Sex-Based Biomedical Research Policy Needs an Implementation Plan

“The NIH announced last May that it will begin developing policies and guidelines to ensure that preclinical research funded by the NIH includes both male and female animals and cells; however, as of today, there has been no implementation of that promised policy.”

In February 2014, the Leadership Council of the Women's Health Research Institute, a multidisciplinary panel of renowned researchers, scientists and clinicians, wrote a letter to the NIH Director Francis Collins urging that policies be developed to require the inclusion of sex as a variable in all research and the reporting of the sex of animals and cells in all NI refunded basic research. The NIH announced last May that it will begin developing policies and guidelines to ensure that preclinical research funded by the NIH includes both male and female animals and cells; however, as of today, there has been no implementation of that promised policy. Here, we discuss the state of scientific inquiry related to sex/gender in biomedical research and again call upon the NIH to disseminate a policy that requires basic scientists and clinical investigators to describe sex in research in the same way that they report time, temperature and dose. Furthermore, we challenge scientists to include both male and female animals to promote comparison of results.

Since the passage of the NIH Revkalization Act in 1993, there has been an increased enrollment of women in clinical trials, thereby demonstrating that enacted public policies can change the way scientists conduct their work. Unfortunately, nearly two decades later, the proportion of women enrolled in nonsex-specific studies remains inadequate (43% in 2004, 38% in 2009), outcome by sex has not been reported in 64% of studies, and sex-specific analyses remain low [1,2]. The Women's Health Research Institute (WHRI) at Northwestern University is committed to the full inclusion of both sexes in all levels of medical research, from basic science to translational exploration and, ultimately, to clinical research. Advocacy related to this issue has been a driving force behind our Institute since its inception in 2007. In February 2014, the Leadership Council of WHRI wrote a letter to Francis Collins, Director of the NIH, to advocate for the development and implementation of guidance and policies requiring sex inclusion in all NIH-funded basic research (Supplementary data; see online at www.futuremedicine.com/doi/full/10.2217/WHE.15.28). Shortly thereafter, the NIH announced its decision to develop policies “that require applicants to report their plans for the balance of male and female cells and animals in preclinical studies” [3]. Unfortunately, no such policy has appeared to date. We see XX and XY as ‘gateway chromosomes’ to understanding sex-based biology and create personalized treatments and medicines. We believe that instituting sex inclusion requirements within NIH-funded basic science will ignite a new generation of scientific discovery and precision medicine. Here, we again call upon the NIH to act on this very important issue by providing policy guidance on sex inclusion in biomedical research grants.

Lack of female cells & animals in basic science research

There is a misconception that the 1993 NIH Revitalization Act addressed sex inequities at all levels of research. To clarify, this legislation focused only on the inclusion of women and minorities in clinical research and neither addressed sex equity nor the inclusion of both sexes in basic research using animals and cells. When it comes to inclusion of sex as a variable in basic bench research – the less expensive precursor to clinical research – the numbers are disarmingly grim. To better determine the extent of the problem, members of our Leadership Council began reviewing high-impact journals to determine the status of cell and animal sex inclusion in each of their disciplines. In one published study, Yoon et al. evaluated all publications in five major surgery journals in 2011 and 2012 and found that 32% of the peer-reviewed publications studying animals or cells did not report the sex of the animals studied [4]. When the manuscript did report the sex, 80% studied only males and only 3% studied both sexes. For female prevalent diseases such as thyroid and cardiovascular diseases, only 12% of the publications studied females. Similarly, in a review of 1244 neuroscience papers that used rodent models published in five major journals between June 2011 and May 2012, researchers found that only 42% reported the sex of the rodents [5]. Of those papers that did report sex, females were only studied 24% of the time. An ongoing assessment of dermatology journals found that 59% of cultured cell lines were not identified by sex and that most studies utilized cells obtained from male foreskin; 37% of papers studied only male skin cells while a mere 2.5% studied only female cells. Only 1.5% of papers actually compared female versus male cells for differences [haugh & kong, pers. comm.]. These studies reveal the magnitude of the problem and emphasize the risk we take by not requiring or reporting the inclusion of sex as a variable in all cell, animal and human studies. Including only one sex in research studies limits our understanding of disease pathogenesis and the discovery of novel therapies that may be more effective – or conversely, might cause devastating complications – in one sex or the other. There are many drugs that have been shown to have different efficacy and exhibit different side effect profiles in men and women. Postmarketing side-effect and toxicity surveillance of Zolpidem, for instance, revealed the exquisite sensitivity of females to this sedative agent [6], and resulted in the US FDA reducing the recommended dose for adult females by half. This serious mislabeling can be avoided by systematic attention to analysis of sex differences in basic and clinical research as well as increased efforts to include women in clinical trials. The promise of precision medicine is that we will one day be able to optimize individual benefit while avoiding individualized patient harm. An essential component of achieving this goal is including both sexes in cellular, tissue and laboratory animal basic science inquiries. If our nation fails to act on our proposed initiative, we will continue to place females at risk of unnecessary harm.

