OBJECTIVES: Non-inferiority and clinical equivalence clinical trials can be used to determine whether a health technology is, at least, no worse than an existing treatment. There is a large body of literature and guidance on this topic, with substantial variation in definitions and practice, which can make it challenging to robustly demonstrate or assess claims of non-inferiority or clinical equivalence. This study aimed to provide actionable recommendations in the appraisal of claims of non-inferiority and clinical equivalence.

METHODS: International guidelines and published literature were reviewed to identify approaches for the conduct and reporting of non-inferiority or clinical equivalence studies. Guidelines from health technology assessment (HTA) and regulatory bodies were considered, and literature reviews from 2010 to 2023 were identified. The results of the reviews were supplemented with findings from an expert panel and synthesized to form a series of recommendations, using case studies from the National Institute for Health and Care Excellence (NICE).

RESULTS: The majority of guidelines (13/14) discussed, to varying extents, methods to determine the non-inferiority margin and how the analysis should be conducted. Despite this, the rationale for the margin was not reported in over 50% of 273 blinded randomized controlled trials between 1966 and 2015. Evidence of non-inferiority or clinical equivalence presented in NICE Medical Technology Evaluation Program appraisals (for health technologies) is often of lower quality than in Technology Appraisal appraisals (for pharmaceuticals), increasingly concluding that further evidence generation is required.

CONCLUSIONS: Despite clear guidance, the quality of reporting in non-inferiority and clinical equivalence trials is consistently poor. Prior to presentation of trial evidence, HTA submissions that claim non-inferiority or equivalence should present the technical, biological and/or pharmacokinetic reasonings that support the claim. HTA bodies should introduce more precise definitions of non-inferiority and clinical equivalence so that evidence standards are more likely to be met.