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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

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

cder dct mission statement for counter terrorism goals
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

biodefense approvals
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”
bio homeland defense approvals
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

expedite ct drug development
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)
ct products
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
slide9

Challenge (from Friedlander et al 1993)

Survival

TOC

End of treatment

federal register notice finding of safety efficacy
Federal Register Notice: Finding of Safety & Efficacy

November 2, 2001:

Federal RegisterNotice: Doxycycline and Penicillin G Procaine Administration for Inhalational Anthrax (Post-Exposure)

federal register notice publication of finding of safety and efficacy
“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
animal rule subpart i
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

animal rule requirements
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
pyridostigmine bromide
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
funding mechanisms
Funding Mechanisms
  • Grants (RFA)
  • Contracts (RFP)
  • Inter-Agency Agreements (IAG’s)
  • Project BioShield (legislation pending)
counter terrorism studies in special populations
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)

leveraging resources
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