Looking ahead in early-phase trial design to improve the drug development process: examples in oncology

Background: Clinical trial design must consider the specific resource constraints and overall goals of the drug development process (DDP); for example, in designing a phase I trial to evaluate the safety of a drug and recommend a dose for a subsequent phase II trial. Here, we focus on design considerations that involve the sequence of clinical trials, from early phase I to late phase III, that constitute the DDP. Methods: We discuss how stylized simulation models of clinical trials in an oncology DDP can quantify important relationships between early-phase trial designs and their consequences for the remaining phases of development. Simulations for three illustrative settings are presented, using stylized models of the DDP that mimic trial designs and decisions, such as the potential discontinuation of the DDP. Results: We describe: (1) the relationship between a phase II single-arm trial sample size and the likelihood of a positive result in a subsequent phase III confirmatory trial; (2) the impact of a phase I dose-finding design on the likelihood that the DDP will produce evidence of a safe and effective therapy; and (3) the impact of a phase II enrichment trial design on the operating characteristics of a subsequent phase III confirmatory trial. Conclusions: Stylized models of the DDP can support key decisions, such as the sample size, in the design of early-phase trials. Simulation models can be used to estimate performance metrics of the DDP under realistic scenarios; for example, the duration and the total number of patients enrolled. These estimates complement the evaluation of the operating characteristics of early-phase trial design, such as power or accuracy in selecting safe and effective dose levels.