1. 1 FDA Regulation of Cellular, Tissue, and Gene Therapies Celia M.Witten, Ph.D., M.D. Director, Office of Cellular, Tissue, and Gene Therapies, FDA Phacilitate Cell and Gene Therapy Forum 2010 Washington, D.C.

2. 2 Outline Overview of Office and Regulations Update on Recent Guidances and Meetings Current Activities/Future Opportunities

3. 3 FDA Organization Office of the Commissioner Office of Combination Products CBER (Center for Biologics Evaluation and Research): vaccines, blood and blood products, human tissue/tissue products for transplantation, cell therapy, gene therapy, donor screening tests for blood and tissue safety, devices CDRH (Center for Devices and Radiological Health): devices for treatment, implants, diagnostic devices CDER (Center for Drug Evaluation and Research): drugs, monoclonal antibodies, therapeutic proteins) CVM CFSAN NCTR

4. 4 CBER Organization Immediate Office of Director Office of Blood Research and Review Office of Cellular, Tissue and Gene Therapies Office of Vaccines Research and Review Office of Compliance and Biological Quality Office of Biostatistics and Epidemiology Office of Communication, Training and Manufacturers Assistance Office of Management

5. 5 Office of Cellular, Tissue, and Gene Therapies Celia M.Witten, Ph.D, M.D., Director Stephanie Simek, Ph.D., Office Deputy Director Richard McFarland, Ph.D, M.D. Associate Director for Policy Suzanne Epstein, Ph.D., Associate Director for Research Patrick Riggins, Ph.D., Director RPM Division of Cellular and Gene Therapies Raj Puri, Ph.D., M.D., Director Division of Human Tissues Ellen Lazarus, M.D., Director Division of Clinical Evaluation and Pharmacology/Toxicology Vacant

6. 6 OCTGT Products Cellular therapies Tumor vaccines and immunotherapy Gene therapies Tissue and tissue based products Xenotransplantation products Combination products Devices used for cells/tissues Donor screening tests (for use with cadaveric blood samples)

7. 7 Premarket Review Pathways Biologics Regulations IND – Investigational New Drug BLA- Biologics License Application Device Regulations IDE- Investigational Device Exemption PMA- Premarketing Application HDE- Humanitarian Device Exemption Combination products Pathway determined: Primary mode of action- RFD process (Office of Combination Products) Previous intercenter agreements and precedents

8. 8 Update on Recent Guidances and Meetings

9. 9 Workshops 2008-2009 FDA/NIAID Workshop: Animal Models for the Treatment of Acute Radiation Syndrome — September 27, 2008 FDA/NIH/CIBMTR/ASBMT Workshop: Clinical Trials Endpoints for Acute Graft-Versus-Host Disease After Allogeneic Hematopoietic Stem Cell Transplantation — March 13, 2009 FDA/NCI Workshop: Therapeutic Cancer Vaccines Considerations for Early Phase Clinical Trials Based on Lessons Learned from Phase III — October 27, 2009

10. 10 Workshops 2008-2009, cont’d NIH/JDRF/FDA Workshop: Next Generation Beta- Cell Transplantation — November 9, 2009 Public Workshop: Emerging Arborviruses: Evaluating the Threat to Transfusion and Transplantation Safety — December 14-15, 2009

11. 11 Recent Advisory Committee Meetings April 10-11 2008: Cellular Therapies Derived from Human Embryonic Stem Cells Scientific Considerations for Pre-Clinical Safety Testing Response to September 2005 Review of OCTGT Research Program FDA Somatic Cell Therapy Letter Update: OCTGT Guidance Development Program May 14-15 2009: The potential for Chlamydia trachomatis and Neisseria gonorrhea transmission by certain human cells, tissues, and cellular and tissue- based products (HCT/Ps) Animal models for porcine xenotransplantation products intended to treat Type 1 diabetes or acute liver failure Clinical issues related to the FDA draft guidance “Preparation of IDEs and INDs for Products Intended to Repair or Replace Knee Cartilage.” October 9 2009: Isolagen Therapy for moderate to severe nasolabial fold wrinkles

