1. Pharmacogenetics: Global Regulatory Issues ASENT 13 th Annual Meeting Bethesda, MD February 26, 2011 Issam Zineh, PharmD, MPH Associate Director for Genomics Office of Clinical Pharmacology Center for Drug Evaluation and Research/US FDA

2. 2 Overview What is Pharmacogenetics and Why Do We Care? Policy, Drug Development, and (a few) Regulatory Question Marks Race, Ethnicity, and Variable Drug Response Summary and Conclusions These are my views and not necessarily FDA’s; no conflicts of interest to report.

3. 3 Problem Statement: Predicting Drug Response is a Game of Chance Modified from Spear at al 2001 [PMID 11325631] Effectiveness Rate

4. 4 Pharmacogenomics/genetics Pharmacogenomics (PGx): The study of variations of DNA and RNA characteristics as related to drug response. Pharmacogenetics (PGt): A subset of PGx; the study of variations in DNA sequence as related to drug response. ICH E15: Definitions for Genomic Biomarkers, Pharmacogenomics, Pharmacogenetics, Genomic Data and Sample Coding Categories. April 2008.

5. 5 Kola and Landis 2004 [PMID 15286737] | Arrowsmith 2011 [PMID 21283095] 60% 37% 50% Why Else Do We Care?

6. 6 Calendar years; NDAs and BLAs include supplements CDER Genomics Group Review Activity: 2008 - 2010

7. 7 Regulatory Guidance 2005Guidance on PG Data Submissions Concept Paper on Drug-Diagnostic Co-Development 2007Companion Guidance on PG Data Submissions Guidance on PG Tests and Genetic Tests for Heritable Markers 2010ICH E16 Concept Paper on PG Biomarker Qualification: Format and Data Standards Guidance on Chronic Hepatitis C Virus Infection: Developing Direct-Acting Antiviral Agents for Treatment Guidance on Qualification Process for Drug Development Tools 2011Guidance on Clinical PG: Premarketing Evaluation in Early Phase Clinical Studies PreparationGuidance on Clinical Trial Designs Employing Enrichment Designs to Support Approval of Human Drugs and Biological Products

8. 8 FDA and EMA Position on PG in Early Phase Trials ConditionFDAEMA Collect and retain DNA ◘◘ Consent for exploratory studies ◘□ Polymorphic metabolism (major) – pro/retrospective ◘■ Variable PK, safety concerns, ethnic differences, prodrugs – pro/retrospective ◘◘ + PG interaction (PK or PD) – prospectively exclude, dose-adjust, stratify ◘■ Genome-wide/ comprehensive ADME genotyping ◘◘ Retrospective exposure/response, population PK ◘◘ DDI studies – exclude poor metabolizers ◘◘ ■ required ◘ recommended □ not addressed

9. 9 Pharmacogenomic Maneuvers in Drug Development Experimental evidence for PGx interaction Restricted FIH/DDI/HV trials Enriched/ stratified trials* ---------- Optimize efficacy - - - Minimize risk ---------- Stratified dosing Labeling Phase 4Phase 3Phase 2Phase 1Nonclinical Major polymorphic pathways Stratified dose-finding ADME Intrinsic/ extrinsic factors Safety Metabolism, transport Drug-target interactions Nonclinical safety Efficacy Safety D/R, C/R Intrinsic/ extrinsic factors KnowledgeKnowledge * Can also be retrospectively derived

10. 10 Dosing 1.Under what circumstances should we prospectively require genotype-guided dosing (e.g., risk-based)? 2.Are retrospective/population PK analyses adequate to guide PGx-dosing decisions? 3.How do we accrue an adequate safety database in Phase 1/2 to inform Phase 3 design and dosing decisions? 4.Co-development imperative?

11. 11 Subgroups, Stratification, Enrichment, Safety 1.At what point does the Agency determine what is “prospective-retrospective” (considering missing data, bias, multiplicity and confounding)? 2.How can claims of superiority be obtained for drug responder subgroups (or nonresponders to the comparator)? 3.When is stratified randomization and fallback testing indicated, preferred? 4.How much data are needed in the “biomarker- negative” subgroup to support the biomarker’s utility? 5.How much confirmatory evidence is required for safety biomarkers relative to efficacy biomarkers?

12. 12 Overview What is Pharmacogenetics and Why Do We Care? Policy, Drug Development, and (a few) Regulatory Question Marks Race, Ethnicity, and Variable Drug Response Summary and Conclusions These are my views and not necessarily FDA’s; no conflicts of interest to report.

13. 13 Race/Ethnicity as an Added Dimension Huang and Temple 2008 [PMID 18714314]

14. 14 Taylor et al 2004 [PMID 15533851] BiDil: Meditations on Race and Ethnicity ↓43%

15. 15 Is it Wrong to “Biologize” Race? Not understanding the reasons for the difference in treatment effect by race did not justify withholding the treatment from those who could benefit from it. –Imperfect, crude proxy (but temporarily useful) –FDCA requirement for effectiveness Race and other demographic characteristics have long been important to consider in analysis of trials and as a matter of equity and justice. –Subgroup analyses per guidance –Differences are expected Temple and Stockbridge 2007 [PMID 17200223]

16. 16 Race/Ethnicity may be a Proxy for Drug Response Heritability pharmgkb.org CYP2C19 PMs 2% Caucasian 4% AA 14% Chinese BiDil Marker 40% Caucasian 68% AA 87% African

17. 17 Maximizing the Explanatory Power of Genetics Heterogeneity in drug response, exposure, or AEs by race and/or study country is not uncommon –Trial designs –Eligibility criteria –Patient characteristics –Differences in SOC or background treatment –Differences in prevalence of important gene variants Particularly relevant in global research ICH E15 –Characterization in a population relevant to the new region of the PK, and where possible, PD and dose response for PD endpoints. This characterization could be performed in the foreign region in a population representative of the new region or in the new region. ICH E15: Ethnic Factors in the Acceptability of Foreign Data

18. 18 Summary Genetic variability is determinant of variable drug response Race, ethnicity, and genetic background are related and important considerations in drug development (e.g., in interpretation of data from and planning of “foreign” trials) Regulatory policy and drug development practices are evolving with respect to PGx The hope is to enhance product development, regulatory review, and clinical use These are my views and not necessarily FDA’s; no conflicts of interest to report.

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