1. CBER FDA Science Board Office of Cellular, Tissue, and Gene Therapies (OCTGT) Kathryn C. Zoon, PhD October 25, 2002

2. CBER Regulation of Biological Products Based on Sound Science, Law and Public Health Impact ReviewResearchSurveillance Policy Compliance 100 years of Flexible Regulation

3. CBER Why? l Increase in regulatory activities in the areas of cellular and tissue-based products, gene therapies, and all forms of stem cell transplantation. l Consolidation of products into one office – Products getting more complex – New science advances – Need for seamless and transparent coordination and communication

4. CBER Cell and Gene Therapy INDS Reviewed by CBER Total Cell Therapy = 812 Total Gene Therapy = 384 38 combination products reviews

5. CBER Mission l Regulatory and review responsibilities: – Tissues – Cellular and Tissue-based products – Gene Therapies – Xenotransplantation – Unique assisted reproduction (ooplasm transfer) – Combination Products containing living cells/tissues l Assure the safety, identity, purity and potency of novel products

6. CBER Expertise l Molecular and cell biology l Viral and nonviral gene therapy vectors l Nucleic acid chemistry l Genomics l Proteomics l Tissue and Organ Regeneration l Developmental and Reproductive Biology l Stem Cell Biology and Physiology l Medical l Pharmacology/Toxicology

7. Division of Cellular & Gene Therapies Dr. Phil Noguchi, Director Division of Clinical Evaluation & Pharmacology/Toxicology (Vacant) Office of Cellular, Tissue, and Gene Therapies Dr. Philip Noguchi, Office Director (Acting) Dr. Joyce Frey-Vasconcells, Deputy Office Director(Acting) Regulatory Management Staff Acting Chief, Ms. Andrea Wright Division of Human Tissues Dr. Ruth Solomon, Division Director (Acting)

8. Lab of Molecular Immunology and Virology Dr. Eda Bloom, Chief Lab of Stem Cell Biology Dr. Stephen Bauer, Chief (Acting) Division of Cellular and Gene Therapies Dr. Raj Puri, Director (Acting) Cell Therapy Branch Dr. Darin Weber, Chief (Acting) Lab of Molecular Tumor Biology Dr. Raj Puri, Chief Gene Therapy Branch Dr. Stephanie Simek, Chief (Acting) Lab of Immunology and Developmental Biology Dr. Suzanne Epstein, Chief

9. Human Tissue and Reproduction Branch Martha Wells, Branch Chief (Acting) Division of Human Tissues Dr. Ruth Solomon, Division Director (Acting)

10. Clinical Evaluation Branch Dr. Cynthia Rask, Chief (Acting) Division of Clinical Evaluation & Pharmacology/Toxicology (Vacant) Pharmacology/Toxicology Branch (Vacant)

11. Good Manufacturing Practices Full GMP 21 CFR 210, 211 Product Characterization Step-wise Approach to Application of Regulatory Requirements Full characterization 21 CFR 610 Phase III Phase I Phase II Pre-clinical Prior to Phase I : need product safety testing and basic characterization info QA &QC, Clinical Monitoring Program

12. CBER Ex Vivo Transduced CD34+ Cells Expressing HSV tk Growth factors PBSC CD34+ Selection Retroviral Viral vector Flt-3, CSF, Fibronectin CD34+ transduction CD34+ expressing HSV tk Anti-CD34+ MoAB

13. CBER Biological – Medical Device Combination Products Biological Products Combination Products Medical Devices + Replace Repair Restore Regenerate

14. CBER General Principles l Novelty of the drug l Extent previously studied l Known or suspected risks l Developmental phase l Building process

15. Risk based Approach to Regulation of Cells and Tissues l Provide a unified regulatory framework l Provide greater flexibility and innovation in this field of medicine l Provide a tiered regulatory approach with the level of regulation proportional to the degree of risk l Risk determines level of regulation – Low Risk – tissues, Section 361, PHS – High Risk – Preapproval, Section 351, PHS or FD&C

16. CBER The New U.S. FDA “Tissue Rules” l Establishment Registration & Product Listing Rule (Final – 1/2001) Notify FDA of location and tissue products prepared l Donor Eligibility Rule (Proposed) Properly screen and test donors for communicable diseases l Good Tissue Practices (GTP) Rule (Proposed) Proper handling, processing and storage of tissue Record keeping and facility cleaning

17. Biosafety Testing for Cellular & Tissue-Based Products Raw materials Master Cell Bank Working Cell Bank Master Viral Bank In-process material Final Product Biosafety must be assessed at all stages of manufacturing  Type and timing of testing depends on stage of product manufacturing, source of material and manipulation (e.g., genetic modification).  Refer to ICH Guidance Documents for additional information

18. CBER Regulatory Concerns Common to ALL Cellular Components l Product Safety – Donor screening and testing – Product testing Adventitious agents, tumorigenicity, pyrogenicity – Biocompatibility testing with device l Product Characterization – Identity, purity, potency, viability, stability

19. CBER Regulatory Concerns Common to ALL Cellular Components l Manufacturing Process – cGMPs – Control of product and process – Qualification of reagents – Segregation and tracking different donors/different lots l Reproducibility/Consistency of Product Lots – Development of in-process and lot release specifications – Ensure efficacy Not dependent on autologous, allogeneic, or cell lines

20. CBER Clinical Efficacy Trial Design l Size of Trial – Expected frequency and size of effect/benefit – Disease indication and stage of disease Chronic disease vs. life-threatening – Patient Selection – Meaningful Endpoints – Potential Toxicity Need to balance potential risk vs. potential benefits – Existing therapies – Safety database Like products vs. novel

21. CBER One Size does NOT! Fit ALL Flexibility Required

22. CBER What are we doing? l Continue to take an active role with other organizations – Must Work Together!! – FDA/NIH working group on Stem Cells – FDA representative on RAC for Gene Transfer Products – FDA industry working group to develop the Adenoviral Reference Material – just released – Establishing a working group for comparability for cellular products l Enhance our regulatory research to improve product safety for “new” product classes

23. CBER What are we doing? Public Discussions l BRMAC – Pancreatic Islets – March 2000 – Human Stem Cells for Neurological Disorders – July 2000 – Lentiviral Vectors – October 2001 – Ooplasm Transfer in Assisted Reproduction – May 2002 – Inadverent Germline Transmission – May 2002 l Workshops – ICH Gene Therapy Workshop – Sept. 2002 – Stem Cells and Regenerative Medicine: Shaping the FDA Regulatory Approach, Natcher Aud. NIH, April 7-8, 2003

24. CBER What are we doing? l Guidances – updates and new – Somatic Cell and Gene Therapy Splitting into two documents – –Somatic Cell Therapy – specifics for cell types –Gene Therapy – specifics for vector types – Guidance for Reviewers – Reviewer Template Cell Therapy Products Gene Therapy Products l Post slides on CBER website l Try to take CBER booth to many conferences – have relavent guidances available, CD