Evaluation of dependent variable, time effect, covariates, and covariation structure in concentration-QTc modeling: A simulation study.

The revised ICH E14 Question and Answer (R3) document issued in December 2015 enables pharmaceutical companies to use concentration-QTc (C-QTc) modeling as the primary analysis for assessing QTc prolongation risk of new drugs. A new approach by including the time effect into the current C-QTc model is introduced. Through a simulation study, we evaluated performances of different C-QTc modeling with different dependent variables, covariates, and covariance structures. This simulation study shows that C-QTc models with ΔQTc being dependent variable without time effect inflate false negative rate and that fitting C-QTc models with different dependent variables, covariates, and covariance structures impacts the control of false negative and false positive rates. Appropriate C-QTc modeling strategies with good control of false negative rate and false positive rate are recommended.