Posted September 27, 2017

Geoffrey Manley, Ph.D., University of California, San Francisco

Traumatic brain injury (TBI) is one of the most common injuries suffered by active duty Service members, with mild TBI accounting for 15-20% of combat deployment-related injuries during Operations Iraqi and Enduring Freedom. TBI may cause significant morbidity, affecting a person's physical, cognitive, emotional, psychological, and social well being. Researchers have spent years trying to identify better ways to diagnose and treat TBI. For the last two decades, numerous therapeutics and diagnostic devices that have shown promise in pre-clinical animal models have failed in clinical efficacy trials. As such, these clinical trials have yielded no new US Food and Drug Administration (FDA)-approved therapeutics or devices for the treatment and diagnosis of acute TBI. The clinical trial failures for TBI to date have been attributed to the complex and heterogeneous nature of TBI; this has hindered the identification of appropriate biomarker and outcome measures in the targeted population to address specific contexts of use for the targeted drugs and devices. Many of the outcome measures used in trials to date are not well characterized and validated across the spectrum of injury. Currently, patients are classified into three TBI severity categories: mild, moderate, or severe, based on the Glasgow Coma Scale (GCS). These three categories are insufficient and do not take into account pathophysiology of injury. The Glasgow Outcome Scale-Extended (GOS-E) is the gold standard primary outcome measure that is currently used in clinical trials, but it does not adequately measure or discriminate improvements in outcomes.

To encourage collaboration and accelerate research toward the discovery of new diagnostics and therapeutics for TBI, the FDA launched the Critical Path Initiative (CPI) in 2004. In response to the CPI, the US Department of Defense�s (DoD) Joint Program Committee 6/Combat Casualty Care Research Program offered the Fiscal Year 2013 (FY13) TBI Endpoints Development (TED) Award mechanism to solicit applications proposing a collaborative, multidisciplinary research effort focused on improving the diagnosis and treatment of TBI. The team, led by Dr. Geoffrey Manley of the University of California, San Francisco, was the awardee of the TED Initiative. The TED research team consists of leading academic clinician-scientists, as well as industry leaders in biotechnology and image technology, patient advocacy organizations, regulatory authorities at the FDA, and philanthropies. The TED Initiative works cooperatively with and leverages resources from the Transforming Research and Clinical Knowledge in TBI (TRACK-TBI), Chronic Effects of Neurotrauma Consortium (CENC), and Concussion Research Consortium (CRC). The TED Initiative aims to identify clinical outcome assessments (COAs) and blood-based and neuroimaging biomarkers to develop more precise TBI diagnostic tools, clinical endpoints, and effective TBI therapies. In addition, the TED Initiative strives to accelerate the validation of TBI drug and device development processes in the context of regulatory science.

A comprehensive overview of accomplishments from the TED Initiative was recently published in the Journal of Neurotrauma.¹ Over the past 2 years, the TED Initiative�s expert working groups (EWGs) in neuroimaging, blood-based biomarkers, and clinical outcome assessments (COAs) have enhanced collaboration through conferences, initiated seed projects, and curated and harmonized the seven study TED Metadataset, with diverse data that will be sufficiently powered to discern signals between and among neuroimaging and blood-based biomarkers as well as COAs. Two TBI Consensus Conferences were held by the TED Initiative in February 2015 and April 2017. A proposal focused on prognostic neuroimaging biomarkers submitted by members of the Neuroimaging EWG to the FDA�s Medical Device Development Tools (MDDT) Program was the first proposal to be accepted by the Center for Devices and Radiological Health (CDRH) into the Incubator Phase of the MDDT Pilot Program, and is now moving toward the validation phase. Moreover, the FDA has recognized the role and efforts of the TED Initiative in advancing TBI regulatory science via two major communications: a Letter of Support from the Center for Drug Evaluation and Research and a Recognition of Research Support Letter from the CDRH.

Beginning in early 2016, during Phase I of the effort, the TED Government Steering Committee selected four short term seed projects (summarized below). The seed projects were designed to advance regulatory validation studies of biomarkers and COAs through the use of the TED Metadataset and leveraging of the ongoing efforts in TRACK-TBI, CENC, and CRC.

