The evolving role of placebo in non-inferiority trials: A scoping review

BACKGROUND: Non-inferiority trials can be used for efficacy endpoints or safety endpoints, with indirect and direct comparison to placebo. A less common application of this design involves using placebo as the proposed intervention to challenge standard practices that lack evidence of efficacy. However, the methodology of using a placebo in a non-inferiority trial is poorly described in the literature. We performed a scoping review to map how placebo is utilized in randomized controlled trials with a non-inferiority design, with particular attention to studies positioning placebo as a proposed alternative to existing, but unproven, interventions. METHODS: We conducted a scoping review of randomized controlled trials using non-inferiority designs with a placebo arm, searching six databases without date or language restrictions. Eligible studies were primary randomized controlled trials with at least one placebo arm evaluated under a non-inferiority hypothesis. Data extraction focused on study characteristics, design elements, rationale for non-inferiority design and margin, and analytical practices. RESULTS: Of 6897 studies screened, 94 met inclusion criteria. Three primary study types were identified: safety (63%), deprescription (20%), and shorter-course (13%) trials. There has been increased use of deprescription and shorter-course studies since 2017. One-third (35%) hypothesized that placebo was non-inferior to active treatment, predominantly in deprescription and shorter-course trials focused on antibiotic use. Most studies (94%) applied non-inferiority analysis to primary outcomes, yet only 22% provided a rationale for non-inferiority design, and despite 96% prespecifying non-inferiority margin, only 41% justified the margin. While 71% used intention-to-treat analysis, only 53% conducted per-protocol analysis. Graphical representation of non-inferiority margins and confidence intervals was reported in 23% of studies. CONCLUSION: Placebo is increasingly used in non-inferiority trials aimed at evaluating the necessity of standard interventions, including safety, deprescription, and shorter-course designs. However, many trials lack critical methodological transparency. Future studies should clearly justify non-inferiority designs and margins, use both intention-to-treat and per-protocol analyses, and adhere to the Consolidated Standards of Reporting Trials reporting guidelines to enhance interpretability and rigor.