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Early Investigation of QTc Liability

The Role of Multiple Ascending Dose (MAD) Study

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Abstract

The International Conference on Harmonization (ICH) guidance note E14 requires a thorough QT (TQT) study to characterize proactively the potential of a new drug to affect cardiac repolarization, as determined by prolongation of the corrected QT (QTc) interval. A typical TQT study is reviewed herein with a discussion on various practical issues concerning the use of a supratherapeutic dose, establishing assay sensitivity, the application of QT rate-correction methods, and restricting analyses of ECGs and plasma samples to key timepoints.

We then discuss, and provide examples of, how multiple ascending dose (MAD) study protocols can be modified to integrate robust ECG monitoring and analyses to gather key information provided by a TQT study. Among the main advantages of this approach are the ability to study the ECG effects of a wide range of doses to the maximum tolerated doses, eliminating routine analyses at unnecessary timepoints, making early go-no-go decisions, making phase II studies more efficient and, if necessary, being able to implement rigorous ECG monitoring in populations and pivotal studies of regulatory interest. If clear evidence for the presence or absence of QTc effect is found, the data from a modified MAD study may support a request for a waiver from the requirement to conduct a TQT study. In the event that a TQT study is considered unnecessary, there are obvious significant savings without compromising collection of vital safety data.

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Acknowledgements

The authors have completed the Unified Competing Interest form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author). The authors have not received any financial support for writing this article. Rashmi Shah was formerly a Senior Clinical Assessor at the Medicines and Healthcare products Regulatory Agency (MHRA), London, UK, and the ICH E14 Topic Leader, representing the EU. Joel Morganroth is the Chief Cardiac Consultant of eResearchTechnology Inc (eRT), Philadelphia, PA, USA, which provides cardiac safety services to the drug development community. Both authors now provide expert consultancy services on the development of new drugs to a number of pharmaceutical companies.

The views expressed in this paper are those of the authors and do not necessarily reflect the views or opinions of their affiliates, any regulatory authorities or any of their advisory bodies.

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Authors and Affiliations

  1. Rashmi Shah Consultancy Ltd, 8 Birchdale, Gerrards Cross, Buckinghamshire, SL9 7JA, UK

    Rashmi R. Shah

  2. eResearch Technology, Philadelphia, Pennsylvania, USA

    Joel Morganroth

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  1. Rashmi R. Shah
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Correspondence to Rashmi R. Shah.

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Shah, R.R., Morganroth, J. Early Investigation of QTc Liability. Drug Saf 35, 695–709 (2012). https://doi.org/10.1007/BF03261967

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