title: Performance characteristics for some typical QT study designs under the ICH E-14 guidance.
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.
authors.affiliation: Pfizer Inc., Ann Arbor, Michigan, USA.
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Hutmacher
authors.forename: Sunny
authors.initials: S
authors.lastname: Chapel
authors.forename: Marilyn A
authors.initials: MA
authors.lastname: Agin
authors.forename: Joseph C
authors.initials: JC
authors.lastname: Fleishaker
authors.forename: Richard L
authors.initials: RL
authors.lastname: Lalonde
mesh_terms: D002986:Clinical Trials as Topic / Q000379:methods / Q000592:standards*; D004562:Electrocardiography; D017408:Guidelines as Topic / Q000592:standards*; D006339:Heart Rate / Q000187:drug effects*; D006801:Humans; D008133:Long QT Syndrome / Q000139:chemically induced* / Q000175:diagnosis / Q000503:physiopathology; D015201:Meta-Analysis as Topic