No abstract

After several drugs were removed from the market in recent years because of death due to ventricular tachycardia resulting from drug-induced QT prolongation (Khongphatthanayothin et al., 1998; Lasser et al., 2002; Pratt et al., 1994; Wysowski et al., 2001), the ICH Regulatory agencies requested all sponsors of new drugs to conduct a clinical study, named a Thorough QT/QTc (TQT) study, to assess any possible QT prolongation due to the study drug. The final version of the ICH E14 guidance (ICH, 2005) for "The Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Nonantiarrhythmic Drugs" was released in May 2005. The purpose of the ICH E14 guidance (ICH, 2005) is to provide recommendations to sponsors concerning the design, conduct, analysis, and interpretation of clinical studies to assess the potential of a drug to delay cardiac repolarization. The guideline, however, is not specific on several issues. In this paper, we try to address some statistical issues, including study design, primary statistical analysis, assay sensitivity analysis, and the calculation of the sample size for a TQT study.

The ICH E14 guidance (ICH, 2005) recommend that a concurrent positive control should be included in a thorough QTc clinical trial to validate the study. The ICH E14 guidance (ICH, 2005) state that "The positive control should have an effect on the mean QTc interval of about 5 ms (i.e., an effect that is close to the QTc effect that represents the threshold of regulatory concern, around 5 ms)". This task may be carried out through some statistical tests. The current practice is to test at each time point where QT measurements are collected. This method is usually not efficient. In this article, I discuss two types of statistical procedures. The first one is a local statistical test to make a time-point-specific claim, i.e., to claim a mild QTc effect due to the positive control at some specific time points. A different approach, named as a global test, is also proposed, to make a general claim that the mean difference of the positive control and placebo after baseline adjustment will be about 5 ms without specifying at which time points. An example will be used to illustrate how to apply the two procedures. How to best allocate sample size in a parallel QTc study is also discussed in this paper.