The Use of Blood-Based Biomarkers to Improve the Design of Clinical Trials of Traumatic Brain Injury

Despite extensive research focusing on development of therapeutics for traumatic brain injury (TBI) and success in preclinical trials, numerous phase 3 clinical trials have been failed mainly due to heterogeneity of TBI and poor diagnostic and outcome prediction tools currently available to make a proper assessment of type of injury and patient status. Current TBI diagnostics is mainly centered on neurological assessment (e.g., Glasgow Coma Scale) and neuroimaging, which can be subjective, not sensitive, and/or often not available. Over last decade, several clinical studies suggest that rapid and continuous monitoring and analysis of biomarkers on presented in blood after TBI could serve as reliable and useful tool to distinguish type of injury, predict secondary insult, and evaluate efficacy of therapeutic interventions and that use of biomarkers in combination with current disease monitoring and management tools could improve clinical trials for TBI drug development. Repetitive assessments of certain biomarkers could provide valuable information regarding patient's status and response for the treatment. In addition, stratification of the patients on the basis of diagnostic and predictive biomarker profiles assessed at admission will improve both patient safety and accuracy treatment outcome assessments in clinical trials. Finally, the analysis of patients groups based on surrogate endpoint after completion of trial will allow identifying populations of patients to whom the treatment is beneficial or establish possible contradictions. In this chapter, we discuss current clinical studies on biomarkers of TBI, their association with TBI outcomes, secondary insults, and the ability of biomarkers to distinguish type of injury and correlation with treatment. We summarize the key steps including validation of surrogate endpoints and statistical data analysis in the development of diagnostic and predictive biomarkers to improve clinical trials outcomes.