The importance of inclusion in clinical trials

Photo: Getty Images
Photo: Getty Images

Yesterday was International Women’s Day (IWD), an annual celebration of the social, economic, cultural and political achievements of women, and a reminder of the importance of gender equality and women’s empowerment.

The inclusion of women - both cisgender and trans - in arenas ranging from the boardroom and political stage to the bright lights of Hollywood is certainly something to be celebrated. But it’s the inclusion of women and gender minorities in another, less celebrated, less public, arena that I wish to highlight today.

Over the last few years, I have evolved from student to staff member at the University of Oxford, and have been working in communications for the Nuffield department of primary care health sciences (NDPCHS) for some 13 months now. The field of primary care health science is one focused on providing accessible and comprehensive healthcare services to individuals and communities. Crucial to this mission are clinical trials, which provide important evidence-based information on the safety and efficacy of new treatments and interventions that can be used in primary care settings.

The clinical trials unit in my department is housed in a rather scruffy, labyrinthine building, where several trial teams operate - harried trial managers, statisticians, study co-ordinators, endlessly patient research nurses, and data managers - toil away daily, ensuring that the trials they are conducting will advance medical knowledge and contribute to the development of new treatments and interventions. Part of this work is ensuring that their trials are appropriately diverse and accurately reflect current population demographics in the UK.

A brief note on terminology. By "sex", I mean the biological variable traditionally reported on in clinical trials - chromosomal differences that determine not only reproductive ability, but differing physiological processes and organs. "Gender" on the other hand, is the social construct informed by self-representation, social, and cultural views of sex.

It should come as no surprise that historically, women tended to be excluded from clinical trials for a multiplicity of reasons based on both sex and gender, including concerns about their reproductive capacity, the potential impact of hormonal fluctuations on study results, perceived complexity, and higher costs. In the US, for example, it wasn’t until 1993 that Congress passed the NIH Revitalisation Act, which mandated the inclusion of women and people of colour in clinical trials.

Historically, it was commonly assumed that women were not significantly different from men except in regards to their reproductive system, and therefore, data collected from clinical studies on men (usually Caucasian males) could simply and easily be applied to women too. We know now that this isn’t the case.

Some diseases, such as breast cancer and urinary incontinence, disproportionately affect women. Women also experience certain conditions, such as cardiovascular disease, differently to men and thereby may respond differently to treatments that have been tested almost exclusively on a male cohort.

There are also sex-based differences when it comes to the metabolisation and processing of drugs. In women, factors such as higher body fat composition, lower body weight, slower kidney and gastrointestinal functions, and less intestinal enzymatic activity affect their pharmacokinetics.

Response to drugs also differs between men and women, primarily due to sex hormones, which are themselves influenced by menstruation, contraceptives, pregnancy and menopause. For example, the same dose of Zolpidem (brand name Ambien, a commonly used medication for insomnia) in women as in men can cause two times the drug levels due to differences in metabolism.

The need for inclusion in clinical trials goes beyond sex and gender differences. It’s vitally important that people from minority racial/ethnic communities are included, alongside people living with chronic comorbidities and disabilities.

How can we change this? One option is to design trials with flexible schedules, to accommodate for family responsibilities that might otherwise limit the amount of time a woman is available to participate. One trial I’m working on, Panoramic (The platform adaptive trial of novel antivirals for early treatment of Covid-19 in the community) seeks to find out in which people new antiviral treatments for Covid-19 in the community reduce the need for hospital admission and get better sooner. The beauty of Panoramic is that participants can take part from the comfort of their own home, with no face-to-face visits required.

Another option is to challenge the idea commonly held by study sponsors and investigators that it takes more time and money to recruit women.

It’s also important to ensure that outreach and recruitment efforts are sensitive to the fact that one’s gender, sex, race, and socioeconomic background might impact one’s understanding of clinical trials and therefore willingness to participate.

I spoke with my colleague Melanie, who noted that one of the main barriers preventing women and gender minorities from accessing clinical trials is the fact that most trials are set up using the template of what has worked before.

"Adapting templates can be difficult, particularly for trials testing medication, because you still need to make sure the safety aspects are included, especially around contraception, fertility, and pregnancy," she said.

Take it from me - updating protocols, passing amendments, even getting something as simple as a poster approved - takes a great deal of time and patience. And sometimes, time is of the essence. The Covid-19 pandemic, for example, occasioned a desperate need for early, reliable data on treatments, especially for clinically vulnerable populations.

There is a continued need for research in the areas of sex-based biology, discrepancies in healthcare needs between men and women, acknowledgement and reduction of health inequalities between genders, and provision of evidence-based information to help women make informed decisions about their healthcare.

"More work needs to be done to ensure that trials are inclusive, while still able to protect the safety of the participants," Melanie said.

It’s a tricky balance. But there’s hope: "thankfully, steps are being made in the right direction and hopefully the more people work to make trials inclusive the easier it will become".

- Jean Balchin, a former English student at the University of Otago, is studying at Oxford University after being awarded a Rhodes Scholarship.