International Women's Day: Celebration and challenge

The Society is proud to be celebrating women in pharmacology this International Women’s Day by sharing stories and asking you to tell us about the women in pharmacology who inspire you. In addition to celebration, this year’s theme is #choosetochallenge:



As we set out in our new Vision for equality, diversity and inclusion, we want everyone to have the opportunity for a successful career in pharmacology and the opportunity to benefit from research. Therefore, this year, the Society chooses to challenge the continued bias towards the male sex in pre-clinical research, and the under-representation of women, and pregnant women, in clinical research^[1][2].

Women make up around 50% of the global population, but of course are not a single group. The intersection of different identities, backgrounds and experiences mean that it is important to recognise and address where women might be particularly marginalised or have specific barriers to overcome. Research must represent, and involve, all people who stand to benefit from it.
 
If we understand how sex differences influence physiology and the response to medicines in pre-clinical research, we can help ensure a smooth transition from clinical development into practice. Conversely, a bias towards studying male physiology and the male drug response may be harmful if this leads to inappropriate treatment recommendations for female bodies^[3].

The US National Institutes of Health implemented a requirement for inclusion of both male and female samples in 2016. A recent retrospective analysis of impact concluded there have been notable improvements in reporting in 2019 compared with 2009^[4]. The number of pharmacology articles reporting use of both sexes remained static. However, pharmacology was the only biological discipline to demonstrate a significant increase in sex-based analyses over the ten-year period:  from 19% to 48%. In 2019, The British Journal of Pharmacology set expectations that sex should be considered an experimental variable in all studies submitted for publication^[5], and we hope this move will support positive trends in research practice for the discipline.  

Watch Professor Clare Stanford discuss the BJP editorial:


The representation of women in clinical research has been improving since the introduction of the 1993 National Institute of Health (NIH) Revitalization Act (amended in 2001). The Act requires that researchers funded by the US NIH include women as well as men in clinical studies and analyse their results by sex or gender. There is limited data on the impact of this (and other requirements) on representation, but a recent small study noted persistent lower representation of women in phase I studies (at 22%). Phase II/III trials were more equitable, with an average of 48% (range 25%-87%) of women included in trials across nine drugs approved by the FDA since the legislation.

A 2016 study^[6] looked at randomised controlled trials (RCTs) published in The Lancet and the New England Journal of Medicine showed representation of women at 40%. This was an improvement on a comparable study published in 2009, which showed representation at 37%. However, the authors stress that inclusion of women was “not linked to meaningful analysis of outcomes by sex”. In some disease areas, this translates to disproportionate negative impacts on health outcomes. For example, The Lancet have recently launched^[7] a Commission on Women and Cancer to examine the intersection of social inequality, cancer risk, and outcomes, and the status of women in society. Their Commission on Women and Cardiovascular Disease^[8] aims to address known research gaps and barriers that mean women with this disease still have worse outcomes than men.

Watch Dr Lauren Walker talk about considering female physiology in research:
   
Further, the thalidomide tragedy^[9] of the 1960s led to development of important regulatory processes designed to promote safety. Part of the resulting legislation was to exclude pregnant women and women of child-bearing age from clinical trials. Whilst well-intentioned, this protectionist policy has meant there are gaps in our knowledge about the effects of drugs in pregnancy, and a legacy of paternalism when it comes to women’s ability and right to make informed choices about their participation in research.
 
For example, concerns about a newly introduced antiretroviral, dolutegravir, potentially causing neural tube defects led many countries (primarily in sub-Saharan Africa) to ban its use for women aged 15-49^[10], although with more data evidence accrued to refute these concerns. However, the decision led to community protests from women who wanted freedom to make an informed choice, arguing that they valued the health benefits of the drug (the prior standard of care, efavirenz, caused toxicity to the central nervous system) - and just because they were of childbearing ‘potential’ did not mean they wanted to or would conceive. Uganda responded with a nuanced approach, putting in place measures that required proof that women had received the information and advice they needed to make an individual choice before they could receive the drug^[11].
 
Dr Catriona Waitt, Reader in Clinical Pharmacology at the University of Liverpool, studies HIV drugs in pregnant and breastfeeding mothers and their infants and her unit in Uganda was involved in supporting the response to the dolutegravir safety alert. Reflecting on the balance of risk when it comes to including pregnant women in clinical trials, she said:

The issue of inclusive clinical trials is an important one: women are not as well-represented in research as they should be. More women should be involved with research, and more pregnant women should be too. This is about making sure research is undertaken in the populations who are likely to benefit from the treatment– and to identify risk factors for particular groups. At the same time, I think we need to take a cautious approach particularly with novel compounds and where the actual risk vs benefit for that pregnant woman and infant might be less clear. Decisions will also be influenced by the risk posed by the disease itself. This is something our research group has considered in detail for HIV^[12], and I think the lessons apply more broadly.
 
