Perspectives on Licensing Vaccines by the Animal Rule

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• Perspectives on Licensing Vaccines by the Animal
  Rule

Mary Kate Hart, Ph.D. Director, Nonclinical
Research DynPort Vaccine Company LLC, A CSC
Company
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Overview

• Vaccine development by DynPort Vaccine Company
  LLC (DVC) perspectives and considerations
• The Animal Rule what it is and what it is not
• DVCs approach to meeting the Animal Rule
  requirements

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Vaccine Development by DVC Perspectives and
Considerations
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Bona fides

• DVC has been engaged in advanced development of
  biodefense products since 1998.
• Product portfolio includes
• Live bacterial vaccine (tularemia)
• Live viral vaccines (Venezuelan equine
  encephalitis virus Cell Culture Smallpox
  Vaccine)
• Inactivated viral vaccines (seasonal and pandemic
  influenza with Baxter)
• Recombinant peptide vaccines (plague, anthrax,
  botulinum neurotoxin)
• Plasma-derived biotherapeutics (BioScavenger with
  Baxter)
• Therapeutic immunoglobulin (Vaccinia immune
  globulin)
• Customers include Department of Defense, National
  Institutes of Allergy and Infectious Diseases and
  Department of Health and Human Services
• Licensed one of the first biodefense-specific
  products

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Perspectives on Biodefense Vaccines

• Developing vaccines for biodefense
• What are we building?
• What are the customers requirements?
• What are the risks?

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What are we building?

• The most important criterion build with the end
  in sight.
• Proof-of-Concept does not ensure a viable
  product.
• Product developers need clear requirements
• What is an acceptable level of protection?
• What is the final indication?
• What is the final format expected to be?
  (Single-dose, multi-dose, filled syringes,
  something else?)
• What is a licensable product?
• Product plan should not radically change over
  time
• Product development plans must be flexible, but
  cannot be anarchistic. Government customer may
  require forward planning (4-5 years) to ensure
  funding is available.
• Animal Rule provides many daunting challenges,
  and approach to compliance should be set early.

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What are the requirements?

• We need to know
• Nature and identity of threat
• Level of protection required
• Onset vs. duration of protection
• Administration strategy
• Storage conditions
• Initial delivery amount
• Ongoing requirements
• Regulatory strategy

• Because
• Specificity of the response
• Nonclinical and clinical study design
• Administration and testing paradigm
• Clinical strategy
• Formulation, stability and format
• Manufacturing strategy
• Manufacturing strategy
• Overall program design (licensed vs. unlicensed)

Deviations from the plan always result in
significant cost and schedule ramifications. A
clear plan for development of the product is
necessary in advance, and modifications should be
made only when absolutely necessary.
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Risk Management is Crucial to Success

• Murphys Law is first, last and always the
  operating principle.
• Development of biodefense medical countermeasures
  is inherently a high-risk enterprise
• Lack of prior art (make it up as you go).
• Compliance with the Animal Rule new licensure
  strategy.
• The product may not work as expected.
• Logistics of countermeasure use still being
  worked out.

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The Animal Rule What it is and What it is Not
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FDA Animal Rule

• Allows for approval of vaccines in which efficacy
  testing in humans is unethical
• Is not a shortcut to approval, or applicable to
  products that can be licensed by other approaches
• Need to understand pathophysiology of the disease
• Use dosages scaled to reproduce the human
  response
• Well-controlled animal studies will provide data
  that are likely to predict a benefit in humans
• Demonstrate effect in two species
• nonhuman primates NHPs
• Rodents
• Additional considerations available in Concept
  Paper (e.g., use of well-characterized materials)

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Animal Rule Challenges

• Meet the traditional licensure requirements AND
• Design proof-of-concept studies
• Demonstrate relevance of animal model
• Model considerations small and large animal
  models desired
• Provide rationale for use of Animal Rule
• Define protection
• Good Documentation Practices essential
• Design of Animal Rule studies
• Determine correlate that predicts clinical
  benefit
• Support selection of human dosage
• Good Laboratory Practices required
• Efficacy demonstrated in animals
• Bridge from animals to human response to predict
  clinical benefit

