U.S. Food and Drug Administration

1. U.S. Food and Drug Administration Notice: Archived Document The content in this document is provided on the FDA’s website for reference purposes only. It was current when produced, but is no longer maintained and may be outdated.

2. C B E R FDA Update on Cord Blood Regulation: New Guidance Ellen F. Lazarus, M.D., FCAP Director, Division of Human Tissues Office of Cellular, Tissue, and Gene Therapy

3. How does FDA regulate cord blood for autologous use and use in first or second-degree relatives? Regulated solely under Section 361 of the Public Health Service Act, from which the HCT/P regulations derive (21 CFR 1271 Subparts A-F), unless more than minimally manipulated; for non-homologous use; or combined with another article with some exceptions such as preserving and sterilizing agents (§1271.10) • Establishment registration and listing rule • Donor eligibility and CGTP rules • Reporting and labeling requirements • Inspection, import, and enforcement provisions

4. How does FDA regulate cord blood from unrelated donors? • Regulated as HCT/P under 21 CFR Part 1271 Subparts A-D (Registration, DE, and CGTP rules) • Also regulated as a drug under the FD&C Act and as a biological product under Section 351 of the PHS Act, and therefore additional regulations apply • Labeling and advertising (21 CFR Part 201 and 202) • CGMPs (Part 211) • IND regulations (Part 312) • Licensing and general biological products standards (Parts 600, 601, 610)

5. Phase-in period for IND and BLA requirements Until very recently (last week), FDA has delayed implementation of Investigational New Drug and Biologics License Application requirements for minimally manipulated unrelated allogeneic hematopoietic stem/progenitor cell products (HPC)

6. Cord Blood Guidance - History • 1997 - FDA initiates HCT/P regulations • 1998 - FR notice: Request for Proposed Standards – Minimally manipulated unrelated allogeneic cord blood and PBSCs intended for hematopoietic reconstitution • Requested that interested public submit data and recommendations for • Establishment controls • CMC - processing and product standards • Stated that if adequate information is submitted to show safety and efficacy, FDA intends to issue guidance containing controls and standards (pathway to licensure) • Announced intention to phase-in implementation of IND and BLA requirements • Most of the docket information pertained to cord blood • 2003 – Convened Advisory Committee (BRMAC) on cord blood scientific issues

7. Draft Guidance – Provided recommendations for streamlined pathway to cord blood licensure • 2007 – CBER published draft • Applies to minimally manipulated allogeneic unrelated HPC-C intended for hematopoietic reconstitution in patients with hematological malignancies • Manufacturer can rely on data in docket – does not have to submit clinical data if follow recommendations in guidance • License would apply to current and previously manufactured HPC-C, where comparability and conformance with CGMPs are demonstrated • Applicant can use an alternative approach if it satisfies the applicable regulatory requirements

8. Comments to the Docket • Comment period Jan - April 2007 • 23 comments submitted • Received comments on scope/clinical indications; access to cord blood already banked in public inventories; and international exchange of cord blood • Other major comments addressed specific CMC and regulatory issues

9. Public Discussion of Draft GuidanceFDA Advisory Committee Cell, Tissue, and Gene Therapy AC meeting on March 30, 2007 convened to discuss draft guidance • FDA provided overview of the guidance • Dr. Rubinstein (NYBC) presented current and historical data on cord blood manufacturing, utilization, and clinical outcomes • Open Public Hearing – comments from representatives of industry • Committee members addressed FDA questions • Discussed access to cord blood units already in inventories • Recommended additional clinical indications – other malignancies and nonmalignant conditions normally considered for BMT • Expressed concern about feasibility of licensure of HPC-C at all non-US banks that list their products in international registries

10. 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/GuidanceComplianceRegulatoryInformation/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/GuidanceComplianceRegulatoryInformation/Guidances/Blood/UCM187146.pdf

11. 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

12. 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 • Comments received on the December 2006 draft guidance were considered; this HPC-C Licensure Guidance finalizes the draft guidance • Some comments expressed the 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 them

13. HPC-C Licensure Guidance contents • Background/Scope • Applicable regulatory requirements • License application procedure • CMC section • Establishment description section • Guidance on applicable regulations • Postmarketing activities

