1. Age, Race and Sex Subgroup Analysis: Review of Drug Protocols Submitted to the FDA Pellavi Sharma, MPH, Ellen Pinnow, MS, Theresa Toigo, RPh, Janelle Derbis PharmD, Pamela Scott, Ph.D., Kathleen Uhl, M.D. FDA Office of Women’s Health and Office of Special Health Issues November 2007

2. Disclaimer The views expressed in this presentation are solely the views of the presenter. They do not represent the Food and Drug Administration.

3. FDA Regulations Require Investigational New Drug applications (IND) annual reports to include the number of patients entered into studies to date, stratified by gender, age, and race. (21 CFR 312.33) Investigational New Drug applications (IND) annual reports to include the number of patients entered into studies to date, stratified by gender, age, and race. (21 CFR 312.33) New Drug Applications (NDAs) to present safety and efficacy date by gender, age, and race. (21 CFR 314.50(d)(5)(v) and (vi)(a) New Drug Applications (NDAs) to present safety and efficacy date by gender, age, and race. (21 CFR 314.50(d)(5)(v) and (vi)(a)

4. FDA Policy Analysis of subpopulations are called for in many other documents. Analysis of subpopulations are called for in many other documents. 1988 FDA Guideline on the Format of Clinical and Statistical sections of NDAs 1988 FDA Guideline on the Format of Clinical and Statistical sections of NDAs 2005 FDA Race and Ethnicity Guidance 2005 FDA Race and Ethnicity Guidance 2005 FDA Conducting a Clinical Safety Review Guidance 2005 FDA Conducting a Clinical Safety Review Guidance ICH (International Conference on Harmonization) E-3 provisions ICH (International Conference on Harmonization) E-3 provisions ICH Common Technical Document Guidance ICH Common Technical Document Guidance

5. 1992 GAO Report Women’s Health: FDA Needs to Ensure More Study of Gender Differences in Prescription Drug Testing Women’s Health: FDA Needs to Ensure More Study of Gender Differences in Prescription Drug Testing Concluded that data were not often analyzed for gender differences. Concluded that data were not often analyzed for gender differences. Source: http://archive.gao.gov/d35t11/147861.pdf

6. 2001 GAO Report Women Sufficiently Represented in New Drug Testing but FDA Oversight Needs Improvement Women Sufficiently Represented in New Drug Testing but FDA Oversight Needs Improvement Discovered that half of the data submitted to FDA did not conduct these analyses. Discovered that half of the data submitted to FDA did not conduct these analyses. Source: http://www.gao.gov/new.items/d01754.pdf

7. Literature Review Multiple studies highlight that preplanning subgroup analyses will: Multiple studies highlight that preplanning subgroup analyses will: Ensure enough power Ensure enough power Conduct these analyses Conduct these analyses Clinically justified Clinically justified Provide further hypothesis for study Provide further hypothesis for study Can adjust dose and monitor adverse events Can adjust dose and monitor adverse events

8. Literature Review (2) Post-hoc subgroup analysis pose more challenges Post-hoc subgroup analysis pose more challenges Validity Validity Interpretation Interpretation Insufficient documentation Insufficient documentation

9. Purpose The purpose of this study was to determine if protocols submitted to the FDA, included a plan to conduct subgroup analysis. The purpose of this study was to determine if protocols submitted to the FDA, included a plan to conduct subgroup analysis.

10. Regulatory Process Preclinical Testing IND Submitted to FDA Clinical Testing NDA Submitted to FDA for review and approval Lab & animal studies Phase 1: Determine safety & dose Phase 2: Efficacy & side effects Phase 3: Monitor adverse rxns from long-term use Assess safety & biological activity 70% of drugs pass 33%27%20% 1-3 yrs Avg. 18 mths. 30 Day Review Range 2-10 yrs Avg. 5 yrs for all phases total 2 mths-3 yrs Avg. 24 mths Women’s Health: FDA Needs to Ensure More Study of Gender Differences in Prescription Drug Testing Source 1992 GAO Report Women’s Health: FDA Needs to Ensure More Study of Gender Differences in Prescription Drug Testing