1. Dr. Joe Giacino at Harvard Medical School/Spaulding Rehabilitation Hospital developed an evidence-based COA platform (EBCOP) which evaluates the validity of a given COA within a specific context of use. Dr. Giacino expects the algorithm, currently in pilot testing, will be able to be a drug development tool that will help researchers and clinicians determine the suitability of specific outcomes with respect to the objectives of clinical trials.
2. Cognition is an ideal endpoint measure for many potential drug interventions in TBI. While there are a large number of cognitive endpoints in the field, none are well defined with wide acceptability and validity for TBI. Dr. Grant Iverson at Harvard Medical School/Spaulding Rehabilitation Network seeks to address this gap by developing and validating composite cognition endpoints with wide functional ranges and appropriate sensitivity for TBI drug trials.
3. In the advancement of TBI blood-based biomarkers, a major challenge is regulatory readiness for these candidate biomarkers, partially due to the fact that multiple assays use different biomarker references, which complicates cross-validation of results. Complete assay performance characteristics and comparability of recombinant versus naturally occurring human biomarkers are not well established. The TED seed project led by Dr. Kevin Wang at the University of Florida, is working toward addressing gaps for a series of candidate biomarkers. The results of this work will benefit researchers, advanced developers, and biotechnology firms that are currently working toward FDA approval of biomarker assays.
4. In the context of brain injury, computed tomography (CT) positive versus negative findings are the only FDA-accepted biomarkers for use in clinical trials. Currently, no neuroimaging technique, however, has sufficient resolution for proper stratification of injury grade in TBI. Dr. Esther Yuh at the University of California, San Francisco and colleagues seek to address this critical biomarker gap by establishing CT and magnetic resonance imaging (MRI) prognostic biomarkers for mild to moderate TBI. As a part of this effort, the TED team has been able to work with the FDA as part of the CDRH MDDT program. This is a significant first step in establishing improved neuroimaging biomarkers for TBI that can be used to improve clinical trial design and outcome.

Phase II of the TED Initiative will continue efforts to advance the most promising TBI outcomes, with respect to regulatory science, and is moving forward on a fifth sub-study: Although the TED Metadataset is a rich resource of TBI data it is limited by a lack of robust control data, a near-universal gap in the field of TBI. To the cohort of matched orthopedic injury populations already being collected as part of the TRACK-TBI study, with critical funding from DoD, the TED Initiative team is leveraging the TRACK-TBI network to collect uninjured patient control data, or "friend" controls. The orthopedic injury and friends control datasets will greatly improve the robustness of the TED Metadataset for use in the TED Initiative and other efforts.

Recent results published in the Journal of Neurotrauma² highlight the need for a multidimensional set of outcome domains that include neurocognitive and emotional functioning in order to obtain a more comprehensive understanding of TBI recovery. Additionally, use of these outcome domains will improve the selection of key clinical outcome measures for TBI research and clinical trials. Earlier this year, TED Initiative investigators presented work from both the TED Initiative and the related TRACK-TBI efforts at the National Neurotrauma Society Meeting (July 2017) and plan to present work at the Military Health Systems Research Symposium (August 2017).

By the time of its anticipated completion in 2019, the TED Initiative plans to have validated diagnostic endpoints that will not only improve TBI diagnosis at the point of injury, but also influence outcome measures for TBI clinical trials and TBI recovery. In addition, the TED Initiative aims to create a streamlined process for FDA endorsement of novel biomarkers and outcome measures. This multidisciplinary effort, which includes collaboration with the Critical Path Institute (C-Path), enables integration of information from the TED Initiative and the C-Path�s Coalition Against Major Diseases, with the intention of applying relevant findings to other neurological diseases.

Publications:

¹Manley GT, Mac Donald CL, Markowitz AJ, et al. 2017. The traumatic brain injury endpoint development (TED) initiative: progress on a public-private regulatory collaboration to accelerate diagnosis and treatment of traumatic brain injury. J. Neurotrauma. 2017 March 31. (epub ahead of print).

²Nelson LD, Ranson J, Ferguson AR, et al. 2017. Validating multidimensional outcome assessment using the TBI common data elements: an analysis of the TRACK-TBI pilot sample. J. Neurotrauma. 2017 June 8. (epub ahead of print).

Links:

Public and Technical Abstracts: TBI Endpoints Development (TED)

http://tbiendpoints.ucsf.edu

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