This story is part of a series on Diversity in Clinical Trials, which will explore the impacts of drug development using data that does not reflect the diverse U.S. population.
To read more in this series, please visit the "Diversity in Clinical Trials" Issue in Focus page here.
Scientists began to realize in the 1990s that cardiovascular disease — the most prevalent cause of death worldwide — manifests differently in women than men, as women's hearts are about two-thirds the size of men's. While women and minorities are getting more attention around this disease, drug trials are still not addressing their physiological differences.
"We don't know how women react to the same kind of drugs that men do," said Cathy Lewis, the American Heart Association's national communications senior manager. "We just don't have those results."
Cardiovascular disease was historically thought of as a man's disease, and women have made up just 20% to 30% of drug and device trials for the condition, according to American Heart Association, or AHA, board member Stacey Rosen, a cardiologist and vice president of women's health at the Katz Institute for Women's Health at North Shore-LIJ Health System in New York. But women experience different symptoms than men, a fact that not all physicians recognize, the Women's Heart Alliance said.
"The majority of primary care doctors probably are still not comfortable taking care of heart disease in women, or even identifying and modifying risk factors," Rosen said.
While cardiovascular disease trial enrollment rates for women have increased to around 40% to 45%, which is "still not great, honestly," Rosen said, minorities continue to be underrepresented in drug trials. Appropriate analyses of each demographic group are needed to parse the unique effects of the drug or device on a population, according to Rosen.
"When you look by race and ethnicity, we're doing a little bit better with white women in the U.S., but black [and] Latino women have very low levels of participation," Rosen said.
The result is drugs on the market that could be harmful to certain populations. For instance, angiotensin-converting enzyme, or ACE, inhibitors, one of the most commonly prescribed medicines for high blood pressure, have been found to be unsafe for black patients. ACE inhibitors can cause potentially life-threatening swelling under the skin called angioedema and significantly reduced blood pressure.
Angiotensin II receptor blockers, or ARBs, another commonly prescribed cardiovascular medication, were also flagged as potentially dangerous for black patients in a 2018 publication in the journal Sage.
Popular versions of these drugs include Novartis AG's ACE inhibitor Lotensin and ARB drug Diovan.
Even though these risks for black patients — who see significantly higher incidence of cardiovascular disease compared to white patients — are well known, the Sage article said experts are still unsure why the side effects occur.
"There should be no naiveté here. This is so explicit throughout the literature, it's a recurring pattern that continues unimpeded," former AHA president Clyde Yancy said.
Reaching underrepresented populations
Cardiovascular disease drug development has slowed in recent years, due in part to the hefty costs associated with the larger trials that are necessary, and the complex disease population. But some companies are still forging ahead.
Amarin Corp. PLC, awaiting an FDA decision for expanded use of its fish-oil-derived drug Vascepa, conducted an 8,179-participant global trial called Reduce-It that evaluated the reduction of cardiovascular events over seven years. The trial included approximately 29% women and about 9.8% nonwhite patients. Amarin had trial sites across the southeast U.S., including Alabama, Georgia, Louisiana, Mississippi, North Carolina and South Carolina, a region with a higher black population and prevalence of disease.
The Medicines Co., which recently concluded late-stage trials for a cholesterol-lowering medicine called inclisiran, saw somewhat similar enrollment numbers, recruiting about 65% male patients in its global 501-patient phase 2 study Orion-1. The study enrolled about 93% white participants. All other races or ethnicities were labeled "other" and not broken down further, according to the trial's full results published in the New England Journal of Medicine.
The AHA has implemented certain initiatives to focus on cardiovascular disease in women and minorities, such as Go Red for Women and Strategically Focused Research Networks, or SFRNs. The SFRNs program identifies certain cardiovascular areas of interest, including disparities, hypertension, prevention, obesity and children's health, and connects them to specific health centers across the U.S.
Go Red for Women joined Verily Life Sciences LLC's tech-powered clinical research program Project Baseline in February 2019, bringing together a repository of women willing to participate in clinical research and studies.
Rosen said the groups have tailored recruitment efforts based on the targeted demographic, leveraging community groups such as hospital-based nursing staff and predominantly African American churches.
The repository is privy to studies including Verily's Project Baseline Health Study, which is collecting health information including cardiovascular disease risk; Verily's Heart Biomarker Study focused on the genetic cardiovascular disease risk factor lipoprotein(a); and others vetted through the combined initiative, Rosen said.
Joining forces with Verily also means leveraging the Alphabet Inc. subsidiary's technology and data capabilities, according to Rosen. Computer power and big data can be advantageous for evaluating cardiovascular disease patients who have more than one condition — an issue that would traditionally exclude them from clinical trials.
Verily returns data to participants as well, for example by providing "touch points" for participants in the health study through a mobile app so that information is captured throughout the day, Verily Product Marketing Manager Emily Friedman said.
The lack of two-way communication during traditional clinical trials, particularly the lack of returned personal results, has been cited as a point of skepticism and reluctance to participate in clinical trials, according to a 2018 survey of black men by the Center for Healthy African American Men through Partnerships.
"The most important thing there is really that two-way exchange in research," Friedman explained.
An investigational version of Verily's Study Watch is being used in Project Baseline.
The investigational version of Verily's Study Watch is being used in research in order to gain more information on how the wrist-worn wearable reads different populations or different skin tones, as well as environmental activity such as movement, Friedman said.
Achieving 'real change' through engagement
Digital wearables like the Study Watch have arrived at the forefront of cardiovascular monitoring. AHA President Robert Harrington said the intersection of consumer and health technology may "democratize research," leading to more widespread and available clinical research across all populations.
Similarly, "siteless" clinical trials employing telemedicine and wearable technology, such as Johnson & Johnson's virtual stroke prevention program evaluating atrial fibrillation in over 2,000 patients using a heart rate-measuring patch, have been touted by industry members as a way to transcend geographic roadblocks in particular.
"Where we're going, we don't need more trial sites," said Joseph Kim, Eli Lilly and Co.'s senior adviser of clinical innovation.
But Yancy cautioned that engaging communities is still key to achieving more diversity in clinical trials. Research — siteless or not — requires active identification and engagement of overlooked communities, such as with AHA's SFRNs, Yancy said.
"The goal is, are we engaging people," Yancy said. "[The AHA's initiatives represent] the kind of real change that makes a difference and allows us to not continue to bemoan the underrepresentation of women and minorities. ... These are the things that have to be done differently."