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Transcript of The Defense Medical Research and Development Program Defense Medical Research and Development...
The Defense Medical Research and Development Program
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 CoordinatorUS 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
COL Dallas C. Hack M.D. 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 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 3
TBI Complexity(120,000 foot view)
Who is susceptible?
What is injured?
(Epidemiology/Pathobiology/
Models)
What facilitates recovery?
(Epi/Patho/Models/Metrics)
Genetics/Epi-
genetics
Co-Morbidities
Baseline Function
Age & Gender
Protective Gear
Family History
(violence/abuse/poverty)
When was the injury?
How was it injured?
What are the
effects?
Resilience
PlasticityPolicy
TherapiesBiomarkers/
Metrics
GeneralHealth/
Education
Early Identification & Treatment
Clinical Practice
Guidelines
COL Dallas C. Hack M.D. UNCLASSIFIED 6
Co-Morbidities Associated with mTBI and PTSD
PTSD N=23268.2%
2.9%16.5%
42.1%
6.8%
5.3%
10.3%
12.6%
TBIN=22766.8%
Chronic Pain N=27781.5%
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
Traumatic Brain Injury: Comorbidities
http://www.cdc.gov/traumaticbraininjury/statistics.html Accessed 17 Oct 2012
*http://dx.doi.org/10.1016/j.jsr.2012.08.011 Accessed 13 Mar 2013
1.9 million *
Comorbidity Examples
Sleep disorders Vestibular disorders
Substance abuse Visual disorders
Psychiatric illness Cognitive disorders
Total: >3.6 million *
COL Dallas C. Hack M.D. UNCLASSIFIED 7
2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 20120
5,000
10,000
15,000
20,000
25,000
30,000
Garrison Associated Deployment Associated
DoD: Garrison vs. Deployed TBI
• 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
Num
ber
of T
BI
Cas
es
Wor
ldw
ide
Source: Armed Forces Health Surveillance Center
DoD TBI Cases Worldwide 2000-2013
COL Dallas C. Hack M.D. UNCLASSIFIED 8
Timeline: Key TBI Policies
2006/2007 2008 2009 2010 2011 2012
OctoberASD(HA) released a memorandum providing a standard TBI, severity of brain injury stratification, and a uniform reporting process
AprilArmy and USMC revise Purple Heart criteria
AprilVersion 3 of MACE released
JuneArmy publishes DA EXORD 242-11 mandating TBI training
MayDoD requires mandatory cognitive baselines on SMs (NCAT/ANAM)
JuneDTM 09-033 signed
SeptemberDoDI 6490.11 published
JuneDoD releases 2012 MACE and Concussion Management Algorithms
AugustMACE implemented
MayMandatory TBI screening at LRMC for all MEDEVACs
SummerMAJ Bell pilots Concussion Care Center at FOB Shank
MayUSFOR-A Policy Letter #40, Afghanistan Theater Concussive Care
AprilVA-DoD CPGs
MayNCAT Clinical Recommendation (CR)
April-JulyDriving and Cognitive Rehab CRs
August & SeptemberDizziness and neuroendocrine CRs
COL Dallas C. Hack M.D. UNCLASSIFIED 9
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)
Mandatory 24-hrs
downtime, medical eval, and reporting
COL Dallas C. Hack M.D. UNCLASSIFIED 10
Theater TBI Medical Guidance
2012 Concussion Management Algorithms (CMAs)
2012 Military Acute Concussion Evaluation (MACE)
COL Dallas C. Hack M.D. UNCLASSIFIED 11
Traumatic Brain Injury: 2014
ClassificationGCS
(Glasgow Coma Scale)
OutcomeGOS
(Glasgow Outcome Scale)
Mild
Severe
Concussion
DeathVegetative
Good Recovery
A Complex and Heterogeneous Disease
COL Dallas C. Hack M.D. UNCLASSIFIED 12
Disease Classification: Cancer
bioinformatic analyses
AMLALL
Modern disease classification is a mixture
of anatomic, cellular, physiologic, metabolic,
immunologic, and genetically defined diseases
COL Dallas C. Hack M.D. UNCLASSIFIED 13
INJURYOUTCOME
A Fragmented Approach to TBI Research
Genomics MRI
CT
PTSDRehabPET
Proteomic Biomarkers
EEG
COL Dallas C. Hack M.D. UNCLASSIFIED 14
Solution: Integration Across Disciplines and Research Studies
InjuryCharacteristics
TimePatient
Characteristics
COL Dallas C. Hack M.D. UNCLASSIFIED 15
Big Picture Solutions: Collaborative, Integrated, Multidimensional Research Networks
NCAA-
DOD
CENTER-TBI
TRACK-TBI
C-LEARN
NCAA-15 yr
CRC GE-NFL
TED
CENC
Time
Patient Characteristics
InjuryCharacteristics
COL Dallas C. Hack M.D. UNCLASSIFIED 16
Study Landscape
126MONTHS
YEARSTBI
TRACK-TBI
CENTER-TBI
MissionConnect
ADNI-DOD
NCAA Long term Follow-up (15 yr)
INTRuST
CENC
Canadian Pediatric Mild TBI Study
Project Head to Head
Army STARRS
NCAA-DoD Grand ChallengeTED (Endpoints)
BTEC Dynamic Model
COL Dallas C. Hack M.D. UNCLASSIFIED 17
17
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 [RaDaR]
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. CollaborationsCENC, NCAA, ACR [Epic], TBI-Trac©, Track-TBI, ADAPT, Latin America.
