Simulation of clinical trials: a review with emphasis on the design issues

Simulation is a widely used tool to investigate real-world systems in a large number of fields, including clinical trials for drug development, since real trials are costly, frequently fail and may lead to serious side effects. This paper is a survey of the statistical issues arising in these simulated trials, with particular emphasis on the design of such virtual experiments, stressing similarities and differences with the design of real trials. We discuss the aims and peculiarities of the simulation models used in this context, including a brief mention of metamodels, and different validating techniques. We illustrate each specific issue through one or more studies recently reported in the medical and/or pharmaceutical literature. We end the paper with some challenging questions on the scientific rigour, ethics and effectiveness of simulation in clinical research, and the interesting research problem of how to integrate virtual and physical experiments in a clinical context.