1. MATERIALS AND METHODS Tracking Women’s Participation and Sex Analyses in Late-Phase Clinical Trials of New Molecular Entity (NME) Drugs and Biologics Approved by the FDA between 2007 and 2009 Rita Poon 1, Keshav Khanijow 1,Sphoorti Umarjee 1, Lei Zhang, Ph.D. 2, Emmanuel Fadiran, Ph.D. 1, Monica Yu 1, Ameeta Parekh, Ph. D. 1 1 Office of Women’s Health, 2 Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD CONCLUSIONS  Women’s participation in late-phase clinical trials of approved NME drugs has remained consistent around 50% based on reports in the last 10 years. Differences in women’s participation each year may be due to sex differences in disease prevalence for which some of the new drugs are indicated.  Although efficacy and safety analyses by sex are being conducted FDA reviewers, 27%(efficacy) and 13%(safety) of the sex analyses presented in the reviews of NDAs are only exploratory because the clinical studies lacked statistical power. Similarly, 55%(efficacy) and 29%(safety) of the sex analyses presented in the reviews of BLAs are only exploratory.  Previous studies on women’s participation in clinical trials of approved biologics examined overall clinical trial participation. Since this study focused on late phase clinical trials, a trend could not be determined for the extent of women’s participation nor for the performance of sex-specific data analyses.  Sponsors developing therapeutic products and FDA reviewers should continue efforts to ensure adequate participation of women in clinical trials and conduct analyses of efficacy and safety by sex to determine optimal treatment needs. RESULTS (CONT’D) INTRODUCTION Data from late-phase clinical trials (LPCTs) are used to evaluate the efficacy and safety of drugs and biologics. Adequate participation of women in clinical trials is an important public health issue for determining potentially different treatment responses and patient outcomes by sex. As such, the FDA has made several efforts to ensure adequate representation of women in clinical trials and sex analyses for its regulated products through guidelines and regulations including the following: Objectives: Determine the participation of women in LPCTs of New Molecular Entity (NME) drugs and biologics approved from 2007 to 2009 Determine any trends in participation compared to past reports by the General Accountability Office (GAO) in 2001 and Yang, et al. 2009. Track sex analyses conducted by the FDA for these therapeutic products PARTICIPATION OF WOMEN IN LATE-PHASE CLINICAL TRIALS OF APPROVED DRUGS PRESENTATION OF SEX ANALYSES IN FDA REVIEWS OF APPROVED DRUGS PRESENTATION OF SEX ANALYSES IN FDA REVIEWS OF APPROVED BIOLOGICS Women’s participation ranges from 39%-52% in the last 10 years, but no trend could be observed when compared to the last two reports by the GAO in 2001 and by Yang, et al. 2009. *Yang et al. (2009) included Phase 4 studies Participation Data Collection Obtained list of NME drugs and biologics approved between 2007 and 2009 from Drugs@FDA website Accessed NME NDA (New Drug Application) and BLA (Biologic Licensing Application) submissions from FDA Electronic Document Rooms and evaluated for LPCT participation data by clinical study Assessed for participation data by sex in Late-phase clinical trials (LPCTs)- Defined as Phase 2, Phase 2/3 or Phase 3 studies with objectives to study the efficacy and/or safety of the therapeutic product in a patient population Excluded NMEs for sex-specific indications, pediatric indications, or those without clinical data Prevalence Data Collection Compared women’s participation data with women’s disease prevalence data Determined background rate of indicated population by disease (i.e. HIV) or diagnostic (i.e. medical imaging ), not symptom. For example: Searched Pubmed.gov database for key words: “Gender,” “Prevalence,” or “Epidemiology,” + Disease/Diagnostic Found most recent peer-reviewed journal article or public U.S. government database (i.e. from CDC or NIH) of studies conducted in