A covariate-adjustment regression model approach to noninferiority margin definition.

To maintain the interpretability of the effect of experimental treatment (EXP) obtained from a noninferiority trial, current statistical approaches often require the constancy assumption. This assumption typically requires that the control treatment effect in the population of the active control trial is the same as its effect presented in the population of the historical trial. To prevent constancy assumption violation, clinical trial sponsors were recommended to make sure that the design of the active control trial is as close to the design of the historical trial as possible. However, these rigorous requirements are rarely fulfilled in practice. The inevitable discrepancies between the historical trial and the active control trial have led to debates on many controversial issues. Without support from a well-developed quantitative method to determine the impact of the discrepancies on the constancy assumption violation, a correct judgment seems difficult. In this paper, we present a covariate-adjustment generalized linear regression model approach to achieve two goals: (1) to quantify the impact of population difference between the historical trial and the active control trial on the degree of constancy assumption violation and (2) to redefine the active control treatment effect in the active control trial population if the quantification suggests an unacceptable violation. Through achieving goal (1), we examine whether or not a population difference leads to an unacceptable violation. Through achieving goal (2), we redefine the noninferiority margin if the violation is unacceptable. This approach allows us to correctly determine the effect of EXP in the noninferiority trial population when constancy assumption is violated due to the population difference. We illustrate the covariate-adjustment approach through a case study.