Ethical implications of time frames in a randomized controlled trial in acute severe traumatic brain injury.

OBJECTIVES To analyze factors determining the time between injury and study drug administration (SDA) in a randomized controlled trial (RCT) of acute severe traumatic brain injury (TBI) and to discuss the ethical implications. METHODS Time frames prior to SDA, differentiated per country, were analyzed in a recently conducted RCT in severe TBI. Per protocol, the time window for SDA was 6 h after injury. We selected patients for whom written proxy consent (PC) was obtained prior to SDA (n=631). RESULTS The time between injury and admission to the neurotrauma center (NTC) varied per country from 1.16 to 2.35 h, but CT scan was obtained on average within 1h of admission. The median time between injury and CT scan was within 3 h in all but one country. The broadest time window was observed between CT scan and obtaining required PC (1.71-2.74 h). The median time between injury and PC varied between countries from 3.75 to 5.00 h. After consent had been obtained, almost all patients subsequently received study drug within 1 h. In 85.3% of all cases time between injury and SDA exceeded 4 h, in 60% 5 h. CONCLUSIONS The requirement of written PC causes a significant delay in SDA in TBI. With deferred consent, the first dose of an investigational drug could potentially be administered directly after completion of the admission CT scan, which reduce the time to SDA by 50%. We argue that randomization under deferred consent is ethically defendable for emergency research in severe TBI. Recommendations for patient protection are proposed.