| The FDA's E14 Guidance for Industry addresses the concern that some non-cardiac drugs can alter cardiac repolarization; thereby increasing the likelihood of cardiac arrhythmias which can be fatal. Due to limitations of the current E14 approach to assess QT prolongation risks of non-antiarrhythmic drugs, Concentration-QT (C-QT) analyses have been used in conjunction with E14 analysis to determine whether a drug prolongs QT. Standardization of C-QT analysis methods is needed to facilitate meta-analyses across studies to gain insights into various designs and risk-related issues. The main objectives were: (1) to develop a standardized approach for C-QT models to be used in Thorough QT (TQT) studies, (2) to evaluate the operating characteristics of C-QT models using simulations, and (3) to apply C-QT models to real datasets and compare results to E14 Primary Analysis. In this investigation, several base models were explored and based on simulations, false negative rates and bias in slope and intercept for the C-QT linear and nonlinear models were analyzed. Multiple scenarios were explored including effects of high variability of slope, effects of ignoring hysteresis, and effects of uncertainty of Cmax. A final C-QT analysis model was chosen to compare with E14 analyses using real TQT datasets. Finally, a dQTc method was chosen as a preferred C-QT analysis approach that may be used for analysis of future TQT studies. |
