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

2. Anthrax
From Collier and Young, Sci. Am. March 2002

3. Mechanism of Action of Anthrax Toxin

4. 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

5. 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

6. 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

7. 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: , 2002
Allows animal efficacy data to be used as a basis for approval, when human efficacy studies are not ethical or feasible to conduct

8. 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”.

9. Animal Rule Criteria FDA will rely on animal efficacy data only where:
There is a reasonably well-understood pathophysiological mechanism of the toxicity of the substance and its prevention or substantial reduction by the product
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

10. Application of Final Rule (continued)
FDA will rely on animal efficacy data only where:
The animal study endpoint is clearly related to the desired benefit in humans, generally the enhancement of survival or prevention of major morbidity
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)

11. Previous CBER-sponsored workshops
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

12. Animal Rule Criteria: PA-based Anthrax Vaccines
FDA will rely on animal efficacy data only where:
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

13. Animal Rule Criteria: PA-based Anthrax Vaccines
FDA will rely on animal efficacy data only where:
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

14. Animal Rule Criteria: PA-based Anthrax Vaccines
FDA will rely on animal efficacy data only where:
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

15. Animal Rule Criteria: PA-based Anthrax Vaccines
FDA will rely on animal efficacy data only where:
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?

16. 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

17. Presentations NIH Studies CDC Studies CBER Perspective
Ed Nuzum, D.V.M., Ph.D, Chief, Biodefense Vaccines and other Biological Products Development Section, NIAID, NIH
CDC Studies
Conrad Quinn, Ph.D., Chief, Microbial Pathogenesis and Immune Response Laboratory, NCIRD, CDC
CBER Perspective
Drusilla Burns, Ph.D., Chief, Laboratory of Respiratory and Special Pathogens, CBER, FDA