CBER Presentation

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FDA Update: Relevant to Reproductive Establishments

Martha A. Wells, MPH, RAC
Division of Human Tissues
Office of Cellular, Tissue, and Gene Therapies
Center for Biologics Evaluation and Research (CBER), FDA
martha.wells@fda.hhs.gov

American Association of Bioanalysts Annual Meeting
College of Reproductive Biology Symposium
May 17,2007, Orlando, FL

Will Cover in This Talk

  • FDA Requirements: History/Applicability
  • Registration and Listing
  • Donor Eligibility (DE) Requirements
  • Current Good Tissue Practice (CGTPs)
  • Testing Guidance – Pooled specimens for Nucleic Acid Tests (NAT) / diagnostic tests
  • Specific donor eligibility questions
  • Inspectional information

21 CFR Part 1271

Regulation Subparts Proposed Final Effective Date
Establishment Registration and Product Listing 1998 2001 2001 for establishments regulated under 1270
2004 for newly regulated establishments
Donor Eligibility 1999 2004 May 25, 2005
Current Good Tissue Practice (CGTP): Inspection and Enforcement 2001 2004 May 25, 2005

Applicable FDA Requirements for Reproductive Establishments

  • Registration and listing if the establishment performs any manufacturing function and doesn’t fit any of the 1271.15 exemptions
  • Donor eligibility
    • Required for donors of semen and oocytes if anonymous or directed
    • Recommended for donors of embryos if both gametes were from the sexually intimate partner
  • Current Good Tissue Practice – only parts applicable
    • 1271.150(c ) manufacturing arrangements
    • 1271.155 exemptions and alternatives
  • Inspections and enforcement

Registration Form FDA 3356

Sample registration form FDA 3356

Registration and Listing

  • Annual update required in December
  • Electronically registered establishments were notified via email last year
  • Electronic registration is encouraged
    • 63% did so last year
  • Changes to Form 3356 being considered
    • To capture more information about the HCT/Ps listed
    • Assist in planning inspections

Registration and Listing

  • Changes to HCT/P listing are required within 6 months
  • Change of ownership or location required within 5 days
  • Inactivation—check box #2(d)

Sample checkbox with 4 choices. A. Initial Registration/Listing, b. Annual Registration/Listing, C. Change in Information, D. Inactive

Failure to Register

Registration and Listing

  • Total (as of 3/8/07) = 2550 (488 inactive)
  • Musculoskeletalocular = 846
  • Hematopoietic stem cell = 623
  • Reproductive = 604
  • International = 174 (mostly stem cell)
Pie chart divided into 4 areas: Inact: 19%, Rep 24%, HPC 24%, MS/Oc 33%

 

Registration and Listing

  • 604 establishments list reproductive HCT/Ps / 2061 total actively registered HCT/P establishments
  • 89 registered that only list semen
    • Cryobanks – anonymous donors
    • Andrology labs store semen for procedures for intimate couples
  • 24 registered that only list oocytes
    • Banks that store oocytes
    • Matching agencies
  • Registration of establishment that only administer donor history questionnaires, but do not determine donor eligibility - currently under discussion

CBER/CDER Proposed Registration & Listing Rule: Foreign and Domestic Establishments
(would effect Part 1271)

  • Published August 29, 2006
  • Comment period extended/ended 1/26/07
  • 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 Determination

  • Required for anonymous/directed donors
  • Procedures/records required
  • Summary of records must accompany the HCT/P
  • Collection of blood specimen within certain time periods before or after recovery
  • Required screening – within a reasonable time period before or after recovery
    • Donor medical history interview
    • Physical examination

Donor Eligibility - Semen

  • Anonymous – 6 month cryopreservation in quarantine with negative re-test/screen before release
  • Directed/known – no quarantine
    • Recent screen (interview and physical exam)
    • Collect blood specimen within 7 days before recovery
    • If test/screen positive the donor is ineligible but can be used with physician notification, and labeling
  • DE is required if the intent is to use a gestational carrier/surrogate

Donor Eligibility - Oocytes

  • Anonymous
    • Recent negative screening
    • Collect blood specimen within 30 days before recovery
  • Directed/Known
    • Recent screen (interview and physical exam)
    • Collect blood specimen within 30 days before recovery
    • If test/screen positive – ineligible but still can be used with physician notification and labeling
  • DE is required if intent is to use a gestational carrier/surrogate

Exceptions: Donor Eligibility Not Required

  • For reproductive cells or tissues donated by a sexually intimate partner (SIP) of the recipient for reproductive use (1271.90(a)(2))
  • For cryopreserved cells or tissue for reproductive use, other than embryos, exempt at the time of donation (autologous or SIPs) that are subsequently intended for directed donation (1271.90(a)(3)) provided that:
    • Additional donations are unavailable, for example, due to the infertility or health of a donor; and
    • Appropriate measures are taken to screen and test the donor(s) before transfer to the recipient
  • For cryopreserved embryos from SIPs and subsequently intended for donation (1271.90(a)(4)):
    • Anonymous or directed
      • To another couple or individual
      • To a gestational carrier
    • Test/screen recommended at time of donation.
    • Special labeling required
    • If a qualified 3rd party donor is used – embryos can still be donated
  • Note: DE is required for SIP gamete donors intending to form an embryo for use in gestational carrier

Required Labeling for Exceptions 1271.90(b)

