1. Draft Guidance for Industry Minimally Manipulated, Unrelated, Allogeneic Placental/Umbilical Cord Blood Intended for Hematopoietic Reconstitution in Patients with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submitted to docket and published literature permit development of recommendations for applying for licensure Published draft guidance January 2007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 Draft Guidance Open for public comment Comment period ends April 17, 2007 Represents FDA’s current thinking; does not establish legally enforceable responsibilities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 Indication specified in Draft Guidance Hematopoietic reconstitution (engraftment) outcomes defined in 1998 FR notice Preponderance of data submitted to docket describing cord blood transplant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 requirements of 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. 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 10 8 /HPC-C Based on 20 kg recipient dose of ≥ 2.5 x 10 7 /kg and 70% post-thaw recovery = 1.7 x 10 7 /kg –Viable nucleated cells ≥ 85% –Viable CD34+ cells ≥ 1.25 x 10 6 /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. Correlation of CFU and CD34+ cells in HPC-C Log CD34 + (x 10 4 ) Log All CFU (x 10 4 ) 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 –D isadvantage : 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