Center for Drugs: CT Medical Countermeasures Dianne Murphy, M.D.

Transcript Center for Drugs: CT Medical Countermeasures Dianne Murphy, M.D.

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) November 6, 2003 FDA Science Board

CDER/ DCT :

Mission Statement for Counter-Terrorism Goals

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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

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1973: Atropen 1983: Pralidoxime (2-PAM) autoinjectors 1990: Diazepam autoinjector 1992: Sodium Thiosulfate Injection 2000: SERPACWA 2002: ATNAA February, 2003: Pyridostigmine Bromide

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1st APPROVAL UNDER “ANIMAL EFFICACY RULE”

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

Opportunities to Accelerate Approval: 1. Regulatory Mechanism 2. Funding Mechanisms

Expedite CT Drug Development

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FDA-sponsor collaboration early in drug development (Pre-IND)

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Study design, including endpoints (esp. animal models) “Fast Track” designation during clinical development “Accelerated Approval

” (Subpart H)

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Use of clinical efficacy surrogate “Animal Rule”

(Subpart I)

CT Products

Subpart H (Clinical Efficacy Surrogate) Ciprofloxacin:

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Surrogate Markers: Cmax/MIC>10 is desirable range

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Non-Human Primate Animal Model Critical Element

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Human Pathophysiology from Sverdlovsk Safety Data Enormous Limited but adequate pediatric data

Cipro: Surrogate Marker Anthrax Monkey Data - Cipro

Co n t ro l Ci p ro 020 80

Challenge (from Friedlander et al 1993)

Co n t ro l V a c c i n e P e n Ci p ro Do x y Do x y + V a c c

End of treatment

Federal Register Notice: Finding of Safety & Efficacy

November 2, 2001: Federal Register Notice: Doxycycline and Penicillin G Procaine Administration for Inhalational Anthrax (Post-Exposure)

“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:

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Prussian Blue– call for NDA’s in Federal Register Notice – January 2003

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Ca- and Zn- DTPAs

***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

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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

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Safety Database Approved as Mestinon (“high dose”)

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for myasthenia gravis Pre-exposure antidote against soman (nerve agent). Given to troops during 1991 Gulf War

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Efficacy Based on effects documented in Rhesus and Guinea Pig Fundamental understanding of mechanism Ability to understand and explain differences among species

Funding Mechanisms

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Grants (RFA)

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Contracts (RFP)

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Inter-Agency Agreements (IAG’s)

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Project BioShield (legislation pending

)

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:

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a. Amoxicillin PK: Pregnancy and Postpartum –

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(contract: University of Washington, Seattle, Center of Excellence b. Cipro and Doxy: lactating women and elderly (contract: Indiana School of Medicine, Center of Excellence)

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c. PK/PD: Gent, Azithro, & Cipro: Pregnancy of (contract with University of Wisconsin, Madison)

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d. Fetal Safety: Cipro, Doxy, Amoxicillin, Azithro Exposure to CT Countermeasures (contract with Vanderbilt University, Nashville)

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

Food-born Pathogens and Countermeasures

November 6, 2003 FDA Science Board

Pathogen

E. coli Shigella Salmonella Listeria Campylobacter Yersinia enterocolitica

Bacteria

Approved Drug:

Specific Indications Cipro, TMP/Sulfa, Furoxone Cipro, TMP/Sulfa, Furoxone, Ampicillin Cipro, Pen G Chloro, Pen G, Erythro, Doxy et al.

Cipro

Protozoa