Transcript In memory, Dr. Eda T. Bloom –

In memory, Dr. Eda T. Bloom
Photo credit,
Susan Wong
Immunology researcher – Mentor
Regulator – Public health policy contributor
Treasured colleague and friend
We mourn this great loss.
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Center for Biologics Evaluation and Research
OCTGT Office Site Visit,
Report, and Response
Suzanne Epstein, Ph.D.
Associate Director for Research, OCTGT
April 11, 2008, CTGTAC meeting
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OCTGT Office Site Visit,
Report, and Response
Office-wide site visit held on September 29, 2005, as part of
CBER research management initiative.
Purpose of today's session:
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Respond to site visit committee recommendations.
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Indicate to those who review our programs that their input
has an impact.
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Provide information in an open, public setting about our
research programs and reviews of them.
Transparency, accountability.
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Outline of this talk
 Introduction to OCTGT, products it
regulates, and its programs
 Office site visit process and report
 OCTGT research management:
progress responsive to the report
 Examples of OCTGT research
initiatives
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OCTGT Mission
Facilitate development of, approval of, and
access to safe and effective medical products
retroviral
vector
cell therapy for cardiac repair
cellular therapy for cancer
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OCTGT Structure
*Acting
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DCGT Structure
Division of Cellular and Gene Therapies
Raj Puri, Ph.D., M.D., Division Director
Kimberly Benton, Ph.D., Deputy Director
Gene Therapies Branch
Daniel Takefman, Ph.D., Chief
Cell Therapies Branch
Keith Wonnacott, Ph.D., Chief
Gene Transfer and
Immunogenicity Branch
Andrew Byrnes, Ph.D., Chief*
Tumor Vaccines and
Biotechnology Branch
Raj Puri, Ph.D., M.D., Chief*
Cellular and Tissue
Therapy Branch
Steven Bauer, Ph.D., Chief*
*Acting
Currently 10 PIs
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Products Regulated
by OCTGT
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Cellular therapies
Gene therapies
Tumor vaccines and immunotherapy
Tissue and tissue-based products
Xenotransplantation products
Combination products
Devices related to cell/tissue products
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OCTGT regulatory portfolio
and activities
 Over 1100 active INDs, IDEs, master files, consult
reviews. Thousands of amendments per year.
 One licensed product, a growing number of products
in phase 3
 Devices: 510ks, PMAs, HDEs
 Tissue regulations
 Pre-INDs, pre-pre-IND advice
 Advisory committee meetings
 Inspections
 Enforcement actions
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OCTGT Research Strategies
We review new types of products. To facilitate their progress
towards delivering public health benefit, CBER must work at
the cutting edge, help define cutting edge issues. Our role:
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Stay ahead of the curve to prepare the
way for anticipated products.

Perform studies relevant to entire
product classes.
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Make results public and thus accessible
to all sponsors, to advance the entire
field.
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OCTGT Research Areas
Virology
Immunology
Cell biology/differentiation, stem cell biology
Cancer biology
Biotechnology
Microarray, flow cytometry, proteomics
Clinical trial design
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Office Site Visit Process
 Why held: To obtain suggestions concerning OCTGT research
from experts in appropriate scientific and clinical fields.
 Who the reviewers were : 11 experts from academia, gov't,
industry on CTGTAC Research Review Subcommittee.
 What we provided: Extensive briefing package: OCTGT's
regulatory roles, research programs, research management
approaches, publications; oral presentations at the site visit.
 Benefits: Insights, suggestions from the subcommittee.
Transparency, accountability. Opportunity to inform
stakeholders about what we do.
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Research Management:
Office Site Visit Process, cont'd
 Report: Draft subcommittee report went to CTGTAC.
After presentations at a public meeting on February
10, 2006, the report was approved by the CTGTAC.
 Follow-up: Today's meeting. Briefing package for
this meeting contains more detailed responses.
 Other CBER site visits: Office site visits have also
reviewed research programs in other CBER offices
(Blood, Vaccines). Reports received.
Response of OBRR presented at the Blood Products
Advisory Committee public meeting, 8-16-07.
Vaccine response pending.
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OCTGT Office Site Visit
Report recommendations
Commented on research management
• Explicit research priorities, horizon scanning, annual
program reporting and assessment
• Internal resources and outside funding
• Recruitment and retention: mentoring, professional
development
• Communication and collaboration
• Important that the management process "stimulates
innovation and creative problem solving."
