Transcript FDA’s Role in Licensing Pandemic Influenza Vaccines

Regulation of Vaccines:
Challenges and Opportunities
Erik A. Henchal, Ph.D.
Associate Director
Office of Vaccines Research and Review
CBER/FDA
U.S. Vaccines
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Regulated by FDA Center for Biologics
Evaluation and Research (CBER) Office of
Vaccines Research and Review (OVRR)
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Authority resides in Section 351 of the
U.S. Public Health Service Act and the
Federal Food, Drug and Cosmetic Act.
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Thorough review of laboratory and clinical
data to ensure the safety, efficacy, purity
and potency of these products.
CBER’s Approach
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Regulation Goal: Balanced, Flexible, Responsive
 Assure the safety and rights of subjects
 Protect the public health
 Facilitate technological innovation & product development
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Influences
 Available scientific knowledge, pre-clinical, clinical
knowledge & experience
 Scientific research
 Crises/ tragic events
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Appropriate Risk Management
OVRR Supports the Critical Path Towards
Safe and Effective Vaccines
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Speed development of new technologies and facilities
Improved manufacturing methods
Improved evaluation tools and reference standards
Streamlined pre-clinical and clinical evaluations
Improved international cooperation
Effective vaccine review and release
Improved safety
Stages of Vaccine Review and Regulation
Clinical Investigational Plan
BLA
IND
Phase 1
Phase 2
Phase 3
Safety
Immunogenicity
Immunogenicity
Safety
Dose Ranging
Efficacy
Safety
Immunogenicity
IND = Investigational New Drug Application;
BLA = Biologics License Application
Data to
support
approval;
Inspection
Phase 4
Inspection
Safety
Efficacy
Lot Release
BLA
Supplement
Post-approval
Changes:
New Indications
Dosing
Manufacture
Equipment/
Facilities
PDUFA Meetings
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Type A: Immediately necessary for an otherwise
stalled drug development program (i.e. critical
path meeting). Scheduled within 30 days of written
request.
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Type B: pre-IND; certain end of phase I; end of
phase 2 and pre-BLA meetings. Scheduled within
60 days of written request.
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Type C: Any other meeting. Scheduled within 75
days of written request.
See Guidance for Industry: Formal Meetings With Sponsors and
Applicants for PDUFA Products http://www.fda.gov
Vaccine Licensure
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Vaccine development and commercialization
are complex processes.
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Licensure based upon demonstration of safety
and effectiveness, and ability to manufacture
in a consistent manner.
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The FDA is committed to fostering the
efficient, and rapid development of vaccines
needed for the public health.
Facilitating the Development and
Evaluation of New Vaccines
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Anticipating and Addressing the Regulatory Issues
for New Products
 General regulatory issues applicable to many
products or product classes
 Cell substrate issues
 Improved test methods (sensitivity, reliability,
etc.)
 Improved standards
 Product specific issues
 Correlates of protection necessary for efficacy
evaluation
 Improved assays (e.g., potency, efficacy)
 Animal models for efficacy evaluation
CMC Development
SAFETY INFORMATION
Source characterization
Components info.
Product Characterization
Testing/Qualification/
Clearance of impurities,
contaminants
DEVELOPMENT ACTIVITIES
Product Characterization
Specification Development
Formulation Development
Stability Studies
Component Characterization/ Manufacturing Process
Qualification
Control & Validation
Assay Development/ Validation
Process control esp. for
safety processes (e.g.,
sterilization, virus
clearance)
Incremental CMC
Discovery
Pre-clinical
Phase 3
Phase 1
Phase 2
BLA
CMC Content
Source Material
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Cells, Viruses, Banking Systems
 Origin/ Method of collection
 History (potential exposure)
 Manipulation, establishment of banks,
cryopreservation
 Testing – Source/ source material
(e.g., Microbiology, endogenous/ adventitious
agents, (bovine/ porcine), identity, purity, activity,
replication competent viruses)
Genetic material
 Origin
 Gene modification, construction of vector, purification
 Testing (e.g., sequencing)
CMC Content - Source Material
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Evaluation
 Risk assessment of parent cells - history, potential
exposure to viral agents
 Screening donors for risk factors, absence of disease
markers
Testing for viruses
 Endogenous virus testing
 Donors, animals, host cells, cell banks, EPC
 General and Species specific tests
 FDA-approved tests if available
Control
 Establishing & maintaining cell banks, viral seeds under
cGMP’s
 Closed herds & flocks, sentinel animals
 Quarantine until testing and control assures/ establishes
safety
CMC Contents - Components
All components (e.g., raw materials, excipients,
reagents, ancillary products) used in production
 Safety and quality of material
 Source, screening, testing
 Use in process, (evaluated in context of use)
 Known/ potential toxicities
 Penicillin, MTX, residual chemicals
 What is the amount in final product? Consider
testing, qualification study
 FDA-approved products (e.g., albumin) preferred
 Clinical-grade preferred
 Combination products (biologic, drug, device)
Develop qualification program during development
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What are cGMPs?
