CBER Presentation

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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Draft Guidance

  • For comment purposes only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)
      • 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
  • Identity: HLA typing, confirmatory typing using attached segment, ABO/Rh

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
 
Updated: March 15, 2007