Arrhythmogenic liability screening in cardiovascular safety pharmacology: Commonality between non-clinical safety pharmacology and clinical thorough QT (TQT) studies

Abstract

Multiple ECG analysis strategies are used in safety pharmacology in a framework focused on accurate ECG complex interval quantification and arrhythmia detection. Automated arrhythmia detection is commonly used in the clinic and adapted tools may be used to facilitate analysis of large non-clinical datasets in safety pharmacology. The ICH E14 guideline (for Thorough QT Studies (TQT) conducted in healthy volunteers) supports manual and semi-automated ECG evaluation by skilled readers with a single operator analyzing all the ECG recordings from a given subject to minimize observer bias. Both fully automated and semi-automated ECG analysis programs may be used in safety pharmacology studies. Based on power analysis, a group size of approximately n=18 per study arm is the minimal requirement in TQT studies to provide the sensitivity to detect a 5ms QT interval prolongation. This sample size differs markedly from common safety pharmacology non-clinical study designs. New technologies such as the jacketed external telemetry (JET) ECG system may facilitate achievement of a smaller group size in integrated cardiovascular safety pharmacology risk assessment. TQT and cardiovascular safety pharmacology studies share several common experimental and scientific limitations which may benefit from technological advances. Sensitivity expectations in non-clinical studies should be commensurate with sample size and further investigations including power analyses and comparison between fully automated and semi-automated ECG analysis may help better characterize detection thresholds. Reducing overall variability, increasing reproducibility of ECG interval measurements and enhancing arrhythmia detection strategies are the cornerstones of data analysis in cardiovascular safety pharmacology and will likely continue to attract considerable attention in the safety pharmacology community.