Vaccine or gene therapy vector - PowerPoint by kif12001

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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




                                                       2
              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.
                                                            3
           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
                                         4
                            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                5
OCTGT Structure




                  *Acting




                            6
                        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
  Gene Therapies Branch                  Immunogenicity Branch
Daniel Takefman, Ph.D., Chief          Andrew Byrnes, Ph.D., Chief*


                                          Tumor Vaccines and
    Cell Therapies Branch
                                         Biotechnology Branch
Keith Wonnacott, Ph.D., Chief
                                       Raj Puri, Ph.D., M.D., Chief*

                       Cellular and Tissue
                         Therapy Branch             *Acting
                    Steven Bauer, Ph.D., Chief*
                                                    Currently 10 PIs   7
        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



                                              8
         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                                  9
             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.

                                                          10
         OCTGT Research Areas

Virology
Immunology
Cell biology/differentiation, stem cell biology
Cancer biology
Biotechnology
   Microarray, flow cytometry, proteomics

Clinical trial design


                                              11
                 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.

                                                               12
            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.
                                                         13
            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
                                                       14
       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
                                                 15
    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.
                                                      16
        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




                                                        17
     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


                                                         18
           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


                                                              19
            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)
                                                       20
           Horizon Scanning:
   How 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.




                                                        21
         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.




                                                        22
   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.


                                                         23
      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




                                                              24
        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.
                                                          25
     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
                                                           27
          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

                             LTR   gag   pol   env   LTR


   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.


                                                           29
             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:                                      AdV
                                                     KC
   •   Block scavenger receptors  better ability   DNA

       of adenovirus vectors to reach targets
   •   Hurdle identified in the path to effective
       therapy using lower, safer doses
                                                       30
  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             fat            Do NIST
           differentiation,                    measurements
               Limiting              cartilage
                                               correlate with
               dilution
               analysis              bone        progenitor
                                               frequencies?
                                                        31
MSCs: various donors, passages
   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)



 Cell therapies for radiation exposure
                                                             N1-N9 for flu A
                                                         Basis of flu A subtypes
                                                           Example: H1N1

                                                         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




                                                    32
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

                                              33
  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
                                         34
        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.



                                                    35
              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..."




                                                          36
                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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