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Current Good Manufacturing Practices
(cGMP) cover a broad range of principles,
methods, and practices that are implemented
during product development and documented
to ensure consistent manufacture of quality
products
Good Laboratory Practices (GLPs) support
the conduct of nonclinical laboratory studies;
purpose is to ensure the quality and integrity
of the safety data; support IND and BLA’s
cGMPs
CMC
Review
Submitted
Inspection
Companion
On-site
•Personnel
•Quality Control
•Source Material
•Facilities
•Components
•Manufacturing Process •Equipment
•Process Controls
•Laboratory Control
•Analytical Procedures •Component Control
•Specifications
•Production Control
•Stability
•Distribution
•Records
•Labeling
cGMPs
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Recommend that cGMPs be in effect for
manufacture of products used in clinical
IND studies - starting with Phase 1 studies
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Follow general approaches and principles
that are broadly applicable, tailor cGMP
application to product, process and facility
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Assess risks and take appropriate actions
Process Validation – Considerations
Reasons for Validation
 Quality cannot be inspected or
tested into the finished product
“Quality
By Design”
 Quality safety and effectiveness
must be designed and built into the
raw material properties product
 Each step must be controlled to
maximize the probability that the
process
finished product meets all
conditions
specifications
environmental
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Design
Space
Process Validation – Considerations
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Foundation for validation
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Process and product understanding
“knowledge”
 Well
defined and designed product and
manufacturing process to consistently deliver high
quality product
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Accurate measure and control of variability
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Consider all sources of variability
Product lifecycle impact
 Supported by documentation, data
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Expediting the Review Process:
Formal Mechanisms
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BLA Standard Review: 10 month review
Clinical Efficacy Supplement
 10 month review
CMC Supplement
 4 month review
Priority Review
 6 months
Fast Track
Accelerated Approval
 http://www.fda.gov/cber/guidelines.htm
Fast Track
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Incorporates an end of Phase I meeting
Allows for more frequent communications
with the FDA
May allow for a “rolling” review of the BLA
May allow for an accelerated approval of the
product
Designed to facilitate the development and
expedite the review of new drugs that are
intended to treat serious or life-threatening
conditions and that demonstrate the
potential to address unmet medical needs.
Accelerated Approval
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Surrogate endpoints likely to predict clinical
benefit (314.510, 601.40).
Post-licensure studies required (usually
ongoing) to demonstrate effects on clinical
outcomes.
Restrictions on use or distribution possible.
Potential problems obtaining controlled data.
Withdrawal if agreements violated/not safe &
effective.
Can approve through regular mechanisms with
validated surrogate.
Challenges
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Epidemiology may preclude “field trials”, the usual
source of efficacy data
May not be able to conduct human challenge or
protection studies for ethical or cultural considerations
Animal Rule
21 CFR 314.600
FDA may approve a product for which …
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Human safety has been established, and
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“Animal Rule” requirements are met – 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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Not an approach that will necessarily expedite
approval.
Examples of Potential Agents for “Animal
Rule” Applications
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Smallpox
Anthrax
Botulism
Plague
Tularemia
Viral hemorrhagic fevers
Alphaviruses
SARS
Animal Rule Considerations
 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 (unless there is already a sufficiently
characterized model) expected have a response
predictive for humans.
 The animal study endpoint is clearly related to the
desired benefit in humans: enhancement of survival or
prevention of major morbidity.
 Kinetics and pharmacodynamics of the product or other
relevant data or information in animals and humans
allows selection of an effective dose in humans.
Emergency Use Authorization (EUA)
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Secretary of HHS can declare an emergency after Secretary
of Defense, Homeland Security, or HHS determines an
emergency (or potential for) exists.
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Secretary of HHS can authorize use of an unapproved
product or unapproved use of an approved product if:
 Agent can cause serious or life-threatening disease or
condition;
 No adequate and sufficiently available approved
alternative;
 Product’s known and potential benefits must outweigh
known and potential risks; and
 The product may be effective.
Granted for up to 1 year, or until termination of
declaration or revocation; can be renewed.
CBER Available Information
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Internet www.fda.gov/cber
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Fax Information System
 In US toll-free: 1-888-CBER-FAX (1-888223-7329)
 Outside US: 301-827-3844
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Manufacturers assistance:
[email protected]
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CBER Voice Information System at:
 1-800-835-4709 or 301-827-1800
Summary
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The U.S. FDA is facilitating the development,
production and regulatory review of vaccines.
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Many opportunities exist to seek FDA review of
developmental plans.
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Risk management throughout the vaccine
development life cycle is critical.
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Flexible regulatory approaches are available,
especially for serious or life threatening
conditions or unmet medical needs.