The analysis of titration studies in phase III clinical trials

Abstract

Clinical trials commonly employ the titration design for certain drugs such as antihypertensives. In a Phase III trial the design has purposes distinct from those of a Phase I or II trial, as well as from those of a trial with a parallel design. In this paper we compare the titration design with the usual parallel design in their respective purposes for Phase III trials, explore the relevant questions addressed, and examine typical data from such trials. We also discuss work which focuses primarily on the Phase I or II titration trials. We formulate the problem in the framework of a one-way contingency table augmented with incomplete data and obtain the maximum likelihood estimates of the parameters and their estimated variances/covariances via the EM algorithm. An example of a Phase III study of an antihypertensive agent illustrates the proposed procedure.