Chemical and Biological Defense Program (CBDP): Capabilities for Countering the Threat

MG Donna Barbisch, USA Director, CBRN Integration April 26, 2005

Chemical and Biological Defense Program (CBDP) Program Organization

DATSD(CBD)

2

An Integrated Systems Approach to Counter the Threat

CB Threats & Hazards

Agent Delivery Doses on Target Downwind Dispersal Doses Absorbed

Sustained Combat Power

Symptoms Medical Treatment Medical Pretreatment Individual & Collective Protection Information Systems Contamination Avoidance and NBC Battle Management (Detection, Identification, Reconnaissance & Warning) Installation Force Protection Decontamination, Restoration

3

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

missions. concurrently with these added

4

Chemical and Biological Defense:

Strategic Framework

DoD Mission

Provide integrated chemical and biological defense capabilities to effectively execute the National Military Strategy.

6

Strategic Imperatives

•

Eliminate technological surprise.

•

Make the threat irrelevant.

•

Detect the threat.

•

Protect against the threat.

•

Eliminate the threat.

7

Enabling the Vision

•

Doctrine

•

Organization

•

Training

•

Materiel

•

Leader development

•

Personnel

•

Facilities Oversight – Coordination – Integration

8

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

9

Behind the Scenes of Drug Development

Target selection & validation Discovery Development

Target -receptor; -ion channel; -transporter; -enzyme; - signalling molecule Drug Candidate safety testing Studies of Disease Mechanisms

The Drug Discovery Process

Molecular Studies Lead Search -Develop assays (use of automation) -Chemical diversity -Highly iterative process Human Studies Phases I,II, III Animal Studies - relevant species - transgenic KO/KI mice - conditional KOs - agonists/antagonists - antibodies - antisense - RNAi Lead optimization -selectivity -efficacy in animal models -tolerability: AEs mechanism based or structure-based?

-pharmacokinetics -highly iterative process Drug Approval and Registration

Development

Pre-Clinical

Pharmacology Safety Assessment Toxicology Drug Metabolism (ADME) Pharmaceutical R&D Formulation Process R&D Chem Eng. R&D Manufacturing Bio Process R&D Clinical Investigator & patient Clinical Pharmacology Clinical Research Statistics & Epidemiology Data Coordination Research Information Systems Information Services Regulatory Affairs Project Planning & Management Marketing

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!!!

Investigational New Drug application

IND

Clinical Trials

Phase I

20 - 100 healthy volunteers take drug for about one month

Product Profile Marketing SOI Information Learned 1. Absorption and metabolism 2. Effects on organs and tissue 3. Side effects as dosage is increased

Remote data entry

Phase II

Several hundred health-impaired patients Treatment Group Control Group

Information Learned 1. Effectiveness in treating disease 2. Short-term side effects in health -impaired patients 3. Dose range Phase III

Hundreds or thousands of health impaired patients

Information Learned 1. Benefit/risk relationship of drug 2. Less common and longer term side effects 3. Labeling information Compassionate Use

Clinical Trials Continued

Submit to Regulatory Agencies Advisory Committee APPROVAL PROCESS

(Ex. FDA)

Regulatory Review Team Reviews, comments, and discussions Drug Co./Regulatory liaison activities New Drug Application (NDA) APPROVAL

Worldwide Marketing Authorization (WMA) in other countries

Mo d elling Drug Discovery —Convergence of Disciplines Combinatorial Chemistry Synthetic Chemistry Patent Law Novel Molecule Intellectual Property Physiology Information Technology Design Structural Activity Biochemistry Physiology Metabolism Safety Pharmaco dynamics Physiology Pharmacology Safety Assessment

In Vivo

Pharmacology Pathology activity Pharmacokinetic Properties Immunology DMPK Physiology Behavior Physical Chemistry Physiology Enzymology

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

Bumps in the Road

NDA

–

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

• –

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

22

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

Phase 2 Clinical Studies

IND

•

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

• –

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

Phase 4 Studies

NDA

–

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

29

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

900 800 700 600 500 400 300 200 100 0 1,800 1,700 1,600 1,500 1,400 1,300 1,200 1,100 1,000 FY04 • • Budget Request

Defense Health Program Military Construction (USAMRIID) CBDP Procurement CBDP Advanced Development CBDP Science & Technology Base

FY05 FY06 FY07 FY08 FY09 FY10

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

FY11 30

Enhanced Planning Process (EPP) Results T&E Infrastructure Improvements

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

RDT&E Improvements

Additional Emphasis: • S&T for NTA detection • Bio point and standoff detection • Medical Prophylaxis • Battle Analysis • Decontamination • Bio Defense Initiatives • Chem point detection 31

T&E Infrastructure Investment Explosive test (simulant only) Aerosol exposures test chamber Fort Detrick, MD “Bang Box”, Dugway CB Simulant Test Grid Dugway Proving Ground UT High Containment BL4 lab, USAMRIID Fort Detrick MD CB Aerosol Test Chamber Fort Detrick, MD Man In Simulant Test (MIST) Chamber

32

33

The Problem

Slow drug development process leads to economic and social catastrophe jeopardizing national security

10+ years > $800M

Attack with new threat DHS funds to NIAID No national strategy, clear responsibility or federal funding to shorten this cycle Early Stage Research 10+ years Lead Discovery 2+ years Preclinical Development 2-5 years Clinical Development Production Models 5-8 years Safe & effective countermeasure Bioshield FDA Approval 1 year Production Procurement

34

R&D - Test and Evaluation

Vaccine/Drug Discovery Vaccine/Drug Development Industry Academia NIAID /NIH DHS/NBACC Other Government Research

DoD

• GLP

Testing/

• Phase 1 Safety trials

Process BioShield Industry Process FDA-Licensed Vaccines Drugs Diagnostics

DoD/Military tech base Genomics/Proteomics Basic Research Product Transition

Production Distribution Storage

Testing Bottleneck

Funding has increased For the “Attractive Work” Funding is needed For the “Unglamorous Work”

35

Future Emphasis: Systems Biology Today’s Threats

Anthrax Smallpox Botulinum Plague Tularemia Ebola/Filo Hemorrhagic Fever Encephalitis SARS Influenza Ricin/SEB, others

Bioengineered Modes of Action

Receptor Binding Signal Transduction Decoys Immune Avoidance Parallel Systems Approach Translation/Transcription Immune Deregulation Replication Virulence Expression

Solutions

• • • • • •

Target 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 Process Analysis Broad Spectrum

36

Viral Disease

37

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 38

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

39

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

40

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

41

Questions?

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

42