Bridging the Gap Between Explanatory and Pragmatic Trials in Inflammatory Bowel Disease

Randomized controlled trials (RCTs) are the gold standard for assessing the efficacy and safety of medical interventions. Randomized controlled trials conducted for registrational purposes in inflammatory bowel disease (IBD) face many unique challenges, one of which is their inability to capture the diverse and complex presentations of IBD seen in real-world settings. Highly restrictive eligibility criteria are a key contributor, as they aim to isolate treatment effects but by the very nature of their design create a “trial population” that may differ substantially from real-world patients.1,2 Such RCTs in IBD exclude types of patients that are routinely encountered in daily clinical practice, such as those with peri-anal disease, inflammatory strictures, proctitis, pouchitis, ostomies, dominant extraintestinal manifestations, multi-biologic exposure, or mild or severe disease presentations, resulting in homogeneous trial populations that fail to reflect the complexities encountered in routine clinical care.3,4 However, it is critical to recognize that pivotal RCTs designed for regulatory approval, are explanatory by design. Their primary focus is to demonstrate efficacy—not effectiveness—under highly controlled conditions in order to definitively establish benefits over placebo/active comparator if those differences truly exist, or to detect an excess of harms. Strict inclusion and exclusion criteria limit variability and control confounding factors, enhancing internal validity but often at the expense of external validity or generalizability.5 This is in contrast to pragmatic trials which are designed to test the benefit of interventions in routine clinical practice (testing effectiveness). While real-world evidence is valuable, it can never substitute for RCTs due to the inherent inability to balance comparative treatment groups on known or unknown confounders, meaning that causality cannot be reliably established.6 Thus, designing clinical trials that are more reflective of the populations we see in practice is one way of enhancing their external validity. This includes reducing bureaucratic barriers, such as overly rigid eligibility criteria, and implementing adaptive trial designs that maintain scientific rigor while improving inclusivity.6

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