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. 2020 Jun 10;29(6):868–875. doi: 10.1089/jwh.2019.8084

Filling the Regulatory Gap: Potential Role of Institutional Review Boards in Promoting Consideration of Sex as a Biological Variable

Korrina A Duffy 1,✉, Tracy A Ziolek 2, C Neill Epperson 1
PMCID: PMC7718845  PMID: 32267784

Abstract

Consideration of sex differences in biomedical research is crucial to ensure the safety and effectiveness of drugs and devices for both sexes and to improve the rigor and reproducibility of scientific discoveries. Historically, women were underrepresented in clinical research and sex differences typically were not considered. The U.S. Food and Drug Administration (FDA) and the National Institutes of Health (NIH) have played a role in improving the representation of women in clinical trials and in encouraging the consideration of sex differences. As it is not appropriate for all studies to be reviewed by the FDA nor do all studies have NIH funding, this results in a regulatory gap. We propose that local institutional review boards (IRBs) and institutional animal care and use committees (IACUCs) provide greater oversight by encouraging researchers to consider sex as a biological variable (SABV) during protocol review. In this perspective article, we review how FDA and NIH policies have fostered change and highlight how IRBs and IACUCs could encourage investigators to consider SABV.

Keywords: sex as a biological variable, women, institutional review boards, institutional animal care and use committees, preclinical and clinical research

Introduction

Historically, medical research assumed that men and women were essentially the same—that women were like men but with hormones that fluctuated and bodies that could become pregnant. For these reasons as well as a desire to protect women from experimental risk, men were considered the simpler and safer sex to study and, thus, became the model for modern medicine.1,2 Over the years, however, this assumption that women were essentially men with a different reproductive system has been challenged by a preponderance of evidence indicating that not only does every cell have a sex,3 but that sex differences emerge across system levels in ways that are often complex, sometimes unexpected, and not necessarily dependent on sex hormones.3–8 The lesson learned is that it is imperative to consider sex as a biological variable (defined as characteristics encoded in DNA, such as reproductive organs and other physiological and functional characteristics9). Underrepresenting women in clinical trials and ignoring the potential effect of sex can have dangerous consequences for the health of women and for the rigor and reproducibility of science.

Consideration of Sex Matters

Health consequences

Women have been at a higher risk of harm from drugs and devices historically, and unfortunately, this continues to be the case.10 Compared to men, women experience adverse drug reactions more frequently and severely.11 The male bias in preclinical and clinical research has had dangerous consequences for women once a drug has been marketed.12 Aside from drugs having greater risks, women are also more likely to suffer complications from medical devices,13 which have not always been designed with consideration for how women differ from men physiologically and anatomically. Historically, drugs and devices have been more likely to be tested on men during clinical trials, and now that these products have been broadly marketed, women are paying the price in the form of higher morbidity and mortality.10,13

Scientific concerns

In the wake of the widespread reproducibility crisis in science, it has become clear that ignoring sex differences—which are pervasive and often clinically significant3–8—may compromise the validity of clinical research and contribute substantially to the problem of reproducibility.14 For example, many studies demonstrate that sex can moderate key outcomes.15–19 Ignoring sex in these studies would have led to very different conclusions. In an effort to improve the rigor and reproducibility of research studies, the National Institutes of Health (NIH) now requires all NIH-funded research to consider sex as a biological variable (SABV).9 The goal is for researchers to consider the possibility of sex differences from hypothesis development to study design to interpretation and generalization of results. Considering sex differences at every stage of the research process and across the translational continuum is expected to enhance the reproducibility of science and create an optimal risk/benefit profile for both sexes for new drugs and devices.

Policy Recommendations and Requirements: Slow But Steady Progress

Over the past few decades, the Food and Drug Administration (FDA) (the world's most influential regulator of drugs and devices) and the NIH (the world's largest public funder of biomedical research) have played a role in improving the representation of women in clinical trials and in encouraging reporting of sex differences (for a detailed overview of key policies, see Mazure and Jones1). In this next section, we briefly review the policies that the FDA and NIH have enacted that have fostered improvements (Table 1).

