J Crohns Colitis. 2022 Oct 11:jjac150. doi: 10.1093/ecco-jcc/jjac150. Online ahead of print.
ABSTRACT
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, 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.
PMID:36219564 | DOI:10.1093/ecco-jcc/jjac150
