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November 10, 2020updated 12 Nov 2020 1:53pm

How Covid-19 has put clinical research’s diversity problem in the spotlight

Covid-19 clinical trials have been criticised for their lack of patient diversity, despite the illness disproportionately affecting BAME people. Natalie Healey explores why diversity in clinical trial recruitment is so challenging to get right and what could help pharmaceutical companies overcome the barriers.

By Natalie Healey

Clopidogrel, an antiplatelet drug used to prevent heart attacks in high-risk patients, is one of the most prescribed medicines worldwide. But it protects some people better than others. Since 2010, clopidogrel has carried a black box warning cautioning that some patients might metabolise the medication poorly, making it less effective.

In 2014, researchers at St Louis University School of Medicine found that race might have something to do with this discrepancy. Their study showed African Americans taking clopidogrel for a year had a 7.2% risk of death, twice that of white patients prescribed the same drug (3.6%). The St Louis team found African American trial participants were at greater risk of bleeding and death if they carried certain gene variants for liver enzymes called cytochrome P450s (CYPs) that metabolise clopidogrel to its active form.

“Previous studies looking at CYP gene variants and their effects on risks of repeat heart attacks, bleeding and death have included predominantly Caucasian patients of European ancestry,” cardiologist and lead author Sharon Cresci noted at the time. “There is almost no data, until now, about these variants in African Americans.”

It’s a similar story for the blood-thinner warfarin, which gained FDA approval in 1954. People of African descent are at higher risk of experiencing major bleeding from the drug than white patients. But this association has only been recently uncovered. If clinical trials prioritised participant diversity from the start, race-related risks like these could be identified much earlier.

Executive director of US charity Clinical Research Pathways Marjorie A Speers is passionate about expanding access to experimental treatments. “African Americans represent about 13% of our population but fewer than 5% of those who participate in clinical trials,” she reveals. “That is of concern because when a new drug or device is tested, we don’t know whether it’s going to respond the same way, in terms of safety and efficacy, in people who are genetically different.”

The disparity is even greater for those of Latino origin. Latinos represent 18% of the US population but only 1% of clinical trial volunteers.

Covid-19 research called out

Early on in the coronavirus pandemic, it became clear that Black, Asian and minority ethnic groups (BAME) were disproportionately affected by Covid-19 and more likely to experience serious illness compared to white people.

As the world races to develop a vaccine and find treatments to end the crisis, diversity in clinical research is rightly in the spotlight. After all, a breakthrough medicine isn’t much good if it doesn’t help the people who need it most.

But both the Oxford University and AstraZeneca vaccine trial in the UK and Moderna’s study in the US have been criticised for the overwhelming whiteness of the participants. A recent editorial in the New England Journal of Medicine (NEJM) called on government agencies, research funders and journals to prioritise diversity in Covid-19 research.

The authors pointed out that in a Gilead-funded trial testing the efficacy of antiviral drug remdesivir for SARS-CoV-2, only one out of every ten patients given the medication was Black.

A harrowing past

While researchers know their work should be as diverse as possible to ensure a new medicine is equally safe and effective for all populations, recruiting certain groups for trials has always been challenging. A major hurdle is mistrust in clinical research.

That isn’t unsurprising when you consider trials like the Tuskegee Syphilis Study, conducted between 1932 and 1972 by the US Public Health Service. Researchers enrolled 600 African American sharecroppers from Alabama, of whom 399 were found to have syphilis. The men were told they would receive free healthcare in exchange for joining the study, but participants with the sexually transmitted disease were never told of their diagnosis, despite the stark complications of the condition (such as neurological illness, blindness and death) and risk of infecting others.

Instead, the men were told they were being treated for ‘bad blood’ and were given placebos and other ineffective therapies even though penicillin, the standard treatment for syphilis, was made available in 1947.

Another example is Henrietta Lacks, a Black tobacco farmer whose cancer cells were taken without her consent in the 1950s. These cells, that scientists call HeLa, became one of the most important tools in medicine and are now a multimillion-dollar industry. But Lacks’ family didn’t see a penny of the profits, despite scientists revealing her name publicly and giving her medical records to the media.

Considering the problematic history of medical trials, Speers believes researchers could be doing far more to gain public trust and communicate the benefits of participating in clinical research to underrepresented groups.

Proactive engagement

One potential solution is to conduct work at institutions in areas with a large proportion of people from unrepresented ethnic groups, says Speers. This suggestion is echoed in the NEJM paper. “Why aren’t we putting up infrastructure for clinical trial sites in areas that were heavily hit by Covid?”, asked lead author Daniel Chastain, a pharmacist at the University of Georgia, in the accompanying press release.

Pharmaceutical companies and contract research organisation should also be looking at the diversity of their workforce, as well as their trial participants. “It’s important to have physicians, clinical investigators and research staff who represent those minority populations,” Speers says. “People trust people who look like them.”

She believes researchers need to put more work into identifying suitable patients for trials. Advertising on the radio or in a newspaper isn’t enough. She hopes more research groups will recruit patient navigators to go out and actively look for relevant trial participants in the community. “We can’t sit in the office,” she says. “We have to deal with these mistrust issues head-on.”

It’s a tactic that has worked for HIV and AIDS research conducted by the National Institute of Health, Speers points out. The body directly reached out to patients, asking how they could conduct studies people would want to participate in.

“They found you have to talk about HIV in the way the people who are at risk, or who have the disease, talk about it,” says Speers. “And then by working with them over time, simply engaging them in terms of how the study is designed and conducted and sharing results, you build up trust.” That trust means when you want to test a new medicine or start a new trial, you already have those links to the community.

Speers is hopeful that Covid-19 has brought about greater awareness of healthcare inequalities. Provided that pressure keeps up, it could lead to more inclusive medical research. But she believes regulators should be mandating (rather than just recommending) diversity in clinical trials. That might mean delayed approval for some compounds. But this could lead to safer, better medicines for all in the long term.

“For really meaningful change, I do think there needs to be a regulation,” says Speers. “That’s the only way we’re going to have social justice in health research.”

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