With holiday gatherings commencing and COVID-19, flu, and respiratory syncytial virus (RSV) cases rising, it’s reasonable to expect that, in addition to sharing infections, many families will soon be trading observations on how men and women manage illness differently.
While this may offer fodder for dinner table debates and good-natured ribbing between spouses or siblings, the difference in men and women’s manifestation of illnesses and their responses to medicines has important scientific implications. Yet, women—and females of other species—were long systematically excluded from investigative clinical trials of drugs, biologics, and medical devices.
Many factors contributed to this exclusion, including limited understanding of the contribution of sex and gender to health, societal biases, and government policy.
This article considers the history of exclusion of females from research trials, its impact, and the progress which has been made in rectifying it.
Defining sex
An organism’s sex is determined by its sex chromosome complement, which in humans is either XX (female) or XY (male). Although sex is often thought of as categorizing an organism as a whole, almost every individual cell of an animal has sex chromosomes.
Importantly, women aren’t just smaller versions of men and the difference between the sexes is not limited to reproductive organs. When it comes to interactions with pharmaceuticals, there can be significant differences between men and women in pharmacokinetics—the concentration of a drug in blood or other tissues and or excretion—and pharmacodynamics—the effect of a drug on the body.
Unfortunately, differences in pharmacodynamics haven’t always been recognized before drugs have been approved and in widespread use. A 2001 report by the General Accountability Office (GAO) found that eight of the ten prescription drugs withdrawn from the U.S. market in the four preceding years posed greater health risks to women than to men.
Explanations for exclusion
A longstanding explanation for excluding female mice from investigative trials was the belief that fluctuating hormones of their estrous cycles made them intrinsically more variable and that their inclusion could increase research costs. In fact, a 2014 meta-analysis of 293 research articles specific to mice found “variability was not significantly greater in females than males for any endpoint and was substantially greater in males for several traits.”
In humans, women’s menstrual cycles were frequently cited as a source of variability, with the potential to raise study costs. However, as the Board on Health Sciences Policy of the Institute of Medicine observed in 1993, the very existence of cyclic changes made it important to understand their impact.
Women of childbearing age—defined as any premenopausal woman—were frequently excluded from research trials out of concern that they could become pregnant during the course of a study. Researchers argued that pregnancy could increase variability and that the drug or device under investigation could pose a threat to a developing fetus.
While this concern for the unborn was sometimes attributed to moral and religious principles, it also reduced researchers’ potential liability in a litigious culture that was learning to be skeptical of pharmaceutical manufacturers.
A question of autonomy
The thalidomide crisis of the 1950s opened the public’s eyes to the teratogenic potential of drugs and disabused the medical community of the belief that drugs did not cross the placenta. Public concern over the use of drugs in pregnancy was compounded in the 1970’s when researchers linked diethylstilbestrol (DES)—a drug which had been prescribed to prevent miscarriage—to cervical and vaginal cancers in the daughters of women who used it.
To many, the Food and Drug Administration (FDA) seemed only to be acting in the best interests of women and protecting the unborn when, in 1977, it officially recommended excluding premenopausal women from all phase I and phase II drug trials.
To others, the recommended exclusion—which applied regardless of a woman’s express wishes or whether she practiced abstinence, was a lesbian, or adhered to a strict regimen of birth control—seemed like an overreach.
Reflecting the political and social climate of the time (Roe v. Wade had been decided just four years earlier) feminists argued that such exclusion deprived them of the opportunity to make decisions about their own health and bodies.
Ethicists noted that the specific exclusion of women from early phase drug testing was contrary to the idea of autonomy, an essential component of “Respect for Persons,” one of the key principles of ethical research identified by the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research in the Ethical Principles and Guidelines for the Protection of Human Subjects of Research, also known as the Belmont Report. A blanket exclusion of women also ignored the direction of the Nuremberg Code that human subjects should be “able to exercise the power of choice.”
Medical implications
Beyond raising social and ethical concerns, the exclusion of women from early phase testing had important scientific and medical implications. As the American Medical Association’s Council on Ethical and Judicial Affairs observed, “(t)he results of medical research on men (were) generalized to women without evidence of applicability to women.”
