Researchers take cues from the past to ensure diversity in COVID-19 clinical trials

When the coronavirus pandemic hit last year, ravaging communities of color harder than any other, researchers knew they needed to find effective treatments and vaccines – and find them fast. Just as urgently, they needed to include people of color in the clinical trials that were testing those vaccines. These, after all, were the people being hospitalized and dying from the disease at rates up to three times higher than whites.

But getting people of color to sign up for those trials was not going to be an easy sell. Researchers were combatting misinformation not just about the virus, but also about what the trials involved. And community mistrust over historical injustices and exclusions from past research was not helping.

For some researchers, little of this struck them as new. Several landmark trials funded by the National Heart, Lung, and Blood Institute (NHLBI) to reduce the burden of high blood pressure – particularly in African Americans – faced similar challenges. But those trials were ultimately successful, and researchers say it’s because they used a variety of recruitment strategies that ensured not just more minority participants, but more women, too.

Take the Systolic Blood Pressure Intervention Trial (SPRINT), which evaluated the benefits of maintaining a new target for the top number in a blood pressure reading. Starting in 2010, the trial adopted a wide variety of recruitment activities that set a standard for current day trials.

Thomas Ramsey, Ph.D., an epidemiologist at the University of Alabama at Birmingham oversaw, managed, and tracked the recruitment activities of 19 clinical sites in one of the five clinical center networks in SPRINT. He said that mass mailings featured images of people from all segments of the population. The mailers targeted potential participants based on age, race, gender, and zip code, and those who were within a reasonable commute of one of the 102 medical centers and clinical practices across the United States and Puerto Rico that enrolled trial participants.

Volunteers soon began responding from all over, and that targeted outreach allowed the clinical centers to rapidly change their focus based on the enrollment needs of the trial. Meanwhile, other volunteers were responding because of referrals by SPRINT staff, healthcare providers, and friends.

“When volunteers had questions about the trial, they could call the local participating clinical site and speak with nurses and physicians, many of whom were African American or Puerto Rican,” Ramsey said. “Some participants were regular patients of a clinical site and already knew the medical staff.”

By 2013, the recruitment efforts had paid off. SPRINT had screened nearly 15,000 volunteers – a third as a result of the mailings, half because of referrals – and was able to enroll more than the 9,250 adult participants it needed for the trial. Participants were all aged 50 and older and at risk for cardiovascular disease. More than one-third were women and nearly half were minorities.

In the end, SPRINT provided a major contribution to hypertension research. It showed that achieving the lower blood pressure goal of 120 mm Hg, instead of 140 mm Hg, reduced the rate of cardiovascular events by about 25% and the overall risk of death by 27%. The results were so positive – and conclusive – that NIH stopped the SPRINT trial early, after a little over three years of follow-up, and disseminated the findings.

SPRINT built on prior large, landmark hypertension trials, such as the Systolic Hypertension in the Elderly Program (SHEP), which started in 1984 and randomized 4,736 people. Of the participants, 663 were African American and 2,700 were women.

The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) was the first to enroll enough Black and Latino participants to effectively compare the impact of blood pressure lowering medications in preventing cardiovascular events in those populations.

To enroll those participants, researchers recruited at more than 600 clinics and health centers across the United States, Canada, Puerto Rico, and the U.S. Virgin Islands. And in the end they surpassed their target, recruiting more than 42,000 participants aged 55 and older. Of those, 15,904 were African American, nearly 7,000 were Hispanic, and nearly half were women.

One key finding of ALLHAT, said Jackson Wright, M.D., Ph.D., was that of the three newer and more costly classes of blood pressure lowering medications, two medications (ACE inhibitors and alpha-blockers) were less effective in lowering blood pressure and less effective in preventing cardiovascular complications of hypertension among Black Americans, compared to the much cheaper medications like thiazide-type diuretic medication. These types of diuretics are now one of the first types of medications recommended to control blood pressure in this population.

“The treatment of high blood pressure in the population at highest risk for complications from this condition led to revisions in treatment guidelines worldwide because of the Black patients recruited into ALLHAT,” said Wright, emeritus professor of medicine at the University Hospitals Cleveland Medical Center, an affiliate hospital of Case Western Reserve University. Wright also served as chair of the executive committee and vice chair of the trials’ steering committee.

Barry Davis, M.D., Ph.D., who served as director and principal investigator of ALLHAT, attributed the relatively large number of people of color, in part, to the diverse team running the study itself. “We made sure that there was African American representation on the steering committee, on the regional coordinator teams that closely monitored enrollment experience at clinical sites, and among many of the clinical site investigators,” said Davis, professor of biostatistics at the University of Texas Health Science Center at Houston School of Public Health.

SHEP, SPRINT and ALLHAT took effort and a lot of commitment, but the lessons learned were big. And today, similar lessons are being used as NIH works with trusted community leaders to help get out facts and dispel myths and misinformation about vaccines, treatments and the real workings of clinical trials, said George Mensah, M.D., director of NHLBI’s Center for Translation Research and Implementation Science.

Moderna’s vaccine trial launched in July 2020 and more than a month later, it had only enrolled 1,200 African Americans and fewer than 3,000 Hispanics towards its overall goal of 30,000 participants. “The low enrollment of minorities was a clear concern,” Mensah said. “If we continued as usual, most of the study slots would have been filled by white participants. So there was a pause [in general enrollment] to allow the slow rate of enrollment by racial and ethnic minorities to increase and meet goals.”

Other critical strategies, Mensah added, included regular meetings to address challenges that communities of color were facing. Moderna established a diversity advisory board that met weekly to review goals, challenges, and opportunities. And it ran ads with culturally tailored messages and held town halls and other events with trusted leaders. The NIH-wide Community Engagement Alliance (CEAL) Against COVID-19 Disparities and strategic partners such as the COVID-19 Prevention Network (CoVPN) supported those efforts and undertook complimentary engagement and outreach activities.

Those messages apparently got through. Of the 30,000 participants recruited for Moderna’s vaccine trial, and the 40,000 for Pfizer’s, more than a third were people of color. But as more vaccines and treatments for COVID-19 related illnesses continue to get developed, more volunteers will be needed. And NIH’s CEAL is working with communities across the country to address the misinformation and mistrust that might deter participation in COVID-19 vaccine trials – or in any other trials that could lead to beneficial scientific discoveries.

“We know these strategies work,” Mensah said, “And other COVID-19 vaccine and treatment trials that have started can learn from them – and have a better chance of success.”