1. Cellular Tissue and Gene Therapies Research Site Visit Celia M.Witten, Ph.D., M.D. Director, Office of Cellular, Tissue, and Gene Therapies September 29, 2005

2. Outline Office Overview Research Vision Products Regulated Organizational Structure Regulatory challenges and opportunities Research program areas

3. OCTGT Mission Facilitate development, approval, and access to safe and effective medical products

4. Science in Research and Review: Critical Path Initiative Bring scientific advances to medical product development process (simulation models, validated biomarkers, new clinical trial designs) Stimulate development of applicable research programs in critical path scientific areas, aim to develop techniques that address challenges encountered during product development Regulatory guidance/practice and standards to reflect best available science, integrate FDA involvement

5. Patients Research Community FDA PublicSponsors Practitioners/Societies Payors

6. OCTGT Research Vision Facilitate critical path development Identify cross-cutting/or applied science/biomedical technology issues Resolve scientific questions critical to regulation

7. Setting Priorities Resources are limited Are we investing our energies in the most important activities? Are resources distributed in accordance with our priorities? Challenge: our scope is large

8. OCTGT Regulation Cellular therapies Tumor vaccines Gene therapies Tissue and tissue based products Xenotransplantation products Combination products Devices used for cells/tissues Anti-idiotype antibodies

9. Office of Cellular, Tissue, and Gene Therapies Celia M.Witten, Ph.D, M.D. Office Director Stephen Hilbert, Ph.D., M.D. Acting Deputy Director Suzanne Epstein, Ph.D., Associate Director for Research Division of Cellular and Gene Therapies Raj Puri, Ph.D., M.D., Director Stephanie Simek, Ph.D., Deputy Director Division of Human Tissue Products Ruth Solomon, M.D., Director Division of Clinical Evaluation and Pharmacology/Toxicology Recruiting

10. Regulatory Challenges/Scientific Opportunities How is the product made and characterized? What level of safety assurance is needed for beginning clinical trials? Clinical study design

11. Product Manufacture and Characterization Cell or tissue source Processing and manufacturing Product identity and purity Measuring product potency Manufacturing change/comparability study Stability data

12. Product Safety Donor testing and screening Microbiological testing of the final product Safety testing on critical reagents Replication competence Product tracking for patient specific products

13. Product Safety, Continued Dosing? Toxicity? Immunogenicity? Proof of concept? Product administration? Safety monitoring?

14. Clinical Study Design: Early Phase Product development versus research What is the appropriate patient population? (“orphan” indications, heterogeneous patients, pediatric issues) How can patients be best monitored for safety Dose escalation plan/dose selection

15. Clinical Study Design Method of product administration Goal of treatment Timing of evaluations/study duration Standard of care Concomitant treatment

16. Clinical Study Design: Therapeutic Tumor Vaccines Timing of response Immunological response in subpopulation Objective of treatment: halt disease progression versus tumor regression

17. Regulation of Human Tissue Registration and Listing of Establishments Donor Eligibility Good Tissue Practices Final Rules published All effective May 25, 2005

18. Scope: 1271.1(b) Articles containing or consisting of human cells or tissues that are intended for implantation, transplantation, infusion, or transfer “361” registration and inspection “351” biological products subject to licensure “HCT/Ps regulated under FDCA”: medical devices subject to clearance/approval

19. Hot Topics Minimal manipulation/homologous use Devices used to make/process cells and tissues CGTP implementation, CGTP/GMP International harmonization Adverse events Donor screening/testing Cord blood Pancreatic islet cells Tumor vaccines clinical study design Potency assays Iterative changes in product design

20. Outreach Activities Long-Term Follow-up Workshop June 2004 ASGT Stakeholder’s Meeting April 7 and 8, 2005 BIO Liaison Meeting July 2005 ICH: Fall workshop on oncolytic virus

21. Outreach Activities ISCT Liaison meeting June 2005 ISCT Symposium September 2005 Cancer Vaccine Consortium Workshop November 2005

22. Guidance Documents Draft Guidance for Industry: Gene Therapy Clinical Trials - Observing Participants for Delayed Adverse Events - 8/23/2005Draft Guidance for Industry: Gene Therapy Clinical Trials - Observing Participants for Delayed Adverse Events Draft Guidance for FDA Review Staff and Sponsors: Content and Review of Chemistry, Manufacturing, and Control (CMC) Iformation for Human Gene Therapy Investigational New Drug Applications (INDs) - 11/8/2004Draft Guidance for FDA Review Staff and Sponsors: Content and Review of Chemistry, Manufacturing, and Control (CMC) Iformation for Human Gene Therapy Investigational New Drug Applications (INDs) Draft Guidance for Reviewers: Instructions and Template for Chemistry, Manufacturing, and Control (CMC) Reviewers of Human Somatic Cell Therapy Investigational New Drug Applications (INDs) - 8/15/2003Draft Guidance for Reviewers: Instructions and Template for Chemistry, Manufacturing, and Control (CMC) Reviewers of Human Somatic Cell Therapy Investigational New Drug Applications (INDs) Guidance for Industry: Supplemental Guidance on Testing for Replication Competent Retrovirus in Retroviral Vector Based Gene Therapy Products and During Follow-up of Patients in Clinical Trials Using Retroviral Vectors - 10/18/2000Guidance for Industry: Supplemental Guidance on Testing for Replication Competent Retrovirus in Retroviral Vector Based Gene Therapy Products and During Follow-up of Patients in Clinical Trials Using Retroviral Vectors Guidance for Industry: Guidance for Human Somatic Cell Therapy and Gene Therapy - 3/30/1998

23. Tissue Regulation Websites http://www.fda.gov/cber/tissue/docs.htm Draft Guidance for Industry: Eligibility Determination for Donors of Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps) - 5/20/2004

24. Research Program Areas Virology –Retroviruses, adeno, herpes, PERV Immunology –Host-vector interactions, transplant rejection Cell biology –Control of differentiation in animal models, stem cell biology Cancer biology –Molecular biomarkers, animal models Biotechnology –Microarray, proteomics, flow cytometry, transgenics

25. Thank You