Enabling robust assessment of QTc prolongation in early phase clinical trials

Since the implementation of the International Conference on Harmonization (ICH) E14 guideline in 2005, regulators have required a “thorough QTc” (TQT) study for evaluating the effects of investigational drugs on delayed cardiac repolarization as manifested by a prolonged QTc interval. However, TQT studies have increasingly been viewed unfavorably because of their low cost effectiveness. Several researchers have noted that a robust drug concentration‐QTc (conc‐QTc) modeling assessment in early phase development should, in most cases, obviate the need for a subsequent TQT study. In December 2015, ICH released an “E14 Q&As (R3)” document supporting the use of conc‐QTc modeling for regulatory decisions. In this article, we propose a simple improvement of two popular conc‐QTc assessment methods for typical first‐in‐human crossover‐like single ascending dose clinical pharmacology trials. The improvement is achieved, in part, by leveraging routinely encountered (and expected) intrasubject correlation patterns encountered in such trials. A real example involving a single ascending dose and corresponding TQT trial, along with results from a simulation study, illustrate the strong performance of the proposed method. The improved conc‐QTc assessment will further enable highly reliable go/no‐go decisions in early phase clinical development and deliver results that support subsequent TQT study waivers by regulators.