New considerations in the design of clinical trials for traumatic brain injury.

Randomized controlled trials in traumatic brain injury (TBI) pose several complicated methodological challenges related to the heterogeneity of the population. Several strategies have been proposed to deal with these challenges. Recommendations presented by the International Mission for Prognosis and Analysis of Clinical Trials in TBI (IMPACT) study group include the use of relatively broad enrollment criteria combined with covariate adjustment for strong predictors of outcome in the analysis phase, rather than the use of strict enrollment criteria. Furthermore, an ordinal rather than a dichotomized analysis of the Glasgow Outcome Scale - the outcome measure in most TBI trials - will increase the statistical power significantly. This review discusses the issue of heterogeneity in TBI trials and summarizes the value of different innovative methods for the design and statistical analysis of randomized controlled trials in TBI. Future directions highlight the opportunities offered by alternative strategies, such as comparative effectiveness research, to investigate the clinical benefits of established and novel therapies in TBI.