It seems like a no-brainer. If a company wants to treat everyone who has a certain disease with its new drug, then it should test that drug in, well, everyone.
But that isn’t always the case, even today. This summer, researchers called out Gilead Sciences for failing to “provide equal representation of Black, Latinx and Native Americans” in its clinical trials for Veklury, the first FDA-approved treatment for COVID-19.
The researchers analyzed the demographics of several data sets for the drug, also known as remdesivir, finding that Black Americans made up 11% of the participants in a 397-patient study and 20% of a larger study involving more than 1,000 patients.
Those figures don’t look too shabby next to national demographics, where Black Americans make up about 13% of the U.S. population. But they fall short in a pandemic that has disproportionately affected Black people and other people of color. In Alabama, for instance, Black or African American people comprise 27% of the population but account for 43% of COVID-19 cases. Hispanic or Latinx people are also overrepresented in COVID-19 case data in Alabama and other states.
“If clinical trials do not include diversity among their participants, it can lead to skewed results and inaccurate research,” said Shmuel Shoham, M.D., an associate professor at the Johns Hopkins University School of Medicine. “A clinician or a patient may conclude that the results don’t apply to them or, conversely, think that they do when in fact they may not.”
Despite these challenges, experts agree that the pandemic could mark a turning point for diversity in clinical trials. It has catapulted the issue to the fore for multiple reasons.
“We do see that COVID-19 is disproportionately impacting patients from minority communities, specifically Black and Hispanic patients because they are front-line workers. They weren’t able to work from home like some of us who had that luxury,” said Raolat Abdulai, M.D., clinical research director at Sanofi. “The other thing was the murder of George Floyd earlier this year. It was really a view into systemic injustice and racism that was right in front of your eyes, so these two impacts together, as well as other events of racism, really brought the issue of inequality and equity to the forefront.”
Another reason was the indiscriminate nature of SARS-CoV-2, the virus that causes COVID-19. No one is safe until we have drugs and vaccines to treat and prevent infection.
“COVID impacts everyone. The virus does not care whom it infects,” Shoham said. And that, for many, has illustrated the importance of testing drugs and vaccines in different groups of people.
“We come to COVID from a range of backgrounds. Some people can isolate within their own home, others cannot. Some can get the best available medical care as soon as they need it, others cannot. Some can shrug off the virus with a few days of feeling miserable, others develop devastating complications,” Shoham added. “While the virus and the treatments that we study to address it are the same, the people who are impacted in real life are not.”
In the early days of the pandemic, Genentech, like other drugmakers, searched its stable of approved drugs for anything that could be repurposed for COVID-19. One of them, Actemra, has been on the market for years as a treatment for rheumatoid arthritis, and the company figured it might help tamp down inflammation in patients with COVID-19.
“Because it was being used off-label extensively around the world, we felt obligated to do a risk-benefit assessment,” said Jamie Freedman, M.D., Ph.D., head of U.S. medical affairs at Genentech.
It carried out a global, placebo-controlled trial of Actemra dubbed COVACTA and “discovered a racial disparity signal,” leading it to kick off a second trial aimed at recruiting minority patients, called EMPACTA. More than 85% of the EMPACTA participants were racial minorities, including 55% who were Hispanic or Latinx, about 15% who were Black and 12% who were Native American.
“We did it to answer the question, is there a difference in how minorities respond to and tolerate the drug?” Freedman said. “Both trials have been completed. COVACTA was negative overall and interestingly, EMPACTA was positive for the primary endpoint—it was able to reduce progression to mechanical ventilation in hospitalized patients by 44%.”
So, if diverse trials can be so informative, why do companies keep running into “racial disparity signals?”
For one, pharma and biotech companies tend to approach large academic institutions to run their trials, because they have the infrastructure to do it and have a large enough pool of patients from which to recruit patients, Freedman said. Problem is, going to the same big centers means running into the same patients over and over again.
And there’s an understandable mistrust of clinical research in minority populations thanks to clinical trials like those conducted in prison inmates or the infamous Tuskegee Institute syphilis study, Abdulai said.
“It looked at the natural history of syphilis despite the fact there was a cure, penicillin, available for syphilis at the time. Men were enrolled in this trial without the true knowledge of the reasons, as well as the fact that there was a cure,” she added. “We have put the burden of clinical trials on populations that are vulnerable, but the benefits of these trials have not been felt by these populations.”
Cost and accessibility can also be factors. Would-be trial participants may need to take long trips on public transportation to the trial site and/or take time off work to get involved, which isn’t always easy, said Scott Lipkin, chief research officer at the Miami Cancer Institute. And billing rules from the Centers for Medicare & Medicaid Services may exclude certain patients from taking part.
“Part of what we do is explain to patients before they enter a trial what they would be on the hook for,” Lipkin said. “Having that conversation is important, but it essentially eliminates a segment of the population. That segment that is being eliminated are those that would otherwise be considered underserved.”
Short of changing the laws for clinical trial billing, there are steps companies and trial sites can take to boost diversity. Instead of going to the usual suspects, Genentech is working with OneOncology, a network of community-based cancer centers, to bring personalized care to diverse communities.
Designing trials differently could help, too. The COVID-19 pandemic has made remote healthcare the norm, including telehealth visits and digital tools that “we toyed about with pre-COVID-19, but did not use as frequently as we do now,” Lipkin said. Using these tools in clinical trials could open them up to patients who can’t always take days off to complete their site visits.
Companies like Bristol Myers Squibb are working on programs aimed at boosting diversity not just in clinical trial participants, but also in the investigators running those trials. Through the nonprofit Bristol Myers Squibb Foundation, the company will train and develop 250 new racially and ethnically diverse clinical investigators.
“We find clinical trial sites where there are diverse investigators have a better rapport and trust with the community—believe it or not, you like and trust the people who talk like you and look like you,” said Samit Hirawat, M.D., chief medical officer of BMS.
Finally, trial sites can make sure they’re communicating with potential participants in the best way.
“We’re in Miami and 70% of Miami is Latino, so right off the bat, every clinical trial we open, we translate all of our documents into Spanish,” Lipkin said. “If you’re in Detroit, Michigan and have a large Hmong population, you need to make that choice as to whether or not you’re going to invest because it’s rather expensive to get translated documents … It can oftentimes be a big investment that a sponsor or third party may or may not pay for. That’s an important role a site can take.”
Of course, it always helps to have direction from the top. Lipkin thinks it’s no coincidence that the FDA published new guidance in November to broaden eligibility criteria for clinical trials and thereby boost the participating of underrepresented groups.
The Pharmaceutical Research and Manufacturers of America followed suit with its first industrywide set of principles on clinical trial diversity. The principles, which will take effect in April 2021, focus on four main areas: building trust and acknowledging the historic mistrust of clinical trials within Black and other minority communities, reducing barriers to clinical trial access, using real-world data to enhance information on diverse populations beyond product approval and enhancing information about diversity and inclusion in clinical trial participation.