Arguments against the study of both sexes at the preclinical research level center around duplication of efforts, increased costs and additional time. Yet, we argue that full sex inclusion at this ‘less expensive’ end of the research pipeline will save money, effort and time in the long run. Learning that men and women respond differently to drugs and devices at the clinical research phase could delay or terminate further clinical development, while sex-specific adverse events that arise even later, during the postmarket surveillance phase, may require removal of a treatment from the market entirely. Both of these are potentially quite costly, but avoidable, consequences. The study of both sexes at the preclinical level, in animals and cells, may also help to improve subsequent decisions regarding clinical trial study design. If we can learn where sex matters during the early phases of research, we can reduce costs in the later testing phases, reduce the risk of adverse events and improve the efficacy of drugs and devices [7].

Precision medicine requires an enlightened workforce

President Barack Obama's recent announcement about the Precision Medicine Initiative is encouraging and reinforces the need for individualized research and care. Research institutions are developing powerful new technologies and tools that enable basic scientists to explore the most finite and complex details of cell function – using proteomics, metabolomics, genomics and large-scale computational biology and data analysis. These tools will help build the evidence needed to individualize medicine but will not be sufficient if sex-based variation is not explored at a cellular and molecular level, such that basic science discovery accurately translates into better, more personalized clinical care [8].

It is in the best interest of research universities and medical schools to ensure that clinicians and scientists remain at the forefront of biomedical research that takes into account sex and gender. In 1996, the American Board of Internal Medicine released a set of recommendations to include awareness of sex differences in medical school curricula. A decade later, an independent survey found that few medical schools had fully incorporated sex-based curricula or offered clerkships in women's health [9]. As we continue to learn more about sex differences that impact health beyond the reproductive system, it becomes imperative that we include instruction on sex differences in our medical school curriculum and in continuing education programming for medical school and clinical research faculty.

Opportunities to report sex as a variable

Publication of research in the peer-reviewed literature is one of the hallmarks of a successful academic career and is required for advancement and recognition in academia. Publications also open doors to further exploration of new and innovative ideas. Yet, as already noted, many published articles failed to adequately report the sex of the study subjects, animals, or cells used in the research. Editors of peer-reviewed journals are in a unique and powerful position to require full disclosure from authors on sex inclusion in their submitted research papers. This is one area in which progress in sex inclusion in biomedical research is accelerating at a substantial clip; enlightened journal editors have made great strides in encouraging researchers to be more inclusive in their future study designs. In direct response to the findings by Yoon et al. [4] on the lack of reporting of sex in surgical journals, more than 30 prestigious journals have begun requiring authors to report the sex of their study subjects, animals, and cells as part of the submission process [10]. It is now imperative that university-based institutional review boards (which provide oversight for clinical studies) and animal care and use committees (which provide oversight for animal-based studies) develop application forms that specifically ask for sex inclusion criteria as part of each study protocol. This will ensure that clinical researchers and basic scientists alike are aware of sex inclusion policy requirements when designing their studies.

Conclusion

The data are in – sex inclusion is of critical importance to the creation of a productive and precise medical pipeline. The NIH agrees, and it is time that it introduces a clear policy guideline that will ensure sex inclusion in biomedical research, moving our community forward toward better science and better medicine.

Future perspective

We call upon the NIH to enact a policy that requires inclusion of male and female animals in extramural grants and intramural science, unless there is a clear scientific justification where studying both sexes would not be appropriate (e.g., study of prostate cells or prostate cancer). We call upon the NIH to require press releases from NIH to note the sex of animals in research breakthroughs. We call upon the NIH to mandate all publications with NIH dollars include the sex of the animals studied.