FDA Regulation of Bacterial Vaccines

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. 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 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

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 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…

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

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 • 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

21. The beginning?