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

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

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

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

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

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 VKORC1 Genotype 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

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  

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

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