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.
The investigators analyzed 85,133 electrocardiograms (ECGs) recorded in 484 subjects from 5 thorough QT/QTc studies (3 using Holter devices, 2 using 12-lead ECGs) for inadvertent limb lead interchanges using a dedicated quality control process in a central ECG laboratory. Limb lead interchanges were present in 2919 (3.4%) ECGs in 17.9% of subjects and were more frequent with Holter devices (7.5% vs 0.8%, P < .0001), where leads remain connected for prolonged periods, affecting data from several time points. Left arm-left leg interchange was seen in 54% of 12-lead ECGs and right arm-left arm interchange in 38%. The ECG device itself could identify 21.7% of interchanges, whereas experienced readers blinded to subject and visit identified 79% of interchanges; 21% of interchanges were identified only during the quality control process. If correctly identified, QT measurement could be performed in a precordial lead. If undiagnosed, incorrect QT interval measurements and morphological diagnosis may confound results.
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