Keywords: thorough qt,e14,concentration-qt
Since the adoption of ICH E14 in May of 2005, almost all new drugs have been required to be evaluated for the potential to cause QTc prolongation in a so-called thorough QT study. This requirement was triggered by several drug withdrawals in the 1990s for arrhythmias associated with QT prolongation. The implementation of the ICH E14 has been successful in the sense that no new drugs have been withdrawn from the market due to unexpected QT prolongation.
An alternative approach to thorough QT studies could be assessment of the QT effects in early clinical studies such as single and multiple ascending dose studies, which typically evaluate dose levels that exceed those evaluated in later studies. To assess the QT effects in early clinical studies it is necessary to employ concentration-QTc analysis, as the number of subjects per dose-group is too small for traditional by-time analysis performed in thorough QT studies. In December of 2015, the Questions and Answers document for ICH E14 was amended to allow for use of concentration-QTc analysis as the primary endpoint and thus allowing for using early clinical studies to serve as a replacement for thorough QT studies. This talk will focus on providing an overview of the requirements for an early clinical study to serve as a replacement for a thorough QT study, statistics on concentration-QTc related submissions and common review issues and good practices for using concentration-QTc analysis for the primary endpoint.