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.

Noninferiority testing for matched‐pair ordinal data with misclassification

“…Several approaches have been suggested to calculate the noninferiority margin. One common approach is the fixed‐margin method based on the effect of the active control in historical studies . The value recommended in the FDA guidance is the lower bound of the 95% CI of the estimated effect of a single placebo‐controlled trial or a meta‐analysis of such trials.…”

“…One common approach is the fixed-margin method based on the effect of the active control in historical studies. 1,41 The value recommended in the FDA guidance is the lower bound of the 95% CI of the estimated effect of a single placebo-controlled trial or a meta-analysis of such trials. Alternatively, a specific proportion of the observed treatment effect of the active control is used as the margin, which aims to reflect the largest loss of effect that would be clinically acceptable.…”

Handling an uncertain control group event risk in non-inferiority trials: non-inferiority frontiers and the power-stabilising transformation

“…• ݊ ଵ , ݊ be the sample sizes, with allocation ratio ‫ݎ‬ = ݊ ଵ /݊ . Several recommendations have been given regarding choice of the most appropriate noninferiority margin 3,6 , involving both clinical and statistical considerations. Whilst sample size calculations allow for stochastic variation between the true control event risk ߨ and its final observed estimate ߨ ො , they do not allow for substantial misjudgment in the envisaged truth.…”

Noninferiority drug trials fail to report adequate methodological detail: an assessment of noninferiority trials from 2010 to 2015

“…Noninferiority (NI) trials are prevalent in many therapeutic areas and are used to evaluate new drugs [1e4]. When reading NI trials, one must pay special attention to the justification for the NI margin [5,6]. With the NI margin being a key part of NI trial design, any questionable justification for the choice of the NI margin can lead to incorrectly declaring a new drug a reasonable alternative to the current standard therapy.…”