Donor Eligibility Final Rule and Guidance Questions and Answers
What is the purpose of the donor eligibility final rule?
The donor eligibility rule requires human cell, tissue, and cellular and tissue-based product (HCT/Ps) establishments to screen and test cell and tissue donors for risk factors for, and clinical evidence of, relevant communicable disease agents or diseases [1271.1(a)]. FDA believes that these requirements will increase the safety of HCT/Ps, and public confidence in their safety, by preventing the introduction, transmission and spread of communicable disease.
What do I do if I have questions about the HCT/P rules?
If you have questions, please contact the Center for Biologics Evaluation and Research, Food and Drug Administration, 1401 Rockville Pike, suite 200N, Rockville, MD 20852-1448, 800-835-4709 or 301-827-1800. Questions may also be submitted via e-mail to: email@example.com (industry) or firstname.lastname@example.org (consumers and health care professionals).
What rules has FDA issued regarding HCT/Ps?
FDA published a set of 3 rules in order to implement its proposed approach to the regulation of HCT/Ps, which was announced in 1997. The first rule on registration and listing was finalized on January 19, 2001. By March 29, 2004, FDA expected all establishments that recover, process, store, label, package or distribute HCT/Ps, or that screen or test the donor of the HCT/Ps, to be registered with FDA and list their HCT/Ps. The donor eligibility rule was the second rule that was finalized on March 25, 2004. FDA also finalized the third rule on current good tissue practice on November 24, 2004. The donor eligibility rule and the current good tissue practice rule became effective on May 25, 2005.
When did the donor eligibility rule become effective?
The donor eligibility rule became effective on May 25, 2005. FDA chose a 12-month effective date to provide sufficient time for training and implementation to ensure compliance.
Do the requirements in this rule apply to HCT/Ps recovered before the effective date?
The requirements apply to HCT/Ps recovered on or after the effective date of May 25, 2005.
Did FDA already have requirements for tissue donor screening and testing prior to the donor eligibility rule?
FDA has regulated human tissue intended for transplantation under 21 CFR 1270, since 1993. Part 1270 contains requirements for determining the suitability of a donor of human tissue intended for transplantation, as well as requirements for written procedures, record keeping and inspection. These requirements apply to certain tissues (e.g., musculoskeletal, skin, vascular, and ocular) recovered prior to May 25, 2005 and certain diseases (HIV, hepatitis B and hepatitis C).
Who does the donor eligibility rule apply to?
The donor eligibility rule, codified in 21 CFR 1271 (subpart C), applies to donors of HCT/Ps recovered on or after May 25, 2005, and requires screening and testing of donors for risk factors for, and clinical evidence of, infection due to relevant communicable disease agents and diseases [1271.1(b)]. For instance, the rule applies to donors of hematopoietic stem/progenitor cells derived from peripheral and umbilical cord blood (e.g., cord blood); reproductive cells and tissue (e.g., semen, oocyte, embryo), human dura mater, and human heart valves, in addition to donors of musculoskeletal, skin, vascular, and ocular tissue. The donor eligibility rule also applies to donors of HCT/Ps regulated as drugs, devices, and/or biological products under the Federal Food Drug and Cosmetic (FD&C) Act or section 351 of the Public Health Service Act.
What is meant by a "donor eligibility determination"?
A donor eligibility determination is based on donor screening and testing for relevant communicable disease agents and diseases. A donor eligibility determination is required for all donors of cells or tissues used in HCT/Ps, with some exceptions [1271.45(b)].
What is a "relevant communicable disease agent or disease"?
The donor eligibility rule identifies specific diseases and disease agents, which are relevant to all HCT/Ps. It also identifies specific diseases and disease agents, which are relevant only to certain kinds of HCT/Ps (i.e., because there is a risk of transmission only through certain HCT/Ps) [1271.3(r)(1)].
