Discussion

The introduction of more advanced therapies over the last decade has been essential to improving patient outcomes by providing more options for patients. RCTs are essential to demonstrate effectiveness and safety prior to FDA approval and these results are foundational for developing guidelines for clinical practice and shared decision-making with patients. Compared to results from 2012, our study findings demonstrate potential improvement with 42.7% of patients now considered trial eligible for at least one study although there remains considerable potential for improvement to include a broader range of patients.

Our study’s findings emphasize that the exclusion of patients from randomized clinical trials (RCTs) is primarily driven by their current or historical use of medications. However, other factors such as Clostridium difficile infection, colon dysplasia, anemia, and the extent of the disease also play pivotal roles, highlighting the complex landscape of patient eligibility. These criteria can be categorized as either modifiable or non-modifiable.

Non-modifiable exclusion criteria are factors inherent to the patient or disease—such as colon dysplasia or disease extent—that cannot be altered by clinicians or addressed through changes in study design. In contrast, modifiable exclusion criteria represent factors for which intervention may improve trial eligibility and can be further categorized based on whether modification occurs at the clinician or trial-design level.

Clinician-modifiable factors, such as anemia or infection, can often be identified early and addressed through supportive care measures (eg, iron supplementation or antimicrobial therapy), allowing patients to later qualify for trial participation. In our analysis, clinician-modifiable factors accounted for 34.26% of the six most common exclusion criteria. These factors are therefore important to recognize, as they may lead to temporary delays in treatment initiation or trial enrollment rather than permanent exclusion.

Trial-design-related factors may also be further conceptualized as modifiable or non-modifiable. However, within this category, some exclusions remain effectively non-modifiable (eg, exceeding the allowable number of prior biologics or prior exposure to the investigational agent), whereas others—such as current medication use—may be potentially modifiable through defined washout periods. Importantly, washout requirements must be carefully considered, as interrupting therapy in patients with moderate to severe UC may increase the risk of disease flare or progression. Taken together, these findings highlight that expanding trial eligibility will likely require both optimization of clinician-modifiable factors and thoughtful reconsideration of trial design–related restrictions to meaningfully improve patient participation.

Randomized controlled trials (RCTs) face the challenging task of maintaining internal validity to insure accurate and reliable results, often at the expense of external validity, thereby limiting the generalizability of their findings to broader patient populations. Additionally, referral center bias from tertiary referral center certainly impacts trial eligibility as the patient population tends to skew toward more refractory, more medication-experienced with a greater likelihood of disease or medication-related complications. Demographic factors such as ethnicity, educational level, language comprehension, occupation, insurance status, and geography are known to impact successful clinical trial recruitment. Additionally, a sizeable number of potentially eligible patients lack access to an established IBD clinical trials program as most IBD RCTs take place in a small number of clinical trial programs, often located within metropolitan areas.3

Concerns regarding the accessibility of trials and the underrepresentation of minorities in RCTs were the focus of the American Gastroenterological Association (AGA) IBD roundtable with discussions emphasizing the need to expand RCT networks and provide support to overcome healthcare disparities and socioeconomic differences.9 Other trial-modifiable factors that should be explored include shorter washout phases, innovative and more inclusive trial designs, especially during the maintenance phases which account for the prior medication exposures expected in a moderate to severe UC patient population. Additionally, there must be discussions about eliminating placebo arms which lead to ethical dilemmas as placebo-treated patients are more likely to experience disease flares with associated adverse events particularly when existing FDA approved agents could have been given instead.10 Alternative randomized controlled trial designs, such as open-label trials, should be considered to ensure all patients receive active treatment.

Like many tertiary referral centers, our institution is not immune to referral bias and cares for patients with more complex, treatment-refractory disease and greater prior therapy exposure. As a result, the rate of trial ineligibility in our cohort may be higher than in community practice, and true eligibility in the broader IBD population may be underestimated. Therefore, the generalizability of our findings to community-based settings should be interpreted with caution.

Over the past decade, there has been some improvement in patient inclusion within randomized clinical trials, yet significant challenges remain. Expanding trial networks and addressing healthcare disparities are crucial steps to enhance patient participation and external validity. Future efforts must prioritize inclusive and adaptive trial designs to better represent the diverse patient population.