Traumatic brain injury (TBI) is a major health and socio-economic problem throughout the world. Many randomized controlled trials (RCTs) have been performed to investigate the effectiveness of new therapies, but none have convincingly demonstrated benefit. Clinical trials in TBI pose complex methodological challenges and meeting these requires new approaches. The challenges are related to the heterogeneity of head injuries, to optimum analysis of outcome and to aspects of the design of trials. To address these, we have created the IMPACT database on TBI through merging individual patient data from eight RCTs and three observational surveys. This database forms a culture medium in which innovative approaches to improving trial design and analysis are being explored. We hypothesize that the statistical power of TBI trials may be increased by adjusting for heterogeneity with covariate adjustment and/or prognostic targeting, by exploiting the ordinal nature of the Glasgow Outcome Scale and by relating the outcome obtained in individual patients to their baseline prognostic risk. Extensive prognostic analysis was required as a first step towards our aim of optimizing the chance of demonstrating benefit of new therapies in future trials. The fruits of this analysis are reported in detail in the subsequent reports in this issue of the Journal of Neurotrauma. The results will lead to the development and validation of new prognostic models, which will be applied to deal with heterogeneity. The findings will be synthesized into recommendations for the design and analysis of future RCTs, with the expectation of increasing the likelihood of demonstrating the benefit of a truly effective new therapy or therapeutic agent in victims of a head injury.