Defining the noninferiority margin and analysing noninferiority: An overview

Abstract

Noninferiority trials are used to assess whether the effect of a new drug is not worse than an active comparator by more than a noninferiority margin. If the difference between the new drug and the active comparator does not exceed this prespecified margin, noninferiority can be concluded. This margin must be specified based on clinical and statistical reasoning; however, it is considered as one of the most challenging steps in the design of noninferiority 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 noninferiority. Three methods are commonly used to analyse noninferiority trials: the fixed-margin method; the point-estimate method; and the synthesis method. This article provides an overview of analysing noninferiority and choosing the noninferiority margin.

Keywords: biostatistics; clinical trials; drug regulation; methodology; randomized controlled trials.

© 2017 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.

Figures

Figure 1

Analysing noninferiority by comparing the confidence interval (CI) of the relative risk to a predefined margin. (1) and (2) Noninferiority was not demonstrated because the upper limit of the CI exceeded the margin. (A), (B), (C) Noninferiority was demonstrated because the upper limits of the CI did not exceed the margin

Figure 2

Analysing noninferiority of ximelagatran to warfarin using the relative risk. (1) Noninferiority margin for the fixed margin method. (2) Noninferiority margin for the point‐estimate and synthesis method. (*) The original confidence interval (CI) from SPORTIF V trial that was used to analyse noninferiority with the fixed‐margin and the point‐estimate methods. Noninferiority was not demonstrated with the fixed‐margin method and with the point‐estimate methods because the upper limit of the CI exceeded both margins (1.38 and 1.66). (&) The adjusted CI of SPORTIF V trial in the synthesis method. Noninferiority was not demonstrated because the upper limit of the CI is > the margin (1.66). (A), (B), (C) Noninferiority would have been demonstrated for all methods if the CI lies in one of the three positions in A, B or C

Figure 3

Analysing noninferiority of ximelagatran to warfarin using the risk difference. (1) Noninferiority margin for the fixed margin method. (2) Noninferiority margin for the point‐estimate and the synthesis method. (*) The original confidence interval (CI) from SPORTIF V trial that was used to analyse noninferiority with the fixed‐margin and the point‐estimate methods. Noninferiority was not demonstrated with the fixed‐margin method because the upper limit of the CI was > the margin (0.98%), whereas it was demonstrated with the point‐estimate because the upper limit of the confidence was the margin (1.88%). (A), (B), (C) Noninferiority would have been demonstrated for all methods if the CI lies in one of the three positions in A, B or C