Medical research historically assumed the male body was the universal baseline for health and disease. For decades, standard clinical trials predominantly used male subjects, creating a significant knowledge deficit regarding female physiology and drug response. This systemic exclusion failed to account for biological variability between the sexes, leading to a gap in understanding how diseases manifest and how treatments work in women. Consequently, medical treatments and diagnostic standards developed from this narrow perspective were applied to half the population without sufficient evidence.
The Era of Exclusion
The historical exclusion of women from medical studies, particularly drug trials, was driven by scientific convenience and protective concerns. Following the thalidomide tragedy in the 1950s and early 1960s, regulatory bodies adopted highly cautious policies regarding women of childbearing potential. In 1977, the U.S. Food and Drug Administration (FDA) formally recommended excluding women who could become pregnant from Phase I and early Phase II drug trials, except for studies involving life-threatening conditions. Intended to protect a potential fetus, this policy was often broadly interpreted by researchers to exclude virtually all premenopausal women.
Beyond safety concerns, researchers widely believed that hormonal fluctuations associated with the female reproductive cycle would “confound” or complicate study results. They often preferred the perceived simplicity of the male system, viewing it as more physiologically stable for testing purposes. This assumption led to the widespread use of male cells, animals, and humans in research, establishing the male body as the standard in biomedical science. This practice persisted from the 1950s through the early 1990s, severely limiting data on how drugs and medical interventions affect women.
The Turning Point: Policy Mandates
The systematic exclusion began to face serious challenge in the early 1990s, driven by growing advocacy and congressional scrutiny over the lack of data on women’s health. The most significant shift occurred in 1993 with the passage of the National Institutes of Health (NIH) Revitalization Act. This act was the first legislation to legally mandate the inclusion of women and minorities in all NIH-funded clinical research.
The law stipulated that NIH must ensure women are included as subjects in every research project it supports, unless a compelling rationale justifies their exclusion. Crucially, the legislation also required clinical trials to allow for a valid analysis of whether the variables studied affect women differently than other participants. This requirement moved the focus beyond mere inclusion toward mandatory sex-specific data analysis. Following the NIH mandate, the FDA released its “Guideline for the Study and Evaluation of Gender Differences in the Clinical Evaluation of Drugs” in July 1993, advising investigators to include women in early-phase drug research.
Consequences of Past Exclusion
The long-standing practice of conducting research primarily on male subjects resulted in medical standards that often failed women, particularly in diagnosis and drug treatment. A stark example is cardiovascular disease, the leading cause of death for women, where symptoms often differ from the classic presentation studied in men. Women are more likely to experience symptoms like shortness of breath, nausea, or jaw pain, rather than the textbook crushing chest pain, leading to misdiagnosis or delayed care.
A major consequence has been the development of drug dosages based on male metabolism, which leads to higher rates of adverse reactions in women. Women often metabolize drugs differently and eliminate them from the body more slowly, resulting in higher drug concentrations when given the same dose as men. For instance, the sleep medication zolpidem (Ambien) was found to linger longer in women’s systems, causing next-morning impairment and leading the FDA to recommend halving the dosage for women in 2013. The exclusion of women from trials meant that many medications approved before 1993 carried an increased risk of side effects, with women experiencing adverse drug reactions nearly twice as often as men.
Current Standards and Remaining Gaps
Today, the NIH policy requires the consideration of sex as a biological variable (SABV) in all phases of research, from the earliest cell and animal studies through to human clinical trials. This means researchers must not only include female subjects but also actively analyze and report findings separately by sex to identify differences.
Despite these mandates, gaps in representation persist, particularly in the earliest stages of drug development. Women remain underrepresented in Phase I trials and in certain disease areas like cardiovascular disease and psychiatry. Furthermore, while inclusion has improved, many studies that enroll women still fail to adequately analyze or report the data separately by sex, undermining the purpose of the inclusion mandates. Ongoing challenges include limited funding for research focused specifically on women’s health issues beyond reproductive health, and the continued exclusion of pregnant women from many trials, creating a lasting knowledge gap for this population.