Performance characteristics for some typical QT study designs under the ICH E-14 guidance

Journal of Clinical Pharmacology
Matthew M HutmacherRichard L Lalonde

Abstract

The International Conference on Harmonization (ICH) guidance for clinical evaluation of QT prolongation (E14) affected drug development by advocating that a thorough QT study (TQT) be conducted during development to assess the QT prolongation liability of a compound. The ICH E14 Statistics Group shortly thereafter recommended that a noninferiority intersection-union test (IUT) be used to exclude a clinically worrisome QT prolongation. Recent analyses have indicated that the IUT might be overly conservative with respect to excluding QT prolongation. This report assesses the IUT false positive rate for 4 recently conducted TQT trials using simple simulation experiments. Positive TQT study rates ranged from negligible to nearly 60% depending on study design, sample size, and patient status, despite no drug effect. Addition of clinically nonmeaningful QT prolongations (up to 5 milliseconds) increased the positive study rate to 80% for 1 particular study design. Ultimately, these results reveal significant limitations of the IUT with respect to excluding an effect and study interpretation for certain trial designs.

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Citations

Jan 18, 2013·European Journal of Clinical Pharmacology·Shuying Yang, Misba Beerahee
Aug 1, 2012·Drug Safety : an International Journal of Medical Toxicology and Drug Experience·Rashmi R Shah, Joel Morganroth
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Apr 8, 2021·Journal of Pharmacokinetics and Pharmacodynamics·Peter L Bonate

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