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
Jan 29, 2016
Office of Blood Research and ReviewOverview of Research
Jay S. Epstein, M.D.Director, OBRR, CBER
Blood Products Advisory Committee MeetingMarch 10, 2006
Vision for CBER
INNOVATIVE TECHNOLOGY ADVANCING PUBLIC HEALTH
• Protect and improve public and individual health in the US and, where feasible, globally
• Facilitate the development, approval and access to safe and effective products and promising new technologies
• Strengthen CBER as a preeminentregulatory organization for biologics
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
DirectorJay S. Epstein, M.D.
Deputy Director
Jonathan Goldsmith, M.D.
Associate Director for Research Vacant (Dr. C.D. Atreya, Acting)
Associate Director for Regulatory AffairsVacant (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
DirectorHira L. Nakhasi, Ph.D.
Deputy DirectorPaul Mied, Ph.D.
Division of Hematology
DirectorBasil Golding, M.D.
Deputy DirectorSusan Abbondanzo, M.D.
Division of Blood Applications
DirectorAlan E. Williams, Ph.D.
Deputy DirectorSharyn Orton, Ph.D.
OFFICE OF BLOODRESEARCH AND
REVIEW
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
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 WorkloadCY 2004*
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 WorkloadCY 2005
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
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
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
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
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
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
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
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
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 virusesVAC: VacciniaVAR: Variola (Smallpox)MPV: Monkeypox VirusesCPV: Cowpox VirusesNOVAC: All Pox viruses but VacciniaEBO: Ebola VirusesVE: Venezuelan Equine Encephalitis VirusesVETD: VE Trinidad DonkeyMBG: Marburg Viruses
BA1
BA2
BA3
IC
LT3
LT2
LT1
FT3
FT2
FT1
YP3
YP2
YP1
POX a+
CPV a+
POX b+
VAC a+VAC b+
VAR a+
MPV a+
NOVAC 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 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
WNV 1b
VE 8b
VE8c
VE TD a
VE TD bVE TD c
WNV 1c
HCV-b
MBG 1a
MBG 1b
WNV 3a
MBG 2c
WNV 3b
WNV 3c8a
HCV-a
MBG 2a
MBG 2b
HCV-c
HBV 2c
VE 8a
MBG 1c
HBV 1a
HBV 1b
HIV-a
HVB 2c
HTLV3b
HTLV 3a
HIV-c
HIV-b
HTLV4 b
HBV 2a
HTLV4a
HTLV 3c
HTLV4c
G 1 G2G3
4 internal control probes (Human rRNA gene)
Group 3: Blood Borne VirusesWNV: West Nile VirusesHCV: Hepatitis C VirusesHBV: Hepatitis B VirusesHIV: Human Immunodeficiency VirusesHTLV: Human T-cell Leukemia Viruses
Results of detection in pathogen-spiked blood – 50 cells/ml
Bacillusanthracis
livestockvaccinestrain
Francisellatularensis
Live VaccineStrain
Yersiniapseudotub.
IC
IC
IC
IC
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
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
0 10 20 30 40 50 60 700
50
100 virus only 8hrs 24hrs 48hrs 168hrs
Time (days)
% S
urv
ival
VIGa at 40mg/mouse
Pre-Exposure Prophylaxis with VIGIV
40 mg VIGIV given i.p. to mice at indicated times pre- exposure to 106 PFU of vaccinia NYCBOH
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
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
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
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
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)
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
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