Defense Medical Research and Development Program

1. Defense Medical Research and Development Program Building the foundation and accelerating the science: DoD TBI research COL Dallas C. Hack M.D. Brain Health/Fitness Research Program Coordinator US Army Medical Research and Materiel Command June 24, 2014 The views expressed in this presentation are those of the author and do not reflect official policy or position of the Department of the Army, Department of Defense or the U.S. Government. I have no relevant financial relationships to disclose. UNCLASSIFIED

2. Bottom Line • TBI is a continuum of extremely heterogeneic insults to the sub cellular and cellular structure and function of the brain; effects can be life-long • Co-morbidities (PTS, Pain, Depression) are more the rule than the exception, complicating study • Currently, physical/mental rest and education are the only validated “treatments” and there are no FDA approved therapies • Regulatory science is inadequate—a reflection of the state of the science in general. Need for validated “endpoints” for both diagnosis and treatment • Because of our limited understanding of the pathobiology, along with a paucity of biomarkers, correlating the human condition with animal models involves a degree of subjective interpretation that is scientifically tenuous and leads to an inability to even compare one model to another • The relationships between TBI, neurodegeneration and Chronic Traumatic Encephalopathy are yet to be clearly defined • Does recovered meanrecovered or does it mean compensated? • Because of the inherent complexity of the CNS, we must be prepared for instances where we must dismiss reductionism and use evidence-based “what works” (i.e. some things may simply not be knowable with current technologies) • Despite all of the above, we DO find ourselves at a “tipping point” where coordinated foundational efforts will establish the basis for future studies and real, evidence-based progress in the diagnosis and treatment of TBI

3. TBI Complexity(120,000 foot view) Clinical Practice Guidelines General Health/ Education Genetics/Epi-genetics TherapiesBiomarkers/Metrics Resilience Family History (violence/abuse/poverty) Co-Morbidities What facilitates recovery? (Epi/Patho/Models/Metrics) What is injured? (Epidemiology/Pathobiology/Models) Who is susceptible? Policy Plasticity Baseline Function Early Identification & Treatment Age & Gender What are the effects? Protective Gear When was the injury? How was it injured?

4. Lessons Forgotten and Re-Learned

5. Lessons Learned & Re-learned

6. Chronic Pain N=277 81.5% Co-Morbidities Associated with mTBI and PTSD 16.5% Traumatic Brain Injury: Comorbidities PTSD N=232 68.2% 2.9% 10.3% 42.1% 12.6% 6.8% 5.3% TBI N=227 66.8% 1.9 million * Total: >3.6 million * Lew, et al: “Prevalence of Chronic Pain, Posttraumatic Stress Disorder, and Persistent Postconcussive Symptoms in OIF/OEF Veterans: Polytrauma Clinical Triad”, Dept. of Veterans Affairs, Journal of Rehabilitative Research and Development, Vol. 46, No. 6, 2009, pp. 697-702, Fig. 1 http://www.cdc.gov/traumaticbraininjury/statistics.html Accessed 17 Oct 2012 *http://dx.doi.org/10.1016/j.jsr.2012.08.011Accessed 13 Mar 2013

7. DoD: Garrison vs. Deployed TBI DoD TBI Cases Worldwide 2000-2013 • 83% of all DoD TBIs from 2000-2012 occurred away from combat • Bottom Line: TBI will remain an military concern long after withdrawal from Afghanistan Number of TBI Cases Worldwide Garrison Associated Deployment Associated Source: Armed Forces Health Surveillance Center

8. Timeline: Key TBI Policies June DoD releases 2012 MACE and Concussion Management Algorithms June Army publishes DA EXORD 242-11 mandating TBI training May Mandatory TBI screening at LRMC for all MEDEVACs April Version 3 of MACE released October ASD(HA) released a memorandum providing a standard TBI, severity of brain injury stratification, and a uniform reporting process April-July Driving and Cognitive Rehab CRs April Army and USMC revise Purple Heart criteria May USFOR-A Policy Letter #40, Afghanistan Theater Concussive Care April VA-DoD CPGs Summer MAJ Bell pilots Concussion Care Center at FOB Shank September DoDI 6490.11 published May NCAT Clinical Recommendation (CR) August MACE implemented May DoD requires mandatory cognitive baselines on SMs (NCAT/ANAM) June DTM 09-033 signed August & September Dizziness and neuroendocrine CRs

