Chemical and Biological Defense Program (CBDP):

Capabilities for Countering the Threat

MG Donna Barbisch, USA

Director, CBRN Integration

April 26, 2005

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Chemical and Biological Defense Program (CBDP) Program Organization

DATSD(CBD)

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An Integrated Systems Approach toCounter the Threat

CB Threats & HazardsCB Threats & Hazards

AgentDeliveryAgent

DeliveryDoses on

TargetDoses on

Target

DownwindDispersal

DownwindDispersal

DosesAbsorbed

DosesAbsorbed

SymptomsSymptoms

Sustained Combat PowerSustained Combat Power

Medical Pretreatment

ContaminationAvoidance andNBC Battle Management(Detection, Identification, Reconnaissance & Warning)

Individual & Collective Protection

Decontamination,Restoration

Medical Treatment

Information Systems

Installation ForceProtection

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Chemical Biological Defense Program Paradigm Shift

Prior to the transformation, the major focus to provide improved capabilities for the warfighter to survive, fight, and win on any battlefield contaminated with chemical and biological weapons.

The current paradigm shift directs both a broadening and deepening of the CBDP. • CBRN consequence management (about 1997) • Force protection (in 1999)• Homeland Defense (in 2002)• Visibility of “radiological and nuclear” aspects of the program (2003)• Inclusion of the US Coast Guard• Transition from Threat Based to Capabilities Based Process

This broadening requires a carefully developed program strategy to ensure that warfighter capabilities are maintained and advanced concurrently with these added missions.

Chemical and Biological Defense:

Strategic Framework

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DoD Mission

Provide integrated chemical and biological defense capabilities

to effectively execute the National Military Strategy.

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Strategic Imperatives

• Eliminate technological surprise.

• Make the threat irrelevant.

• Detect the threat.

• Protect against the threat.

• Eliminate the threat.

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Enabling the Vision

• Doctrine

• Organization

• Training

• Materiel

• Leader development

• Personnel

• Facilities

Oversight – Coordination – Integration Oversight – Coordination – Integration

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Transforming

• New Team Focused on:

– Defining Equities Across DoD

– Streamlining Processes

– Synchronizing Effort

– Improving Efficiency

– Optimizing Capability

– Promoting Interoperability

BOTTOM LINE: EFFECTIVE SOLUTIONS

IN THE HANDS OF THE USER

Behind the Scenes of Drug Development

Drug Candidatesafety testing

Animal Studies- relevant species - transgenic KO/KI

mice- conditional KOs

- agonists/antagonists- antibodies- antisense

- RNAi

Studies ofDisease Mechanisms

Human Studies Phases I,II, III

Target-receptor; -ion channel; -transporter;

-enzyme; - signalling molecule

Lead Search-Develop assays (use of automation)

-Chemical diversity-Highly iterative processMolecular Studies

The Drug Discovery Process

Lead optimization-selectivity

-efficacy in animal models-tolerability: AEs mechanism-

based or structure-based?-pharmacokinetics

-highly iterative process

Drug Approvaland Registration

Target selection & validation

Discovery Development

Development

Pharmaceutical R&DFormulation

Clinical Investigator& patient

Clinical PharmacologyClinical Research

Statistics & EpidemiologyData Coordination

Research Information SystemsInformation Services

Regulatory AffairsProject Planning & Management

Marketing

Process R&DChem Eng. R&DManufacturing

Bio Process R&D

Safety AssessmentToxicology

Drug Metabolism(ADME)

Pharmacology

Pre-Clinical

Clinical

Target Selection & Validation

• Define the unmet medical need (disease)

• Understand the molecular mechanism of the disease

• Identify a therapeutic target in that pathway (e.g gene, key enzyme, receptor, ion-channel, nuclear receptor)

• Demonstrate that target is relevant to disease mechanism using genetics, animal models, lead compounds, antibodies, RNAi, etc.

Discovery

• Develop an assay to evaluate activity of compounds on the target

- in vitro (e.g. enzyme assay)

- in vivo (animal model or pharmacodynamic assay)

• Identify a lead compound

– screen collection of compounds (“compound library”)

– compound from published literature

– screen Natural Products

– structure-based design (“rational drug design”)

• Optimize to give a “proof-of-concept” molecule—one that shows efficacy in an animal disease model

• Optimize to give drug-like properties—pharmacokinetics, metabolism, off-target activities

• Safety assessment, Preclinical Candidate!!!

