Considering Sex as a Variable in Clinical Trials

January 23, 2018

Cathleen Dohrn, PhD
Nicole C. Woitowich, PhD

Article

Applied Clinical Trials

A sex-bias that significantly impacts the advancement of women’s health exists in both preclinical and clinical research.

Over the last several decades, advances in biomedical and clinical research have improved the health and well-being of all people. Some of the progress has been aided by the landmark policy set forth by the National Institutes of Health (NIH) two years ago requiring investigators to consider sex as a biological variable. In fact, there is a Resolution in Congress to declare January 25^th as National Women’s Health Research Day, thanks to the strong efforts of organizations like the Women’s Health Research Institute at Northwestern University. Despite this progress, a sex-bias that significantly impacts the advancement of women’s health exists in both preclinical and clinical research. Particularly, on the second anniversary of the NIH policy that requires investigators to consider sex as biological variable (SABV) in preclinical research, reflection on the recent history of women in research is warranted.

Historical perspective

In the past, females have been underrepresented in research studies due to the assumption that biological sex-differences did not exist outside of the reproductive system. In addition, protectionist views towards women and the roles as mothers, perhaps well-intentioned following the thalidomide tragedy of the 1960’s, led to an exclusion of women of childbearing years in clinical trials (FDA, 1977). In 1985, a report from the U.S. Public Health Service Task Force suggested that the exclusion of women from research was detrimental to women’s health (U.S. Public Health Service, 1985). While the Federal Drug Administration (FDA) issued a preclinical guidance to include female animals in 1988, it wasn’t until 1993 that they provided the guidance that pharmacokinetics and pharmacodynamics (PK/PD), safety, and efficacy, should be evaluated in both sexes. In that same year, the NIH Revitalization Act of 1993 mandated that women should be included in all NIH-funded clinical research (NIH, 1993).

While these guidelines applied to clinical research conducted in humans, female cells and animals remained under-utilized or unreported in basic science research. Within the last several years, a number of reports have demonstrated a sex-bias in biomedical research and advocated for policies to mandate sex-inclusion at the cellular and animal level and sex-specific analyses and reporting of data (Beery & Zucker, 2011; NIH, 2012; Woodruff, 2014; Clayton & Collins, 2014). On January 25, 2016, the NIH established a policy which requires investigators to “consider sex as a biological variable,” (NIH, 2015). While this policy does not mandate the use of both sexes in basic science research, it does require that investigators provide strong rationale for single-sex studies.

Sex and gender in preclinical and clinical research

In the context of preclinical and clinical research, it is essential to define both sex and gender. Sex is a biological entity, defined by the sex chromosomes and is manifested through various biochemical and cellular processes. Gender, on the other hand, is a socio-cultural construct that shapes the roles, attitudes, and behaviors associated with being male or female. Animals, cells, and humans have a sex, whereas only humans have both a sex and gender. Given that the sex of an individual can influence various biological processes, it is no surprise that various diseases and disorders impact men and women differently. For example, there are a spectrum of diseases or conditions that disproportionately affect women-for example, in the United States, women:

· make up almost two-thirds of the Alzheimer’s Disease population (Alzheimer’s Association, 2018);

· are three times more likely to have an autoimmune disease compared to men (Jacobson et al., 1997);

· are twice as likely to suffer from temporomandibular joint disorders (Warren, 2001);

· and, have a greater lifetime risk of developing asthma (American Lung Association, 2010).

Likewise, gender also plays a significant role in health and disease, shaping lifestyle choices from occupation, nutrition, and environment, to access to healthcare and doctor-patient interactions (Mastroianni, et al., 1994).

Impact of sex-based research in drug development

Given the fundamental sex differences in biology, treatments that are largely developed and evaluated in men may perform differently in women. We know that women are at nearly a two-fold greater risk of experiencing adverse drug reactions (ADR) than men (Tharpe, 2011). Forty percent of the drugs that were withdrawn from the U.S. market between 1997 and 2000 were found to pose greater health risks for women than men (Rabesandratanav, 2014). As recently as 2013, ADRs resulted in a label change for the popular sleep medication, zolpidem (AmbienÒ, Sanofi), when the FDA recognized a delayed clearance rate in women compared to men.

However, even with these increased risks, there continues to be a paucity of data differentiating the safety and efficacy of medications commonly prescribed to women (Geller, et al., 2017; Clayton & Tannenbaum, 2016). The differentiation between the sex-related data should start early in the drug development process, with preclinical and translational medicine (Clayton, 2016), and carry through to current clinical trials. In preclinical trials, the percentage of preclinical manuscripts that included females has actually dropped from 8% in 1991 to 2% in 2011 (Yoon, 2014). Physicians believe that discussions about clinical trials should be part of standard of care (CenterWatch, 2017)-this holds true for both men and women. Nonetheless, in data gathered for NIH-funded Clinical Trials, the percentage of women enrolled remained static between 2004 and 2015 (~45%). However, the analysis of the data by sex was only seen in 28% of these trials in 2015 (Geller, 2017).

Conclusion

Sex has not historically been considered as a biological variable, yet there has been guidance in place for clinical research since the 1990’s and for non-clinical research since January 25, 2016. The Institute of Medicine and National Research Council reported that the morbidity rates of women in the US are rising, while those of men are falling (2013). Is this because research is not considering sex as a biologic variable often enough? Basic science, translational, and clinical researchers in both academia and industry should thoughtfully consider how sex and gender influences their research questions and desired outcomes. In addition, collaborative partnerships and open-dialogue between academia and industry can help identify areas where sex- and gender-based research are needed to improve the health of both men and women.

References

FDA, 1977. https://www.fda.gov/scienceresearch/specialtopics/womenshealthresearch/ucm472932.htm

U.S. Public Health Service, 198.5 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1424718/

FDA, 1987.

https://www.fda.gov/scienceresearch/specialtopics/womenshealthresearch/ucm472932.htm

FDA, 1993.

https://www.fda.gov/scienceresearch/specialtopics/womenshealthresearch/ucm472932.htm

Beery & Zucker, 2011. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3008499?

NIH, 2012. https://www.ncbi.nlm.nih.gov/books/NBK84192/

Woodruff et al., 2014. https://www.ncbi.nlm.nih.gov/m/pubmed/24506076

Clayton and Collins, 2014. https://www.ncbi.nlm.nih.gov/pubmed/24834516

NIH, 2015. https://grants.nih.gov/grants/guide/notice-files/NOT-OD-15-102.html