Transcript 01_Barbisch Drug Development

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)
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An Integrated Systems Approach to
Counter the Threat
Sustained Combat Power
CB Threats & Hazards
Agent
Delivery
Doses on
Target
Downwind
Dispersal
Doses
Absorbed
Symptoms
Medical Treatment
Medical Pretreatment
Individual & Collective Protection
Contamination
Avoidance and
NBC Battle Management
(Detection, Identification,
Reconnaissance & Warning)
Installation Force
Protection
Information Systems
Decontamination,
Restoration
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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.
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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.
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Chemical and Biological
Defense:
Strategic Framework
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
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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
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Behind the Scenes of
Drug Development
Target selection &
validation
Studies of
Disease Mechanisms
Discovery
Development
Target
Drug Candidate
-receptor; -ion channel; -transporter;
-enzyme; - signalling molecule
safety testing
The Drug Discovery Process
Lead Search
Molecular Studies
-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 mechanismbased or structure-based?
-pharmacokinetics
-highly iterative process
Drug Approval
and Registration
Development
Pre-Clinical
Pharmacology
Safety Assessment
Toxicology
Process R&D
Chem Eng. R&D
Manufacturing
Drug Metabolism
(ADME)
Pharmaceutical R&D
Formulation
Clinical Investigator
& patient
Clinical Pharmacology
Clinical Research
Clinical
Statistics & Epidemiology
Data Coordination
Research Information Systems
Information Services
Bio Process R&D
Regulatory Affairs
Project Planning & Management
Marketing
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
Phase I
Product Profile
Marketing SOI
20 - 100 healthy volunteers take
drug for about one month
Information Learned
IND
1. Absorption and metabolism
2. Effects on organs and tissue
3. Side effects as dosage is increased
Remote data entry
Clinical
Trials
Phase II
Several hundred health-impaired patients
Treatment Group Control Group
Phase III
Hundreds or thousands of healthimpaired patients
Compassionate Use
Information Learned
1. Effectiveness in treating disease
2. 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
Clinical
Trials
Continued
Advisory
Committee
Regulatory
Review Team
APPROVAL
PROCESS
(Ex. FDA)
Reviews,
comments, and
discussions
Submit to
Regulatory Agencies
New Drug
Application
(NDA)
Drug Co./Regulatory
liaison activities
APPROVAL
Worldwide Marketing Authorization (WMA) in other countries
Drug Discovery—Convergence of Disciplines
Synthetic
Chemistry
Combinatorial
Chemistry
Modelling
Novel
Molecule
Information
Technology
Patent Law
Intellectual Property
Design
Structural
Activity
Physiology
Biochemistry
Physiology
Safety
Metabolism
Safety
Assessment
In Vivo activity
Pharmacology
Pharmaco-
Physiology
dynamics
Pharmacology
Pharmacokinetic
Properties
Immunology
DMPK
Behavior
Pathology
Physiology
Physical Physiology Enzymology
Chemistry
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
• File New Drug Application
NDA
– 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
• 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 Clinical Studies
IND
– 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
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FY06 President’s Budget
(DoD CB Defense Program + Defense Health Program for Construction of
USAMRIID Improvements)
Defense Health Program
Military Construction (USAMRIID)
1,800
Budget
Request
1,700
1,600
1,500
1,400
1,300
1,200
CBDP Procurement
($ in millions)
1,100
1,000
900
800
700
600
CBDP Advanced Development
500
400
300
200
CBDP Science & Technology Base
100
0
FY04
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
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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
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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
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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
Early Stage
Research
10+ years
Safe & effective
countermeasure
No national strategy, clear responsibility
or federal funding to shorten this cycle
Lead
Discovery
2+ years
Preclinical
Development
2-5 years
Clinical Development
Production Models
5-8 years
Bioshield
FDA
Approval
Production
Procurement
1 year
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R&D - Test and Evaluation
Vaccine/Drug Discovery
Industry
Vaccine/Drug Development
DoD
• GLP
• GMP
• Phase 1 Safety
trials
Academia
Testing/
Proofing
NIAID/NIH
DHS/NBACC
Process
Other Government Research
DoD/Military tech base
Genomics/Proteomics
Product
Transition
BioShield
Industry
Process
FDA-Licensed
Vaccines
Drugs
Diagnostics
Production
Distribution
Storage
Basic Research
Testing Bottleneck
Funding has increased
For the “Attractive Work”
Funding is needed
For the “Unglamorous Work”
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Future Emphasis:
Systems Biology
Today’s Threats
Modes of Action
Parallel
Systems
Approach
Anthrax
Receptor Binding
Smallpox
Signal Transduction
Botulinum
Decoys
Plague
Immune Avoidance
Tularemia
Translation/Transcription
Ebola/Filo
Immune Deregulation
Hemorrhagic
Fever
Replication
Virulence Expression
Encephalitis
SARS
Influenza
Solutions
Target Agent Commonalities
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Block Key Receptors
Inhibition by Small Molecules
Modulate Immunity
Change Gene Expression
Block Protein Actions
Modulate Physiologic Impacts
Ricin/SEB, others
Bioengineered
One PIECE at a time
Process Analysis
Broad Spectrum
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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
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