Conducting the non-inferiority test for the means with unknown coefficient of variation in a three-arm trial

Abstract

Background: The non-inferiority test is a reasonable approach to assessing a new treatment in a three-arm trial. The three-arm trial consists of a placebo, reference, and an experimental treatment. The non-inferiority is often measured by the mean differences between the experimental and the placebo groups relative to the mean differences between the reference and the placebo groups.

Methods: To cope with possible estimation distortion due to the allowance of heteroskedasticity, we adjust the measurement of non-inferiority by the incorporation of coefficient of variation (CV) of the experimental, the reference and the placebo groups. In this research, we propose a generalized [Formula: see text]-value based method (GPV-based method) to facilitate non-inferiority tests for the means with unknown coefficient of variation in a three-arm trial.

Results: The simulation results show that the GPV-based method can not only adequately control type I error rate at nominal level better but also provide power higher than those from Delta method and the empirical bootstrap method, which verifies the feasibility of our adjustment.

Conclusions: We revise the measurement of non-inferiority by deducting the CV of each kind of treatment from the average effect of trials. CVs are included in the non-inferiority explicitly to help prevent possible estimating distortion if heteroskedasticity is allowed. Through the simulation study, the performance of GPV-based method for facilitating non-inferiority tests for the means with unknown CV in a three-arm trial is better than those from empirical bootstrap method and Delta method for small, medium and large sample sizes. Hence, the GPV-based method is recommended to be used to conduct the non-inferiority test for the means with unknown CV in a three-arm trial. The GPV-based method still performs well in non-normality cases.

Keywords: Coefficient of variation; Generalized p-value; Heteroskedasticity; Non-inferiority test; Searls’ estimator.