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Thorough QT Studies: Questions and Quandaries
Marek Malik1, Christine E Garnett, Joanne Zhang
1Division of Cardiac and Vascular Sciences, St George's, University of London, London, UK. marek.malik@btinternet.com
Drug Safety
|December 17, 2009
Summary
Thorough QT/QTc studies (TQTS) standardize drug safety assessments, but challenges remain in their design and interpretation. Optimizing TQTS protocols is crucial for accurately evaluating drug proarrhythmic risk.
Area of Science:
- Cardiovascular Pharmacology
- Clinical Trial Design
- Regulatory Science
Background:
- The International Conference on Harmonisation E14 Guidance standardized thorough QT/QTc studies (TQTS).
- Despite standardization, challenges persist in TQTS design, conduct, and interpretation.
- TQTS aim to identify drugs with excluded proarrhythmic risk for regulatory benefit-risk assessment.
Purpose of the Study:
- To review and address common problems in TQTS design, conduct, and interpretation.
- To provide suggestions for categorizing and quantifying proarrhythmic risk when TQTS are positive.
- To discuss the conceptual need for TQTS and limitations of clinical registries.
Main Methods:
- Review of TQTS design principles, including drug dosing and single-dose acceptability.
- Assessment of positive controls, placebo control, and ECG assessment frequency.
- Discussion of statistical analyses (central tendency, outlier, baseline adjustment) and concentration-QTc modeling.
Main Results:
- Appropriate drug doses for TQTS should be based on maximum tolerable dose, not therapeutic dose.
- Concentration-QTc modeling can omit standard therapeutic dose testing, especially for negative studies.
- Moxifloxacin 400 mg is proposed as a 'gold standard' assay sensitivity test, with careful placebo control and appropriate statistical analysis being essential.
Conclusions:
- TQTS design and interpretation require nuanced approaches, avoiding mechanistic stereotypes.
- Relating QTc changes to drug plasma levels is critical for accurate risk assessment.
- Optimized TQTS protocols are essential for reliable evaluation of drug proarrhythmic liability.
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