Health outcomes in women vs. men and why clinical trials are so important for tackling gender-based health disparities

What contributes to different health outcomes in women vs. men

Factors that contribute to different health outcomes in women are widespread, ranging from how the social norms, expectations and responsibilities placed on women can impact their access to healthcare services and research settings, through to molecular and cellular differences between men and women.¹ Physiological variations may translate into differences in pharmacokinetics and/or pharmacodynamics for specific drugs, meaning that medications can work or be processed differently in people of different sexes.²

Given my background in pharmacovigilance, I’m acutely aware that too many medications have been developed and approved which have later proven to be sub-optimal or even unsafe for women. For example, the medication Dofetilide was approved in 1999 to help control irregular or fast heart rhythms (atrial fibrillation). Despite this, it was only in 2018 that a study found that the recommended twice daily dose was too high in over half of female participants, as they developed other abnormal heart rhythms which could carry a risk of cardiac arrest.³ In the original phase III DIAMOND study there were only 61 women compared to 188 men in the treatment arm, with females constituting less than a quarter of all trial participants.⁴ Sadly, this gender divide in clinical trials is often seen. Only in the last decade has this been highlighted as a cause of significant concern.

The sex and gender gap in scientific research

An unequal gender divide isn’t just present in late-stage human trials, but also in early-stage cell and animal testing. It was recently found that fewer than half of in vitro studies report the sex of their cells, and where they do, they are more likely to use cells which are male.⁵ In another study across ten fields of biology, it was found that 80% of the animals used in early-stage research were male.⁶ Given these findings, it is perhaps unsurprising that women are 50-75% more likely to experience adverse drug reactions than men.⁷

One reason why this gender imbalance has been historically overlooked is because of the so-called ‘bikini medicine’ approach, a worrying misconception that women’s health only differs from men’s in the parts of the body that a bikini would cover. Sadly, this perception is still evident in scientific research today. Analysing the health content of around 1,500 articles from major medical journals, a study found that the proportion of women’s health content focused on reproductive health had increased between 2010-2020, whereas areas such as cardiovascular disease, infectious diseases, and musculoskeletal disorders – which pose a greater burden to women worldwide – were under-represented.⁸‘⁹

This dominant focus on reproductive health, combined with overwhelmingly male-centric preclinical and clinical datasets, has contributed to worse health outcomes in women across a range of areas. For example, women are more likely to suffer with chronic pain and experience a higher chance of diagnosis later than men across hundreds of diseases, including some types of cancer.¹⁰‘¹¹

Why does this gap exist?

The current underrepresentation of women in research stems from several historical failings and has been perpetuated by societal factors. In 1977, due to the thalidomide tragedy and concerns about potential risks to foetal health, the Food and Drug Administration (FDA) recommended excluding women of childbearing potential, including those using contraception or with vasectomised partners, from early-stage drug trials.

While this blanket FDA exclusion rule was lifted almost three decades ago, low participation amongst women persists for several reasons. One significant concern is the potential ethical, financial and legal risks that sponsors may face if a female participant becomes pregnant during a trial. This concern stems from the need to ensure the safety of both the mother and foetus, which adds complexity to the study protocols and increases liability for sponsors. Moreover, woman may experience a greater risk of adverse reactions to medications and interventions compared to men, which may also lead to added burdens such as the disruption of daily activities, decreased quality of life, and increased financial costs.⁷‘¹² These adverse reactions may deter some women from participating in clinical trials.

Additionally, motherhood, resulting in juggling multiple responsibilities, and caregiving commitments shouldered by many women often mean they lack the time to participate in research. Furthermore, study design can be complicated due to age-related changes, such as the menopause which may introduce additional variables and considerations that need to be accounted for in the design and methodology of the trial.

What is being done to combat this issue?

It is essential that scientific research, from a cellular level, through animal testing and into clinical trials, particularly early phase trials, include more female representation to ensure better health outcomes and safety of healthcare interventions for women. This is not only for ethical and moral reasons, but to ensure more rigour and richness in the pursuit of understanding human biology, which could pave the way for future breakthroughs.

