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Statistical Evaluation of QT/QTc Interval Prolongation

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Statistical Methods in Biomarker and Early Clinical Development

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Abstract

QT interval prolongation is a measure of delayed cardiac repolarization that could lead to the development of cardiac arrhythmias, namely torsade de pointes (TdP). TdP is a serious toxicity associated with some non-antiarrhymic drugs. The magnitude of QT prolongation has been used as an imperfect surrogate for TdP. In this chapter, we review statistical considerations for the evaluation of QT/QTc interval prolongation. Regulatory history and scientific background are provided in Sect. 1. Section 2 is devoted to the design and analysis of thorough QT study (i.e., TQT) as a way of evaluating QT prolongation risk, as recommended by ICH E14. In Sect. 3, an alternative to TQT study, concentration–QTc (i.e., CQT) analysis is discussed. The CQT approach has been adopted by ICH E14 R3 as an acceptable alternative to TQT for the evaluation of QT prolongation risk.

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Author information

Authors and Affiliations

  1. MyoKardia Inc., South San Francisco, CA, USA

    Liang Fang

  2. Gilead Sciences Inc., Seattle, WA, USA

    Winnie Weng

  3. Airbnb Inc., San Francisco, CA, USA

    Lu Wang

  4. Facebook Inc., Menlo Park, CA, USA

    Xiaoru Wu

Authors
  1. Liang Fang
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  2. Winnie Weng
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  3. Lu Wang
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  4. Xiaoru Wu
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Corresponding author

Correspondence to Liang Fang .

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Editors and Affiliations

  1. MyoKardia Inc., South San Francisco, CA, USA

    Liang Fang

  2. BioMarin Pharmaceutical Inc., San Rafael, CA, USA

    Cheng Su

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Fang, L., Weng, W., Wang, L., Wu, X. (2019). Statistical Evaluation of QT/QTc Interval Prolongation. In: Fang, L., Su, C. (eds) Statistical Methods in Biomarker and Early Clinical Development. Springer, Cham. https://doi.org/10.1007/978-3-030-31503-0_13

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