[vc_row full_width=”stretch_row” gap=”35″][vc_column][vc_column_text]With holiday gatherings commencing and COVID-19, flu, and respiratory syncytial virus (RSV) cases rising, it\u2019s reasonable to expect that, in addition to sharing infections, many families will soon be trading observations on how men and women manage illness differently.<\/p>\n
While this may offer fodder for dinner table debates and good-natured ribbing between spouses or siblings, the difference<\/a> in men and women\u2019s manifestation of illnesses and their responses to medicines has important scientific implications. Yet, women\u2014and females of other species\u2014were long systematically excluded from investigative clinical trials of drugs, biologics, and medical devices.<\/p>\n Many factors contributed to this exclusion, including limited understanding of the contribution of sex and gender to health, societal biases, and government policy.<\/p>\n This article considers the history of exclusion of females from research trials, its impact, and the progress which has been made in rectifying it.<\/p>\n An organism\u2019s sex is determined by its sex chromosome complement, which in humans is either XX (female) or XY (male). \u00a0Although sex is often thought of as categorizing an organism as a whole, almost every individual cell<\/a> of an animal has sex chromosomes.<\/p>\n Importantly, women aren\u2019t 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\u2014the concentration of a drug in blood or other tissues and or excretion\u2014and pharmacodynamics\u2014the effect of a drug on the body.<\/p>\n Unfortunately, differences in pharmacodynamics haven\u2019t always been recognized before drugs have been approved and in widespread use. A 2001 report<\/a> by the General Accountability Office (GAO) found that eight of the ten prescription drugs withdrawn from the U.S. market in the four preceding years posed greater health risks to women than to men.<\/p>\n 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<\/a> of 293 research articles specific to mice found \u201cvariability was not significantly greater in females than males for any endpoint and was substantially greater in males for several traits.\u201d<\/p>\n In humans, women\u2019s 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<\/a> in 1993, the very existence of cyclic changes made it important to understand their impact.<\/p>\n Women of childbearing age\u2014defined as any premenopausal woman\u2014were 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.<\/p>\n While this concern for the unborn was sometimes attributed to moral and religious principles, it also reduced researchers\u2019 potential liability in a litigious culture that was learning to be skeptical of pharmaceutical manufacturers.<\/p>\n The thalidomide<\/a> crisis of the 1950s opened the public\u2019s eyes to the teratogenic<\/a> 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\u2019s when researchers linked diethylstilbestrol (DES<\/a>)\u2014a drug which had been prescribed to prevent miscarriage\u2014to cervical and vaginal cancers in the daughters of women who used it.<\/p>\n 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<\/a> excluding premenopausal women from all phase I and phase II drug trials.<\/p>\n To others, the recommended exclusion\u2014which applied regardless of a woman\u2019s express wishes or whether she practiced abstinence, was a lesbian, or adhered to a strict regimen of birth control\u2014seemed like an overreach.<\/p>\n 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.<\/p>\n Ethicists noted that the specific exclusion of women from early phase drug testing was contrary to the idea of autonomy, an essential component of \u201cRespect for Persons,\u201d 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<\/a><\/em>, also known as the Belmont Report<\/em>. A blanket exclusion of women also ignored the direction of the Nuremberg Code<\/a> that human subjects should be \u201cable to exercise the power of choice.\u201d<\/p>\n 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\u2019s Council on Ethical and Judicial Affairs observed<\/a>, \u201c(t)he results of medical research on men (were) generalized to women without evidence of applicability to women.\u201d<\/p>\n In 1985, the report<\/a> of the Public Health Service Task Force on Women\u2019s Health Issues convened by the U.S. Department of Health and Human Services concluded that, \u201cA 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.\u201d<\/p>\n 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.<\/p>\n The GAO subsequently concluded<\/a> that neither encouragement nor \u201curging<\/a>\u201d was sufficient to affect change in clinical research. \u00a0In 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.<\/p>\n It fell to Congress to act.<\/p>\n The 103rd<\/sup> Congress, which convened in 1993, was primed to act on issues of women\u2019s, 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.<\/p>\n Waxman and Kennedy\u2019s bill, The National Institutes of Health (NIH) Revitalization Act of 1993<\/a> 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\u2019s Health (ORWH) a permanent office within NIH.<\/p>\n The tide had begun to turn. But imbalances in research were not immediately eliminated and continue to persist<\/a>.<\/p>\n Exclusion by design has never been the only barrier to women\u2019s participation in clinical trials. Social constructs can also work to limit women\u2019s availability to participate. Writing in the Journal of the American College of Cardiology<\/a>, Louise Pilote and Valeria Raparelli argued that \u201ccaretaking roles and low socioeconomic status\u201d often prevent women from enrolling in clinical trials.<\/p>\n 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 \u201c(i)nclusion of pregnant women in clinical treatment trials is urgently needed to identify effective COVID-19 treatment for this population.\u201d<\/p>\n But progress towards inclusion has been made. Today, under the NIH\u2019s Sex as a Biological Variable policy, researchers must consider sex in study design and analysis, as well as reporting. And while the NIH\u2019s 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\u2019s Health.<\/a><\/p>\n As neurobiologist Lawrence Cahill, PhD, observed in conversation<\/a> with the ORWH, \u00a0“addressing assumptions about sex in preclinical research is not a woman\u2019s health issue, it\u2019s an issue of good science.\u201d<\/p>\n 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.<\/em><\/p>\n The National Academies of Sciences, Engineering, and Medicine (NASEM) defines<\/a> sex as a \u201cmultidimensional construct based on a cluster of anatomical and physiological traits (sex traits).\u201d<\/em><\/p>\n By contrast, gender is defined as a \u201cmultidimensional construct that links gender identity, gender expression, and social and cultural expectations about status characteristics, and behavior that are associated with sex traits.\u201d<\/em><\/p>\n Listen closely to the television advertisement<\/a> for a pre-exposure prophylaxis (PrEP) drug for human immunodeficiency virus currently running on television and you\u2019ll hear the disclaimer that it has \u201cnot been studied in people assigned female at birth.\u201d \u00a0<\/em><\/p>\nDefining sex<\/h3>\n
Explanations for exclusion<\/h3>\n
A question of autonomy<\/h3>\n
Medical implications<\/h3>\n
Legislation<\/h3>\n
Ongoing issues<\/h3>\n
\nBut what about gender?<\/strong><\/h3>\n