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

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