What is a sex difference?
According to the Institute of Medicine Report Exploring the Biological Contributions to Human Health: Does Sex Matter?, a sex difference is defined as a difference due to the sex chromosome or sex hormones. Gender refers to a difference between men and women that occurs due to cultural or social variations in a particular sex. As it will often not be clear whether an observed difference in safety or efficacy is due to gender or sex, the FDA has used the terms interchangeably to describe any difference--cultural or social, genetic or hormonal--between males and females.
What is the FDA doing to promote a better understanding of sex differences?
Research has shown that sex as a variable contributes to differences in the safety and efficacy of drugs, biologics, and devices. To better understand the biologic basis for sex differences, the FDA Office of Women’s Health (OWH) advocates for the participation of women in clinical trials, supports scientific research within and outside the FDA, and provides training and other resources for health professionals.
- Women’s Participation in Clinical Trials
- Research Initiatives - OWH-supported research studies, workshops, and publications
- Web-based Training Courses: The Science of Sex and Gender in Human Health (joint project with the NIH Office of Research on Women’s Health)
Regulations and Guidance Documents on Research on Sex Differences
1977 FDA Guidance General Considerations for the Clinical Evaluation of Drugs Effectively excluded women of childbearing potential from participation in clinical trials(PDF - 1.4MB) 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. 1988 FDA Guidance for the Format and Content of the Clinical and Statistical Section of an Application(PDF - 1.1MB)
recommended that industry provide an integrated summary of effectiveness, integrated summary of safety, and recommended data analysis by gender, race and age.
1992 GAO report Women’s Health: FDA Needs to Ensure More Study of Gender Differences in Prescription Drugs Testing.(PDF - 2.8MB)
The results of this report demonstrated that women were not included in clinical trials in proportion to their population inflicted with the indication.
1993 FDA Guidance Study and Evaluation of Gender Differences in the Clinical Evaluation of Drugs(PDF - 1.8MB)
effectively reversed the 1977 guidance.
1994 FDA OWH established and begins advocating for the inclusion of women in clinical trials.(PDF - 26KB) 1995 FDA Vaginal Contraceptive Guidance(PDF - 465KB)
Facilitates the development of vaginal contraceptive drug products.
1998 The Investigational New Drug Applications and New Drug Applications Regulation
requires manufacturers to tabulate trial participation for investigational new drugs. It also requires New Drug Applications to submit analyses for safety and effectiveness by gender, age and racial subgroups (CFR 312.33 and 314.50)
1999 FDA Guidance for Industry Population Pharmacokinetics.(PDF - 135KB)
Explains when to conduct a population PK study to better understand possible variability in dosing, safety and efficacy of medication.
2000 Amendment to the Clinical Hold Regulations for Products Intended for Life-Threatening Diseases Permits FDA to stop 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 (CFR 312.42). 2001 GAO Report Drug Safety: Most Drugs Withdrawn in Recent Years Had Greater Health Risks for Women(PDF - 421KB)
This book explores the health issues associated with sex and gender.
2001 Guidance on Bone Sonometer PMA Applications.
, Developed as a special controls guidance to support the reclassification of bone sonometers into Class II.
2002 Congressional mandate calls for an "agency-wide database focused on women's health activities.”(PDF - 249KB)
FDA responded by exploring the potential for a searchable database to assess the participation of women and track women’s health activities.
2002 FDA Guidance on Establishing Pregnancy Exposure Registries.(PDF - 268KB)
Explains the need for pregnancy exposure registries, the structure of pregnancy exposure registry studies, when these studies should be conducted.
2003 FDA Guidance Estrogen and Estrogen/Progestin Drug Products to Treat Vasomotor Symptoms & Vulvar & Vaginal Atrophy Symptoms-Recommendations for Clinical Evaluation.(PDF - 198KB)
, Provides recommendations to industry on studies of estrogen and estrogen/progestin drug products.
2004 FDA Guidance for Industry on Labeling for Combined Oral Contraceptives.(PDF - 92KB)
Describes recommended labeling for health care providers and patient instructions for combined oral contraceptives (OC’s) that contain estrogen and progestin.
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.
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.
2005 FDA Reviewer Guidance Evaluating the Risks of Drug Exposure in Human Pregnancies(PDF - 352KB)
This guidance is intended to help FDA staff evaluate human fetal outcome data generated after medical product exposures during pregnancy.
- 2011 Draft Guidance for Industry and Food and Drug Administration Staff - Evaluation of Sex Differences in Medical Device Clinical Studies (PDF - 941KB)
- 2014 Guidance for Industry and Food and Drug Administration Staff - Evaluation of Sex-Specific Data in Medical Device Clinical Studies (PDF - 941KB)