title: Comparison of design strategies for a three-arm clinical trial with time-to-event endpoint: Power, time-to-analysis, and operational aspects.
abstract: To optimize resources, randomized clinical trials with multiple arms can be an attractive option to simultaneously test various treatment regimens in pharmaceutical drug development. The motivation for this work was the successful conduct and positive final outcome of a three-arm randomized clinical trial primarily assessing whether obinutuzumab plus chlorambucil in patients with chronic lympocytic lymphoma and coexisting conditions is superior to chlorambucil alone based on a time-to-event endpoint. The inference strategy of this trial was based on a closed testing procedure. We compare this strategy to three potential alternatives to run a three-arm clinical trial with a time-to-event endpoint. The primary goal is to quantify the differences between these strategies in terms of the time it takes until the first analysis and thus potential approval of a new drug, number of required events, and power. Operational aspects of implementing the various strategies are discussed. In conclusion, using a closed testing procedure results in the shortest time to the first analysis with a minimal loss in power. Therefore, closed testing procedures should be part of the statistician's standard clinical trials toolbox when planning multiarm clinical trials.
authors.affiliation: F. Hoffmann-La Roche Ltd, Basel, Switzerland.
authors.forename: Elina
authors.initials: E
authors.lastname: Asikanius
authors.affiliation: F. Hoffmann-La Roche Ltd, Basel, Switzerland. kaspar.rufibach@roche.com.
authors.forename: Kaspar
authors.initials: K
authors.lastname: Rufibach
authors.affiliation: German CLL Study Group, Department I of Internal Medicine, University Hospital Cologne, Cologne, Germany.
authors.forename: Jasmin
authors.initials: J
authors.lastname: Bahlo
authors.affiliation: F. Hoffmann-La Roche Ltd, Basel, Switzerland.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Bieska
authors.affiliation: F. Hoffmann-La Roche Ltd, Basel, Switzerland.
authors.forename: Hans Ulrich
authors.initials: HU
authors.lastname: Burger
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D002699:Chlorambucil / Q000627:therapeutic use; D002986:Clinical Trials as Topic / Q000379:methods* / Q000592:standards; D003627:Data Interpretation, Statistical; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy; D012107:Research Design / Q000592:standards*; D013997:Time Factors
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D002699:Chlorambucil; C543332:obinutuzumab
keywords: Bonferroni correction; Closed hypothesis test; Familywise error rate; Multiarm clinical trial; Multiplicity