Performance characteristics for some typical QT study designs under the ICH E-14 guidance.
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.
Hutmacher
Matthew M
MM
Pfizer Inc., Ann Arbor, Michigan, USA.
Chapel
Sunny
S
Agin
Marilyn A
MA
Fleishaker
Joseph C
JC
Lalonde
Richard L
RL
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