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Development Timeline Traditional Approach
IND
BLA
RD
Pre- Clinical
Phase 1
Phase 2
Phase 3
FDA Approval
To the Market
Clinical Studies
6.5
YEARS
7
1.5
TOTAL 15 years
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Development Timeline Animal Rule Approach
IND
BLA
RD
Pre- Clinical
Phase 1
Phase 2
Phase 3
To the Market
FDA Approval
Animal Rule Efficacy Studies
TOTAL Unknown
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Animal Rule-Based Vaccine Development

• Pathway to Licensure is a work in progress
• Uncertain requirements from a regulatory
  standpoint
• Conservative approaches in determining what is
  acceptable
• There are NO licensed vaccines that demonstrate
  efficacy by the Animal Rule
• Detailed planning essential due to government
  funding restrictions
• Changes in protocols affect schedule/cost and can
  result in major delays
• NHP availability
• Facility expertise and availability

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DVCs Approach to Meeting the Animal Rule
Requirements
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DVC Vaccine Program Technical Approach

• Expertise and coordination between technical
  areas
• Science technical oversight and integration
• Quality oversight of product and clinical
  studies
• Regulatory FDA communications, strategy for
  licensure
• Manufacturing material for clinical and
  nonclinical studies
• Nonclinical animal studies (safety,
  immunogenicity, efficacy)
• Clinical Phase 1,2,3 safety and immunogenicity
  trials

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Balance Manufacturing Development, Animal
Model Development and the Human Response
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DVC Program Technical Approach

• Science technical oversight and integration
• Quality oversight of product and clinical
  studies
• Regulatory FDA communications, strategy for
  licensure
• Manufacturing material for clinical and
  nonclinical studies
• Nonclinical animal studies (safety,
  immunogenicity, efficacy)
• Clinical Phase 1,2,3 safety and immunogenicity
  trials

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Regulatory FDA Interactions

• Pre-IND meeting
• IND submitted with all development plans included
• Type C meetings
• Discussion of aspects of technical development
  plan
• Study designs provided for comment prior to
  conducting the study
• Timing of interactions is critical
• Too soon insufficient detail to receive specific
  comments
• Too late cost and schedule impacts due to FDA
  comments

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FDA Communication

• Close FDA communication is vital no vaccine has
  yet been licensed under the Animal Rule
• Workshops
• Working groups
• Formal meetings
• Review of strategy
• Review of study protocols

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DVC Program Technical Approach

• Science technical oversight and integration
• Quality oversight of product and clinical
  studies
• Regulatory FDA communications, strategy for
  licensure
• Manufacturing material for clinical and
  nonclinical studies
• Nonclinical animal studies (safety,
  immunogenicity, efficacy)
• Clinical Phase 1,2,3 safety and immunogenicity
  trials

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Development of a Manufacturing Process

• Phase 1
• Emphasis on Safety
• Source characterization
• Raw materials traced and qualified
• Characterization of purified bulk and FDP
• Testing /clearance of Impurities
• Description of manufacturing
• Assay development
• Formulation
• Quality

• Phase 2
• Scientific Evaluation
• Purified bulk and FDP characterization
• Assay development
• Increased stability
• Continued formulation development
• Product characterization
• Change Control
• Reference standard
• Quality

• Phase 3
• Control and Validation
• Process optimized
• Process and assay Validation
• Specifications
• Consistency Lot production
• Quality

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DVC Program Technical Approach

• Science technical oversight and integration
• Quality oversight of product and clinical
  studies
• Regulatory FDA communications, strategy for
  licensure
• Manufacturing material for clinical and
  nonclinical studies
• Nonclinical animal studies (safety,
  immunogenicity, efficacy)
• Clinical Phase 1,2,3 safety and immunogenicity
  trials