Table 1.

Historical Milestones Related to the Inclusion of Women and the Consideration of Sex Differences in Clinical Research and Clinical Trials

Year Event Implications
1977 FDA guidance20 Recommended that women of childbearing potential be excluded from early phase clinical trials
1985 US PHSTF report21 Concluded that excluding women from clinical research was detrimental to women's health
1986 NIH policy22 Recommended that grant applicants include women in clinical research
1987 FDA guidance23 Recommended that animals of both sexes be included in preclinical drug safety studies for products targeted for use by both sexes
1988 FDA guidance24 Recommended that sex-specific safety and efficacy analyses be conducted for drug studies in humans
1990 GAO report25 Concluded that NIH guidelines were not being followed
1992 GAO report26 Concluded that women were underrepresented in drug trials and that sex-specific analyses were done in <50% of drug trials
1993 NIH Revitalization Act27 Required women be included in all government-funded clinical research
1993 FDA guidance28 Removed 1977 restriction on early phase clinical trials and recommended clinical trials enroll participants in proportion to disease prevalence
1994 NIH regulation29 Required women to be included in all NIH-funded clinical research and phase 3 clinical trials to include enough women to test for sex differences
1994 IOM report30 Recommended that men and women be enrolled in clinical trials such that results were applicable to both sexes
1998 FDA regulation31 Required new drug applications to report sex-specific safety and efficacy results
2000 GAO report32 Concluded that adherence to NIH guidelines had improved, but while women were adequately represented, analyses by sex were still rarely conducted
2000 FDA regulation33 Allowed the FDA to halt research on drugs for life-threatening conditions if either sex were excluded based on risks to their reproductive potential
2001 GAO report34 Concluded that FDA was not monitoring reporting of sex differences for drug safety and effectiveness
2014 FDA report35 Outlined an action plan to improve the collection and availability of demographic subgroup data
2015 GAO report36 Recommended that NIH improve oversight on analysis of sex differences
2016 NIH regulation9 Required that all biomedical research include a representative sample of both sexes to test for sex differences
2019 FDA program37 Implemented the CDRH Health of Women Program to better assure the safety and effectiveness of medical devices in women
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FDA, Food and Drug Administration; GAO, Government Accountability Office; NIH, National Institutes of Health.

FDA oversight

In 1993, the FDA reversed its 1977 guidance that restricted women of childbearing potential from participating in early phase clinical trials and instead recommended that clinical trials enroll participants in proportion to the disease prevalence in men and women.28 Since this policy change, the participation of women in phase 1 clinical trials has increased modestly,34,38–41 but by 2015, women still only comprised a third of participants in phase 1 clinical trials (Table 2). The 1977 guidance discouraging women of childbearing potential from initial small-scale trials had the effect of leading to a widespread exclusion of women in later large-scale trials.30 However, the potential for pregnancy was not the only barrier preventing women from being included in clinical trials: hormonal fluctuations related to the menstrual cycle were considered to create unwanted complexity and cost to clinical trials.1 The 1993 guidance and other policy recommendations and mandates (Table 1) ultimately led to more adequate representation of women in later phase clinical trials26,41–43 (Table 3)—although women continue to be underrepresented at a statistically significant level in antiviral,42,43 pulmonary,41,43 and some cardiovascular44 clinical trials in proportion to their representation in the disease population (ratio <0.80).

Table 2.

