title: Enabling robust assessment of QTc prolongation in early phase clinical trials.
abstract: 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.
authors.affiliation: Merck & Co., Inc., North Wales, PA, USA.
authors.forename: Devan V
authors.identifier: 0000-0002-0316-7362
authors.initials: DV
authors.lastname: Mehrotra
authors.affiliation: Merck & Co., Inc., North Wales, PA, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Fan
authors.affiliation: Merck & Co., Inc., North Wales, PA, USA.
authors.forename: Fang
authors.initials: F
authors.lastname: Liu
authors.affiliation: Merck & Co., Inc., North Wales, PA, USA.
authors.forename: Kuenhi
authors.initials: K
authors.lastname: Tsai
mesh_terms: D001145:Arrhythmias, Cardiac; D002986:Clinical Trials as Topic; D015195:Drug Design; D015507:Drugs, Investigational; D004562:Electrocardiography; D006801:Humans; D008133:Long QT Syndrome
chemical_list: D015507:Drugs, Investigational
keywords: ICH E14; QT interval; electrocardiogram; exposure-response; mixed effects model