11. Methods 883 protocols submitted between Jan 1, 2002 and April 30, 2002 883 protocols submitted between Jan 1, 2002 and April 30, 2002 Excluded Excluded 99 Male only or female only indications 99 Male only or female only indications 59 Pediatric indications 59 Pediatric indications 13 Draft protocols 13 Draft protocols 56 protocols who planned to enroll men only or women only 56 protocols who planned to enroll men only or women only 437 Early phase trials due to small sample size 437 Early phase trials due to small sample size Examined remaining 219 protocols to determine if subgroup analysis was planned a priori Examined remaining 219 protocols to determine if subgroup analysis was planned a priori

12. Methods (2) Reviewed protocols to determine If subgroup analysis was planned If subgroup analysis was planned If specific subgroup analyses were planned including: If specific subgroup analyses were planned including: Sex Sex Race Race Age Age Study site Study site What statistical methods, if any, were outlined in protocols conducting analysis What statistical methods, if any, were outlined in protocols conducting analysis

13. Protocols that planned a subgroup analysis One or more subgroup analyses planned 48 (21.9%) Sex Analysis 20 (9%) Race and Ethnic Group Analysis 9 (4.1%) Age Analysis 17 (7.8%) Study Site Analysis 18 (8.2%) Results

14. Results (2) Planned Sample Size Number of studies planning any subgroup analysis Greater than 200 34 out of 48 studies 81 to 200 9 studies 20 to 80 4 studies 1 study did not report a sample size

15. Results (3) Study Phase Number of studies planning any subgroup analysis Phase 2 1 study (2.0%) Phase 3 43 studies (89.5%) Phase 4 4 studies (8.3%)

16. Results (4) Anti-Infectives 10 protocols (0%) Anti-Viral 6 protocols (0%) Metabolic & Endocrine 26 protocols (0%) Oncology 16 protocols (0%) Pulmonary 12 protocols (0%) Medical Imaging & Radiopharmaceutical 3 protocols (0%) * Not specifying doesn’t imply that subgroup analysis was not undertaken by sponsors. No Prospectively Planned Subgroup Analysis

17. Results (5) Neuropharmacologic 37 protocols (13.5%) Cardio-Renal 26 protocols (4.2%) Anti-Inflammatory 22 protocols (13.7%) Anesthetic, Critical Care, Addiction 19 protocols (26.3%) Dermatologic & Dental 18 protocols (16.7%) G.I. & Coagulation 11 protocols (9.1%) Special Pathogen & Immunologic 11 protocols (9.1%) Reproductive & Urologic 3 protocols (25%) Prospectively Planned Subgroup Analysis

18. Results (6) Methodology varied among protocols Methodology varied among protocols Planned descriptive analyses Planned descriptive analyses Specific methods: Specific methods: ANOVA ANOVA Tests for interaction Tests for interaction

19. Limitations Although protocols may not pre- specify subgroup analysis, sponsors may conduct these and report results in their New Drug Applications. Although protocols may not pre- specify subgroup analysis, sponsors may conduct these and report results in their New Drug Applications. Follow up is needed to evaluate enrollment, if subgroup analysis was done and how it was done on those drugs that did enter the market. Follow up is needed to evaluate enrollment, if subgroup analysis was done and how it was done on those drugs that did enter the market.

20. Conclusion FDA encourages inclusion of diverse populations in drug development and provides guidance for analyses of subpopulations. FDA encourages inclusion of diverse populations in drug development and provides guidance for analyses of subpopulations. FDA requires the analyses of safety and efficacy data by gender, age and racial subgroups. FDA requires the analyses of safety and efficacy data by gender, age and racial subgroups. If analyses were planned then they should be specified up front in the protocol. If analyses were planned then they should be specified up front in the protocol. Results show inconsistent pre-planning. Results show inconsistent pre-planning.

21. Acknowledgement This project was supported in part by an appointment to the Research Participation Program at the U.S. Food and Drug Administration administered by the Oak Ridge Institute for Science and Education through a contract with the FDA.

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