Adding experimental arms to platform clinical trials: randomization procedures and interim analyses.
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ABSTRACT:
SUBMITTER: Ventz S
PROVIDER: S-EPMC5862294 | biostudies-literature | 2018 Apr
REPOSITORIES: biostudies-literature
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Adding experimental arms to platform clinical trials: randomization procedures and interim analyses.
Ventz Steffen S Cellamare Matteo M Parmigiani Giovanni G Trippa Lorenzo L
Biostatistics (Oxford, England) 20180401 2
Multi-arm clinical trials use a single control arm to evaluate multiple experimental treatments. In most cases this feature makes multi-arm studies considerably more efficient than two-arm studies. A bottleneck for implementation of a multi-arm trial is the requirement that all experimental treatments have to be available at the enrollment of the first patient. New drugs are rarely at the same stage of development. These limitations motivate our study of statistical methods for adding new experi ...[more]
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Project description:BackgroundExperimental treatments pass through various stages of development. If a treatment passes through early-phase experiments, the investigators may want to assess it in a late-phase randomised controlled trial. An efficient way to do this is adding it as a new research arm to an ongoing trial while the existing research arms continue, a so-called multi-arm platform trial. The familywise type I error rate is often a key quantity of interest in any multi-arm platform trial. We set out to clarify how it should be calculated when new arms are added to a trial some time after it has started.MethodsWe show how the familywise type I error rate, any-pair and all-pairs powers can be calculated when a new arm is added to a platform trial. We extend the Dunnett probability and derive analytical formulae for the correlation between the test statistics of the existing pairwise comparison and that of the newly added arm. We also verify our analytical derivation via simulations.ResultsOur results indicate that the familywise type I error rate depends on the shared control arm information (i.e. individuals in continuous and binary outcomes and primary outcome events in time-to-event outcomes) from the common control arm patients and the allocation ratio. The familywise type I error rate is driven more by the number of pairwise comparisons and the corresponding (pairwise) type I error rates than by the timing of the addition of the new arms. The familywise type I error rate can be estimated using Šidák's correction if the correlation between the test statistics of pairwise comparisons is less than 0.30.ConclusionsThe findings we present in this article can be used to design trials with pre-planned deferred arms or to add new pairwise comparisons within an ongoing platform trial where control of the pairwise error rate or familywise type I error rate (for a subset of pairwise comparisons) is required.
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