Single-stage, three-arm, adaptive test strategies for non-inferiority trials with an unstable reference

Abstract

For indications where only unstable reference treatments are available and use of placebo is ethically justified, three-arm 'gold standard' designs with an experimental, reference and placebo arm are recommended for non-inferiority trials. In such designs, the demonstration of efficacy of the reference or experimental treatment is a requirement. They have the disadvantage that only little can be concluded from the trial if the reference fails to be efficacious. To overcome this, we investigate novel single-stage, adaptive test strategies where non-inferiority is tested only if the reference shows sufficient efficacy and otherwise δ-superiority of the experimental treatment over placebo is tested. With a properly chosen superiority margin, δ-superiority indirectly shows noninferiority. We optimize the sample size for several decision rules and find that the natural, data driven test strategy, which tests non-inferiority if the reference's efficacy test is significant, leads to the smallest overall and placebo sample sizes. We proof that under specific constraints on the sample sizes, this procedure controls the family-wise error rate. All optimal sample sizes are found to meet this constraint. We finally show how to account for a relevant placebo drop-out rate in an efficient way and apply the new test strategy to a real life data set.

Optimization of the two‐stage group sequential three‐arm gold‐standard design for non‐inferiority trials

“…While Homma and Daimon already present operating characteristics for optimally chosen allocation ratios for their rerandomization procedure, one could try to find optimal design parameters for this design with added futility boundaries or an additional group sequential recruitment stage. Another interesting modification of the gold-standard design, introduced by Brannath et al 31 is the idea of adaptively switching from testing non-inferiority of treatment against control to testing delta-superiority of treatment over placebo in cases where the control treatment turns out to be non-effective. Especially in group sequential recruiting procedures, this modification might also benefit from optimal design parameter choices.…”