Percent of Women in Pooled Clinical Trials Requiring Food and Drug Administration Review

Report Years Early phase
 Late phase
NMEs NDAs BLAs
GAO26 1988–1991   44%  
Evelyn et al.38 1995–1999 22% 48%  
GAO (2001)34,a,b 1998–2000 25% 58%  
Yang et al.39,a,c 2000–2002 27% 53%  
Pinnow et al.40 2006–2007 31%    
Poon et al.42,a,d 2007–2009   45% 57%
Eshera et al.43 2010–2012   45% 65%
Chen et al.41,e 2013 29% 51%/49%  
  2014 34% 41%/38%  
  2015 29% 49%/39%  
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Representation of women in clinical trials based on data obtained from NMEs approved by the FDA. Early phase trials were phase 1 trials and late phase trials were phases 2 and 3 trials (unless these were otherwise noted). Late phase trials subdivided into two types of NMEs: NDAs and BLAs. All reports excluded sex-specific drugs. This table is an extension of the data originally compiled in Chen et al.41

a

The original report did not exclude sex-unknown participants. Percent of sex-unknown participants by report: 11% for early phase and, for late phase, report excluded sex-unknown participants (GAO, 2001), 12% for early phase and 3% for late phase (Yang et al.39), and 4% for late phase (Poon et al.42). To make the percentages comparable across reports, the percent of women in the table is based on a recalculation that excluded sex-unknown participants.

b

Early phase trial data based on investigational new drug annual reports.

c

Early phase trials included phases 1 and 1/2 and late phase trials included phases 2/3, 3, and 4 trials.

d

Late phase trials included phases 2/3 and 3 trials.

e

Reported findings by year and by clinical trial phase whereas the other reports pooled participants across the range of years. Under NDAs column, reported as percent of women in phase 2 trials and phase 3 trials since these were reported separately. Combined NDAs and BLAs.

BLAs, biologics license applications; NDAs, new drug applications; NMEs, new molecular entities.

Table 3.

Adequate Representation of Women in Clinical Drug Trials Reviewed by the Food and Drug Administration

Report Year Adequately represented (%)
GAO26,a,b 1988–1991 37%
Poon et al.42,c,d 2007–2009 64%
Eshera et al.43,c,e 2010–2012 82%
Chen et al.41,b,f 2013–2015 83%
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Four reports considered whether women were adequately represented within clinical drug trials. The percentage represents the percent of drugs in which women were adequately represented in the clinical trials for those drugs relative to their prevalence in the disease population. Although the reports calculated adequate representation slightly differently from one another, the trend is clear: women are increasingly represented adequately within clinical drug trials.

a

Adequate representation was defined as the percent of drugs in which women were represented in the clinical trials for a given drug within ±10% of their prevalence in the disease population.

b

Adequate representation was defined as the percent of indications (multiple drugs under the same indication) in which the ratio of the proportion of women in the clinical trials for a given indication relative to the proportion of women in the disease population was between 0.8 and 1.2.

c

Adequate representation was defined as the percent of drugs in which the ratio of the proportion of women in the clinical trials for a given drug relative to the proportion of women in the disease population was between 0.8 and 1.2.

d

Included phases 2/3 and 3 trials.

e

Included phases 2 and 3 trials.

f

Included phases 1, 2, and 3 trials.

In response to a 1992 General Accounting Office (GAO; name changed to Government Accountability Office in 2004) report revealing that sex-specific analyses were not being reported >50% of the time,26 the FDA passed a regulation in 1998 mandating that new drug applications present sex-specific safety and efficacy data.31 Following the mandate, sex-based reporting increased substantially34,39,41–43,45—from 47% before the mandate26 to 93% as of 2013–201541 (Table 4). Sex-based reporting has had a clinical impact, leading to drug label changes. For example, the labeling for amlodipin (Norvasc®) used to treat hypertension and coronary artery disease and rosiglitazone (Avandia®) used to improve glycemic control now provide warnings of increased risk for adverse events in women. In addition, the labeling for zolpidem (Ambien®) used to treat insomnia now recommends a lower dose for women due to greater side effects when women are dosed according to previous drug labeling.46,47

Table 4.

