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Author: Dallas C. Hack
More than 30 clinical trials of pharmaceutical products to treat traumatic brain injury (TBI) have failed and the US Food and Drug Administration (FDA) has not approved any diagnostics or therapies for TBI.
Since 2007 the Department of Defense (DOD) has been the largest funder of TBI research. However, any policy recommending use of unapproved regulated medical products can be approved only by the president. The repeated trial failure has had a direct impact on the DOD’s ability to field regulated products for the care of servicemembers who suffer a TBI, whether in combat or in training.
Traumatic brain injury is a continuum of heterogenic insults to the subcellular and cellular structure. The current approach using the Glasgow Coma Scale (GCS) to categorize TBI is the equivalent of describing cancer as mild, moderate, and severe and then expecting that one treatment will cure all cancer.
The use of progesterone to treat TBI has been researched extensively, with more than 200 preclinical studies as well as successful phase I and phase II trials. Yet two high-profile clinical trials to validate the use of progesterone as a treatment for TBI were terminated for futility in 2014 (Manley 2015; Skolnick et al. 2012; Wright et al. 2014).
Analysis showed that the participants, enrolled based on the GCS, were heterogeneous—multiple causes may contribute to the same GCS score, including diffuse axonal injury, diffuse swelling, contusion, and hematoma. In addition, the measure of effect, the Glasgow Outcome Scale Extended (GOSE), was too insensitive to show a significant difference between treatment and control groups. The GOSE is essentially a disability score rather than a strict measure of brain function.1
Another challenge in treating TBI is to understand which cases will have lingering or delayed effects from a blow to the head. Frequently, TBI patients can pass a neurocognitive test within days after the injury, but when challenged more significantly—such as with multitasking or with low levels of hypoxia as experienced at 7,500 feet—they show deficits on the same neurocognitive tests. Functional magnetic resonance imaging (fMRI) and high-density electroencephalography (EEG) show that the brains of these individuals have not returned to normal months later even when the patients appear normal based on the single neurocognitive test administered.
Recent Clinical Trials: Challenges and Analysis
Difficulties experienced in moving TBI-related products through the clinical trial and regulatory process in two diagnostic efforts prompted the DOD to reevaluate the entire paradigm of TBI clinical trials.
Two Challenging Experiences
The first effort, involving a quantitative EEG (QEEG) system (figure 1) with machine learning to screen for changes in brain function after an impact to the head (Ayaz et al. 2015), entailed more than 18 months of discussions with the FDA before arriving at agreement to use the comparison measure of a positive computed tomography (CT) scan and a mutually agreed indication for use. The pivotal trial was successful and the device received clearance from the FDA as an indicator of whether a CT scan was indicated by the New Orleans Criteria. In other words, the QEEG is being compared to a test for brain bleeding, not a test of brain dysfunction. A brain injury involving bleeding is likely more serious than a concussion not involving bleeding.
The second effort, which included a blood test for proteins usually not present without a brain injury (Papa et al. 2012a,b), had a similar course before being cleared to perform the pivotal trial. The 2,000-patient multicenter international clinical trial has now been completed and, if the analysis is successful, an application should be filed, again as a comparison with a CT scan. Previous trials with these biomarkers have shown virtually complete sensitivity but less than 25 percent specificity in mild TBI (GCS 13–152): the blood test simply detected brain injuries that did not have associated bleeding.
Truly a better comparison measure than the CT scan is needed. The difficulty in arriving at agreed measures was judged to be due to the lack of validation trials of other measures according to regulatory standards. The regulatory science is inadequate, but is a reflection of the state of the more general science in the field of TBI.
The TBI field has been very introspective, with numerous analyses of the causes of failed clinical trials (Bullock et al. 2002; Burke et al. 2015; Dickinson et al. 2000; Farin and Marshall 2004; Kabadi and Faden 2014; Li et al. 2014; Loane and Faden 2010; Maas et al. 1999, 2010; Narayan et al. 2002; Tolias and Bullock 2004)—a much higher ratio of review than other fields, such as Alzheimer’s disease or stroke, which each have in excess of 300 failed clinical trials. The results of the analyses have recurring themes; in summary, the main recommendations are to
DOD Efforts to Improve TBI Clinical Trials
The DOD initiated two foundational efforts to solve the fundamental difficulties with past clinical trials. In 2011 the DOD and the Centers for Disease Control and Prevention (CDC) funded a cooperative effort to review the total English language scientific literature with the goal of developing an evidence-based definition of concussion. The review determined that the literature did not provide enough granularity for a definitive definition but served as a first step for a systematic review of “prevalent and consistent indicators,” identified as
(1) observed and documented disorientation or confusion immediately after the event, (2) impaired balance within 1 day after injury, (3) slower reaction time within 2 days after injury, and/or (4) impaired verbal learning and memory within 2 days after injury. [Carney et al. 2014, p. S3]
This is insufficient to define the enrollment criteria for an enriched study cohort. The DOD therefore initiated, in collaboration with the Brain Trauma Foundation, the Brain Trauma Evidence Consortium with the following four mission areas:
The DOD’s second major initiative, the TBI Endpoints Development (TED) consortium, commenced in September 2014 (figure 2). Formulated to address the inadequate endpoints (CT scan and/or GOSE) currently validated for clinical studies of regulated products, this two-phase effort will first evaluate the multitude of existing assessments and select the measures with the highest amount of evidence supporting their use in the regulatory process. Phase two will validate the selected measures with processes that meet the FDA’s qualification process for drug development tools.
