Taking Research and Development to the Clinic: Issues for Physicians AAAS/FDLI Colloquium I Diagnostics and Diagnoses Paths to Personalized Medicine Howard Levy, MD, PhD Johns Hopkins University June 1, 2009

What is Personalized Medicine? Biomarkers and genetic tests Customization of medical care to the individual patient All aspects of carenot 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 Utility Does the biomarker improve clinical care? Pharmacogenetics Predictive testing Faster or more precise diagnostics

Clinical Utility What 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

Intl Warfarin PGx Consortium N Engl J Med 360(8): February 19, 2009

Warfarin PGx Clinical Utility Likely to achieve therapeutic dose faster Relatively easy to order & receive results Often covered by 3 rd parties Algorithm 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 Its tough to make predictions, especially about the future -Dan Quayle, Casey Stengel, et al. The future aint 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 1000s 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 SNPs: OR (usually ) Family History: intermediate

Heritability Proportion of disease predisposition that is due to inherited factors SNPssmall 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 2 o 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 3 rd 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