Statistical Issues Including Design and Sample Size Calculation in Thorough QT/QTc Studies∗

∗The opinions presented here do not necessarily represent those of the US Food and Drug Administration.

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.

Key Words:

• QT/QTc interval
• Sample size
• Study design
• Thorough QT/QTc (TQT) study

ACKNOWLEDGMENT

We thank Dr. Yi Tsong for suggestions on an early version of the manuscript. We are also grateful for the numerous discussions with Dr. Norman Stockbridge.

Notes

∗(1) α = 0.05.

(2) 1 − β = 0.85.

(3) Independent assumption across all time points.

(4) A flat shape with the magnitude of the maximal QTc effect over all time points.

(5) Δ: the vector for the true mean difference to be detected.

∗(1) α = 0.05.

(2) 1 − β = 0.85.

(3) Assume a simple compound symmetry structure for the variance-covariance matrix and ρ = 0.5.

(4) Δ: the vector for the true mean difference to be detected.

∗FPP derived in the table is based on the constant true mean difference being 3 ms, σ = 10 ms, and sample size from Table 10, i.e., 52, 61, and 67 subjects for L = 5, 10, and 15, respectively.

∗The opinions presented here do not necessarily represent those of the US Food and Drug Administration.