Complex Intervention Trials

Clinical trial methodology was developed for pharmaceutical drug development and evaluation. In recent years, trials have expanded to an increasingly diverse range of interventions. The term complex intervention describes treatments that are multicomponent and include clustering due to specific components, such as the healthcare provider, which cannot be separated from the package of treatment and influence treatment outcomes. This chapter provides an overview of the main considerations in the design and analysis of complex interventions trials. Initial development of complex interventions is a multidisciplinary endeavor and requires rigorous qualitative and quantitative methods. Understanding both the intervention components and how they interact is crucial for successful development and evaluation of the intervention. Published guidance on methods for feasibility, piloting, or early phase trials of complex interventions is scarce. However, there are well-established methods for phase III trials of multicomponent interventions that involve clustering. The most commonly used methods, including individually randomized trials with random effects for clusters, cluster randomized trials, and stepped-wedge cluster randomized trials, are described. Analysis focuses on generalized linear (mixed) models; methods for sample size estimation that accommodate the extra variance related to clustering are also provided for a range of designs in this setting. With careful attention to the correlation structure induced by the chosen design, results can be analyzed in standard statistical software, although small numbers of clusters, and/or small within-cluster sizes, can cause convergence problems. Statistical analysis results of complex interventions trials, including those relating to components of the intervention, need to be considered alongside economic, qualitative, and behavioral research to ensure that complex interventions can be successfully implemented into routine practice.