ICH E14 Q & A (R1) document: perspectives on the updated recommendations on thorough QT studies
Rashmi R Shah1, Joel Morganroth
1Rashmi Shah Consultancy Ltd, Gerrards Cross, UK. clinical.safety@hotmail.co.uk
British Journal of Clinical Pharmacology
|August 22, 2012
Summary
The International Conference on Harmonization E14 guidance on thorough QT/QTc (TQT) studies has been updated. Recommendations address gender representation, QTc changes in late-stage development, and QT interval correction methods for drug safety evaluation.
Area of Science:
- Pharmacology
- Clinical Trial Design
- Cardiology
Background:
- The International Conference on Harmonization (ICH) E14 guidance outlines requirements for thorough QT/QTc (TQT) studies to assess drug-induced QT interval prolongation.
- An Implementation Working Group (IWG) provides clarifications and addresses ambiguities related to TQT study conduct.
- Recent updates to the IWG's Questions and Answers document (April 2012) focus on critical aspects of TQT study design and analysis.
Purpose of the Study:
- To provide observations and recommendations on key issues raised in the updated ICH E14 IWG guidance.
- To discuss the implications of gender differences on QT effects and the adequacy of QT correction methods.
- To propose approaches for evaluating QTc changes in late-stage clinical development and ensuring high-quality ECG data.
Main Methods:
- Review of existing evidence regarding QT effects in different genders and the efficacy of the Fridericia correction.
- Analysis of recommendations concerning study population demographics, particularly gender balance.
- Consideration of strategies for ECG monitoring and data quality in late-phase clinical trials.
Main Results:
- Evidence suggests that the greater QT effect observed in females is not solely due to differences in drug exposure.
- The Fridericia correction is considered adequate for the majority of TQT studies.
- Recommendations are made for balanced gender representation and subgroup analyses by demographics in TQT studies.
Conclusions:
- Balanced gender representation in TQT studies is recommended unless otherwise justified.
- Subgroup analyses by gender and ethnicity are advised for positive studies.
- High-quality ECG data, potentially requiring centralized reading, is crucial, especially in late-phase trials, with locally read ECGs acceptable only if quality is guaranteed.
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