Update Topics Previously Presented to the CPSC Clinical

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

CPSC n n n Established - May 2002 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

Topic: Identifying Patient Subgroups at Risk for Toxicity (11/02 and 4/03) n Summary points – Proposed a quantitative method based on n relative mean exposure in test (e. g. , renal impairment) and reference populations (e. g. , healthy volunteers), distribution of exposure values, and 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

Topic: Applications of Other Quantitative Methods for Dosing Adjustments (11/02 and 4/03) n 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)

Topic: Identifying Patient Subgroups at Risk for Toxicity (11/02 and 4/03) n 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

Topic: Utility Function to Optimize Dosing Strategies (11/02 and 4/03) n n 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 – 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

Topic: Use of E/R in the Pediatric Decision Tree (11/02 and 4/03) n 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) computeraided pediatric template for study design

Topic: Use of E/R in the Pediatric Decision Tree (11/02 and 4/03) n 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 n n 4 scientists have been hired under contract steering committee has been established research has commenced 12 month milestones

Topic: Genetic Polymorphism of TPMT (11/02 and 4/03) n 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 6 MP including dosing adjustments based on genotypes

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

Topic: Evaluation and Labeling of Drug Interactions of NMEs (4/03) n 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

Topic: Evaluation and Labeling of Drug Interactions of NMEs (4/03) n 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

Topic: EOP 2 A Meetings (11/03) n n Summary points – Presented and received input on the goals, process, obstacles and metrics of success of the new EOP 2 A meeting – Received input on concept paper intended to serve as basis of a Guidance for Industry Status = Ongoing – CDER has had 4 EOP 2 A 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 Q 1 of 2005

Topic: Quantitative Analysis of QT (11/03) n n 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 – Approaching standardization of study design and data analysis – Recommendations to the CDER QT WG

Topic: Drug Interactions Involving CYP 2 B 6 and 2 C 8 (11/03) n n Summary points – Presentation of current understanding inhibition of CYP 2 C 8 - and CYP 2 B 6 -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 – CPSC input seriously considered by CDER DDI WG in context of guidance revision

Reflections on the CPSC as a Forum or Mechanism for Science Discussion n n 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) 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

Topics for November 3 -4, 2004 n n n Pharmacogenetics – UGT 1 A 1 polymorphism and its relation to the PGx of irinotecan Drug interactions – Metabolism- and transporter-based interactions relative to the revised Guidance of Industry Pharmacometrics – Critical path initiative related to greater use of biomarkers and their systematic progression to potential surrogate markers