Commented on product areas
Gene therapy, cell therapy, combination products,
xenotransplantation, counter-terrorism, tumor
vaccines, bioinformatics
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Research management initiatives
Progress responsive to Site Visit recommendations:
 CBER Research Leadership Council
 Communication strategies, in OCTGT and outside
 OCTGT research collaborations
 Examples of other OCTGT activities and interactions
 Horizon scanning
 Explicit OCTGT research priorities
 Recruitments
 Funding sources
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Research management: CBER Research
Leadership Council initiatives
RLC Includes both researcher-reviewers and regulatory
scientists from each Office, plus Center
management.
Goal: Transparent procedures shared across Offices,
explicit priorities.
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CBER priorities identified and announced.
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Office priorities identified from workload analysis
and horizon scanning. Research programs expected
to address them.
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Evaluation of research programs linked to budgets.
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In development: Automated analysis of regulatory
workload, scientific expertise database.
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Research management initiatives:
Communication tools within OCTGT
 Work-in-progress talks
 Web site: annual reports, brief summaries
 Input from staff regarding priorities, recruitments
 OCTGT leadership meeting in November, 2007, to
discuss research, priorities
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Research management, Communication
Tools beyond OCTGT
 FDA: Briefings of Center and Agency leadership
 FDA Science Board review of research at all centers
 New FDA web site
 Communication with stakeholders:
32 OCTGT research publications in FY 07
Regulatory publications
Talks at scientific conferences, workshops, meetings of
advisory committees
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OCTGT Research Collaborations
 Government: NCI, NHLBI, NINDS, NICHD, NIMH, NIAID, NIDCR,
NIH Mouse imaging facility, Vaccine Research Center, NIST,
CDC, National Toxicology Program with NIEHS*
 Academia: Mayo Clinic, Georgetown Univ., M.D. Anderson,
Catholic Univ. of Leuven - Belgium, Scripps Inst., New Jersey
Medical School, Naval Medical Center, Universities of Georgia,
Michigan, Maryland, and California San Diego
* NTP collaboration also includes partnerships with University of
Washington, Cincinnati Children's Research Hospital, and
Hamburg University
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Examples of other OCTGT
activities and interactions
October, 2007 Tissue Processing Workshop
October, 2007 Workshop on Clinical Use of Biomarkers
December, 2007 FDA/NIST Cell Scaffold Workshop
FDA Interdisciplinary Pharmacogenomic Review Group
Ongoing partnerships:
 NCI/Interagency Oncology Task Force
 Multi-Agency Tissue Engineering Science (MATES)
Interagency Working Group
 Biomarker Consortium (multiple agencies, sectors)
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Horizon Scanning:
How OCTGT Identifies Research Priorities
 Product trends noted from submissions and presubmission inquiries, conferences, literature.
 Anticipate areas of major product activity, related
Critical Path issues.
 Monitor for gaps and weaknesses or redundancies
in our expertise, and address them.
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FY08 OCTGT Research Priorities
1. Development and evaluation of methods and standards
for improved product characterization, including
definition of product biomarkers predictive of safe,
effective, and consistent product performance.
2. Development and evaluation of non-clinical methods
informative about the safety and efficacy of CTGT
products.
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FY08 OCTGT Research Priorities, cont'd
3. Participation in CBER-, FDA-, and DHHS-wide initiatives
including risk assessment, clinical trial design and
monitoring, development of biomarkers, counterterrorism, pandemic influenza preparedness, and
HIV/AIDS programs, as well as OCTGT-specific
initiatives in these areas.
4. Improvement of the microbial safety of human tissue
products by development and evaluation of methods
for better processing conditions, pathogen
inactivation, and/or pathogen detection.
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DCGT PI recruitments, 2000-2006
 Scientific gap identified, field of expertise endorsed by
Center Director's office
 Open, public recruitment with search committee
Last five PI recruitments: All from outside the government.
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Development and cell fate
Viral vectors (adeno, herpes)
Organ development
Proteomics
American Univ.
Johns Hopkins, U. Chicago
Jackson Laboratories
Univ. of Kansas
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Current recruitment in a new area:
Tissue safety
2005
Tissue industry first required to report adverse events
2006
147 adverse reactions reported, though not proven
due to the tissue
2006
Human Tissue Task Force established, new regulatory
activities planned
2007
The public health issues highlighted scientific gaps,
led to planning a laboratory program in DCGT to
work on tissue safety. Coordination with Division of
Human Tissues and the Office of Compliance and
Biologics Quality. Recruitment in progress.
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Recruitments: Virology, Immunology
Virology:
Investigator recruited to start a new program in DCGT.
