Irene O. Aninye, PhD, Chief Science Officer at the Society for Women’s Health Research, examines the consequences of overlooking sex and gender differences in research and clinical care
The crux of a research design – from basic research to clinical trials – is the manipulation of variables. Which variables are independent, dependent, and controlled? How many variables will be studied? How many samples will be required? While the combinations of approaches are limitless, every final research plan has its limitations.
In the end, the core question is: how well is a study positioned to provide solutions for the groups it was intended to serve? Unfortunately, when the target audience is women, too many biomedical research studies are inadequately designed to provide good health solutions. A key omission in their capacity to address the unique health needs of women is the study and analysis of sex and gender differences in health and disease.
Sex and gender differences in health and disease
Gender health gaps in the United States, and even globally, are irrefutable. Sex, gender, and hormones profoundly contribute to distinct bodily processes and health outcomes. The historic undervaluation of these factors and over-reliance on male subjects in medical research has led to myriad health disparities for women. Lupus is an autoimmune disease that disproportionately affects women, who comprise 90% of diagnosed cases. Psoriatic arthritis has similar prevalence between the sexes but affects women differently than men; women are less likely to respond to certain treatments or achieve remission than male counterparts. Menopause, a life stage exclusive to women, prompts hormonal and physiological changes that drive very different health outcomes in older age for women and men. When the incidence or pathology of a disease skews for one group, neglecting inquiry into these causes leaves blind spots in our ability to navigate health for all.
A history of gender bias and exclusion
Less than 50 years ago, U.S. Food & Drug Administration (FDA) guidelines advised against the participation of women of child-bearing potential in the clinical evaluation of drugs. Concerns lay primarily in the unknown impact on maternal and infant health. Studies with male animal and human subjects were just presumed easier, not having to consider hormonal cycling throughout menstruation, drug effects on fetal development (teratology), or estrogen depletion during menopause – but these are all key factors that have since been demonstrated to influence disease pathology and drug metabolism, among other aspects of health.
These factors cannot and should not be ignored simply on the basis of complexity and cost. But at the time, the medical research community failed to do what it is essentially charged to do – to pursue strategies to answer the hard and much-needed questions to improve human health.
Persistent advocacy from scientists, healthcare providers, and other partners levied inquiry into these error-driven policies and focused on educating policymakers about their pitfalls and opportunities to safely update these gender-biased practices. In 1993, the National Institutes of Health Revitalization Act mandated the appropriate inclusion of women in clinical trials to better understand sex differences in diseases and therapeutics. However, the paradigm was not so easily unraveled and re-written throughout the research community. Study designs now required strategies to investigate sex differences throughout the biomedical discovery continuum – from cell line development and animal husbandry to clinical trial recruitment and retention. Many scientists, however, were not sufficiently trained to execute these studies. Even today, biomedical research funding in the United States still favors men; diseases that disproportionately affect women are underfunded, while diseases that predominantly affect men are overfunded with respect to disease burden.
Learning from the past
Previous single-sex cardiovascular disease studies failed to illuminate the differential preventive effects of low-dose aspirin in women versus men. In 2013, insufficient sex-based analysis in the administration of zolpidem, an insomnia drug, caused the FDA to revise dosing guidance that indicated slower metabolism in women compared to men. Most recently, the launch of COVID-19 vaccines in 2021 had no accompanying guidance for pregnant and lactating populations, as they were not included in the early clinical studies, leaving them vulnerable and without scientific evidence to make informed decisions about their and their baby’s health during a frightening pandemic. These examples illustrate why there is never an acceptable time to ignore sex differences in research.
While studies that were not originally designed to examine sex differences often lack the statistical power to perform such retroactive subgroup analyses, the future is hopeful. With advancements in digital technology and Machine Learning algorithms, there could be potential to re-analyze data in search of sex and gender nuances. And the more we educate about the long-term benefits of studying sex and gender in biomedical research, the more likely it is to be included from the start.
This brings us back to the foundation of research: how well is a study positioned to provide solutions for the groups it was intended to serve? Overlooking the gender gap is unacceptable because we now have the tools. With intentional engagement of women across the biomedical ecosystem, we will actualize the answer to this question loudly and clearly: by involving women at all levels of biomedical research, from lead investigators to clinical trial participants, studies are powerfully positioned to provide solutions personalized for women and applicable for all. Thank you for asking.
