Defining the non-inferiority margin and analyzing non-inferiority: An overview

Non-inferiority trials are used to assess whether the effect of a new drug is not worse than an active comparator by more than a non-inferiority margin. If the difference between the new drug and the active comparator does not exceed this pre-specified margin, non-inferiority can be concluded. This margin must be specified based on clinical and statistical reasoning; however, it is considered as one the most challenging step in the design of non-inferiority trials. Regulators recommend that the margin should be defined based on the historical evidence of the active comparator (the latter is often the well-established standard treatment of the disease), which can be performed by different approaches. There are several factors and assumptions that need to be accounted for during the process of defining the margin and during the analysis of non-inferiority. Three methods are commonly used to analyze non-inferiority trials: the fixed-margin method, the point-estimate method, and the synthesis method. This article provides an overview of analyzing non-inferiority inferiority and choosing the non-inferiority margin.