title: Unique challenges in clinical trials in traumatic brain injury.
abstract: Clinical trials in traumatic brain injury have shown little success in providing an evidence base for the introduction of successful new therapies into clinical practice. In addition to the problems that are common to all such studies in critical illness, trials in traumatic brain injury are complicated by the extremely short temporal window for intervention, failure of many candidate drugs to cross the blood-brain barrier, ethical and regulatory obstacles associated with research in subjects who cannot provide consent, the tendency to use small sample sizes in anticipation of unrealistic treatment benefits, and difficulty in translating experimental success into clinical practice. This article reviews the potential causes of these problems and suggests some solutions. These include the changes in regulatory frameworks that are making waived consent an acceptable strategy once more, and an increasing trend toward appropriately large trials. Other encouraging developments include the increasing use of human experimental medicine strategies before phase III trials to assess blood-brain barrier penetration and dose ranging, and provide proof of concept and proof of mechanism. Novel approaches to trial design, such as sliding dichotomy, coupled with robust outcome prediction models, can increase statistical power and improve trial design.
authors.affiliation: Division of Anaesthesia, University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom. dkm13@wbic.cam.ac.uk
authors.forename: David K
authors.initials: DK
authors.lastname: Menon
mesh_terms: D001930:Brain Injuries / Q000628:therapy*; D002986:Clinical Trials as Topic / Q000941:ethics* / Q000331:legislation & jurisprudence*; D003422:Critical Care; D006801:Humans; D007258:Informed Consent / Q000331:legislation & jurisprudence; D009102:Multiple Organ Failure / Q000150:complications; D017063:Outcome Assessment, Health Care; D018401:Sample Size