12. 12 Safety of Cell Therapies Derived from Human Embryonic Stem Cells CTGT Advisory Committee April 10, 2008 Safety Concerns Product Characterization Trial Design

13. 13 CTGTAC April 10, 2008 Major Considerations Stronger than usual proof of concept evidence may be required The dose of cells administered to humans should be below the minimum number of cells observed to form tumors in animal models First in man clinical applications should be picked carefully due to inherent risks Long term follow up recommended due to perceived risk

14. 14 Guidances 2009

15. 15 Cord Blood Guidance – Hot Off the Press Final Guidance for Industry: Minimally Manipulated, Unrelated Allogeneic Placental/Umbilical Cord Blood Intended for Hematopoietic Reconstitution for Specified Indications (HPC-C Licensure Guidance) - 10/20/09 http://www.fda.gov/downloads/BiologicsBloodVaccines/Guidance ComplianceRegulatoryInformation/Guidances/Blood/UCM187144.pdf Draft Guidance for Industry and FDA Staff: IND Applications for Minimally Manipulated, Unrelated Allogeneic Placental/Umbilical Cord Blood Intended for Hematopoietic Reconstitution for Specified Indications (Draft HPC-C IND Guidance) – 10/20/09 http://www.fda.gov/downloads/BiologicsBloodVaccines/Guidance ComplianceRegulatoryInformation/Guidances/Blood/UCM187146.pdf

16. 16 Phase-in period for IND and BLA requirements, and comment period With publication of these HPC-C guidance documents, FDA is also announcing that the phase-in implementation period for IND and BLA requirements for these products will end in 2 years after date of publication (October 20, 2011) Sponsors are encouraged to send in IND and BLA applications as soon as possible to allow sufficient time for review, comment, and resubmission as needed to complete all actions by the end of this 2 yr period Submit your comments on the draft IND guidance within 90 days of publication, to ensure that we can consider your comments before beginning work on the final version

17. 17 What is the purpose of the HPC-C Licensure Guidance, and why is there companion Draft HPC-C IND Guidance? The HPC-C Licensure Guidance provides recommendations to manufacturers applying for licensure of minimally manipulated, unrelated allogeneic placental/umbilical cord blood, for specified indications Stakeholder input received on the December 2006 draft guidance were considered; this HPC-C Licensure Guidance finalizes the draft guidance Input included comments on importance of access to and availability of HPC-C products that do not meet standards for licensure and therefore cannot be licensed; agency recognizes importance of these products and published draft guidance addressing IND submissions for these products

18. 18 Tissue Guidance Documents Draft Guidance for Industry: Current Good Tissue Practice (CGTP) and Additional Requirements for Manufacturers of Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps)  January 2009 Draft Guidance for Industry: Use of Serological Tests to Reduce the Risk of Transmission of Trypanosoma cruzi Infection in Whole Blood and Blood Components for Transfusion and Human Cells, Tissues, and Cellular and Tissue-Based Products  March 2009

19. 19 Product-Specific Guidances Draft Guidance for Industry: Somatic Cell Therapy for Cardiac Disease — March 2009 Guidance for Industry: Considerations for Allogeneic Pancreatic Islet Cell Products — September 2009 Draft Guidance for Industry: Clinical Considerations for Therapeutic Cancer Vaccines — September 2009

20. 20 Current Activities/Future Opportunities Tissue Safety Stem Cells Gene Therapy International Engagements International Engagements

21. 21 Goals for Tissue Safety Enhance processes for adverse reaction report investigation and evaluation Increase collaboration with professional organizations and State public health authorities Improve outreach to consumers and health care providers Encourage reporting, educate on tissue safety

