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

BACKGROUND: Noninferiority and equivalence trials evaluate whether an experimental therapy's effect on the primary endpoint is contained within an acceptable margin compared with 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 noninferiority and equivalence oncologic trials registered at ClinicalTrials.gov. Data were extracted from each trial's registration page and primary manuscript. RESULTS: We identified 65 noninferiority and 10 equivalence trials that collectively enrolled 61 632 patients. Of these, 61 (81%) trials demonstrated noninferiority or equivalence. A total of 65 (87%) trials were justified in the use of a noninferiority or equivalence design either because of an inherent advantage (53 trials), a statistically significant quality-of-life improvement (6 trials), or a statistically significant toxicity improvement (6 trials) of the interventional treatment relative to the control arm. Additionally, 69 (92.0%) trials reported a prespecified noninferiority or equivalence margin of which only 23 (33.3%) provided justification for this margin based on prior literature. For trials with time-to-event primary endpoints, the median noninferiority margin was a hazard ratio of 1.22 (range = 1.08-1.52). Investigators reported a per-protocol analysis for the primary endpoint in only 28 (37%) trials. CONCLUSIONS: Although most published noninferiority and equivalence trials have clear justification for their design, few provide rationale for the chosen margin or report a per-protocol analysis. These findings underscore the need for rigorous standards in trial design and reporting.