CTGTAC meeting March 30, 2007

1. Draft Guidance for IndustryMinimally Manipulated, Unrelated, Allogeneic Placental/Umbilical Cord Blood Intended for Hematopoietic Reconstitution in Patients with Hematological Malignancies CTGTAC meeting March 30, 2007

2. Overview • Background/History • Purpose/Scope of Guidance • License Application Procedure • Chemistry, Manufacturing & Controls • Applicable Regulatory Requirements HCT/Ps, Compliance with cGMPs • Postmarketing activities • Next steps

3. Background (1) • History of promulgation of HCT/P regulations • Proposed a tiered approach • Implemented by promulgating 3 final rules • Unrelated allogeneic hematopoietic stem/progenitor cells including cord blood (HPC-C) meet criteria for regulation as biological products under PHS Act (systemic effect) • Subject to IND and BLA requirements

4. Background (2) • Summary of 1998 FR notice: Request for Proposed Standards • Requested submission of comments • Establishment controls • CMC controls-processing & product standards • For minimally manipulated unrelated allogeneic cord blood and PBSC

5. Background (3) • Summary of 2003 BRMAC on cord blood • FDA provided analysis of clinical outcome data • Committee discussed safety & efficacy issues • CBER task force determined data submitted to docket and published literature permit development of recommendations for applying for licensure • Published draft guidance January 2007

6. Draft Guidance • Open for public comment • Comment period ends April 17, 2007 • Represents FDA’s current thinking; does not establish legally enforceable responsibilities • Recommendations, unless specific regulatory or statutory requirements cited • Can use an alternative approach

7. Purpose • Recommends ways for cord bank to apply for licensure for specified indications • Explains applicable regulations in Title 21 of the Code of Federal Regulations • Provides other information about the manufacture of HPC-C and how to comply with the applicable regulatory requirements

8. Scope (1) • Covers cord blood products that are: • Minimally manipulated; and • Intended to be used in recipients unrelated to the donor

9. Scope (2) • Does not cover: • PBSC • Other cord blood products (e.g. more than minimally manipulated, and/or for other indications) • Cord blood for autologous/family-related use (though encourage following these recommendations)

10. Indication specified in Draft Guidance • Hematopoietic reconstitution (engraftment) outcomes defined in 1998 FR notice • Preponderance of data submitted to docket describing cord blood transplant outcomes in patients with hematologic malignancies (approximately 65-70%) • Numerous other indications – much less data (all genetic disease 25%, SAA/FA 5%)

11. Data needed to support other indications • Data demonstrating safety and efficacy of HPC-C for transplantation in patients with other diseases/disorders, for example • Engraftment • Survival • Measures of mitigation of defect (e.g. immune reconstitution; increase in level of metabolic enzyme; correction of hemoglobinopathy) • Subject of committee discussion

12. Use of this Guidance to apply for a Biologics License • Manufacturer demonstrates in application that they have followed guidance recommendations • Manufacturer may modify any procedure in guidance • Evidence demonstrating modification will provide assurances of safety, purity, potency, and effectiveness • Guidance provides specific recommendations if manufacturer wishes to rely on data in the docket • Biologics license would apply to HPC-C manufactured at time of and subsequent to approval of the license application

13. Do cord blood manufacturers have to use this Guidance when applying for a license? • No. However, a manufacturer who does not use this guidance must submit a BLA for their HPC-C containing the following data: • Studies demonstrating that the product meets requirementsof safety, purity, and potency (21 CFR 601.2) • nonclinical laboratory studies • clinical studies • Recommend consultation with CBER about alternative approaches

14. License Application Procedure

15. License Application Procedure • Form FDA 356h – Application to Market a New Drug, Biologic, or an Antibiotic Drug for Human Use • Where to submit – Document Control Center (address provided) • Guidance describes information to include and • What action FDA will take

16. Information to Include • Index • Representative draft labeling • Summary of information submitted • CMC – 21 CFR 314.50(d); § 601.2 • Full description of manufacturing process and SOPs for critical procedures, assays • Summary validation data • Establishment description – § 600.10 • Other attachments, including citation to data in docket

17. What action will FDA take? • Review application • Schedule prelicense inspection as soon as possible after receiving complete application • If application not complete, FDA will identify/advise establishment of additional information that they will need to submit

