Drug, Healthcare and Patient Safety (Apr 2018)
Evaluating cardiac risk: exposure response analysis in early clinical drug development
Abstract
Julie Grenier,1 Sabina Paglialunga,2 Bruce H Morimoto,2 Robert M Lester3 1Data Management and Biometric, Celerion, Montreal, QC, Canada; 2Scientific Affairs, Celerion, Lincoln, NE, USA; 3Global Clinical Research, Celerion, Tempe, AZ, USA Abstract: The assessment of a drug’s cardiac liability has undergone considerable metamorphosis by regulators since International Council for Harmonization of Technical Requirement for Pharmaceuticals for Human Use E14 guideline was introduced in 2005. Drug developers now have a choice in how proarrhythmia risk can be evaluated; the options include a dedicated thorough QT (TQT) study or exposure response (ER) modeling of intensive electrocardiogram (ECG) captured in early clinical development. The alternative approach of ER modeling was incorporated into a guidance document in 2015 as a primary analysis tool which could be utilized in early phase dose escalation studies as an option to perform a dedicated TQT trial. This review will describe the current state of ER modeling of intensive ECG data collected during early clinical drug development; the requirements with regard to the use of a positive control; and address the challenges and opportunities of this alternative approach to assessing QT liability. Keywords: concentration-effect modeling, thorough QT study, intensive ECG collection, intersection union test, QT/QTc, assay sensitivity, positive control, moxifloxacin
