Overview of the ICH E14/S7B: Questions and Answers

Drug-induced prolongation of the QT interval of the electrocardiogram and its association with potentially fatal arrhythmias known as torsades de pointes (TdP) has remained a significant burden in pharmaceutical drug development, leading to drug withdrawal from the marketplace and late-stage attrition in research and development. This chapter provides an overview of the regulatory guidance that emerged to address this issue with an emphasis on the latest questions and answers that were developed to connect the existing nonclinical and clinical guidelines for scenarios where the nonclinical data are informative in clinical study implementation and evaluation. Based on the last two decades of scientific and technological advances, the applicable experimental models including nonclinical in silico, in vitro, and in vivo core battery and follow-up studies conducted to best practices are described with subsequent considerations relevant for developing an integrated risk assessment considering the early phase I clinical data. In addition, current challenges and future directions of the regulatory process are discussed.