14. What information is contained in the HPC-C Licensure Guidance? • Scope of the Guidance (products covered), historical background, and how to use the Guidance when you apply for a BLA • Applicable regulatory requirements – explains which regulations apply to HPC-Cs for unrelated allogeneic use • License application procedure – Form FDA 356h, information to include, and actions that FDA will take

15. What HPC products does the HPC-C Licensure Guidance cover? • Placental/umbilical cord blood products that are: • Minimally manipulated • Intended for hematopoietic reconstitution in patients with any of the following diseases: • Hematological malignancies • Certain lysosomal storage and peroxisomal enzyme deficiency disorders • Hurler Syndrome (MPS I) • Krabbe Disease (Globoid Leukodystrophy) • X-linked Adrenoleukodystrophy • Primary immunodeficiency diseases • Bone marrow failure • Beta thalassemia; and • Intended to be used in recipients unrelated to the donor

16. What about HPC-C for family-related use? We encourage manufacturers of cord blood products for autologous use or use in first- or second-degree relatives to follow the recommendations concerning manufacture and how to comply with the regulatory requirements in the HPC-C Licensure Guidance, even though their products may not require premarket review

17. Information in the HPC-C Licensure Guidance – CMC • Contains a Table summarizing characteristics of the cord blood used to obtain the clinical data submitted to the docket to demonstrate safety, purity, and potency of HPC-C; applicant expected to obtain similar results if citing docket • Describes manufacturing information that should be submitted, including SOPs, validation data (including data on HPC-Cs in inventory to demonstrate comparability), control of aseptic manipulations, and processing and test methods validation data

18. HPC-C already in inventories • License would apply to HPC-C previously manufactured using the same procedures where documentation is provided: • Demonstrating their comparability, and that they were manufactured in accordance with CGMP and other applicable regulatory requirements • License would apply to HPC-C in inventory that were previously manufactured using different procedures, provided that: • Manufacturer submits a separate validation summary, and • Includes data demonstrating comparability of previously manufactured HPC-C to the currently manufactured HPC-C, and providing evidence that methods, facilities, and controls used for manufacture conformed to CGMP and other applicable regulatory requirements

19. Information in the HPC-C Licensure Guidance: Establishment Description • Provides guidance on the content and format of information to be submitted in this section of the BLA • Floor diagram, personnel and product flow, HVAC, facility controls, computer systems • Contamination/cross-contamination issues including equipment cleaning and validation; containment features

20. Information in the HPC-C Licensure Guidance – cont. • Guidance on applicable regulations – Establishment registration and listing; CGMP; and CGTP, and recommendations for complying with those regulations • Postmarketing activities • Recommendation for clinical outcome data received from transplant centers - analyze to determine whether adverse outcomes may be due to problems with product manufacture • Explanation of the BLA reporting requirements: changes to the approved BLA, adverse experiences, and biologic product deviations

21. What are the major changes from the draft guidance?

22. Title The title has changed, to reflect the difference in the scope of the HPC-C Licensure guidance: • Draft Guidance for Industry: Minimally Manipulated, Unrelated Allogeneic Placental/Umbilical Cord Blood Intended for Hematopoietic Reconstitution in Patients with Hematologic Malignancies • Guidance for Industry: Minimally Manipulated, Unrelated Allogeneic Placental/Umbilical Cord Blood Intended for Hematopoietic Reconstitution for Specified Indications

23. Scope • The scope of the guidance was changed to expand the list of intended clinical uses for the HPC-C covered by the Guidance; based on public comment, AC recommendations, and additional data submitted to the docket

24. What HPC products does the HPC-C Licensure Guidance cover? Placental/umbilical cord blood products that are • Minimally manipulated • Intended for hematopoietic reconstitution in patients with any of the following diseases: • Hematological malignancies • Certain lysosomal storage and peroxisomal enzyme deficiency disorders • Hurler Syndrome (MPS I) • Krabbe Disease (Globoid Leukodystrophy) • X-linked Adrenoleukodystrophy • Primary immunodeficiency diseases • Bone marrow failure • Beta thalassemia; and • Intended to be used in recipients unrelated to the donor

