Simultaneous False-Decision Error Rates in Master Protocols with Shared Control: False Discovery Rate Perspective

Abstract

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.