Percent of Drugs (Food and Drug Administration-Based Reports) or Studies (National Institutes of Health-Based Reports) That Considered Sex in the Analyses

FDA-based reports Year Analyzed sex
 Justified why not
NDAs BLAs
GAO26 1988–1991 47%    
FDA45 1995–1999   37%  
GAO (2001)34 1998–2000 72%    
Yang et al.39,a 2000–2002 71%    
Poon et al.42 2007–2009 74% 64%  
Eshera et al.43 2010–2012 95% 81%  
Chen et al.41,a,b 2013–2015 93%   7%
NIH-based reports
Vidaver et al.54,c 1993–1998 20–26%  
Geller et al.55,d 2004 13% 20%
Geller et al.56,e 2009 25% 11%
Geller et al.52 2015 26% 2%
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For FDA-based reports, NMEs were divided into two types: NDAs and BLAs. For each type of NMEs (NDAs and BLAs), the percent that analyzed sex represents the percent of NMEs that included at least one clinical trial in which sex-specific analyses for safety and efficacy were done. For NIH-based reports, the percent that analyzed sex represents the percent of published studies in which sex was accounted for within a given study.f For those that did not analyze sex, the percent that justified why not were those with a clear rationale. This table is an extension of the data originally compiled in Chen et al.41 In part, the discrepancy between the percentages for FDA-approved clinical trials and NIH-funded clinical research can be explained by their unit of measurement: FDA-based reports looked at whether sex-specific analyses for safety and efficacy were done at all across all clinical trials for a NME whereas NIH-based reports looked at whether sex was accounted for within a given study.

a

Reported NDAs and BLAs together, but the vast majority were NDAs.

b

Unclear if the original investigators justified why sex was not analyzed, but Chen et al.41 stated that of the seven drugs that lacked both analyses, six drugs were for rare diseases and did not have enough participants and one drug was for a disease predominantly in women and did not have enough male participants.

c

Estimate calculated based on the fact that Vidaver et al.54 reported that “approximately 80%” of studies included women and, of those, “a quarter” to “a third” analyzed data by sex.

d

Included federally funded randomized controlled trials (83% of which were NIH funded) that began after 1994 and were published in 2004.

e

Included federally funded randomized controlled trials (94% of which were NIH funded) that began after 1994 and were published in 2009.

Despite these successes, recent examples still exist in which women were excluded or sex differences were not analyzed. For example, the preexposure prophylaxis trials of an HIV drug (coformulated tenofovir alafenamide and emtricitabine) excluded cisgender women because of perceived enrollment challenges, and then, because drug levels in the rectal and vaginal mucosa might affect the efficacy of the drug differently, the drug was not approved for use in “those who have receptive vaginal sex,” that is, cisgender women.48 Another example of needed improvement: in 2015, only 66% of medical device studies even reported the sex of participants and only 17% conducted analyses by sex.49

NIH oversight

Despite NIH guidelines (1986) recommending to grant applicants that women be included unless a clear rationale could be provided,22 the policy was applied inconsistently.25 The NIH Revitalization Act (1993) directed the NIH to establish guidelines for the inclusion of women and minorities in clinical research.27 Even though benchmarks for participation were not mandated, women were required to be included in all appropriate government-funded clinical research. In addition, phase 3 clinical trials were required to include a sufficient number of women such that potential sex differences could be identified. In 2000, a GAO report concluded that the NIH had made significant progress in including women in clinical research32 and, ever since, women have continued to be adequately represented in NIH-funded clinical trials reported at the aggregate level.32,50,51 Although disparities may be present within certain disease areas, a 2015 GAO report indicated that these data are not routinely available and considered it to be a major shortcoming that needs to be remedied.36 Two publications demonstrate that critical disparities in the inclusion of women remain. In 2015, 15% of NIH-funded randomized controlled trials published in prominent medical journals enrolled <30% women,52 and some less recent evidence reveals disparities in cardiovascular randomized controlled trials funded by the National Heart, Lung, and Blood Institute.53 Although NIH policies have been successful in achieving adequate representation of women, the NIH lacks oversight on whether analyses of outcomes by sex are planned and conducted,32,36 and, therefore, reporting of sex differences has remained low (Table 4).52,54–56 In 2015, 72% of NIH-funded randomized clinical trials published in prominent medical journals either did not include sex in their analyses or did not provide an explanation why not.52

