Evaluation and management of cardiac safety using the electrocardiogram in oncology clinical trials: focus on cardiac repolarization (QTc interval).
Non-antiarrhythmic drugs have been reported to prolong the QTc interval and induce potentially fatal ventricular tachyarrhythmias. An increasing number of drugs that are used for treating malignancies are no exception. Therefore, both oncologists and regulators expect sponsors of oncology drugs to evaluate, during the development of the drugs, their effects on the electrocardiogram (ECG), particularly on the QTc interval. In the case of agents that cannot be administered to healthy volunteers, the primary approach is to carry out an intense ECG evaluation, employing robust ECG recordings, during early-phase clinical trials, together with characterization of the concentration-QTc interval relationship, and follow this up with an appropriate intensity of ECG monitoring in the later phases of development. This article describes the broad principles of these approaches, including recommendations for exclusion criteria (relative to baseline QTc interval and to cardiac comorbidity); it also describes methods for conducting ECG monitoring and a proposed scheme for the management of any QTc-related effects that may emerge.
Morganroth
J
J
eResearchTechnology, Philadelphia, Pennsylvania, USA. Jmorganroth@ert.com
Shah
R R
RR
Scott
J W
JW
D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D002986:Clinical Trials as Topic / Q000379:methods; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D016903:Drug Monitoring / Q000379:methods*; D004562:Electrocardiography; D006801:Humans; D008133:Long QT Syndrome / Q000139:chemically induced*; D009369:Neoplasms / Q000188:drug therapy; D018579:Patient Selection; D012307:Risk Factors
D000970:Antineoplastic Agents