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Scott Stibitz, Ph.D.

Center for Biologics Evaluation and Research (CBER), FDA

Bethesda, Maryland

FDA Regulation of

Bacterial Vaccines

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)

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 DevelopmentVaccine Development

Pre INDPre IND

DevelopmentDevelopmentof Rationaleof RationaleBased on Based on DiseaseDiseasePathogenesisPathogenesis

Identify Identify Product Product Component(s)Component(s) Antigen(s),Antigen(s), adjuvant, etc.adjuvant, etc.

Development Development ofofManufacturing Manufacturing Process,Process,Preclinical Preclinical StudiesStudies

INDIND

ClinicalClinicalStudies,Studies,Additional Additional Non-clinical Non-clinical Development Development & Studies, & Studies, Scale-up and Scale-up and refinement of refinement of manufacturing manufacturing processprocess

IND = Investigational New Drug applicationIND = Investigational New Drug application

Stages of Vaccine Review and Regulation

Clinical Investigational Plan

Phase 1SafetyImmuno-genicity

Phase 2Immuno-genicitySafetyDose Ranging

Phase 3EfficacySafetyImmuno-genicity

BLA Data to support approval;Inspection

Phase 4InspectionSafetyEfficacyLot Release

BLA SupplementPost-approvalChanges:New IndicationsDosingManufactureEquip./Facilities

IND

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

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-INDMeeting:ManufacturingProduct Lot ReleaseAnimal safety &immunogenicityPhase 1 protocol

End-of-Phase 2Meeting:Efficacy trial protocol(s)Phase 1/2 dataUpdate:* Product, etc.Assay dataRationale

Pre-BLAMeeting:Clinical datasummary: S & EUpdate:* Product, etc.Outline of BLA

IND = Investigational New Drug ApplicationBLA = 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?