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.

Blinded sample size recalculation in adaptive enrichment designs

“…Trial duration as a metric is more common in event‐driven trials, for example, time to first analysis was considered and discussed by Asikanius et al. (2016) in an event‐driven trial comparing different strategies to decide on the set of final hypotheses.…”

“…This may be counterbalanced by fewer patients needed, attaining the same statistical power due to the enrichment, and therefore decreasing the trial duration. Trial duration as a metric is more common in event-driven trials, for example, time to first analysis was considered and discussed by Asikanius et al (2016) in an event-driven trial comparing different strategies to decide on the set of final hypotheses.…”