Testing for Positive Control Activity in a Thorough QTc Study∗

∗This paper does not represent the official position of US Food and Drug Administration.

Abstract

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.

Key Words:

• Assay sensitivity
• QTc interval
• Statistical testing
• Thorough QTc study

ACKNOWLEDGMENTS

I thank Dr Yi Tsong for his encouragement for the manuscript. I thank Dr. Kooros Mahjoob for the discussion about optimal sample size calculation. Thanks also go to Dr. Stella Machado for her useful and careful comments. I am most grateful for the numerous discussions on the topic with Dr. Norman Stockbridge and for his helpful suggestions.

Notes

^aBonferroni adjustment by 11 time points.

^bBonferroni adjustment by 4 time points.

^aSample size needed for the trial based on the optimal sample size distribution except for moxifloxacin arm.

^bSample size needed for the trial except for moxifloxacin arm if each arm is getting an equal sample size.

K = 4, α = 0.05, β = 0.85, σ = 10 ms, D = [8, 8, 11, 9]′, n _P  = 59.

∗This paper does not represent the official position of US Food and Drug Administration.