1. Introduction to the Meeting Introduction to the Meeting Advisory Committee for Pharmaceutical Sciences Clinical Pharmacology Subcommittee November 17-18, 2003 Lawrence J. Lesko, Ph.D., FCP Office of Clinical Pharmacology and Biopharmaceutics, CDER, FDA

2. Review of Meetings to Date 1st: October 22-23, 2002 2nd: April 22-23, 2003 3rd: November 17-18, 2003 Input of the CPSC has had a significant impact on the progress made in each of the topic areas discussed at both of these meetings

3. Main Focus Has Been on Risk Risk assessment –science-based estimates of a risk faced by a special population under- and over-exposed to a drug treatment Risk management –taking action to reduce the risk through dosing adjustment or appropriate label language

4. New FDA Strategic Plan “…a key element of FDA’s new strategic plan is efficient risk management…” “…to use the best biomedical science to achieve our health policy goals…” “…to make new treatments and technology less risky, with greater predictability and less time from concept to bedside…” http://www.fda.gov/oc/mcclellan/strategic.html

5. Scope of Topics Quantitative Risk Analysis Using Exposure-Response Relationships Pediatric PK and Analysis of FDA Pediatric Database Pharmacogenetics: Improvement in Existing Therapies Metabolism- and Transport-Based Drug Interactions

6. Update on Topic Quantitative Risk Analysis Using Exposure- Response Relationships Basically finalized a systematic pharmacometric methodology to apply to dose adjustments –apply to efficacy and/or safety biomarkers and/or clinical endpoints, often taken together, to assess risk/benefit –integrating into routine NDA reviews and, in the future, early meetings with sponsors Evaluation of utility function is a work in progress –approaches discussed at prior meetings have raised awareness and issues –need future dialogue with physicians and statisticians

7. Today’s Meeting-Topic 1 Introduce a new proposal for an end-of-phase 2A (EOP2A) meeting between FDA and industry Discuss topics for this meeting revolving around evaluation of E-R and prospective dose selection Show case studies of E-R analysis from NDA reviews as models for EOP2A meetings

8. Today’s Meeting-Topic 2 Methodology for evaluating QT 1. Points-to-consider for PK-PD (QT) study design 2. Use of clinical trial simulation to optimize study design for PK-PD (QT) evaluation 3. Case study illustrating pharmacometric considerations arising from NDA review of QT data

9. Update on Topic Pediatric PK and Analysis of FDA Pediatric Database PPK study design template –basically complete and utilized as alternative to determining PK in pediatrics –further work on simulation to optimize number of samples, sampling times and number of patients Pediatric database analysis –retrospective evaluation has been challenging and not very successful incomplete datasets, non-optimal study designs etc –likely undertake more selective, case-by-case analysis of pediatric vs adult data

10. Today’s Meeting-Topic 3 Re-visit the clinical pharmacology principles of the pediatric decision tree with case studies Present a quantitative method to determine similarity in E-R relationships FDA perspective and an academic perspective on experience using the pediatric decision tree

11. Update on Topic Pharmacogenetics: Improvement in Existing Therapies Polymorphism in metabolizing enzymes that determine variability in drug exposure –focus CYP 2D6, 2C19, 2C9 and TPMT Additional discussion of TPMT and modification of thiopurine labels –pediatric subcommittee of ODAC in July 2003 many issues raised (need, cost, predictive value etc) recommended including PG information in label test should not be required before receiving drug

12. Today’s Meeting-Topic 4 Shift discussion to the question: what should be done in new drug development for substrates metabolized by polymorphic enzymes? Three expert perspectives: academic, industry and clinician Discussion will influence recommendations in a general pharmacogenetic guidance under development

13. Update on Topic Metabolism- and Transport-Based Drug Interactions Introduced topic as foundation for subsequent discussion –increased awareness of emerging mechanisms of drug interactions and what to do about them –revision of drug interaction guidance in progress

14. Today’s Meeting-Topic 5 Get more specific: what should be done to in consideration of new drug interactions of emerging clinical importance Expert opinion on evaluation of CYP 2B6- and CYP 2C8-based metabolic drug interactions Discussion will impact future regulatory advice on these issues

15. Summary We are asking for CPSC input and advice on 5 separate topics Specific questions to focus discussion will accompany each topic We are confident that your input will help us improve and refine our thinking about these topics