1. Chemical and Biological Defense Program (CBDP): Capabilities for Countering the Threat MG Donna Barbisch, USA Director, CBRN Integration April 26, 2005

2. 2 Chemical and Biological Defense Program (CBDP) Program Organization DATSD(CBD)

3. 3 An Integrated Systems Approach to Counter the Threat CB Threats & Hazards Agent Delivery Agent Delivery Doses on Target Doses on Target Downwind Dispersal Downwind Dispersal Doses Absorbed Doses Absorbed Symptoms Sustained Combat Power Medical Pretreatment Contamination Avoidance and NBC Battle Management (Detection, Identification, Reconnaissance & Warning) Individual & Collective Protection Decontamination, Restoration Medical Treatment Information Systems Installation Force Protection

4. 4 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.

5. Chemical and Biological Defense: Strategic Framework

6. 6 DoD Mission Provide integrated chemical and biological defense capabilities to effectively execute the National Military Strategy.

7. 7 Strategic Imperatives Eliminate technological surprise. Make the threat irrelevant. Detect the threat. Protect against the threat. Eliminate the threat.

8. 8 Enabling the Vision Doctrine Organization Training Materiel Leader development Personnel Facilities Oversight – Coordination – Integration

9. 9 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

10. Behind the Scenes of Drug Development

11. Drug Candidate safety testing Animal Studies - relevant species - transgenic KO/KI mice - conditional KOs - agonists/antagonists - antibodies - antisense - RNAi Studies of Disease 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 process Molecular Studies The Drug Discovery Process Lead optimization -selectivity -efficacy in animal models -tolerability: AEs mechanism- based or structure-based? -pharmacokinetics -highly iterative process Drug Approval and Registration Target selection & validation DiscoveryDevelopment

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

13. 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.

14. 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!!!

15. Clinical Trials Product 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 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 Compassionate Use Phase II Several hundred health-impaired patients Treatment Group Control Group Phase III Hundreds or thousands of health- impaired patients Investigational New Drug application IND Phase I 20 - 100 healthy volunteers take drug for about one month Remote data entry

16. Clinical Trials Continued APPROVAL PROCESS (Ex. FDA) Reviews, comments, and discussions Drug Co./Regulatory liaison activities APPROVAL Submit to Regulatory Agencies Advisory Committee Regulatory Review Team New Drug Application (NDA) Worldwide Marketing Authorization (WMA) in other countries

17. Drug Discovery—Convergence of Disciplines Patent Law Combinatorial Chemistry Synthetic Chemistry Physical Chemistry Physiology Biochemistry DMPK Enzymology Immunology Pharmacology Information Technology Mo d elling Physiology Safety Assessment Metabolism Pharmacology Pathology Behavior Novel Molecule Intellectual Property Structural Activity Pharmacokinetic Properties In Vivo activity Safety Design Pharmaco- dynamics Physiology

18. Assignment of Drug Review

19. 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

20. 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.”

21. 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)

22. Summary Overview of Phases and Process of Drug Development 22

23. 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

24. 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”)

25. 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

26. 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.

27. New Drug Development Process IND Institutional Review Board (IRB) –Protection of human subjects in clinical trials –Written informed consent (signed) before study begins

28. 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

29. Summary 29

30. 30 FY06 President’s Budget (DoD CB Defense Program + Defense Health Program for Construction of USAMRIID Improvements) 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

31. 31 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

32. 32 T&E Infrastructure Investment High Containment BL4 lab, USAMRIID Fort Detrick MD High Containment BL4 lab, USAMRIID Fort Detrick MD CB Simulant Test Grid Dugway Proving Ground UT CB Simulant Test Grid Dugway 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 Man In Simulant Test (MIST) Chamber

33. 33

34. 34 The Problem Slow drug development process leads to economic and social catastrophe jeopardizing national security 10+ years > $800M Early Stage Research Lead Discovery Preclinical Development Clinical Development Production Models FDA Approval 2+ years 2-5 years5-8 years1 year Production Procurement 10+ years No national strategy, clear responsibility or federal funding to shorten this cycle Bioshield Attack with new threat Safe & effective countermeasure DHS funds to NIAID

35. 35 R&D - Test and Evaluation Vaccines Drugs Diagnostics Vaccine/Drug Development Industry Academia Genomics/Proteomics Other Government Research Testing/ Proofing Process Industry Vaccine/Drug Discovery Testing Bottleneck NIAID /NIH DoD/Military tech base Process Production Distribution Storage FDA-Licensed Funding has increased For the “Attractive Work” Funding is needed For the “Unglamorous Work” BioShieldDoD Basic Research DHS/NBACC GLP GMP Phase 1 Safety trials Product Transition

36. 36 Today’s Threats Anthrax Smallpox Botulinum Plague Tularemia Ebola/Filo Hemorrhagic Fever Encephalitis SARS Influenza Ricin/SEB, others Future Emphasis: Systems Biology Bioengineered Modes of Action Receptor Binding Signal Transduction Decoys Immune Avoidance 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 timeBroad SpectrumProcess Analysis Parallel Systems Approach

37. 37 Viral Disease

38. 38 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

39. 39 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

40. 40 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

41. 41 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

42. 42 Questions? http://www.acq.osd.mil/cp