18. Chemistry, Manufacturing and Controls (CMC)

19. CMC: HPC-C Description and Characterization (1) Table A: Required and recommended tests and results • Safety • ID testing – required (maternal blood sample) • All tests negative except for non-treponemal test for syphilis when confirmatory test negative; CMV • Sterility testing – required (cord blood* and pre-cryopreservation sample) • Negative • Hemoglobin (cord blood sample) • No homozygous hemoglobinopathy *Cord blood = cord blood before undergoing volume reduction

20. CMC: HPC-C Description and Characterization (2) Table A: Required and recommended tests and results • Purity and potency(pre-cryopreservation sample) • TNC ≥ 5.0 x 108/HPC-C • Based on 20 kg recipient dose of ≥ 2.5 x 107/kg and 70% post-thaw recovery = 1.7 x 107/kg • Viable nucleated cells ≥ 85% • Viable CD34+ cells ≥ 1.25 x 106/HPC-C • Based on CD34+ cells ≥ 0.25% prior to freezing

21. CMC: HPC-C Description and Characterization (3) Table A: Required and recommended tests and results • Identity • HLA typing (cord blood sample) • Confirmatory HLA typing (attached segment) • ABO/Rh (cord blood sample)

22. CMC: Manufacturer information (1) • Identification • Name(s), address(es), FDA registration number(s), other organizational information for each manufacturer • Including those under contract, agreement, other arrangement to perform a manufacturing step; for example, • Collection sites • Laboratories performing donor testing for relevant communicable disease agents and product sterility testing

23. CMC: Manufacturer information (2) • Contamination precautions • Description of in-process controls to prevent or identify contamination or cross-contamination • Avoid simultaneous manipulation of more than one HPC-C in a single area • Precautions taken to prevent contamination and cross-contamination by equipment • Narrative description of procedures/facility/equipment design features • Narrative description of manufacturing area – collection, volume reduction, packaging, labeling, cryopreservation, storage, and shipping

24. CMC: Methods of manufacturing (1) • SOPs to submit with license application • Collection • Processing • Volume reduction; cryopreservation; frozen storage; lot release • Selection • Data management; search request; donor matching to candidate recipients; selection of HPC-C • Shipping and handling • Shipping to transplant center; thawing and preparation for administration; emergency product recovery • Validation data summary • Recommend data from 3 consecutive, separate HPC-Cs

25. CMC: Methods of manufacturing (2) • Flow charts • Complete visual representation of manufacturing process flow, including list of in-process controls, and tests performed at each step • Includes information on transfers • Microbiology • Includes description of presterilized equipment and containers • Control of aseptic manipulations • Includes description of process parameters that are monitored; procedures used to monitor bioburden/sterility; conditions and time limits for process steps

26. Other Important CMC Information • Description of container closure system • Can reference NDA, 510(k), or MF • Provide evidence of container and closure integrity for duration of proposed storage period • Environmental assessment – 21 CFR Part 25 • Applicant may submit request for categorical exclusion

27. Other Important CMC Information • Methods validation/verification • Infectious disease tests – licensed/approved/cleared • Other tests – sterility, TNC, HLA, ABO/Rh, other • Labeling – see Guidance Section VII.B.2

28. HPC-C previously manufactured Subject of committee discussion

29. HPC-C previously manufactured using the same procedures • License would apply to HPC-C previously manufactured in accordance with the information provided in the license application, where documentation is provided to demonstrate their comparability to HPC-C currently manufactured

30. HPC-C previously manufactured using different procedures • Cord blood processing methods have changed over time • Any change has potential to affect safety and quality To include under BLA: • Must demonstrate comparability of previously manufactured HPC-C to the currently manufactured HPC-C • Must provide evidence that methods, facilities, and controls used for manufacture conformed to CGMP and other applicable regulatory requirements

31. Recommended approach for demonstration of comparability • Separate validation summaries • Data on product characteristics: • TNC count • Viable CD34+ cell content • Colony forming units (CFU) • Alternative methods • Clinical outcome data • Medical literature citation

32. Correlations among TNC, CD34+ cells, and CFU in HPC-C • TNC and CD34+ cell dose have been shown to correlate with engraftment • Increase in TNC associated with shortened time to engraftment • CD34+ cell dose associated with incidence and rate of neutrophil recovery • Correlation between viable CD34+ cell number and CFU reported

33. Log All CFU (x 104) Log CD34+ (x 104) Correlation of CFU and CD34+ cells in HPC-C Cairo et al. 2004; Blood, 104:11, Abstract #406.

