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

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

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

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

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

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

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

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. Discovery Development Target selection & validation Studies ofDisease Mechanisms Target -receptor; -ion channel; -transporter;-enzyme; - signalling molecule Drug Candidate safety testing • Lead Search • -Develop assays (use of automation) • -Chemical diversity • -Highly iterative process Human Studies Phases I,II, III Molecular Studies Animal Studies - relevant species - transgenic KO/KI mice - conditional KOs - agonists/antagonists - antibodies - antisense - RNAi Drug Approval and Registration Lead optimization -selectivity -efficacy in animal models -tolerability: AEs mechanism- based or structure-based?-pharmacokinetics -highly iterative process The Drug Discovery Process

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

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. Phase I Product Profile Marketing SOI 20 - 100 healthy volunteers take drug for about one month 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 Information Learned Control Group 1. Effectiveness in treating disease 2. Short-term side effects in health -impaired patients 3. Dose range Treatment Group Phase III Information Learned Hundreds or thousands of health-impaired patients 1. Benefit/risk relationship of drug 2. Less common and longer term side effects 3. Labeling information Compassionate Use Clinical Trials Investigational New Drug application IND

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

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

18. Assignment of Drug Review

19. New Drug Development ProcessPre-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 ProcessNDA • 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 ProcessNDA • 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

23. New Drug Development ProcessIND • 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 ProcessIND • 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 ProcessIND • 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 ProcessNDA • 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 ProcessIND • Institutional Review Board (IRB) • Protection of human subjects in clinical trials • Written informed consent (signed) before study begins

28. New Drug Development ProcessIND 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

30. FY06 President’s Budget(DoD CB Defense Program + Defense Health Program for Construction of USAMRIID Improvements) Defense Health Program Military Construction (USAMRIID) Budget Request CBDP Procurement CBDP Advanced Development CBDP Science & Technology Base • 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. Enhanced Planning Process (EPP) Results

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

34. The ProblemSlow drug development process leads to economic andsocial catastrophe jeopardizing national security 10+ years > $800M Attack with new threat Safe & effective countermeasure Bioshield DHS funds toNIAID No national strategy, clear responsibility or federal funding to shorten this cycle Early Stage Research Lead Discovery Preclinical Development Clinical Development Production Models FDA Approval Production Procurement 10+ years 2+ years 2-5 years 5-8 years 1 year

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

36. Future Emphasis:Systems Biology • Modes of Action • Receptor Binding • Signal Transduction • Decoys • Immune Avoidance • Translation/Transcription • Immune Deregulation • Replication • Virulence Expression • Today’s Threats • Anthrax • Smallpox • Botulinum • Plague • Tularemia • Ebola/Filo • Hemorrhagic Fever • Encephalitis • SARS • Influenza • Ricin/SEB, others Parallel Systems Approach • Solutions • Target Agent Commonalities • Block Key Receptors • Inhibition by Small Molecules • Modulate Immunity • Change Gene Expression • Block Protein Actions • Modulate Physiologic Impacts Bioengineered One PIECE at a time Process Analysis Broad Spectrum

37. Viral Disease

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