Raju Kucherlapati, Ph.D.

Harvard Medical School

Partners Healthcare

Genetics and Genomics in Clinical Medicine

Healthcare Issues

Healthcare costs are rising rapidlyCosts of drug development at all

time highEstimated cost of a new drug 800 MM

Drugs are not effective in all patientsSome cancer drugs are effective in less than 20% of patients

Drug related adverse events are a major cause of ER visits

Even when drugs are effective severe adverse reactions can cause major problems

GENETICS AND GENOMICS CAN HELP

“I believe we are moving into a remarkable and powerful new era in medicine and particularly in prescription drugs. I’d refer to it as an era of personalized medicine.”

Michael Leavitt, Secretary HHS January 18, 2005

National Thought Leaders on Personalized Medicine

What is Personalized Medicine?

The right drug or treatment, at the right time, for the right patient, at the right

cost everytime

Personalized medicine requires genetic or other type of testing

How fast the test results are available becomes critical

Future of Medical Care

• A revolution in medical practice and care has to take place• Personalized Medicine is a part of this revolution• Some would consider the notion of Personalized Medicine to

be similar to many earlier disruptive technologies such as color television and personal computers

• Implementation of Personalized Medicine would require changes in many paradigms that include• More discoveries• Effectiveness• Support of Regulatory agencies• Positive cost/benefit ratio• Rapid test results• Physician and Public Education• Effective IT support to manage and interpret results

August 2007

Genome-Wide Association Analysis Identifies Loci for Type 2 Diabetes and Triglyceride LevelsDiabetes Genetics Initiative of Broad Institute of Harvard and MIT, Lund University, and Novartis Institutes of BioMedical Research et al

Discoveries are becoming more rapid

Effectiveness

Effectiveness can be measured by clinical data

Retrospective studies

Prospective clinical trials

Examples of a prospective clinical trails

For new drugs – Herceptin, Gleevec

For approved drugs - Warfarin

Genetics of Warfarin dosing

More than 20 million prescriptions of Warfarin every year and 2 million new patients/year are prescribed Warfarin. It is the most effective oral anticoagulant drug

Warfarin anticoagulation is prescribed to achieve a target INR. Excessive dosing precipitates hemorrhage. Inadequate dosing predisposes to stroke and pulmonary embolism. Dosing nomograms work poorly. Trial and error predominates.

CYP 2C9 VKORC1Genotype Dose Haplotype Dose*1/*1 7.2 mg A/A 2.7 mg

*1/*2 4.1 mg A/B 4.9 mg *1/*3

*2/*2 1.4 mg B/B 6.2 mg*2/*3

*3/*3

We are now conducting a clinical trial to test the hypothesis

August 16, 2007  

PERSONAL DOSEIn Milestone, FDA PushesGenetic Tests Tied to DrugAgency Seeks to TameRisks of Blood Thinner;Some Doctors ProtestBy ANNA WILDE MATHEWSAugust 16, 2007; Page A1

Regulatory Activity

FDA Approves Label Change for Warfarin

FDA Approves Genetic Testing Labeling For Blood-thinning Drug

August 18, 2007

"Today's approved labeling change is one step in our commitment to personalized medicine. By using modern science to get the right drug in the right dose for the right patient, FDA will further enhance the safety and effectiveness of the medicines Americans depend on,"

Andrew C. von Eschenbach, M.D.Commissioner of FDA

Cost/Benefit Analysis for Warfarin testing

“We estimate that formally integrating genetic testing into routine warfarin therapy could allow American warfarin users to avoid 85,000 serious bleeding events and 17,000 strokes annually. We estimate the reduced health care spending from integrating genetic testing into warfarin therapy to be $1.1 billion annually, with a range of about $100 million to $2 billion.”

Andrew McWilliam, Randall Lutter and Clark Nardinelli Office of Policy and Planning at the FDA

AEI-BROOKINGS JOINT CENTER FOR REGULATORY STUDIES November 2006

Time to Getting Test Results

For Warfarin testing turn around times are 7-10 days

Too late for clinical dosing decisions

Need to have answers within 24 hours, preferably a few hours

Ideal situation is POC diagnostic or a local lab that provides results fast

Need to get the result into the electronic medical record

Need to provide a dosing recommendation

We now provide Warfarin test results within 24 hours

Genetic data in EMR

Test Results in EMR

First Genetics Based Clinical Decision Support Rule

The Ultimate Goal

Genetic variation

Genetic expression

Proteomic expression

Personalized Healthcare

The patient has disease X, subclass Y, which will likely respond to drug Z

Clinical data

Megabytes – Gigabytes

of Data Per Patient