Pathway to Licensure for Protective Antigen-based Anthrax Vaccines for a Post- exposure Prophylaxis Indication Using the Animal Rule.

Pathway to Licensure for Protective Antigen-based Anthrax Vaccines for a Post-exposure Prophylaxis Indication Using the

Animal Rule

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Anthrax

From Collier and Young, Sci. Am. March 2002

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Mechanism of Action of Anthrax Toxin

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PA-based Anthrax Vaccine Design

• Based on PA

• Elicits toxin neutralizing antibodies

• AVA is currently licensed for pre-exposure prophylaxis (0 and 4 weeks, 6, 12 and 18 months)

• rPA vaccines are being developed

• No vaccine is yet licensed for post-exposure prophylaxis

From Sellman et al. J. Biol. Chem. 276:8371

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Post-exposure Scenario

• Exposure is likely to come without warning

• A full course of antibiotics (60 days) would be initiated as quickly as possible

• Vaccine would be administered on an accelerated schedule

• Antibiotics kill vegetative bacteria but not spores

• Spores can lie dormant for long periods of time

• Vaccine would protect against residual spores that germinate after 60 days

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Anthrax Vaccines and the “Animal Rule”

• Human efficacy studies are not feasible because of the low incidence of naturally occurring anthrax

• Human challenge studies would not be ethical because of the rapid progression and lethal nature of the disease

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The “Animal Rule”

“New Drug and Biological Drug Products; Evidence Needed to Demonstrate Effectiveness of New Drugs When Human Efficacy Studies Are Not Ethical or Feasible”

Federal Register 67: 37988-37998, 2002

Allows animal efficacy data to be used as a basis for approval, when human efficacy studies are not ethical or feasible to conduct

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Animal Rule Approval Standard (21 CFR 601.90)

FDA may grant marketing approval of a product, for which safety has been established in humans, based on adequate and well-controlled animal studies, the results of which establish that the product “is reasonably likely to provide clinical benefit in humans”.

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Animal Rule Criteria

FDA will rely on animal efficacy data only where:

1. There is a reasonably well-understood pathophysiological mechanism of the toxicity of the substance and its prevention or substantial reduction by the product

2. The effect is demonstrated in more than one animal species expected to react with a response predictive for humans, unless the effect is demonstrated in a single animal species that represents a sufficiently well-characterized animal model for predicting the response in humans

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Application of Final Rule (continued)

FDA will rely on animal efficacy data only where:

3. The animal study endpoint is clearly related to the desired benefit in humans, generally the enhancement of survival or prevention of major morbidity

4. The data or information on the kinetics and pharmacodynamics of the product or other relevant data or information in animals and humans allows selection of an effective dose in humans

(for vaccines, the vaccine dose given to humans should elicit an immune response in humans comparable to the immune response achieved in animals that were protected by the vaccine)

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• Anthrax Vaccines: Efficacy Testing and Surrogate Markers of Immunity, April 23, 2002

• Anthrax: Bridging Correlates of Protection in Animals to Immunogenicity in Humans, November 8-9, 2007

Previous CBER-sponsored workshops

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Animal Rule Criteria: PA-based Anthrax Vaccines

FDA will rely on animal efficacy data only where:

1. There is a reasonably well-understood pathophysiological mechanism of the toxicity of the substance and its prevention or substantial reduction by the product

Previous workshops: Pathogenic mechanisms of B. anthracis and information on the mechanism of protection by PA-based vaccines were reviewed and were thought to be reasonably well understood

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Animal Rule Criteria: PA-based Anthrax Vaccines

FDA will rely on animal efficacy data only where:

2. The effect is demonstrated in more than one animal species expected to react with a response predictive for humans, unless the effect is demonstrated in a single animal species that represents a sufficiently well-characterized animal model for predicting the response in humans

Previous workshops: NHP and rabbits are appropriate animal models since the pathology and immune response are similar to those seen in humans

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Animal Rule Criteria: PA-based Anthrax Vaccines

FDA will rely on animal efficacy data only where:

3. The animal study endpoint is clearly related to the desired benefit in humans, generally the enhancement of survival or prevention of major morbidity

Previous workshops: Animal study designs were discussed and agreed upon including route of exposure and endpoints (survival).

Consensus was reached that the first three criteria of the Animal Rule had been fulfilled

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Animal Rule Criteria: PA-based Anthrax Vaccines

FDA will rely on animal efficacy data only where:

4. The data or information on the kinetics and pharmacodynamics of the product or other relevant data or information in animals and humans allows selection of an effective dose in humans

What immune marker should be used to link animal protection data to humans?

What is the appropriate animal study design to determine protective immune marker levels?

How should animal protection data be bridged to humans?

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Purpose of Discussion

• A strategy for bridging animal protection data to humans would provide manufacturers with a possible pathway to follow during development of PA-based anthrax vaccines for a post-exposure prophylaxis indication

• Guidance regarding bridging strategies would facilitate design and execution of pivotal studies, thereby expediting vaccine development

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Presentations

NIH StudiesEd Nuzum, D.V.M., Ph.D, Chief, Biodefense Vaccines and

other Biological Products Development Section, NIAID, NIH

CDC StudiesConrad Quinn, Ph.D., Chief, Microbial Pathogenesis and

Immune Response Laboratory, NCIRD, CDC

CBER PerspectiveDrusilla Burns, Ph.D., Chief, Laboratory of Respiratory and

Special Pathogens, CBER, FDA