CBER Presentation

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FDA Update

Martha A. Wells, MPH
Division of Human Tissue
OCTGT, CBER, FDA

PharmaConference HCT/P Meeting
January 24, 2007
San Antonio, TX

FDA Update

  • Registration and Listing
  • Donor Eligibility
  • Current Good Tissue Practices (CGTPs)
  • Exemptions and Alternatives
  • Adverse Reactions (AR)
  • Human Cells, Tissue, and Cellular and Tissue Based Products (HCT/P) Deviations
  • New Publications??

Registration

  • Annual update of registration required in December
  • Establishments registering electronically did not receive mailed forms this year, only email notification
  • Changes to listing are required within 6 months
  • Change of ownership or location required within 5 days
  • Inactivation-check box #2(d)
  • Electronic registration is encouraged

Failure to Registration

  • If you do not register or renew your registration annually, you will receive a letter telling you to do so in April.
  • If you still do not register, we will e-mail the responsible person listed in the registration database; CBER's Office of Compliance will contact district offices to follow-up
  • A failure to register notice has been posted on CBER's website

Registration/Listing

  • Total (as of 1/07) = 2418 (457 inactive)
    • Musculoskeletal/ocular = 1199
    • Hematopoietic stem cell = 628
    • Reproductive = 638
    • International = 136 (mostly stem cell)
  • Information: www.fda.gov/cber/tiss.htm
  • Questions: tissuereg@fda.hhs.gov

Proposed Rule for Registration and Listing for Foreign and Domestic Establishments

  • Published August 29, 2006
  • Comment period extended to January 26, 2007
  • Public meeting 12/11/06 discussed proposed changes to National Drug Code system
    • Would effect HCT/Ps licensed as biological products (e.g., hematopoietic stem cells and other cell therapy products)
    • Assigned by FDA
    • Must be on the product label

Proposed Registration/Listing Rule Changes to Part 1271

  • New definitions: importer, US agent
  • Would require electronic registration unless a waiver is granted
  • Foreign establishments importing HCT/Ps would submit information on all known US consignees
  • Changes to ownership or location would be reported within 30 days rather than 5 days

Donor Eligibility

  • Final Guidance will publish soon
  • Donor screening tests for testing HCT/P Donors listed at www.fda.gov/cber/tissue/prod.htm
    • Licensed donor screening tests includes sample type; whether licensed for cadaveric
    • Cleared Nucleic Acid Test (NAT) for Chlamydia trachomatis and Neisseria gonorrhea

CGTPs

  • Draft guidance in progress
  • Input from AATB, EBAA, and others
  • Guidance for Industry: Compliance with 21 CFR 1271.150(c)(1) Manufacturing Arrangement, September 2006
    • Discusses your responsibility for ensuring the establishments with which you have manufacturing arrangements are in compliance with CGTP requirements
    • Provides examples for doing so

Exemptions and Alternatives

  • Can request from donor eligibility and CGTP requirements
  • Must be accompanied by supporting documentation justifying the request
  • OCTGT SOPP 9151   6/13/06
    • Division of Human Tissues coordinates
    • Consults experts outside of division
    • Draft letter presented to Tissue Policy Team for discussion/concurrence
    • Center Director sign-off

Adverse Reactions

  • Adverse reaction means a noxious and unintended response to any HCT/P for which there is a reasonable possibility that the HCT/P caused the response
  • Manufacturers must submit a MedWatch 3500A to FDA within 15 days of receipt of information
  • And submit follow-up MedWatch report within 15 days of receipt of new information from the investigation

Adverse Reaction Reporting

  • Manufacturers must investigate:
    • Any adverse reaction involving a communicable disease related to an HCT/P that they made available for distribution.
  • Manufacturers must report to FDA
    • An adverse reaction involving a communicable disease if it:
      • Is fatal
      • Is life-threatening
      • Results in permanent impairment of function or permanent damage to body structure; or
      • Necessitates medical or surgical intervention, including hospitalization

How are Adverse Reactions Reported to FDA?

