Accessing Results
• EHRs Can also prompt provider to order/use tests
• PHRs
• Information sharing between providers Does the data already exist?
• Privacy & Security
PM Challenges
Clinical Utility• Better assessment of health factors
Genetic Environmental
• Better tools to combine environment, family history & biomarkers
• Studies of actual clinical outcomes (Hype Hope Reality)