In addition, "relevant communicable disease agent or disease" includes a disease agent or disease:
(i) For which there may be a risk of transmission by an HCT/P, either to the recipient of the HCT/P or to those people who may handle or otherwise come in contact with it, such as medical personnel, because the disease agent or disease:
(A) Is potentially transmissible by an HCT/P and
(B) Either of the following applies:
(1) The disease agent or disease has sufficient incidence and/or prevalence to affect the potential donor population, or
(2) The disease agent or disease may have been released accidentally or intentionally in a manner that could place potential donors at risk of infection;
(ii) That could be fatal or life-threatening, could result in permanent impairment of a body function or permanent damage to body structure, or could necessitate medical or surgical intervention to preclude permanent impairment of body function or permanent damage to a body structure; and
(iii) For which appropriate screening measures have been developed and/or an appropriate screening test for donor specimens has been licensed, approved, or cleared for such use by FDA and is available.
FDA has recently issued final guidance stating that FDA believes that the following disease agents and diseases, not specifically listed under 21 CFR 1271.3(r)(1) are relevant under 21 CR 1271.3(r)(2): West Nile Virus, Sepsis, and Vaccinia (the agent in the smallpox vaccine). Accordingly, FDA requires that establishments screen donors for these diseases.
How is eligibility of a potential HCT/P donor determined?
If you are the establishment responsible for making the donor eligibility determination, you must determine whether a donor is eligible based upon the results of donor screening and testing. A potential HCT/P donor is eligible if donor screening indicates that the donor is free from risk factors for, and clinical evidence of, infection due to a relevant communicable disease agent or disease, is free from communicable disease risks associated with xenotransplantation, and the results of donor testing for relevant communicable disease agents or diseases are negative or nonreactive [1271.50].
Who makes the donor eligibility determination for HCT/P donors?
A responsible person makes this determination [1271.50(a)]. A responsible person is one who is authorized, trained and qualified to perform this task [1271.3(t)].
What happens to the HCT/P before completion of the donor eligibility determination?
The HCT/P from this donor is kept "in quarantine." This means that the HCT/P is identified in some manner to prevent its improper release, in a physically separate area clearly identified for such use or through use of other procedures, such as automated designation [1271.3(q)]. An HCT/P in quarantine can still be shipped, provided that it is accompanied by records containing a distinct identification code and indicating that the donor eligibility determination has not been completed and that the HCT/P should not be implanted, transplanted, infused, or transferred until completion of the donor eligibility determination, except in cases of urgent medical need under 21 CFR 1271.60(d) [1271.60(d)].
Can you administer an HCT/P if the donor eligibility determination has not been completed?
If there is an urgent medical need for the HCT/P [1271.60(d)] then administration of an HCT/P may occur before donor eligibility determination is completed. An urgent medical need means that no comparable HCT/P is available and the recipient is likely to suffer death or serious morbidity without the HCT/P [1271.3(u)]. If you make an HCT/P available for use under urgent medical need, you must utilize special labeling. [1271.60(d)(2)]. The HCT/P must be accompanied by the results of any donor screening and testing that has been performed and a list of required screening and testing that has not yet been completed [1271.60(d)(2)]. You must document that you notified the physician using the HCT/P that the testing and screening were not complete [1271.60(d)(3)]. You must complete the donor eligibility determination during or after the use of the HCT/P and you must notify the physician of the results of the determination [1271.60(d)(4)].
How do you store an HCT/P from an ineligible donor?
If you store an HCT/P from a donor who has been determined to be ineligible, you must store or identify the HCT/P in a physically separate area clearly identified for such use, or follow other procedures, such as automated designation, that are adequate to prevent improper release until destruction or other disposition of the HCT/P [1271.65(a)].
Are there uses for an HCT/P from an ineligible donor?
There are limited uses for HCT/Ps from donors determined to be ineligible. For example, the HCT/P may be used in a first-degree or second-degree blood relative. Reproductive cells or tissue from a directed reproductive donor (i.e., the donor and recipient know each other before donation) may be used. If there is an urgent medical need, the HCT/P may be used. The HCT/P must have special labeling, and the physician must be notified of the results of screening and testing [1271.65(b)].
What does "donor screening" mean for HCT/P donors?
Donor screening consists of reviewing the donor's relevant medical records for risk factors for, and clinical evidence of, relevant communicable disease agents and diseases [1271.75]. These records include a current donor medical history interview (with the donor or another individual who is able to provide information about the donor's medical history and relevant social behavior), a current physical assessment, and, if available, medical records, laboratory test results, coroner and autopsy reports, and records or other information received from any source pertaining to risk factors for relevant communicable disease (e.g., social behavior, clinical signs and symptoms of relevant communicable disease, and treatments related to medical conditions suggestive of risk for relevant communicable disease) [1271.3(s)].
