Use of ECGs in Support of Cardiac Safety in Phase II and III Clinical Trials

Abstract

Drugs in clinical development that potentially have effects on cardiac safety based on nonclinical data or findings in phase I, may require systematic cardiac safety assessments throughout phases II and III. Of major concern are drugs which cause the lethal, but rare, ventricular arrhythmia, torsades de pointes (TdP). Indeed, drugs intended for the general population that cause a one in one million incidence of TdP can be a significant public health concern (1,2). This risk cannot be adequately addressed in typical drug development programs by arrhythmia monitoring or adverse event reporting. However, drugs known to cause TdP are known to reproducibly perturb cardiac ventricular repolarization, an effect that is manifest on the standard 12-lead electrocardiogram (ECG) as prolongation of the QTc interval. Thus, QTc and the degree to which it is prolonged, is used as a surrogate marker for a drug’s potential to cause TdP. This chapter will focus on the use of standard 12-lead ECGs in phases II and III clinical development to assess a drug’s effect on cardiac intervals, durations, and morphologic patterns.