Use of ANOVA to estimate inter- and intra-reader variability for a group of readers in thorough QT/QTc studies

Clinical Pharmacology and Therapeutics
M NatekarD R Karnad

Abstract

The E14 guidelines of the International Conference on Harmonization require that all new drugs that have systemic bioavailability be subjected to a thorough QT/QTc study to look for possible effects on cardiac repolarization. Recent publications have discussed various aspects of thorough QTc studies. The thorough QTc study is designed to detect a mean drug-induced QTc prolongation of >5 ms with an upper bound of the 95% one-sided confidence limits of >10 ms. The E14 guideline has spelled out the procedures to be followed in a thorough QT/QTc study, including choice of subjects, methods of electrocardiogram (ECG) acquisition, details of ECG analysis, and statistical analysis of the study data. Since the measurement of the QT interval is a relatively subjective assessment, the ECGs must be analyzed in a central ECG laboratory by "a few skilled readers." In order to maintain quality in ECG interpretation, the E14 guidelines have two requirements. First, as a measure of the assay sensitivity, the study must include an active control known to prolong the QTc interval. Second, a certain percentage of ECGs must be subjected to an inter- and intra-reader variability analysis; these data are submitted to the regulatory authorities along...Continue Reading

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Citations

Sep 2, 2008·Journal of Clinical Pharmacology·Marek MalikDavid Madge
Feb 14, 2014·Annals of Noninvasive Electrocardiology : the Official Journal of the International Society for Holter and Noninvasive Electrocardiology, Inc·Vaibhav SalviSnehal Kothari

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