34. Types of samples available for comparability studies (1) • Segment • Cell sample attached to HPC-C container • Advantage: • Exposed to same processing, freezing and storage conditions as HPC-C • Low risk of mislabeling between segment and HPC-C • Disadvantage: • Limitation on the amount of sample for testing • Finite number of segments

35. Types of samples available for comparability studies(2) • Cryovial sample • Processed similarly as HPC-C but separate aliquot • Advantage: • Increased number of aliquots may be stored • Cryovial sample retrieval does not affect HPC-C • Disadvantage: • Sample may not be representative of HPC-C • May be exposed to different freezing and storage conditions • Increased risk of mislabeling between cryovial and HPC-C

36. Types of samples available for comparability studies (3) • HPC-C unit • Advantage • Most representative of product received by patients • Sufficient samples for testing • Disadvantage: • HPC-C unit cannot be used for transplant

37. Establishment Description

38. Establishment Description (1) • General Information • Floor diagram, location of major equipment • Description of processing areas • Activities in adjacent areas • Product, personnel, equipment and waste flows • Specific Systems • Source of water used in processing, if applicable • Heating, ventilation, and air conditioning • Facility controls • Including environmental monitoring program • Computer systems • Information and validation summaries for systems that control critical manufacturing processes; examples provided

39. Establishment Description (2) • Contamination/Cross-Contamination Issues – supplements information in the CMC section • Equipment cleaning procedures and validation • Certification of cleaning validation for removal of product residues • Containment features • Air handling (where appropriate) • Procedures for decontamination and equipment cleaning when there is a breach in container integrity

40. Applicable Regulations and Post marketing Activities

41. Applicable Regulatory Requirements (1) • Manufacturer and product subject to all applicable regulatory requirements: • Prelicense inspection (42 U.S.C. § 262) • 21 CFR Parts 210 and 211 (CGMP) • 21 CFR Part 600 (Biological Products: General) • 21 CFR Part 601 (Licensing) • 21 CFR Part 610 (Biological Products Standards) • 21 CFR Parts 201, and 610 Subpart G (Labeling) • 21 CFR Part 202 (Advertising)

42. Applicable Regulatory Requirements (2) • 21 CFR Part 1271 HCT/P regulations: • Establishment Registration and Listing • Donor Eligibility • Current Good Tissue Practice (CGTP) • More specific regulations supersede more general • Compliance with CGMP would result in compliance with applicable CGTP requirements, with some exceptions

43. Applicable Regulatory Requirements(3) • CGTP (not covered under CGMP) • Donor eligibility • Prevention of spread of communicable disease • Manufacturing arrangements • Exemptions and alternatives

44. Applicable CGMPs (1) • Quality control unit • Personnel • Buildings and facilities • Equipment • Predistribution shipments and control of components, containers, and closures • Production and process controls -process validation

45. Applicable CGMPs (2) • Packaging and labeling controls • Includes physical separation from other operations; distinct identification code; expiration dating determined by stability testing; shipping containers and conditions to be maintained during transit • Label and labeling content to be submitted • Prescription drug labeling • Package label – partial label may be used • Subject to bar code label requirements

46. Applicable CGMPs (3) • Holding and distribution • Laboratory controls • Testing for safety, potency, identity; stability program • Records and reports • Failure investigations • Tracking • Complaints • Returned and salvaged HPC-C

47. Postmarketing Activities (1) • Clinical Outcome Data Collection • Recommend analysis of clinical data from transplant centers as quality indicator • Should evaluate data to determine whether adverse experiences or other unexpected outcomes may be due to manufacturing problems

48. Postmarketing Activities (2) • Changes to be Reported (21 CFR 601.12) • Adverse Experience Reporting - (21 CFR 600.80) • Biologic Product Deviation Reporting - (21 CFR 600.14)

49. Next steps Review and address comments to docket • Finalize Guidance • Intend to include date for implementation of IND/BLA requirement (ending period of delayed implementation of IND requirement) • License applications accepted at any time

50. Unrelated allogeneic PBSC (HPC-A) • Also subject of 1998 FR notice • Considerations for HPC-A regulatory approach: • HPC-A often requires limited manufacturing beyond recovery, testing, labeling, distribution • Post-recovery manufacturing steps may be performed in laboratory at transplant center • Most HPC-A manufacturing performed by establishments participating in the NMDP registry • Other issues: Donor mobilization, cell selection/depletion, DLI • Subject of committee discussion