Design Issues in Noninferiority/Equivalence Trials

Abstract

When designing a noninferiority/equivalence trial, the sponsor intends to show efficacy by demonstrating that a new treatment is as good as or not worse than a known effective treatment by a small predefined margin. To confirm noninferiority/equivalence of the new treatment to an active control, "sensitivity-to-drug-effects" and "assay sensitivity, " as defined in the International Conference on Hamnization (ICH) E l 0 Guideline (1,2) must be supported. Otherwise, a finding of mere nonsigni3cant difference between treatments in the traditional setting of significance testing leaves the question unanswered: Would the trial have concluded noninferiority while the new treatment was, in fact, inferior?This paper first reviews the choice of control and the crucial issues of sensitivity-todrug-effects and assay sensitivity. Then, it discusses the choice of the noninferiority/ equivalence margin and the forms of the null and alternative hypotheses and confidence intervals. Finally, it addresses the inherent difficulties and some useful design alternatives to the noninferiority/equivalence trials.

Non-inferiority trial of two commercial zilpaterol HCl brands in <em>Bos indicus</em> cattle under humid tropical conditions

“…Since the interest is primarily one-sided, such trials are named "non-inferiority" trials to show that the new treatment is not inferior to the standard treatment by more than a small, predefined margin. 1 Demand for bovine meat has steadily increased in recent decades, 2 and pharmacological intervention with zilpaterol hydrochloride (ZH) has been used to increase production. This drug has been approved by health authorities in the USA, 3 Mexico, 4 South Africa 5 and Canada.…”

Abbreviated Infusion of Eptifibatide After Successful Coronary Intervention

“…Categorical data were compared with the chi-square tests. The primary and secondary end points were analyzed using the test statistic described for a 1-sided null hypothesis that 18-h infusion of eptifibatide is superior to Ͻ2-h infusion of eptifibatide (17). Mean differences and the respective 1-sided, upper bound of the 95% confidence interval were computed for 3 key subgroups including diabetic patients treated with insulin or oral agents; adequate clopidogrel pre-treatment; and presentation with ACS or recent MI.…”

Distribution of therapeutic response in asthma control

“…Equivalence boundaries have not been unequivocally established. Experience from development of alternative propellant programmes, general publications [6] and regulatory recommendations [7] suggest a zone of equivalence of ¡0.5 or a third of the difference between active and placebo treatment. This placebocontrolled study provides an opportunity to ascertain assay sensitivity as well as validate the boundaries chosen, but these critical results are not presented.…”