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Center for Drugs: CT Medical Countermeasures

Center for Drugs: CT Medical Countermeasures. Dianne Murphy, M.D. Director Office of Counterterrorism & Pediatric Drug Development (OCTAP) Center for Drug Evaluation and Research (CDER). CDER/ DCT : Mission Statement for Counter-Terrorism Goals.

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Center for Drugs: CT Medical Countermeasures

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  1. Center for Drugs: CT Medical Countermeasures Dianne Murphy, M.D. Director Office of Counterterrorism & Pediatric Drug Development (OCTAP) Center for Drug Evaluation and Research (CDER) FDA Science Board

  2. CDER/DCT:Mission Statement for Counter-Terrorism Goals • Identify gaps in current medical counter-measures (MCM) • Identify gaps in knowledge base necessary for approval of specific MCM • Construct an action plan Assure availability of S&E drugs to treat victims of terrorist attack

  3. Biodefense Approvals • 1973: Atropen • 1983: Pralidoxime (2-PAM) autoinjectors • 1990: Diazepam autoinjector • 1992: Sodium Thiosulfate Injection • 2000: SERPACWA • 2002: ATNAA • February, 2003: Pyridostigmine Bromide • 1st APPROVAL UNDER “ANIMAL EFFICACY RULE”

  4. Bio/Homeland Defense Approvals* • 1979: Potassium Iodide (KI) • 2000: Cipro for Anthrax (PEP) • 2001: Doxycycline and Procaine Penicillin G for Anthrax PEP (FR notice)* • 2002: Thyrosafe, KI 65 mg • February 2003: Prussian Blue (FR notice)* • June 2003: Pediatric Atropine Injection • September 2003: Ca- and Zn- DTPAs (finding of safety and efficacy) • October 2003: Prussian Blue Radiogardase *Not true “approval” but Federal Register notice of Agency finding of Safety and Efficacy

  5. Opportunities to Accelerate Approval:1. Regulatory Mechanism2. Funding Mechanisms

  6. Expedite CT Drug Development • FDA-sponsor collaboration early in drug development (Pre-IND) • Study design, including endpoints (esp. animal models) • “Fast Track” designation during clinical development • “Accelerated Approval”(Subpart H) • Use of clinical efficacy surrogate • “Animal Rule”(Subpart I)

  7. CT Products Subpart H(Clinical Efficacy Surrogate) • Ciprofloxacin: • Surrogate Markers: Cmax/MIC>10 is desirable range • Non-Human Primate Animal Model Critical Element • Human Pathophysiology from Sverdlovsk • Safety Data Enormous • Limited but adequate pediatric data

  8. Cipro:Surrogate MarkerAnthrax Monkey Data- Cipro

  9. Challenge (from Friedlander et al 1993) Survival TOC End of treatment

  10. Federal Register Notice: Finding of Safety & Efficacy November 2, 2001: Federal RegisterNotice: Doxycycline and Penicillin G Procaine Administration for Inhalational Anthrax (Post-Exposure)

  11. “Federal Register Notice: publication of finding of safety and efficacy” • “FDA reviews the available data on a drug product and makes a determination • FDA’s findings are published in the FR • The FR Notice may reference a Guidance on how to submit a New Drug Application • FR notice may also reference draft labeling • Examples: • Prussian Blue– call for NDA’s in Federal Register Notice – January 2003 • Ca- and Zn- DTPAs

  12. Animal Rule(Subpart I*) • “Evidence Needed to Demonstrate Effectiveness of New Drugs When Human Efficacy Studies Are Not Ethical or Feasible” • Federal Register (final rule): 5/31/02 • 21 CFR 314.600-650 & 601.90-95* *Subpart H in CBER regulations

  13. Animal Rule Requirements • Understanding of the drug’s mechanism • Efficacy extrapolation from animal models to predict human response • Understand interspecies differences where they exist • “Two Animal Rule” - NOT ! • Animal and human pharmacokinetic data are used to select an effective dose in humans • Safety assessment must involve humans

  14. Pyridostigmine bromide Safety Database • Approved as Mestinon (“high dose”) • for myasthenia gravis • Pre-exposure antidote against soman (nerve agent). Given to troops during 1991 Gulf War Efficacy • Based on effects documented in Rhesus and Guinea Pig • Fundamental understanding of mechanism • Ability to understand and explain differences among species

  15. Funding Mechanisms • Grants (RFA) • Contracts (RFP) • Inter-Agency Agreements (IAG’s) • Project BioShield (legislation pending)

  16. Counter-Terrorism Studies in Special Populations • In fiscal year 2002, we funded several studies via the Office of Women's Health (OWH). These studies included: • a. Amoxicillin PK: Pregnancy and Postpartum – (contract: University of Washington, Seattle, Center of Excellence • b. Cipro and Doxy: lactating women and elderly (contract: Indiana School of Medicine, Center of Excellence) • c. PK/PD: Gent, Azithro, & Cipro: Pregnancy of (contract with University of Wisconsin, Madison) • d. Fetal Safety: Cipro, Doxy, Amoxicillin, Azithro - Exposure to CT Countermeasures (contract with Vanderbilt University, Nashville)

  17. Leveraging Resources • NIAID/USAMRIID – Plague NHP Studies • CDC – Human clinical trials in areas with endemic plague • Databases from HMO’s and others: long-term antibiotic data use • NIAID and academic institutions: smaller bridging animal models

  18. Food-born Pathogens and Countermeasures FDA Science Board

  19. Bacteria

  20. Protozoa

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