  • On container or accompanying tissue
  • “NOT EVALUATED FOR INFECTIOUS SUBSTANCES” unless all applicable screening and testing performed (not if (b)(6) label used)
  • “WARNING: Advise recipient of communicable disease risks” if
    • DE determination not performed or not completed, or
    • Results of screening or testing positive
    • Not applicable to autologous tissues
  • Use the Biohazard legend if results of screening or testing are positive
  • “WARNING: Reactive test results for (name of disease agent or disease)” in the case of reactive test result
  • “Advise recipient that screening and testing of the donor(s) were not performed at the time of cryopreservation of the reproductive cells or tissue, but have been performed subsequently for 1271.90 (a)(3) or (4)

CGTP Requirements for Reproductive Establishments

  • Manufacturing arrangements -1271.150(c)
    • Ensure that an establishment (e.g., testing lab) that performs a step in manufacture for you (under contact, agreement, or other arrangement) is in compliance with applicable requirements
    • Guidance published – September 2006
  • Exemptions and Alternatives - 1271.155
    • From DE or CGTP requirements
    • Must be consistent with the goals of protecting the public health and/or preventing the introduction, transmission, or spread of communicable disease

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

  • Published 1/23/2007 for immediate implementation
  • Applicable to certain HCT/Ps from living donors recovered after 5/25/2005 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

Testing Guidance, continued

  • Limited to two testing situations
    • Used a diagnostic test when a donor screening test available
    • Performed Nucleic Acid Test (NAT) using pooled samples rather than individual sample
  • Pertains to recently regulated living donors of HCT/P (hematopoietic stem/progenitor cells) and reproductive cells and tissues
  • HCT/P deviation reports not required for reproductive cells and tissue (only for hematopoietic stem cells from first or second degree blood relatives)

Testing Guidance: Donor Retesting

  • If retesting is performed, FDA is exercising enforcement discretion for distribution/ release from inventory
    • Recommends using original donor sample
    • New sample OK
    • Tested in accordance with the manufacturer’s instructions and found negative/nonreactive
  • If retesting is not feasible, because
    • Retained specimen is not available; or
    • Donor cannot be located or refuses to be retested, then…

Testing Guidance: Donor Retesting Not Feasible, continued

Cryopreserved embryos formed for SIPs using a 3rd party gamete donors can be distributed (FDA is exercising enforcement discretion):

  • Documentation in accompanying records and in files why retesting not feasible
  • Physician notification
  • Labeled “WARNING: Advise patient of communicable disease risks”
  • If pooled NAT was used – list NAT test used and result in summary of records and add qualifier, “not performed according to the manufacturer’s instructions”
  • If diagnostic test was used—list diagnostic test performed and result in summary of records and add qualifier, “diagnostic tests used, instead of donor screening tests
  • Cryopreserved semen or oocytes from anonymous or directed donors
    • If retesting is not feasible,
    • HCT/Ps must not be distributed

Donor Eligibility Questions

  • Do I have to test all donors for CMV and HTLV? (No, only leukocyte rich HCT/Ps – semen)
  • My donor lived in Europe for more than 5 years, may I accept her to donate? (Only for directed donation)
  • Donor testing was not completed, may I proceed with a transfer if the recipient consents? (No)
  • Donor test came back positive for chlamydia, may I proceed? (Only for directed donation)
  • May I use a donor who had chlamydia, gonorrhea or syphilis and was treated? (Yes, if disease and treatment occurred more than 12 months ago and donor tests negative now)
  • Do I have to perform a DE determination for the SIP donors when a gestational carrier is used? (Yes)
  • May cryopreserved embryos formed from an untested SIP and a qualified 3rd party donor be donated? (Yes)
  • May I use a donor that tests positive with an antibody screening test, but confirmatory test is negative? (No, except if syphilis test)
  • If a donor is tested after February 23, 2007 using pooled NAT or diagnostic tests where a screening test is available, may I release any cryopreserved HCT/Ps from this donor if I retest? (No)
  • My donor recently had a tattoo, can she donate? (Yes if sterile procedures were used)
  • Do I have to screen and test a gestational carrier and her partner (No)

Reproductive Establishment Inspections Accomplished

  • 155 inspections / 50 received listing of observation
  • 45.7 average hours/inspection
  • 2 warning letters
  • 3 untitled letters

Inspectional Observations

  • Failure to establish and maintain procedures [1271.47(a)] including

    • Donor eligibility determination
    • Donor screening
    • Donor testing

  • Failure to follow procedures for all steps in donor screening and DE determination [1271.47(a)]

  • Failure to establish and maintain accurate records [1271.55(d)] including

    • Medical evaluation forms

  • Inadequate screening for risk factors/clinical evidence of communicable disease [1271.75(a)]

  • Acceptance of HCT/P from ineligible donors [1271.50]

  • Donor Testing Deviations:

    • Not testing for communicable diseases [1271.85]
    • Not using FDA licensed/approved/cleared kits [1271.80(c)]
    • Incorrect timing of specimen collection [1271.80(b)]

  • Not testing for communicable diseases [1271.85(a) and (c)]. Donors determined eligible and product released though testing not completed for:

    • anti-HIV-1/2
    • anti-HCV
    • Chlamydia trachomatis
    • Neisseria gonorrhea

CBER CONTACT INFORMATION

 
Updated: August 9, 2007