Examples
Worked examples
- Is an instance
A clinical-stage sponsor conducting a Phase 1 first-in-human trial incorporates intensive serial 12-lead electrocardiograms (ECGs) time-matched with pharmacokinetic sampling across single and multiple ascending dose cohorts, utilizing concentration-QTc (C-QTc) modeling under the ICH E14/S7B Q&A framework to exclude an effect on QTc exceeding 10 milliseconds, thereby satisfying clinical cardiac safety requirements without requiring a standalone Thorough QT study.
- Is an instance
A pharmaceutical company conducting a dedicated randomized, double-blind, placebo- and positive-controlled crossover Thorough QT (TQT) study in 48 healthy volunteers, administering therapeutic and supratherapeutic doses of an investigational small molecule alongside 400 mg oral moxifloxacin as an active positive control to confirm assay sensitivity.
Counter-examples
Looks similar, but isn't
- Not an instance
Routine safety ECG monitoring in a Phase 2 proof-of-concept trial that collects baseline and periodic post-dose ECGs without time-matched pharmacokinetic sampling, predefined baseline-subtracted placebo adjustments, or validated assay sensitivity controls does not satisfy the requirements of an ICH E14 Thorough QT evaluation.
Editorial commentary
ICH E14, titled The Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs, is an ICH harmonised tripartite guideline from the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use. Its current Step 4 version is dated 12 May 2005, and it was recommended for adoption by the regulatory bodies of the European Union, Japan and the USA. It describes how a sponsor evaluates whether a new drug delays cardiac repolarization, seen on an electrocardiogram (ECG) as QT interval prolongation, which is linked to the arrhythmia Torsade de Pointes (TdP).
What ICH E14 is and who uses it
The guideline applies to non-antiarrhythmic drugs. Regulatory affairs teams, clinical pharmacologists, cardiac safety specialists and biostatisticians at sponsors and contract research organisations use it when planning a development programme and the clinical sections of a marketing application (see IND and NDA submissions and the regulatory affairs guide for the pharmaceutical industry). Because the QT interval varies with heart rate, studies report a heart-rate-corrected value, QTc.
The thorough QT/QTc study
The guideline centres on the “thorough QT/QTc study”, which it describes as typically carried out in healthy volunteers rather than in people at increased risk of arrhythmia. Its purpose is to determine whether a drug has a threshold pharmacologic effect on cardiac repolarization, and so whether QT/QTc should be studied intensively in later development. Features set out in the guideline include:
- Positive control: a concurrent positive control group is used to establish assay sensitivity. The control should have an effect on mean QT/QTc of about 5 ms, close to the threshold of regulatory concern, so that the study shows it can detect such an effect.
- Threshold of regulatory concern: around 5 ms. A study is negative when the upper bound of the 95% one-sided confidence interval for the largest time-matched mean effect of the drug on QTc excludes 10 ms; the guideline says this gives reasonable assurance that the mean effect is not greater than around 5 ms. Otherwise the study is termed positive.
- Consequence of the result: a positive study influences how QT/QTc and related events are evaluated in later-phase trials.
When a thorough QT study cannot be run in healthy volunteers
The guideline notes that some drugs, for example cytotoxic cancer drugs, cannot be studied in healthy volunteers for safety or tolerability reasons. In such cases the study can often be conducted in patient populations; where that is not possible, other ways of detecting effects on the QT/QTc interval need to be developed.
Clinical events and later-phase evidence
The guideline also lists clinical events to compare between treated and control patients, particularly when there is evidence of a QT/QTc effect: Torsade de pointes, sudden death, ventricular tachycardia, ventricular fibrillation and flutter, syncope and seizures. It adds that TdP is very infrequently captured in clinical databases, so failing to observe it is not sufficient grounds for dismissing a possible proarrhythmic effect. Study conduct generally follows ICH E6(R3) Good Clinical Practice, and the resulting reports are filed within the ICH M4 Common Technical Document. For how sponsors and CROs divide this work, see the pharmaceutical CRO sector overview.
Questions and answers documents
The FDA lists the guidance as “E14 Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs”, with a Questions and Answers (R3) document dated June 2017 that revises the November 2008 ICH E14 Questions and Answers document. The EMA and ICH publish the guideline and its supporting documents on their own pages, listed below.
Frequently asked questions
What is ICH E14?
An ICH harmonised guideline on clinically evaluating QT/QTc interval prolongation and proarrhythmic potential of non-antiarrhythmic drugs; the current Step 4 version is dated 12 May 2005.
What is a thorough QT study?
A study, typically in healthy volunteers, that determines whether a drug has a threshold effect on cardiac repolarization, using a concurrent positive control to establish assay sensitivity.
What result counts as negative?
One in which the upper bound of the 95% one-sided confidence interval for the largest time-matched mean QTc effect excludes 10 ms.
What if the drug cannot be given to healthy volunteers?
The guideline says the study can often be run in patients, and otherwise other ways of detecting QT/QTc effects need to be developed.
Sources
Checked 2026-11-07.
- ICH. E14 Guideline, Current Step 4 version dated 12 May 2005. https://database.ich.org/sites/default/files/E14_Guideline.pdf
- U.S. FDA. E14 Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/e14-clinical-evaluation-qtqtc-interval-prolongation-and-proarrhythmic-potential-non-antiarrhythmic
- EMA. ICH E14 scientific guideline. https://www.ema.europa.eu/en/ich-e14-clinical-evaluation-qt-qtc-interval-prolongation-proarrhythmic-potential-non-antiarrhythmic-drugs-scientific-guideline
Machine-readable encodings
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