Inferiority Index and Margin in Noninferiority Trials

Abstract

The specification of a margin in a noninferiority trial is often subject to challenge and disagreement. One reason for the contentious discussion is the concern about the validity of the constancy and assay sensitivity assumptions that accompany all such trials. But the main reason for disagreement is the subjectivity associated with the different current procedures that are used to determine the noninferiority margin. This article introduces the concept of an inferiority index between two distributions and establishes its link to an effect measure. Through this relationship, the inferiority index can be used as a standard measure to assess the degree of tightness of any given noninferiority margin and, in conjunction with clinical knowledge and available historical data, it can also guide the selection of a margin. Specifically, this relationship is investigated under survival, normal, and binomial distributions. A general theorem is given that establishes the asymptotic normality of a test statistic for the noninferiority hypothesis defined by the noninferiority margin so derived. Some examples from noninferiority trials are used to illustrate the usefulness of the inferiority index.

Keywords: :

• Bioequivalence
• Biosimilarity
• Comparative effectiveness
• Inferiority index
• Noninferiority margin
• Safety assessment