A prospectively planned cumulative meta-analysis applied to a series of concurrent clinical trials

Abstract

Sequential designs are now a familiar part of clinical trial methodology. In particular, the triangular test has been used in several individual studies. Methods of combining studies are also well-known from the literature on meta-analysis. However, the combination of the two approaches is new. Consider the situation where a series of studies is to be conducted, following broadly similar protocols comparing a new treatment with a control treatment. In order to obtain an answer as quickly as possible to an efficacy or safety question it may be desirable to perform a cumulative meta-analysis on one particular variable. This could, for example, be the primary efficacy variable, an expensive assessment conducted in only a subgroup of patients, or a serious side-effect. To allow for the size of the treatment difference varying from study to study we might wish to provide a global estimate. Hence a random effects combined analysis, within a sequential framework, would appear to be appropriate. A methodology which utilizes efficient score statistics and Fisher's information is presented. Simulations show that the proposed methodology will achieve the specified error probabilities with reasonable accuracy provided that any random effect is relatively small. Ignoring random effects when they are present can lead to inaccuracies. A simulated example illustrates a number of practical issues.