Clinical trial diversity efforts should be taking place during the study design phase, says the FDA’s Andrew Farb.

Lack of diversity in clinical trial populations can affect the generalizability of the results, and a new review suggests that in valvular heart disease trials, the level of representation hasn’t budged over more a decade and a half.

Between 2005 and 2020, the proportion of older patients, women, and racial and ethnic minorities did not increase in any appreciable way, note Kriyana P. Reddy (University of Pennsylvania, Philadelphia), and colleagues in a paper published online July 26, 2023, in JAMA Cardiology. Many studies did not even publish a breakdown of the results by key groups of interest.

“The biggest takeaway that I had is that race and ethnicity are reported in a very small proportion of clinical trials, and when they are reported, it seems that minority populations are underrepresented and socioeconomic status is not reported at all,” senior author Ashwin S. Nathan, MD (University of Pennsylvania), told TCTMD.

While it might seem like an easy fix to incorporate these elements, “it’s something that has been a focus of discussion, but also something that hasn’t been mandated by the government when trials are run,” he added. “The lack of a mandate may be one of the reasons for the underrepresentation we are seeing.”

The findings regarding enrollment patterns in the study are “consistent with the pivotal trials submitted to support US Food and Drug Administration approval of the transcatheter devices to treat severe aortic stenosis and functional severe mitral regurgitation,” note Andrew Farb, MD (FDA, Silver Spring, MD), and colleagues in an accompanying editorial. Taken together, the study and the pivotal trials create “some uncertainty into whether the observed results are generalizable to all patients,” they add.

Valvular heart disease trials are not alone in their underrepresentation in this area, with similar observations over the years in RCTs involving CAD, heart failure, arrythmia, hypertension, and CVD.

Recently, President Biden signed the Consolidated Appropriations Act of 2023, which requires that investigational studies of drugs and devices have a diversity action plan. It also requires the FDA “to issue a study diversity action plan guidance, which will include recommendations on setting enrollment goals that consider (1) the estimated disease/condition prevalence or incidence for which the medical product is being investigated; (2) what is known about the intended use patient population; and (3) potential barriers to enrolling a diverse patient cohort,” Farb et al write.

Less Than 10% Report Race/Ethnicity

For the study, the researchers examined 139 surgical or transcatheter valve trials, 75% of which involved aortic valve disease. Among the 51,527 participants (mean age 68.4 years), the proportion of women enrolled in valvular heart disease trials, overall 41.1%, remained steady between 2005 and 2020 remained steady.

Female patients had higher rates of representation in trials co-funded by a university and industry than in those co-funded by government and industry (61.5% vs 35.2%; P < 0.001), and in device trials rather than in medical therapy trials (43.1% vs 39.3%; P < 0.001).

Of the less than 10% of trials that reported race and ethnicity, trial-level representation did not change over time across populations that included American Indian/Alaska Native, Asian, Black/African American, Hispanic, and Native Hawaiian/Pacific Islander. Black/African American patients accounted for a little over 4% of all trial populations, followed by Hispanic and Asian patients at 2.4% and 0.3%, respectively.

Greater proportions of American Indian/Alaska Native, Asian, Black/African American, Hispanic, and Native Hawaiian/Pacific Islander patients were seen in device and surgery trials than in medical therapy trials (16.7% vs 3.6%; P < 0.001), and in industry-funded trials than in government-funded trials (35% vs 12.5%; P < 0.001). Compared with aortic valve studies, there was greater representation of these groups in mitral valve trials (22.9% vs 6.9%; P < 0.001).

Trials that tended to have a higher proportion of women were not predictive of greater representation of racial and ethnic minority patients.

While the age of trial participants increased nonsignificantly over time, patients in aortic valve trials were an average of 15 years older than those in mitral valve studies (P < 0.001). The highest mean age was seen in trials that were multiregional as opposed to exclusively European or North American participants.

Planning and Equity

“Planning for increased clinical trial diversity needs to take place during the study design phase,” Farb and colleagues say. “Critical to understanding device safety and effectiveness in different groups is a standardized collection of race and ethnicity data and prespecified subgroup analyses.”

In addition to the legislation passed by President Biden, the study authors say, companies who sponsor trials “will need to explain how they intend to meet diversity action plan enrollment goals,” and the FDA will hold a public workshop to solicit input on increasing enrollment of underrepresented groups.

“It’s important to understand generalizability of safety and efficacy, but also to make sure that all patient populations have access to novel therapies because valvular heart disease is life-threatening. Sometimes a clinical trial is the last option for a patient, making it important to maintain equity,” Nathan added. “I think regulatory agencies have an obligation to include that in their thought processes in terms of how trial designs are conducted and then subsequently executed and reported.”

He added that refining the scope of diversity, equity, and inclusion in clinical trials also represents an opportunity for collaboration between regulatory agencies, industry, and academic research organizations to ensure that all stakeholders are involved from the beginning to make the trial as inclusive as possible.