Most Placebo-Controlled Trials in Inflammatory Bowel Disease were Underpowered Because of Overestimated Drug Efficacy Rates: Results from a Systematic Review of Induction Studies
Bibliographic record
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 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.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.274 | 0.523 |
| Meta-epidemiology (narrow) | 0.003 | 0.003 |
| Meta-epidemiology (broad) | 0.015 | 0.025 |
| Bibliometrics | 0.016 | 0.016 |
| Science and technology studies | 0.001 | 0.003 |
| Scholarly communication | 0.007 | 0.007 |
| Open science | 0.004 | 0.003 |
| Research integrity | 0.004 | 0.003 |
| Insufficient payload (model declined to judge) | 0.004 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; the direct Gemma label and the distilled Codex classifier agree on what is shown here.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".