Published in FDA Announcement
On May 25, 2005, FDA’s final rule, “Eligibility Determination for Donors of Human Cells, Tissues, and Cellular and Tissue-Based Products,” became effective, modified by an interim final rule published and made effective on the same day. This is one of three FDA regulations on good tissue practice, along with rules on “Establishment Registration and Listing,” and “Current Good Tissue Practice for Manufacturers of Human Cellular and Tissue-Based Products.” The interim final rule on donor eligibility modifies the original final rule, published on May 25, 2004, with respect to the timing of certain testing requirements for egg and embryo donors, and certain labeling requirements.
ASRM has worked closely with the FDA throughout the development of the tissue-related rules and guidance, submitting comments on each of the proposed rules and meeting with FDA staff a number of times. To address concerns about the original final rule’s timing requirements for infectious disease testing for egg and embryo donors, representatives from ASRM and SART met with FDA officials in April 2005. FDA’s interim final rule reflects these efforts, as FDA was receptive to ASRM’s and SART’s explanations regarding the impracticability and negative consequences of some of the testing requirements. FDA crafted modifications to the rule which allow our members to continue to offer donor egg and donor embryo services that maintain patient safety without greatly increasing expense and inconvenience. The final regulations reflect a better understanding that reproductive cells and tissues are unique and cannot be viewed as just another type of donor tissue.
All of the tissue rules are issued under FDA’s authority to make and enforce regulations necessary to prevent the introduction, transmission, or spread of communicable diseases. Citations in these documents are to the relevant sections of Title 21 of the Code of Federal Regulations (C.F.R), and the text of the regulations can be viewed in the final pages of both donor eligibility rules, which can be linked above. In addition, FDA issued a draft “Guidance for Industry” document regarding the donor eligibility final rule, which provides more detailed guidance regarding how to comply with the regulations. The agency also issued a set of Questions and Answers which further explain the changes made to the final rule by the interim final rule. This Question and Answer document modifies some of the guidance provided in the “Guidance for Industry” document that was issued along with the initial final rule.
The following summary of the rule is intended to help ASRM members understand the ways the rule will affect their procedures. It is not the rule. Users should not rely on this summary when making changes in their protocols but should refer to the rules themselves , published in the Federal Register and cited above, and to FDA’s draft guidance documents, posted on the FDA web-site and also cited above.
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The title of this final rule, which originally referred to “donor suitability”, is the most immediately noticeable change made from the proposed rule. Although the term “donor suitability” is widely used in blood and tissue establishments, FDA recognized that the term “unsuitable,” applied to a donor, might take on an unintended meaning and chose to substitute a more neutral term. A donor is “ineligible” if either screening or testing indicates the presence of a communicable disease or of risk factor for a communicable disease. All donors of cells or tissues used in human cellular or tissue-based products (HCT/Ps) must be determined eligible, based on screening and testing for relevant communicable disease agents and diseases, except as provided under 21 C.F.R. §1271.90.
THREE CATEGORIES OF REPRODUCTIVE DONORS
There are three categories of reproductive donors subject to three different sets of requirements under 21 C.F.R. §1271.90.
anonymous donor- to whom all relevant donor-eligibility screening and testing requirements apply. Anonymous semen donors must pass all screens and tests required under §§1271.75 and 1271.80. A new test specimen from these donors must be collected at least six months after their semen donation and it must test negative for relevant communicable diseases in order for the semen donation to be eligible. The semen donation must be quarantined until this re-testing is complete. (§1271.60(a)).
directed reproductive donor- whose reproductive cells and tissue may be used even if the donor is determined ineligible. A directed donation involves the designation of a specific potential recipient, but does not involve a sexually intimate partner. (§1271.3(l)). The distinction was made between directed reproductive donors and anonymous donors to respect the existence of relationships between people who know each other and have made a joint decision for the recipient to conceive a child. Directed donations of semen are excepted from the six-month retesting requirement applicable to anonymous donations (21 C.F.R. §1271.85(d)).
sexually intimate partner- for whom testing and screening are not required. (§1271.90 (2)).
