Eric I Rossman, Todd A Wisialowski, Hugo M Vargas, Jean-Pierre Valentin, Michael G Rolf, Brian M Roche, Steve Riley, Michael K Pugsley, Jill Nichols, Dingzhou Li, Derek J Leishman, Robert B Kleiman, Andrea Greiter-Wilke, Gary A Gintant, Michael J Engwall, Annie Delaunois, Simon Authier
The ICH E14/S7B Questions and Answers (Q&As) guideline introduces the concept of a "double negative" nonclinical scenario (negative hERG assay and negative in vivo QTc study) to demonstrate that a drug does not produce a clinically relevant QT prolongation (i.e., no QT liability). This nonclinical "double negative" data package, along with negative Phase 1 clinical QTc data, may be sufficient to substitute for a clinical Thorough QT (TQT) study in some specific cases. While standalone GLP in vivo cardiovascular studies in non-rodent species are standard practice during nonclinical drug development for small molecule programs, a variety of approaches to the design, conduct, analysis and interpretation are utilized across pharmaceutical companies and contract research organizations (CROs) that may, in some cases, negatively impact the stringent sensitivity needed to fulfill the new Q&As...
May 8, 2023: Journal of Pharmacological and Toxicological Methods