Design of Vaccine Equivalence/Non-Inferiority Trials with Correlated Multiple Binomial Endpoints

Abstract

Immunogenicity trials that study the immune responses to vaccination are often used in the vaccine development process as alternatives to clinical efficacy trials. The comparisons of immune responses among various treatment groups are conducted in a non-inferiority or equivalence framework. When there exists a level of immune response that correlates with protection against disease, it is of interest to compare the proportion of responders as defined as response above a specific level or as a predefined increase in immune levels for post-vaccination levels above pre-vaccination levels. Since vaccines often contain several antigens, the correlations between the immune responses need to be taken into account in the analysis. In this paper, we describe appropriate testing methods for demonstrating the non-inferiority/equivalence of two treatments on each of the binomial endpoints. We conduct a comprehensive simulation study to shed light on how the Type I error and power are affected and to what extent when correlated multiple binomial endpoints are present in the vaccine trials. We also illustrate the computation of power for assessment of non-inferiority/equivalence in real studies.

Key Words:

• Equivalence
• Multiple binomial endpoints
• Non-inferiority
• Power
• Proportion
• Type I error

Notes

ACT: actual structure; IND: independence structure.

ACT: actual structure; IND: independence structure.