Cryopreserved reproductive cells or tissues (sperm, eggs, embryos) originally collected and stored for autologous use or for use by a sexually intimate partner may later be used for a directed or anonymous donation, subject to certain requirements.
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TESTING AND SCREENING REQUIREMENTS
Virtually all donors other than sexually intimate partners must be screened for risk factors and clinical evidence of communicable diseases. (§1271.75). This screening requires a review of relevant medical records, including a donor medical history interview and physical exam. The screening for donors of reproductive cells or tissues must specifically address risk factors for, and evidence of:
Human transmissible spongiform encephalopathy, including Creutzfeldt-Jakob)
Treponema pallidum; and
Communicable disease risks associated with xenotransplantation
Chlamydia trachomatis; and Neisseria gonorrhea
In addition, donors of viable leukocyte-rich cells or tissue (which includes semen but not oocytes or embryos), also must be screened for:
In addition to the screening described above, donor specimens must be tested in a CLIA certified (or CLIA-exempt) lab for certain communicable diseases. (§1271.80). Virtually all donors of reproductive cells or tissues, other than sexually intimate partners, must be tested for the following:
(Note: in the case of oocytes retrieved through non-vaginal laparascopy, and therefore not exposed to the genitourinary tract, testing for chlamydia and gonorrhea is not required)
Donors of viable, leukocyte-rich cells or tissue (which includes semen but not oocytes or embryos) also must be tested for:
(Note: a positive CMV result does not make the donor ineligible, but you must establish and maintain a Standard Operating Procedure governing the release of HCT/Ps from CMV positive donors. Results of CMV testing must accompany each HCT/P. (§1271.55(b).)
The lab must use FDA licensed, approved or cleared donor screening tests according to the manufacturer’s instructions. If no donor screening test is available (as in the cases of chlamydia and gonorrhea), testing may be done using an FDA licensed, approved, or cleared test for the disease in an asymptomatic, low-prevalence population.
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Timing of Testing and Labeling Requirements
Specimens for donor testing generally must be collected at the time of recovery of cells or tissues from the donor. If this isn’t feasible, however, most types of specimens may be collected for testing up to 7 days before or after recovery of sperm for donation. Specimen collection may be done up to 30 days before recovery of eggs intended for donation. The 30 day testing window for egg donors is an improvement over the original final rule, which required specimen collection at the time of recovery or within 7 days before or after recovery. Donations from anonymous semen donors must be quarantined until donors are retested and again determined eligible at least 6 months after the date of donation.
Donors of cryopreserved embryos that, although originally exempt from the donor eligibility requirement (because donors are sexually intimate partners) are later intended for anonymous or directed donation are exempt from the rule’s screening and testing requirements. The rule requires that “when possible”, screening and testing of donors be performed before transfer of donated embryos to the recipient. Nevertheless, failure to screen and test will not prevent the embryo from being transferred. Rather, embryos for which the donors were neither screened nor tested will be required to bear labeling which instructs physicians to advise recipients of this fact and of the risk of communicable disease. When embryo donors are screened and tested only upon the couple’s decision to donate – and not at the time of cyropreservation – the HCT/P must be labeled to inform physicians accordingly. The interim final rule also provided that when it is not physically possible to include the required warnings on the HCT/P container (e.g., because the container is too small), the warning language must, instead, be placed on labeling that accompanies the HCT/P.
Eggs and embryos need not be quarantined.
In the preamble to the proposed rule, FDA stated that reproductive cells and tissues that can reliably be stored should be quarantined for at least 6 months so that the donor could be retested and determined to eligible. FDA listed spermatozoa and sperm progenitor cells as examples of those that maintain function and integrity during storage. ASRM submitted comments to FDA urging them not to require storage of oocytes and embryos, and in the final rule FDA did clarify that they did not intend the quarantine and retesting requirement to apply to embryos and oocytes. The six-month quarantine requirement in §1271.60(a) and the re-testing requirement in §1271.85(d) apply only to anonymous semen donors.
