Defense Medical Research and Development Program Building the

Defense Medical Research and Development Program Building the foundation and accelerating the science: Do. D TBI research The Defense Medical Research and Development Program 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

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 mean recovered 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 COL Dallas C. Hack M. D. UNCLASSIFIED 2

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

Lessons Forgotten and Re-Learned COL Dallas C. Hack M. D. UNCLASSIFIED 4

Lessons Learned & Re-learned COL Dallas C. Hack M. D. UNCLASSIFIED 5

Traumatic Brain Injury: Comorbidities Co-Morbidities Associated with m. TBI and PTSD Chronic Pain N=277 81. 5% 10. 3% 16. 5% 2. 9% PTSD N=232 68. 2% 42. 1% 12. 6% 1. 9 million * 6. 8% 5. 3% Total: >3. 6 http: //www. cdc. gov/traumaticbraininjury/statistics. html million Accessed * 17 Oct 2012 TBI N=227 66. 8% 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: //dx. doi. org/10. 1016/j. jsr. 2012. 08. 011 Accessed 13 Mar 2013 Comorbidity Examples COL Dallas C. Hack M. D. Sleep disorders Vestibular disorders Substance abuse Visual disorders Psychiatric illness Cognitive disorders UNCLASSIFIED 6

Do. D: Garrison vs. Deployed TBI Do. D TBI Cases Worldwide 2000 -2013 Number of TBI Cases Worldwide 30 000 25 000 20 000 15 000 10 000 5 000 0 2001 2002 2003 2004 2005 2006 Garrison Associated 2007 2008 2009 2010 2011 2012 Deployment Associated • 83% of all Do. D TBIs from 2000 -2012 occurred away from combat • Bottom Line: TBI will remain an military concern long after withdrawal from Afghanistan Source: Armed Forces Health Surveillance Center COL Dallas C. Hack M. D. UNCLASSIFIED 7

Timeline: Key TBI Policies October ASD(HA) released a memorandum providing a standard TBI, severity of brain injury stratification, and a uniform reporting process 2006/2007 May Mandatory TBI screening at LRMC for all MEDEVACs April Version 3 of MACE released April-July Driving and Cognitive Rehab CRs April Army and USMC revise Purple Heart criteria April VA-Do. D CPGs 2008 June Army publishes DA EXORD 242 -11 mandating TBI training 2009 Summer MAJ Bell pilots Concussion Care Center at FOB Shank August MACE implemented May Do. D requires mandatory cognitive baselines on SMs (NCAT/ANAM) COL Dallas C. Hack M. D. May NCAT Clinical Recommendation (CR) June DTM 09 -033 signed UNCLASSIFIED May USFOR-A Policy Letter #40, Afghanistan Theater Concussive Care 2011 2010 June Do. D releases 2012 MACE and Concussion Management Algorithms 2012 September Do. DI 6490. 11 published August & September Dizziness and neuroendocrine CRs 8

TBI Theater Policy: Potentially Concussive Events Involvement in a vehicle blast event, collision, or rollover 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) COL Dallas C. Hack M. D. UNCLASSIFIED Mandatory 24 -hrs downtime, medical eval, and reporting 9

Theater TBI Medical Guidance 2012 Military Acute Concussion Evaluation (MACE) COL Dallas C. Hack M. D. 2012 Concussion Management Algorithms (CMAs) UNCLASSIFIED 10

Traumatic Brain Injury: 2014 Classification Outcome GCS GOS (Glasgow Coma Scale) (Glasgow Outcome Scale) Seve d Mil re th a e D Veg etat ery v o c e R d o o G Concussion A Complex and Heterogeneous Disease COL Dallas C. Hack M. D. ive UNCLASSIFIED 11

Disease Classification: Cancer ALL AML bioinformatic analyses Modern disease classification is a mixture of anatomic, cellular, physiologic, metabolic, immunologic, and genetically defined diseases COL Dallas C. Hack M. D. UNCLASSIFIED 12

A Fragmented Approach to TBI Research EE Proteomic Biomarkers CT Genomics G MRI PET Rehab D S T P INJURY OUTCOME COL Dallas C. Hack M. D. UNCLASSIFIED 13

Solution: Integration Across Disciplines and Research Studies Injury Characteristics Patient Characteristics COL Dallas C. Hack M. D. Time UNCLASSIFIED 14

Big Picture Solutions: Collaborative, Integrated, Multidimensional Research Networks Injury Characteristics CENC CENTERTBI CLEARN TRACK -TBI TED NCAADOD CRC NCAA 15 yr Patient Characteristics COL Dallas C. Hack M. D. Time GENFL UNCLASSIFIED 15

Study Landscape TRACK-TBI CENTER-TBI CENC Mission Connect INTRu. ST Canadian Pediatric Mild TBI Study ADNI-DOD Project Head to Head NCAA Long term Follow-up (15 yr) Army STARRS NCAA-Do. D Grand Challenge TBI COL Dallas C. Hack M. D. 6 MONTHS BTEC Dynamic Model 12 TED (Endpoints) YEARS UNCLASSIFIED 16

Brain Trauma Evidence-Based Consortium Current Status of B-TEC Efforts 1. Concussion Guidelines Part 1. Systematic Review of Prevalent Indicators Publication in submission 2. Raw Data Review [Ra. Da. R] First re-analysis of concussed sample [N = 650] complete. Data mining project scheduled for late winter. Draft diagnostic criteria by June. 3. Dynamic Model Initiative First meeting held September 2013. Second meeting to be held January 16 -17, 2014 [Boston]. 4. Collaborations CENC, NCAA, ACR [Epic], TBI-Trac©, Track-TBI, ADAPT, Latin America. 5. Living Guidelines Completed transition of Pediatric Guidelines to new model. Adult guidelines 4 th edition in process, to be complete by Spring 2014 COL Dallas C. Hack M. D. UNCLASSIFIED 17 17

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 COL Dallas C. Hack M. D. UNCLASSIFIED 18

FITBIR Data Repository: Federal Interagency TBI Research A collaboration between NIH and Do. D to develop a biomedical informatics system to accelerate scientific discovery and treatment in Traumatic Brain Injury Database with multiple contributors and multiple accessors COL Dallas C. Hack M. D. UNCLASSIFIED 19 19

Presidential Executive Order 31 Aug 2012: Improving Health Care for Veterans, Service Members, and Military Families Affected by TBI Sec. 5. Improved Research and Development – Do. D, 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 COL Dallas C. Hack M. D. UNCLASSIFIED 20

National Research Action Plan • Response to President Obama’s 2012 Executive Order • Interagency Collaboration: – Do. D, 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 COL Dallas C. Hack M. D. UNCLASSIFIED 21

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

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

Summary • Do. D 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 COL Dallas C. Hack M. D. UNCLASSIFIED 24

Questions? COL Dallas C. Hack M. D. UNCLASSIFIED 25