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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

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Taking research and development to the clinic issues for physicians

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
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
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

Using a Biomarker


Clinical utility
Clinical Utility

Does the biomarker improve clinical care?

  • Pharmacogenetics

  • Predictive testing

  • Faster or more precise diagnostics


Clinical utility1
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

Pharmacogenetics


Warfarin dosing
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
Int’l Warfarin PGx Consortium

N Engl J Med

360(8):753-764

February 19, 2009


Warfarin pgx clinical utility
Warfarin PGx Clinical Utility

  • Likely to achieve therapeutic dose faster

  • Relatively easy to order & receive results

  • Often covered by 3rd parties

  • Algorithm freely available

  • Improved efficacy & fewer adverse events?

    • Seems likely

    • Still being studied


Warfarin pgx clinical utility1
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
Drug Metabolism: CYP450

  • >50% of all drugs

  • Prodrug  Active Drug

  • Active  Inactive

  • Relevant Factors:

    • Other drugs

    • Diet & environment

    • Genetic variants


Cyp450 pgx clinical utility
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
Genetic Determinism

Belief that clinical outcomes are inexorably defined by genetic factors

Ignores:

  • Genetic/epigenetic modifiers

  • Environmental modifiers

  • Variable expression

  • Reduced penetrance


Predictive testing
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
Genetic Risk Assessment

  • Family History

    • Varies over time

  • DNA variants

    • Stable over time

    • Relative risk


Gwas genome wide association studies
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
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
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
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
The Fallacy of Genetic Determinism

Positive tests ≠ Disease

Negative tests ≠ Health


Clinical utility of genetic testing for common disease
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 disease1
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 disease2
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
PM Opportunities

  • Improved diagnostics

  • Improved therapeutics

  • Improved health maintenance

  • More efficient use of time

  • Lower health care costs

  • Patient & physician satisfaction


Pm challenges
PM Challenges

Clinician Education

  • Test indications

  • Test validity

  • Result interpretation

  • Clinical utility

  • Integration into clinical care


Clinician education
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 challenges1
PM Challenges

Test Validity

  • Transparency

    • Providers lack time & knowledge to evaluate

  • Regulation

    • Slows progress, limits access, ↑ cost

  • Paternalism vs. Autonomy


Pm challenges2
PM Challenges

Test Ordering & Payment

  • Facilitating ordering the correct test

  • DTC testing vs. physician gatekeeper

  • 3rd party payers

  • Paternalism vs. Autonomy


Pm challenges3
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 challenges4
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
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


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