The six-month quarantine requirement in §1271.60(a) and the re-testing requirement in §1271.85(d) apply only to anonymous semen donors. Also, you do not have to obtain a specimen for testing at each donation from a repeat anonymous donor, so long as the initial specimen was tested and you do not release any of the donations until after the donor has been retested at least six months post-donation.
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Small practices do not have to comply with the screening and testing requirements if they are only doing artificial inseminations with semen from anonymous or directed reproductive donors obtained from a semen bank (§1271.15(d)) (The semen bank should be doing the screening and testing of donors) or with semen collected at the practice for immediate use in insemination of the donor’s sexually intimate partner (§1271.15(e)).
However, if the semen is not immediately used for insemination, but is instead stored, the practice would be required to comply with registration and listing rules (21 C.F.R. Part 1271 subpart B) and certain other requirements dealing with minimal standard operating procedures, record-keeping and labeling. Recovery of semen from anonymous or directed donors for artificial insemination presents additional risks, and practices performing these services are required to comply with the registration and listing rules and all of the donor screening and testing, standard operating procedures, record-keeping, and labeling requirements in part 1271 of the regulations.
STORAGE OF QUARANTINED AND INELIGIBLE DONOR SPECIMENS
Physical separation between HCT/Ps from eligible and quarantined or ineligible donors is not required. However, you are required to either store or identify cells or tissues from ineligible donors in a physically separate area clearly identified for such use or to follow other procedures that prevent improper release, such as automated designation, until destruction of the HCT/P or other disposition in accordance with the regulations. (§1271.65(a)). Quarantined HCT/Ps awaiting completion of a donor eligibility determination must be clearly identified as quarantined, and easily distinguished from HCT/Ps available for release. A separate freezer may not be necessary for ineligible specimens; adequate physical separation may include storage on a separate shelf in a refrigerator or freezer that also contains shelves storing HCT/Ps in quarantine or from eligible donors.
DIRECTED DONATION FROM INELIGIBLE DONOR
Patients wishing to use a directed donor may do so, even if that donor is determined to be ineligible, but the donor eligibility screening and testing still must be performed in virtually all cases, and it is essential that the patient who chooses to use a directed donation from an ineligible donor be fully informed of the risks. To comply with this, the establishment conducting the donor eligibility determination must notify the physician using the HCT/P from the ineligible directed donor of the results of the testing and screening and the container must be labeled with warnings and labeled as a biohazard. (§1271.65(b)). The establishment need not document the physician’s agreement to explain the disease risks to the recipient of the tissue or to obtain the recipient’s consent to use the HCT/P. FDA recognizes that physicians are already under legal and ethical obligations requiring them to discuss such risks with their patients and obtain their consent.
STANDARD OPERATING PROCEDURES
In addition to regulating the testing and screening of donors for relevant communicable diseases and quarantine and storage of HCT/Ps, FDA determined that regulations requiring the maintenance of records and the establishment of standard operating procedures are necessary as well to prevent the transmission of disease. Section 1271.47(a) requires that you establish and maintain written procedures for all steps performed in testing, screening, determining donor eligibility and complying with all other requirements of part C. A responsible person must review and approve all procedures before implementation (§1271.47(b)) and written procedures must be available to all personnel (§1271.47(c)) Departures from established procedures must be documented at the time of their occurrence (§1271.47(d)).
In general, the HCT/P must have a distinct identification code (not including the donor’s name, Social Security number, or medical record number) affixed to its container. However, in the case of autologous or directed reproductive donations, the donor’s name and other identifying information may be included on the labeling. This code must relate the HCT/P to the donor and to all records pertaining to the donation. A set of records must accompany each HCT/P, including a statement of the donor’s eligibility or ineligibility based on screening and testing and a summary of the results used to make that determination. Donor eligibility records must be maintained for 10 years. (§1271.55).
This Web page contains links to miscellaneous U.S. Food and Drug Administration (FDA) announcements that ASRM felt were relevant enough to archive on the ASRM Web Site. You can visit the FDA's web site at http://www.fda.gov/