The New England Journal of Statistics in Data Science

Platform trials are multiarm clinical studies that allow the addition of new experimental arms after the activation of the trial. Statistical issues concerning “adding new arms”, however, have not been thoroughly discussed. This work was motivated by a “two-period” pediatric osteosarcoma study, starting with two experimental arms and one control arm and later adding two more pre-planned experimental arms. The common control arm will be shared among experimental arms across the trial. In this paper, we provide a principled approach, including how to modify the critical boundaries to control the family-wise error rate as new arms are added, how to re-estimate the sample sizes and provide the optimal control-to-experimental arms allocation ratio, in terms of minimizing the total sample size to achieve a desirable marginal power level. We examined the influence of the timing of adding new arms on the design’s operating characteristics, which provides a practical guide for deciding the timing. Other various numerical evaluations have also been conducted. A method for controlling the pair-wise error rate (PWER) has also been developed. We have published an R package, PlatformDesign, on CRAN for practitioners to easily implement this platform trial approach. A detailed step-by-step tutorial is provided in Appendix A.2.

Phase I trials investigate the toxicity profile of a new treatment and identify the maximum tolerated dose for further evaluation. Most phase I trials use a binary dose-limiting toxicity endpoint to summarize the toxicity profile of a dose. In reality, reported toxicity information is much more abundant, including various types and grades of adverse events. Building upon the i3+3 design (Liu et al., 2020), we propose the Ti3+3 design, in which the letter “T” represents “total” toxicity. The proposed design takes into account multiple toxicity types and grades by computing the toxicity burden at each dose. The Ti3+3 design aims to achieve desirable operating characteristics using a simple statistics framework that utilizes“toxicity burden interval” (TBI). Simulation results show that Ti3+3 demonstrates comparable performance with existing more complex designs.