For which relevant communicable disease agents and diseases are all HCT/P donors screened?
All HCT/P donors are screened for risk factors for, and clinical evidence of, relevant communicable disease agents and diseases, including HIV, hepatitis B, hepatitis C, human transmissible spongiform encephalopathy (e.g., Creutzfeldt-Jakob Disease), and Treponema pallidum (the agent of syphilis) and communicable disease risks associated with xenotransplantation [1271.75(a)].
For which additional relevant communicable disease agents and diseases are donors of viable, leukocyte-rich HCT/Ps screened?
In addition to those relevant communicable diseases for which all HCT/P donors must be screened (see 1271.75(b)), donors of viable, leukocyte-rich HCT/Ps are also screened for risk factors for, and clinical evidence of, relevant cell-associated communicable disease agents and diseases, including human T-lymphotropic virus (HTLV).
For which relevant communicable disease agents and diseases are all HCT/P donors tested?
All HCT/P donors must be tested for HIV-1, HIV-2, hepatitis B, hepatitis C, and Treponema pallidum [1271.85(a)]. The specific tests that are recommended to adequately and appropriately reduce the risk of transmission of relevant communicable disease are discussed in the Guidance for Industry: Eligibility Determination for Donors of Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps).
For which additional relevant communicable disease agents and diseases are donors of viable, leukocyte-rich cells and tissues tested?
In addition to those relevant communicable diseases for which all HCT/P donors must be tested (see 1271.85(a)), donors of viable, leukocyte-rich cells and tissue are also tested for HTLV-I and II. Also, although Cytomegalovirus (CMV) is not a relevant communicable disease, these donors must be tested for evidence of infection due to CMV, and procedures governing the release of an HCT/P from a CMV-positive donor must be developed by the establishment [1271.85(b)(2)].
When must you collect a specimen from an HCT/P donor for testing?
You must collect the donor specimen at the time of recovery of the cells or tissue from the donor; or up to 7 days before or after recovery. For donors of peripheral blood stem/progenitor cells, oocytes and bone marrow (if not excepted under section 1271.3(d)(4)), you may collect the donor specimen for testing up to 30 days before recovery [1271.80(b)].
Where is the testing of blood specimens from HCT/P donors performed?
Required testing must be performed by a laboratory that is either certified to perform such testing on human specimens under the Clinical Laboratory Improvement Amendments of 1988 (42 U.S.C. 263a) and 42 CFR Part 493, or has met equivalent requirements, as determined by the Centers for Medicare and Medicaid Services [1271.80(c)].
What type of test is used for HCT/P donors?
You must use an appropriate FDA-licensed, approved, or cleared donor screening test, in accordance with the manufacturer's instructions. If applicable, a test specifically labeled for cadaveric specimens must be used when available [1271.80(c)].
Is plasma dilution a consideration when performing the test on a post-mortem specimen from an HCT/P donor?
You must consider a donor ineligible if plasma dilution sufficient to affect the results of communicable disease testing is suspected, unless you test a pre-transfusion specimen or use an appropriate algorithm designed to evaluate volumes of fluids administered in the 48 hours before specimen collection, and the algorithm shows that plasma dilution sufficient to affect test results has not occurred [1271.80(d)(2)]. An example of an algorithm is given in the final donor eligibility guidance.
What records must accompany an HCT/P after the donor eligibility determination is complete?
Once a donor-eligibility determination has been made, the accompanying records must include a distinct identification code that relates the HCT/P to the donor and to all records pertaining to the HCT/P, a statement that the donor has been determined to be eligible or ineligible, and a summary of records used to make the donor eligibility determination [21 CFR 1271.55(a)].
How long must records pertaining to HCT/P donor eligibility determination be kept?
Records pertaining to a particular HCT/P must be retained for 10 years after the date of administration, or if this date is not known, then at least 10 years after the date of distribution, disposition, or expiration of the HCT/P, whichever is later [1271.55(d)(4)].
What procedures are required for donor eligibility determination of HCT/Ps?
