title: Designing multi-arm multi-stage clinical trials using a risk-benefit criterion for treatment selection.
abstract: Multi-arm clinical trials that compare several active treatments to a common control have been proposed as an efficient means of making an informed decision about which of several treatments should be evaluated further in a confirmatory study. Additional efficiency is gained by incorporating interim analyses and, in particular, seamless Phase II/III designs have been the focus of recent research. Common to much of this work is the constraint that selection and formal testing should be based on a single efficacy endpoint, despite the fact that in practice, safety considerations will often play a central role in determining selection decisions. Here, we develop a multi-arm multi-stage design for a trial with an efficacy and safety endpoint. The safety endpoint is explicitly considered in the formulation of the problem, selection of experimental arm and hypothesis testing. The design extends group-sequential ideas and considers the scenario where a minimal safety requirement is to be fulfilled and the treatment yielding the best combined safety and efficacy trade-off satisfying this constraint is selected for further testing. The treatment with the best trade-off is selected at the first interim analysis, while the whole trial is allowed to compose of J analyses. We show that the design controls the familywise error rate in the strong sense and illustrate the method through an example and simulation. We find that the design is robust to misspecification of the correlation between the endpoints and requires similar numbers of subjects to a trial based on efficacy alone for moderately correlated endpoints.
authors.affiliation: Medical and Pharmaceutical Statistics Research Unit, Department of Mathematics and Statistics, Lancaster University, Lancaster, U.K.
authors.forename: Thomas
authors.identifier: http://orcid.org/0000-0002-1096-188X
authors.initials: T
authors.lastname: Jaki
authors.affiliation: Medical and Pharmaceutical Statistics Research Unit, Department of Mathematics and Statistics, Lancaster University, Lancaster, U.K.
authors.forename: Lisa V
authors.initials: LV
authors.lastname: Hampson
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000627:therapeutic use; D001562:Benzimidazoles / Q000627:therapeutic use; D001565:Benzoates / Q000627:therapeutic use; D017326:Clinical Trials, Phase III as Topic; D003198:Computer Simulation; D003657:Decision Making; D023381:Endpoint Determination; D006679:HIV Seropositivity; D006801:Humans; D007333:Insulin Resistance; D015233:Models, Statistical; D061214:Patient Safety; D012107:Research Design; D018401:Sample Size; D000077333:Telmisartan
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001565:Benzoates; D000077333:Telmisartan
keywords: familywise error rate; multi-arm multi-stage (MAMS); multiple endpoints; safety; treatment selection