Principles of Clinical Trials: Bias and Precision Control

The fundamental difference distinguishing observational studies from clinical trials is randomization. This chapter provides a practical guide to concepts of randomization that are widely used in clinical trials. It starts by describing bias and potential confounding arising from allocating people to treatment groups in a predictable way. It then presents the concept of randomization, starting from a simple coin flip, and sequentially introduces methods with additional restrictions to account for better balance of the groups with respect to known (measured) and unknown (unmeasured) variables. These include descriptions and examples of complete randomization and permuted block designs. The text briefly describes biased coin designs that extend this family of designs. Stratification is introduced as a way to provide treatment balance on specific covariates and covariate combinations, and an adaptive counterpart of biased coin designs, minimization, is described. The chapter concludes with some practical considerations when creating and implementing randomization schedules. By the chapter’s end, statistician or clinicians designing a trial may distinguish generally what assignment methods may fit the needs of their trial and whether or not stratifying by prognostic variables may be appropriate. The statistical properties of the methods are left to the individual references at the end.