Geographic and Demographic Representation in Industry-Sponsored, US-Based Clinical Trials of Systemic Lupus Erythematosus Therapies

To the Editor:

Clinical research into potential therapies for systemic lupus erythematosus has increased over the last two 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 lupus trials.(2) However, little is known about trials supporting new drug development, including their representativeness of the US population with lupus, or the distribution of US enrollment sites. To address these evidence gaps, we assessed geographic and demographic enrollment for industry-sponsored lupus clinical trials.

We identified clinical trials of small molecules or biologics for systemic lupus erythematosus 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 one 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 Centers for Disease Control and Prevention lupus registries.(5) PPRs between 0.80 and 1.20 indicated adequate representation.(6) This study used public, nonidentifiable data and was exempted from institutional review board review.

We identified 144 industry-sponsored lupus clinical trials, including 107 investigating therapies for systemic lupus erythematosus and 37 specifically for renal manifestations of lupus. The median number of trials per therapy was 1 [interquartile range (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 3,454 US sites were reported, including 2,565 (74.26%) in large metropolitan counties and 237 (6.86%) in small- or non-metropolitan counties (Table 1). Only 164 sites (4.75%) were in medically underserved counties. The geographic distribution of US sites was similar for multinational and US-only clinical trials.

Table 1:

Characteristics of US enrollment sites reported for industry-sponsored lupus clinical trials.

		Trials (No.)	US enrollment sites
			Sites (No.)	Enrollment site designations (No., %)d				Medically underserved area (No., %)e
				Large metropolitan	Medium metropolitan	Small metropolitan	Non- metropolitan
All trials		144	3454	2565 (74.3)	652 (18.9)	201 (5.8)	36 (1.0)	164 (4.7)
Year of study start	2002 – 2009	29	621	445 (71.7)	135 (21.7)	38 (6.1)	3 (0.5)	17 (2.7)
	2010 – 2017	59	1534	1130 (73.7)	294 (19.2)	96 (6.3)	14 (0.9)	82 (5.3)
	2018 – 2024a	56	1299	990 (76.2)	223 (17.2)	67 (5.2)	19 (1.5)	65 (5.0)
Study indication	Systemic lupus erythematosus	107	2827	2090 (73.9)	523 (18.5)	179 (6.3)	35 (1.2)	146 (5.2)
	Renal lupusb	37	627	475 (75.8)	129 (20.6)	22 (3.5)	1 (0.2)	18 (2.9)
Type	Small molecule	37	922	697 (75.6)	168 (18.2)	43 (4.7)	14 (1.5)	45 (4.9)
	Biologic	107	2532	1868 (73.8)	484 (19.1)	158 (6.2)	22 (0.9)	119 (4.7)
Enrollment sites	US only	28	271	209 (77.1)	39 (14.4)	23 (8.5)	0 (0)	16 (5.9)
	Multi-national	116	3183	2356 (74.0)	613 (19.3)	178 (5.6)	36 (1.1)	148 (4.6)
Trial status	Completed or terminated	99	2590	1888 (72.9)	510 (19.7)	165 (6.4)	27 (1.0)	123 (4.7)
	Otherc	45	864	677 (78.4)	142 (16.4)	36 (4.2)	9 (1.0)	41 (4.7)

^aThe time period “2018-2024” includes 4 clinical trials registered prior to, but started after, January 01, 2023.

^b“Renal lupus” refers to clinical trials evaluating therapies for the treatment of lupus nephritis, including active nephritis, membranous nephropathy, or prevention of renal disease flare.

^c“Other” trial status includes clinical trials that are not yet recruiting, recruiting or enrolling by invitation, active (not recruiting), withdrawn, or with unknown status.

^dEnrollment site designations are based on National Center for Health Statistics Urban-Rural Classification, last updated 2013, with “Large metropolitan’ including large central and fringe metros, and “Non-metropolitan” including micropolitan and noncore areas.

^eMedically underserved designations are based on Health Resources and Services Administration designation of “medically underserved areas” lacking access to primary care services at the county level, last updated 2023.

There were 85 completed or terminated trials with reported results (Table 2). Female participants were adequately represented relative to the US population with lupus (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 three periods of study start dates (2002-2008, 2009-2015, 2016-2022).

Table 2:

Enrollment demographics for completed and terminated, industry-sponsored lupus clinical trials.

