Clinical remission in paired phase two and three studies in inflammatory bowel disease: a systematic review with meta-analysis

Abstract

Discrepancies in phase two and three studies can result in significant patient and financial burden, as well as the nonapproval of potentially efficacious drugs. We aimed to determine whether this discrepancy exists for clinical trials in inflammatory bowel disease (IBD). Electronic databases (MEDLINE and Embase) and clinical trial repositories were searched from 1 January 1946 to 12 March 2021, for paired phase two and three studies of advanced therapies for Crohn’s disease and ulcerative colitis. The primary outcome was to compare clinical remission rates between paired phase two and three studies for Crohn’s disease and ulcerative colitis. Multivariable mixed-model meta-analysis was performed to calculate odds ratios (OR) with 95% confidence intervals (CI). The Cochrane risk-of-bias tool was used to grade the risk of bias. Of 2642 studies, 29 were included. Fifteen were phase three, 11 were phase two, one was phase one/two, and two were phase two/three. There were no differences in clinical remission rates between phase two and three studies for Crohn’s disease (OR, 1.07; 95% CI, 0.86–1.34; P = 0.54) and ulcerative colitis (OR, 0.81; 95% CI, 0.48–1.36; P = 0.43). Furthermore, there was a lack of any appreciable differences in study characteristics, inclusion criteria and patient demographics among paired phase two and three studies. Most studies were considered low risk of bias. Overall, paired phase two and three studies demonstrate similar clinical remission rates for advanced therapies in IBD. Whether this applies to newer outcomes, such as endoscopic and mucosal healing remains to be determined.

Comparison of treatment effect between phase 2 and phase 3 trials in patients with inflammatory bowel disease

“…In UC trials, the primary endpoint was clinical remission for 14 studies (five phase 2 and 9 phase 3) and clinical response for one phase 2 and two phase 3 studies. Clinical outcomes were mostly evaluated using the full MS except for the upadacitinib trials and the mirikizumab phase 3 trial (using the adapted MS) and for one other study using the Ulcerative Colitis Clinical score 8 . Definitions used for clinical outcomes are detailed in Table 2.…”

“…Clinical outcomes were mostly evaluated using the full MS except for the upadacitinib trials and the mirikizumab phase 3 trial (using the adapted MS) and for one other study using the Ulcerative Colitis Clinical score. 8 Definitions used for clinical outcomes are detailed in Table 2 . Among the six phase 2 trials, 4 were positive for the primary endpoint, followed by at least one positive phase 3 trial for the primary outcome.…”

“…A recent review did not find any differences in the clinical remission rates between paired phase 2 and 3 studies in CD and UC, but they did not evaluate other outcomes. 8 We aimed to determine whether treatment effects observed in phase 3 trials investigating the efficacy of biologics and small molecule drugs in IBD differed from those in the phase 2 trial that preceded them.…”

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

“…Treatment effect sizes are dependent on the difference in event rates in the active treatment arm and the placebo arm—the latter was ignored in previous studies comparing phase 2 and 3 trials in rheumatology and IBD ( 8 , 56 ). Smaller-than-expected treatment effect sizes across clinical trial phases can be the result of lower rates of remission in the active arm or higher rates of remission in the placebo arm, or both.…”

“…A systematic review and meta-analysis exploring clinical remission in paired phase 2 and 3 studies in IBD trials was recently published ( 56 ). No difference in rates of clinical remission between trial phases was found.…”