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Performance Characteristics for Some Typical QT Study Designs Under the ICH E-14 Guidance

From Pfizer Inc., Ann Arbor, Michigan (Mr Hutmacher, Dr Chapel, Dr Agin, and Dr Lalonde) and St. Louis, Missouri (Dr Fleishaker). Mr Hutmacher and Dr Chapel are currently employees of Ann Arbor Pharmacometrics Group Inc, Ann Arbor, Michigan. Dr Agin is currently an employee of MM&T Associates LLC, Ann Arbor, Michigan. Dr Lalonde is currently an employee of Pfizer Inc, New London, Connecticut.

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.

Key Words: Thorough QT study • intersection-union test • bootstrap

Address for correspondence: Richard L. Lalonde, PharmD, Clinical Pharmacology, Pfizer Global Research and Development, 50 Pequot Avenue, New London, CT 06320; e-mail: richard.lalonde{at}pfizer.com.

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