		Trials (No.)	Racea												Ethnicityb
			Black			American Indian/Alaska Native			Asian			White			Hispanic
			Trials reporting (%)	PPR (Median, IQR)	P value	Trials reporting (%)	PPR (Median, IQR)	P value	Trials reporting (%)	PPR (Median, IQR)	P value	Trials reporting (%)	PPR (Median, IQR)	P value	Trials reporting (%)	PPR (Median, IQR)	P value
All trials		99	71 (72)	0.4 (0.2 - 0.6)	-	52 (53)	0.2 (0 - 1.1)	-	69 (70)	2.1 (0.6 - 3.7)	-	72 (73)	1.0 (0.8 - 1.2)	-	47 (47)	1.0 (0.8 - 1.7)	-
Year of study start	2002 – 2008	23	15 (65)	0.5 (0.3 - 0.8)	.21	8 (35)	0 (0 - 0.1)	.39	14 (61)	1.0 (0.6 - 3.2)	.72	16 (70)	1.1 (0.8 - 1.2)	.51	5 (22)	0.9 (0.9 - 1.0)	.98
	2009 – 2015	47	36 (77)	0.4 (0.2 - 0.5)		27 (57)	0.3 (0 - 1.2)		35 (74)	2.1 (0.6 - 3.6)		36 (77)	1.0 (0.7 - 1.2)		25 (53)	1.2 (0.8 - 1.8)
	2016 – 2022	29	20 (69)	0.3 (0.2 - 0.5)		17 (59)	0.7 (0 - 1.3)		20 (69)	2.3 (0.7 - 4.8)		20 (69)	1.1 (0.8 - 1.1)		17 (59)	1.3 (0.9 - 1.8)
Study indication	Systemic lupus erythematosus	78	55 (71)	0.4 (0.3 - 0.6)	.60	41 (53)	0.4 (0 - 1.3)	.09	53 (68)	1.5 (0.5 - 2.7)	<.001	56 (72)	1.1 (1.0 - 1.2)	<.001	38 (49)	1.0 (0.9 - 1.7)	.84
	Renal lupusc	21	16 (76)	0.4 (0.2 - 0.7)		11 (52)	0 (0 - 0.5)		16 (76)	5.3 (3.2 - 7.1)		16 (76)	0.6 (0.6 - 0.8)		9 (43)	1.3 (0.6 - 1.7)
Type	Small molecule	25	19 (76)	0.4 (0.3 - 0.6)	.83	16 (64)	0.2 (0 - 1.3)	.98	19 (76)	2.1 (0.6 - 4.4)	.94	20 (80)	1.1 (0.7 - 1.2)	.94	19 (76)	1 (0.7 - 1.7)	.73
	Biologic	74	52 (70)	0.4 (0.2 - 0.6)		36 (49)	0.2 (0 - 0.9)		50 (68)	2.1 (0.6 - 3.4)		52 (70)	1.0 (0.8 - 1.2)		28 (38)	1.1 (0.9 - 1.6)
Enrollment sites	US only	19	8 (42)	1.1 (0.8 - 1.5)	<.001	7 (37)	0 (0 - 0.4)	.14	8 (42)	0.5 (0.3 - 0.6)	.002	8 (42)	1.0 (0.8 - 1.1)	.99	5 (26)	0.8 (0.5 - 0.9)	.02
	Multi-national	80	63 (79)	0.3 (0.2 - 0.5)		45 (56)	0.3 (0 - 1.3)		61 (76)	2.4 (0.9 - 4.2)		64 (80)	1.0 (0.8 - 1.2)		42 (53)	1.3 (0.9 - 1.8)

Abbreviations: PPR, participation-to-prevalence ratio; IQR, interquartile range.

Enrollment differences across study characteristics were evaluated using Kruskal-Wallis tests. Statistical tests are two-sided, with significance defined as P < .0025.

^aRace categorization is based on United States Census Bureau categories for race reporting.

^bEnrollment by participant ethnicity exclude 7 clinical trials for which “Hispanic” was reported as a race rather than as an ethnicity.

^c“Renal lupus” refers to clinical trials evaluating therapies for active lupus nephritis, membranous nephropathy, or prevention of renal flare; due to unavailability of lupus nephritis-specific prevalence estimates from the CDC registries, trial enrollment was compared to overall lupus prevalence estimates.

Our analyses of industry-sponsored clinical trials investigating lupus 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 lupus. These findings suggest that evidence potentially supporting new lupus 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 United States.(7) Restrictive screening practices may also disproportionately exclude participants from minoritized populations, who are more likely to experience severe lupus 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. FDA has amended drug labels to reflect evidentiary gaps for new drugs, including belimumab, highlighting the uncertainty resulting from underrepresentation in clinical trials.(1)

Our analyses were limited by reliance on publicly available registrations and publications, which inconsistently report enrollment demographics. Trial registrations do not report screened participant demographics, enrollment by site, or the proportion of non-enrolling sites. In addition, PPRs for multinational trials reflect both US and non-US enrollment. However, 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 lupus trials.(2) Increasing clinical research diversity remains a goal of lupus 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. 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 lupus.