5. Living GuidelinesCompleted transition of Pediatric Guidelines to new model. Adult guidelines 4th edition in process, to be complete by Spring 2014
COL Dallas C. Hack M.D. UNCLASSIFIED 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
COL Dallas C. Hack M.D. UNCLASSIFIED 19
19
Database with multiple contributorsand multiple accessors
A collaboration between NIH and DoD to develop a biomedical informatics system to accelerate scientific discovery and treatment in Traumatic Brain Injury
FITBIR Data Repository: Federal Interagency TBI Research
COL Dallas C. Hack M.D. UNCLASSIFIED 20
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
– 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
COL Dallas C. Hack M.D. UNCLASSIFIED 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
COL Dallas C. Hack M.D. UNCLASSIFIED 22
Return to Duty/Disability/Reclassification AssessmentContinuing Education and Reinforcement for Servicemembers, Leaders and Service Providers
Continuum of TBI CareDetermines Research Approach
RESEARCH NEEDS
SOLUTIONS
RDT&E: Injury Prevention Combat Casualty Care
Psych Health and Related Symptoms
19 studies (8*)$21,235K
51 studies (24*)$97,851K
90 studies (39*)$96,612K
148 studies (64*)$253,492K
6 studies (4*)$4,764K
59 studies (32*)$72,548K
531 studies, active 2007-2013Total investment $720,786K
Head Impact/ Blast InjurySensors and Dosimeters
Improved, objective (and standardized)
RTD assessments and guidelines
Drugs, nutraceuticals,
nutrition. neuromodulation: (Cranial Nerve
Stimulation)
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
Objective Assessments:
Quantitative EEG (qEEG) and
smooth pursuit eye tracking.
BANDITS= biomarker
assessment for neurotrauma diagnosis &
improved triage system.
Neuropathology
studies of military
TBI
Cognitive, Behavioral,
Motor,Sensory,
Endocrine effects; Chronic
Traumatic Encephalopathy (CTE) and other
neuro-degenerative
diseases
13 studies (4*)$45,892K
9. Identify, Monitor for and Treat Late and
Chronic Effects
8. Return to Duty
7. TBI/ Concussion
Recovery
6. TBI/ Concussion Treatment
5. TBI/ Concussion Assessment
4. TBI/ Concussion Screening
(DoD Guidelines
3. Possible Concussive
Event (PCE) via Impact or Blast
2. TBI/ Concussion Prevention/ Education &
Training
Medical Standards for Protective
Equipment
Objective Measure of Head
Impact/Blast Exposure
Valid Criteria & Objective
Servicemembers/ Concussion
Screening Tool
Portable Fieldable Diagnostic Device
(In Theatre & Garrison)
Pharmaceutics & Surgical Technology
Recovery Timecourse & Rehabilitation
Valid RTD Standards & Measures of
Rehabilitation
Define and treat co-morbidities and chronic effects
23 October 2013*Closed Studies as of 1 September 2013
11 studies (8*)$9,193K
1. Basic Science & Epidem
iology: 134 studies (77*), $119,199K
COL Dallas C. Hack M.D. UNCLASSIFIED 23
DoD Joint Program CommitteeStrategic Research Planning Process
User Needs and State of Practice Analysis
Requirement-based Capability Gap Prioritization
Research Prioritization Factors(Portfolio Balance, Political, Intramural Lab Capabilities,
etc.)Research Prioritization
Strategic Planning
Portfolio Analysis• Create database• Analyze
Intramural and Extramural Investments
• Identify Areas for Resolution
• Identify Findings for Transition
Implementation Plan
Implementation Barriers Analysis
(Manpower, Federal Acquisitions Regulation, Budget Related, Size of
Portfolio)
Resource
Allocation(DHP, Army,
SBIR)
State of Science/Research
Research Gaps Identification
Review and Analysis(Army, Navy, Air Force, Marines,
VA, ASD/HA, NIH, NIMH, Academic Subject Matter
Experts)
Program Announcements/
Requests for Proposals/Broad
Agency Announcement
Transition of select Materiel Solutions to
Advanced Development
Dissemination of knowledge/ Clinical Practice Guidelines
COL Dallas C. Hack M.D. UNCLASSIFIED 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