1. Division of Bacterial, Parasitic and Allergenic Products OVRR/CBER/FDA

2. Laboratory Mission and Functions Research Review Post-licensure surveillance –Inspection/compliance –Lot release testing/protocol review –Label/promotional activity review Consultations with outside organizations Assure Safe and Effective Products for Immunological Control of Bacterial, Parasitic and Allergenic Agents Affecting Human Health

3. DBPAP Role in Regulatory Review and Approval Pre-IND IND License Meeting with sponsors to provide guid- ance Rev. of orig. Submission & all subsequent ammendments Tech. Advice for product and assay development Rev. product manf. data & determin- ation of prod. specs. Meet with sponsors Present prod. To Advisory Comm. Meet with spon- sors Eval. Assays to measure clinical response to prod. Eval. product characterization methods & assays Rev. of final prod. manuf. process, in- cluding in process & final product specs. Est. lot release protocols for CBER product release Conduct pre-approval inspection of the facility

4. DBPAP Role in Regulatory Review and Approval Pre-IND IND LicensePost Licensure Review of Biological Deviation reports from industry Participation in biannual inspections of licensed products Review of post approval commitments Review of subsequent supplements for changes to maufacture or additional indications Meet with sponsors

5. Possible New or Improved Products Respiratory Pathogens –Streptococcus pneumoniae –Mycobacterium tuberculosis –Pseudomonas aeruginosa –Neisseria meningitidis A,B,C,Y,W125 –Group B Streptococci –Bordetella pertussis –Chlamydia pneumoniae –Corynbacterium diphtheriae –Non-typeable H. influenzae –Moraxella catarrhalis Sexually Transmitted Pathogens –Neisseria gonorrheae –Chlamydia trachomatis Pathogens Encountered by Penetrating Inoculation –Borrelia burgdorfi –Plasmodium species –Leishmania species –Clostridium tetani –Staphylococcus aureus –Schistosoma species –Trypanosoma cruzi Special Pathogens (BT) –Bacillus anthracis –Clostridium botulinum –Franciscella tularensis –Yersinia pestis

6. Possible New or Improved Products Diarrhea-Causing Pathogens –Enterotoxigenic E. coli –Shigella species –Vibrio cholerae –Campylobacter jejuni Other Mucosally-Trafficking Pathogens –Clostridium difficile –Salmonella typhi –Mycobacterium leprae –Helicobacter pylori –STEC and EPEC Allergenic Antigens –Latex –Cockroach –Short ragweed Skin Test Antigens –PPD –Coccidioidin –Leishmania

7. Division of Bacterial, Parasitic and Allergenic Products (DBPAP) Laboratory of Immunobiochemistry Jay Slater, M.D.-Chief Immediate Office of the Director Richard Walker, Ph.D.-Director Milan Blake, Ph.D.-Deputy Director Regulatory Staff Administrative Staff Laboratory of Methods Development and Quality Control Bruce Meade, Ph.D.-Chief Laboratory of Respiratory and Special Pathogens Drusilla Burns, Ph.D.-Chief Laboratory of Bacterial Polysaccharides Milan Blake, Ph.D.- Acting Chief Laboratory of Enteric and Sexually Transmitted Diseases Dennis Kopecko, Ph.D.-Chief Laboratory of Mycobacterial Diseases and Cellular Immunology Sheldon Morris, Ph.D.-Chief Laboratory of Bacterial Toxins Willie Vann, Ph.D.-Chief Laboratory of Biophysics Richard Pastor, Ph.D.-Chief

8. Laboratory of Methods Development and Quality Control Research activities: Develop and evaluate –Quality control methods for bacterial vaccines –Serological methods for immune response measurement –Animal models Gastrointestinal anthrax Bioassays for potency and toxicity Issues and observations –Recruiting for 1 position –Lab chief

9. Laboratory of Biophysics Areas of Research Characterization of biopolymers (polysaccharides, proteins DNA) and macromolecular assemblies (vaccine/adjuvant complexes, membranes, micelles). High-end instrumentation, including NMR, light scattering, mass spec. Computer simulation methods for molecular modeling and analysis of complex data. Issues and Observations Integration as CBER high technology resource under review

