OBJECTIVES: Demonstrating non-inferiority of a new technology against comparators is pivotal in streamlined cost-comparison appraisals (sCCAs) conducted by the National Institute for Health and Care Excellence (NICE). We investigated the methodological challenges and interpretation of the non-inferiority assumption in NICE’s sCCAs.

METHODS: All NICE sCCAs between January 2023 and May 2024 were reviewed. The analysis focused on the indirect treatment comparison (ITC) methodology, interpretation, and uncertainties, EAG critique and the NICE committee’s final appraisal decision.

RESULTS: Eight appraisals (8.8%) were sCCAs. All sCCAs received positive recommendation. Two used direct head-to-head and 6 used ITC data for comparative evidence. The ITCs included the full population (n=1), only subgroups (n=3) and both (n=2). ITC network was aligned (n=6) or included other comparators beyond the decision problem (n=2). However, the latter was not deemed to bias the results. All ITCs included multiple efficacy endpoints, alongside safety. EAG considered the methodology appropriate despite some limitations, which related to potential sources of study heterogeneity and limited available data. None defined a non-inferiority or equivalence margin. EAG considered reasonable to assume non-inferiority between intervention and comparators in all sCCAs, as none of the uncertainties were critical, but highlighted that cautious interpretation is needed in the absence of statistical non-inferiority or equivalence testing. Clinical expert opinion was important to support the non-inferiority assumption in 3 sCCAs, drawing on clinical experience and common mechanism of action.

CONCLUSIONS: More guidance is needed to support the assessment of non-inferiority in sCCAs. The terminologies should be standardized, as ‘similarity’, ‘non-inferiority’ and ‘equivalence’ are used interchangeably. Non-inferiority margins need to be defined and reflect changes in outcome that are clinically relevant for the patient. A framework and criteria to seek clinical expert opinion might reduce decision-making uncertainty, especially when limited evidence base poses challenges to a conclusive ITC interpretation.