A Simulation Study of Power in Thorough QT/QTc Studies and a Normal Approximation for Planning Purposes
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INTERVAL PROLONGATION
447
A Simulation Study of Power in Thorough QT/QTc Studies and a Normal Approximation for Planning Purposes
Balakrishno Hosronr Northern Illinois Universiv, DeKalb, Illinois Cbarlrs Lockr Abbott Labomtoris, Abbott Park, Illinois
Key Words QT; Thorough QT/QTc study; Power: Simulation
Corrrrpondrncr Address Balahishna Hosmane, Division of Statistics, Northern Illinois University, DeKalb, IL 60115 USA (email: [email protected]).
INTRODUCTION Evaluation of new drugs for unwanted effects on electrical properties of the heart is receiving heightened attention from pharmaceutical companies and regulatory agencies. This attention arises from recent scientific research that links drug effects in cellular ion channels to changes in electrical characteristics of the electrocardiogram (ECG) that predict clinically important cardiac arrhythmias (1). For most non-antiarrhythmic drugs under development that are new chemical entities, a step of the development is a study that definitively characterizes the effect of the drug on the QT interval of an ECG and on QTc interval (QT interval corrected for heart rate). This study is referred to as a thorough QT/QTc study. Unless the study demonstrates conclusively that the drug has little or no increasing effect on the QTc interval mean, more than the usual procedures are likely to be required in phase I11 to assess the drug with respect to proarrhythmic events. It is expected that a dose considerably higher than the therapeutic range of doses will be evaluated in the thorough QT/QTc study unless safety concerns preclude the study of such a high dose.
Unless ethical concerns prevent it, the study is performed in healthy volunteers to reduce variability and speed enrollment. An appropriate positive control will normally be expected in the study to confirm the ability of the study to distinguish between placebo and a small effect that represents little concern. A necessary condition for concluding that the drug has little or no potential for causing arrhythmias is that the thorough QT/QTc study data must support a formal claim of noninferiority to placebo. Furthermore, because there is some uncertainty regarding when a drug has its peak effect, the comparison with placebo must be done at several times relative to dosing. A crucial issue is what the noninferiority margin should be. With a noninferiority margin as small as 8 ms, clinical studies face significant challenges because of the substantial variability in QT intervals. Apart from the problems of signal acquisition and measurement, QT intervals are characterizedby substantial inter- and intrasubject variability. Given the number of important intersubject covariates, the proposed treatments are often presented in a crossover study so that treatment differences are taken within each subject.
InfolmatlonJourael, Vd.39, pp. 447-455,2005 0092-8615/2005 Printed in the USA. All rights mmed. cowright 0 2005 Drug Information Association, Inc.
448
QT/QTc
Hosmane,Locke
INTERVAL PROLONGATION
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