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

Int’l Warfarin PGx Consortium

N Engl J Med360(8):753-764February 19, 2009

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.

The Fallacy of Genetic Determinism

Positive tests ≠ Disease

Negative tests ≠ Health

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)

The Art of Medicine• Evidence-based medicine

Based on population studies

• Individual people Autonomous Variably reliable Ever-changing environment

• Personalized Medicine Requires knowing & monitoring the patient

and therapy at the individual level