For example, in Ebola outbreaks, pregnant women have a very high mortality without treatment - and all reported newborns died without treatment. Therefore, with regard to Ebola, a far greater risk is ethically acceptable and can be taken earlier in the pipeline of drug development. At the other extreme would be a novel compound which is being tested for non-inferiority against an existing safe and efficacious therapy, for example a new agent of a known class of drug. In such a situation, the potential benefit to a pregnant woman is far smaller, and clinical trials in pregnancy should not be rushed.

Watch Dr Waitt discuss the change in mindset that is needed when talking about women in research:


You can also watch Dr Waitt also discuss research in pregnant women and explain how research can support freedom of choice regarding breastfeeding.

Several funders of clinical trials are making headway in terms of ensuring applicants for funding consider diversity in their trial design. Wellcome, for example, expect the demographic of trial participants to represent the population needing the healthcare intervention^[13]. The NIHR Include project^[14] is examining how to improve inclusion of underrepresented groups into clinical research. In the US, the FDA has specific guidance^[15] in relation to the collecting and reporting of race and ethnicity data so that it is representative of the real-world burden of disease. The UK regulator, the Medicines and Healthcare products Regulatory Agency (MHRA) is exploring with other regulators how evidence on benefits and risks of medicines in pregnancy and breastfeeding can be obtained earlier in a medicine’s development^[16], and the UK has launched a new partnership to support clear and consistent evidence-based guidance on medicines for pregnant and breastfeeding women^[17]. To mark International Women’s Day, the UK government has launched a call for evidence to better understand women’s experiences of the health and care system, with the aim of developing a Women’s Health Strategy.

Further, the European Commission has recently announced that it will require grant recipients to incorporate sex and gender analyses into the design of research studies^[18].

Ultimately, people should be at the centre of health research. In striving for sex and gender equality in research, this means asking women what they want from their healthcare, understanding perceptions of research or equity of access to it - and working in partnership with women and across the research system to fully realise the benefits of evidence-based healthcare.
 
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Get in touch with us via policy@bps.ac.uk to share research or contributions to inclusive pharmacology and drug development.

If you feel there is anything else we should be thinking about or focusing on, please also get in touch. To discuss this work, please contact Anna Zecharia via email (anna.zecharia@bps.ac.uk) or through the BPS Community.

Read our Vision for Equality, Diversity & Inclusion (EDI) in pharmacology.
Read a summary of the results of our external review.
Read our exploration of what diversity means to the Society.

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References:

1. Ravindran, S et al (2020) Making pharmaceutical research and regulation work for women. BMJ 2020;371:m3808
2. Mazure, C.M. & Jones, D.P. (2015) Twenty years and still counting: including women as participants and studying sex and gender in biomedical research. BMC Women’s Health 15:94
3. Franconi F. et al (2007) Gender differences in drug response. Pharmacology Research 55 (2):81-95
4. Woitowich, N.C., et al (2020). A 10-year follow-up study of sex inclusion in the biological sciences. eLife 9: e56344
5. Docherty, J.R., et al (2019), Sex: A change in our guidelines to authors to ensure that this is no longer an ignored experimental variable. Br J Pharmacol, 176: 4081-4086
6. Avery, E. & Clark, J. (2016) Sex-related reporting in randomised controlled trials in medical journals. 388(10062):2839-2840
7. Ginsburg, O. & Horton, R. (2020) A Lancet Commission on women and cancer. 396(10243):11-13
8. Mehran, R. et al (2019). The Lancet Commission on women and cardiovascular disease: time for a shift in women's health. 393(10175):967-968
9. Kim, J.h. & Scialli, A.R. (2011). Toxicological Sciences. 122(1):1–6
10. Mofenson, L.M. et al (2019) J Int AIDS Soc. 22(7):e25352
11. Odongpiny Laker, E.A. et al (2020). Drug Saf. 43(11):1133-1140
12. Fairlie, L. et al (2019). J Int AIDS Soc. 22(9): e25372
13. Clinical Trials Policy. Wellcome. Available online (Last accessed 4 March 2021).
14. Improving inclusion of under-served groups in clinical research: Guidance from INCLUDE project. National Institute for Health Research. Available online (Last accessed 4 March 2021).
15. Enhancing the Diversity of Clinical Trial Populations – Eligibility Criteria, Enrolment Practices, and Trial Design Guidance for Industry. FDA-2019-D-1264. FDA. Available online (Last accessed 4 March 2021).
16. Nooney, J. et al (2021) Assuring Access to Safe Medicines in Pregnancy and Breastfeeding. Clinical Pharmacology & Therapeutics. doi: 10.1002/cpt.2212. Online ahead of print.
17. New partnership pledges clear and consistent evidence-based guidance on medicines for pregnant and breastfeeding women. (2021) UK Government. Available online (last accessed 4 March 2021).
18. Editorial: Accounting for sex and gender makes for better science. (2020) Nature. Available online (Last accessed 4 March 2021).