Gender equality in scientific research could bring with it significant economic impact at the individual and national level. According to recent projections, tackling the 25% disparity in the time spent by women in "poor health" compared to men could lead to an annual economic boost of at least $1 trillion globally by 2040.¹³

Encouragingly, steps are being developed to try to address gender inequalities in clinical trials. For example, the UK Health Research Authority (HRA) and Medicines and Healthcare products Regulatory Agency (MHRA) are working on new inclusion criteria for all clinical trials conducted in the UK to ensure greater diversity in research. These inclusion goals aim to prevent people with disabilities and women of childbearing age, including pregnant women, from being automatically excluded from trials. However, while this is an important step, guidelines alone are not enough. There needs to be more innovation in trial design, utilising technological advancements and tapping into real world data sources to support a decentralised approach, to help stimulate more female recruitment and at home self-sampling to alleviate the inequality burden further.

What steps are NWEH taking?

At NWEH, one of our core priorities is ensuring diversity and inclusivity in clinical trials, including women and hard-to-reach populations, to ensure trial outcomes and future treatments are inclusive and applicable to the widest possible patient demographic. As mentioned, decentralised trials harnessing real world data sources and innovative technological solutions that reduce the burden on clinical trial participants are essential to enabling wider and more diverse participation, and NWEH’s unique systems are well suited to supporting the delivery of these types of trials.

Women need the tools to take more control and ownership of their involvement in clinical research. Instead of waiting for regulatory requirements to drive change it is our ambition to make it possible for women to take an active step in increasing their inclusion in scientific research.

If you would like to get involved, please get in touch via the contact for below.

Claire Williams

Head of Pharmacovigilance and Regulatory Services

References:

1. Mauvais-Jarvis F, et al. Sex and gender: modifiers of health, disease, and medicine [published correction appears in Lancet. 2020 Sep 5;396(10252):668]. Lancet. 2020;396(10250):565-582.

2. Brabete AC, et al. A Sex- and Gender-Based Analysis of Adverse Drug Reactions: A Scoping Review of Pharmacovigilance Databases. Pharmaceuticals (Basel). 2022 Feb 28;15(3):298.

3. Pokorney SD, et al. Dofetilide dose reductions and discontinuations in women compared with men. Heart Rhythm. 2018 Apr 1;15(4):478–84.

4. Pedersen OD, et al. Efficacy of dofetilide in the treatment of atrial fibrillation-flutter in patients with reduced left ventricular function: a Danish investigations of arrhythmia and mortality on dofetilide (diamond) substudy. Circulation. 2001 Jul 17;104(3):292-6.

5. Kim JY, et al. Sex omission and male bias are still widespread in cell experiments. Am J Physiol Cell Physiol. 2021 May 1;320(5):C742-C749.

6. Beery AK, et al. Sex bias in neuroscience and biomedical research. Neurosci Biobehav Rev. 2011 Jan;35(3):565-72.

7. Rademaker M. Do women have more adverse drug reactions? Am J Clin Dermatol. 2001;2(6):349-51.

8. Hallam L, et al. Does Journal content in the field of women’s health represent women’s burden of disease? A review of publications in 2010 and 2020. J. Women’s Health. 2022 May 1;31(5):611–9.

9. Global Burden of Disease Collaborative Network. Global Burden of Disease Study 2019. Last accessed February 2024: VizHub - GBD Compare (healthdata.org)

10. Samulowitz A, et al. "Brave Men" and "Emotional Women": A Theory-Guided Literature Review on Gender Bias in Health Care and Gendered Norms towards Patients with Chronic Pain. Pain Res Manag. 2018 Feb 25;2018:6358624.

11. Westergaard D, et al. Population-wide analysis of differences in disease progression patterns in men and women. Nat Commun. 2019 Feb 8;10(1):666.

12. Zopf Y, et al. Women encounter ADRs more often than do men. European Journal of Clinical Pharmacology. 2008 Jul 5;64(10):999–1004.

13. Ellingrud K et al., Closing the women’s health gap: A $1 trillion opportunity to improve lives and economies. McKinsey Health Institute. 2024 Jan 17. https://www.mckinsey.com/mhi/our-insights/closing-the-womens-health-gap-a-1-trillion-dollar-opportunity-to-improve-lives-and-economies