1. DEPARTMENT OF HEALTH CENTER FOR BIOLOGICS AND HUMAN SERVICESEVALUATION and RESEARCH AND HUMAN SERVICES EVALUATION and RESEARCH Update on OCTGT Guidance Development Program Cellular, Tissue, and Gene Therapies Advisory Committee Meeting April 11, 2008

2. 2 FDA Good Guidance Practices (GGP)  Ensures proper development, formatting, processing, routing, and use of FDA guidance documents  Mandated by “Food and Drug Administration Modernization Act of 1997" (FDAMA)  Administrative Practices and Procedures; Good Guidance Practices,” 21 CFR 10.115  CBER SOPP 8002  Annual Guidance Agenda published in Federal Register

3. 3 Guidance Documents  Documents prepared for FDA staff, applicants/sponsors, and the public that:  Describe the agency’s interpretation of or policy on a regulatory issue;  Relate to the processing, content, and evaluation/approval of submissions;  Relate to the design, production, manufacturing, testing, labeling, and promotion of regulated products;

4. 4 Other Documents  Guidance documents do NOT include documents related to:  Internal FDA procedures;  Agency reports;  General information provided to consumers or health professionals;  Speeches;  Journal articles and editorials;  Media interviews and press materials;  Warning letters;  Memoranda of understanding;  Other communications or actions taken by individuals at FDA or directed to individual persons or firms;  Documents directed at public health emergencies

5. 5 Guidance Documents  Guidance documents are intended to represent our current thinking on matters discussed in the documents.  CBER staff may depart from guidance documents only with appropriate justification and supervisory concurrence (21 CFR 10.115(d)(3)).  Any consistent deviation from a guidance document indicates that we should revise it

6. 6 Level 1 Guidance Documents  Federal Register announcing the availability of the draft guidance for public comment  Placed on CBER web site  FDA offers a comment period (usually 60 to 90 days)  After reviewing the public comments, CBER will revise the guidance  Federal Register, announcing the availability of the final guidance.  The public may submit comments on the final guidance at any time.  CBER may issue a level 1 guidance for immediate implementation

7. 7 Level 2 Guidance Documents  All guidance documents not considered to be Level 1  Level 2 documents set forth existing practices or minor changes in interpretation or policy

8. 8 Communication with the Public During Guidance Development  When considering the development of guidance  CBER may freely discuss issues with the public.  If the issues to be addressed are particularly complex or controversial  Holding a public meeting  Holding advisory committee meeting on the issues  Before drafting the guidance  Once preparation of a draft guidance document has been initiated  Specifics of the guidance are not discussed with the public.  When the guidance has been issued in draft  Issues related to the draft guidance may be discussed  Issues related to specific intentions regarding the finalization of the guidance are not discussed  21 CFR 10.80  FDA may solicit information from the public at any time during the guidance development process.

9. 9 Published Guidances in Current FDA Annual Guidance Agenda (71 FR 51225, September 1, 2006)   Umbilical Cord Blood Intended For Hematopoietic Reconstitution in Patients With Hematological Malignancies  Draft, 1/2007  CTGTAC Discussions- 2/2003, 3/2007   Preparation of Investigational Device Exemptions and Investigational New Drugs for Products Intended to Repair or Replace Knee Articular Cartilage  Draft 7/2007  CTGTAC Discussions- 3/2005

10. 10 Published Guidances in Current FDA Annual Guidance Agenda (71 FR 51225, September 1, 2006)   Validation of Rapid Microbiological Methods for Assessing Sterility of Cellular and Gene Therapy Products  Draft 2/2008   Certain Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps) Recovered From Donors Who Were Tested For Communicable Diseases Using Pooled Specimens or Diagnostic Tests  Final, 1/2007

11. 11 Additional Published Guidances 2006- 2007   Regulation of Human Cells, Tissues and Cellular and Tissue-Based Products (HCT/Ps)- Small Entity Compliance Guidance  Immediate Implementation, 8/2007   Eligibility Determination for Donors of Human Cells, Tissues and Cellular and Tissue-Based Products  Final 8/2007   Cell Selection Devices for Point of Care Production of Minimally Manipulated Autologous Peripheral Blood Stem Cells (PBSCs)  Draft 7/2007   Class II Special Controls Guidance Document: Cord Blood Processing System and Storage  Immediate Implementation, 1/2007

12. 12 Additional Published Guidances 2006- 2007   Gene Therapy Clinical Trails – Observing Subjects for Delayed Adverse Events  Final 11/2006  CTGTAC Discussions- 3/1999, 11/2000, 4/2001, 10/2001   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  Immediate Implementation, 11/2006  CTGTAC Discussions- 3/1999, 11/2000, 4/2001, 10/2001

