1. Regulation of Vaccines: Challenges and Opportunities
Erik A. Henchal, Ph.D. Associate Director
Office of Vaccines Research and Review CBER/FDA

2. U.S. Vaccines
Regulated by FDA Center for Biologics Evaluation and Research (CBER) Office of Vaccines Research and Review (OVRR)
Authority resides in Section 351 of the U.S. Public Health Service Act and the Federal Food, Drug and Cosmetic Act.
Thorough review of laboratory and clinical data to ensure the safety, efficacy, purity and potency of these products.

3. CBER’s Approach Regulation Goal: Balanced, Flexible, Responsive
Assure the safety and rights of subjects
Protect the public health
Facilitate technological innovation & product development
Influences
Available scientific knowledge, pre-clinical, clinical knowledge & experience
Scientific research
Crises/ tragic events
Appropriate Risk Management

4. OVRR Supports the Critical Path Towards Safe and Effective Vaccines
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

5. Stages of Vaccine Review and Regulation Clinical Investigational Plan
Phase 4
Inspection
Safety
Efficacy
Lot Release
Clinical Investigational Plan
BLA
Data to support approval;
Inspection
IND
Phase 1
Safety
Immuno-
genicity
Phase 2
Immuno-genicity
Safety
Dose Ranging
Phase 3
Efficacy
Safety
Immuno-genicity
BLA Supplement
Post-approval
Changes:
New Indications
Dosing
Manufacture
Equipment/
Facilities
IND = Investigational New Drug Application;
BLA = Biologics License Application

6. PDUFA Meetings
Type A: Immediately necessary for an otherwise stalled drug development program (i.e. critical path meeting). Scheduled within 30 days of written request.
Type B: pre-IND; certain end of phase I; end of phase 2 and pre-BLA meetings. Scheduled within 60 days of written request.
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

7. Vaccine Licensure
Vaccine development and commercialization are complex processes.
Licensure based upon demonstration of safety and effectiveness, and ability to manufacture in a consistent manner.
The FDA is committed to fostering the efficient, and rapid development of vaccines needed for the public health.

8. Facilitating the Development and Evaluation of New Vaccines
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

9. DEVELOPMENT ACTIVITIES
CMC Development
SAFETY INFORMATION
Source characterization
Components info.
Product Characterization
Testing/Qualification/ Clearance of impurities, contaminants
Process control esp. for safety processes (e.g., sterilization, virus clearance)
DEVELOPMENT ACTIVITIES
Product Characterization
Formulation Development
Component Characterization/
Qualification
Assay Development/ Validation
Specification Development
Stability Studies
Manufacturing Process
Control & Validation
Incremental CMC
BLA
Phase 3
Discovery
Phase 2
Phase 1
Pre-clinical

10. CMC Content Source Material
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)

11. CMC Content - Source Material
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

12. 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

13. What are cGMPs?
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

14. cGMPs CMC Review Inspection Submitted On-site Companion Personnel
Source Material
Components
Manufacturing Process
Process Controls
Analytical Procedures
Specifications
Stability
Personnel
Quality Control
Facilities
Equipment
Laboratory Control
Component Control
Production Control
Distribution
Records
Labeling

15. cGMPs
Recommend that cGMPs be in effect for manufacture of products used in clinical IND studies - starting with Phase 1 studies
Follow general approaches and principles that are broadly applicable, tailor cGMP application to product, process and facility
Assess risks and take appropriate actions

16. Process Validation – Considerations
Reasons for Validation
Quality cannot be inspected or tested into the finished product
Quality safety and effectiveness must be designed and built into the product
Each step must be controlled to maximize the probability that the finished product meets all specifications
“Quality
By Design”
raw material properties
Facilitate process/ product understanding & process improvement - post-approval changes
Implementation/ enhancement of modern quality system for FDA & Manufacturers
Add desired state
While 1987 guideline provides useful information, additional considerations need further elaboration
PAT started before CGMP same true for PV thinking
Control of variability from multiple sources
raw/ materials components
manufacturing process operations
process
conditions
environmental
Design Space

17. Process Validation – Considerations
Foundation for validation
Process and product understanding “knowledge”
Well defined and designed product and manufacturing process to consistently deliver high quality product
Accurate measure and control of variability
Consider all sources of variability
Product lifecycle impact
Supported by documentation, data

18. Expediting the Review Process: Formal Mechanisms
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

19. Fast Track 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.

20. Accelerated Approval
Surrogate endpoints likely to predict clinical benefit ( , ).
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.

21. Challenges
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

22. Animal Rule 21 CFR 314.600 FDA may approve a product for which …
Human safety has been established, and
“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.
Not an approach that will necessarily expedite approval.

23. Examples of Potential Agents for “Animal Rule” Applications
Smallpox
Anthrax
Botulism
Plague
Tularemia
Viral hemorrhagic fevers
Alphaviruses
SARS

24. 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.

25. Emergency Use Authorization (EUA)
Secretary of HHS can declare an emergency after Secretary of Defense, Homeland Security, or HHS determines an emergency (or potential for) exists.
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.

26. CBER Available Information
Internet
Fax Information System
In US toll-free: CBER-FAX ( )
Outside US:
Manufacturers assistance:
CBER Voice Information System at: or

27. Summary
The U.S. FDA is facilitating the development, production and regulatory review of vaccines.
Many opportunities exist to seek FDA review of developmental plans.
Risk management throughout the vaccine development life cycle is critical.
Flexible regulatory approaches are available, especially for serious or life threatening conditions or unmet medical needs.