Today, women make up approximately 49 percent of participants involved in medical research trials — a number that legally wasn’t required to exist in the United States before 1993 (1).
You read that right; It wasn’t until the early 90’s that Congress decided to mandate the inclusion of women in research sponsored by the National Institute of Health (NIH). They did this to observe any differences in health outcomes and effects that may result from gender — a key difference that had previously never really been deemed important enough to consider…
“Many clinical trials ran under an unspoken assumption that the only difference between women and men was their sexual and reproductive organs. Women were, in essence, considered small men.”
— Dr. Regine Douthard
In reality, there exists a range of biological and physiological differences between the sexes — from circulating levels of endogenous hormones, like estradiol and testosterone, to metabolic enzymes, plasma proteins, muscle mass, and even percentage body fat.
By not taking any of these factors into account before the legislation in 1993, it’s no wonder why women’s health continues to lag. This article attempts to break some of it down.
*For purposes of this article, the terms “man” and “woman” are being used to reflect a binary notion of biological sex. This is not to dismiss the sociocultural understanding of gender as a construct, nor the validity of non-binary individuals. The definitions of what it is to be a man or woman are infinitely more complex — and distinctly not characterized by sex.
What Is Clinical Research?
To fully grasp the long-term exclusion of women from clinical research, it’s important to understand the four key areas encompassed by the term. Namely, these are:
- Epidemiology — the study of patterns, risk factors, and disease mechanisms within a given population or populations.
- Clinical research trials — the testing and evaluation of health outcomes and effects following medical intervention
- Behavioral studies — the understanding of human behavior in the context of medicine and health
- Health services — the assessment of how people access health services as well as their interactions with health care providers
While the study of epidemiology, human behavior, and health services are all vital to the field of modern medicine in their own way, clinical research trials are really what lies at the heart of all medical advancements today.
Not only do clinical trials help us test and measure the effects of new surgical devices or drug combinations, but they also provide us with invaluable data on the different ways human beings might be impacted by specific types of intervention — from people with chronic illness to acute injury, and everyone in between. From a healthcare perspective, clinical trials are the reason scientists and doctors know how to save lives…
So, aside from the obvious issues, a gender discrepancy might pose, some major reasons why the restriction of clinical trials exclusively to the male population poses some serious problems for another half of the (penis-less) world.
Sex Differences in Clinical Trials
Take heart disease, the number one killer of US women, for example. Data shows that women with heart disease consistently and significantly have worst outcomes here than men, with research indicating that women are seven times more likely to be misdiagnosed and discharged from the hospital while having a heart attack (2).
A build-up of cholesterol plaque can present differently — both visually and symptomatically — in the arteries of a male versus a female, with life or death consequences for those a diagnosis might miss.
Because the vast majority of clinical trials on cardiovascular health are predicated on male sufferers of the disease, women are at an immediate disadvantage when receiving adequate medical attention for their health.
Drastic differences between the sexes exist for more than just one disease, affecting diagnosis rates, severity, and overall outcomes, too (3).
Studies show that women have a 20–70% higher risk of developing lung cancer for men and women who smoke the same number of cigarettes. Other issues such as STIs also disproportionally affect women regarding susceptibility, the expression of symptoms, and the possibility of long-term complications (4, 5).
With that said, women are perhaps most significantly impacted when it comes to prescription drugs, as most of the medicine we use day-to-day would have been clinically tested and approved long before 1993. As a result, research on how women might be uniquely affected by these drugs has only recently begun to emerge, and, safe to say; there is still so much that remains to be sufficiently understood (6).
In an analysis of prescriptions drugs that were withdrawn from the market between 1997 and 2001, researchers found that 8 of the 10 drugs that they tested posed “significantly greater health risks for women” due to unaccounted for pharmacodynamic (PD) and pharmacokinetic (PK) differences resulting from sex (7).
Pharmacodynamic (PD) is the scientific term for studying what the drug does to the body, while pharmacokinetic (PK) study entails the interaction of what the body does to the drug.
For example, because women tend towards having a higher percentage of body fat, any drugs containing lipophilic agents (chemical compounds with the ability to dissolve in fat) risk undergoing an increased rate of distribution within the body, resulting in an array of potentially dangerous effects (8,9).
In this sense, differences in body size and body composition between the genders can lead to the same dosage of a drug having a much stronger effect in an average female body than an average male, with consequences for both PD and PK reactions. Here, administering drugs based on a fixed dosage and not the body weight and composition of the patient is highlighted.
While the gender gap pertaining to clinical trials is slowly but surely improving, there is still evidence that women, and especially minorities, are overall less likely to seek participation in research than men (10).
With a dark history of discriminatory medical practice and a generally ignorant and unethical past approach to women’s issues, the field of medicine has a long way to go in proving its safety and efficacy in the protection of female health. Critical differences between the genders require an examination at all levels, from genetic and cellular, to organismal and social.
…and no, women are not to be considered “just small men.”
Alexandra Walker-Jones — May 2021
Text References:
- Feldman S, Ammar W, Lo K, Trepman E, van Zuylen M, Etzioni O. Quantifying Sex Bias in Clinical Studies at Scale With Automated Data Extraction. JAMA Netw Open. 2019;2(7):e196700. doi:10.1001/jamanetworkopen.2019.6700
- Nabel EG. Coronary heart disease in women — an ounce of prevention. N Engl J Med. 2000 Aug 24;343(8):572–4. doi: 10.1056/NEJM200008243430809. PMID: 10954767.
- Pinn VW. Sex and gender factors in medical studies: implications for health and clinical practice. JAMA. 2003 Jan 22–29;289(4):397–400. doi: 10.1001/jama.289.4.397. PMID: 12533102.
- National Institute on Drug Abuse Treatment Clinical Trials Network. [accessed 2015 Dec 6]; Successfully Including Women in Clinical Trials. A Guide for Researchers. Available athttps://www.drugabuse.gov/sites/default/files/womens-brochure_1025-004_508.pdf
- Centers for Disease Control and Prevention. [accessed 2015 Nov 28]; Ten ways STDs impact women differently from men. Available at http://www.cdc.gov/std/health-disparities/stds-women-042011.pdf
- Liu, K. A., & Mager, N. A. (2016). Women’s involvement in clinical trials: historical perspective and future implications. Pharmacy practice, 14(1), 708. https://doi.org/10.18549/PharmPract.2016.01.708
- Heinrich, J., Gahart, M. T., Rowe, E. J., & Bradley, L. (2001). Drug safety: most drugs withdrawn in recent years had greater health risks for women. A letter to The Honorable Tom Harkin, The Honorable Olympia J. Snowe, The Honorable Barbara A. Mikulski, United States Senate, The Honorable Henry Waxman, House of Representatives. Washington DC: United States General Accounting Office.
- Parekh A, Fadiran EO, Uhl K, Throckmorton DC. Adverse effects in women: implications for drug development and regulatory policies. Expert Rev Clin Pharmacol. 2011 Jul;4(4):453–66. doi: 10.1586/ecp.11.29. PMID: 22114855.
- Pardue, M. L., & Wizemann, T. M. (Eds.). (2001). Exploring the biological contributions to human health: does sex matter?
- National Institutes of Health (US). Office of Extramural Research, NIH Outreach Notebook Committee, & NIH Tracking/Inclusion Committee. (2002). Outreach Notebook for the Inclusion, Recruitment, and Retention of Women and Minority Subjects in Clinical Research: Principal Investigators’ Notebook (№3). National Institutes of Health, Office of Research on Women’s Health, Office of Extramural Research, NIH Outreach Notebook Committee, NIH Tracking, and Inclusion Committee.
