Mixed Model for Repeated Measures with Application to Cardiodynamic Electrocardiogram (ECG) Assessment

Music City Center 

Per the International Council on Harmonisation clinical (ICH E14) guidance in 2005, all new chemical entities (NCEs) with systemic exposure should undergo an evaluation as to whether they cause an effect on the heart rate QTc before marketing, as pronounced QTc prolongation in susceptible patients may lead to a potentially lethal ventricular arrhythmia called torsades de pointes (TdP). Therefore, the cardiodynamic ECG assessment is performed, among which the by-time point analysis and concentration-QTc analysis are the two main analyses, based on mixed models for repeated measures of ECGs and concentrations. Since ICH E14 Questions & Answers (R3) was released in 2015, the latter analysis has served as an alternative to the former analysis as the primary basis for decisions to classify the risk of a drug, which has been the primary analysis for most ECG evaluation in early clinical trials. Model description, model assumptions, sample size determination, and goodness-of-fit will be introduced for the concentration-QTc analysis with application to case studies with healthy subjects or patients at this presentation.

cardiodynamic ECG assessment

concentration-QTc analysis

by-time point analysis 

Biopharmaceutical Section