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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
1
Overview
• Vaccine development by DynPort Vaccine Company LLC (DVC):
perspectives and considerations
• The Animal Rule: what it is and what it is not
• DVC’s approach to meeting the Animal Rule requirements
Proprietary
2
Vaccine Development by DVC:
Perspectives and Considerations
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3
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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4
Perspectives on Biodefense Vaccines
• Developing vaccines for biodefense
– What are we building?
– What are the customer’s requirements?
– What are the risks?
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5
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:
• Because:
– 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
– 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
• Murphy’s 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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8
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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11
Development Timeline – Traditional Approach
IND
R&D
PreClinical
BLA
Phase 1
Phase 2
Phase 3
FDA
Approval
To the
Market
Clinical Studies
YEARS 6.5
7
1.5
TOTAL: 15 years
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Development Timeline – Animal Rule Approach
IND
R&D
PreClinical
BLA
Phase 1
Phase 2
Phase 3
Animal Rule – Efficacy Studies
To the
FDA
Approval Market
TOTAL: Unknown
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13
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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DVC’s 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
Justify why human
trials are not feasible or
ethical; justify
appropriateness of
selected animal models
CGMP
Demonstrate manufacturing
consistency – effective change
control
Correlate of Protective Immunity
GDP/
GLP
Bridge to human response; support
selection of human effective dose
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GCP
17
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
Proprietary
18
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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19
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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20
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
Proprietary
21
Development of a Manufacturing Process
Phase 1
Emphasis on Safety
Phase 2
Scientific Evaluation
Phase 3
Control and Validation
– Source characterization
– Raw materials traced and
qualified
– Characterization of
purified bulk and FDP
– Testing /clearance of
Impurities
– Description of
manufacturing
– Assay development
– Formulation
– Quality
– Purified bulk and FDP
characterization
– Assay development
– Increased stability
– Continued formulation
development
– Product
characterization
– Change Control
– Reference standard
– Quality
– Process optimized
– Process and assay
Validation
– Specifications
– Consistency Lot
production
– Quality
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22
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
Proprietary
23
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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26
Development of Animal Models
PreClinical
Phase 1
Phase 2
Emphasis on development Scientific evaluation,
prevalidation studies
• The studies often use
research-grade products • FDA communication on
animal model design
• Proof-of-concept studies
• Animal studies to
• Develop and present a
support design of
regulatory strategy
pivotal studies
Phase 3
Control and validation
• Facility, process and
assay validation
complete
• Demonstrate efficacy
in animal models
(GLP)
• Nonclinical safety studies • Change control (how do • Collect supportive
manufacturing changes data from clinical
affect product
study
performance in animal
models)
• Reproductive toxicity
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27
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
Animal Rule Requirements
Study Design
Understand the disease
• Lethal dose for 50% of animals (LD50);
natural history (pathophysiology)
Demonstrate efficacy in more than one
species which react as humans would with
similar endpoint (e.g., survival)
• Test article administration combined with
an active challenge
• Evaluate immune response
• Establish assay to be used as correlate
• Breakthrough of protection
Select effective human dosage
• Establish vaccination regimen that
induces immune response similar to that
observed in the clinic. Demonstrate
efficacy in challenge study
• Evaluate dosage in clinical trials
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29
Bridging the Immune Response – Vaccine Example
Clinical Study
Efficacy Study
Human Sample
NHP Sample
Immunology Assay
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30
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
Proprietary
31
DVC Clinical Efforts
IND
R&D
PreClinical
BLA
Phase 1
Phase 2
Phase 3
Animal Rule – Efficacy Studies
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To the
FDA
Approval Market
32
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
program’s cost and likely extend the time to licensure.
• FDA communication is essential for success.
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33
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
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