Allocation in platform trials to maintain comparability across time and eligibility.

Abstract

Platform trials, with arms entering and leaving the trial over time, are complex. In addition to trial changes over time, certain arms in a platform may come with patient restrictions. Both of these issues (time and eligibility) can create biases in comparing active arms to control. The largest of these biases, using non-concurrent controls or including control patients that were ineligible for an active arm, have been extensively discussed in the literature. Here we show that even restricting to concurrent, eligible controls can induce biases if proper allocation ratios are not maintained throughout the platform. We also build on results in Ventz et al. Biostat., 19:199-215, 2018 to describe an algorithm that guarantees comparability between active and control groups in arm analyses in both time and eligibility, and allows for both re-randomization of patients and two-stage randomization procedures. The resulting method is both flexible and easily implemented, allowing robust comparisons when assumptions that underlie alternative randomization methods are in doubt.