United States or Europe to determine epidemiological data for women Noted if background rate has not been studied or could not be determined for a disease or diagnostic Sex Analyses Tracking Accessed FDA Medical and Statistical Reviews of approved NMEs on DRUGS@FDA website Sex analysis was tracked using the following coding system: RESULTS Women’s participation in NDA LPCTs varied widely by indication depending on the background rate by sex of the disease or indication. Drugs indicated for HIV and Gout had the lowest ratio of women’s participation compared to women’s disease prevalence with 0.51 and 0.28, respectively. *Of the sex analyses presented, 27% (efficacy) and 13% (safety) are exploratory  Presentation of sex analyses for both efficacy and safety (74%) has slightly increased since GAO 2001’s report of 72% and Yang, et al. 2009 report of 71%**. **Phase 4 studies were included in the analysis by Yang, et al. 2009 7 of 11 BLAs (64%) had both efficacy and safety sex analyses. 68 Total NMEs approved 2007-2009: 57 NDAs, 11 BLAs 7 NME NDAs were excluded from study (2 pediatric indication, 4 sex-specific indication, 1 no clinical data available) No NME BLAs were excluded from study PARTICIPATION OF WOMEN IN LATE-PHASE CLINICAL TRIALS OF APPROVED BIOLOGICS 37 of 50 NDAs (74%) had both efficacy and safety sex analyses. 8 of the 11 approved biologics had more than 65% women’s participation in LPCTs. 4 of the biologics had indications with a higher disease prevalence in women compared to men [Rheumatoid arthritis (2), Idiopathic thrombocytopenic purpura (1), and Cervical Dystonia (1)] Previous studies on women’s participation in biologics clinical trials included all phases rather than focus on Late-s, thus there is no comparable data set to observe trends. * Of the sex analyses presented, 55% (efficacy) and 18% (safety) are exploratory  Previous studies by GAO 2001 and Yang, et al. 2009 did not report participation data in clinical trials of approved biologics, thus no trends could be reported. Conclusive Sex Analysis 73% Conclusive Sex Analysis 87% Conclusive Sex Analysis 45% 27%13% Conclusive Sex Analysis 71% REFERENCES Government Accountability Office (GAO). (2001b). Women's health: Women sufficiently represented in new drug testing, but FDA oversight needs improvement. Available: at http://www.gao.gov/new.items/d01754.pdf. Accessed December 29, 2011. Yang, Y., Carlin, A.S., Faustino, P.J., Pagán Motta, M.I., Hamad, M.L., He, R., Watanuki, Y., Pinnow, E.E., Khan, M.A. (2009). Participation of women in clinical trials for new drugs approved by the Food and Drug Administration in 2000-2002. Journal of Women’s Health, 18(3), 303-310. The Office of Women's Health (OWH) at the FDA was established in 1994. The OWH missions are to: (1)advocate for inclusion of women in clinical trials and analysis of sex/gender effects (2)Protect and advance the health of women through policy, science, and outreach. OWH has supported several studies to assess women’s participation in clinical trials for drugs, devices, and biologics. Indication in LabelDisease/Diagnostic Prevalence Search Term Opioid used to accelerate gastrointestinal recovery after partial large or small bowel resection surgery with primary anastomosis Bowel resection surgery Topical Corticosteroid indicated for the treatment of inflammation and pain associated with ocular surgery Cataract surgery Treats the involuntary movements (chorea) of Huntington’s DiseaseHuntington’s Disease MRI contrast agent to detect and characterize lesions in adults with known or suspected focal liver disease Non-alcoholic fatty liver disease Indicated in combination with G-CSF to mobilize hematopoietic stem cells to the peripheral blood for collection and subsequent autologous transplantation in patients with non- Hodgkin’s lymphoma and multiple myeloma Non-Hodgkin’s lymphoma Ratio of Women’s Participation to Women’s Prevalence: BLAs approved in 2007-2009 Ratio of Women’s Participation to Women’s Prevalence: NDAs approved in 2007-2009