Clinical Trials

Product Profile Marketing SOIProduct Profile Marketing SOI

Information Learned

1. Absorption and metabolism

2. Effects on organs and tissue

3. Side effects as dosage is increased

Information Learned

1. Effectiveness in treating disease2. Short-term side effects in health -impaired patients

3. Dose range

Information Learned

1. Benefit/risk relationship of drug

2. Less common and longer term side effects

3. Labeling information

Compassionate Use

Phase IISeveral hundred health-impaired patients

Treatment Group Control Group

Phase IIIHundreds or thousands of health-

impaired patients

InvestigationalNew Drug application

IND

Phase I20 - 100 healthy volunteers take

drug for about one month

Remote data entry

Clinical Trials

Continued

Clinical Trials

ContinuedAPPROVALPROCESS

(Ex. FDA)

Reviews,comments, and

discussions

Drug Co./Regulatoryliaison activities

APPROVAL

Submit toRegulatory Agencies

AdvisoryCommittee Regulatory

Review Team

New DrugApplication

(NDA)

Worldwide Marketing Authorization (WMA) in other countries

Drug Discovery—Convergence of Disciplines

Patent LawCombinatorialChemistry

SyntheticChemistry

PhysicalChemistry

Physiology

Biochemistry

DMPK

Enzymology

Immunology

Pharmacology

InformationTechnology

Modelling

Physiology

SafetyAssessment

Metabolism

Pharmacology

Pathology

Behavior

NovelMolecule

Intellectual Property

StructuralActivity

PharmacokineticProperties

In Vivo activity

Safety

Design

Pharmaco-

dynamics

Physiology

Physiology

Physiology

Assignment of Drug Review

New Drug Development Process

Pre-Clinical Research• Making the drug

– Synthesis and Purification

– Complicated, time-consuming, costly

• Animal Testing

– 2 or more species; 1 rodent, 1 non-rodent

– Short-term Testing; 2 weeks to 3 months

– Long-term Testing; Few weeks – several years

New Drug Development Process

NDA• Bumps in the Road

– If FDA decides that the benefits of a drug outweigh the risks, the drug will receive approval and can be marketed in the US.

– But, if FDA decides there are problems with the NDA or if more information in necessary to make a determination, the FDA may decide that a drug is “approvable” or “not approvable.”

New Drug Development Process

NDA• File New Drug Application

– Formal step that a sponsor takes to ask that the FDA consider approving a new drug for marketing in the US

– NDA includes all animal and human data and analyses of the data, as well as information about how the drug behaves in the body and how it is manufactured

– FDA Review Period: Std 10 mo; Fast Track: 6 mo (priority)

Summary Overview of Phases and Process of Drug Development

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New Drug Development Process

IND

• Phase 1 Clinical Studies

– Initial introduction of drug into humans

– Usually conducted in healthy volunteers

– Typical range, 20 to 80 subjects

– Primary purpose is “Safety”

• Drug side effects, metabolism and excretion

New Drug Development Process

IND• Phase 2 Clinical Studies

• Emphasis is on effectiveness (50-300)

• Obtain preliminary data on whether drug works in people with disease or condition

– Controlled trials [active drug vs. inactive substance (placebo) or different drug]

• Safety continues to be evaluated

• Sponsor/FDA Meeting (“End of Phase 2”)

New Drug Development Process

IND• Phase 3 Clinical Studies

– Phase 3 begins if evidence of effectiveness is present in Phase 2 [generally 2 adequate well-controlled studies]

– No. of subjects:

• Few hundred to 3000

• Orphan pop. = rare disease

• Study different dosages

– Studies gather more information on safety and effectiveness

New Drug Development Process

NDA• Phase 4 Studies

– Post-marketing study commitments are studies required of or agreed to by a sponsor that are conducted after FDA has approved a product for marketing. Additional data on a product’s safety, efficacy, or optimal use.

New Drug Development Process

IND

• Institutional Review Board (IRB)

– Protection of human subjects in clinical trials

– Written informed consent (signed) before study begins

New Drug Development Process

IND

Pre-IND Meeting

• Sponsor/FDA Meeting

– Early stage meetings provides opportunity to discuss data requirements and resolve any scientific issues prior to IND submission

Summary

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FY06 President’s Budget(DoD CB Defense Program + Defense Health Program for Construction of

USAMRIID Improvements)

0

100

200

300

400

500

600

700

800

900

1,000

1,100

1,200

1,300

1,400

1,500

1,600

1,700

1,800

FY04 FY05 FY06 FY07 FY08 FY09 FY10 FY11

($ in

mill

ion

s)

CBDP Science & Technology Base

CBDP Advanced Development

CBDP Procurement

Defense Health Program Military Construction (USAMRIID)

Budget Request

FY06 Highlights• Near-Term Shift in Emphasis to Address Future Challenges (NTAs,

Emerging Threats) and Improve the T&E Infrastructure• Long term trend to Provide Advanced Capabilities to the Warfighter

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Enhanced Planning Process (EPP) Results

T&E Infrastructure Improvements

RDT&E Improvements

• CB T&E Facilities• NTA Test Chamber• USAMRIID (DHP)

