Non-Inferiority Margins in Randomized Controlled Trials in Abdominal Surgery – a Systematic Review
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Importance
Non-inferiority trials are becoming increasingly popular in abdominal surgery. The non-inferiority margin is critical in the interpretation and conclusion of these trials.
Objective
This systematic review aims to assess the methodological and reporting quality of non-inferiority randomized controlled trials in abdominal surgery.
Evidence Review
Non-inferiority trials were systematically identified by searching Ovid Medline, Embase and the CENTRAL databases from 2006 until December 2025. Randomized controlled trials in adult patients with any type of abdominal surgical intervention in at least one trial arm and a sample size ≥100 were eligible for inclusion. The primary outcome was the definition of the non-inferiority margin. Secondary outcomes were the reporting of the non-inferiority margin, the robustness of its estimation, the uncertainty of the point estimate and the adequacy of conclusions.
Findings
A total of 11’045 trials were identified, of which 101 were eligible, enrolling 44’370 patients. Most trials provided a rationale for the non-inferiority design, while six (5.9%) trials did not. Previous literature was commonly used (n=56; 55.4%), but the non-inferiority margin was most often based on a clinical fixed margin or on historical comparison of the treatment and the active comparator. Based on the margin, investigators tolerated substantially worse outcomes of the treatment compared to the comparator.
Conclusions were appropriate based on the confidence interval and the predefined non-inferiority margin in 88 (87.1%) of trials. The clinical judgement of the conclusion was overall adequate. Confidence interval estimations were reported in 16 (15.8%) of trials. Simulation studies were limited by the reporting quality.
Conclusions and Relevance
Clinical fixed margins are commonly used in abdominal surgery non-inferiority randomized controlled trials, however, substantial shortcomings in reporting limit the interpretability and reproduction of study findings. Based on the findings of this study, guidance on surgical-specific non-inferiority margin definitions is needed.
KEY POINTS
Question
How are non-inferiority margins estimated in surgical randomized controlled trials?
Findings
In this systematic review, non-inferiority margins were nearly always numerically defined, but reporting of how they were estimated was poor. Most frequently, clinical fixed margins were utilized and previous evidence was either ignored or not included at the design stage. The selected margins often tolerated substantially worse outcomes in the treatment group compared to the comparator.
Meaning
Improved reporting and guidance on the conduct of surgical non-inferiority trials are required.
