1. Introduction to the Topics Lawrence J. Lesko, Ph.D., FCP Office of Clinical Pharmacology Center for Drug Evaluation and Research Food and Drug Administration Advisory Committee for Pharmaceutical Sciences Clinical Pharmacology Subcommittee October 18-19, 2006 Rockville, Maryland

2. Efficacy Pharmacogenetics of Tamoxifen Topic #1

3. One Size Fits All? Industry, regulatory agencies, physicians and patients want a better understanding of which patients should receive which drugs Once that decision is made, we want to know which patient should receive which dose Critical to understand the concept of exposure Lazarou J, Pomeranz BH and Corey PN; JAMA, 1998; 279:1200-1205

4. Dose of a drug is a poor predictor of response Drug therapy is individualized based on age, sex, body weight, diet, drug interactions and organ function Initial choice of a drug, and the dosage regimen, is determined by estimating the exposure and PK properties of the drug in an individual patient If situations lead to higher or lower exposure, product labels recommend dose reductions or dose increases Genetic variants of CYP can enzymes result in 10-100-fold differences in exposure compared to nongenetic factors First Principles of Drug and Dose Selection: The Exposure Concept

5. Application to Label Updates: Framework of Criteria Clear definition of phenotype Phenotype is serious and relatively common Strong genotype-phenotype relationship Sufficient sample size to identify relevant variants Plausible mechanistic (biological) hypothesis Adequate evidence of association –Retrospective, observational case-control studies –Data reflective of real-world practice –Prescribers practice according to standard of care –Analytical validation of genotype –Potential bias introduced by unmeasured factors –Consistency across studies and demographics

6. Regulatory Basis for Adding Genetic Tests to Label “If evidence is available to support the safety and effectiveness of the drug only in selected subgroups of the larger population with a disease, the labeling shall describe the evidence and identify specific tests needed for selection and monitoring of patients who need the drug.” - 21 CFR 201.57

7. Drugs and Recommendations for Label Updates at Prior Meetings Drug or Drug Class Polymorphic Enzyme Advisory Committee Action Taken Consequence of Genotype 6-MPTPMT CPSC, 11/03 Label Updated Risk of Toxicity IrinotecanUGTCPSC, 11/04 Label Updated Risk of Toxicity Warfarin CYP 2C9 and VKORC1 CPSC, 11/05 Label Being Updated Risk of Toxicity

8. Update on Warfarin Re-Labeling Committee voted almost unanimously to recommend updating the warfarin label with 2C9 and VKORC1 information WARNING: BLEEDING RISK [Added to label at request of FDA on October 6, 2006] Warfarin sodium can cause major or fatal bleeding. Bleeding is more likely to occur during the starting period and with a higher dose (resulting in a higher INR). Risk factors for bleeding include high intensity of anticoagulation (INR >4.0), age ≥65, highly variable INRs, history of gastrointestinal bleeding, hypertension, cerebrovascular disease, serious heart disease, anemia, malignancy, trauma, renal insufficiency, concomitant drugs (see PRECAUTIONS), and long duration of warfarin therapy. Regular monitoring of INR should be performed on all treated patients. Those at high risk of bleeding may benefit from more frequent INR monitoring, careful dose adjustment to desired INR, and a shorter duration of therapy. Patients should be instructed about prevention measures to minimize risk of bleeding and to report immediately to physicians signs and symptoms of bleeding (see PRECAUTIONS: Information for Patients). http://www.fda.gov/medwatch/safety/2006/coumadin_PI_april2006.pdf and http://www.fda.gov/medwatch/safety/2006/coumadin_medguide.pdf

9. What About the 2C9 and VKORC1 Information? Final stage of negotiating label language to include genetic information in Coumadin R label as recommended by CPSC –We hope to accomplish this within next 3 months Numerous clinical trials planned or launched to validate dosing algorithms and study clinical outcomes* Several diagnostics companies have launched 2C9 and VKORC1 tests –No FDA-approved tests at the present time * Tham L., Goh B, Nafziger, A et al, Clin Pharmacol Ther 2006; 80(4), 346-355.

10. Designing an Effective Risk Communication Strategy What is the most effective way for communicating issue-specific risks to patients and health care providers? –How do they apply to drugs? genetics? Exploring focused risk communication strategies internally at FDA –Example: Information sheets for health care providers that contain information also useful to patients Work in progress and further discussions are planned –May discuss at future CPSC

11. Topic #2 Drug Transporters Interactions

12. Background We have the ability to predict drug-drug interactions at the CYP level as a risk management strategy This has facilitated drug development and regulatory decision-making –Determine if NME is an inhibitor of, or a substrate for, CYP enzymes –Decide if an in vivo study is needed or not for labeling purposes –If an in vivo study is necessary Determine what substrates should be given with the NME Determine what inhibitors should be given with the NME Guidance for Industry: Drug Interaction Studies (Draft) published on September 11, 2006 http://www.fda.gov/cder/guidance/6695dft.pdf

13. Transporters Knowledge of transporters in major organs and tissues and their role has dramatically increased Challenges for NME development –Which transporters are important and should be studied? –Do transporter and enzyme interactions co-exist? –Can drugs interact through multiple transporters? –Can in vitro studies obviate need for in vivo studies? –What are best probe transporter substrates and inhibitors? Several previously unexplained, clinically important drug-drug interactions can now be explained by transporter mechanisms

14. Topic #3 Drug-Disease-Placebo Models

15. Background End-of-Phase 2A concept paper published by FDA October 16, 2003 –Commenced a 2 year pilot project period with up to 24 EOP2A meetings between sponsors and FDA Data package and analysis should include –E/R analysis for safety and efficacy –Quantitative modeling and simulation of clinical trials –Analysis of disease progression There have been about 10-12 EOP2A meetings –Motivated development of drug-disease models in 8 or so different diseases http://www.fda.gov/ohrms/dockets/ac/03/briefing/3998B1_01_Topic%201-Part%20A.pdf

16. Disease Progression Models Many traditional drug approvals based on partial or full relief of disease symptoms Both new and old drugs can modify disease processes that cause clinical phenotypes –Mechanisms may not always be understood –They can potentially slow or halt disease progression How can disease models be built and data analyzed to document evidence of effect on disease progression? –Placebo response data, different time points of measuring response, new mathematical approaches to analyze longitudinal changes in biomarkers or clinical outcomes

17. Parkinson’s Disease Tremor Rigidity Akinesia Postural changes. How Can One Detect and Analyze Changes in the Unified Parkinson Disease Rating Scale (UPDRS) Total Score As Evidence of Slowing or Halting Disease Progression?

18. Thanks for you attention lawrence.lesko@fda.gov.hhs