Transcript Research Office of Blood Research and Review Site Visit for

Office of Blood Research and Review
Site 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 preeminent
regulatory 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.)
Director
Jay S. Epstein, M.D.
OFFICE OF BLOOD
RESEARCH AND
REVIEW
Deputy Director
Jonathan Goldsmith, M.D.
Associate Director for Regulatory Affairs
Mary Elizabeth Jacobs, Ph.D.
Associate Director for
Policy
(Susan Zullo, M.D.,
Acting)
Associate Director for Medical Affairs
(vacant)
Policy and
Publication Staff
Division of Emerging &
Transfusion
Transmitted Diseases
Division of Hematology
Division of Blood
Applications
Director
Hira L. Nakhasi, Ph.D.
Director
Basil Golding, M.D.
Director
Alan E. Williams, Ph.D.
Deputy Director
Paul Mied, Ph.D.
Deputy Director
Susan Abbondanzo, M.D.
Deputy Director
Sharyn Orton, Ph.D.
OBRR Review Workload
CY 2004
510(k)s
PMAs
PMSs
Received
Completed
70 (4 Special)
81 (8 Special)
2
1
22 (15 PMS30)
(A)NDA/sup 69 (Incl 1 NDA)
BLAs
BLSs
6
1040
27 (14PMS30)
89
6
1206
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
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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
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Barcode rule
Draft UDHQ
NAT for HIV-1 and HCV
Evaluation of Oxygen Therapeutics
WNV screening
OBRR Highlights in FY’04-5
• Workshops
–
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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
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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
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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
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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)
IC
YP
1
BA1
YP
2
B
A2
YP3
Group 2: Bioterror Viruses
FT
1
B
A3
IC
POX a+
IC
POX
b+
EBO
1a
VE
2a
VE
5a
VE
8a
MB
G 1a
HC
V-a
HIV
-a
POX
c+
EBO
1b
VE
2b
VE
5b
VE
8b
MB
G 1b
HC
V-b
HIV
-b
EBO
VA
1c
C
a+
VAC b+ EBO
2a
VE
2c
VE
5c
VE8
c
MB
G 1c
HC
V-c
HIV
-c
VE
3a
VE
6a
VE
TD a
MB
G 2a
HB
V 1a
HTL
V 3a
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 VE
V
VE
VE
MB
HBG3
HTL
POX: Pox viruses
2b
GFT2 1
AR
3b
6b
TD
G 2b
V
V
a+
G2
b
1b
3b
VAC: Vaccinia
FT
EBO
VE
VE
VE
HV
MPV a+
MB
HTL
3
2c
3b
6c
TD
B 2c
G
2c
V
3c
VAR: Variola (Smallpox)
c
EBO
CPV
LT
VE
VE
WN
HB
HTL
MPV: Monkeypox Viruses
gp a
a+
1
4a
7a
V 3a
V 2a
V
4a
CPV: Cowpox Viruses
NOV
EBO
VE
VE
W
WN
HB
HTL
LT
AC
gp
b
4b
7b
N
V 3b
V 2c
V
2
NOVAC: All Pox viruses but Vaccinia
a+
V
4b
IC
LT
VE
WN
WN
VE
HTL
1b
NOVAC EBO
VE
EBO: Ebola Viruses
3
gp c
7c
V 1c
V
8a
V
b+
4c
3c8a
4c
VE: Venezuelan Equine Encephalitis Viruses
VETD: VE Trinidad Donkey
IC
4 internal control probes (Human rRNA gene)
MBG: Marburg Viruses
Results of detection in pathogen-spiked blood – 50 cells/ml
Bacillus
anthracis
Francisella
tularensis
livestock
vaccine
strain
Live
Vaccine
Strain
Yersinia
pseudotub.
Critical Path Opportunity: Counterterrorism – Safety
of Smallpox Vaccination
Issue
• Smallpox vaccination can cause lifethreatening 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
Pre-Exposure Prophylaxis with VIGIV
virus only
8hrs
24hrs
48hrs
168hrs
% Survival
100
50
0
0
10
20
30
40
50
60
70
Time (days)
VIGa at 40mg/mouse
40 mg VIGIV given i.p. to mice at indicated times preexposure to 106 PFU of vaccinia NYCBOH
Critical Path Opportunity: HemoglobinBased 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: HemoglobinBased 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!