Additional Emphasis:• S&T for NTA detection• Bio point and standoff detection• Medical Prophylaxis• Battle Analysis• Decontamination • Bio Defense Initiatives • Chem point detection

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T&E Infrastructure Investment

High Containment BL4 lab, USAMRIID

Fort Detrick MD

High Containment BL4 lab, USAMRIID

Fort Detrick MD

CB Simulant Test GridDugway Proving Ground UT

CB Simulant Test GridDugway Proving Ground UT

Aerosol exposures test chamber

Fort Detrick, MD

Aerosol exposures test chamber

Fort Detrick, MD

CB Aerosol Test Chamber Fort Detrick, MD

CB Aerosol Test Chamber Fort Detrick, MD

Explosive test(simulant only)Explosive test(simulant only)

“Bang Box”, Dugway“Bang Box”, Dugway

Man In Simulant Test (MIST) Chamber

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The ProblemSlow drug development process leads to economic

andsocial catastrophe jeopardizing national security

10+ years > $800M

Early StageResearch

LeadDiscovery

PreclinicalDevelopment

Clinical DevelopmentProduction Models

FDAApproval

2+ years 2-5 years 5-8 years 1 year

ProductionProcurement

10+ years

No national strategy, clear responsibility or federal funding to shorten this cycle

Bioshield

Attack with new threat

Safe & effectivecountermeasure

DHS funds toNIAID

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R&D - Test and Evaluation

VaccinesDrugsDiagnostics

Vaccine/Drug Development

IndustryIndustry

AcademiaAcademia

Genomics/ProteomicsGenomics/Proteomics

Other Government ResearchOther Government Research

Testing/Proofing

Process

Industry

Vaccine/Drug Discovery

Testing Bottleneck

NIAID/NIHNIAID/NIH

DoD/Military tech baseDoD/Military tech base

Process

ProductionDistributionStorage

FDA-Licensed

Funding has increasedFor the “Attractive Work”

Funding is neededFor the “Unglamorous Work”

BioShieldDoD

Basic ResearchBasic Research

DHS/NBACCDHS/NBACC

• GLP• GMP• Phase 1 Safety

trials

ProductTransition

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Today’s ThreatsAnthrax

Smallpox

Botulinum

Plague

Tularemia

Ebola/Filo

Hemorrhagic Fever

Encephalitis

SARS

Influenza

Ricin/SEB, others

Future Emphasis:Systems Biology

Bioengineered

Modes of ActionReceptor Binding

Signal Transduction

Decoys

Immune Avoidance

Translation/Transcription

Immune Deregulation

Replication

Virulence Expression

SolutionsTarget Agent Commonalities• Block Key Receptors• Inhibition by Small Molecules • Modulate Immunity• Change Gene Expression• Block Protein Actions• Modulate Physiologic Impacts

One PIECE at a time Broad SpectrumProcess Analysis

ParallelSystemsApproach

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Viral Disease

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Broad Spectrum Therapies for Novel Biodefense Threats

• $100M funding in FY06- Budget Activities BA1-BA5 - 76% in Science and Technology Base

• Transformational Approaches will be applied – leverage genomics, proteomics and systems biology data explosion

• Technical and program advisory leadership from team of nationally recognized experts - BW defense, microbiology, drug development- Will draw heavily from commercial and academic performers

• Basic Research/Science ($28M)- Directed at common pathways (modes of action) in pathogen host

response- Find novel intervention points

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Broad Spectrum Therapies for Novel Biodefense Threats (Cont’d)

• Applied Research/Science ($18M)- Directed at expanding technologies- Speed the cycle from discovery to license application

• Advanced Science/Tech Development ($30M)- Aimed at quick wins based on new compounds and

technology approaches demonstrating current success- Strategy to deliver products with IND approval (Phase 1

trials) for BioShield acceptability and further investment

• Advanced Component Development and System Demonstration ($24M)

• Ultimate goal is defeat of genetically engineered biological threat

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Emerging Threats: Path Forward

• Anticipate the threat

• Deliver New capabilities Short Term and Long Term

• Exploit Existing Med CM as Well as Survey Existing Therapeutics

• Major Investments Needed in Host-pathogen Infection Process to Identify Common Targets for Broad-spectrum Drugs

• Push Developments to Diagnostics, Therapeutics and Pretreatment Portfolios

• Needs to Harness all of the Major Bioinformatics and Molecular Biology Breakthroughs

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Conclusion

• Finish What we Started on Classic Threats

– Legacy Products Need Investment to Take These Threats Away from the Enemy

• The Good Old Days are over

– Next Generation Threats Need New Thinking, Bold Approaches and Harnessing Information Revolution in Biology

• Best Approach for Long-term Threats is Looking for Common Virulence Pathways

– Defeat Next Generation Threats by Attacking Problem at the Common Host Response Pathways

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Questions?

http://www.acq.osd.mil/cp