office of blood research and review site visit for research
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Office of Blood Research and Review Site Visit for Research. Jay S. Epstein, M.D. Director, OBRR, CBER July 22, 2005. OBRR Functional Statement. - PowerPoint PPT PresentationTRANSCRIPT
Office of Blood Research and ReviewSite Visit for Research
Jay S. Epstein, M.D.
Director, OBRR, CBER
July 22, 2005
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
• Additionally, we collaborate in larger CBER programs (e.g. tissue safety, xenotransplantation, HIV immunology, vaccine development, etc.)
DirectorJay S. Epstein, M.D.
Deputy Director
Jonathan Goldsmith, M.D.
Associate Director for Regulatory AffairsMary 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
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
Received Completed
510(k)s 70 (4 Special) 81 (8 Special)
PMAs 2 1
PMSs 22 (15 PMS30) 27 (14PMS30)
(A)NDA/sup 69 (Incl 1 NDA) 89
BLAs 6 6
BLSs 1040 1206
OBRR Review WorkloadCY 2004
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
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
–
Correlation of Product Responsibilities and Research in OBRR: DETTD
• 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: DH• 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: DBA
• 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
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
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
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
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
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
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
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 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.
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.
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
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 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!