title: Use of ANOVA to estimate inter- and intra-reader variability for a group of readers in thorough QT/QTc studies.
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 with the study results.
authors.affiliation: Quintiles ECG Services, Mumbai, India. mili.natekar@quintiles.com
authors.forename: M
authors.initials: M
authors.lastname: Natekar
authors.forename: V
authors.initials: V
authors.lastname: Mahajan
authors.forename: A
authors.initials: A
authors.lastname: Satra
authors.forename: M
authors.initials: M
authors.lastname: O'Kelly
authors.forename: D R
authors.initials: DR
authors.lastname: Karnad
mesh_terms: D000704:Analysis of Variance; D002317:Cardiovascular Agents / Q000494:pharmacology / Q000627:therapeutic use; D004562:Electrocardiography / Q000187:drug effects; D006801:Humans; D008133:Long QT Syndrome / Q000175:diagnosis* / Q000188:drug therapy / Q000503:physiopathology; D015588:Observer Variation; D017410:Practice Guidelines as Topic
chemical_list: D002317:Cardiovascular Agents