25. CMC section changes HPC-C Description and Characterization section revised to address comments to the docket on types of samples and frequency of testing for some of the recommended and required safety tests listed in the Table • Now only recommends a single HPC-C sample for sterility testing, rather than both a cord blood (unprocessed) sample and a HPC-C pre-cryopreservation sample; sample for sterility testing may be obtained before or after addition of cryoprotectant • Includes option to perform Hb testing using an appropriate donor sample; red cell sample obtained after processing may be used with appropriately validated reagents or test systems

27. CMC section changes – cont. • The Manufacturer section addresses appropriate precautions to prevent cross-contamination when the same area or equipment is used to process more than one HPC-C at a time; previously this section only recommended avoiding the simultaneous manipulation of more than one HPC-C in a single area • A section providing a more detailed description of container closure systems and related requirements and recommendations is added

28. Computer Systems • The Establishment Description section on Computer Systems includes more information about resources for information on software regulation and validation

29. Reserve Samples • According to 21 CFR 211.170(a), an appropriately identified reserve sample that is representative of each product shall be retained for 1 year after the expiration date of the product • The Reserve Samples section (VII.B.14.f.) contains a clarification that the expiration date of the thawed HPC-C may be used to determine the length of time that the HPC-C reserve samples must be retained

30. References and footnotes have been updated • Guidance for Industry on container closure systems for packaging human drugs and biologics; and • Draft Guidance for Industry on labeling for human prescription drug and biological products – implementing the new content and format requirements • Draft Guidance for Industry on validation of rapid microbiological methods for sterility testing of cellular and gene therapy products

31. Draft Guidance for Industry and FDA Staff: Investigational New Drug Applications for Minimally Manipulated, Unrelated Allogeneic Placental/Umbilical Cord Blood Intended for Hematopoietic Reconstitution for Specified Indications

32. Draft HPC-C IND guidance • Published for comment • Describes FDA’s current thinking and should be viewed as a recommendation except where specific regulatory requirements are cited • Submit comments within 90 days of publication of the draft guidance to ensure that we consider your comment before we begin work on the final version • Electronic comments to http://www.regulations.gov • Written comments to: Division of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852

33. Purpose of the Draft HPC-C IND Guidance • Situations when there will not be a suitable licensed cord blood product for a patient in need and an unlicensed product may be the best match • If unlicensed HPC-C are made available for clinical use, an IND is required • Advice for potential sponsors for submission of an IND for HPC-C for specified indications, when the HPC-Cs are not licensed and are needed for treatment of a patient with a serious/life-threatening disease and there is no satisfactory alternative treatment • Sponsor may be cord bank, registry, or physician (sponsor-investigator) • Outlines the minimum information to be included in an IND • Sponsors may submit one IND to cover the use of multiple HPC-C, or submit a separate IND for each single-patient use

34. To which unlicensed HPC-C does the Draft HPC-C IND Guidance apply? • Made available for transplantation in cases when no satisfactory alternative treatments are available • Intended for hematopoietic reconstitution in patients with the clinical indications listed in the HPC-C licensure guidance

35. Products the Draft HPC-C IND guidance covers • Placental/umbilical cord blood products that are: • Minimally manipulated • Intended for hematopoietic reconstitution in patients with any of the following diseases: • Hematological malignancies • Certain lysosomal storage and peroxisomal enzyme deficiency disorders • Hurler Syndrome (MPS I) • Krabbe Disease (Globoid Leukodystrophy) • X-linked Adrenoleukodystrophy • Primary immunodeficiency diseases • Bone marrow failure • Beta thalassemia; and • Intended to be used in recipients unrelated to the donor

36. Draft HPC-C IND Guidance addresses access issues • Manufactured in non-US cord blood establishments, listed in international registries, and selected for treatment of a patient in the US • Manufactured in US cord blood establishments before BLA approved and not shown to meet licensing criteria (e.g., not shown to be comparable to other licensed HPC-C in inventory – see slide #15) • Prospectively manufactured in the US and do not meet licensing criteria but for which there is no satisfactory alternative (e.g., for purpose of assuring diversity of HLA phenotypes)

