Clinical Trials in Pediatric Traumatic Brain Injury: Unique Challenges and Potential Responses

Abstract

In order to optimize pediatric traumatic brain injury translational and clinical research, scientific and ethical challenges need to be recognized and addressed. Having recently conducted a multisite phase II safety/feasibility trial of magnesium sulfate as a neuroprotective agent, we supplement our own experience by a mini review of similar studies, identifying challenges and possible responses from the perspective of families, investigators, funding agencies and society.

Factors affecting consent in pediatric critical care research

“…A recent large trial in PICU [7] also did not find a difference in illness severity between those in whom consent was and was not obtained. Furthermore, studies suggest that the PICU is a unique environment [14], and that PICU families prioritize their needs differently than those in NICU families [15]. Prior studies also suggest a difference between adult and pediatric informed consent processes [16,17].…”

Challenges Enrolling Children Into Traumatic Brain Injury Trials: An Observational Study

“…3,4 Despite the frequency of TBI, its substantial impact on the health of children, and decades of research on the topic, there are no proven effective treatments for TBI. [5][6][7] Many previous therapeutic trials for TBI in both children and adults have failed for several reasons, including: (1) the small number of patients with moderate-tosevere TBI available to be studied at any one center, (2) the heterogeneity of TBIs and difficulty in controlling for this heterogeneity, (3) the variability in intra-and interinstitutional approaches to the treatment of patients with TBIs, (4) the difficulty in enrolling subjects within the therapeutic window of a treatment, and (5) ethical and regulatory obstacles associated with research in emergency settings, including the difficulty in obtaining timely written informed consent. [5][6][7][8] In addition, legal guardians are frequently not available in the narrow therapeutic window of potential therapies.…”

“…15 There are several examples of pediatric TBI trials that failed to accrue sufficient numbers of children due to several factors such as limited numbers of eligible children at any one site, difficulties with informed consent, and arrival of subjects outside the therapeutic window of the study intervention. 5,8 The obstacles to successful pediatric TBI trials have not been sufficiently addressed or overcome. Given the history of prior unsuccessful pediatric TBI trials, it is necessary to conduct pretrial feasibility planning work to maximize the likelihood of a successful trial.…”

“…Given the history of prior unsuccessful pediatric TBI trials, it is necessary to conduct pretrial feasibility planning work to maximize the likelihood of a successful trial. 5,6,8 Conducting large clinical trials in head-injured children is difficult and requires a multidisciplinary approach. 5,17 The Pediatric Emergency Care Applied Research Network (PECARN) was established to overcome the barriers of conducting research pertaining to acutely ill and injured children during all phases of emergency care and has a history of successful completion of large multicenter clinical trials.…”

“…5,6,8 Conducting large clinical trials in head-injured children is difficult and requires a multidisciplinary approach. 5,17 The Pediatric Emergency Care Applied Research Network (PECARN) was established to overcome the barriers of conducting research pertaining to acutely ill and injured children during all phases of emergency care and has a history of successful completion of large multicenter clinical trials. [18][19][20][21][22][23][24][25] Due to the promising preclinical and phase II studies for the use of progesterone for adult TBI, PECARN investigators were funded to conduct feasibility planning for a clinical trial of progesterone and other promising agents for TBI in children.…”