Some issues for the evaluation of noninferiority trials.

Although published noninferiority trials (NITs) generally conclude that the experimental intervention being studied is noninferior compared with standard therapy or active control, NIT quality is often not satisfactory. We have proposed 14 questions to assist in evaluating the clinical evidence of the experimental versus standard therapy. The aim of these questions is to critically appraise NITs and support proper interpretation of study results. Readers should not only consider whether the confidence interval of the primary effect measure falls within the prespecified noninferiority margin (thus concluding noninferiority), but also assess the similarities between primary and secondary outcomes for the experimental and standard therapy. To conclude noninferiority conceptually is to synthesize evidence from both the current NIT comparing experimental therapy with standard therapy and historical data comparing standard therapy with placebo control. Therefore, readers should use external data sources (e.g., historical data) to validate the study design (e.g., selection of standard therapy, effect measure and the noninferiority margin), and assess the uncertainty of findings due to differences between the observed and expected incidence rates, follow-up time, effects of adjuvant therapy and the secondary outcomes of therapies. Following an explanation of the 14 questions, we then apply the questions to a NIT on intraoperative radiation therapy for early stage breast cancer, as an example.