Pilot–pivotal trials for average bioequivalence

Before carrying out a full scale bioequivalence trial, it is desirable to conduct a pilot trial to decide if a generic drug product shows promise of bioequivalence. The purpose of a pilot trial is to screen test formulations, and hence small sample sizes can be used. Based on the outcome of the pilot trial, one can decide whether or not a full scale pivotal trial should be carried out to assess bioequivalence. This article deals with the design of a pivotal trial, based on the evidence from the pilot trial. A two-stage adaptive procedure is developed in order to determine the sample size and the decision rule for the pivotal trial, for testing average bioequivalence using the two one-sided test (TOST). Numerical implementation of the procedure is discussed in detail, and the required tables are provided. Numerical results indicate that the required sample sizes could be smaller than that recommended by the FDA for a single trial, especially when the pilot study provides strong evidence in favor of bioequivalence.     

Nonparametric equivalence testing with respect to the median difference

The problem of comparing two independent groups of univariate data in the sense of testing for equivalence is considered for a fully nonparametric setting. The distribution of the data within each group may be a mixture of both a continuous and a discrete component, and no assumptions are made regarding the way in which the distributions of the two groups of data may differ from each other – in particular, the assumption of a shift model is avoided. The proposed equivalence testing procedure for this scenario refers to the median of the independent difference distribution, i.e. to the median of the differences between independent observations from the test group and the reference group, respectively. The procedure provides an asymptotic equivalence test, which is symmetric with respect to the roles of ‘test’ and ‘reference’. It can be described either as a two‐one‐sided‐tests (TOST) approach, or equivalently as a confidence interval inclusion rule. A one‐sided variant of the approach can be applied analogously to non‐inferiority testing problems. The procedure may be generalised to equivalence testing with respect to quantiles other than the median, and is closely related to tolerance interval type inference. Copyright © 2009 John Wiley & Sons, Ltd.     

CONSTRUCTING MORE POWERFUL EXACT TESTS OF EQUIVALENCE FROM BINARY MATCHED PAIRS

In randomized clinical trials, it is often necessary to demonstrate that a new medical treatment does not substantially differ from a standard reference treatment. Formal testing of such ‘equivalence hypotheses’ is typically done by combining two one‐sided tests (TOST). A quite different strand of research has demonstrated that replacing nuisance parameters with a null estimate produces P‐values that are close to exact ( Lloyd 2008a ) and that maximizing over the residual dependence on the nuisance parameter produces P‐values that are exact and optimal within a class ( Röhmel & Mansmann 1999 ; Lloyd 2008a ). The three procedures – TOST, estimation and maximization of a nuisance parameter – can each be expressed as a transformation of an approximate P‐value. In this paper, we point out that TOST‐based P‐values will generally be conservative, even if based on exact and optimal one‐sided tests. This conservatism is avoided by applying the three transforms in a certain order – estimation followed by TOST followed by maximization. We compare this procedure with existing alternatives through a numerical study of binary matched pairs where the two treatments are compared by the difference of response rates. The resulting tests are uniformly more powerful than the considered competitors, although the difference in power can range from very small to moderate.