FDA Regulation
of
Bacterial Vaccines
Scott Stibitz, Ph.D.
Center for Biologics Evaluation and
Research (CBER), FDA
Bethesda, Maryland
1
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 PSProtein conjugate
• Recombinant antigens: (investigational)
• Vectored and DNA vaccines: (investigational)
Licensed biological products, including
vaccines, must be:
•
•
•
•
Safe
Pure
Potent
Manufactured consistently according to
Current Good Manufacturing Practices
(CGMPs)
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.”
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.”
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.”
Vaccine Development
Pre IND
Development
of Rationale
Based on
Disease
Pathogenesis
Identify
Product
Component(s)
Antigen(s),
adjuvant, etc.
IND
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
Stages of Vaccine Review and Regulation
Clinical Investigational Plan
Phase 4
Inspection
Safety
Efficacy
Lot
Release
IND
BLA
Phase 1
Phase 2
Phase 3
Safety
Immunogenicity
Immunogenicity
Safety
Dose
Ranging
Efficacy
Safety
Immunogenicity
Data to
support
approval;
Inspection 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.)
FDA’s Primary Objectives in
Reviewing an IND
• 21 CFR 312.22(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
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
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
FDA Potency Regulations
• 21 CFR 600.3 (s):
– The word potency is interpreted to mean the
specific ability or capacity of the product…to
effect a given result.
• 21 CFR 610.10:
– 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…
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
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.
Vaccine Nonclinical Studies
 Product Characterization
 Attenuation (Live Organisms)
 Inactivation/Reversion
 Absence of Adventitious Agents
 Pyrogenicity
 Potency, Immunogenicity
 Challenge/Protection Studies
 Toxicity study (novel products)
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
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)
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
Meetings with FDA
(21 CFR 312.47)
Phase 1
Phase 2
Phase 3
License
Application
Pre-IND
Meeting:
End-of-Phase 2
Meeting:
Pre-BLA
Meeting:
Manufacturing
Product
Lot Release
Animal safety &
immunogenicity
Phase 1 protocol
Efficacy trial
protocol(s)
Phase 1/2 data
Update:*
Product, etc.
Assay data
Rationale
Clinical data
summary:
S&E
Update:*
Product, etc.
Outline of BLA
IND = Investigational New Drug Application
BLA = Biologics License Application
Available Resources
• CBER/FDA main web site
– http://www.fda.gov/cber/
• CBER webpage on submitting an IND
– http://www.fda.gov/cber/ind/ind.htm
• CBER FAQs
– http://www.fda.gov/cber/faq.htm
• Food and Drug Related Laws
– http://www.fda.gov/opacom/laws/
• Code of Federal Regulations (CFR)
– http://www.gpoaccess.gov/cfr/index.html
• CBER Guidance Documents
– http://www.fda.gov/cber/guidelines.htm
• BSE/TSE issues including estimating risk
– http://www.fda.gov/cber/bse/bse.htm
The beginning?