Paths to Successful Translation of New Therapies for Severe Traumatic Brain Injury in the Golden Age of Traumatic Brain Injury Research: A Pittsburgh Vision

Abstract

New neuroprotective therapies for severe traumatic brain injury (TBI) have not translated from pre-clinical to clinical success. Numerous explanations have been suggested in both the pre-clinical and clinical arenas. Coverage of TBI in the lay press has reinvigorated interest, creating a golden age of TBI research with innovative strategies to circumvent roadblocks. We discuss the need for more robust therapies. We present concepts for traditional and novel approaches to defining therapeutic targets. We review lessons learned from the ongoing work of the pre-clinical drug and biomarker screening consortium Operation Brain Trauma Therapy and suggest ways to further enhance pre-clinical consortia. Biomarkers have emerged that empower choice and assessment of target engagement by candidate therapies. Drug combinations may be needed, and it may require moving beyond conventional drug therapies. Precision medicine may also link the right therapy to the right patient, including new approaches to TBI classification beyond the Glasgow Coma Scale or anatomical phenotyping-incorporating new genetic and physiologic approaches. Therapeutic breakthroughs may also come from alternative approaches in clinical investigation (comparative effectiveness, adaptive trial design, use of the electronic medical record, and big data). The full continuum of care must also be represented in translational studies, given the important clinical role of pre-hospital events, extracerebral insults in the intensive care unit, and rehabilitation. TBI research from concussion to coma can cross-pollinate and further advancement of new therapies. Misconceptions can stifle/misdirect TBI research and deserve special attention. Finally, we synthesize an approach to deliver therapeutic breakthroughs in this golden age of TBI research.

Keywords: clinical trial design; combination therapy; consortium; neuroprotection; pharmacodynamics/response biomarker; phenotyping; quantitative systems pharmacology; rehabilitation; target engagement; traumatic brain injury (TBI).

FIG. 1.

Frequency histogram of the number of publications listed in PubMed for the search terms TBI and treatment. A marked uptick is seen after 2011. Note that the value for 2018 is based on the accessing of PubMed on September 3, 2018. TBI, traumatic brain injury.

FIG. 2.

Strategies in both the pre-clinical and clinical arenas that will be presented and discussed in this review to facilitate therapy development and successful clinical translation in the setting of severe traumatic brain injury. Please see text for details. PD, pharmacodynamics; PK, pharmacokinetics.

FIG. 3.

Publications of studies on drug therapies in rat, mouse, and pig models of TBI since 1980 based on interrogation of PubMed. An extensive repository of information on the effects of a wide variety of therapies on outcomes in pre-clinical models of TBI, particularly in rodents, represents a resource that merits more comprehensive and systematic evaluation, particularly for future consortium-based testing of therapies across models and species. Please see text for details. TBI, traumatic brain injury.

FIG. 4.

Construct of a possible approach to therapy development for severe TBI from drug selection and initial screening, through to small animal testing with pharmacodynamics/response biomarkers addressing target engagement readouts, then progressing to conventional small and large animal in vivo testing, and finally on to clinical feasibility and safety trials and ultimately phase III trials. The clinical trials could represent either conventional severe TBI populations across the full spectrum or phenotype-based trials using either standard or advanced trial designs. Feedback loops to inform earlier screening approaches on their ability to predict at more advanced levels are also shown. Please see text for details. GFAP, glial fibrillary acidic protein; pNF-H, phospho-neurofilament-H; TBI, traumatic brain injury.