Sex as a Biological Variable

On this page: Understanding sex differences at FDA | Historical information | Women in clinical trials | Related links

Understanding sex differences at FDA

Research has shown that biological differences between men and women (differences due to sex chromosome or sex hormones) may contribute to variations seen in the safety and efficacy of drugs, biologics, and medical devices. FDA’s regulations and guidance acknowledge that understanding mechanisms of sex differences in medical product development is crucial for regulatory decisions and optimal treatment outcomes.  

FDA’s Office of Women’s Health (OWH) advocates for the participation of women in clinical trials, supports scientific sex differences research within and outside FDA, and provides sex differences training and other resources for health professionals. 

Historical information

The timeline below provides information about key reports, policies, and other FDA actions related to sex and gender considerations. These materials are available in the public FDA.gov archive; this information is provided for historical context, and should not be considered the most current information. 

Historical timeline (1977-2016)

• 1977 FDA Guidance General Considerations for the Clinical Evaluation of Drugs (PDF, 1.4MB, ARCHIVED) - Exclusion of women of childbearing potential from participation in Phase 1 and early Phase 2 clinical trials.
• 1985 Content and Format of a New Drug Application (21 CFR 314.50 (d)(5)(v)) - FDA’s first requirement to analyze specific subgroups including pediatric, geriatric, and patients with renal failure to evaluate evidence in support of dosing modifications in these population subsets. However, it omitted important subgroups including those of gender and race.
• 1988 FDA Guideline for the Format and Content of the Clinical and Statistical Sections of an Application (PDF, 1.1MB, ARCHIVED) Recommends data analysis of safety, effectiveness and clinical pharmacology studies by sex, race and age.
• 1989 FDA Guidance for Industry: Study of Drugs Likely to be Used in the Elderly (PDF, 1.2MB, ARCHIVED) Recommends pharmacokinetic screen of Phase II/III trials and data analysis by age and sex.
• 1992 GAO report Women’s Health: FDA Needs to Ensure More Study of Gender Differences in Prescription Drugs Testing -The results of this report concluded that women were not adequately included in clinical trials based on the proportion of women with the diseases for which the studied drugs were intended. Also, trial data was often not analyzed for sex differences in therapeutic response.
• 1993 FDA Guidance Study and Evaluation of Gender Differences in the Clinical Evaluation of Drugs (PDF, 1.8MB, ARCHIVED) Recommends pharmacokinetics and pharmacodynamics in women, pharmacokinetic screen as a tool to detect differences, analysis of safety and efficacy by sex.
• 1994 FDA OWH established (Federal Register notice) - OWH begins advocating for the inclusion of women in clinical trials.
• 1998 Demographic Rule – Amendments to Content and Format of a New Drug Application (21 CFR 314.50 (d)(5) - This final rule, known as the “Demographic Rule” revised the NDA content and format regulations at 21 CFR 314.50 to require effectiveness data to be presented by gender, age and racial subgroups and dosage modifications be identified for specific subgroups. Also requires safety data be presented by gender, age and racial subgroups; and that safety data from other subgroups of the populations of patients treated be presented, as appropriate.
• 1998 Investigational New Drug (IND) Applications – Annual Reports (21 CFR 312.33) - Requires investigational new drug (IND) data regarding participation in clinical trials be presented in annual reports by sex, age, and race.
• 2000 Office of Women's Health Scientific Research Program Accomplishments Report (ARCHIVED)
• 2000 Amendment to the Clinical Hold Regulations for Products Intended for Life-Threatening Diseases (21 CFR 312.42) (ARCHIVED) - Permits FDA to place a clinical hold on IND studies for treatment of a serious or life-threatening disease if women or men are excluded from a clinical trial due to reproductive potential.
• 2001 GAO Report Drug Safety: Women Sufficiently Represented in New Drug Testing, but FDA Oversight Needs Improvement - The report concluded that all of the new drug applications examined (NDAs approved Aug 1998-Dec 2000) included enough women to demonstrate statistically that the drug was effective in women. Overall, women were 52 percent of the study participants in the NDAs included in the study. The proportion of women included in the study varied by stage of drug development (22% in initial small-scale safety trials, 56% in late phase trials).
