1. Laboratory of Methods Development and Quality Control Laboratory Overview September 22, 2005

2. LMDQC research and regulatory activities  Goal:Testing specialists; activities not limited to a specific product area  Clinical Immunoassay Assays used for clinical evaluation -Development of animal models that support “Animal Rule”  Product Testing and Quality Control Tests for potency, toxicity, and purity  Implementation of laboratory quality system Quality control of official testing activities

3. Laboratory of Methods Development and Quality Control

4. Laboratory History  September 1997 (last site visit) Laboratory of Pertussis -Biochemistry (Burns) -Applied Immunology and Vaccine Evaluation (Meade)  February 1998 Assumed responsibilities for anthrax vaccines  October 1999 Laboratory of Respiratory and Special Pathogens Laboratory of Methods Development and Quality Control

5. LMDQC vs. LRSP LRSP:Product area specialists “Is it the right test?” (Relevance) -Is the test addressing the appropriate characteristic of the product and/or immune response? LMDQC: Testing specialists “Is the test right?” (Reliability) -Is the test adequately designed and controlled? -Is the test adequate for intended purpose?

6. Laboratory of Methods Development and Quality Control  Regulatory Review (i.e., non-laboratory regulatory activities) Quality Control Laboratory (product testing)  Research Research program under review  Specific products Pertussis Anthrax (1998) Others

7. Overview of Regulatory Activities

8. LMDQC Regulatory Activities  Licensing Pre-approval -Investigational New Drug applications (IND) -Biologic Product License applications (BLA) Post-approval -Supplements to BLA (manufacturing +/or clinical) Product areas -Pertussis, anthrax, diphtheria, cholera, Lyme, typhoid, malaria “Animal Rule” -Animal models used to evaluate efficacy -Assays used to demonstrate that the functional immune response in humans is comparable to that shown to be protective in relevant animal models

9. LMDQC Regulatory Activities  Establishment inspections Product experts for pre and post-approval inspections  Lot release Prior to commercial distribution, lots of licensed vaccine must be released by CBER based on: -Review of documentation on manufacturing and testing -Testing (optional) of submitted samples  International harmonization and standardization  CBER initiative to implement quality system LMDQC lot release coverage -6 licensed products with pertussis component -1 licensed anthrax vaccine

10. Overview of Research Activities

11. Areas of responsibility: research  Clinical Immunoassay (Bruce Meade) Assays used in clinical evaluation -Humans -Animal models in support of licensing: “Animal Rule”  Product Testing and Quality Control (Juan Arciniega) Tests for potency, toxicity, and purity

12. Clinical Immunoassay Projects (Meade)  Pertussis Vaccine Serologic Diagnosis of Pertussis -Development and evaluation of simple, easily transferable immunoassay for IgG anti-PT -Collaboration with CDC Statistical Methods: Use of Coefficient of Variation -Nomogram Safety and immunogenicity of 4th and 5th doses of DTaP  Anthrax Vaccine Collaborative Study: Anthrax Clinical Immunoassays

13. Product Testing and Quality Control Projects (Arciniega)  Pertussis Vaccine Projects Refinement of a toxicity test for acellular pertussis vaccines International Collaborations: Pertussis Test Methods  Anthrax Vaccine Projects Anthrax Vaccine Potency Test Development -Mouse immunogenicity model Anthrax Vaccine Standards Development Anthrax Vaccine Formulation Studies HPLC Methods for Monitoring Antigens and In-Process Control  Diphtheria Vaccine Projects

14. Relevance of Research to Regulation State-of-the-art knowledge of the areas we regulate First-hand expertise to Design and evaluate tests used in assessment of product quality and effectiveness Troubleshoot problems encountered by manufacturer Contribute to international harmonization Design the efficacy studies for vaccines licensed under the Animal Rule Credibility in the field Problem solving approach

15. Impact of Research on Regulatory Mission: Examples  Acellular pertussis vaccines Clinical immunoassay -Developed procedures -Served as international reference laboratory -Applied immunoassays to clinical studies CBER mouse immunogenicity test served as basis for potency test described in WHO guidelines and EP monographs  Anthrax vaccine Applying bioassay experience to animal efficacy models Developing mouse immunogenicity test (potency) Assisting in optimizing and standardizing assays for clinical and product evaluation  Diphtheria vaccine Participating in collaborations aimed at development of alternative animal models