FDA Updates ICH E14 Q&A Modelling in QTc Prolongation Studies

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.

https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM073161.pdf

”ICH guideline E14: the clinical evaluation of QT/QTc interval prolongation and proarrhythmic potential for non-antiarrhythmic drugs (R3) – questions and answers”

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