Design Issues in Noninferiority/Equivalence Trials
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0092-8615M Copyright 0 1999 Drug Information Association Inc.
DESIGN ISSUES IN NONINFERIORITY/ EQUIVALENCE TRIALS* IRVINGK. HWANG,PHD President, Irving Consulting Group, Pluckemin, New Jersey
TOSHIHIKO MORIKAWA, PHD General Manager, Data Management and Biostatistics, Takeda Chemical Industries, Ltd., Osaka, Japan
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/equivalenceof 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 difficultiesand some useful design alternatives to the noninferiority/equivalence trials. Key Words: Noninferiority; Equivalence; Superiority; Sensitivity-to-drug-effects; Assay sensitivity; Drug effect size; Noninferiority/equivalence margin
INTRODUCTION THE PLACEBO-CONTROLLED doubleblind trial has been the gold standard in drug development for many decades. It continues to provide a useful means to demonstrate the efficacy of a new test drug in a confirmatory way by showing its superiority to placebo. With the existence of drugs of proven effi-
Presented and discussed at the 5th Annual DIA “Japan Biostatistics Meeting,” September 4-5, 1998, Tokyo, Japan. Reprint address: Irving K. Hwang, PhD, Irving Consulting Group, P.O. Box 258, Pluckemin, NJ 07978-0258. *The majority of the work was initiated during the ICH E-10 Expert Working Group (EWG): Lk.Hwang is deputy topic leader, PhRMA and Dr. Morikawa is topic leader, JPMA.
cacy, the conduct of clinical trials with placebo as the control sometimes poses an ethical dilemma. As more and more effective drugs become available and fewer and fewer breakthrough new drugs emerge, the objective of clinical investigation changes. Oftentimes, it seeks noninferiority or equivalence of the new drug rather than its superiority to an existing effective standard drug in active controlled trials. In regions such as the European Union (EU) and Japan rather than the United States, the objectives of active controlled trials are usually not only to prove effcacy, but also to assess relative efficacy (andor safety) of the new test drug to the standard treatment. Active-controlled clinical trials, with an intention to demonstrate efficacy by showing the new test treatment to be s
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