Tests of noninferiority via rate difference for three-arm clinical trials with placebo.

In assessing a noninferiority trial, the investigator intends to show efficacy by demonstrating that a new experimental drug/treatment is not worse than a known active control/reference by a small predefined margin. If it is ethically justifiable, it may be advisable to include an additional placebo group for internal validation purpose. This constitutes the well-known three-arm clinical trial with placebo. In this paper, we study two asymptotic statistical methods for testing of noninferiority in three-arm clinical trials with placebo for binary outcomes based on rate difference. They are sample-based estimation method and restricted maximum likelihood estimation method, respectively. We investigate the performance of the proposed test procedures under different sample size allocation settings via a simulation study. Both methods perform satisfactorily under moderate to large sample settings. However, the restricted maximum likelihood estimation method usually possesses slightly smaller actual type I error rates, which are relatively close to the prespecified nominal level, while the sample-based method can be expressed in a simple closed-form format. Real examples from a pharmacological study of patients with functional dyspepsia and a placebo-controlled trial of subjects with acute migraine are used to demonstrate our methodologies.