The New England Journal of Statistics in Data Science

Master protocol is a type of trial designs where multiple therapies and/or multiple disease populations can be investigated in the same trial. A shared control can be used for multiple therapies to gain operational efficiency and gain attraction to patients. To balance between controlling for false positive rate and having adequate power for detecting true signals, the impact of False Discovery Rate (FDR) is evaluated when multiple investigational drugs are studied in the master protocol. With the shared control group, the “random high” or “random low” in the control group can potentially impact all hypotheses testing that compare each of the test regimens and the control group in terms of probability of having at least one positive hypothesis outcome, or multiple positive outcomes. When regulatory agencies make the decision of approving or declining one or more regimens based on the master protocol design, this introduces a different type of error: simultaneous false-decision error. In this manuscript, we examine in detail the derivations and properties of the simultaneous false-decision error in the master protocol with shared control under the framework of FDR. The simultaneous false-decision error consists of two parts: simultaneous false-discovery rate (SFDR) and simultaneous false non-discovery rate (SFNR). Based on our analytical evaluation and simulations, the magnitude of SFDR and SFNR inflation is small. Therefore, the multiple error rate controls are generally adequate, further adjustment to a pre-specified level on SFDR or SFNR or reduce the alpha allocated to each individual treatment comparison to the shared control is deemed unnecessary.

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.