Use of ANOVA to Estimate Inter‐ and Intra‐reader Variability for a Group of Readers in Thorough QT/QTc Studies

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. 1 Recent publications have discussed various aspects of thorough QTc studies. 2 , 3 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. 1 , 2 , 3 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.” 1 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. 1 2 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 with the study results. 1 Clinical Pharmacology & Therapeutics (2008) 83 , 3, 489–491.doi: 10.1038/sj.clpt.6100481