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Critical Issues

• What is the intended label indication?
• How does disease in the animal model compare to
  human disease? Are sufficient hallmarks covered?
• Demonstrating correlate of protective immunity in
  animals, including humans
• Is the mechanism of protection clearly defined?
• Are functional in vitro assays available?
• Is the challenge material characterized and have
  the route and dosage been determined?
• Breakthrough of protection?
• How is protection defined?
• Are there multiple subtypes to consider?
• Statistical considerations?
• May need multiple animal models to satisfy Animal
  Rule requirements

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Nonclinical Strategy for Vaccines

• Demonstrate Safety (Tox studies)
• Model selection Animal studies must demonstrate
  that the vaccine is likely to clinically benefit
  humans.
• Enable selection of a protective dosage for
  humans.
• Identify a marker of immunity that predicts
  protection and can be measured in both animals
  and humans.
• Mechanism of protection is it known?
• Pivotal animal studies
• Demonstrate efficacy
• Bridge immune responses to human immune responses

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Considerations for Animal Model Selection

• Species
• Susceptibility to pathogen by the route of
  exposure intended for the label indication
• Similarity to human response
• Display similar characteristics to human disease
  and pathogenesis
• Immune response
• Endpoints of study
• Manipulations required
• Cost
• Facility space and required biosafety containment
  level
• Availability of sufficient animals

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Development of Animal Models
Pre- Clinical
Phase 1
Phase 2
Phase 3

• Emphasis on development
• The studies often use research-grade products
• Proof-of-concept studies
• Develop and present a regulatory strategy
• Nonclinical safety studies

• Scientific evaluation,
• prevalidation studies
• FDA communication on animal model design
• Animal studies to support design of pivotal
  studies
• Change control (how do manufacturing changes
  affect product performance in animal models)

• Control and validation
• Facility, process and assay validation complete
• Demonstrate efficacy in animal models (GLP)
• Collect supportive data from clinical study
• Reproductive toxicity

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Proof-of-Concept Studies

• Good Documentation Practices
• Identification and development of relevant animal
  models
• Preferably more than one animal species
• Animal study endpoint is clearly related to the
  desired benefit in humans
• Route of administration
• Adjuvant requirement
• Formulation optimization
• Dose and schedule requirements
• Animal data supports effective dose in humans
• Immunological Response
• Development of assays to detect response

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Addressing the Requirements
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Bridging the Immune Response Vaccine Example
Vaccination
Vaccination
Efficacy Study
Clinical Study
Human Sample
NHP Sample
Immunology Assay
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DVC Program Technical Approach

• Science technical oversight and integration
• Quality oversight of product and clinical
  studies
• Regulatory FDA communications, strategy for
  licensure
• Manufacturing material for clinical and
  nonclinical studies
• Nonclinical animal studies (safety,
  immunogenicity, efficacy)
• Clinical Phase 1,2,3 safety and immunogenicity
  trials

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DVC Clinical Efforts
IND
BLA
RD
Pre- Clinical
Phase 1
Phase 2
To the Market
Phase 3
FDA Approval
Animal Rule Efficacy Studies
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Conclusions

• The Animal Rule is a last-resort approach to
  vaccine licensure, with unique challenges and no
  exceptions to the licensure requirements under
  other regulations.
• The challenges may be met with careful planning
  and coordination of technical activities.
• No vaccines have been licensed to date using this
  new regulatory approach. This adds risk to a
  program.
• Licensure under the Animal Rule will increase the
  programs cost and likely extend the time to
  licensure.
• FDA communication is essential for success.

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Acknowledgments

• Chemical Biological Medical System-Joint Vaccine
  Acquisition Program (CBMS-JVAP), Department of
  Defense (DoD) Contract DAMD 17-98-C-8024
• National Institute Of Allergy and Infectious
  Diseases, National Institutes of Health,
  Department of Health and Human Services, Contract
  No. N01-AI-50041