Multiplicity in confirmatory clinical trials: a case study with discussion from a JSM panel.

An invited panel session was conducted in the 2012 Joint Statistical Meetings, San Diego, California, USA, to stimulate the discussion on multiplicity issues in confirmatory clinical trials for drug development. A total of 11 expert panel members were invited and 9 participated. Prior to the session, a case study was previously provided to the panel members to facilitate the discussion, focusing on the key components of the study design and multiplicity. The Phase 3 development program for this new experimental treatment was based on a single randomized controlled trial alone. Each panelist was asked to clarify if he or she responded as if he or she were a pharmaceutical drug sponsor, an academic panelist or a health regulatory scientist.

Assessment of type I error rate associated with dose-group switching in a longitudinal Alzheimer trial.

In clinical trials, there always is the possibility to use data-driven adaptation at the end of a study. There prevails, however, concern on whether the type I error rate of the trial could be inflated with such design, thus, necessitating multiplicity adjustment. In this project, a simulation experiment was set up to assess type I error rate inflation associated with switching dose group as a function of dropout rate at the end of the study, where the primary analysis is in terms of a longitudinal outcome. This simulation is inspired by a clinical trial in Alzheimer's disease. The type I error rate was assessed under a number of scenarios, in terms of differing correlations between efficacy and tolerance, different missingness mechanisms, and different probabilities of switching. A collection of parameter values was used to assess sensitivity of the analysis. Results from ignorable likelihood analysis show that the type I error rate with and without switching was approximately the posited error rate for the various scenarios. Under last observation carried forward (LOCF), the type I error rate blew up both with and without switching. The type I error inflation is clearly connected to the criterion used for switching. While in general switching, in a way related to the primary endpoint, may impact the type I error, this was not the case for most scenarios in the longitudinal Alzheimer trial setting under consideration, where patients are expected to worsen over time.

Gatekeeping procedures in dose-response clinical trials based on the Dunnett test.

This paper discusses multiple testing procedures in dose-response clinical trials with primary and secondary endpoints. A general gatekeeping framework for constructing multiple tests is proposed, which extends the Dunnett test [Journal of the American Statistical Association 1955; 50: 1096-1121] and Bonferroni-based gatekeeping tests developed by Dmitrienko et al. [Statistics in Medicine 2003; 22:2387-2400]. The proposed procedure accounts for the hierarchical structure of the testing problem; for example, it restricts testing of secondary endpoints to the doses for which the primary endpoint is significant. The multiple testing approach is illustrated using a dose-response clinical trial in patients with diabetes. Monte-Carlo simulations demonstrate that the proposed procedure provides a power advantage over the Bonferroni gatekeeping procedure. The power gain generally increases with increasing correlation among the endpoints, especially when all primary dose-control comparisons are significant.