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.

Comparison of Two Methods of Estimating Reader Variability in QT Interval Measurements in Thorough QT/QTc Studies

“…Since both these methods are simplistic and do not take into account that the fact that 40 ECGs are read by the same reader, or that in the grouped analysis design, the same ECG is analyzed by 12 different readers, an ANOVA method has been described which uses the interaction between ECG, readers and the Lead used to measure QT interval to provide an overall estimate of reader variability . Using this method, the mean of SDs of the 1000 samples were comparable for grouped and pairwise analysis design and for data from the grouped analysis design analyzed by pairwise comparisons.…”

“…In addition, data were also analyzed by a previously described three‐way interaction ANOVA model which used ECG (ECGs 1 to 40), ECG lead and reader (Readers 1 to 12) as factors for estimation of inter‐reader variability and ECG, ECG lead and read (Read I or Read II) as factors for intra‐reader variability . The square root of the residual variance from this ANOVA model gives an estimate of the overall reader variability (similar to SD from the other methods).…”

Near‐Thorough QT Study as Part of a First‐In‐Man Study

“…The ICH E14 regulatory guidance and standard requirements by regulatory bodies prescribe several mandatory components for TQT studies, 1 including the positive control investigation (ie, a pharmacological intervention known to prolong the heart‐rate‐corrected QTc interval to an expected level) and electrocardiographic (ECG) monitoring covering the pharmacokinetic profile of both the parent compound and known metabolites. Although not strictly required by regulatory guidance, verification of ECG measurements is not infrequently performed by independent laboratories 2 . In addition, the US Food and Drug Administration (but presently not other regulatory bodies) requires submission of electronic ECG waveforms 3 for regulatory review.…”