Office of Blood Research and Review Site Visit for Research

1. Office of Blood Research and ReviewSite Visit for Research Jay S. Epstein, M.D. Director, OBRR, CBER July 22, 2005

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 • Additionally, we collaborate in larger CBER programs (e.g. tissue safety, xenotransplantation, HIV immunology, vaccine development, etc.)

4. Director Jay S. Epstein, M.D. Deputy Director Jonathan Goldsmith, M.D. Associate Director for Regulatory Affairs Mary Elizabeth Jacobs, Ph.D. Associate Director for Medical Affairs (vacant) Associate Director for Policy (Susan Zullo, M.D., Acting)   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. ReceivedCompleted 510(k)s70 (4 Special)81 (8 Special) PMAs21 PMSs22 (15 PMS30) 27 (14PMS30) (A)NDA/sup69 (Incl 1 NDA)89 BLAs 66 BLSs10401206 OBRR Review Workload CY 2004

6. 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

7. Organization and Oversight of Research in OBRR • OBRR research is organized in parallel with product review down to the branch level. Funds are allocated by the Office Director. • Oversight of research is primarily by the Division Directors with input from the Office Director. • CBER coordination is accomplished through the Acting Liaison for Research (Dr. Nakhasi) in cooperation with the other Division Directors. • Publications are reviewed by the Division Director and the Office Director. • Laboratories have external site visits Q 4 years

8. Product Responsibilities Retroviral donor screening and diagnostic tests Hepatitis donor screening tests Emerging viral agents Tests for bacterial, parasitic and unconventional agents Areas of Research HIV, HTLV, HBV, HCV and HAV epidemiology, pathogenesis, diagnostic methods WNV detection and infectivity CJD/vCJD detection and decontamination Parasitic vaccines Ad hoc studies (Vaccinia, HHV-8, SARS, SENV, etc.) Correlation of Product Responsibilities and Research in OBRR: DETTD

9. Product Responsibilities Plasma-derived products (IGIV, albumin, coagulation products) Blood and blood component collection devices Hemoglobin-based oxygen carrying solutions Plasma expanders Bacterial detection devices Areas of Research Characterization and standardization of plasma derivatives Functional studies of platelets Chemistry and mechanism of toxicity of HBOC’s Bacterial detection methods HIV vaccine immunology Correlation of Product Responsibilities and Research in OBRR: DH

10. Product Responsibilities Blood and plasma licenses Blood establishment software Blood grouping and HLA reagents Areas of Research Donor epidemiology Validation of donor questionnaires Shortage monitoring Component QC Specificity of blood grouping reagents Correlation of Product Responsibilities and Research in OBRR: DBA

11. 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 • Tests for West Nile virus • Tests for bacterial contamination • Guidance and Rulemaking • Barcode rule • Draft UDHQ • NAT for HIV-1 and HCV • Evaluation of Oxygen Therapeutics • WNV screening

12. OBRR Highlights in FY’04-5 • Workshops • Plasma freezing • Platelet standards • Evaluating safety and efficacy of IGIV • Intl.Working group for Standardization of Gene Amplification Technology (SoGAT) • 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

14. 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

15. OBRR Research Highlights in FY’04-5 • Development of reference reagents for HIV and WNV NAT • Evaluation of diagnostic significance of emerging HIV variants • 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 • Establishment of standards for thrombin and anti-D Ig • Murine model to study pharmacogenomics of Factor IX • Mechanism of toxicity of a specific HBOC • Modeling of TSE decontamination methods • TSE risk assessment for plasma derivatives • Tracking fatalities from TRALI • Cognitive evaluation of the donor history questionnaire • Statistical QC methods for blood components

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

17. Critical Path Opportunity: Detection of Blood Borne Pathogens, cont. Actions • Develop and evaluate “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 • Proof of concept for novel assay development

18. 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 IC IC IC YP1 POX a+ G2 G3 G 1 POX b+ EBO 1a VE 2a VE 5a VE 8a MBG 1a HCV-a HIV-a BA1 YP2 POX c+ BA2 YP3 EBO 1b VE 2b VE 5b VE 8b MBG 1b HCV-b HIV-b 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 EBO 1c VE 2c VAC a+ BA3 VE 5c VE8c MBG 1c HCV-c HIV-c FT1 VE 3a VE 6a VAC b+ EBO 2a VE TD a MBG 2a HBV 1a HTLV 3a EBO 2b VAR a+ VE 3b VE 6b FT2 VE TD b MBG 2b HBV 1b HTLV 3b FT3 EBO 2c VE 3b VE 6c VE TD c HVB 2c MPV a+ MBG 2c HTLV 3c EBO gp a CPV a+ LT1 VE 4a VE 7a WNV 3a HBV 2a HTLV 4a NOVAC a+ EBO gp b VE 4b VE 7b WNV 1b WNV 3b HBV 2c HTLV 4 b LT2 IC LT3 EBO gp c VE 7c WNV 1c WNV 3c8a VE 8a HTLV 4c NOVAC b+ VE 4c 4 internal control probes (Human rRNA gene) IC Results of detection in pathogen-spiked blood – 50 cells/ml Bacillus anthracis livestock vaccine strain Francisella tularensis Live Vaccine Strain Yersinia pseudotub.

19. 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

20. 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

21. Pre-Exposure Prophylaxis with VIGIV 40 mg VIGIV given i.p. to mice at indicated times pre- exposure to 106 PFU of vaccinia NYCBOH

22. 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

23. 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

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

25. Critical Path Opportunity:Monitoring of Blood and Reagent Shortages During Emergencies Issue • No rapid and reliable mechanisms currently exist for objective assessment of blood component, reagent, or supply shortages during regional or national emergencies.

26. Critical Path Opportunity:Monitoring of Blood and Reagent Shortages During Emergencies Actions • OBRR developed and piloted TRANS-Net, a Web-based system to permit direct reports of shortages and their medical impact from all US blood centers and transfusion services. Outcomes • DHHS plans to incorporate TRANS-Net capabilities into a blood monitoring system installed in the DHHS Secretary’s Operations Center (SOC) that is activated in emergencies.

27. Critical Path: Potential Initiatives • Detection of blood-transmissible agents • Nucleic acid based tests for bacteria and parasites • Nanoparticle-based diagnostics for multiplex detection of blood borne and CT agents • Diagnostic implications of HIV and HBV variants • 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

28. 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)

29. 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 blood borne infections through testing and inactivation/removal of pathogens • Characterization and standardization of blood products • Methodologies for product review and surveillance • Thank you for our site visit!