Key to this effort is the substantial involvement of the FDA in shaping, selecting, managing, and executing the TED initiative. It is anticipated that TED will lead to an expanded pathway for product approval and enable successful clinical trials that validate products to diagnose and treat TBI.
Other Major Initiatives
The current research landscape includes a wide range of studies—ranging from preclinical to clinical, acute to postmortem, premorbid to long-range effects, and from pilot to large multinational—with funding by government, academic, industry, and nonprofit entities. Following are examples of large studies currently under way:
In addition, as outlined in the National Research Action Plan (DOD/VA/DHHS/DOEd 2013), the principal investigators of larger government studies have coordinated numerous study protocol elements, case report forms, biomarkers, imaging studies, and biospecimens, for the most part contributing all the collected data to the Federal Interagency Traumatic Brain Injury Research (FITBIR; https://fitbir.nih.gov/) data repository. FITBIR is a joint effort of the DOD and NIH that will make federally funded research data available to other researchers through a governance process. This level of coordination and data transparency will allow much more information to be gained from the data collected than the isolated studies of the past.
Two main corrections are needed for future TBI trials: enrichment of the study population and validation of multiple, meaningful primary, coprimary, and secondary endpoints to assess efficacy. These changes, together with diagnostic or therapeutic products developed to address the pathophysiology of the disease process, will lead to approved products and techniques that will improve outcome for the millions who suffer a traumatic brain injury each year.
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Bullock MR, Merchant RE, Choi SC, Gilman CB, Kreutzer JS, Marmarou A, Teasdale GM. 2002. Outcome measures for clinical trials in neurotrauma. Neurosurgical Focus 13(1):ECP1.
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DOD/VA/DHHS/DOEd [Department of Defense/Department of Veterans Affairs/Department of Health and Human Services/Department of Education]. 2013. National Research Action Plan Responding to the Executive Order: Improving Access to Mental Health Services for Veterans, Service Members, and Military Families. Available at https://www.whitehouse.gov/sites/default/files/uploads/ nrap_for_eo_on_mental_health_august_2013.pdf.
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Maas AI, Roozenbeek B, Manley GT. 2010. Clinical trials in traumatic brain injury: Past experience and current developments. Neurotherapeutics 7(1):115–126.
Manley GT. 2015. TBI Endpoints Development (TED) Initiative: A Collaborative for Advancing Diagnosis and Treatment of TBI. Presentation at Consensus Conference 1, February 2–3, Bethesda, MD. Available at https://tbiendpoints.ucsf.edu/sites/tbiendpoints.ucsf. edu/files/Consensus%20Conference%20Slides.pdf.
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Papa L, Lewis LM, Falk JL, Zhang Z, Silvestri S, Giordano P, Brophy GM, Demery JA, Dixit NK, Ferguson I, and 9 others. 2012a. Elevated levels of serum glial fibrillary acidic protein breakdown products in mild and moderate traumatic brain injury are associated with intracranial lesions and neurosurgical intervention. Annals of Emergency Medicine 59:471–483.
Papa L, Lewis LM, Silvestri S, Falk JL, Giordano P, Brophy GM, Demery JA, Liu MC, Mo J, Akinyi L, and 6 others. 2012b. Serum levels of ubiquitin C-terminal hydrolase distinguish mild traumatic brain injury from trauma controls and are elevated in mild and moderate traumatic brain injury patients with intracranial lesions and neurosurgical intervention. Journal of Trauma and Acute Care Surgery 72:1335–1344.
Skolnick BE, Maas AI, Narayan RK, van der Hoop RG, MacAllister T, Ward JD, Nelson NR, Stocchetti N. 2014. A clinical trial of progesterone for severe traumatic brain injury. New England Journal of Medicine 371:2467–2476.
Tolias CM, Bullock MR. 2004. Critical appraisal of neuroprotection trials in head injury: What have we learned? NeuroRx: Journal of the American Society for Experimental NeuroTherapeutics 1(1):71–79.
Wright DW, Yeatts SD, Silbergleit R, Palesch YY, Hertzberg VS, Frankel M, Goldstein FC, Caveney AF, Howlett-Smith H, Bengelink EM, and 303 others. 2014. Very early administration of progesterone for acute traumatic brain injury. New England Journal of Medicine 371:2457–2466.
1 Of note, the participants in both trials had improved outcomes from a traditional standard of care, based on adherence to care protocols.
2 A GCS score of 3–8 denotes a severe brain injury and 9–12 moderate injury.