Final Concept Paper
ICH S7B and E14 Q&A
Endorsed by the MC with support of the Assembly on 15 November 2018

Type of Harmonisation Action Proposed: Q&A to S7B and E14
Statement of the Problem:
ICH S7B 1 and ICH E142 were finalized in May 2005 and describe non-clinical and clinical risk assessment
strategies to inform the potential risk for proarrhythmia of a test substance and contribute to thedesign 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
non-clinical assays. Guidance is needed regarding best practices for the design, conduct, analysis,interpretation and reporting of in vitro, in silico and in vivo non-clinical assays in order for these assays
to influence non-clinical and clinical evaluation.
ICH E14 identifies non-clinical data as a factor that can be used to reduce the need for a TQT study(Sec. 2.1). Since the implementation of E14, there is no consensus on how non-clinical data can beused to influence the design and/or interpretation of a clinical QT study. There are several clinicalscenarios that could benefit from high quality non-clinical data such as clinical QT assessments thatare confounded by issues like heart rate changes, inability to test a sufficiently high multiple of theclinically relevant exposure to waive the positive control (Q&A 5.1), and when a TQT study is not
feasible in healthy volunteers (Q&A 6.1).
ICH S7B recommends Follow-up Studies (Sec. 2.3.5) to inform the integrated risk assessment if a test
articles blocks the hKV11.1 IKr current (hERG) or prolongs the QT interval. These could include the test
article effects on additional ionic currents, and the use of in vitro and in vivo assays. Newer assays andtechnologies such as in silico ventricular models, and human primary and induced pluripotent stem
cell-derived cardiomyocytes, can provide insights into the relative proarrhythmic liability of test
articles. Guidance is needed on when and how these novel approaches play a role in determining theproarrhythmic risk to inform clinical development.

Issues to be Resolved:
We propose two sequential stages of Q&A as detailed below. This two-stage strategy will 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 firststage of the proposed harmonisation work is to provide clarity on how to standardize assays such as

1

The Non-clinical Evaluation of the Potential for Delayed Ventricular Repolarization (QT Interval Prolongation by Human
Pharmaceuticals).
2
The Clinical Evaluation Of QT/QTc Interval Prolongation And Proarrhythmic Potential For Non-Antiarrhythmic Drugs E14

International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use
ICH Secretariat, Route de Pré-Bois 20, P.O. Box 1894, 1215 Geneva, Switzerland
Telephone: +41 (22) 710 74 80 - admin@ich.org, http://www.ich.org

1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 andsubsequent clinical assessment. These efforts will provide a customizable non-clinical strategy thatis more informative for clinical development.
Stage 1:Create Q&A(s) for S7B and E14 on in vitro, in silico and in vivo assay standardization andapplication, while considering the impact of these recommendations on clinical situations
where current E14 methodology is problematic. For example, clinical QT assessments that areconfounded by issues such as heart rate changes, inability to test a supratherapeutic
concentration, and absence of a placebo group, etc. (see ‘Proposed Q&As’ below). Write Q&Afor S7B on principles for proarrthymia risk prediction models.
Stage 2:Create Q&A(s) for S7B and E14 on how to use the proarrythmia prediction algorithms or modelresults (see ‘Proposed Q&As’ below).
The following are examples of the issues likely to be addressed in S7B Q&A(s).
••Experimental protocol standardization considerations avoiding inconsistencies and pitfalls involtage clamp protocols, in silico model use and interpretation of in vitro human myocyte
studies, for example, defining experimental conditions (including best practice), data quality
and reporting standardsGeneral principles for proarrhythmia models, metrics to be used for proarrhythmic prediction,and implementation of the models (will include examples)

Guidance would be provided on how these studies can inform clinical trial design and interpretationof ECG and/or adverse event data (e.g., biological plausibility considerations in causality assessments).
Recommendations regarding the use of human cardiomyocytes for the assessment ofelectrophysiologic effects of drugs as an alternative to the currently listed animal derived single- andmulticellular preparations would reduce unnecessary animal use.
In Stage 1, we foresee addressing the following potential scenarios in one or more E14 Q&As on how
non-clinical data could be used:•••

To supplement phase 1 ECG evaluation when the exposure margin is insufficient to waive
positive control in the concentration response analysis.
To support an uninterpretable QT assessment for a drug that causes large heart rate increases(e.g., >20 beats/minute).
To supplement the QT assessment when a specific study cannot be conducted because ofsafety concerns with healthy volunteers, for example oncology, and feasibility concerns inpatients.

In Stage 2 we will consider, the following topics pending sufficient data are available to support therevision of E14 Q&A additions.
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use
ICH Secretariat, Route de Pré-Bois 20, P.O. Box 1894, 1215 Geneva, Switzerland
Telephone: +41 (22) 710 74 80 - admin@ich.org, http://www.ich.org

2Non-clinical proarrhythmia models and ECG biomarker data to:•••Help define low (or no) risk test articles that might not require detailed QT focused clinicalevaluation.
Influence the intensity of ECG monitoring in late phase trials.
Inform the intensity of ECG monitoring and inform eligibility criteria, prohibited concominant
medications, stopping rules and considerations for labeling for drugs with uncertain
proarrhythmic potential, for example QT prolongation in the range of 5-20 ms.

If it is determined that enough data do not exist, the implementation working group (IWG) will makerecommendations for what additional data are required.

Type of Implementation Working Group Recommended:
Since implementation of ICH S7B and E14 in 2005, there have been multiple Q&As developed for E14.
Thus, the ICH E14 working groups have consisted of clinical experts with detailed knowledge ofthorough QT studies and concentration-QT modeling. The current proposed Q&As focus on nonclinical in vitro and in silico methods. In addition to retaining clinical expertise, additional experts inthe following areas should contribute to the IWG: (1) the cellular electrophysiological mechanisms ofTdP initiation, (2) the ability to interpret patch clamp drug block data using in vitro cell lines withheterologous expression of ion channels and/or in vitro cardiomyocytes, (3) developing or interpreting
electrophysiological computer models. Since non-clinical assays may have an impact on how to
perform early clinical studies and in the interpretation of clinical study results, it is also important toinclude clinical expertise on the IWG.

Proposed Timeline:Nov. 2018
Dec. 2018-June 2019
June 2019-June 2019
June 2019-June 2020
June 2020
Jan. 2019-June 2020
June 2020

Finalize Concept Paper and detailed work plan for IWG
Refine scope of first stage Q&As for S7B and E14 and develop draft textMeet Face-to-Face at ICH Meeting to finalize scope of first stage Q&AsRefine text of first stage Q&As for S7B and E14
Meet Face-to-Face at ICH Meeting to finalize first stage Q&As for S7B and E14
Discuss potential second stage Q&As for E14 and generating any data neededFinalize timeline for second stage Q&AInternational Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use
ICH Secretariat, Route de Pré-Bois 20, P.O. Box 1894, 1215 Geneva, Switzerland
Telephone: +41 (22) 710 74 80 - admin@ich.org, http://www.ich.org

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