Designing a seamless phase II/III clinical trial using early outcomes for treatment selection: An application in multiple sclerosis

Abstract

In recent years adaptive seamless phase II/III designs (ASDs) allowing treatment or dose selection at an interim analysis have gained much attention because of their potential to save development costs and to shorten time-to-market of a new compound compared to conventional drug development programmes with separate trials for individual phases. In this paper, we describe an ASD with treatment selection based on early outcome data, specifically considering the situation where no final outcomes are observed at the time of the interim analysis. Bringing together combination tests for adaptive designs and the closure principle for multiple testing, control of the familywise type I error rate in the strong sense is achieved. Furthermore, a simulation model is proposed based on standardized test statistics that allows the generation of virtual trials for a variety of outcomes. We use this simulation model to investigate the actual type I error rate of the proposed testing procedure and find that the familywise type I error rate is controlled as expected. The method is often conservative, with the degree of conservatism depending on the correlation between early and late outcome, the true mean values of the early outcome in the different treatment groups and the selection rule. The investigations are motivated and illustrated by an application of the proposed design and simulation model to progressive multiple sclerosis.

A Comparison of Methods for Treatment Selection in Seamless Phase II/III Clinical Trials Incorporating Information on Short-Term Endpoints

“…In the calculation of selection probabilities below, the true variances and correlation will be used. In the simulations, estimates obtained from the data will be used in place of the true values, as suggested by Stallard (2010) and Friede et al (2011).…”

“…Treatment selection under the method described by Stallard (2010) makes use of short-term endpoint data combined with any available long-term data. In contrast, Friede et al (2011) propose a method of treatment selection that uses only short-term endpoint data. Both approaches base the final inference on the long-term endpoint data only, though they differ in the way in which data from the two stages of the trial are combined.…”

“…Two alternative methods for incorporating early endpoint data in phase II/III clinical trials have been proposed by Stallard (2010) and Friede et al (2011). The methods differ in the way in which the treatment to continue to the second stage is chosen.…”

“…Dragalin (2011) discusses the potential for the use of adaptive designs in all phases of development, including discussion of phase II/III trials, in central nervous system studies. Chataway et al (2011) and Friede et al (2011) propose a phase II/III seamless adaptive design for use in secondary progressive multiple sclerosis trials.…”

The quality of reports of randomized trials in multiple sclerosis: a review

“…So we have entered a new era of RCT in MS: since patients are enrolled in trials which are more and more benign and the use of placebo has become ethically questionable 2 new design strategies are required to handle this evolution, and a large effort is devoted to study, among other strategies, the validation of surrogate outcomes 3,4 and the application of adaptive designs. 5,6 Therefore, after about 20 years of RCT history in MS, the aim of this paper is to review the quality of RCT in MS reports from 1993 to 2010. In this last decade, the quality of RCT reporting has in general constantly improved, with many journals having statistical refereeing and clearer guidelines to authors.…”