1. Inclusion of Women in Clinical Trials & Drug Development Regulatory Perspective Ameeta Parekh, Ph.D. R&D Director Office of Women’s Health Food & Drug Administration November 10, 2009 American Association of Pharmaceutical Scientists Annual Meeting Los Angeles

2. OVERVIEW Historical framework Historical framework –Women in clinical studies Regulatory framework Regulatory framework –Regulations, guidances, practices –Regulatory Initiatives: Bio-informatics

3. SUBSTANTIATION OF GAPS Numerous reports: 1. Government - NIH, AHRQ, GAO, FDA under-representation, analysis 2. Institute of Medicine (IOM) Report contribution of sex as a biological variable 3. Peer-reviewed Publications

4. A LOOK BACK IN TIME 1985 US Public Health Task Force Reported that historical lack of focus on women’s health issues deprived women of proper health care and health information 1985 US Public Health Task Force Reported that historical lack of focus on women’s health issues deprived women of proper health care and health information 1986 NIH established voluntary policy to include women in clinical research 1986 NIH established voluntary policy to include women in clinical research 1990 GAO report criticizing implementation of 1986 policy 1990 GAO report criticizing implementation of 1986 policy 1990 NIH Office of Research on Women’s Health established 1990 NIH Office of Research on Women’s Health established

5. AHRQ Publication No. 03-E035 May 2003 Peer Reviewed Literature Research in the last 20 years … excluded women entirely or included only limited numbers of women and minorities findings specific to women are NOT providedOften findings specific to women are NOT provided ~20 percent of the articles provided separate findings for women~20 percent of the articles provided separate findings for women Many tests and therapies used clinically are based on studies conducted predominantly in menMany tests and therapies used clinically are based on studies conducted predominantly in men

6. Excluded women of childbearing potential from participation in early studies of drugs Excluded women of childbearing potential from participation in early studies of drugs 1977 REGULATION: General Considerations for the Clinical Evaluation of Drugs

7. SOCIETY RESPONDS Critics of 1977 guideline Critics of 1977 guideline –Precludes a female’s ability to make a decision –Violates principle of autonomy (informed consent) Advocacy Groups Advocacy Groups –Females denied access to important and innovative therapies

8. Congress Responds The public including many women’s groups lobby Congress The public including many women’s groups lobby Congress 1994 - Created by Congressional mandate 1994 - Created by Congressional mandate “...Establish an Office of Women’s Health..” at FDA “...Establish an Office of Women’s Health..” at FDA –“Correct gender disparities in FDA drug, device, biologics testing and regulation policy” –“Oversee the implementation of revised clinical trial guidelines with respect to representation of women…” –“Coordinate PHS women’s health policy with the PHS Office of Women’s Health and other PHS agency offices…”

9. 1993 GUIDELINE: Study and Evaluation of Gender Differences in the Clinical Evaluation of Drugs Reversed the 1977 Policy Reversed the 1977 Policy Collection and analysis of data on sex differences Collection and analysis of data on sex differences –Effectiveness –Adverse effects –Pharmacokinetics (PK) Can reduce risk of fetal exposure through protocol design Can reduce risk of fetal exposure through protocol design

10. Women were NOT ADEQUATELY INCLUDED in clinical studies 60% of drugs – representation of women less than prevalence with disease Data NOT analyzed for SEX differences Lack of understanding of sex/gender differences FDA OWH: 1994 1992 GAO Report REPORT ON FDA

11. NDA SUBMISSIONS: Requires information on: Trial participation Safety Effectiveness Data evaluated by: “Gender” (sex) Age Race 1998 REGULATION: Investigational New Drug Applications (INDs) and New Drug Applications (NDAs) ( “Demographic Rule”) 21 CFR 314.50 and 21 CFR 312.33

12. 1998 REGULATION (cont) IND Annual Reports IND ANNUAL REPORTS: Requires tabulation of the number of participants according to: “Gender” (sex) Age Race

13. 2000 REGULATION (amendment): Clinical Hold Regulations for Products Intended for Life-Threatening Diseases Permits FDA to stop studies under an IND for treatment of a life- threatening disease if women are excluded due to reproductive potential

14. 2001 GAO Report  Appropriate numbers of women in NDAs  Analysis by sex was NOT consistently present  Participation of women is similar to that of men except: Earliest phasesEarliest phases Some therapeutic areas (e.g., CVD)Some therapeutic areas (e.g., CVD) REPORT ON FDA

15. FDA…. Not there yet  FY2002 - Congressional Mandate  “…create a database focused on women’s health activities, to include demographic data in clinical trials” Needed: Needed:  track this in an quick  Ability to track this in an quick  Automated process   Data Standards   Information/Knowledge Management   IT infrastructure & advances

16. DATA STANDARDS

17. Male Female Male Female M F M F Man Woman Man Woman M W M W 0 1 0 1 1 0 1 0 1 2 1 2 Any Combination or others Any Combination or others SUBJIDSEX 0001M 0002F 0003F 0004M 0005F Study #1IDGENDERA1Male A2Male A3Female A4Female A5Male USUBIDSEX000110 000121 000131 000140 000151 PTIDGENDER00011 00021 00032 00042 00051 Study #2 Study #3 Study #4

18. DATA STANDARD FOR SEX M, F, U M, F, U Male, female, unknown Male, female, unknown

19. In Closing…… Historical framework Historical framework –Women in clinical studies FDA OWH 1994 Regulatory framework Regulatory framework –Regulations, guidances, etc. –Bio-informatics, and many other innovations to close the knowledge gap