1. Office of Blood Research and Review Overview of Research Jay S. Epstein, M.D. Director, OBRR, CBER Blood Products Advisory Committee Meeting March 10, 2006

3. OBRR Functional Statement OBRR is the primary FDA component responsible for facilitating the development, approval, and access to safe and effective blood products. More specifically OBRR performs scientific functions related to regulation of: –Blood derived and analogous products –Medical devices used to test, collect, process or store donated blood –Retroviral diagnostic tests

4. Director Jay S. Epstein, M.D. Deputy Director Jonathan Goldsmith, M.D. Associate Director for Research Vacant (Dr. C.D. Atreya, Acting) Associate Director for Regulatory Affairs Vacant (Dr. S. Nedjar, Acting) Associate Director for Medical Affairs (Vacant) Associate Director for Policy (vacant) Policy and Publication Staff Division of Emerging & Transfusion Transmitted Diseases Director Hira L. Nakhasi, Ph.D. Deputy Director Paul Mied, Ph.D. Division of Hematology Director Basil Golding, M.D. Deputy Director Susan Abbondanzo, M.D. Division of Blood Applications Director Alan E. Williams, Ph.D. Deputy Director Sharyn Orton, Ph.D. OFFICE OF BLOOD RESEARCH AND REVIEW

5. OBRR Product Responsibilities Division of Blood Applications –Blood and plasma licenses –Blood establishment software –Blood grouping and HLA reagents Division of Emerging and Transfusion Transmitted Diseases –Blood donor screening tests for infectious agents –Retroviral diagnostics Division of Hematology –Bacterial detection devices –Plasma-derived products (IGIV, albumin, coagulation products) –Blood and blood component collection devices –Hemoglobin-based oxygen carrying solutions

6. Received Completed 510(k)s 69 (4 Special) 81 (8 Special) PMAs 2 1 PMSs 22 (15 PMS30) 27 (14PMS30) (A)NDA/ sup 68 (Incl 1 NDA) 87 BLAs 15 6 BLSs 1037 1212 *revised OBRR Review Workload CY 2004*

7. Received Completed 510(k)s 57 (9 Special) 53 (7 Special) PMAs 7 0 PMSs 12 (6 PMS30) 13 (7 PMS30) (A)NDA/ sup 30 (Incl 1 NDA) 18(Incl 1 NDA) BLAs 18 12 BLSs 767 724 OBRR Review Workload CY 2005

8. OBRR Highlights in FY’04-5 Product development and approval –Rapid test for HIV-1/2 on oral fluid –Barcode scanner for unit/recipient matching –Stand-alone CAI system –New immunohematology, anti-D and IGIV products –NAT for HBV –Tests for bacterial contamination –Novel test for anti-HBc –WNV assay for donor screening –Platelet pooling and store set –New hepatitis B immune globulin –First immune globulin for subcutaneous use

9. OBRR Highlights in FY’04-5 Guidance and Rulemaking –Barcode rule –Draft UDHQ –NAT for HIV-1 and HCV –Evaluation of HBOC –WNV screening –Automated platelet collection –Collection of disease-associated SP –Clinical trials of IGIV in PID

10. OBRR Highlights in FY’04-5 Workshops –Plasma freezing –Platelet standards –Review standards for IGIV –Society for Gene Amplification Technology –IPFA/PEI NAT Workshop –Product development for rare plasma protein disorders –Leukocyte reduction Review Management –Office SOP’s (510(k), BLA/BLS, industry meetings) –Review checklist for apheresis components

11. Special Role for OBRR Research Unique position to identify cross-cutting issues Opportunity to coordinate efforts across the spectrum of blood issues and amongst diverse industries involved in manufacturing blood and blood products –Product characterization –Safety and efficacy determinations –Supply impacts Resolve scientific questions critical to regulation Enhance scientific quality of product reviews Maintain capacity to investigate product failures

12. Historical Examples of Critical Path Research in OBRR 1950’s - Stability of albumin 1960’s - Clotting factor potency 1970’s - Toxicity of PPF from PKA 1980’s - HIV safety of plasma fractions 1990’s - HCV safety of IGIV 2000’s – Ongoing initiatives NAT for HIV and HCV Toxicity of hemoglobin solutions TransNet model for monitoring blood shortages Donor screening for West Nile Virus Products to address bioterrorism

13. OBRR Research Highlights in FY’04-5 –Establishment of standards for thrombin and anti-D Ig –Development of nucleic acid standards for HIV and WNV –Mapping murine genes that control the antibody response to FIX –Chemistry of O-Raffinose Cross-linked hemoglobin –Tracking fatalities from TRALI –Cognitive evaluation of the donor history questionnaire –Statistical QC methods for blood components –Modeling TSE decontamination methods –TSE risk assessment for plasma derivatives –Oligonucleotide chip to detect bloodborne pathogens –Development of NAT for detection of malaria –Investigation of possible viremia after smallpox vaccination –Effect of smallpox vaccination on donor screening tests

15. Critical Path Opportunity: Detection of Blood Borne Pathogens Issue Blood safety –Need for development of technologies and methodologies that can screen blood donors for a large number of pathogens simultaneously

