Study Finds Many Randomized Clinical Trials Have Poorly Justified Exclusion Criteria

Credit: photon_photo | stock.adobe.com

A new analysis published by JAMA Network Open identified room for improvement in the exclusion criteria of randomized clinical trials (RCTs) that highlight the need to improve equity and representation in both trial design and reporting. Although the study authors found that the majority of exclusion criteria in RCTs can be justified, more than half contain at least one exclusion that lacks sufficient justification, with the most common exclusions affecting people who are pregnant or lactating, individuals with communication barriers, and those who are uninsured.¹

“(RCTs) are the criterion standard in medical research, and their findings have the potential to impact patient care around the world,” the study authors wrote. “Although eligibility criteria play a critical role in selecting at-risk patient populations and reducing confounding, overly stringent exclusion criteria may limit the reproducibility of trial findings, leading to a lack of generalizability. This issue may stem from limitations in study design, limited diversity and representation in research teams, and the need for patient and community engagement. These limitations in the design of RCTs may result in the exclusion of patients on the basis of age, sex, and disability.”¹

The current study comes during a time in which the recent progress regarding improved diversity, equity, and inclusion (DEI) in drug development could be undone as many companies are pulling back on their DEI initiatives. However, an analysis by the Tufts Center for the Study of Drug Development recently published by Applied Clinical Trials notes that recent FDA regulatory requirements for Diversity Action Plans and growing evidence regarding the effect of DEI practices may help to maintain this progress.²

“Despite sensationalized headlines and heated discourse about the merit and value proposition of DEI initiatives, efforts to improve access and inclusion will move forward in 2025 in select ways,” the Tufts authors wrote. “At the national-level, funding to study racial disparities has not dissipated. The National Institute on Minority Health and Health Disparities at the National Institute of Health, for example, has continued to see healthy funding in 2023 and 2024 for research on improving health disparities among marginalized communities. Momentum will also come from the FDA’s June 2024 draft guidance requiring pharmaceutical companies to disclose strategies and tactics that they plan to implement to address enrollment and retention of racial minority participants in their studies.”²

For the current study, the authors sought to determine whether exclusion criteria for RCTs published by The Lancet, British Medical Journal, Journal of the American Medical Association, New England Journal of Medicine, and Annals of Internal Medicine are justifiable, potentially justifiable, or poorly justifiable.

Investigators conducted a systematic sampling review of parallel-group RCTs published between January 1, 2018, and February 23, 2023. These RCTs included adult patients in intensive care units (ICUs) and those that enrolled critically ill patients needing life-sustaining interventions that are generally initiated in the ICU.

The authors included 75 studies from a total of 225 that fit their criteria. The median amount of exclusion criteria in each analyzed trial was 19, comprising 1455 total exclusion criteria. These criteria were associated with the risk of adverse reactions to interventions (20.8%), lack of consent (8.2%), and treatment limitation decisions (6.7%). The authors found that 74.2% of exclusion criteria were strongly justified, 20.4% were potentially justified, and 5.4% were poorly justified.

Among the 78 criteria identified by the authors as being poorly justified, pregnancy (24.4%), communication barriers (14.1%), lactation (12.8%), and lack of health insurance (12.8%) were the most common. A total of 60.0% of the studies included in the analysis had at least one poorly justified exclusion criteria, according to the study authors.

“This study demonstrated that the majority of exclusion criteria in critical care RCTs were strongly justifiable; however, 60% of RCTs had at least 1 poorly justified exclusion criterion,” the authors concluded. “Across poorly justified criteria, the exclusion of pregnant persons was common. The majority of trials had White male first or last authors and few were from LMICs, highlighting the limited global representation across high-impact journals. We encourage investigators to carefully consider exclusion criteria when designing RCTs to improve equitable access to trial participation and the generalizability of trial findings. We also recommend that journals mandate clear justification of all exclusion criteria to aid in broadening participant representation.”¹

References

1. Heirali A, Heybati K, Sereeyotin J, et al. Eligibility Criteria of Randomized Clinical Trials in Critical Care Medicine. JAMA Netw Open. 2025;8(1):e2454944. doi:10.1001/jamanetworkopen.2024.549442

2. Kim J.; Getz K. Is There Progress Amidst the Swinging Diversity Pendulum? Applied Clinical Trials. Web article. Published January 14, 2025. Accessed January 21, 2025. https://www.appliedclinicaltrialsonline.com/view/progress-swinging-diversity-pendulum