Traumatic Brain Injury Endpoints Development (TED) Initiative – Seed Project Awards

As of 2015, no drug has been approved by the US Food and Drug Administration (FDA) to treat traumatic brain injury (TBI). Decades of well-designed clinical trials have failed. The TED Initiative, funded by the Department of Defense, with support from a robust private-public partnership, is a 5-year direct collaboration between leading academic clinician-scientists, the FDA, industry leaders in biotechnology and imaging technology, philanthropies, and patient advocacy groups. Our ultimate goal is to advance the design of clinical trials that will lead to the first successful treatments of acute TBI.

Through early and iterative collaboration with FDA, TED’s overarching aims are to provide the field with a set of validated tools for TBI research; to precisely diagnose this multi-dimensional condition, to accurately stratify patients into trials based on characteristics of their injury, reliably measure the effects of injury over time, and to confirm that experimental drugs and devices are engaging their molecular target at the dose and schedule tested. Such tools will overcome the inherent limitations of the long-used symptom-based TBI classification approaches that divide patients into crude categories of mild, moderate, and severe, using the Glasgow Coma Scale (GCS); outcomes have traditionally been measured using the equally rudimentary Glasgow Outcome Scale-Extended (GOS-E). These measures do not permit mechanistic targeting for clinical trials or detection of differential effectiveness among TBI phenotypes. The GOS-E and GCS, along with head CT, are currently the only FDA-accepted tools for stratifying patients into TBI clinical trials and measuring outcomes.

The Seed Projects are designed to encourage investigators to identify and work toward validation of TBI COAs, blood-based biomarkers, and neuroimaging biomarkers using novel and traditional methodologies that will be presented to the FDA as validated endpoints and outcomes. These endpoints should support enrichment of patient selection/stratification for TBI clinical trials, and/or may serve as treatment endpoints. Seed projects must address the goals and bridge research gaps identified by the TED Steering Committee and its Government Steering Committee (GSC) . Seed Projects, in most cases, will focus on integrated and systematic analysis of the TED Metadataset for either: (i) existing clinical or imaging data, and/or (ii) collection of new data from existing biosamples. Applicants are encouraged to collaborate with private industry partners to leverage resources.

Projects should address one or more of the following goals:

A. Research to support TBI clinical outcome assessment tools that are suitable for use in clinical trials. Currently, almost all severe TBI therapeutic trials use incidents of adverse events (e.g., mortality) as a short-term outcome measure; the GOS, GOS-E, and Disability Rating Scale (DRS) are employed as long-term (3-6 month) primary endpoints for assessing drug efficacy. Most of these tools were developed for more severe forms of TBI, thus they may not be sufficiently sensitive to detect the diverse neurobehavioral deficits that can result from mild/moderate TBI. Validation of additional COAs could help enhance and improve these aspects of TBI clinical trials.

B. Research to support the use of TBI diagnostic biomarkers (blood-based and imaging) for patient stratification that are acceptable for use in therapeutic trials submitted to the FDA; to enrich for TBI populations that might be most responsive to treatment, to ultimately enhance and improve TBI therapeutic trials.

C. Research to support the use of TBI predictive biomarkers for patient stratification that are acceptable for use in therapeutic trials submitted to the FDA; to enrich for TBI patients that are likely to develop persistent post-concussive symptoms, to ultimately enhance and improve TBI therapeutic trials.

D. Research to support the use of pharmacodynamic biomarkers that are acceptable for use in therapeutic trials submitted to the FDA; to track whether therapeutic agents are effectively reaching their targets and exerting beneficial effects. The use of a TBI pharmacodynamic biomarker in conjunction with primary outcome data could provide more detailed insights as to why clinical efficacy is not demonstrated in subsets of subjects and help shed light on future improvements of drug trials of the same or related compounds.