In memory, Dr. Eda T. Bloom

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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
• Respond to site visit committee recommendations.
• Indicate to those who review our programs that
  their input has an impact.
• 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 Transfer and Immunogenicity Branch Andrew
Byrnes, Ph.D., Chief
Gene Therapies Branch Daniel Takefman, Ph.D.,
Chief
Tumor Vaccines and Biotechnology Branch Raj
Puri, Ph.D., M.D., Chief
Cell Therapies Branch Keith Wonnacott, Ph.D.,
Chief
Cellular and Tissue Therapy Branch Steven
Bauer, Ph.D., Chief
Acting Currently 10 PIs
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Products Regulated by OCTGT

• 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

• Stay ahead of the curve to prepare the way for
  anticipated products.
• Perform studies relevant to entire product
  classes.
• 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 ManagementOffice 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.
• CBER priorities identified and announced.
• Office priorities identified from workload
  analysis and horizon scanning. Research programs
  expected to address them.
• Evaluation of research programs linked to
  budgets.
• 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 ScanningHow OCTGT Identifies Research
Priorities

• Product trends noted from submissions and
  pre-submission 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, counter-terrorism, 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.
• Development and cell fate American Univ.
• Viral vectors (adeno, herpes) Johns Hopkins, U.
  Chicago
• Organ development Jackson Laboratories
• Proteomics 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)
• 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
• Office Site Visit Report
• Briefing materials for the FDA Science Board

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OCTGT projects Gene therapy risks, with
National Toxicology Program, NIEHS

• Recognized need for new pharm-tox models.
• Preclinical model for assessing risk of
  retroviral vector-mediated insertional
  tumorigenesis, will permit comparing
  modifications, new vectors.
• 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

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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
Do NIST measurements correlate with progenitor
frequencies?
MSCs various donors, passages
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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
• Cell therapies for radiation exposure

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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 Prioritizationas 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.