CBER Presentation
BMT Tandem Meeting - Regulatory Issues Session
Ellen Lazarus, MD, FCAP
Division of Human Tissues
FDA CBER OCTGT
Guidance for Industry
Minimally Manipulated, Unrelated, Allogeneic Placental/Umbilical Cord Blood Intended for Hematopoietic Reconstitution in Patients with Hematological Malignancies
January 17, 2007
72 FR 1999
Draft Guidance
- For comment purposes only
- Comment period ends April 17, 2007
- Does not establish legally enforceable responsibilities
- Represents FDA's current thinking
- Recommendations, unless specific regulatory or statutory requirements cited
- Can use an alternative approach
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
Scope
- Covers cord blood products that are:
- Minimally manipulated; and
- Intended for hematopoietic reconstitution in patients with hematological malignancies; and
- Intended to be used in recipients unrelated to the donor
- 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)
Why is the indication limited?
- Cord blood regulated as HCT/P
- Homologous use broadly defined - hematopoietic reconstitution
- 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%)
Use of this Guidance
- Demonstrate that you have followed recommendations
- You may modify any procedure in guidance
- Present evidence demonstrating that modification will provide assurances of safety, purity, potency, and effectiveness
- License would apply to HPC-C manufactured after approval, and to HPC-C previously manufactured in accordance with the information provided in the license where documentation provided to demonstrate comparability
- You may submit BLA containing your own data from clinical studies
Background
- History of promulgation of HCT/P regulations
- Summary of 1998 FR notice: Request for Proposed Standards
- Summary of 2003 BRMAC cord blood meeting
- Determination that data submitted to docket and published literature permit development of BLA recommendations
Applicable Regulatory Requirements
- Prelicense inspection
- 21 CFR Parts 210 and 211 (CGMP), 600 (Biological Products: General), 610 (Biological Products Standards), 201 and 610 Subpart G (labeling), 202 (advertising)
- 21 CFR 1271 HCT/P regulations
- More specific regs supercede more general
- Compliance with CGMP would result in compliance with applicable CGTP requirements, with some exceptions
- Use Section VII of Guidance as a reference
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)
- What information to include
- What action FDA will take
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
What action will FDA take?
- Review application
- Schedule prelicense inspection as soon as possible after receiving complete application
- If application not complete, identify/advise you of additional information that you will need to submit
Chemistry, Manufacturing and Controls (CMC) Section
- HPC-C Description and Characterization
- Manufacturers
- Methods of Manufacturing
- Container Closure System
- Environmental Assessment
- Methods Validation/Verification
- Labeling
Required and recommended test results
- Safety: ID testing, Sterility testing, Hb
- Purity and potency (pre-cryopreservation)
- 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
- Identity: HLA typing, confirmatory typing using attached segment, ABO/Rh
-
TNC > 5.0 x 108/HPC-C
Manufacturer information
- Identification
- Includes FDA registration number, contract manufacturers (collection sites, labs performing RCDAD and product sterility testing)
- Floor diagrams
- Not necessary for collection sites
- Contamination precautions
Methods of manufacturing
- SOPs to submit
- Collection, processing, selection, shipping and handling (including thawing and preparation for administration, salvage
- Validation data summary
- Recommend data from 3 consecutive, separate HPC-Cs
HPC-C manufactured using different procedures
- Separate validation summary including data demonstrating:
- Comparability between the previously manufactured HPC-C and those manufactured currently
- Product characteristics
- Clinical outcome data
- References on comparability in Guidance
- Evidence that methods, facilities, and controls used for manufacture conform to CGMP and other applicable regulatory requirements
Other 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
- May submit request for categorical exclusion
- Methods validation/verification
- Infectious disease tests - licensed/approved/cleared
- Other tests - sterility, TNC, HLA, ABO/Rh, other
- Labeling - see guidance Section VII.B.2
Establishment Description
- General Information
- Floor diagram
- Description of processing areas
- Activities in adjacent areas
- Product, personnel, equipment and waste flows
- Specific Systems
- Water, HVAC, facility controls, computer systems
- Contamination/Cross-Contamination Issues
- Equipment cleaning, air handling, decontamination
Guidance on Applicable Regulations
- Describes applicable provisions in the HCT/P regulations, CGMPs, biologics regulations in 21 CFR Parts 600 - 680
- Formatted to follow CGMP subparts
- Establishment Registration and Listing
- Current Good Manufacturing Practice (CGMP) and Current Good Tissue Practice (CGTP)
- Label and Labeling content
- Holding and Distribution
- Laboratory Controls
- Records and Reports
- Failure investigations, tracking, complaints, returned and salvaged HPC-C
Postmarketing Activities
- Clinical Outcome Data Collection
- Recommend analysis of clinical data from transplant centers as quality indicator
- Should evaluate data to determine whether AEs or other unexpected outcomes may be due to manufacturing problems
- Changes to be Reported (21 CFR 601.12)
- Adverse Experience Reporting (21 CFR 600.80)
- Biologic Product Deviation Reporting (21 CFR 600.14(d))
Next steps
- Review and address comments
- ? Public meeting
- Finalize Guidance
- Intend to include date for implementation of IND/BLA requirement (ending period of IND enforcement discretion)
- License applications accepted at any time
Device Final Rule and Special Control Guidance
- Rule classifies cord blood processing system and container into class II (special controls) - published 1/31/07
- Guidance for Industry: Class II Special Controls Guidance Document - Cord Blood Processing Systems and Storage Containers
- Describes means by which the cord blood processing system and container may comply with the requirement of special controls for class II devices
- Immediately in effect but subject to comment in accordance with the agency's good guidance practices
Guidance: HCT/Ps Tested Using Pooled Specimens or Diagnostic Tests
- Published 1/23/07; for immediate implementation
- Comments to the docket accepted
- For HCT/Ps recovered after 5/25/06 to 30 days after publication
- Addresses:
- Distributed HCT/Ps and those in inventory
- Need for HCT/P deviation reports if distributed
- Retesting/labeling for future distribution of HCT/Ps in inventory
- FDA is exercising enforcement discretion to allow distribution of these HCT/P
- Limited to the two testing deficiencies
- Pertains to recently regulated living donor HCT/P (hematopoietic stem/progenitor cells and reproductive cells and tissues)
- For distributed HCT/Ps, deviation reports only required for hematopoietic stem cells from first or second degree blood relatives
- One report for all affected HCT/Ps
Testing Guidance: HCT/P Retesting Before Distribution
- Recommend using original donor sample
- Tested in accordance with the manufacturer's instructions and found negative/nonreactive
- New specimen OK
- If retesting not feasible
- Documentation recommended in files
- Physician notification
- Labeled "WARNING: Advise patient of communicable disease risks"
Testing Guidance: Retesting Donors
- If you cannot retest the donor, you can distribute these in-inventory HCT/P:
- Hematopoietic stem/progenitor cells (other than autologous)
- Cryopreserved embryos formed using 3rd party gametes
- If you cannot retest the donor, you cannot distribute cryopreserved semen or oocytes from anonymous or directed donors