Evaluation of Drug Effects on Cardiac Conduction
Recent advances in electrocardiographic monitoring and waveform analysis have significantly improved the ability to detect drug-induced changes in cardiac repolarization manifested as changes in the QT/corrected QT interval. These advances have also improved the ability to detect drug-induced changes in cardiac conduction. This White Paper summarizes current opinion, reached by consensus among experts at the Cardiac Safety Research Consortium, on the assessment of electrocardiogram-based safety measurements of the PR and QRS intervals, representing atrioventricular and ventricular conduction, respectively, during drug development.
The assessment of drug-induced changes in cardiac electrical activity remains a key component in the development of safe pharmacotherapeutic agents. Prior efforts to evaluate cardiac safety have focused on changes in cardiac repolarization (and, specifically, the QT interval on the electrocardiogram [ECG]), partly because of the ICH E14 Guideline (Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs), the maturation of systems for ECG monitoring and analysis, and the evolution of the thorough QT/corrected QT interval (QTc) study. As a result of these advances, further resolution of drug effects on cardiac conduction (manifesting as changes in the PR and QRS intervals) has been realized. To aid in the interpretation of these new data, a Cardiac Safety Research Consortium subgroup was established to foster stakeholder discussion about PR and QRS interval assessments in drug development. Evolving data sets are providing information regarding appropriate techniques, expected variability, and overall use of evaluating drug-induced changes in the PR and QRS intervals during early-phase clinical drug development. However, limited clinical experience related to sustained changes of these intervals in different patient populations serves to constrain defining specific recommendations regarding acceptable limits for such drug-induced changes. This White Paper summarizes discussions within the Cardiac Safety Research Consortium and focuses on what is known, not known, and controversies regarding the use of PR and QRS intervals in drug development. In addition, we believe that this study will be useful to those engaged in or regulating drug development activities. We suggest that the relative lack of knowledge about these ECG-based safety measurements as end points will be considered when applying the concepts discussed, and we hope that this White Paper will spur much-needed research in this area. The opinions and conclusions expressed in this article are solely the views of the authors and do not represent the new regulatory policy.
Abstract and Introduction
Abstract
Recent advances in electrocardiographic monitoring and waveform analysis have significantly improved the ability to detect drug-induced changes in cardiac repolarization manifested as changes in the QT/corrected QT interval. These advances have also improved the ability to detect drug-induced changes in cardiac conduction. This White Paper summarizes current opinion, reached by consensus among experts at the Cardiac Safety Research Consortium, on the assessment of electrocardiogram-based safety measurements of the PR and QRS intervals, representing atrioventricular and ventricular conduction, respectively, during drug development.
Introduction
The assessment of drug-induced changes in cardiac electrical activity remains a key component in the development of safe pharmacotherapeutic agents. Prior efforts to evaluate cardiac safety have focused on changes in cardiac repolarization (and, specifically, the QT interval on the electrocardiogram [ECG]), partly because of the ICH E14 Guideline (Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs), the maturation of systems for ECG monitoring and analysis, and the evolution of the thorough QT/corrected QT interval (QTc) study. As a result of these advances, further resolution of drug effects on cardiac conduction (manifesting as changes in the PR and QRS intervals) has been realized. To aid in the interpretation of these new data, a Cardiac Safety Research Consortium subgroup was established to foster stakeholder discussion about PR and QRS interval assessments in drug development. Evolving data sets are providing information regarding appropriate techniques, expected variability, and overall use of evaluating drug-induced changes in the PR and QRS intervals during early-phase clinical drug development. However, limited clinical experience related to sustained changes of these intervals in different patient populations serves to constrain defining specific recommendations regarding acceptable limits for such drug-induced changes. This White Paper summarizes discussions within the Cardiac Safety Research Consortium and focuses on what is known, not known, and controversies regarding the use of PR and QRS intervals in drug development. In addition, we believe that this study will be useful to those engaged in or regulating drug development activities. We suggest that the relative lack of knowledge about these ECG-based safety measurements as end points will be considered when applying the concepts discussed, and we hope that this White Paper will spur much-needed research in this area. The opinions and conclusions expressed in this article are solely the views of the authors and do not represent the new regulatory policy.
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