NIH policies have made progress in including women in clinical research, but this has not been the case for female cells, tissues, and animals.57 Recently, however, the NIH announced that sex must be considered as a biological variable (SABV) in all NIH-funded studies from 2016 onward.9 This policy requires all biomedical research involving vertebrate animals and human to consider the possibility of sex differences across the entire research process. This involves using a representative sample and testing for sex differences (unless a compelling justification is provided). Although the policy was only recently initiated, early evidence indicates that the regulation is working: from premandate to postmandate, three times more studies included both sexes and almost four times more studies conducted sex-specific analyses.58 Another study revealed that from 2016 to 2017, the proportion of grants that provided consistent justification for the use of a single sex increased from 44% to 50%.59

Potential Solutions: Local Regulatory Entities

From 1993 to 2016, the FDA and NIH policies have had a largely positive impact. However, may studies do not need FDA approval or do not have NIH funding (e.g., only 6% of trials registered on ClinicalTrials.gov were funded by the NIH in 2014),60 resulting in a regulatory gap with real consequences. For example, a recent review of emergency medicine-related publications reported that nonfederally funded research studies were almost half as likely to report analyses addressing potential sex differences as federally funded studies.61 Likewise, policies before 2016 did not regulate the inclusion of female cells, tissues, and animals, which kept female cells, tissues, and animals strikingly outnumbered and largely excluded, especially compared with clinical research in humans.1 The importance of oversight is clear: 33% of NIH-funded preclinical studies included both sexes, whereas only 22% of those not funded by the NIH did so58 (but see Prakash et al.62 for a relevant counterexample). A recent study reviewing human subjects protocols at a research-intensive academic institution showed that only 12.5% of research being proposed to the institutional review board (IRB) had already been funded by the NIH and 24% of studies had no reported sources of funding,63 suggesting that many studies lack regulation from a funding agency and indicating the need for oversight earlier in the research pipeline. One potential solution lies in broader oversight by local regulatory entities. All human subjects research must be approved by an IRB and all animal model studies must be approved by an institutional animal care and use committee (IACUC).

Institutional review boards

The primary role of the IRB is to ensure that appropriate steps are taken to protect the rights and welfare of research participants. However, the IRB is also tasked with assessing the risks and benefits of the proposed research and ensuring that the study design is sound.64 FDA regulatory requirements state that IRBs should write into their procedures how they will assess potential risks and benefits and how they will determine whether the selection of subjects is equitable.65 Given that the IRB has been granted this responsibility, it seems important that the IRB consider the inclusion of women from the perspective of equitability as well as risks and benefits. As previously described, women and men differ in their risk/benefit profile with respect to a number of medications and medical devices currently used in clinical practice,13 but their risks and benefits regarding agents in the discovery pipeline will remain unknown until women are equitably represented and sex differences are explored.40

The FDA and the Office of Human Research Protections make few mandates but many recommendations for how IRBs should function. Among these, the FDA recommends that IRBs follow their guidelines on the inclusion of women and reporting of sex differences.28 A recent study, however, demonstrated that the IRB is not actually providing this oversight.63 Of protocols submitted to the IRB at a research-intensive university in 2015, 63% focused on topics in which there was at least moderate evidence for sex differences in the literature, but of these protocols, only 5% justified why the researchers chose a particular study population and only 2% stated that the researchers would consider the impact of sex or gender on their results. Therefore, a large gap remains in the consideration of SABV in IRB protocols, and IRBs have the opportunity and responsibility to fill this regulatory gap.

