How to Assess QT Prolongation in Clinical Studies-Implications of the ICH E14 Guidance Document
Year: 2006
Type: article
Abstract: Drug induced QT prolongation and resulting proarrhythmias have caused increasing concern during recent years and led to a number of drug withdrawals from the market, restrictions in the labeling or termination of drugs in development. In May 2005, the 'International Conference on Harmonization....' (ICH) Steering Committee approved two important new guideline documents, which address non-clinical (S7B) and clinical testing (E14) of a new drug's liability to prolong the QT interval. A key feature of the E14 document is the ‘thorough QT study’ and how the results of this study will impact further clinical development of the drug and labeling, if approved. The ‘thorough QT study’ is built on the concept that drugs, which may be proarrhythmic in the targeted patient population can be identified through demonstration of QT prolongation in healthy volunteers exposed to high plasma levels of the drug. Based on experience to-date, this concept retrospectively seems to be correct for all drugs, which have been withdrawn from the market based on proarrhythmic liability. Whether this is also correct for drugs with mild effects on the QT interval irrespective of the underlying mechanism is presently not known. There are large differences in opinion among regulatory authorities in the major regions in regard to the relative importance of non-clinical assays and how to handle the results of the ‘thorough QT study’. These differences have, somewhat contradictory to the ICH concept, not been resolved by the adoption of E14, which handled the differences by the use of a general and less precise language. This commentary describes the content of the E14 document, identifies major areas of controversy between regulators in regard to its interpretation, and how this impacts global drug development.
Authors: Bone DARPO, Maki ITO
Institutions: Karolinska University Hospital, Hyogo Medical University
Language: English
Subfield: Cardiology and Cardiovascular Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W2032961978