1. FDA Regulation of Bacterial Vaccines
Scott Stibitz, Ph.D.
Center for Biologics Evaluation and Research (CBER), FDA
Bethesda, Maryland

2. Types of Bacterial Vaccines
Live, attenuated: Salmonella Ty21A
Inactivated: Diphtheria and Tetanus toxoids
Crude or purified antigens derived from living or killed cells: acellular pertussis antigens, polysaccharides (PS)
Conjugate vaccines: Hib and pneumococcal PS-Protein conjugate
Recombinant antigens: (investigational)
Vectored and DNA vaccines: (investigational)

3. Licensed biological products, including vaccines, must be:
Safe
Pure
Potent
Manufactured consistently according to Current Good Manufacturing Practices (CGMPs)

4. FDA Regulatory Definitions
Safety (21 CFR 600.3(p)): “…the relative freedom from harmful effect to persons affected, directly or indirectly, by a product when prudently administered, taking into consideration the character of the product in relation to the condition of the recipient at the time.”

5. FDA Regulatory Definitions
Purity (21 CFR 600.3(r)): “…relative freedom from extraneous matter in the finished product, whether or not harmful to the recipient or deleterious to the product. Purity includes but is not limited to relative freedom from residual moisture or other volatile substances and pyrogenic substances.”

6. FDA Regulatory Definitions
Potency (21 CFR 600.3(s)): “…the specific ability or capacity of the product, as indicated by appropriate laboratory tests or by adequately controlled clinical data obtained through administration of the product in the manner intended, to effect a given result.”

7. IND = Investigational New Drug application
Vaccine Development
Pre IND
IND
Development
of Rationale
Based on Disease
Pathogenesis
Identify Product Component(s)
Antigen(s),
adjuvant, etc.
Development of
Manufacturing Process,
Preclinical Studies
Clinical
Studies,
Additional
Non-clinical Development & Studies,
Scale-up and refinement of manufacturing process
IND = Investigational New Drug application

8. Stages of Vaccine Review and Regulation
Clinical Investigational Plan
Phase 4
Inspection
Safety
Efficacy
Lot Release
IND
BLA
Data to support approval;
Inspection
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
Equip./Facilities
IND = Investigational New Drug Application; BLA = Biologics License Application
(BLAs analogous to NDAs for Drugs. BLAs & NDAs are marketing applications.)

9. FDA’s Primary Objectives in Reviewing an IND
21 CFR (a)
In all phases of the investigation, to assure the safety and rights of subjects
In Phase 2 and 3, to help assure that the quality of the scientific evaluation of drugs is adequate to permit an evaluation of the drug’s effectiveness and safety

10. CMC Information for Bacterial Vaccines
Strain construction and/or characterization*
Cell banks: methods for manufacture,
characterization*
Fermentation conditions*
Purification methods
Final formulation procedures
In-process testing
Lot release testing
Plan for stability testing
*TSE issues

11. Lot Release Testing
Sterility (microbial purity) – absence of bacterial or fungal contaminants
General safety test - guinea pigs and mice to detect extraneous toxic contaminants
Identity test - e.g. SDS-PAGE, Western blot, immunologic assay or amino acid analysis
Purity - e.g. % moisture, SDS-PAGE, HPLC, endotoxin
Potency - in vivo or in vitro test to assess immunogenicity, antigen content, or chemical composition
Tests for removal of process contaminants, as applicable

12. FDA Potency Regulations
21 CFR (s):
The word potency is interpreted to mean the specific ability or capacity of the product…to effect a given result.
21 CFR :
Tests for potency shall consist of either in vitro or in vivo tests, or both, which have been specifically designed for each product so as to indicate its potency…

13. Product Potency Test
Ideally, predictive of effective human immune response
Ideally, correlation of a lab assay or animal immune response with expected human immunological response in dose-dependent manner
Used to demonstrate that product meets predefined acceptance and/or rejection criteria (lot to lot consistency)
Critical parameter for product stability
Examples:
Live attenuated bacteria - colony forming units
Purified antigen - mouse immunogenicity
Purified polysaccharide - size distribution

14. Vaccine Adjuvants
Adjuvant - an agent that is added to, or used in conjunction with, a vaccine antigen to augment or potentiate (and possibly target) the specific immune response to the antigen
Adjuvants alone are not licensed; each specific vaccine formulation (antigen/adjuvant combination) is licensed
To date, aluminum compounds are the only adjuvants included in currently licensed vaccines
In 2009 FDA licensed Cervarix™ (HPV), that uses aluminum hydroxide and monophosphoryl lipid A (MPL) as an adjuvant and is the first vaccine licensed by the FDA that includes MPL as an adjuvant.

15. Vaccine Nonclinical Studies
Product Characterization
Attenuation (Live Organisms)
Inactivation/Reversion
Absence of Adventitious Agents
Pyrogenicity
Potency, Immunogenicity
Challenge/Protection Studies
Toxicity study (novel products)

16. Nonclinical Safety Studies
Study design based on intended clinical use
Relevant animal model
Vaccine immunogenic in chosen species
Non-human primates usually not necessary
Minimize animal use by combining safety and immunogenicity evaluations
Evaluation of product-specific concerns
Developmental toxicity studies (prior to study specifically enrolling pregnant women)
Safety studies conducted under GLPs
i.e. route of administration, type of response elicited

17. Chlamydia vaccine questions
How much efficacy must be demonstrated?
How long must immunity last?
What about multiple-serotypes?
Is a correlate of immunity or protection necessary?
What about possible exacerbation of disease? (severity or incidence)

18. Possible approaches to exacerbation concerns
Might be worthwhile establishing unambiguously the existence of the problem
Animal model of exacerbation would be very helpful
Establishing an immunological correlate to potential for exacerbation would be helpful

19. Meetings with FDA (21 CFR 312.47)
Phase 1
Phase 2
Phase 3
License
Application
Pre-IND
Meeting:
Manufacturing
Product
Lot Release
Animal safety &
immunogenicity
Phase 1 protocol
End-of-Phase 2
Meeting:
Efficacy trial
protocol(s)
Phase 1/2 data
Update:*
Product, etc.
Assay data
Rationale
Pre-BLA
Meeting:
Clinical data
summary:
S & E
Update:*
Product, etc.
Outline of BLA
IND = Investigational New Drug Application
BLA = Biologics License Application

20. Available Resources CBER/FDA main web site http://www.fda.gov/cber/
CBER webpage on submitting an IND
CBER FAQs
Food and Drug Related Laws
Code of Federal Regulations (CFR)
CBER Guidance Documents
BSE/TSE issues including estimating risk

21. The beginning?