Methods and Applications of Statistics in Clinical Trials, Volume 1: Concepts, Principles, Trials, and Designs

Chapter 39

Large Simple Trials

Mary A. Foulkes

39.1 Large, Simple Trials

Since the launch of the first randomized clinical trials in the middle of the twentieth century, immediate, major, and ubiquitous impacts on clinical practice and public health policy have been the result of very large randomized trials. For example, within hours of the results announced from the first oral polio vaccine field trial, the clarity of those results led to the regulatory approval of the vaccine and then to the rapid immunization of millions. That field trial was large (almost half a million children), simple (capture of incident cases of paralytic polio through public health records), randomized, and double blind [1,2]. The conclusions of that trial were unambiguous, leading to a seismic revolution in the fight against polio. This article describes all the characteristics that differentiate large, simple trials, sometimes called “megatrials” [3], from other types of trial, and we address important clinical questions that can have substantive impact: sizing the trial appropriate to the question, reliance on the bias control of randomization, minimizing the data collection, and other trial processes.

39.2 Small but Clinically Important Objective

The clinical effect size of interest dictates the number of subjects needed (or events observed) in any randomized, controlled trial. To identify a relatively small or moderate but clinically meaningful effect, the number of subjects needed (or number of ...