The document, developed by the Heart Failure Collaboratory, explores barriers and offers solutions.
Much can be done to improve the racial and ethnic diversity represented in heart failure (HF) trials, according to the Heart Failure Collaboratory’s new “call to action.” The document looks at the barriers to registration, while proposing many solutions.
“Certain racial and ethnic populations, particularly blacks and Hispanics, have a greater burden of IC, are less likely to receive optimal disease-modifying treatments, and are more likely to die from IC. Despite this excess risk, these same populations are often the least studied in clinical trials for HFErsilia M. DeFilippis, MD (Columbia University Irving Medical Center, New York, NY), and colleagues write in their article, which was published online recently in JAMA Cardiology.
the Heart Failure Collaborative (HFC), a public-private partnership between the U.S. Food and Drug Administration and a consortium of stakeholders, aims to improve the efficiency of clinical trials and advance the development of HF therapies.
Speaking to TCTMD, DeFilippis said the collaboration between regulators, industry, researchers, healthcare professionals and patient representatives “is a really unique aspect [that] sparked a lot of great discussion. One of the five HFC working groups focuses on “representative populations,” both in terms of setting enrollment standards based on the HF phenotype (e.g., race/ethnicity, gender, age and clinical characteristics such as ejection fraction) and creating new approaches to trial recruitment.
This particular document, she said, arose out of discussions first sparked by the American Heart Association’s decision in late 2020 to denounce structural racism as a driver of cardiovascular inequalities. Meanwhile, amid protests and conversations about race in the United States, “I think we felt each other. . . we were in a good position to try to provide some sort of framework on how to approach this, for lasting solutions, [by] engaging partners at all levels,” DeFilippis recalled.
Most consensus documents and guidelines now recommend four classes of drugs—an angiotensin-neprilysin receptor blocker (RNAI) or renin-angiotensin-aldosterone system antagonist (ACE/ARA inhibitor), a beta-blocker, a mineralocorticoid receptor antagonist (MRA) and a sodium-glucose cotransporter 2 (SGLT2) – a complex and often expensive regimen that can be difficult to achieve, especially in underserved populations with less access to care.
Importantly, “the potential benefit and survival gain with these therapies is really quite impressive,” DeFilippis said, and adds up. She pointed a paper 2020 published in the Lancet which estimates that a 55-year-old patient taking all four agents, compared to someone taking a beta-blocker and an RAAS inhibitor alone, would gain 8.3 years without cardiovascular death or a first hospitalization for HF.
In terms of daily practice, however, physicians must counsel each patient on what to expect. “Suppose you see a black patient with systolic heart failure at the clinic, and he asks you about the safety and effectiveness of these drugs in patients who look like them: we want to have a solid data set to build on,” DeFilippis pointed out.
It’s not just about making sure the drugs are working, but also knowing if there are any danger signs. For example, only 5% of patients enrolled in PARADIGM-HF were black, in part because only 7% of participants in the global trial were from North America. Ten of the black patients had an episode of angioedema, compared to 44 non-black patients. Yet, as researchers note in the International Journal of Cardiologythis equated to rates of 1.8% versus 0.4%.
It is important to have the evidence base to tell black and Hispanic patients what to expect from various treatments. But so are the connections that research efforts can foster with communities, DeFilippis said. “When we are able to enroll patients in these clinical trials and they are introduced to more specialized and broader care teams, I think that has a lot of implications, both for the study and also for overall engagement with the health system. [This] I hope and expect this will translate to better health outcomes, not only for their cardiovascular disease, but also for other chronic conditions.
How will they get to their appointments? How can they complete the tests we are asking for—is that reasonable? How can we use telehealth? Ersilia M. De Filippis
In recent years, as the HFC document notes, the FDA and the US National Institutes of Health have begun to take steps to promote diversity in clinical trials. In 2017, for example, the NIH began requiring phase III clinical trials supported by their agency to collect data on sex, gender, race, and ethnicity. This information must be submitted to the ClinicalTrials.gov registry, and in order to receive a grant, the distribution of these characteristics must reflect the target populations studied.
“Notably, NIH policies only affect federally funded research,” the document points out. “Therefore, FDA policies and guidelines are also critically important in encouraging appropriate representation of private industry and non-federally funded clinical studies and trials.” As recently as November 2020, the FDA updated its clinical trial diversity guidance document, which includes a discussion of eligibility criteria and unnecessary exclusions as barriers to enrollment. Yet the FDA only offers recommendations – there is no legal mandate to follow this advice.
Changes from start to finish
To overcome barriers to diversity, the HFC report offers strategies related to “research study design and site selection” as well as “patient, facility and community engagement.” And finally, it explores “changing the research paradigm”. Each of these three themes is explored in detail, with suggestions for concrete actions to take.
The first step, say the authors, begins with the design of the study. In addition to broad inclusion criteria, another option is to limit overrepresented groups. And, in an aspect unique to IC, the trials should consider different natriuretic peptide thresholds for study entry, since black individuals tend to have lower measures of these biomarkers. Multilingual trial materials, equipment, and staff should be available, a factor that could open the door to more Hispanic patients.
The globalization of HF clinical trials has created additional challenges when it comes to reflecting the racial/ethnic demographics of the United States, they note. Thus, site selection must be deliberate and may require “economic incentives to sustain the centres”, as well as engagement with researchers in other parts of the world.
For DeFilippis, a key area in need of work is addressing the social determinants of health. When designing trials, these barriers should be kept in mind, she advised. “How are they going to get to their appointments?” How can they complete the tests we are asking for—is that reasonable? How can we use telehealth? »
It’s crucial, she says, to work with clinical trial team members who come from affected populations, not only to improve community engagement, but also to understand what’s feasible for trial participants. study in terms of time, professional obligations and transport. The cultural values, language and dynamics of the neighborhood are also important. The idea is to make study participation more accessible, DeFilippis added. “Sometimes it seems so simple, but it’s always very difficult.”
Then there’s the big picture—the research paradigm.
“To improve inequities in HF clinical trials, we need to fundamentally reconsider the way we conduct research and the regulatory environment. In addition to the above strategies, incentives at the sponsor, funder, and federal levels must be better aligned to promote diverse participant enrollment as well as a diverse research enterprise,” the HFC report insists.
New policies could encourage diversity through “’carrots’ such as simplified regulatory review processes or extended patent life,” the authors suggest. In addition to working to increase the number of black and Hispanic trial participants, there is also a need to change the face of trial leadership, they point out: “Leadership from industry sponsors and professional societies can advance the career development of researchers underrepresented in clinical trials and improve the chances of increasing diversity among clinical trial participants.
DeFilippis told TCTMD that the HFC, in addition to extensive advocacy efforts, is currently looking at ways to promote diversity in trial leadership and improve uptake of HF device therapies in underrepresented groups.