Col. Dallas Hack, U.S. Army

Report
Defense Medical Research and Development Program
Building the foundation and
accelerating the science:
DoD 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
CoMorbidities
Baseline
Function
Therapies
Clinical
Practice
Guidelines
What are
the
effects?
Early
Identification
& Treatment
How was
it injured?
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Lessons Forgotten and Re-Learned
COL Dallas C. Hack M.D.
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Lessons Learned & Re-learned
COL Dallas C. Hack M.D.
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5
Traumatic Brain Injury: Comorbidities
Co-Morbidities Associated with
mTBI and PTSD
Chronic Pain
N=277
81.5%
10.3%
16.5%
2.9%
PTSD
N=232
68.2%
42.1%
12.6%
6.8%
1.9 million *
5.3%
Total: >3.6 million *
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://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
Comorbidity Examples
COL Dallas C. Hack M.D.
Sleep disorders
Vestibular disorders
Substance abuse
Visual disorders
Psychiatric illness
Cognitive disorders
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DoD: Garrison vs. Deployed TBI
DoD TBI Cases Worldwide 2000-2013
Number of TBI Cases Worldwide
30,000
25,000
20,000
15,000
10,000
5,000
0
2000
2001
2002
2003
2004
2005
Garrison Associated
2006
2007
2008
2009
2010
2011
2012
Deployment Associated
• 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
Source: Armed Forces Health Surveillance Center
COL Dallas C. Hack M.D.
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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-DoD 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
DoD 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
DoD releases
2012 MACE and
Concussion
Management
Algorithms
2012
September
DoDI 6490.11
published
August & September
Dizziness and
neuroendocrine CRs
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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)
Mandatory
24-hrs
downtime,
medical eval,
and reporting
Exposure to more than one blast
event (the Service member’s
commander shall direct a medical
evaluation)
COL Dallas C. Hack M.D.
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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)
A Complex and Heterogeneous Disease
COL Dallas C. Hack M.D.
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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.
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A Fragmented Approach to TBI Research
Proteomic
Biomarkers
CT
Genomics
PET
Rehab
MRI
INJURY
OUTCOME
COL Dallas C. Hack M.D.
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Solution: Integration Across Disciplines
and Research Studies
Injury
Characteristics
Patient
Characteristics
COL Dallas C. Hack M.D.
Time
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Big Picture Solutions:
Collaborative, Integrated, Multidimensional Research Networks
Injury
Characteristics
CENC
CENTERTBI
CLEARN
TRACK
-TBI
NCAA
DOD
CRC
TED
NCAA15 yr
Time
GENFL
Patient Characteristics
COL Dallas C. Hack M.D.
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Study Landscape
TRACK-TBI
CENTER-TBI
CENC
Mission
Connect
INTRuST
Canadian Pediatric
Mild TBI Study
ADNI-DOD
Project Head to
Head
NCAA Long term
Follow-up (15 yr)
Army STARRS
NCAA-DoD Grand Challenge
TBI
COL Dallas C. Hack M.D.
6
BTEC Dynamic
Model
12
TED (Endpoints)
YEARS
MONTHS
UNCLASSIFIED
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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. 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 4th edition in
process, to be complete by Spring 2014
COL Dallas C. Hack M.D.
UNCLASSIFIED
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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
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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
COL Dallas C. Hack M.D.
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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
– 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
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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.
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Continuum of TBI Care
Determines Research Approach
RESEARCH NEEDS
RDT&E:
Injury Prevention
1. Basic Science & Epidemiology: 134 studies (77*), $119,199K
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
(DoD Guidelines
5. TBI/
Concussion
Assessment
6. TBI/
Concussion
Treatment
7. TBI/
Concussion
Recovery
Valid RTD
Standards &
Measures of
Rehabilitation
Define and treat
co-morbidities and
chronic effects
8. Return to
Duty
9. Identify,
Monitor for and
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*)
$9,193K
Head Impact/
Blast Injury
Sensors and
Dosimeters
19 studies (8*)
$21,235K
23 October 2013
*Closed Studies as of 1 September 2013
COL Dallas C. Hack M.D.
Objective
Assessments:
Quantitative EEG
(qEEG) and
smooth pursuit
eye tracking.
BANDITS=
biomarker
assessment for
neurotrauma
diagnosis &
improved triage
system.
51 studies (24*)
$97,851K
Cognitive,
Behavioral,
Neurological and
Diffusion Tensor
Imaging (DTI),
Magnetic
Resonance
Spectroscopy
90 studies (39*)
$96,612K
Drugs,
nutraceuticals,
nutrition.
neuromodulation
: (Cranial Nerve
Stimulation)
148 studies (64*)
$253,492K
SOLUTIONS
UNCLASSIFIED
Rehabilitation:
Measures/
markers for
rehabilitation
assessment and
development of
useful rehab
approaches
59 studies (32*)
$72,548K
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*)
$4,764K
13 studies (4*)
$45,892K
531 studies, active 2007-2013
Total investment $720,786K
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DoD 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
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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
COL Dallas C. Hack M.D.
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Questions?
COL Dallas C. Hack M.D.
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