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.