A unified theory for sequential clinical trials.

The theory underlying sequential clinical trials is now well developed, and the methodology is increasingly being implemented in practice, both by the pharmaceutical industry and in the public sector. The consequences of conducting interim analyses for frequentist interpretations of data are now well understood. A large number of approaches are available for the calculation of stopping boundaries and for the eventual terminal analysis. In this paper, the principles of the design and analysis of sequential clinical trials will be presented. Existing methods will be reviewed, and their relationships with the general principles will be clarified. Controversies and gaps within the methodology will be highlighted. It is intended that presentation of the subject as a single unified theory will allow the few essential underlying features to be better appreciated.