37. Category A • Non-US HPC-C establishment - existing and future inventory • May choose not to apply for licensure • Products may not meet criteria for licensure • Examples • DE determination performed in accordance with standards of another country, but do not meet all of the requirements in the DE rule (21 CFR 1271 subpart C) • Release criteria different from those recommended in the HPC-C licensure guidance • Minimal information to be included in the IND is summarized in Table A, Column A

38. Category B • Pre-licensure inventory of unlicensed HPC-C that cannot be shown to be comparable to a US establishment’s licensed HPC-C, and needed for treatment of patients with specified serious/life-threatening conditions • Minimal information to be included in the IND is summarized in Table A, Column B

39. Category C • Prospective manufacture of unlicensed HPC-C in a US HPC-C establishment • HPC-Cs not licensable due to failure to meet donor eligibility or other manufacturing criteria • Expected to be uncommon situation • Example • Donors from under-represented populations who may have ID testing results indicating likely recovery from HBV infection, and collection from such donors may be necessary to assure sufficient HLA diversity • Minimum information to be included in the IND is summarized in Table A, Column C

40. Information to include in the IND • Minimum information summarized in Table A • Items listed are examples of the type of information to be included in the IND application; regulations in 21 CFR 312 not listed also apply, except where indicated

41. Labeling element examples • Non-US HPC-C • Supplemental labeling must be in English and include limited summary of manufacturing information and donor eligibility summary of records (for products manufactured after 5/05), among other information • US HPC-C • Supplemental labeling must also include all labeling content described in HPC-C licensure guidance (Section VII.B.12)

42. IND content and format • Cover sheet (Form FDA 1571) required for all categories • Investigator’s brochure describes • Product and its formulation (cell content and additives) • Description of possible risks • Recommended instructions for thaw and administration • Note: IB not required for sponsor-investigators

43. IND content and format – cont. • Protocol section for all categories provides • Brief summary of the study including dosing, recipient safety monitoring and reporting during infusion and post-transplant • Plan for review of clinical outcome data, to determine whether any adverse experiences or other serious or unexpected outcomes may be due to problems with product manufacture

44. IND content and format – cont. • CMC section in IND applications for all categories describes procedures for DE determination for HPC-C manufactured on or after 5/05 • Manufacturers (including non-US) must follow DE rule (21 CFR 1271 Subpart D); if not all requirements for donor screening and testing were met, specified warning statements must appear on label • Category C HPC-C from ineligible donors need appropriate labeling and other manufacturing controls • CMC section in IND applications for category A and B HPC-C manufactured before 5/05 describes donor screening and testing performed to prevent spread of communicable disease

45. IND content and format – cont. • CMC release specifications for non-US HPC-C (category A) include • No evidence of contamination; describe sterility testing performed and provide results • TNC count - define minimum and report • Cell viability – define minimum and report; alternative specifications for cell viability to those recommended in the HPC-C licensure guidance may be submitted in the IND for consideration • HLA, ABO/Rh, and hemoglobin testing results • CMC release specifications for US HPC-C (categories B and C) same as described in licensure guidance, or provide alternative

46. Sponsor and investigator responsibilities 21 CFR 312 Subpart D • Applicable to INDs described in the draft guidance • Draft guidance summarizes responsibilities of sponsors and investigators, and explains who is considered a sponsor or sponsor-investigator

47. Where to seek advice • Pre-IND and pre-BLA meetings are encouraged • Contact OCTGT Regulatory Project Management Branch to schedule: 301-827-5102 Riggins.Patrick@fda.hhs.gov Contact Office of Communication, Outreach and Development (OCOD) with questions about the guidance documents and related issues: 1-800-835-4709 or 301-827-1800 MATT@cber.fda.gov

48. Thanks to AABB, FACT/NETCORD, NMDP, CIBMTR, HRSA, NIH NHLBI, Cord Banks that submitted information to the docket, AC members, and all of you who provided invaluable input and data all along the way! We look forward to hearing from you and reviewing your applications.