FDA has been committed to addressing women’s health since its inception in 1906, as illustrated by events in its history, such as FDA’s reversal of guidance that effectively excluded women of childbearing potential (WOCBP) from clinical studies. Guidance and other FDA regulations are ways in which FDA communicates its current thinking on issues related to FDA regulated products (evaluation, development, etc.). Several of these regulatory documents have addressed women’s health over FDA’s history and have impacted the way in which women are enrolled in clinical trials and sex analyses are conducted. 

1960s

• 1960s Evidence of fetal malformation from thalidomide use in Europe prevented its approval in the United States. It also prompted fears of including women of childbearing potential in clinical trials. [FDA Backgrounder]

1970s

• 1977 FDA Guidance General Considerations for the Clinical Evaluation of Drugs. Exclusion of women of childbearing potential from participation in Phase I and early Phase II clinical trials. - Guidance

1980s

• 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. Regulation
• 1987 FDA Guidance for Industry: Guideline for the Format and Content of the Nonclinical Pharmacology/Toxicology Section of an Application. Provided FDA expectation that both sexes of animals are to be included in pre-clinical drug safety studies for products targeted for use by both sexes. Guidance
• 1988 FDA Guidance for the Format and Content of the Clinical and Statistical Section of an Application. Recommends data analysis of clinical pharmacology studies safety, effectiveness and by sex, race and age. - Guidance
• 1989 FDA Guidance for Industry: Study of Drugs Likely to be Used in the Elderly. Recommends pharmacokinetic screen of Phase II/III trials and data analysis by age and sex. Guidance

1990s

• 1992 GAO report Women’s Health: FDA Needs to Ensure More Study of Gender Differences in Prescription Drugs Testing. The results of this report (from NMEs approved Jan 1988-June 1991) 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. Report
• 1993 FDA Guidance Study and Evaluation of Gender Differences in the Clinical Evaluation of Drugs. Withdrew the restriction (as outlined in the 1977 guidance) on the participation of women of childbearing potential in early clinical trials including clinical pharmacology studies and early therapeutic studies. Recommends pharmacokinetics and pharmacodynamics in women, pharmacokinetic screen as a tool to detect difference, analysis of safety and efficacy by sex. Guidance
• 1997 FDAMA Section 115: Clinical Investigations (b) Women and Minorities Regulation. Requires FDA and NIH along with representatives of the drug manufacturing industry to review and develop guidance on inclusion of women and minorities in clinical trials. Regulation
• 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. Regulation
• 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. Regulation
• 1999 FDA Guidance for Industry Population Pharmacokinetics. Recommends use of population pharmacokinetics to help identify differences in drug safety and effectiveness among population subgroups. Guidance

2000s

• 2000 Amendment to the Clinical Hold Regulations for Products Intended for Life-Threatening Diseases (21 CFR 312.42). 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. Regulation
• 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).  Report
• 2002 FDA Guidance on Establishing Pregnancy Exposure Registries Explains the need for pregnancy exposure registries, the structure of pregnancy exposure registry studies, when these studies should be conducted. Guidance
• 2003 FDA Guidance Estrogen and Estrogen/Progestin Drug Products to Treat Vasomotor Symptoms & Vulvar & Vaginal Atrophy Symptoms-Recommendations for Clinical Evaluation. Provides recommendations to industry on studies of estrogen and estrogen/progestin drug products. Guidance
• 2004 FDA Guidance for Industry on Labeling for Combined Oral Contraceptives. Describes recommended labeling for health care providers and patient instructions for combined oral contraceptives (OC’s) that contain estrogen and progestin. Guidance
• 2004 Guidance for Industry Pharmacokinetics in Pregnancy — Study Design, Data Analysis, and Impact on Dosing and Labeling. Describes a basic framework for designing and conducting PK and PD studies in pregnant women. Recommends how to assess the influence of pregnancy on PK, and where appropriate, the PD of drugs or biologic products. Guidance
• 2005 FDA Guidance for Industry S7B Nonclinical Evaluation of the Potential for Delayed Ventricular Repolarization (QT Interval Prolongation) by Human Pharmaceuticals. Provides recommendations to sponsors concerning the design, conduct, analysis, and interpretation of clinical studies to assess the potential of a drug to delay ventricular repolarization. Guidance
• 2005 FDA Reviewer Guidance Evaluating the Risks of Drug Exposure in Human Pregnancies. This guidance is intended to help FDA staff evaluate human fetal outcome data generated after medical product exposures during pregnancy Guidance

2010s

• 2010 Women’s Health Research: Progress, Pitfalls, and Promise. Committee on Women’s Health Research; Institute of Medicine (IOM) Report
• 2013 Collection, Analysis, and Availability of Demographic Subgroup Data for FDA-Approved Medical Products. 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. Report
• 2014 FDA Action Plan to Enhance the Collection and Availability of Demographic Subgroup Data. 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. Report
• 2014 Evaluation of Sex-Specific Data in Medical Device Clinical Studies: Guidance for Industry and FDA Staff. This guidance outlines FDA’s expectations regarding sex-specific patient enrollment, data analysis, and reporting of study information for medical device applications. Guidance