Addressing Sex Disparities in Clinical Trials
Why is sex in clinical research? Why is it important? Learn all about it and how the sexes are (mis)represented in research.
Capturing Sex in Clinical Research
In the world of health innovation, clinical trials help us understand the efficacy of new technologies with the help of research participants.
Sex and gender are two important measures that need to be captured in clinical trials and research studies. Previously used interchangeably, sex and gender are distinct measures. In clinical research, sex refers to biological, genetic, and physiological processes of the individual. Gender, on the other hand, captures behavioural, psychological, and cultural traits by individuals and is considered a spectrum1 rather than a binary. Sex and gender can both directly impact what is being studied, or become relevant when analyzing research data, and have an impact on how an individual chooses, responds to, and metabolizes to a particular drug.2
Capturing sex is particularly important because in clinical trial research because physiological differences, especially in terms of hormone levels, can impact how an individual responds to a drug or treatment. The problem that we continue to face is that certain sexes are underrepresented in different research areas. Unfortunately, this problem has long-standing roots.
Historical Reasons for Underrepresentation
Unsurprisingly, gender roles and the expected behaviours that are associated with them have played a big role in the underrepresentation of both men and women in certain clinical settings.
Women were discouraged from participating in clinical trials for their believed safety
Women were typically excluded from studies because it was believed that due to fluctuating monthly hormones, it would be very complicated to include them in research3. From a reproduction standpoint, it was also believed that women should be excluded from clinical trials for their own safety. Due to the potential damage of certain drugs during pregnancy, there was a fear of women being hurt if they joined clinical trials, leading to the 1977 FDA guideline which excluded women from participating in clinical trials.4
Men may avoid seeking healthcare & want to appear 'brave' and 'manly'
Gender roles may also be a reason to influence how men and women are treated in research settings. As recently as 2018, a review of 77 research studies found that there were gender biases affecting how men and women were treated and perceived when being treated for chronic pain.5 Researchers found that men were stoic and avoided seeking healthcare and didn’t talk about pain, wanting to appear ‘brave’ and ‘manly.’5 This historic idea of ‘brave men’ is a big contributing factor to men being poorly represented in mental health research and often being missed for mental health diagnoses.6
While researchers, healthcare providers, educators, and much of the world is working towards breaking gender roles and the barriers they have historically presented, there are still gaps in clinical trial research.
Underrepresentation of Sexes in Research
Males Underrepresented in Musculoskeletal & Psychology Research
Unfortunately, the historic underrepresentation of men in psychological research has not seen many strides in the past 15 years.
Men only made up 40% of participants in psychodynamic studies
An analysis of 86 psychodynamic studies from 2007-2017 found that men comprised only 40% of the research sample and the studies they were represented in tended to focus on addiction, meaning they were left out of research on many other disorders.7 Shockingly, 11% of studies had no male participants and 23% only had six or less.7
Continuing with the bias that men are meant to be strong and fight through pain, men are also underrepresented in musculoskeletal clinical trials8 that examine injuries or disorders of the muscles, nerves, tendons, and joints.9
Women Underrepresented in Research On Certain Health Conditions
A study which examined clinical trials conducted between 2000-2020 found that women are underrepresented in clinical trials in cardiology, oncology, neurology, immunology and hematology.8
Women make up a minority of clinical trial participants for conditions where they make up a majority patient population
For example, an analysis of 13,000 clinical trials found that women comprised only 39% of clinical trial participants for cardiovascular disease even though they make up just over half the patient population for this condition (51%).10 In conditions where women make up a majority of the patient population, such as chronic kidney disease (57%), they make up a minority of the clinical trial population (only 42%).10
Consequences of Underrepresentation
The big consequence of misrepresenting the sexes in clinical trials is that the results of these trials inform how doctors and healthcare professionals treat patients. If clinical trials are not representative of both sexes, health practitioners can treat patients based on gendered and possibly inaccurate findings.
