The Clinical Trial Diversity Problem

Clinical trial diversity is an ongoing issue. Historically, many groups have been underrepresented in clinical trials, due to their ethnicity, gender, and socio-economic backgrounds. Fortunately, the pharmaceutical industry as a whole is now working to improve clinical trial diversity.

Reasons for the historical lack of clinical trial diversity

In order to improve overall trial diversity, it is necessary to understand why it has previously been lacking.  First, let’s consider the nature of clinical trials and the barriers that patients face when considering taking part in one.

Time-commitment

Clinical trials can last years and patients may be enrolled for many months. In a Phase 1 clinical trial, which tests the safety of a new compound, participants may need to participate for a week at a time. However, a Phase 2 trial that tests the efficacy of a compound may require a patient’s participation for 6 months or more, sometimes even up to a year. In Phase 3 trials, patients may need to participate for even longer periods.

Depending on the nature of the trial and the compound being tested, participants may not be able to work during the trial, either due to the time commitment required or due to things like side effects. Of course, not everyone is in a position to afford missing months of work. Therefore it is unsurprising that the most affluent patients, who are able to afford time away from their employment, are those most likely to participate in
clinical trials.

Location

In addition to the length of commitment required, clinical trial participants may consider the trial location as a barrier to participation. With many clinical trial sites being in urban areas near hospitals and medical centres, patients who live in more rural settings are less likely to participate. If a clinical trial site has poor transport links this can also be a factor limiting diversity among participants.

Another factor that can limit the diversity of participants in clinical trials is the diversity of the population in the area where the site is located. For instance, a clinical trial site might not be located in an area that has an equivalent population density to the target patient population. For example, in 2020 the Alzheimer’s Association found that many trial sites where memory studies take place are not in areas where high populations of those over 60 years of age live, and many areas that did have high populations didn’t have a trial site within 50 miles.¹

Currently, in the United States, 50% of  FDA clinical trials take place in just 2% of US zip codes.² This means that the same patient populations are continually included in trials while others are excluded. It is clear that the locations we choose to host clinical trials have a significant impact on clinical trial diversity overall.

Practical concerns are not the only factors affecting clinical trial participation and diversity. There are various others to consider. Below we examine ethnicity, race and gender.

Ethnicity and Race

Historically, there are examples of disenfranchised racial groups being taken advantage of in the course of clinical research. In 1932 in the US, the US Public Health Service conducted a syphilis study at Tuskegee, during which they allowed African American men with syphilis to go untreated so scientists could study the effects of the disease. In the 1940s and 50s, The Department of Indian Affairs of Canada conducted a nutritional study at Indigenous residential schools denying adequate nutrition to groups of malnourished children, some of whom died.

Historical studies like these have damaged the trust between minority populations and researchers and this mistrust impacts clinical trials today. In 2020, a global review looking at why patients take part in medical research found that a lack of trust was a common reason for Black and ethnic minority patients not wanting to participate in medical research.³

This mistrust is likely a contributing factor to the underrepresentation of BAME (Black, Asian and Minority Ethnic) patients in clinical trials. In the USA, Black people only comprise 5% of participants in FDA clinical trials, while only 5% of cardiology clinical trial participants are Hispanic.⁴

Gender

In the past, women have been underrepresented in clinical trials. One reason for this prevalent underrepresentation was unjustified concerns that women are difficult to study due to female hormone fluctuations.⁵ A reason for the underrepresentation of women in current trials is due to the adverse effects that trial compounds can have on fertility and child-bearing. In 1977, following adverse side effects from drugs like thalidomide, which caused serious birth defects, the FDA issued a guideline effectively banning women of “childbearing potential” from participating in clinical trials.⁶

While women are no longer banned from clinical trials, there is still a degree of underrepresentation, especially in Phase 1 clinical trials which test the safety of a compound in healthy volunteers. This is because female volunteers are usually only included if reproductive toxicology tests have been conducted first, which naturally reduces the number of female participants. In clinical trials in general, even in cell and animal studies, the majority of study subjects are male.⁷

Why is Diversity in Clinical Trials Important?

