Although various US federal agencies have made improvements to legislation regarding women’s participation in clinical trials over the past few decades, recent studies demonstrate that the underrepresentation of women remains a persistent problem that raises both scientific and ethical concerns.
Even though it has been nearly two decades since the NIH Revitalization Act of 1993 mandated the inclusion of women and minorities in clinical research, the success of the law has been limited, and studies report a consistent shortage of female representation1, 2, 3, 4. For example, a 2006 study examined 661 clinical trials for drugs for non-sex specific cancer types; the researchers found that the average percentage of female participation was 38.8, despite the fact that males and females showed approximately equal rates of affliction for these cancer types3. The statistics illustrate that clinical trials fail to adequately recruit women as subjects, but even more worrisome is the fact that researchers consistently fail to analyze data of clinical trials with sex-specific results in mind2. This creates a serious problem: patients, with no sex-specific data to consider, cannot make informed decisions about undergoing treatment.
Overall, government regulations and the biomedical industry have failed to accomplish sufficient change: a study of clinical trials published over five years even goes so far as to state that the Revitalization Act “does not appear to have improved gender-balanced enrollment or promoted the use of gender-specific analyses in clinical trials”2. The reasons for this trend have roots in both scientific and societal attitudes towards women.
Historically, researchers have excluded women from clinical trials for a host of reasons. Most prominent is the widespread acceptance of the “male medical model” as being applicable to both men and women, with the latter considered a deviation from the standard. It was long thought that findings from studies involving only men were equally applicable to women, as women were thought of as “little men” with different reproductive organs. Although this attitude seems outdated, this subconscious model is still entrenched3.
In addition, the tendency of the medical community to view women as a vulnerable group reflects the paternalistic attitude that to an extent still persists4. The 1977 Food and Drug Administration recommendation that “women of childbearing potential [be] excluded from the earliest dose-ranging studies” mirrors this outlook and effectively violates the principle of informed consent and restricts a woman’s autonomy5.
Another reason behind exclusion is the potential for researchers to confound the effects of hormonal changes during the menstrual cycle with those of the drug6. Consequently, the inclusion of women requires researchers to obtain larger sample sizes for studies, leading to higher costs. The risk of long-term damage to reproductive organs and ensuing potential for lawsuits discourages both sides, researchers and women, from seeking equal representation4. However, such exclusion may not always be intentional: women tend to carry various domestic responsibilities and participation in clinical trials can be time-consuming3.
Despite the challenges of including women in clinical trials, such exclusion is scientifically infeasible – it is for the exact reasons that researchers exclude women that fair inclusion of women in clinical trials is crucial to developing targeted prevention and treatment strategies.
First and foremost, sex cannot be ignored. A 2002 NIH Institute of Medicine report emphasizes that sex is “an important basic human variable that should be considered when designing and analyzing studies in all areas and at all levels of bio-medical and health-related research”7.
The mechanisms of sex-based effects have been documented extensively: differential gene expression and certain sex hormone-mediated biochemical pathways account for these discrepancies8. Although the mechanisms of sex-based differences have been elucidated, the relationship between these facts and differential drug response remains poorly studied. If important sex-based differences can be identified in the early stages of a clinical trial, the later phases “can be designed more suitably to further clinical understanding of the appropriate use of drugs for women”5. Furthermore, women are almost twice as likely to display adverse drug reactions than men, and are also more likely to be hospitalized due to such responses9. Therefore, sex-specific analysis of trial data is urgently needed to identify these adverse drug reactions before a treatment is on the market.
The perception of women as a vulnerable group highlights the conflict between protecting women and denying them access to life-saving technology. This struggle was perhaps best reflected in the HIV therapy trials that took place in the 1990s – although the exposure of women with childbearing potential to experimental treatments was controversial, on certain occasions the potential benefits of access to treatment seemed to outweigh the risks of reproductive damage1. Eventually the 1977 FDA restriction was lifted – premenopausal women are now free to participate in clinical trials. However, the issue of pregnant women still presents a dilemma to researchers. While including pregnant women as subjects is deeply problematic, ignoring the problem is not a viable solution either. A pregnant woman who falls ill and has no choice but to take an unknown drug will essentially “participate in an uncontrolled and unmonitored experiment for which the data will most likely never be assessed”1. In such cases, researchers can collect data from women who had to take unknown drugs while pregnant. For the long term, research to develop viable strategies that eliminate risk to the mother and fetus is a worthy avenue to pursue and should be supported more widely.
Evaluating the issue of underrepresentation of women in clinical trials on a scientific level presents a host of problems; however, this trend is also deeply troubling on an ethical level.
The same repressive attitudes that are present in the medical community stem from the broader treatment of a woman by society. Whether purposely or not, women are still being excluded from trials due to various scientific and societal factors. Ultimately, limiting female participation in effect restricts the right of equal access to treatment.
Furthermore, female underrepresentation is not strictly a woman’s problem. The quality of healthcare that a woman receives affects the health of her children – inclusion of females in clinical trials will therefore have beneficial impacts for both sexes.
As society moves into an age dominated by personalized medicine, it is necessary to build a strong foundation that rests on specificity. Clinical trials for sex-specific conditions like breast and ovarian cancers have found effective methods to recruit women as subjects; therefore, expanding this system to general clinical research is a feasible goal3. Sex is a very broad category compared to other factors that affect responses to medical treatments: ethnicity, regional and cultural aspects, age, body fat content and distribution, and body size5. Addressing the broadest of these factors is a logical starting point for investigating the influence of physiological, cultural, and social environments on responses to treatments. Thus, more rigorous standards to ensure that drug testing is complete with regards to sex-specific effects are crucial transitions into an age of personalized medicine.
Ultimately, the end result of this trend, that “medicine as it is currently applied to women is less evidence-based than that being applied to men,” represents an injustice that is deeply rooted in both scientific and societal mindsets towards women10. Moving beyond these narrow perceptions poses a major shift that has implications for both the health and care of generations to come.
- Berlin J, Ellenberg S. Inclusion of women in clinical trials. BMC Med 2009; 7(56).
- Ramasubbu K, Gurm H, Litaker D. Gender bias in clinical trials: do double standards still apply? J Womens Health Gend Based Med 2001; 10(8):757-64.
- Jagsi R. Under-representation of women in high-impact published clinical cancer research. Cancer. 2009 June 8; 115(14):3293-3301.
- Prout N, Fish S. Participation of Women in Clinical Trials of Drug Therapies: A Context for the Controversies. Medscape General Medicine. 2001 Oct 31; 3(4).
- Merkatz R, Temple R, Sobel S, Feiden K, Kessler D. Women in Clinical Trials of New Drugs — A Change in Food and Drug Administration Policy. N Engl J Med 1993; 329:292-296.
- Inclusion of Women and Minorities in Clinical Research [Internet]. Society for Women’s Health Research; [cited 2012 Jan 16].
- Exploring the biological contributions to human health: Does sex matter? Institute of Medicine (US); 2001 Apr. 24.
- Anderson GD. Sex and racial differences in pharmacological response: Where is the evidence? J Womens Health 2005; 14(1):19-29
- Tharpe N. Adverse drug reactions in women’s health care. J Midwifery Womens Health 2011; 56: 205-213.
- Putting gender on the agenda. Nature. 2010 Jun 9.
- Image credit (Creative Commons): Care, Christiana. “Wilmington Wellness Day 2010.” Flickr. September 17, 2010.