Women’s involvement in clinical trials: historical perspective and future implications
The importance of considering the differences between the male and female sex in clinical decision-making is crucial. However, it has been acknowledged in recent decades that clinical trials have not always adequately enrolled women or analyzed sex-specific differences in the data. As these deficiencies have hindered the progress of understanding women’s response to medications, agencies in the United States have worked towards the inclusion of women in clinical trials and appropriate analysis of sex-specific data from clinical trials. This review outlines the history and progress of women’s inclusion in clinical trials for prescription drugs and presents considerations for researchers, clinicians, and academicians on this issue.
2. Pinn V. Sex and gender factors in medical studies: implications for health and clinical practice. JAMA. 2003;289(4):397-400.
3. Committee on Women’s Health Research, Board on Population Health and Public Health Practice, Institute of Medicine. Women’s health research: progress, pitfalls, and promise. Washington DC: National Academies Press; 2010.
4. National Institute on Drug Abuse Treatment Clinical Trials Network: Successfully Including Women in Clinical Trials, A Guide for Researchers. Available at https://www.drugabuse.gov/sites/default/files/womens-brochure_1025-004_508.pdf (accessed 2015 Dec 6).
5. Centers for Disease Control and Prevention. Ten ways STDs impact women differently from men. Available at http://www.cdc.gov/std/health-disparities/stds-women-042011.pdf (accessed 2015 Nov 28).
6. Miller M. Gender differences in the toxicity of pharmaceuticals- the Food and Drug Administration’s perspective. Int J Toxicol. 2001;20(3):149-152.
7. Woosley R. From benchside to bedside: role of gender-based therapeutics in the clinical care of women. J Womens Health. 1998;7(1)21-23.
8. Beierle, I, Meibohm B, Derendorf H. Gender differences in pharmacokinetics and pharmacodynamics. Int J Clin Pharmacol Ther. 1999;37(11):529-547.
9. Parekh A, Fadiran E, Uhl K, Throckmorton D. Adverse effects in women: implications for drug development and regulatory policies. Expert Rev Clin Pharmacol. 2011;4(4):453-466. doi: 10.1586/ecp.11.29
10. 60 Minutes. CBS Interactive; c2014. [Video], Sex matters: drugs can affect sexes differently; 2014 Feb 9]. Available at: http://www.cbsnews.com/news/sex-matters-drugs-can-affect-sexes-differently/ (accessed 2015 Dec 6).
11. HealthyPeople.gov. Washington DC: Office of Disease Prevention and Health Promotion. Disparities. Available at: http://www.healthypeople.gov/2020/about/foundation-health-measures/Disparities (accessed 2015 Dec 6).
12. Doyal L. Sex, gender, and health: the need for a new approach. BMJ. 2001;323(7320):1061-1063.
13. Parekh A, Sanhai W, Marts S, Uhl K. Advancing women's health via FDA Critical Path Initiative. Drug Discov Today Technol. 2007;4(2):69-73. doi: 10.1016/j.ddtec.2007.10.014
14. National Institutes of Health, Task Force on the Recruitment and Retention of Women in Clinical Research. Science meets reality: recruitment and retention of women in clinical studies, and the critical role of relevance. Bethesda (MD): National Institutes of Health, Office of Research on Women’s Health; 2003 Available at: https://m.repository.library.georgetown.edu/bitstream/handle/10822/547438/SMR_Final.pdf?sequence=1&isAllowed=y (accessed 2015 Oct 24).
15. Schiebinger L. Women’s health and clinical trials. J Clin Invest. 2003;112(7):973-977.
16. Guidelines for the study and evaluation of gender differences in the clinical evaluation of drugs; notice. Fed Regist. 1993 Jul 22;58(139):39406-39416.
17. FDA Regulations, Guidance, and Reports related to Women’s Health. Available at http://www.fda.gov/scienceresearch/specialtopics/womenshealthresearch/ucm472932.htm (accessed 2015 Oct 24).
18. Investigational new drug applications and new drug applications; final rule. Fed Regist. 1998;63(28):6854-6862.
19. Investigational new drug applications; amendment to clinical hold regulations for products intended for life-threatening diseases and conditions; final rule. Fed Regist. 2000;65(106):34963-34971.
20. Food and Drug Asmnistration Office of Women’s Health. Available at http://www.fda.gov/AboutFDA/CentersOffices/OC/OfficeofWomensHealth/default.htm (accessed 2015 Oct 24).
21. National Institutes of Health. Monitoring Adherence To The NIH Policy On The Inclusion Of Women And Minorities As Subjects In Clinical Research. Fiscal Year 2009-2010. Available at http://orwh.od.nih.gov/research/inclusion/pdf/Inclusion-ComprehensiveReport-FY-2009-2010.pdf (accessed 2015 Oct 24).
22. Agenda for Research on Women’s Health for the 21st Century Volume 5: A Report of the Task Force on the NIH Women’s Health Research Agenda for the 21st Century Available at http://www.britecenter.org/wp-content/uploads/2013/02/Psychological-Differences-Between-Men-and-Women-Implications-for-a-Research-Agenda-on-Womens-Physical-and-Mental-Health.pdf (accessed 2015 Oct 24).
23. Prout M, Fish S. Participation of women in clinical trials of drug therapies: a context for the controversies. Medscape Womens Health. 2001 Oct;6(5):1.
