E14 Clinical Evaluation of QT
E14 The Clinical Evaluation of QT/QTc Interval Prolongation and proarrhythmic potential for Non-Antiarrhythmic Drugs
The ICH harmonised Guideline was finalised under Step 4 in May 2005.
This document provides recommendations to sponsors concerning the design, conduct, analysis, and interpretation of clinical studies to assess the potential of a drug to delay cardiac repolarisation.
This assessment should include testing the effects of new agents on the QT/QTc interval as well as the collection of cardiovascular adverse events.
The investigational approach used for a particular drug should be individualised, depending on the pharmacodynamic, pharmacokinetic, and safety characteristics of the product, as well as on its proposed clinical use.
The assessment of the effects of drugs on cardiac repolarisation is the subject of active investigation.
When additional data (non-clinical and clinical) are accumulated in the future, this document may be reevaluated and revised.
Date of Step 4: 12 May 2005
Status: Step 5
Guidelines (Click the links below for complete guidelines)
E14 Q&As Questions & Answers: The Clinical Evaluation of QT/QTc Interval Prolongation and proarrhythmic potential for Non-Antiarrhythmic Drugs
Since reaching Step 4 and publication within the ICH regions, experiences by all parties with the implementation of the E14 Guideline have resulted in the need for some clarification. The Questions and Answers developed by the E14 Implementation Working Group (IWG) are intended to facilitate the implementation of the E14 Guideline by clarifying key issues. The document with the first set of Q&As was finalised under Step 4 in June 2008.
In April 2012, a second set of Q&As was developed and approved by the Steering Committee for integration in the Q&A document (E14 Q&As (R1)).
In March 2014, a third set of Q&As was developed and approved by the Steering Committee for integration in the Q&A document (E14 Q&As (R2)).
In December 2015, the Question #5.1 of the E14 Q&As (R2) was revised to generate harmonised guidance on how concentration response modelling could be used for regulatory decision making. The document was approved by the Assembly for integration in the Q&A document (E14 Q&As (R3)).
Date of Step 4: 10 December 2015
Status: Step 5
Questions and Answers (Click the links below for complete guidelines)
E14 Q&As (R3) Questions and Answers
Endorsed Document (Click the links below for complete guidelines)
WG Presentations / Trainings (Click the links below for complete guidelines)
E14 Q&As (R3) Step 4 Presentation
E14/S&B Questions & Answers: Clinical and Nonclinical Evaluation of QT/QTc Interval Prolongation and proarrhythmic Potential
In November 2018, the Assembly endorsed the establishment of the E14/S7B Implementation Working Group (IWG) for the development of Q&As for the ICH E14 and ICH S7B Guidelines. ICH S7B and ICH E14 describe nonclinical and clinical risk assessment strategies to inform the potential risk for proarrhythmia of a test substance and contribute to the design of clinical investigations. Emergent data over the past several years demonstrate that different experimental results can arise for the same compound as a function of the study conditions used in nonclinical assays. The E14/S7B IWG will build on work done by the former E14/S7B Discussion Group (DG) which discussed the advances in science and methods related to the clinical assessment of QT prolongation and worked on the Comprehensive in vitro Proarrhythmia Assessment (CiPA) initiative.
The E14/S7B IWG will provide guidance regarding best practices for the design, conduct, analysis, interpretation and reporting of in vitro, in silico and in vivo nonclinical assays in order for these assays to influence nonclinical and clinical evaluations. The Q&As will be developed in two stages to allow for more rapid impact of novel approaches on S7B and subsequently E14 for evolving drug candidates, enabling a more efficient, comprehensive and mechanism-driven process. The objective of the first stage of the proposed harmonisation work is to provide clarity on how to standardise assays such as multi-ion channel assays, in silico models, in vitro human primary and induced pluripotent cardiomyocyte assays and in vivo evaluation, and apply these learnings to guide predictions and subsequent clinical assessment. These efforts will provide a customisable nonclinical strategy that is more informative for clinical development.
On 15 and 16 October 2020, a public webinar (ICH WG Presentations and Live Q&A) will be held to provide an overview of the high-level principles and rationale behind the new interconnected Q&As to ICH E14 and S7B and to answer questions received during the webinar. The agenda is available for download and more information, including the link for registration, will be published shortly.
Date of Step 2b: 27 August 2020
Status: Step 3
Q&As (Click the links below for complete guidelines)
Endorsed Documents (Click the links below for complete guidelines)
WG Presentations/Trainings (Click the links below for complete guidelines)
E14/S7B Initial Training Material
E14/S7B Initial Training Material - Example Supplemental File
*These Guidelines Belongs to ICH website.
ICH E14 Clinical Evaluation of QT Guidelines:
