Defense Medical Research and Development Program Building the foundation and accelerating the science: DoD TBI research

The Defense Medical Research and Development Program

Defense Medical Research and Development Program

Building the foundation and accelerating the science:

DoD TBI researchCOL 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


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


Lessons Forgotten and Re-Learned


Lessons Learned & Re-learned


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 ExamplesSleep disorders Vestibular disorders

Substance abuse Visual disorders

Psychiatric illness Cognitive disorders

Total: >3.6 million *


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 o

f TB

I Cas

es

Wor

ldw

ide

Source: Armed Forces Health Surveillance Center

DoD TBI Cases Worldwide 2000-2013


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


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


Theater TBI Medical Guidance2012 Concussion Management

Algorithms (CMAs)2012 Military Acute Concussion

Evaluation (MACE)


Traumatic Brain Injury: 2014

ClassificationGCS

(Glasgow Coma Scale)

OutcomeGOS

(Glasgow Outcome Scale)

Mild

Severe

Concussion

DeathVegetative

Good Recovery

A Complex and Heterogeneous Disease


Disease Classification: Cancer

bioinformatic analyses

AMLALL

Modern disease classification is a mixture

of anatomic, cellular, physiologic, metabolic,

immunologic, and genetically defined diseases


INJURYOUTCOME

A Fragmented Approach to TBI Research

Genomics MRI

CT

PTSDRehabPET

Proteomic Biomarkers

EEG


Solution: Integration Across Disciplines and Research Studies

InjuryCharacteristics

TimePatient

Characteristics


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


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


17

Brain Trauma Evidence-Based Consortium

Current Status of B-TEC Efforts1. 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 GuidelinesCompleted transition of Pediatric Guidelines to new model. Adult guidelines 4th edition in process, to be complete by Spring 2014


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

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


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


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


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


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


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


Questions?

Documents

Defense Medical Research and Development Program Building the foundation and accelerating the science: DoD TBI research