In 1985, the report of the Public Health Service Task Force on Women’s Health Issues convened by the U.S. Department of Health and Human Services concluded that, “A systematic effort must be made to address issues relating to gender bias, in research and clinical practice, that lead to inadequate attention to the needs of women.”
In response to the Task Force report, in 1986 the National Institutes of Health (NIH) took steps to encourage the inclusion of women in the clinical studies it funded, without specifying it as a requirement.
The GAO subsequently concluded that neither encouragement nor “urging” was sufficient to affect change in clinical research. In its 1990 review of grant proposals submitted to NIH, the GAO found that only 30 percent of the proposed investigations into medical conditions affecting both sexes included both male and female research subjects.
It fell to Congress to act.
Legislation
The 103rd Congress, which convened in 1993, was primed to act on issues of women’s, minority, and public health. President George W. Bush had previously vetoed NIH-specific legislation, citing objection to the use of fetal tissue in research. But Representative Henry Waxman (D-CA) and Senator Edward Kennedy (D-MA) recognized an ally in the newly elected President Bill Clinton.
Waxman and Kennedy’s bill, The National Institutes of Health (NIH) Revitalization Act of 1993 addressed issues ranging from AIDS research to health education loans. It also specified that women and minorities must be appropriately represented in NIH-funded clinical research and made the Office for Research in Women’s Health (ORWH) a permanent office within NIH.
The tide had begun to turn. But imbalances in research were not immediately eliminated and continue to persist.
Ongoing issues
Exclusion by design has never been the only barrier to women’s participation in clinical trials. Social constructs can also work to limit women’s availability to participate. Writing in the Journal of the American College of Cardiology, Louise Pilote and Valeria Raparelli argued that “caretaking roles and low socioeconomic status” often prevent women from enrolling in clinical trials.
The study of drugs in pregnancy also remains limited. In 2020, as science scrambled for treatments for COVID-19, pregnant women were not represented in many clinical trials. An article published in the Lancet observed that “(i)nclusion of pregnant women in clinical treatment trials is urgently needed to identify effective COVID-19 treatment for this population.”
But progress towards inclusion has been made. Today, under the NIH’s Sex as a Biological Variable policy, researchers must consider sex in study design and analysis, as well as reporting. And while the NIH’s policies do not apply to privately funded studies, the Food and Drug Administration has been able to exercise authority through its own Office of Women’s Health.
As neurobiologist Lawrence Cahill, PhD, observed in conversation with the ORWH, “addressing assumptions about sex in preclinical research is not a woman’s health issue, it’s an issue of good science.”
But what about gender?
While the terms sex and gender have previously been used interchangeably, they are not synonymous. The distinction between the two has important implications for both science and society.
The National Academies of Sciences, Engineering, and Medicine (NASEM) defines sex as a “multidimensional construct based on a cluster of anatomical and physiological traits (sex traits).”
By contrast, gender is defined as a “multidimensional construct that links gender identity, gender expression, and social and cultural expectations about status characteristics, and behavior that are associated with sex traits.”
Listen closely to the television advertisement for a pre-exposure prophylaxis (PrEP) drug for human immunodeficiency virus currently running on television and you’ll hear the disclaimer that it has “not been studied in people assigned female at birth.”
In the past, this might have been phrased as “in women.” But the use of “assigned at birth” recognizes that the decision as to an individual’s identity was made by someone else. Such sexual assignment may or may not align with an individual’s view of themselves or how they identify to the world.
Like sex, gender can have important implications for an individual’s health, affecting social determinants of health and access to care. But it doesn’t carry with it the same biological impact of sex.
Recognizing the impact of gender on health need not mean dismissing that of biology. And animal studies can help in distinguishing which physical responses to drugs are driven by sex.
“Gender is a social construct that we associate with humans, so animals do not have a gender,” Chyren Hunter, associate director for basic and translational research at the U.S. National Institutes of Health Office of Research on Women’s Health told the MIT Tech Review earlier this year.
NASEM acknowledges that sex assigned at birth “has utility in health contexts— including survey research, clinical trials, public health surveillance, and medical settings—for purposes ranging from clinical decision support to exploring the role of sex traits in health status and the etiology of disease.”