13. 13 Recently Finalized Guidances   Content And Review Of Chemistry, Manufacturing, And Control (CMC) Information For Human Somatic Cell Therapy Investigational New Drug Applications (INDs)  Final 4/2008  CTGTAC Discussions- Topics included in discussion at numerous meetings   Content And Review Of Chemistry, Manufacturing, And Control (CMC) Information For Human Gene Therapy Investigational New Drug Applications (INDs )  Final 4/2008  CTGTAC Discussions- Topics included in discussion at numerous meetings

14. 14 Preparation of IDEs and INDs for Products Intended to Repair or Replace Knee Cartilage  Written by Cross-Center Team  CDRH  CBER  Reflects CTGTAC input  CDRH participated in meeting  March 2005  Leverages ASTM document  Written by ASTM subcommittee  FDA staff participation according to FDA policies and ASTM process

15. 15 Preparation of IDEs and INDs for Products Intended to Repair or Replace Knee Cartilage Scope  IND/IDE products to repair or replace articular cartilage of the knee  Devices  Biologics  Combinations Products  Excludes  Unicondylar and total knee implants  Meniscus replacement products  “361” HCT/P products

16. 16 Preparation of IDEs and INDs for Products Intended to Repair or Replace Knee Cartilage Manufacturing and CMC Information  Brief explanation of requirements for  Devices  Biologics  Combination Products  Tailored for specifics of product composition

17. 17 Preparation of IDEs and INDs for Products Intended to Repair or Replace Knee Cartilage Nonclinical Data and Testing  Purposes of Animal Studies  Biological response to products  Durability of response (1 year)  Toxicology  Dose response  Mechanical Testing  Compare to normal cartilage  Justify why not possible  Biocompatibility  ISO 10993 and/or ASTM F748-04

18. 18 Preparation of IDEs and INDs for Products Intended to Repair or Replace Knee Cartilage Nonclinical Data and Testing  ASTM document- F2451-05, “Standard Guide for in vivo Assessment of Implantable Devices Intended to Repair or Regenerate Articular Cartilage,”  cartilage defect locations;  discussion of articular cartilage defect preparation;  description of gross and histological assessments;  description of various mechanical evaluations and their applicability.

19. 19 Preparation of IDEs and INDs for Products Intended to Repair or Replace Knee Cartilage Clinical Study Protocols  Exploratory Trials-design features  Exploratory Trials-knowledge learned

20. 20 Preparation of IDEs and INDs for Products Intended to Repair or Replace Knee Cartilage Clinical Study Protocols  Confirmatory Trials  Recommend randomized, controlled trial  Double blind  Blinded evaluators of major endpoints  Alternative design may be considered

21. 21 Preparation of IDEs and INDs for Products Intended to Repair or Replace Knee Cartilage Study Endpoints  Clinically meaningful endpoints as primary in confirmatory studies  Improvement in pain  Improvement in physical function

22. 22 Preparation of IDEs and INDs for Products Intended to Repair or Replace Knee Cartilage Study Endpoints Study Endpoints  Examples of secondary endpoints  Arthroscopic examination  Physical examination  Histologic examination at short and long term  Serological assessment for antibody and evidence of inflammation  Synovial fluid examination

23. 23 Preparation of IDEs and INDs for Products Intended to Repair or Replace Knee Cartilage  Investigational Product Administration  Detailed description of procedures  Surgical technique  Plans for post-operative  Follow-up  Length of follow-up to be based on in vivo and in vitro studies  Two-year follow-up for subset of subjects

24. 24 Preparation of IDEs and INDs for Products Intended to Repair or Replace Knee Cartilage Adverse event (AE) reporting  AE reporting per regulations (IND or IDE)  Subsequent surgical interventions  Revision  Removal  Reoperation

25. 25 Resources on the Web  Consolidation of OCTGT guidances  Cellular and Gene Therapies  http://www.fda.gov/cber/genetherapy/gtpubs.htm http://www.fda.gov/cber/genetherapy/gtpubs.htm  Tissues  http://www.fda.gov/cber/tissue/docs.htm http://www.fda.gov/cber/tissue/docs.htm  References for the Regulatory Process for the Office of Cellular, Tissue and Gene Therapies (OCTGT)  www.fda.gov/cber/genadmin/octgtprocess.htm www.fda.gov/cber/genadmin/octgtprocess.htm

26. 26 Summary  FDA guidance process to communicate with stakeholders  Good Guidance Practices (GGP)  Governed by regulations 21 CFR 10.115  OCTGT Recent Guidances  Current Annual Guidance Agenda  Additional Guidances to meet needs arising between Annual Guidance Agendas  FDA Guidance on Cartilage Repair Products  CBER and CDRH Joint Guidance  CTGTAC Meeting provided input for guidance development  Leveraged FDA participation in Standards Development Organization (ASTM)

27. 27 Conclusions  OCTGT has an active guidance development program that includes  Strategic Guidance Planning (Annual Agenda)  Responds to changing needs  OCTGT Guidance Program leverages  Input from CTGTAC meetings  Other public meetings (NIH RAC, Workshops, Scientific Meetings, Industry Liaison Meetings)  Cross-center efforts within FDA  Participation with Standards Development Organizations