  • For Manufacturers:
    • Use Form FDA 3500A (MedWatch)
    • Report w/in 15 days of receipt of information

  • For Voluntary reporters:
    • Use Form FDA 3500 (MedWatch)
    • Recommend prompt reporting to HCT/P establishments

  • FDA MedWatch reporting system
    • http://www.fda.gov/medwatch

Adverse Reactions

  • Guidance for Industry: MedWatch Form FDA 3500A: Mandatory Reporting of Adverse Reactions Related to HCT/Ps www.fda.gov/cber/gdlns/advhctp.htm
  • Provides additional information and instructions for filling out the Medwatch Forms

Adverse Reaction Reports
Internal Procedures

  • SOPP 8508 describes procedures for handling AR reports-coordination by 5 offices in CBER
  • www.fda.gov/cber/regsopp/8508.htm
  • MedWatch reports involving "361" and biological product HCT/Ps come to CBER
  • Follow-up on infectious adverse reactions
  • Interoffice review -discussed at Tissue Safety Team meetings
  • Seek more information from reporter and manufacturer as needed

Adverse Reactions Reported to CBER
(November 05 to December 06)

  • Total reports: 209

  • Product Type
    • Tissue: 161 (77%)
    • Cells: 48 (23%)

  • Tissue Type
    • Bone: 45 (28%)
    • Eye: 39 (24%)
    • Skin: 33 (21%)
    • Soft Tissue: 29 (18%)
    • Cardiac: 10 (6%)

  • Reports from
    • Manufacturers: 54%
    • Healthcare workers: 46%

    Tissue Infectious/Non-infectious----65%/35%

HCT/P Deviation
21 CFR 1271.3(dd)

  • An event that represents a deviation from applicable regulations, standards or established specifications that relate to prevention of communicable disease transmission or contamination, or
  • An unexpected or unforeseeable event that may be related to transmission or potential transmission of a communicable disease or may lead to HCT/P contamination

HCT/P Deviation Reporting
21 CFR 1271.350(b)

  • Required for "361" nonreproductive HCT/Ps recovered on or after 5/25/05
  • Related to a distributed HCT/P
  • Must be investigated
  • Must report those that occurred in your facility or in a facility that performed a manufacturing step for you under contract, agreement or other arrangement
  • Only related to "core" CGTPs (1271.150(b))

When, How, Where

  • As soon as possible, not to exceed 45 days after discovery
  • www.fda.gov/cber/biodev/biodev.htm
  • Form FDA-3486 and instructions
  • Electronically or by mail
  • Indicate HCT/P Deviation Codes

HCT/P Deviation Codes

DE Donor Eligibility
DS Donor Screening
DT Donor Testing
EC Environmental control
SR Supplies and reagents
RE Recovery
PC Processing
LC Labeling control
ST Storage
SD Receipt, Pre-distribution Shipment, Distribution

HCT/P Deviations FY '05 FY '06
Donor Eligibility 8 32
Donor Screening   12
Donor Testing   33
Environmental Control   1
Supplies and Reagents   3
Recovery   2
Processing   14
Labeling Control 1 2
Storage   1
Receipt, Pre-Dist., Distribution 4 43
Not reportable 15 77
Total 28 220

HCT/P Deviation Reports
(Reportable and Non-reportable

  • Musculo-skeletal: 42
  • Skin: 10
  • Ocular: 68
  • Hematopoietic stem cell: 103
  • Somatic cells/leukocytes: 8
  • Reproductive: 4

Draft Cord Blood Guidance

  • Published 1/17/07, comments due by 4/17/07
  • Recommends a path to licensure for establishments that manufacture cord blood for specified indications (hematopoietic reconstitution in patients with hematologic malignancies)


  • Describes FDA's approach to the regulation of cord blood hematopoietic stem/progenitor cells that are:
    • Minimally manipulated
    • Used to replenish the bone marrow in patients with blood-related malignancies and
    • Used in recipients unrelated to the donor of the stem cells
  • Rather than submitting their own clinical data, manufacturers may cite existing data in the docket


  • Guidance also provides recommendations for
    • Content and format of information to be submitted with an application
    • Manufacture of cord blood products
    • How to comply with applicable regulatory requirements

  • Discussion at upcoming advisory committee meeting under consideration

Guidance: HCT/Ps Tested Using Pooled Specimens or Diagnostic Tests

  • Published January 24, 2007
  • For immediate implementation
  • Comments to the docket accepted
  • For HCT/Ps recovered after 5/25/05 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/Ps
  • Limited to the two testing deficiencies
  • Pertains to recently regulated living donors (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: In Inventory HCT/Ps-Retesting Before Distribution

  • Recommended 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/Ps
    • Hematopoietic stem 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

Contact Information

Martha A. Wells, MPH
1401 Rockville Pike HFM-775
Rockville, MD 20852

martha.wells@fda.hhs.gov
301-827-6106
FAX 301-827-2844

 
Updated: March 13, 2007