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In memory, Dr. Eda T. Bloom

Immunology researcher – Mentor Regulator – Public health policy contributor

Treasured colleague and friendWe mourn this great loss.

Photo credit, Susan Wong

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OCTGT Office Site Visit,Report, and Response

Suzanne Epstein, Ph.D.Associate Director for Research, OCTGT

April 11, 2008, CTGTAC meeting

Center for Biologics Evaluation and Research

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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

cell therapy for cardiac repair

cellular therapy for cancer

retroviralvector

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OCTGT Structure

*Acting

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Gene Transfer and Immunogenicity Branch

Andrew Byrnes, Ph.D., Chief*

Division of Cellular and Gene TherapiesRaj Puri, Ph.D., M.D., Division Director

Kimberly Benton, Ph.D., Deputy Director

Tumor Vaccines and Biotechnology Branch

Raj Puri, Ph.D., M.D., Chief*

Cell Therapies BranchKeith Wonnacott, Ph.D., Chief

Gene Therapies BranchDaniel Takefman, Ph.D., Chief

*Acting

Currently 10 PIs

Cellular and Tissue Therapy Branch

Steven Bauer, Ph.D., Chief*

DCGT Structure

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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

VirologyImmunologyCell biology/differentiation, stem cell biologyCancer biologyBiotechnology

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.

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 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.

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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

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

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

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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.

LTR gag pol env LTR

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OCTGT projects: Why are adenovirus vectors cleared so quickly?

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

KCDNA

AdV

Intravenous injection of gene therapy vectors to target disseminated metastatic cancer

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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

MSCs: various donors, passages

bone

cartilage

fatInducedifferentiation,

Limiting dilutionanalysis

Do NIST measurements correlate with

progenitor frequencies?

Approach

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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

Genes encoding variable surface glycoproteins: Hemagglutinin (HA)

H1-H15 for flu ANeuraminidase (NA)

N1-N9 for flu ABasis of flu A subtypes

Example: H1N1

Genes Encoding Conserved Proteins:Matrix (M)

encodes M1 and M2 proteinsNucleoprotein (NP)Basic Polymerase 1 (PB1)Basic Polymerase 2 (PB2)Acidic Polymerase (PA)Nonstructural (NS)

encodes NS1 and NS2 proteins

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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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Retrovirus reference materialCBER; available from ATCC

Adenovirus reference materialConsortium; available from ATCC

External RNA spike-in controls

Quantitative flow cytometry:CBER, NIST; available from NIST

Fluorescent standard solution Fluorescent microbead standard

OCTGT Contribution to Development of Reference Materials

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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 theircontributions to this presentation,

and to the Advisory Committee staff.