Clinical Trial Endpoints for Perianal Fistulizing Crohn's Disease

Perianal fistulizing Crohn's disease (pCD), a structurally damaging condition of the anorectum and perineum, can result in debilitating symptoms and significantly impair quality of life. The lack of high-quality randomized controlled trials (RCTs) with primary endpoints specifically validated for pCD has contributed to suboptimal treatment recommendations. This review discusses considerations for pCD RCTs and provides expert opinion on current endpoints in the context of guidance from regulatory authorities. A challenge designing pCD RCTs is that placebo response rates and treatment effect sizes can change over time and are influenced by surgical and medical interventions that are often required pre-enrollment. Analysis of the main endpoint in 10 pCD phase III/IV RCTs and post hoc analyses highlighted the lack of universal definitions for clinical fistula response/remission. Most trials assessed clinical response based on a physical examination, which has not been formally validated, and one used a combined clinical and radiological response endpoint. Five endpoints evaluating fistula closure/healing, clinical remission, and patient-reported outcomes were deemed to reflect clinically meaningful changes for patients. However, none were considered to be reproducible or show a reasonable effect size with low placebo background noise or response rates. Based on our evaluation, future trials should use coprimary clinical and radiologic assessments to capture both how the patient feels and an objective measure of disease activity. These findings reinforce the need for clearly defined, objective, and standardized endpoints for pCD clinical trials that will enable evaluation of novel therapies to improve patient outcomes.