The Utility of Active-Controlled Noninferiority/Equivalence Trials in Drug Development


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Abstract

Clinical trials designed with the objective of demonstrating that a test treatment is noninferior or equivalent to an active control treatment have long been used in drug development. In general, in order to fulfil the requirement of a New Drug Application, a sponsor needs to conduct randomised clinical trials to demonstrate that the test treatment is effective. With placebo control in the clinical trial, efficacy of the test treatment is demonstrated by showing that the test treatment is statistically and clinically superior to placebo. However, because of the ethical concerns of exposing patients to placebo when there is a proven therapeutic method available, many clinical trials can only be designed with the approved active control treatment. Because of the lack of placebo exposure in the current clinical trial, neither the sponsor nor the regulatory reviewer can assess whether the test treatment is superior to placebo directly. When the concept of noninferiority and equivalence of bioequivalence trials is applied to this type of trial, it complicates the efficacy assessment of the test treatment (superior to placebo) because of the indirectness of the comparison.This article discusses the fundamental concepts of noninferiority and equivalence testing applied in some specific drug products and how they are extended in the application for the interpretation for ‘test treatment is superior to placebo’ assessment. It also discusses why such an application makes the drug evaluation so complicated. The limitations and recommendations for the use of noninferiority or equivalence testing will also be considered.

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