Guidance for Industry: Eligibility Determination for Donors of Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps), released Feb. 28, 2007, includes recommendations made in three previous documents: a draft guidance of the same name published in May 2004; draft Guidance for Industry: Preventive Measures to Reduce the Possible Risk of Transmission of Creutzfeldt-Jakob Disease (CJD) and Variant Creutzfeldt-Jakob Disease (vCJD) by Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps), dated June 2002; and draft Guidance for Industry: Amendment (Donor Deferral for Transfusion in France Since 1980) to Guidance for Industry: Revised Preventive Measures to Reduce the Possible Risk of Transmission of Creutzfeldt-Jakob Disease (CJD) and Variant Creutzfeldt-Jakob Disease (vCJD) by Blood and Blood Products, issued in August 2006. The recommendations in the guidance document should be implemented no later than six months after issuance.
The authors of this new guidance document have made liberal use of Code of Federal Register references throughout the document to enable the reader to link a recommendation to a requirement. Also noted is an expansion of the reference list and corrections to incorrect references that were used in the draft guidance. Organization of the document has improved and establishments will find it easier to use.
A trend noted in the draft guidance continues to be evident in the final recommendations — risk categories that are historical with whole blood donors have been refined to critical elements for HCT/P donors. For example, some “at risk” categories that result in indefinite deferrals for whole blood donors are a five-year deferral from HCT/P donation, and exposure to human vs. synthetic devices and drugs are carefully separated. However, FDA retained the requirement that only reactive test results can be used in determining donor eligibility — repeat blood donors who have been re-entered into the available donor pool, based on repeat reactive test results that did not confirm, are not eligible to donate HCT/Ps. This results in scenarios where donors, while not eligible to donate hematopoietic progenitor cells (HPCs), are eligible to support the HPC recipient with platelets.
Listed below are some of the changes — additions, deletions, and clarification — to the draft guidance.
FDA has placed an emphasis on knowledge of relevant federal regulations and guidance documents, as well as appropriate medical training, for the responsible person authorized to make eligibility determinations.
The relevant communicable disease agents or diseases (RCDADs) list continues to be made of two lists – those listed in 21 CFR 1271.3(r) and others described in 21 CFR 1271.3(r)(2). SARS (severe acute respiratory syndrome) has been struck from the list of identified RCDADs since there has been no confirmation of person-to-person transmission since July 2003. Much of the information on West Nile virus, sepsis and vaccinia has been removed to appendices. FDA will notify establishments through a guidance document if it is determined that the list of RCDADs requires modifications.
Departures are noted to be different from deviations. Departure from procedures normally used in making an eligibility determination must be recorded at the time of the departure, be relevant to preventing risks of communicable disease transmission, and prior to distribution be judged by a responsible person to have not increased the risk of disease transmission. A departure is consistent with applicable regulations, standards, or established specifications. Deviations are defined in 21 CFR 1271.3(dd) and are inconsistent with applicable regulations, standards, or established specifications, or are unexpected or unforeseeable.
Accompanying records may include identifiable information on the donor when the donation is made by a first-degree or second-degree relative. Previously, this was only allowed in the case of an autologous or directed reproductive donation. FDA has incorporated prior verbal clarifications concerning when it is, or is not, necessary for the accompanying records to physically accompany the HCT/P into the operating room or at the bedside, and noted when electronic access to the records may be sufficient.
Specific guidance is given to testing laboratories for record retention if the laboratory is not aware of dates for administration, distribution, disposition or expiration of the product — the record should be retained for at least 10 years after creation.
Guidance for screening an infant donor (one month of age or younger) has been expanded as a reminder that the screening interview must be conducted with someone who is able to provide the information sought in the interview. The guidance then explains that the birth mother must also be screened with a medical history interview. The inference is that two separate interviews / histories must be documented — one for the infant donor and one for the birth mother.
Self-administered questionnaires must be reviewed by an interviewer who should verify the answers with the individual who has filled out the questionnaire. Since this is a self-administered questionnaire the inference is that “answers of interest” should be explored; it is not necessary for the interviewer to re-ask each question.
Draft recommendations for physical examination of a living donor have been tempered by a clarification that only those parts of the body that are necessary to evaluate for RCDADs based upon relevant donor history that has been obtained during the interview and review of available records are required.
FDA identified an additional category of “at-risk” donor that had previously been deferred indefinitely, to now be eligible after a five year period — persons with hemophilia who have received human-derived clotting factor concentrates.
Past diagnoses of clinical, symptomatic viral hepatitis can be mitigated by evidence of Epstein-Barr virus and cytomegalovirus as well as hepatitis A.
Recommendations for West Nile virus (WNV) and variant Creutzfeldt-Jakob disease (vCJD) now include the latest guidance from FDA. 120 days is the appropriate deferral period following diagnosis of WNV or onset of illness, with an added recommendation to seek prior information on WNV test results. The non-specific “headache with fever” question is no longer recommended. Transfusion in France was added to the list of risk exposures for vCJD.
HIV group O explanations include the reminder that screening criteria can be dropped if an HIV antibody test that has been approved by FDA for detection of HIV group O viruses is used.
Use of nucleic acid tests (NAT) is recommended, with a footnote that current manufacturers’ instructions require that HCT/P living donors be tested by individual donation NAT rather than in mini-pools.
Caution is given to HCT/P establishments that obtain test results from an organ procurement organization (OPO). Organ donor screening is allowed to be tested initially in triplicate and the results are interpreted as if single/initial testing had been performed, followed by a duplicate repeat. This is not allowed for HCT/P donors since manufacturers’ inserts do not provide instructions on how to determine if the sample is actually (repeatedly) reactive. If an establishment knows that an OPO has performed testing on the same donor, then the results must be reviewed by the HCT/P establishment. If any one of the three results is reactive, then the donor must be determined to be ineligible.
Pre-mortem samples may be used to test a cadaveric donor, as long as the specimen is collected within 7 days before recovery of the cells or tissues.
Once collected, all specimens should be tested as soon as possible after collection and in accordance with the time limits stated in the manufacturer’s instructions for use of the test kit.
Language explaining an exception for cord blood collection and storage no longer appears in the section on HBV testing.
The draft guidance recommendation for an SOP governing the release of HCT/Ps from donors whose specimens test reactive for CMV seems more useful than the recommendations contained in the new guidance document. The new guidance recommends an SOP regarding donors whose specimens test reactive for CMV. (It is not clear “what” the SOP should describe if it is not release of the product from CMV reactive donors.) Furthermore, FDA notes that the SOP should require that positive CMV results be included in the accompanying records for the HCT/P so that the physician may rely on the information to make informed decisions about the use of an HCT/P in a particular recipient’s situation. (Other recommendations insure that all reactive test results are communicated to the physician prior to distribution of the HCT/P)
Section G. concerning gestational or surrogate carriers is, for the most part, an addition to the guidance, and appears to be very useful guidance for practitioners.
Labeling exceptions due to space constraints are explained.
First-degree relatives are defined as parents, children and siblings.
Second-degree relatives are aunts, uncles, nieces, nephews, first cousins, grandparents, and grandchildren.
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