Randomized clinical trials (RCTs) are often considered the highest level of evidence to guide medical practice. Unlike other clinical studies, well-conducted randomized trials are not susceptible to confounding and thus may provide definitive evidence of causation. As such, this experimental design can allow practitioners to understand the true impact of medical interventions on patient outcomes. Despite this strength, the design, implementation, and application of RCTs in the real world is challenging, especially in the field of oncology. For example, some oncologic trials may evaluate interventions with small expected effect sizes and subsequently require large patient populations, which can be difficult to accrue. Similarly, many of the most valued clinical endpoints, such as overall survival (OS), often can take several years to manifest differences and, thus, trial results may not keep pace with the constantly evolving oncology research landscape.

Perhaps the most difficult obstacle to the real-world utilization of cancer RCTs is disparities in trial enrollment, which may limit the generalizability of trial results to the real-world target population. In fact, numerous studies have shown that trial participants often do not represent the general population for the condition being studied. For example, older individuals, those with poor performance, and those from gender and ethnic minority groups are less likely to be represented in cancer clinical trial populations.1, 2, 3, 4 The underlying etiology and mechanism for clinical trial enrollment disparities is complex and multi-faceted. There are not only societal, cultural, and economic components, but also medical provider and trial design factors, which likely contribute to the consistently observed large-scale enrollment disparities. Therefore, interventions to mitigate such disparities will require multidimensional efforts aimed at addressing the many fundamental root causes.

In this review, we will focus specifically on the impact of trial eligibility criteria as a driver of disparities. We begin by characterizing existing disparities and highlighting the contribution of eligibility criteria to RCT enrollment inequity. We then summarize current ongoing initiatives aimed at improving eligibility criteria and finally conclude with a discussion of potential avenues and strategies to reform eligibility criteria in future cancer clinical trials.