16. Critical Path Opportunity: Detection of Blood Borne Pathogens, cont. Actions Develop “multiplex” NAT and DNA microarrays for blood donor screening Develop and provide FDA reference panels Outcomes Identify critical parameters for assay development Standardized panels used as a target for industry and to assess different assays Reduce the investment costs for industry

17. Microarray for Detection of Blood-borne and BT Pathogens Group 1: Bacteria, and Parasites Ba: Bacillus anthracis (anthrax) Ft: Francisella tularensis (tularemia) LT: Leishmania /Trypanosoma Yp: Yersinia pestes and pseudotuberculosis (plague) Group 2: Bioterror Viruses POX: Pox viruses VAC: Vaccinia VAR: Variola (Smallpox) MPV: Monkeypox Viruses CPV: Cowpox Viruses NOVAC: All Pox viruses but Vaccinia EBO: Ebola Viruses VE: Venezuelan Equine Encephalitis Viruses VETD: VE Trinidad Donkey MBG: Marburg Viruses BA1 B A2 B A3 IC LT 3 LT 2 LT 1 FT 3 FT 2 FT 1 YP3 YP 2 YP 1 POX a+ CPV a+ POX b+ VA C a+ VAC b+ V AR a+ MPV a+ NOV AC a+ NOVAC b+ POX c+ EBO 1a EBO gp a EBO 1b EBO 1c EBO 2a EBO 2b EBO 2c EBO gp c EBO gp b VE 2a VE 2b VE 2c VE 3a VE 3b VE 4a VE 4b VE 4c VE 8a VE 5a VE 5b VE 5c VE 6a VE 6b VE 6c VE 7a VE 7b VE 7c W N V 1b VE 8b VE8 c VE TD a VE TD b VE TD c WN V 1c HC V-b MB G 1a MB G 1b WN V 3a MB G 2c WN V 3b WN V 3c8a HC V-a MB G 2a MB G 2b HC V-c HB V 2c VE 8a MB G 1c HB V 1a HB V 1b HIV -a HV B 2c HTL V 3b HTL V 3a HIV -c HIV -b HTL V 4 b HB V 2a HTL V 4a HTL V 3c HTL V 4c G 1 G2 G3 4 internal control probes (Human rRNA gene) Group 3: Blood Borne Viruses WNV: West Nile Viruses HCV: Hepatitis C Viruses HBV: Hepatitis B Viruses HIV: Human Immunodeficiency Viruses HTLV: Human T-cell Leukemia Viruses Results of detection in pathogen-spiked blood – 50 cells/ml Bacillus anthracis livestock vaccine strain Francisella tularensis Live Vaccine Strain Yersinia pseudotub. IC

18. Critical Path Opportunity: Counterterrorism – Safety of Smallpox Vaccination Issue Smallpox vaccination can cause life- threatening complications in immunodeficient and eczematous individuals Efficacy of Vaccinia immune globulin (VIG) as treatment cannot be tested in humans

19. Critical Path Opportunity: Counterterrorism – Smallpox Vaccination, cont. Actions Development of a SCID mouse model to test efficacy of VIG Outcomes Transfer of methodology to industry Incorporation of this model helps provide a pathway for licensure of new VIGIV products

20. Pre-Exposure Prophylaxis with VIGIV 40 mg VIGIV given i.p. to mice at indicated times pre- exposure to 10 6 PFU of vaccinia NYCBOH

21. Critical Path Opportunity: Hemoglobin- Based Oxygen Carriers Issues Blood availability for trauma victims in rural areas and in disaster situations (e.g., war or bioterrorism attack) Toxicity of early generation of Hb-based oxygen carrying solutions –Vasoconstriction –High blood pressure –Multiple organ damage

22. Critical Path Opportunity: Hemoglobin-Based Oxygen Carriers, cont. Actions Identified the link between the “oxidative chemistry” of a given hemoglobin and its toxicity Developed Endothelial Cell/Animal-based Model Systems to promote understanding of blood substitute toxicity

23. Critical Path Opportunity: Hemoglobin- Based Oxygen Carriers, cont. Outcomes Preclinical testing is becoming more predictive of clinical performance Design of second generation Hb-based blood substitutes was facilitated

24. Critical Path: Potential Initiatives Detection of blood-transmissible agents –NAT to detect bacteria and parasites in blood –Potential role of gene chip and nanotechnology for rapid, multiplexed pathogen detection in blood –Diagnostic and donor screening tests for transmissible spongiform encephalopathies –Establishment of cell lines expressing Toll Like Receptors for detecting microbial components in plasma-derived products

25. Critical Path: Potential Initiatives Assessment of Blood Product Safety –Animal inoculation studies to evaluate the infectivity of WNV at low titer in blood –Animal model to predict immunogenecity of factor VIII products –New NAT standards (e.g. parvovirus B19) Blood Product Potency –Development of an animal model to test function of modified platelets –Standards for additional plasma-derived products (e.g., Alpha 1 PI)

26. Conclusions Research is critical to the OBRR mission Mission-related research facilitates product development on the model of “critical path” The OBRR research program is focused on regulatory concerns related to product safety and efficacy –Prevention and control of bloodborne infections –Characterization and standardization of blood products –Methodologies for product review and surveillance Thank you for review of our site visit!