In memory, Dr. Eda T. Bloom

1. 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.

2. CENTER FOR BIOLOGICS EVALUATION AND RESEARCH CENTER FOR BIOLOGICS EVALUATION AND RESEARCH CENTER FOR BIOLOGICS EVALUATION AND RESEARCH C C C B B B E E E R R R FDA FDA FDA 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

3. 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.

4. 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

5. 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

6. OCTGT Structure *Acting

7. 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

8. 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

9. 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

10. 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.

11. OCTGT Research Areas Virology Immunology Cell biology/differentiation, stem cell biology Cancer biology Biotechnology Microarray, flow cytometry, proteomics Clinical trial design

12. 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.

13. Research Management:Office Site Visit Process, cont'd • Report: Draft subcommittee reportwent 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.

14. 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

15. 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

16. 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.

17. 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

18. 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

19. 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

20. 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)

21. 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.

22. 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.

23. 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.

24. 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

25. 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.

26. Recruitments: Virology, Immunology Virology: Investigatorrecruited 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.

27. 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

28. OCTGT research examples • Examples of current OCTGT research initiatives • More examplesdescribed, and in greater detail, in materials on which reviews were based: • Office Site Visit Report • Briefing materials for the FDA Science Board

29. LTR gag pol env LTR 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 arelong-term, could not be carried out by CBER alone or single sponsors.

30. AdV KC DNA 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

31. fat cartilage bone 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

32. 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

33. 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

34. 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

35. 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.

36. 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..."

37. 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.