Equivalence and non-inferiority trials in the evaluation of non-pharmacological interventions: Rationale, challenges and recommendations

Abstract

Direct comparisons of non-pharmacological interventions are becoming increasingly common. Many randomised clinical trials are designed to assess whether the effect of one intervention is either equivalent to, or not inferior to, that of a criterion standard. This article provides an accessible introduction to such equivalence and non-inferiority designs. Topics covered include the choice of hypothesis and comparator, the choice of equivalence or non-inferiority margin and the benefits and drawbacks of common methods of analysis. While equivalence and non-inferiority trials offer unique possibilities, there are also challenges. Some of these are particularly pronounced in the non-pharmacological setting, such as the difficulty in establishing margins informed by placebo effects and structural barriers to achieving sufficient statistical power. Under-recognised general threats to the equivalence and non-inferiority designs are also discussed, including the threat of poor intervention delivery leading to washed-out effects, the especially pronounced threat of rhetorical € spin' in the reporting of inconclusive findings and the threat of increasingly indirect evidence due to the sequential change of criterion standards. Implications for the non-pharmacological field are brought to the reader's attention, and suggestions are given to improve methodological rigour.