9. TBI Theater Policy:Potentially Concussive Events Involvement in a vehicle blast event, collision, or rollover Mandatory 24-hrs downtime, medical eval, and reporting A direct blow to the head or witnessed loss of consciousness Presence within 50 meters of a blast (inside or outside) Exposure to more than one blast event (the Service member’s commander shall direct a medical evaluation)

10. Theater TBI Medical Guidance 2012 Military Acute Concussion Evaluation (MACE) 2012 Concussion Management Algorithms (CMAs)

11. Traumatic Brain Injury: 2014 Classification GCS (Glasgow Coma Scale) Outcome GOS (Glasgow Outcome Scale) Severe Vegetative Death Mild Concussion Good Recovery A Complex and Heterogeneous Disease

12. ALL AML bioinformatic analyses Disease Classification: Cancer Modern disease classification is a mixture of anatomic, cellular, physiologic, metabolic, immunologic, and genetically defined diseases

13. A Fragmented Approach to TBI Research EEG Proteomic Biomarkers CT PET PTSD Rehab Genomics MRI INJURY OUTCOME

14. Solution: Integration Across Disciplines and Research Studies Injury Characteristics Patient Characteristics Time

15. Big Picture Solutions: Collaborative, Integrated, Multidimensional Research Networks CENC CENTER-TBI InjuryCharacteristics C-LEARN TRACK-TBI TED NCAA- DOD NCAA- 15 yr CRC GE- NFL Time Patient Characteristics

16. Study Landscape TRACK-TBI CENTER-TBI CENC Mission Connect INTRuST Canadian Pediatric Mild TBI Study BTEC Dynamic Model ADNI-DOD Project Head to Head NCAA Long term Follow-up (15 yr) Army STARRS NCAA-DoD Grand Challenge TED (Endpoints) YEARS 6 12 TBI MONTHS

17. Brain Trauma Evidence-Based Consortium 17

18. TBI Endpoints Development • A Phased approach involving key research milestones • Purpose: to identify endpoints that would be acceptable to the FDA in their regulatory review of drugs and devices that are being developed for use in the clinical setting to diagnose or treat mild TBI to moderate TBI • Two Stages: • Stage I (Years 1-2) will enable the team to lay the groundwork for the research and conduct studies required to advance the most promising endpoints • Stage II (Years 3-5) will allow the expansion of the project to proceed to larger-scale validation studies

19. FITBIR Data Repository: Federal Interagency TBI Research A collaboration between NIH and DoD to develop a biomedical informatics system to accelerate scientific discovery and treatment in Traumatic Brain Injury Database with multiple contributors and multiple accessors 19

20. Sec. 5. Improved Research and Development DoD, VA, HHS, and Dept of Ed in coordination with the Office of Science and Technology Policy shall establish a National Research Action Plan within 8 months of the date of this order to improve the coordination of agency research of TBI, PTSD, and other mental health conditions to reduce the number of affected men and women through better prevention, diagnosis, and treatment. National Research Action Plan shall: Establish strategies to establish surrogate and clinically actionable biomarkers for early diagnosis and treatment effectiveness Develop improved diagnostic criteria for TBI Enhance understanding of mechanisms responsible for PTSD, related injuries, and neurological disorders following TBI Foster development of new treatments for these conditions based on better understanding of underlying mechanisms Improve data sharing between agencies and academic and industry researchers to accelerate progress and reduce redundant efforts without compromising privacy Make better use of electronic health records to gain insight into the risk and mitigation of PTSD, TBI, and related injuries Include strategies to support collaborative research to address suicide prevention Presidential Executive Order 31 Aug 2012: Improving Health Care for Veterans, Service Members, and Military Families Affected by TBI

21. National Research Action Plan • Response to President Obama’s 2012 Executive Order • Interagency Collaboration: • DoD, VA, HHS, NIDRR (Dept of Education) • Key Themes Specific to TBI Research: • Biomarkers: (Imaging, proteomic, neurophysiologic, etc.) to diagnose and monitor recovery • Diagnosis: more precise classification system, personalized/targeted diagnosis • Mechanisms: increase understanding of neuropathology • Treatment: identify and validate pharmacologic and rehabilitation treatment options

