Justification, margin values, and analysis populations for oncologic noninferiority and equivalence trials: a meta-epidemiological study

Background Noninferiority (NI) and equivalence trials evaluate whether an experimental therapy’s effect on the primary endpoint (PEP) is contained within an acceptable margin compared to standard-of-care. The reliability and impact of this conclusion, however, is largely dependent on the justification for this design, the choice of margin, and the analysis population used. Methods A meta-epidemiological study was performed of phase 3 randomized NI and equivalence oncologic trials registered at ClinicalTrials.gov. Data was extracted from each trial’s registration page and primary manuscript. Results We identified 65 NI and 10 equivalence trials that collectively enrolled 61,632 patients. Sixty-one trials (81%) demonstrated NI or equivalence. Sixty-five trials (87%) were justified in the use of an NI or equivalence design either because of an inherent advantage (53 trials), a significant quality-of-life improvement (6 trials), or a significant toxicity improvement (6 trials) of the interventional treatment relative to the control arm. Sixty-nine trials (92.0%) reported a prespecified NI or equivalence margin, of which only 23 (33.3%) provided justification for this margin based on prior literature. For trials with time-to-event PEPs, the median NI margin was a hazard ratio of 1.22 (range, 1.08-1.52). Investigators reported a per-protocol (PP) analysis for the PEP in only 28 trials (37%). Conclusions Although most published NI and equivalence trials have clear justification for their design, few provide rationale for the chosen margin or report a PP analysis. These findings underscore the need for rigorous standards in trial design and reporting.