Enrollment Gaps Persist Across Diabetic Macular Edema and Retinal Vein Occlusion Trials
A cross-sectional review of U.S.-based randomized clinical trials in diabetic macular edema and retinal vein occlusion found a persistent mismatch between who entered study populations and who makes up the U.S. population. Across 23 completed phase 3 trials with published results, White participants dominated enrollment, while Hispanic participants were most often missing in numbers that would match the 2010 U.S. Census. The pattern was not subtle. In 22 of the 23 trials, the racial and ethnic distribution differed significantly from Census data.
This matters because retinal vascular disease does not respect the narrow demographics of convenience sampling. DME and RVO are chronic, vision-threatening disorders that affect patients across racial and ethnic groups, yet the evidence base that shapes treatment decisions has not consistently reflected that breadth. When trial populations skew away from the clinic population, confidence in external validity weakens, especially for diseases managed over long periods with repeated intravitreal treatment and close follow-up.
A Narrow Trial Pool After Broad Screening
Investigators screened 169 trials and excluded 146 because they were incomplete, failed to report race and ethnicity, or were not based in the United States. The final analysis included 23 trials: 15 in DME and 8 in RVO. That attrition itself signals a practical problem in interpretation, because the usable evidence base for demographic comparison was far smaller than the overall pool of trials initially identified.
The analysis recorded the number and percentage of participants who identified as American Indian or Alaska Native, Asian, Black, Hispanic, Native Hawaiian or Other Pacific Islander, and White. Because the numbers for American Indian or Alaska Native and Native Hawaiian or Other Pacific Islander were so small, those groups were combined for comparison. The Census benchmark came from the 2010 U.S. data, creating a fixed national reference point for distributional comparison.
White Participants Were Most Often Overrepresented
Across the 23 included trials, there were 7,613 White participants, representing 80.4% of the pooled study population. In the 2010 U.S. Census, White residents accounted for 63.7% of the population. White participants were underrepresented in 2 trials, overrepresented in 14, and neither overrepresented nor underrepresented in 7.
The imbalance was even more striking when viewed against the smallest groups. American Indian or Alaska Native and Native Hawaiian or Other Pacific Islander participants accounted for just 38 participants total, or 0.4% of the pooled trial population, compared with 1.1% in the Census reference group. Asian participants totaled 415, or 4.4%, just below the Census proportion of 4.8%. Black participants numbered 904, or 9.6%, versus 12.6% in the Census. Hispanic participants reached 954, or 10.1%, well below the Census estimate of 16.3%.
One trial population after another failed to reflect the racial and ethnic structure of the U.S. population.
Hispanic Underrepresentation Was the Most Consistent Pattern
Hispanic participants were underrepresented in 15 trials, overrepresented in 2, and proportionate in only 5. Among all the analyzed groups, this was the most consistent shortfall. For a disease burden that tracks with access to screening, diabetes prevalence, insurance coverage, referral patterns, and treatment adherence, underenrollment of Hispanic patients can distort the evidence that guides ophthalmic care.
The same problem appeared in other groups, though less uniformly. Black participants were underrepresented in 9 trials, overrepresented in 2, and proportionate in 11. Asian participants were underrepresented in 10 trials, overrepresented in 4, and proportionate in 8. Even where representation was closer to Census proportions, the balance varied across individual studies, suggesting that recruitment practices, site geography, and eligibility structure likely influenced who actually entered the trial pipeline.
Why Representation Changes the Meaning of Trial Results
RCTs in retinal vascular disease often inform treatment intervals, response expectations, and long-term management strategies for anti-VEGF and related intravitreal therapies. If a trial disproportionately enrolls one racial or ethnic group, the resulting efficacy and safety profile may not fully capture differences in baseline disease severity, comorbid diabetes control, access to routine care, or treatment persistence. Those factors can shape visual outcomes as much as the intervention itself.
In a condition like DME, microvascular injury is influenced by systemic diabetes burden and retinal ischemia; in RVO, venous obstruction, macular edema, and inflammatory signaling can all interact with broader vascular risk. Enrollment that fails to capture the diversity of those underlying drivers can leave trial results less portable to the patients who will receive the therapy in everyday practice.
Significance for Ophthalmic Trial Design
The statistical comparison was stark: the racial and ethnic distribution differed significantly from U.S. Census data in 22 of 23 trials. That result supports a straightforward conclusion for trial design and recruitment strategy. Sites that serve more diverse patient populations, broader geographic sampling, and enrollment practices built to reduce access barriers are likely necessary if future DME and RVO trials are to better mirror the real-world population.
Better representation is not only an equity issue. It is also a validity issue. When trial cohorts lean heavily toward White participants, clinicians must extrapolate beyond the studied population to apply the findings to Hispanic, Black, Asian, and Indigenous patients. The more that extrapolation is required, the less secure the evidentiary foundation becomes.
Limits of the Evidence Base and the Next Recruitment Problem
This analysis was restricted to U.S.-based phase 3 randomized clinical trials with published results and available race and ethnicity data. The use of 2010 Census data provides a stable national benchmark, but it also reflects a single time point rather than changing demographic patterns over the study window from 2004 to 2020. Trial populations also may have been shaped by reporting practices, and many screened studies were excluded because demographic data were absent or incomplete.
Even with those limits, the pattern was consistent enough to be difficult to dismiss. The central gap is not abstract: it is a measurable mismatch between trial enrollment and the population that depends on ophthalmic care. Future studies in diabetic macular edema and retinal vein occlusion will need more deliberate recruitment of underrepresented racial and ethnic minority groups if investigators want the results to travel more faithfully from the research setting to routine retina practice.