1. Update: Topics Previously Presented to the CPSC Clinical Pharmacology Subcommittee (CPSC) of the Advisory Committee for Pharmaceutical Science November 3, 2004 Lawrence J. Lesko, Ph.D., FCP Director, Office of Clinical Pharmacology and Biopharmaceutics Center for Drug Evaluation and Research Food and Drug Administration

2. CPSC Established - May 2002 Established - May 2002 Members - selected for recognized expertise in 3 broad areas of clinical pharmacology Members - selected for recognized expertise in 3 broad areas of clinical pharmacology –Pharmacogenomics –Pharmacometrics –Pediatrics Prior Meetings – October 23, 2002; April 22-23, 2003; November 17-18, 2003 Prior Meetings – October 23, 2002; April 22-23, 2003; November 17-18, 2003

3. Topic: Identifying Patient Subgroups at Risk for Toxicity (11/02 and 4/03) Summary points Summary points –Proposed a quantitative method based on relative mean exposure in test (e.g., renal impairment) and reference populations (e.g., healthy volunteers), relative mean exposure in test (e.g., renal impairment) and reference populations (e.g., healthy volunteers), distribution of exposure values, and distribution of exposure values, and identification of critical cut-off values at high end of distribution curve based on E/R identification of critical cut-off values at high end of distribution curve based on E/R –Calculated probability of a clinically significant response –Proposed a standardized decision tree for dosing adjustments

4. Topic: Applications of Other Quantitative Methods for Dosing Adjustments (11/02 and 4/03) Summary points Summary points –Discussed linkage of population PK with clinical outcomes through examples with unresolved questions (drug-drug interactions) –Discussed E/R methodologies using M/S of AE probabilities through examples (drug-drug interactions) –Discussed decision analysis based on E/R methods for assessing QT risk in special population studies (e.g., elderly)

5. Topic: Identifying Patient Subgroups at Risk for Toxicity (11/02 and 4/03) Status = Implementation in NDA review Status = Implementation in NDA review –Proposed methods, or a variant of them, are routinely used in quantitative analysis of E/R data for efficacy and safety –Primary impact on OCPB recommendations for dosing adjustments in product label

6. Topic: Utility Function to Optimize Dosing Strategies (11/02 and 4/03) Summary points Summary points –Proposed to explore this methodology based on probability of either an AE or absence of toxicity, and magnitude of harm if AE and/or toxicity occurs Status = Postpone further development Status = Postpone further development –Underlying approach was assigning relative “weights” to efficacy and toxicity (e.g., marginal to significant), i.e., defining a TI –Asking clinicians, searching literature was unsatisfactory for defining targets/penalties

7. Topic: Use of E/R in the Pediatric Decision Tree (11/02 and 4/03) Summary points Summary points –Proposed design of a pediatric database to effectively extract new knowledge from in-house studies for revising the pediatric decision tree –Discussed the highest priority queries of such a database (e.g., modeling pediatric clearance as a function of age, adult PK and metabolism) –Proposed a systematic pediatric research project to 1) evaluate trends in E/R with age, 2) develop a standard approach to PPK, and 3) computer- aided pediatric template for study design

8. Topic: Use of E/R in the Pediatric Decision Tree (11/02 and 4/03) Status = Ongoing Status = Ongoing –Progress on database limited by both access to data in files and availability of standard PK and/or PD information –Proposed pediatric research project funded by CDER in June 2003 4 scientists have been hired under contract 4 scientists have been hired under contract steering committee has been established steering committee has been established research has commenced research has commenced 12 month milestones 12 month milestones

9. Topic: Genetic Polymorphism of TPMT (11/02 and 4/03) Summary points Summary points –Presented scientific and clinical evidence linking 3 different TPMT genotypes with incidence of myelosuppression –Discussed general framework for consideration of analytical validation, clinical validity and clinical utility for improving B/R –Discussed actions related to the revision of the label of 6MP including dosing adjustments based on genotypes

10. Topic: Genetic Polymorphism of TPMT (11/02 and 4/03) Status = Complete Status = Complete –July 2003 meeting of Pediatric Oncology Subcommittee recommended revision of 6MP label to include TPMT information in various sections –Negotiations with sponsor complete and updated label for both 6MP and AZA will be available in early 2005

11. Topic: Evaluation and Labeling of Drug Interactions of NMEs (4/03) Summary points Summary points –Presented an in vitro DDI decision tree for CYP enzymes and associated label language –Basis for policy decisions related to NDA review, label language and class distinctions –Discussed DDI studies involving P-GP and by extension transporters in general

12. Topic: Evaluation and Labeling of Drug Interactions of NMEs (4/03) Status = Complete Status = Complete –Revision of Guidance for Industry is near completion –Inclusion of topic and discussion point in OCPB GRP, DDI MAPP, and Cross-labeling MAPP

13. Topic: EOP2A Meetings (11/03) Summary points Summary points –Presented and received input on the goals, process, obstacles and metrics of success of the new EOP2 A meeting –Received input on concept paper intended to serve as basis of a Guidance for Industry Status = Ongoing Status = Ongoing –CDER has had 4 EOP2A meetings to date –From all indications, success and of value to both FDA and sponsors –Draft guidance has undergone internal review and anticipate final guidance in Q1 of 2005

14. Topic: Quantitative Analysis of QT (11/03) Summary points Summary points –M/S approaches and metrics for assessing QTc interval prolongation (maximal change from baseline, area under QTc-time curve etc) –Received input on methodologies being applied to review of NDA QT data Status = Ongoing Status = Ongoing –Approaching standardization of study design and data analysis –Recommendations to the CDER QT WG

15. Topic: Drug Interactions Involving CYP 2B6 and 2C8 (11/03) Summary points Summary points –Presentation of current understanding inhibition of CYP 2C8- and CYP 2B6-mediated interactions –Discussed in vitro – in vivo associations as a basis for guiding clinical DDI studies –Implications for model drugs (e.g., cerivastatin, rosiglitazone, efavirenz) Status = Ongoing Status = Ongoing –CPSC input seriously considered by CDER DDI WG in context of guidance revision

16. Reflections on the CPSC as a Forum or Mechanism for Science Discussion Topics - have been challenging – and diverse as the expertise of its members Topics - have been challenging – and diverse as the expertise of its members Topic Selection - new and important to NDA review (quantitative methods), cutting edge science (drug interactions) and/or have element of controversy (pharmacogenetics) Topic Selection - new and important to NDA review (quantitative methods), cutting edge science (drug interactions) and/or have element of controversy (pharmacogenetics) Value – tremendous, guidance on decision-making, recommendations on specific aspects of topics has influenced our clinical pharmacology program Value – tremendous, guidance on decision-making, recommendations on specific aspects of topics has influenced our clinical pharmacology program Voting – sometimes but primary benefit is from contributions of individual member discussion Voting – sometimes but primary benefit is from contributions of individual member discussion

17. Topics for November 3-4, 2004 Pharmacogenetics Pharmacogenetics –UGT1A1 polymorphism and its relation to the PGx of irinotecan Drug interactions Drug interactions –Metabolism- and transporter-based interactions relative to the revised Guidance of Industry Pharmacometrics Pharmacometrics –Critical path initiative related to greater use of biomarkers and their systematic progression to potential surrogate markers