Most Placebo-Controlled Trials in Inflammatory Bowel Disease were Underpowered Because of Overestimated Drug Efficacy Rates: Results from a Systematic Review of Induction Studies

BACKGROUND AND AIMS: Most pharmaceutical clinical trials for inflammatory bowel disease IBD are placebo-controlled and require effect size estimation for a drug relative to placebo. We compared expected effect sizes in sample size calculations SSCs to actual effect sizes in IBD clinical trials. METHODS: MEDLINE, EMBASE, CENTRAL and the Cochrane library were searched from inception to March 26, 2021, to identify placebo-controlled induction studies for luminal Crohn's disease CD and ulcerative colitis UC that reported an SSC and a primary endpoint of clinical remission/response. Expected effects were subtracted from actual effects, and interquartile ranges IQRs for each corresponding median difference were calculated. Linear regression was used to assess whether placebo or drug event rate misspecifications were responsible for these differences. RESULTS: Of eligible studies, 36.9% 55/149 were excluded because of incomplete SSC reporting, yielding 94 studies 46 CD, 48 UC. Treatment effects were overestimated in CD for remission (-12.6% IQR: -16.3 to -1.6%), in UC for remission (-10.2% IQR: -16.5 to -5.6%) and in CD for response (-15.3% IQR: -27.1 to -5.8%). Differences observed were due to overestimated drug event rates, whereas expected and actual placebo event rates were similar. A meta-regression demonstrated associations between overestimated treatment effect sizes and several trial characteristics: isolated ileal disease, longer CD duration, extensive colitis UC, single-centre, phase 2 and no endoscopic endpoint component UC. CONCLUSION: Overestimation of IBD therapy efficacy rates resulted in smaller-than-expected treatment effects. These results should be used to inform SSCs and trial design for IBD drug development.