The views expressed in this paper are those of the authors and do not necessarily reflect the views or opinions of their affiliates, any regulatory authorities or any of their advisory bodies.
ICH E14 Q & A (R1) document: perspectives on the updated recommendations on thorough QT studies
Version of Record online: 15 MAR 2013
© 2012 The Authors. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society
British Journal of Clinical Pharmacology
Volume 75, Issue 4, pages 959–965, April 2013
How to Cite
Shah, R. R. and Morganroth, J. (2013), ICH E14 Q & A (R1) document: perspectives on the updated recommendations on thorough QT studies. British Journal of Clinical Pharmacology, 75: 959–965. doi: 10.1111/j.1365-2125.2012.04442.x
- Issue online: 15 MAR 2013
- Version of Record online: 15 MAR 2013
- Accepted manuscript online: 21 AUG 2012 04:59AM EST
- Manuscript Accepted: 14 AUG 2012
- Manuscript Received: 18 JUN 2012
The International Conference on Harmonization (ICH) guidance ICH E14 provides recommendations, focusing on a clinical ‘thorough QT/QTc (TQT) study’, to evaluate the QT liability of a drug during its development. An Implementation Working Group (IWG) was also established to assist the sponsors with any uncertainties and clarify any ambiguities. In April 2012, the IWG updated its June 2008 version of the Questions and Answers document to address additional issues. These include the gender of the study population, a reasonable approach to evaluating QTc changes in late stage clinical development and the recommended approach to correcting the measured QT interval. This commentary provides our observations and, when appropriate, recommendations, on these issues. We review briefly evidence that suggests that (i) the greater QT effect observed in females is not entirely related to differences in drug exposure and (ii) the Fridericia correction of measured QT interval is adequate for a majority of TQT studies. Until further evidence suggests otherwise, we recommend balanced gender representation in TQT studies, unless warranted otherwise, and for positive studies, subgroup analysis of key data by common demographic variables including the gender and ethnicity. We provide a general scheme for ECG monitoring in late phase clinical trials and consider that while intensive monitoring and centralized reading of ECGs in late phase clinical trials is the norm when a TQT study is positive, there are other circumstances that also call for high quality ECG reading. Therefore, locally read ECGs should only be acceptable as long as accurate high quality ECG data can be guaranteed.