You must have procedures for all steps that you perform in determining donor eligibility (e.g., testing and screening), and comply with other requirements in the regulations. Before implementing these procedures, a responsible person must review and approve them. The procedures must be available to the personnel. You may use standard procedures prepared by another organization, provided they are consistent with and as stringent as the requirements in this rule [1271.47].
Reproductive Cells and Tissues
What specific exceptions are included in the regulations for donors of reproductive cells and tissues?
- A six-month quarantine for donations and retesting of directed semen donors is not required [1271.85(d)].
- The use of reproductive cells and tissue from directed donors determined to be ineligible is not prohibited [1271.65(b)(ii)].
- Donors who are sexually intimate partners are not required to be screened or tested [1271.90(a)(2)].
- Testing and screening of sexually intimate partners who later decide to donate embryos is not required; however, when possible, appropriate measures should be taken to screen and test the semen and oocyte donors before transfer of the embryos to a recipient [1271.90(a)(4)].
- Under certain circumstances, cryopreserved reproductive cells and tissue, other than embryos, can be used for directed donation, even if the donor(s) were not screened and tested initially, provided that appropriate measures are taken to screen and test the donor(s) before transfer to the recipient [1271.90(a)(3)].
- For anonymous semen donors who make repeated donations, you may perform an abbreviated history [1271.75(e)], and you are not required to collect and test a blood specimen at each donation, provided that complete donor screening and testing is performed at least every 6 months [1271.85(d)].
In addition to the requirements for all HCT/P donors, for which relevant communicable disease agents and diseases are donors of reproductive cells and tissues screened and tested?
Anonymous and directed semen and oocyte donors, and certain embryo donors, are screened and tested for relevant genitourinary disease agents, including Chlamydia trachomatis and Neisseria gonorrhea, at the time of donation. However, anonymous and directed oocyte donors would be exempt from such testing when oocytes are retrieved in a way that ensures freedom from contamination with these disease agents (e.g., nonvaginal laparoscopy). Anonymous and directed semen donors are also screened and tested for HTLV and CMV, because semen is considered leukocyte-rich [1271.85(c)].
What special requirements apply to anonymous semen donors?
Anonymous semen donors who make repeated donations may undergo abbreviated donor screening at each donation to identify any change to risk factors for, and clinical evidence of, relevant communicable disease agents and diseases since the last donation. If you have performed a complete donor screening procedure on an anonymous semen donor within the previous 6 months, you may use an abbreviated donor screening procedure on repeat donations. The abbreviated procedure must determine and document any changes in the donor's medical history since the previous donation that would make the donor ineligible, including relevant social behavior [1271.75(e)].
Semen from anonymous donors must be quarantined for at least six months, at which time the donor must be re-tested [1271.85(d)].
What special requirements apply to directed semen donors?
Directed semen donors must be tested at the time of donation, but do not have to be retested 6 months later (as do anonymous semen donors) [1271.85(d)]. The term "directed reproductive donor" means a reproductive donor who knows and is known by the recipient before donation [1271.3(l)]. Reproductive cells or tissues from a directed semen donor who has been determined to be ineligible (e.g. donors who test positive or indicate a risk factor for a relevant communicable disease) are not prohibited from use. Special labeling of the HCT/P is required to indicate increased risk of relevant communicable disease [1271.65(b)].
Are reproductive cells or tissues donated by a sexually intimate partner screened and tested?
You are not required to make donor eligibility determinations or to perform donor screening or testing for reproductive cells or tissues donated by a sexually intimate partner of the recipient for reproductive use [1271.(a)(2)]. However, special labeling of the HCT/P is required [1271.90(b)].
Guidance for Industry: Eligibility Determination for Donors of Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps), February 2007
What is the purpose of the final guidance on donor eligibility determinations for HCT/Ps?
The final guidance represents the Food and Drug Administration's (FDA's) current thinking on eligibility for donors of human cells, tissues, and cellular and tissue-based products. In guidance, FDA provides recommendations to assist establishments making donor eligibility determinations in complying with the requirements in the donor eligibility regulations under 21 CFR 1271 subpart C.
Does this final guidance on donor eligibility determinations supercede the 1997 guidance titled, "Screening and Testing of Donors of Human Tissue Intended for Transplantation?"
The 1997 guidance remains in effect, but only applies to certain human tissue intended for transplantation recovered prior to May 25, 2005.