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Use of ANOVA to Estimate Inter‐ and Intra‐reader Variability for a Group of Readers in Thorough QT/QTc Studies
Author(s) -
Natekar M,
Mahajan V,
Satra A,
O'Kelly M,
Karnad DR
Publication year - 2008
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1038/sj.clpt.6100481
Subject(s) - qt interval , medicine , repolarization , clinical pharmacology , ventricular repolarization , pharmacology , electrophysiology
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