22. 2. TBI/ Concussion Prevention/ Education & Training Recovery Timecourse & Rehabilitation Pharmaceutics & Surgical Technology Portable Fieldable Diagnostic Device (In Theatre & Garrison) Valid Criteria & Objective Servicemembers/ Concussion Screening Tool Define and treat co-morbidities and chronic effects Valid RTD Standards & Measures of Rehabilitation Objective Measure of Head Impact/Blast Exposure Medical Standards for Protective Equipment Continuing Education and Reinforcement for Servicemembers, Leaders and Service Providers Return to Duty/Disability/Reclassification Assessment Neuropathology studies of military TBI 3. Possible Concussive Event (PCE) via Impact or Blast 4. TBI/ Concussion Screening (DoD Guidelines 9. Identify, Monitor for and Treat Late and Chronic Effects Continuum of TBI CareDetermines Research Approach 6. TBI/ Concussion Treatment 5. TBI/ Concussion Assessment 7. TBI/ Concussion Recovery 8. Return to Duty RESEARCH NEEDS Psych Health and Related Symptoms RDT&E: Injury Prevention Combat Casualty Care 1. Basic Science & Epidemiology: 134 studies (77*), $119,199K Objective Assessments: Quantitative EEG (qEEG) and smooth pursuit eye tracking. BANDITS= biomarker assessment for neurotrauma diagnosis & improved triage system. Cognitive, Behavioral, Motor, Sensory, Endocrine effects; Chronic Traumatic Encephalopathy (CTE) and other neuro- degenerative diseases Cognitive, Behavioral, Neurological and Diffusion Tensor Imaging (DTI), Magnetic Resonance Spectroscopy Rehabilitation: Measures/ markers for rehabilitation assessment and development of useful rehab approaches Nutraceuticals, Standards for Helmets, Education/ CPG’s for Servicemembers, Leaders & Service Providers Drugs, nutraceuticals, nutrition. neuromodulation: (Cranial Nerve Stimulation) Improved, objective (and standardized) RTD assessments and guidelines Head Impact/ Blast Injury Sensors and Dosimeters 11 studies (8*) $9,193K 19 studies (8*) $21,235K 51 studies (24*) $97,851K 90 studies (39*) $96,612K 148 studies (64*) $253,492K 59 studies (32*) $72,548K 6 studies (4*) $4,764K 13 studies (4*) $45,892K 23 October 2013 *Closed Studies as of 1 September 2013 531 studies, active 2007-2013 Total investment $720,786K SOLUTIONS

23. DoD Joint Program Committee Strategic Research Planning Process Requirement-based Capability Gap Prioritization Research Gaps Identification User Needs and State of Practice Analysis State of Science/Research Strategic Planning Research Prioritization Factors (Portfolio Balance, Political, Intramural Lab Capabilities, etc.) Resource Allocation (DHP, Army, SBIR) Research Prioritization Implementation Barriers Analysis (Manpower, Federal Acquisitions Regulation, Budget Related, Size of Portfolio) Program Announcements/ Requests for Proposals/Broad Agency Announcement Implementation Plan Review and Analysis (Army, Navy, Air Force, Marines, VA, ASD/HA, NIH, NIMH, Academic Subject Matter Experts) • Portfolio Analysis • Create database • Analyze Intramural and Extramural Investments • Identify Areas for Resolution • Identify Findings for Transition Transition of select Materiel Solutions to Advanced Development Dissemination of knowledge/ Clinical Practice Guidelines

24. Summary • DoD uses a “continuum of care” model to achieve a comprehensive approach • Objective diagnostics and pharmaceutical treatment represent the largest areas of research investment • Several capabilities have been identified as showing promise for use in the clinic • Imaging, neuroplasticity, and rehabilitation represent the nearest promising research investments • Objective measures of response to treatment remain a focus for accelerating recovery • Partnerships with the VA, NIH, academia, and industry remain vital to success

25. Questions?