Has experience in lentiviral vector research, and as
director of core facility producing adenoviral, AAV, and
lentiviral vectors.
Immunology:
Immune regulation and tolerance identified as gap in
expertise, needed for regulation of gene therapy, cell
therapy, and xeno. Search currently in progress.
These are staff replacements.
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Funding sources
Since CBER scientists are not eligible for many major
grants, we seek other sources of funds to supplement
the internal budget. Mechanisms used: IAG, CRADA
 Interagency Oncology Task Force with National Cancer
Institute
 FDA Critical Path initiative
 Pandemic influenza initiative
 Counter-terrorism (DHHS, NIH/NIAID)
•
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Bioterrorism: infectious agents, emerging threats
Chemical, biological, radiological, and nuclear
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OCTGT research examples
Examples of current OCTGT research initiatives
More examples described, and in greater detail, in
materials on which reviews were based:
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Office Site Visit Report
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Briefing materials for the FDA Science Board
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OCTGT projects: Gene therapy risks, with
National Toxicology Program, NIEHS
LTR
gag
pol
env
LTR
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Recognized need for new pharm-tox models.
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Preclinical model for assessing risk of retroviral
vector-mediated insertional tumorigenesis, will
permit comparing modifications, new vectors.
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The animal studies involve large sample sizes and
are long-term, could not be carried out by CBER
alone or single sponsors.
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OCTGT projects: Why are adenovirus
vectors cleared so quickly?
Intravenous injection of gene therapy vectors
to target disseminated metastatic cancer
 Problem: Adenovirus vectors have poor
pharmacokinetics
 CBER research finding: Adenovirus vectors
rapidly recognized by scavenger receptors and
cleared by Kupffer cells in the liver
 Implications:
•
Block scavenger receptors  better ability
of adenovirus vectors to reach targets
•
Hurdle identified in the path to effective
therapy using lower, safer doses
AdV
KC
DNA
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FDA/NIST collaboration: Improved Characterization
of Human Mesenchymal Stem Cell Based Products
 Goal:
Simple, robust measures that predict
differentiation capability
 NIST: Computerized, high throughput cell measurements
of size, morphology, proliferation rate, biomarker
detection
 DCGT: Quantitative bioassays for frequencies of bone, fat,
and cartilage progenitors
Approach
Induce
differentiation,
Limiting
dilution
analysis
MSCs: various donors, passages
Do NIST
measurements
cartilage
correlate with
progenitor
bone
frequencies?
fat
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OCTGT research projects related to
CBER-, FDA-, and DHHS-wide initiatives
Emergency responses:
Counter-terrorism, pandemic influenza
 Blocking of Ebola virus infection
 New approaches to control of pandemic influenza
Genes encoding variable
surface glycoproteins:
Hemagglutinin (HA)
H1-H15 for flu A
Neuraminidase (NA)
N1-N9 for flu A
Basis of flu A subtypes
Example: H1N1
 Cell therapies for radiation exposure
Genes Encoding
Conserved Proteins:
Matrix (M)
encodes M1 and M2 protein
Nucleoprotein (NP)
Basic Polymerase 1 (PB1)
Basic Polymerase 2 (PB2)
Acidic Polymerase (PA)
Nonstructural (NS)
encodes NS1 and NS2 prote
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OCTGT projects: New technologies
in support of product development
Uses of gene expression microarray,
proteomics
High throughput screening provides detailed
information. Can be used to characterize:
 Cellular products
 Cell substrates for product manufacture
 Patient samples
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OCTGT Contribution to Development of
Reference Materials
 Retrovirus reference material
CBER; available from ATCC
 Adenovirus reference material
Consortium; available from ATCC
 External RNA spike-in controls
Quantitative flow cytometry:
CBER, NIST; available from NIST
 Fluorescent standard solution
 Fluorescent microbead standard
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Summary: Research Prioritization
as an Ongoing Process
 New products present novel scientific and regulatory
challenges and opportunities.
 We identify scientific questions of regulatory
importance and address them.
 Solutions to key problems contribute to patient safety
and product development, inform regulatory
decisions and policy.
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Office Site Visit report
recommendations
"...new treatment modalities like cell and gene therapy
will never move from effective laboratory reagents to
products for patients with disease unless the FDA
maintains a strong cadre of researcher-reviewers..."
"...an active research component within the FDA is
essential..."
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Thank you
to the committee for your attention to CBER
research programs,
to many OCTGT colleagues for their
contributions to this presentation,
and to the Advisory Committee staff.
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