Greg Hileman, Ph.D., Sr. Director and Principle Regulatory Scientist of Cato Research
The International Conference on Harmonization (ICH) last updated its guidance “THE CLINICAL EVALUATION OF QT/QTC INTERVAL PROLONGATION AND PROARRHYTHMIC POTENTIAL FOR NON-ANTIARRHYTHMIC DRUGS (ICH E14 (R3)) in 2005. This month, FDA published the most recent ICH updated list of questions and answers (ICH E14 Q&As ()) related to ICH E14, effectively making it an FDA guidance. R3 included an updated question on the use of concentration-response modeling in lieu of point estimate and confidence interval calculation at Cmax. Important considerations when using modeling include the possibility of pooling data across multiple studies to explore a wider range of exposures than a single thorough QT prolongation study could explore while maintaining a focus on ECG quality and managing trial heterogeneity. If data are available to estimate QT effects at sufficiently high multiples of clinically relevant exposures, a separate positive control may not be required. As always, the focus of the analysis is to exclude a change of 10 ms or more (upper limit of the 90% confidence interval) at relevant concentrations. Significant savings with valid concentration-response modeling may result from predicting results at regimens not studied. A sponsor may be able to avoid certain intrinsic (enzyme induction or inhibition) and extrinsic (DDI) studies by predicting QTc effects. High quality models may aid in deciding inclusion/exclusion criteria or in predicting dose adjustments needed in phase 3 and 4 studies where such factors are encountered.
”ICH guideline E14: the clinical evaluation of QT/QTc interval prolongation and proarrhythmic potential for non-antiarrhythmic drugs (R3) – questions and answers”