22. 22 Relevant Communicable Disease Agents and Diseases Workgroup Define gaps in current knowledge about transmission of infectious diseases by tissue transplantation Develop approaches for leveraging Federal agency and industry research resources for filling gaps Develop policies for screening and testing HCT/P donors for emerging infectious diseases

23. 23 CBER Pilot Biovigilance Projects To assess the value of large medical encounter databases for tissue utilization and safety: Evaluation of system characteristics of eight potential databases Examine infections after certain tissue transplants and identify health information system gaps to enable automated data systems to efficiently monitor infections in recipients Collaboration with Harvard Pilgrim Collaboration with Centers for Medicare and Medicaid Services

24. 24 Trends in Cell Therapy Sources of adult stem cells Placental and amniotic membrane, adipose hESC cells/iPS cells Cell Products designed to induce immune tolerance Xenotransplantation Cells encapsulated in a biomaterial Tissue engineering

25. 25 Trends in Gene Therapy Chimeric Antigen Receptors: Autologous T-cells transduced with retroviral or lentiviral vectors expressing Chimeric Antigen Receptor (CAR) or antigen specific T cell receptor (TCR) Oncolytic Viruses (OV): OV are intended to replicate selectively in tumor tissue, destroying the tumor without causing excessive damage to normal tissues. Bacterial Products/vectors: Live bacterial therapeutics primarily used in cancer indications

26. 26 International Engagements As an emerging product area, cell and gene therapies are prime area for prospective harmonization and convergence of regulatory approaches International Conference on Harmonisation (ICH) FDA-EMEA ATMP “Cluster” Regulatory exchanges

27. 27 ICH Gene Therapy Discussion Group (GTDG) Monitor emerging scientific issues Proactively set out principles that may have a beneficial impact on harmonization Ensure that the outcomes of the GTDG are well understood and widely disseminated Public ICH web page http://www.ich.org/ Public communications papers Public press statements from the ICH SC Public ICH workshops

28. 28 ICH Workshops Workshop on Viral / Vector Shedding, Rotterdam October 30, 2007 ICH Workshop on Oncolytic Viruses, Chicago, November 7, 2005 Presentations at ICH6 on Gene Therapy, Osaka, November 15, 2003 First Workshop on Gene Therapy, Washington, September 9, 2002

29. 29 ICH Considerations Gene therapy is a rapidly evolving field Difficult to write ICH guidelines on gene therapy topics due to flux of the field Consideration papers are a way to proactively set out principles that may have a beneficial impact on harmonization

30. 30 Published ICH Considerations General Principles to Address the Risk of Inadvertent Germline Integration of Gene Therapy Vectors, 10/2006 Oncolytic Viruses, 11/2008 Viral/Vector Shedding, 6/2009

31. 31 FDA-EMEA ATMP “Cluster” Formal cooperation and confidentiality arrangement between FDA and European Medicines Agency (EMEA) for pharmaceuticals initiated 9/03; extended 9/05 to 9/2010 Over time, “clusters” of specific areas of interest were developed for more targeted information exchanges With EMEA product scope enlargement to include tissue engineering with cell and gene therapies (“advanced therapeutic medicinal products” – ATMPs), ATMP “cluster” initiated 2008

32. 32 FDA-EMEA ATMP “Cluster” Regular teleconferences to share thinking on regulatory approaches, both general and specific issues Information sharing on draft documents Engage reciprocally in workshops and advisory committees, working parties

33. 33 Regulatory Exchanges OCTGT has hosted on limited basis regulatory colleagues, Fall of 2009: EMEA ATMP expert Japan Pharmaceutical and Medical Device Agency (PMDA) cell therapy expert OCTGT experts routinely respond to foreign regulatory inquiries, calls for assistance, both through written communication, face-to-face exchanges, presentations at international fora

34. 34 Contact Information Celia Witten, Ph.D., M.D. Office Director, OCTGT CBER/FDA 1401 Rockville Pike (HFM-700) Rockville, MD 20852-1448 301-827-5102 Celia.witten@fda.hhs.gov