Pharmacogenetics: Global Regulatory Issues

1. Pharmacogenetics: Global Regulatory Issues ASENT 13th 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. 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. Problem Statement: Predicting Drug Response is a Game of Chance Effectiveness Rate Modified from Spear at al 2001 [PMID 11325631]

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

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

7. Regulatory Guidance

8. FDA and EMA Position on PG in Early Phase Trials ■ required ◘ recommended □ not addressed

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

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

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

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

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

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

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. 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.