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Thorough QT Studies

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Abstract

The International Conference on Harmonisation E14 Guidance was successful in largely standardizing the conduct of the so-called thorough QT/QTc studies (TQTS). Nevertheless, there is still a spectrum of frequently encountered problems with details of design, conduct and interpretation of TQTS. Several of these challenges are reviewed here, starting with explaining that the TQTS goal is only to identify drugs for which the proarrhythmic risk might be considered excluded for the purposes of regulatory benefit-risk assessment. Suggestions are made on how to categorize and quantify or exclude proarrhythmic risk if the TQTS is positive. There is a conceptual need for TQTS, and this is discussed, together with reasons why restricted clinical registries cannot prove the absence of proarrhythmic liability of any drug.

Appropriate drug doses investigated in TQTS should be derived from the maximum clinically tolerable dose rather than from the known or expected therapeutic dose. With the help of concentration-QTc modelling, the standard therapeutic dose can be omitted from TQTS, especially if the study is expected to be negative. Conditions for single-dose TQTS acceptability are reviewed. The role of the so-called positive control is assessed, contrasting the role of a same-class comparator for the investigated drug. A single 400 mg dose of moxifloxacin is advocated as the present ‘gold standard’ assay sensitivity test. The necessity of careful placebo control is explained and the frequency of ECG assessments is considered. The central tendency and outlier analyses are discussed, together with the correct approaches to baseline adjustment.

The review concludes that the design and interpretation of TQTS must not be approached with mechanistic stereotypes, and highlights the importance of relating the QTc changes to drug plasma levels.

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Acknowledgements

The opinions presented in this review are those of the authors and do not necessarily represent those of the US Food and Drug Administration.

Professor Malik, University of London, is an Honorary Oak Ridge Institute for Science and Education (ORISE) Research Fellow of the US Food and Drug Administration.

No sources of funding were used to assist in the preparation of this review. The authors have no conflicts of interest that are directly relevant to the content of this review.

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Authors and Affiliations

  1. Division of Cardiac and Vascular Sciences, St George’s, University of London, London, UK

    Marek Malik

  2. Pharmacometrics Staff, Office of Clinical Pharmacology, Center of Drug Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland, USA

    Christine E. Garnett

  3. Division of Biometrics VI, Office of Biostatistics/Office of Translational Sciences, Center of Drug Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland, USA

    Joanne Zhang

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Correspondence to Marek Malik.

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Malik, M., Garnett, C.E. & Zhang, J. Thorough QT Studies. Drug-Safety 33, 1–14 (2010). https://doi.org/10.2165/11319160-000000000-00000

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