Scientific Publications by FDA Staff

J Biopharm Stat 2013 Jan;23(1):43-56

On the Designs of Thorough QT/QTc Clinical Trials.

Tsong Y

A thorough QT trial is typically designed to test for two set of hypotheses. The primary set of hypotheses is for demonstrating that the test treatment will not prolong QT interval. The second set of hypotheses is to demonstrate the assay sensitivity of the positive control treatment in the study population. The conventional designs of thorough QT studies are parallel arms and crossover trials. Although the sample size requirements, the time points of analysis, and the durations of drug administration to reach a steady stage are all different between the test and positive control treatments, the trials are often designed with equal study duration and sample size for the different treatment arms or periods. In order to reduce the number of subjects needed for the parallel-arm thorough QT clinical trial, unconventional designs were proposed and used in the recent years. In this article, we review and discuss a few of the designs and propose some additional designs in the form of unbalanced, group sequential, and adaptive designs with the objective to improve trial efficiency or to reduce the risk of unnecessarily exposure of subjects to the potentially harmful positive control treatment.