Institutional animal care and use committees

Local IACUCs are similarly positioned to encourage consideration of sex differences within preclinical studies.66 Given that the underrepresentation of women is far worse for cell, tissue, and animal studies than human studies,57 the IACUC could play a powerful role in regulating research efforts to address sex differences in preclinical studies before potential drugs and devices are studied in humans.66 Identifying sex differences earlier in the drug and device development pipeline has the potential to mitigate risks and costs later on. Although IACUCs are sometimes perceived as a “bureaucratic burden, regulatory necessity, and compliance tool,” a well-functioning IACUC has the potential to enhance the scientific quality of research, ensuring the reproducibility of animals studies and translational success of animal models.67

Practical Steps for How IRBs and IACUCs Could Promote Consideration of SABV

IRBs and IACUCs could draw upon some of the same methods employed by the FDA and NIH to improve representation of women in clinical trials, female animals in preclinical studies, female-derived cells and tissues in basic science research as well as to encourage reporting of outcomes by sex. The IRB and IACUC could train review committees on what it means for researchers to consider SABV9 using the NIH Office of Research on Women's Health online courses that are free and available to the public (https://sexandgendercourse.od.nih.gov).68 Furthermore, to standardize the protocol review process in which reviewers evaluate whether researchers have adequately considered SABV, the IRB and IACUC could provide reviewers with a checklist of questions to guide their evaluation (see below for an example).

  • 1.

    Have the researchers conducted a literature review based on their research question to determine whether sex/gender may play a role?

  • 2.

    Will the researchers include both male and female participants, animals, tissues, or cells in the sample? If not, do the researchers provide a strong justification?

  • 3.

    Will the researchers adequately represent both male and female participants, animals, tissues, or cells in the sample? If not, do the researchers provide a strong justification?

  • 4.

    If including both male and female participants, animals, tissues, or cells, have the researchers considered sex/gender in the design of the study?

  • 5.

    If including both male and female participants, animals, tissues, or cells, have the researchers considered sex/gender in the data analysis plan?

IRB and IACUC reviewers could also draw upon the same decision tree that NIH reviewers use to evaluate SABV in grant applications.69 Like the SABV policy, researchers would be asked to consider SABV, but it would not be a mandate to adequately represent both sexes (with respect to the proportion of the study sample or the disease population) or even include both sexes as long as a compelling justification were provided. An adequate justification could be that the NIH (or another funding agency) that requires consideration of SABV has approved funding for the proposed subject population. The goal is to ensure that researchers consider the possibility that sex differences could matter for their research question early on in the research process. By requiring researchers to consider SABV during protocol submission, the IRB and IACUC could contribute to a research pipeline that requires researchers to consider SABV across the research process—from the review of the protocol to the review of the manuscript.

Despite the fact that research studies submitted to the IRB are often pilot studies with smaller sample sizes, requiring researchers to consider the possibility of sex differences could lead to more informed research questions and better study designs earlier in the research pipeline. For researchers including both sexes, IRBs should require researchers to delineate in their protocols an analysis plan to test for sex differences and encourage researchers to report the results of these analyses regardless of whether or not the study is sufficiently powered to detect an effect (for guidance on analyzing and reporting sex-specific data, see Institute of Medicine70). Even if the study is underpowered to find statistically significant effects, patterns that emerge could be utilized to inform future studies and effect sizes could be included in meta-analyses.

Discussion

Accounting for sex begins with the development of the research question and the design of the study. Regulations that require researchers to considering sex differences at protocol development are critical because the choice of study population, study design, and analytic plan still can be improved upon.71 This role is particularly critical for studies that do not need FDA approval or do not have NIH funding, which might otherwise lack oversight. While a recent review called upon the NIH, FDA, scientific journals, peer reviewers, scientists, and clinicians to foster further change,1 to our knowledge, the potential role of the IRB in promoting consideration of sex within clinical studies has not been discussed in the literature and the potential role of the IACUC has been mentioned only briefly.66 The health of women and the rigor and reproducibility of science will be improved if sex is adequately considered in research studies. The IRB and IACUC are well positioned to encourage researchers to consider SABV early on and could contribute to a research pipeline that produces knowledge that is not only more reliable but more equitable as well.

Author Disclosure Statement

C.N.E. consults for Sage Therapeutics and Asarina Pharma and was an investigator for a multisite clinical trial conducted by Sage Therapeutics. No other authors report commercial relationships with financial interest.

Funding Information

This work was supported by funding from the National Cancer Institute grant number R01 CA215587 (Dr. Epperson).

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