• 2001 Women's Health Science Program - Update to Accomplishments Report (ARCHIVED)
• 2005 Protecting and Advancing the Health of Women - A Congressional Briefing (ARCHIVED)
• 2007 The Food and Drug Administration Office of Women’s Health: Impact of Science on Regulatory Policy. Journal of Women’s Health Vol 16. Obias-Manno D, Scott PE, Kaczmarczyk J, Miller M, Pinnow E, Lee-Bishop L, Jones-London M, Chapman K, Kallgren D, Uhl K.
• 2007 FDA Office of Women’s Health Progress Report: 10 Years and Beyond (PDF, 495KB, ARCHIVED)  
• 2013 FDA Report on Collection, Analysis, and Availability of Demographic Subgroup Data for FDA-Approved Medical Products (ARCHIVED) - In response to FDASIA Section 907, FDA drafted a report to address the extent to which demographic subgroups participate in clinical trials that support applications for new drugs, biologics and devices; whether subgroup analyses of safety and effectiveness are reported to FDA in a manner consistent with FDA requirements and guidance, and whether and how safety and effectiveness data by subgroup is eventually made public.
• 2014 FDA Report on Action Plan to Enhance the Collection and Availability of Demographic Subgroup Data (PDF, 1MB, ARCHIVED) - Action Plan in response to Section 907 of FDASIA which directed FDA to publish and provide to Congress an action plan outlining recommendations for improving “the completeness and quality of analyses of data on demographic subgroups in summaries of product safety and effectiveness data and in labeling”; “on the inclusion of such data, or the lack of availability of such data, in labeling”; and on improving “the public availability of such data to patients, health care providers, and researchers” and to indicate the applicability of these recommendations to the types of medical products addressed in Section 907.
• 2014 Guidance for Industry and Food and Drug Administration Staff - Evaluation of Sex-Specific Data in Medical Device Clinical Studies - This guidance outlines FDA’s expectations regarding sex-specific patient enrollment, data analysis, and reporting of study information for medical device applications.
• 2015 Drug Trial Snapshots - Drug Trials Snapshots provide consumers with information about who participated in clinical trials that supported the FDA approval of new drugs. The information provided in these Snapshots also highlights whether there were any differences in the benefits and side effects among sex, race and age groups.
• 2016 The Food and Drug Administration Office of Women's Health: Impact of Science on Regulatory Policy: An Update. Journal of Women's Health Vol 25. Elahi M, Eshera N, Bambata N, Barr H, Lyn-Cook B, Beitz J, Rios M, Taylor DR, Lightfoote M, Hanafi N, DeJager L, Wiesenfeld P, Scott PE, Fadiran EO, Henderson MB. 
• 2016 Women’s Health Research Roadmap - Provides a strategic plan to address seven priority areas where new or enhanced research is important to FDA regulatory decision making on products impacting women’s health. See Women’s Health Research Roadmap for the current version of this report. 
• 2016 Diverse Women in Clinical Trial Initiative - In collaboration with the NIH Office on Research in Women’s Health, OWH launched this initiative to raise awareness about the importance of participation of diverse groups of women in clinical research, and to share best practices about clinical research design, recruitment, and subpopulation analyses.

Women in clinical trials 

OWH was established by congressional mandate in 1994 to advocate for the participation of women in clinical trials and the analyses of data by sex. OWH supports studies to track the participation of women in clinical trials and collaborates with FDA's centers and external partners to conduct trainings, workshops, outreach, and research to improve clinical trials design, recruitment, and analyses and to support FDA regulatory policy and decision-making.

Information in this section is provided for historical context, and should not be considered the most current information. For current information, see Diverse Women in Clinical Trials, Women’s Health Research, News and Updates, and Education and Training from OWH.

Related links 

• About OWH Research
• Women's Health Research Roadmap
• Gender Studies in Product Development: Historical Overview [ARCHIVED, from a 1995 workshop]