1. Genetics and Genomics in Clinical Medicine
Raju Kucherlapati, Ph.D.
Harvard Medical School
Partners Healthcare

2. GENETICS AND GENOMICS CAN HELP
Healthcare Issues
Healthcare costs are rising rapidly
Costs of drug development at all time high
Estimated cost of a new drug 800 MM
Drugs are not effective in all patients
Some 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

3. National Thought Leaders on Personalized Medicine
“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

4. 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

5. 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

6. Discoveries are becoming more rapid
August 2007
Genome-Wide Association Analysis Identifies Loci for Type 2 Diabetes and Triglyceride Levels
Diabetes Genetics Initiative of Broad Institute of Harvard and MIT, Lund University, and Novartis Institutes of BioMedical Research et al

8. 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

9. 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 2C VKORC1
Genotype Dose Haplotype Dose
*1/* mg A/A 2.7 mg
*1/* mg A/B 4.9 mg
*1/*3
*2/* mg B/B 6.2 mg
*2/*3
*3/*3
We are now conducting a clinical trial to test the hypothesis

10. Regulatory Activity
PERSONAL DOSE In Milestone, FDA Pushes Genetic Tests Tied to Drug
Agency Seeks to Tame Risks of Blood Thinner; Some Doctors Protest
By ANNA WILDE MATHEWS August 16, 2007; Page A1
August 16, 2007

11. 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

12. 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

13. 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

14. Genetic data in EMR

15. Test Results in EMR

16. First Genetics Based Clinical Decision Support Rule

17. Personalized Healthcare
The Ultimate Goal
Clinical data
Personalized Healthcare
Genetic variation
Megabytes – Gigabytes
of Data Per Patient
Genetic expression
The patient has disease X, subclass Y, which will likely respond to drug Z
Proteomic expression