Clinical trial diversity is absolutely vital. It is essential for providing drugs that are as safe and effective as possible for everyone who will use them. The safety and effectiveness of a drug can not be guaranteed for all patient populations unless those populations are properly represented in clinical research. This is because different patient populations can have different responses to treatments.  For example, ACE inhibitors – medications that reduce blood pressure – can be less effective in black patients than in white patients.⁸ Research has also found that women are almost twice as likely to have an adverse reaction to a medication.⁹ Clearly, in order to guarantee the safety and effectiveness of drugs for all those who will use them, it is vital to adequately represent the diversity of the target patient population in clinical trials.

Clinical Trial Diversity – The Current Picture

Currently, there is a degree of lack of diversity in clinical trials. In October 2020 in the UK, only 7% of the 270,000 people recruited for COVID-19 vaccine trials were from ethnic minority groups.¹⁰  In 2021 in the US approximately 80% of participants in FDA-approved trials were white males from affluent socioeconomic backgrounds.¹¹ When it comes to clinical trial diversity, there is clearly room for improvement.

Improving Clinical Trial Diversity

Fortunately, increasing diversity in clinical trials has become more of a priority for regulatory and industry bodies in recent years.  In the EU, for example, EU Clinical Trial Regulation 536/2014 states that the subjects participating in a clinical trial should represent the population groups that are likely to use the medicinal product investigated in the clinical trial. Also, In November 2020, the FDA released new guidance to increase the diversity of clinical trial populations. This guidance includes recommendations such as using trial design to better facilitate diversity and improving enrolment by decreasing patient burden.

In 2021, the UK  set up the Race and Health Observatory (NHSRHO) to examine health inequalities and to identify and reduce health challenges facing minority communities. One way the NHSRHO is trying to improve clinical trial diversity at present is by working to improve access to clinical trials for black and ethnic minority women with breast cancer.

Many large pharmaceutical companies are also committing to improving diversity in clinical trials.  Some measures that big pharma is taking include prioritising population diversity in clinical trial site location selection and creating initiatives to build trust with previously underrepresented population groups.

Although there is still a lot of work to do, clinical trial diversity is starting to improve. One improvement centres on the number of women involved in clinical trials in the US. According to US FDA Drug Trial Snapshots, the number of women who participated in the clinical trials that informed the approval of either new molecular entities or biologic products increased from 40 % in 2015 to 56% in 2020.¹²

Hopefully, we will see many more clinical trial diversity success stories in the future.

Sources

¹ https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz.044244
² https://mdgroup.com/blog/why-we-need-to-improve-diversity-amongst-clinical-trial-participants/#:
³ https://www.sciencedaily.com/releases/2020/03/200316104010.htm
⁴ https://finance.yahoo.com/news/making-research-look-more-patients-134508665.html 
⁵ https://www.sciencedaily.com/releases/2020/08/200812161318.htm
⁶ https://www.womenshealth.gov/30-achievements/04#:~:text=In%201977%2C%20the%20FDA%20issued,populations%20at%20all%20other%20costs.
⁷ https://www.sciencedaily.com/releases/2020/08/200812161318.htm
⁸ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2614386/
⁹ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7275616/
¹⁰ https://www.mantellassociates.com/blog/2022/04/should-diversity-be-mandatory-in-uk-clinical-trials?source=google.com
¹¹https://www.prweb.com/releases/political_squabbles_slow_drug_development_for_rare_diseases/prweb18879956.htm
¹² https://www.sciencedirect.com/science/article/pii/S2666379122000593#tbl1

See also:

Bioinformatics and the Pharmaceutical Industry
Selection Bias in Randomised Trials
The Future of Genomics
Are You Making The Most Of Your Drug Development Data?
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