Clinical Trial Simulation: Planning With the OCTAVE Framework, Implementation and Validation Principles

The adoption of complex innovative clinical trial designs has steadily increased in recent years. These are trial designs that have one or more unconventional features-often resulting in multiple stages-with the goal of improving on conventional single-stage, fixed-setting designs in terms of efficiency, for example, by reducing the required sample size or the time to establish findings about an intervention. The motivation for these designs may not be difficult to follow, but their set-up and implementation is usually more challenging. Statistical properties of these designs can also be difficult to compute. Clinical trial simulation (CTS), which uses software to generate artificial data for learning, can be conducted to identify the (optimal) setting of a clinical trial, evaluate the design's statistical properties under some hypothetical scenarios for sensitivity analysis, and compare different design set-ups and data analysis strategies, all of which contribute to a better understanding of the value of unconventional features before implementing the design in an actual clinical trial. Existing literature on simulation primarily focuses on the evaluation of statistical analysis methods, with less attention on the detailed specification and planning of CTS. This tutorial presents a new framework, called OCTAVE, for outlining the details of CTS, provides practical recommendations for their implementation, and addresses key computational considerations. The target audience is trial statisticians who are involved in designing and analyzing clinical trials. This tutorial covers a range of complex innovative designs, without the expectation that readers are familiar with the mentioned examples.