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Translational Research in Acute Central Nervous System Injury Lessons Learned and the Future

David S. Warner, MD1,2,3; Michael L. James, MD1,4; Daniel T. Laskowitz, MD1,2,4; Eelco F. Wijdicks, MD, PhD5
[+] Author Affiliations
1Department of Anesthesiology, Duke University Medical Center, Durham, North Carolina
2Department of Neurobiology, Duke University Medical Center, Durham, North Carolina
3Department of Surgery, Duke University Medical Center, Durham, North Carolina
4Department of Neurology, Duke University Medical Center, Durham, North Carolina
5Department of Neurology, Mayo Clinic, Rochester, Minnesota
JAMA Neurol. 2014;71(10):1311-1318. doi:10.1001/jamaneurol.2014.1238.
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Importance  Research to improve outcomes from acute central nervous system (CNS) injury has progressed little, although limited examples (eg, induced hypothermia for out-of-hospital ventricular fibrillation cardiac arrest and birth asphyxia and tissue plasminogen activator for ischemic stroke) have proved that it is possible to favorably alter outcome.

Objective  To chronicle the evolution of preclinical research designed to provide therapeutic interventions for acute CNS injury.

Evidence Review  Preclinical literature cited by major clinical intervention trials was systematically assessed with respect to fulfillment of fundamental elements of experimental design in current guidelines.

Findings  Preclinical studies of acute CNS injury to date have a poor record of adhering to basic tenets of experimental design, including randomization, concealment of treatment allocation, definition of sustained robustness of therapeutic benefit, and emulation of clinical disease. Major clinical trials continue to be justified and conducted on the basis of weak preclinical evidence. Publication of preclinical research guidelines and endorsement by scientific journals have been insufficient to alter practice. Novel approaches to preclinical therapeutic development, including multicenter phase 3 trials and preclinical trial registries that document a priori experimental design and primary dependent variables, may overcome this intransigence and enhance possibility for therapeutic breakthroughs.

Conclusions and Relevance  Current knowledge of acute CNS injury dictates that therapeutic discovery and translation apply known tenets of sound experimental design and emulation of the clinical disorder targeted for therapeutic intervention. Peer-review systems must demand these qualities in proposed and published research to assess validity and potential for clinical translation.

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Figure 1.
Phase 3 Preclinical Trial Scheme 1

Alternative preclinical phase 3 drug development stream specific to stroke research using a consortium of laboratories to perform a large-scale preclinical trial to ensure efficacy before proceeding to human studies.79

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Figure 2.
Phase 3 Preclinical Trial Scheme 2

Proposed preclinical phase 3 drug development stream for acute brain injury that uses a consortium of laboratories to examine a spectrum of species to define robustness of efficacy before planning clinical trials.77

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