To the Editor:

Clinical research into potential therapies for systemic lupus erythematosus (SLE) has increased over the last 2 decades, driven by the discovery of new targetable pathways, yet uncertainty persists over which patients benefit from new therapies.1 Black patients and other minoritized populations, which disproportionately experience severe disease, are underrepresented in SLE trials.2 However, little is known about trials supporting new drug development, including their representativeness of the population with SLE in the United States, or the distribution of US enrollment sites. To address these evidence gaps, we assessed geographic and demographic enrollment for industry-sponsored SLE clinical trials (CTs).

We identified CTs of small molecules or biologics for SLE registered on ClinicalTrials.gov by entering “lupus” in the “condition or disease” search field, and included industry-sponsored trials of any phase, registered as of January 1, 2023, with at least 1 US enrollment site. Cutaneous lupus trials were excluded. Each trial’s start date, current status, and investigated therapy characteristics were abstracted, and US enrollment sites were characterized at the county level using the Urban-Rural Classification Scheme,3 and the Medically Underserved Area designation.4 For completed or terminated trials with reported results in ClinicalTrials.gov registrations, conference abstracts, or peer-reviewed publications, participation-to-prevalence ratios (PPRs) were calculated by dividing the percentage of trial participants by sex, race, and ethnicity by each subgroup’s percentage across US Centers for Disease Control and Prevention SLE registries.5 PPRs between 0.80 and 1.20 indicated adequate representation.6 This study used public, nonidentifiable data and was exempt from institutional review board review.

We identified 144 industry-sponsored SLE CTs, including 107 investigating therapies for SLE and 37 specifically for renal manifestations of SLE. The median number of trials per therapy was 1 (IQR 1-2). Among the 144 trials, 28 exclusively enrolled US participants, and 116 enrolled internationally including at least 1 US site. A total of 3454 US sites were reported, including 2565 (74.26%) in large metropolitan counties and 237 (6.86%) in small metropolitan or nonmetropolitan counties (Table 1). Only 164 sites (4.7%) were in medically underserved counties. The geographic distribution of US sites was similar for multinational and US-only CTs.

Characteristics of US enrollment sites reported for industry-sponsored SLE CTs.

There were 85 completed or terminated trials with reported results (Table 2). Female participants were adequately represented relative to the US population with SLE (median PPR 1.0, IQR 1.0-1.0) among 82 trials reporting participant sex. Among 72 trials reporting participant race, representation was inadequate for Black (median PPR 0.4, IQR 0.2-0.6) and American Indian/Alaska Native participants (median PPR 0.2, IQR 0-1.1), and adequate for White participants (median PPR 1.0, IQR 0.8-1.2). Asian participants were overrepresented in trials overall (median PPR 2.1, IQR 0.6-3.7), but underrepresented in trials with US sites only. Among 47 trials reporting participant ethnicity, Hispanic participants were adequately represented (median PPR 1.0, IQR 0.8-1.7). There were no significant differences in enrollment by race or ethnicity across 3 periods of study start dates (2002-2008, 2009-2015, 2016-2022).

Enrollment demographics for completed and terminated, industry-sponsored SLE CTs.

Our analyses of industry-sponsored CTs investigating SLE therapies found concentration of US enrollment sites in large metropolitan areas, and persistent underrepresentation of Black and American Indian/Alaska Native participants relative to the US population with SLE. These findings suggest that evidence potentially supporting new SLE therapies is derived from a subset of patients whose clinical and demographic characteristics may not reflect broader populations. Inadequate representation likely reflects multiple factors, including clinician unfamiliarity with trial eligibility criteria, logistical challenges to patients accessing trial sites, and historic barriers to participation by minoritized populations in the US.7 Restrictive screening practices may also disproportionately exclude participants from minoritized populations, who are more likely to experience severe SLE manifestations,8 and who may derive heterogeneous benefits from treatment.9 Without representative trials supporting new therapies, clinicians must extrapolate from existing data to predict treatment effects for patients from underrepresented populations, or rely instead on older therapies, depriving patients of potentially efficacious new therapies. The US Food and Drug Administration (FDA) has amended drug labels to reflect evidentiary gaps for new drugs, including belimumab, highlighting the uncertainty resulting from underrepresentation in CTs.1

Our analyses were limited by reliance on publicly available ClinicalTrials.gov registrations and publications, which inconsistently report enrollment demographics. Trial registrations do not report screened participant demographics, enrollment by site, or the proportion of nonenrolling sites. In addition, PPRs for multinational trials reflect both US and non-US enrollment. However, the FDA considers data from global sources when evaluating therapies for use in diverse populations.10 Moreover, our findings build upon previous analyses of representation in published SLE CTs.2 Increasing clinical research diversity remains a goal of SLE trialists, who have proposed approaches to fostering participant input and access throughout the drug development process.9 Opportunities exist for sponsors to monitor enrollment and actively recruit investigators in communities underrepresented in previous trials. The FDA may also expand efforts to improve diversity in trials supporting regulatory submissions, to ensure that evidence supporting new therapies reflects the needs of patients with SLE.

JJS had full access to all data in the study and takes responsibility for its integrity and accuracy.

JJS received funding from the Rheumatology Research Foundation Student and Resident Research Award to present a related research abstract at the American College of Rheumatology Convergence 2023 meeting.

JSR received grants from the US Food and Drug Administration (FDA); J&J; Medical Device Innovation Consortium; Agency for Healthcare Research and Quality; National Heart, Lung, and Blood Institute; and Arnold Ventures outside the submitted work. JSR also is an expert witness at the request of relator attorneys, the Greene Law Firm, in a qui tam suit alleging violations of the False Claims Act and Anti-Kickback Statute against Biogen Inc. RR received research support from the Stavros Niarchos Foundation through Yale Law School for a project entitled “Re-envisioning Publicly Funded Biomedical Research and Development,” and the US Food and Drug Administration for a project entitled “Best Practices for Adequately Representing Women, Older Adults and Patients Identifying as Racial and Ethnic Minorities in Oncology Research: A Positive Deviance Approach”; consultant fees for the ReAct-Action on Antibiotic Resistance Strategic Policy Program at Johns Hopkins Bloomberg School of Public Health in 2022, which is funded by the Swedish International Development and Cooperation Agency; and grant support from Arnold Ventures outside the submitted work. JDW is supported by the FDA, J&J through the Yale Open Data Access project, and the National Institute on Alcohol Abuse and Alcoholism of the National Institutes of Health (award 1K01AA028258). JDW served as a consultant to Hagens Berman Sobol Shapiro LLP and Dugan Law Firm APLC. The remaining authors declare no conflicts of interest relevant to this article.