A famous example of how big the real-life consequences of clinical trials can be illustrated by the difference in how women and men experience heart attacks. We’ve heard the classic example of how a heart attack can feel like an ‘elephant sitting on your chest.’ This symptom may be somewhat common for men, but it is often not for women. Women may instead experience shortness of breath, dizziness, light-headedness, or pressure or pain in the lower chest and upper abdomen.11
Women are less likely to survive heart attacks
The symptoms for women might not present as dramatically as the classic depiction of a man clutching his chest in pain; in fact, it might even feel similar to indigestion10 or the flu11 to some women. The consequence, however, is that these lesser known presentations of a heart attack might be partly responsible for women being less likely to survive heart attacks, especially when they’re treated by male physicians.10
Male mortality rate in the USA continues to rise but men aren't properly represented in mental health research
Another vicious cycle that hurts men is their underrepresentation in mental health research and psychiatry trials.8 This underrepresentation is dire because their exclusion means that clinicians are not properly equipped to understand men's response to mental health treatments, a fact made more horrifying due to the rising rate of morbidity and male mortality in the USA due to suicide, violence, and substance abuse.8
Another research study found that there’s a dire need for gender-specific services for men with depression, as the symptoms for depression among men may be atypical.12
How Underrepresentation is Being Addressed
Research organizations have been working hard to ensure that research and clinical trials are inclusive of both genders, having instituted measures to ensure this:
- The Canadian Institutes of Health Research made is so that all grant applications must address whether they have considered sex and gender since 201013
- The Horizon 2020 guideline, released by the European Commission in 2014, made the rules for sex and gender inclusion important elements for grant evaluation and monitoring13
- By 1993 the National Institutes of Health required the inclusion of women in clinical research and by 2015 they required the consideration of sex as a biological variable in study design, analysis, and reporting13
These changes are a step in the right direction to get researchers to seriously consider sex and gender in their research studies, but they are changes that are shockingly recent. Additionally, privately funded research may not need to adhere to these rules.
Researchers can venture to make studies more inclusive by thinking about who will be affected by their study and creating a study design that is inclusive of these individuals and we can do this by going out and joining studies, check out some interesting ones below!
Honeybee
Connects the community with research. Honeybee is a web and mobile app to participate in research, discover yourself, and earn cash and rewards.
References
1. Miller VM. Why are sex and gender important to basic physiology and translational and individualized medicine? American Journal of Physiology-Heart and Circulatory Physiology. 2014;306(6):H781-H788. doi:10.1152/ajpheart.00994.2013
2. Clayton JA, Tannenbaum C. Reporting Sex, Gender, or Both in Clinical Research? JAMA. 2016;316(18):1863-1864. doi:10.1001/jama.2016.16405
3. Brazil R. Why we need to talk about sex and clinical trials. The Pharmaceutical Journal. Accessed August 13, 2021. https://pharmaceutical-journal.com/article/feature/why-we-need-to-talk-about-sex-and-clinical-trials
4. Commissioner O of the. Gender Studies in Product Development: Historical Overview. FDA. Published online February 28, 2020. Accessed August 13, 2021. https://www.fda.gov/science-research/womens-health-research/gender-studies-product-development-historical-overview
5. “Brave Men” and “Emotional Women”: A Theory-Guided Literature Review on Gender Bias in Health Care and Gendered Norms towards Patients with Chronic Pain. Accessed August 13, 2021. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5845507/
6. Smith DT, Mouzon DM, Elliott M. Reviewing the Assumptions About Men’s Mental Health: An Exploration of the Gender Binary. Am J Mens Health. 2018;12(1):78-89. doi:10.1177/1557988316630953
7. Men Underrepresented in Psychological Research Studies. GoodTherapy.org Therapy Blog. Published September 10, 2011. Accessed August 13, 2021. https://www.goodtherapy.org/blog/men-underrepresented-psychological-research-studies/
8. Women and men are each underrepresented in clinical trials of different medical fields. Accessed August 13, 2021. https://news.northwestern.edu/stories/2021/06/women-and-men-are-underrepresented-in-clinical-trials/
9. Work-Related Musculoskeletal Disorders & Ergonomics | Workplace Health Strategies by Condition | Workplace Health Promotion | CDC. Published May 12, 2021. Accessed August 13, 2021. https://www.cdc.gov/workplacehealthpromotion/health-strategies/musculoskeletal-disorders/index.html
10. Why are women still underrepresented in clinical research? — Quartz. Accessed August 13, 2021. https://qz.com/1657408/why-are-women-still-underrepresented-in-clinical-research/
11. Heart Attack Symptoms in Women | American Heart Association. Accessed August 13, 2021. https://www.heart.org/en/health-topics/heart-attack/warning-signs-of-a-heart-attack/heart-attack-symptoms-in-women
12. Stiawa M, Müller-Stierlin A, Staiger T, et al. Mental health professionals view about the impact of male gender for the treatment of men with depression - a qualitative study. BMC Psychiatry. 2020;20(1):276. doi:10.1186/s12888-020-02686-x
13. Sex and Gender Differences Research Design for Basic, Clinical, and Population Studies: Essentials for Investigators | Endocrine Reviews | Oxford Academic. Accessed August 13, 2021. https://academic.oup.com/edrv/article/39/4/424/4967741