A comparison of treatment effect sizes in matched phase 2 and phase 3 trials of advanced therapeutics in inflammatory bowel disease: systematic review and meta-analysis

Abstract

Introduction: Phase 2 trials are fundamental to the rational and efficient design of phase 3 trials. We aimed to determine the relationship of treatment effect size estimates from phase 2 and phase 3 clinical trials on advanced therapeutics in inflammatory bowel disease. Methods: MEDLINE, EMBASE, CENTRAL, and the Cochrane library were searched from inception to December 19, 2022, to identify paired phase 2 and 3 placebo-controlled induction studies of advanced therapeutics for Crohn’s disease (CD) and ulcerative colitis (UC). Treatment effect sizes were expressed as a risk ratio (RR) between the active arm and placebo arm. For the same therapeutics, RR from phase 2 trials were divided by the RR from phase 3 trial to quantify the relationship of effect sizes between phases. Results: Twenty-two studies (9 phase 2 trials, 13 phase 3 trials) were included for CD and 30 studies (12 phase 2 trials, 18 phase 3 trials) for UC. In UC (pooled RR 0.72; 95% confidence interval [CI]: 0.58–0.86; RR <1 indicate smaller treatment effect sizes in phase 2 trials), but not CD (pooled RR 1.01; 95% CI: 0.84–1.18), phase 2 trials systematically underestimated treatment effect sizes for the primary endpoint compared to phase 3 trials. The underestimation was observed for clinical, but not endoscopic endpoints in UC. Conclusions: Treatment effect sizes for the primary and clinical endpoints were similar across clinical trial phases in CD, but not UC, where only endoscopic endpoints were comparable. This will help inform clinical development plans and future trial design.