OIII-A-2Performance characteristics of the analysis method for “thorough QT” studies in ICH E-14

Abstract

BACKGROUND/AIMS The probability of incorrectly concluding QT/QTc prolongation was evaluated using an intersection-union test (IUT - ICH E-14 guidance for “thorough QT” (TQT) studies). Bias in the estimated true mean was also evaluated. METHODS Placebo data from 4 TQT trials (2 parallel with N=30, 24/group and 2 crossover each with N=60) were used. Nonparametric bootstrapping (resampling subjects with replacement) was used to simulate 300 TQT trials under the original study designs. Each simulated trial consisted of placebo data only but with a treatment group designated arbitrarily. A study was considered positive if the maximum confidence bound was greater than 10 ms. Additionally the analysis considered true effects of 0–5 ms and various sample sizes. RESULTS The largest mean difference estimates ranged from 0.5 to 4.0 ms depending on study designs despite the true drug effect of zero. The false positive probabilities ranged from 0–62%. The false positive rate for crossover trials was = 40 and true effects up to 4 msec. For small parallel trials, the false positive rate was up to 62%. Smaller sample sizes and larger true effects increased the false positive rate. CONCLUSIONS The false positive rate and bias for TQT based on the IUT vary with study design, sample size, and the true drug effect. Large sample sizes (N>150/group) may be necessary for parallel trials to avoid incorrect conclusions about QT/QTc prolongation liability for new drugs. Clinical Pharmacology & Therapeutics (2005) 79, P29–P29; doi: 10.1016/j.clpt.2005.12.107