Simulation Practices for Adaptive Trial Designs in Drug and Device Development

Abstract

Adaptive clinical trials are the cornerstone of modern drug and device development. The most recent US legislation calls for higher efficiency in designing clinical trials with emphasis on expanding the utilization of complex innovative designs that cannot be developed without simulations. It is well recognized that clinical trial simulation is a fundamental tool to explore, compare, and understand the operating characteristics, statistical properties, and adaptive decisions embedded in different designs to answer the given research questions. This article provides insights from industry on the development of a simulation report from a group of statisticians brought together under the sponsorship of the Drug Information Association Adaptive Design Scientific Working Group. This effort intends to illustrate the key common elements required to ensure higher consistency and clarity in conducting and reporting simulations of adaptive clinical trials, eliminate unnecessary barriers in communicating technical design aspects to different audiences, and facilitate the assessment of pros and cons of candidate designs. The design-dependent elements of a simulation report applicable to specific types of adaptive trials are presented with the examples of dose-escalation designs, dose-ranging studies, trials with sample size re-estimation and early stopping rules, and confirmatory multistage designs.