10. Laboratory of Bacterial Polysaccharides Areas of Research Characterization of immune responses to polysaccharide and conjugate vaccines Standardization of methods for relevant clinical application Development of novel physical and chemical methods for improved evaluation of licensed and experimental vaccines Characterization of innovative approaches to vaccine development, and evaluation of epidemiologic aspects of vaccine candidates Issues and Observations Polysaccharide immunology group added Mucosal immunity effort recommended Lab go-away to develop focus and transition strategy

11. LABORATORY OF BACTERIAL TOXINS Areas of Research Neurotoxins Group –Mechanism of toxin entry into nerve cells –Interaction toxin with cellular components –Mechanism of toxin persistence Corynebacteria Group –Identification and characterization of iron regulated virulence factors in C. diphtheria Glycobiology Group –Mechanism of bacterial capsular polysaccharide biosynthesis –Binding of neurotoxins to glycolipid receptors Issues and Observations Development of neurotoxin assays Decreased emphasis on B. anthracis Increased emphasis on vaccine design

12. Laboratory of Respiratory and Special Pathogens Areas of Research Bordetella pertussis, Bacillus anthracis, and Yersinia spp. Characterization of Virulence Factors and Studies on Mechanism of Action Studies on Regulation of Gene Expression Animal Models of Infection

13. The Laboratory of Mycobacterial Diseases and Cellular Immunology Areas of Research Evaluation of protective innate and adaptive immune responses to intracellular bacteria Assessment of live attenuated TB vaccine strains and DNA vaccination strategies against tuberculosis Characterization of a unique family of tuberculosis proteins Issues and Observations Malaria effort lacks investigator SVC recommended recruitment of MD with research background in human immune response to study correlations of human and animal responses

14. Laboratory of Enteric and Sexually Transmitted Diseases Areas of Research Invasion mechanisms of enteric pathogens Genetic regulation of bacterial virulence genes Mucosal immunity, dosing and adjuvants Anthrax and Shigella - Genetic analysis and development of live attenuated Salmonella- vectored vaccines Issues and Observations Mucosal Immunity group added STD work moved to LBP

15. Laboratory of Immunobiochemistry Areas of Research Allergen structure and function Immunomodulation of allergic responses Chemokines and chemokine receptors in the modulation of immune responses Issues and Observations Cockroach allergen standardization: collaboration with NIAID Increased attention to human T cell responses to allergens role of endotoxin in the safety and efficacy of allergen vaccines human antibody responses to cockroach allergens Decreased emphasis on latex allergens hymenoptera allergens

16. Promotion Plan

17. DBPAP Funding Salary and OVHD from FDA base Expendibles and Equipment –General FDA Appropriation Division operating funds Special needs funds Per capita distribution of remainder evenly among staff involved –CT Funds Handled similarly to general appropriation Divided among CT staff –Extramural Funds Go directly to recipient –Year End Funds

18. Challenges and Realities Facing Researcher/Reviewers Funding levels uncertain from year to year; dependent upon appropriation process Bureaucratic hurdles Timing of workload determined by sponsor submissions, not by CBER

19. Evaluation Components Review Individual Review Program Comment on Current and Future Directions

20. DBPAP Program Focus Areas Standardization of Assay Methods for Bacterial, Parasitic and Allergenic Substances –LMDQC, LB, LIB, LP, LESTD, LBT, LRSP, LMDCI Pertussis and Other Toxin-Mediated Diseases –LMDQC, LB, LBT, LRSP Mycobacterial and Other Intracellular parasites –LMDCI Mucosal Pathogenesis and Immunization –LESTD Allergenic Products and Allergenic Diseases –LB, LIB Products to Combat Bioterrorism Agents –LMDQC, LB, LESTD, LBT, LRSP, LMDCI New Technologies for Characterization of Biologics –LB

21. Laboratory of Methods Development and Quality Control Areas of Research Develop and evaluate –Quality control methods for bacterial vaccines –Serological methods for immune response measurement –Animal models Gastrointestinal anthrax Bioassays for potency and toxicity Issues and Observations Recruiting for 1 position Lab Chief

22. Bioterrorism Program Research/Review for: –B. anthracis –F. tularensis –Y. pestis –Botulinum toxin Research Areas: –Genetic manipulation and regulation –Virulence factors –Vaccine improvement –Immunologic assay standardization Cutaneous anthrax infection