ICH E14 Q&A(R2) document: commentary on the further updated recommendations on thorough QT studies.

Abstract

The International Conference on Harmonization (ICH) guideline ICH E14, adopted in May 2005, sets out recommendations on the strategy for the clinical evaluation of the QT liability of a drug, whether it is new or an established drug (such as citalopram, ondansetron, saquinavir or dextropropoxyphene) with post-marketing reports of QTc prolongation and/or pro-arrhythmia. It focuses on the need during drug development to conduct a ‘thorough QT/QTc’ study, popularly referred to simply as a TQT study 1. This study is typically conducted in healthy volunteers and serves as the primary method for evaluating the potential effect of non-antiarrhythmic agents on cardiac repolarization. Since its adoption in May 2005, the ICH E14 Implementation Working Group (IWG), established by the ICH Steering Committee to update the guidance as necessary, has helpfully issued three sets Questions and Answers (Q&A) documents with the aim of clarifying some areas of uncertainty concerning the recommendations contained in ICH E14 or to take account of emerging science and technology. The first of these documents (Q&A(R)) was issued in June 2008 2 followed by another (Q&A(R1)) in April 2012 2 and the most recent one (Q&A(R2)) in March 2014 3. In the most recent Q&A document, all 16 questions dealt with by these three Q&A documents have now been consolidated into the following seven key groups of areas that required clarity and/or update: ECG recording methodology Gender Positive control Study design Concentration−response modelling of QTc data Special cases ECG monitoring in late stage clinical trials These efforts by the IWG to provide clarity and/or take account of emerging science are to be applauded and we have previously commented on the Q&A(R1) document issued in April 2012 4. In this current commentary, we begin by discussing four new additional questions answered by the IWG, one question on concentration−response modelling and three on special cases. For the sake of brevity and to avoid unnecessary repetition, we have summarized the IWG answers as best as we can. We then highlight some aspects of the IWG answers regarding ECG recording methodology that appear ambiguous, if not contradictory. We also provide our overall comments on the contents of the three Q&A documents as consolidated now and identify other areas that require attention in the future.