24. Meinert CL, Gilpin AK, Unalp A, Dawson C. Gender representation in trials. Control Clin Trials. 2000;21(5):462-475.
25. General Accounting Office. FDA needs to ensure more study of gender differences in prescription drug testing. 1992 Oct 29. GAO/HRD-93-17
26. Evelyn B, Toigo T, Banks D, Pohl D, Gray K, Robins B, Ernat J. Women’s participation in clinical trials and gender-related labeling: a review of new molecular entities approved 1995-1999. J Natl Med Assoc. 2001;93(12 Suppl):18S-24S.
27. General Accounting Office. Most drugs withdrawn in recent years had greater health risks for women. 2001 Jan 19. GAO-01-286R.
28. General Accounting Office. Women sufficiently represented in new drug testing, but FDA oversight needs improvement. 2001 July. GAO-01-754.
29. Geller S, Koch A, Pellettieri, Carnes M. Inclusion, analysis, and reporting of sex and race/ethnicity in clinical trials: have we made progress? J Womens Health (Larchmt). 2011;20(3):315-320. doi: 10.1089/jwh.2010.2469
30. Geller S, Adams M, Carnes M. Adherence to federal guidelines for reporting of sex and race/ethnicity in clinical trials. J Womens Health. 2006;15(10):1123-1131.
31. Poon R, Khanijow K, Umarjee S, Fadiran E, Yu M, Zhang L, Parekh A. Participation of women and sex analyses in late-phase clinical trials of new molecular entity drugs and biologics approved by the FDA in 2007-2009. J Womens Health (Larchmt). 2013;22(7):604-616. doi: 10.1089/jwh.2012.3753
32. Food and Drug Administration Report Collection, Analysis, and Availability of Demographic Subgroup Data for FDA-Approved Medical Products August 2013. Available at http://www.fda.gov/downloads/RegulatoryInformation/Legislation/SignificantAmendmentstotheFDCAct/FDASIA/UCM365544.pdf (accessed 2015 Oct 24).
33. Johnson P, Fltzgerald, T, Salganlcoff A, Wood S, Goldstein J. Sex-specific medical research: why women’s health can’t wait. A report of the Mary Horrigan Connors Center for Women’s Health & Gender Biology at Brigham and Women’s Hospital. Brigham and Women’s Hospital: 2014 Available at: http://www.brighamandwomens.org/Departments_and_Services/womenshealth/ConnorsCenter/Policy/ConnorsReportFINAL.pdf (accessed 2015 Nov 28).
34. Food and Drug Administration Report. FDA Action Plan To Enhance The Collection And Availability Of Demographic Subgroup Data August 2014. Available at Http://Www.Fda.Gov/Downloads/Regulatoryinformation/Legislation/Significantamendmentstothefdcact/FDASIA/UCM410474.pdf (accessed 2015 Nov 28).
35 Food and Drug Administration Drug Trial Snapshots. Available at http://www.fda.gov/Drugs/InformationOnDrugs/ucm412998.htm (accessed 2015 Nov 28).
36 Buch B. Recent Progress on Demographic Information and Clinical Trials. Available at http://blogs.fda.gov/fdavoice/index.php/2015/02/recent-progress-on-demographic-information-and-clinical-trials/?source=govdelivery&utm_medium=email&utm_source=govdelivery (accessed 2015 Oct 24).
37. National Institutes of Health, Office of Research on Women’s Health, Office of Extramural Research, NIH Outreach Notebook Committee, NIH Tracking and Inclusion Committee. Outreach notebook for the inclusion, recruitment and retention of women and minority subjects in clinical research: principal investigators’ notebook. Bethesda (MD): National Institutes of Health, 2002 Available at: http://orwh.od.nih.gov/research/inclusion/pdf/Outreach-Notebook-021315.pdf (accessed 2015 Nov 28).
38. National Institutes of Health, Office of Research on Women’s Health. Report of the Advisory Committee on Research on Women’s Health: fiscal years 2011-2012: Office of Research on Women’s Health and NIH Support for Research on Women’s Health. Bethesda (MD): U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health; 2013]. NIH Publication No.: 13-7995. Available at: http://orwh.od.nih.gov/research/pdf/ACRWH-Biennial-Report2011-2012-Section508Complete.pdf (accessed 2015 Nov 28).
39. Agency for Healthcare Research and Quality. Health Care Quality and Disparities in Women. Selected Findings From the 2010 National Healthcare Quality and Disparities Reports Available at http://archive.ahrq.gov/research/findings/nhqrdr/nhqrdr10/women.pdf (accessed 2015 Nov 28).
40. Pal S. Inclusion of Women in Clinical Trials of New Drugs and Devices. US Pharm. 2015;40(10):21.
41. Wilcox S, Shumaker S, Bowen D, Naughton M, Rosal M, Ludlam S, Dugan E, Hunt J, Stevens S. Promoting adherence and retention to clinical trials in special populations: a Women’s Health Initiative workshop. Control Clin Trials. 2001;22(3):279-289.
42. McCullough L, Coverdale J, Chervenak F. Preventative ethics for including women of childbearing potential in clinical trials. Am J Obstet Gynecol. 2006;194(5):1221-1227.
43. Wizemann T. Sex-specific reporting of scientific research: a workshop summary. Washington DC: National Academies Press. 2012.