Controlling type I errors for two-stage bioequivalence study designs

Abstract

Recent publications have introduced sequential (two-stage) designs for investigation of bioequivalence in cross-over trials and the occurrence of type I errors have been investigated using trial simulations. They have so far focused on Test:Reference ratio of 0.95 and 0.9 and it has been observed that type I errors above 0.05 may occur. In this paper the behavior of two-stage designs for investigations of bioequivalence is being further investigated, and it is concluded that the existing methods do not universally control type I errors to an acceptable level, and they have the disadvantage of not using the observed Test:Reference from stage 1 in the dimensioning of stage 2. It is observed that type I errors and the alpha at the second stage follow an approximately linear relation in the region of type I errors of 0.05. This principle is used to propose a method that uses both the CV and Test:Reference ratio and which targets specifically a type I error level of 0.05. This is done by using simulation after stage 1 to identify an optimal value for the second alpha. An example is given which illustrates how the method may be associated with both an ethical and economical advantage.

Keywords::

• Bioequivalence
• sequential design
• type I error
• trial simulation
• ethics

Acknowledgment

The author wishes to thank Detlew Labes of CCDRD AG, Neuenhagen, Germany, for very helpful advice and discussions around type I errors.

Declaration of Interest

The author is a consultant to pharmaceutical companies, but is not involved in the development of any product mentioned in this paper. The author reports no conflicts of interest. The author alone is responsible for the content and writing of the paper.