Average Inferiority Measure and Standardized Margins to Address the Issues in Biosimilar Trials

ABSTRACT The choice of similarity or inferiority margins is a key design element for biosimilar and noninferiority (NI) studies. There are three major issues with the current practice of margin specications: the subjectivity in the process of determining the margin, the data variability not considered or only implicitly expressed, and the concern of “biocreep” controversy. In this chapter, an average inferiority measure (AIM) is introduced as a tool for specication of margins to address these issues and the standardized margins derived from AIM re“ect naturally the variability of data. AIM is applied to the normal, binary, and the survival data. A general theorem is obtained to establish the asymptotic normality of a test statistic for the NI hypothesis dened by the standardized margin. We also propose an additional requirement on the treatment effect difference for concluding NI to address the concern of biocreep and show that this additional requirement does not reduce the power when the treatment and control are true equivalent.