/* This contains the proposed amendments to federally mandated Current Good Manufacturing Practices in handling blood, as of Autumn 1993. */
DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR PARTS 606 AND 610
[DOCKET No. 91N-0152]
RIN 0905-AC90
Current Good Manufacturing Practices for Blood and Blood Components; Notification of Consignees Receiving Blood and Blood Components at increased Risk for Transmitting HIV infection
AGENCY: Food and Drug Administration, HHS
ACTION: Proposed rule.
SUMMARY: The Food and Drug Administration (FDA) is proposing to amend the biologics regulations to require that blood establishments prepare and follow written procedures when the blood establishments have collected blood and blood components that are potentially contaminated with human immunodeficiency virus (HIV). This proposal would require that when a donor who previously donated blood subsequently is tested for HIV in accordance with 21 CFR 610.45, and tests repeatably reactive for antibody to HIV, a blood establishment shall perform more specific testing using a licensed test, and notify consignees who received such blood so that appropriate action is taken. Blood establishments and consignees would also be required to quarantine previously collected blood and blood components from such donors. FDA is also proposing that certain transfusion services take steps to notify transfusion recipients. FDA is proposing these rules to help ensure the continued safety of the blood supply, to help ensure that information is provided to users of blood and blood components and to help ensure that transfusion recipients of potentially contaminated blood and blood components may be notified as appropriate. These procedures are commonly referred to as look-back" rules.
DATES: Written comments by August 30, 1993. FDA proposes that any final rule based on this proposal be effective 60 days after date of publication of the final rule.
ADDRESSES: Written comments to the Dockets Management Branch (HFA-205). Food and Drug Administration, rm 1-23, 12420 Parklawn Dr., Rockville, MD 20857.
FOR FURTHER INFORMATION CONTACT: Paula McKeevor, Food and Drug Administration, Center for Biologics Evaluation and Research (HFM-6 35), 1401 Rockville Pike, Rockville, MD 20859-1448, 301-295-9074.
SUPPLEMENTARY INFORMATION:
I. Introduction Part 606 (21 CFR part 606) contains current good manufacturing practices (CGMP's) for blood establishments designed to help ensure the continued safety, purity, potency, and efficacy of blood and blood components. The regulations in this part apply to both licensed and unlicensed blood establishments. Blood establishments include human blood and plasma donor centers, blood banks, transfusion services, other blood product manufacturers and independent laboratories that engage in quality control and testing for registered blood product establishments (21 CFR 607.3(c)). Consignees are included in the definition of blood establishments. In addition, part 610 (21 CFR part 610) provides rules and testing standards generally applicable to biological products, including blood and blood components.
HIV is the virus that causes acquired immunodeficiency syndrome (AIDS) a communicable disease that can be transmitted through blood and blood components contaminated with HIV. FDA has implemented an extensive system of additional testing and donor-screening procedures, performed before, during, and after donation takes place, to help prevent the transfusion of blood components that are potentially contaminated with HIV. Beginning in 1983, the Public Health Service (PHS) issued recommendations that individuals who engaged in high risk practices for AIDS voluntarily refrain from donating blood or plasma. See Morbidity and Mortality Weekly Report (MMWR), 32:101-103, 1983. Beginning in 1985, FDA licensed kits to test for antibody to HIV, and blood banks began testing units of blood and blood components for antibody to HIV (ref. 1). Since 1988, FDA has required that units of blood and blood components be tested for antibody to HIV using licensed tests (21 CFR 610.45). Since 1986, confidential unit exclusion and donor history interviews have become a routine part of the donation procedure, so that donors may indicate confidentially if their units should be excluded from the blood supply. FDA's recommendations regarding these procedures have been revised periodically as additional information regarding the epidemiology of HIV has become available. The most recent recommendation was issued to all registered blood establishments on December 5, 1990 (ref. 2). These procedures are designed to help ensure the continued safety of the blood supply.
As a result of this effort, the possibility of transmitting HIV through blood transfusion has decreased significantly. Within the last 3 years, the risk of HIV transmission via blood transfusion has been estimated to be between 1 in 38,000 and 1 in 153,000. [footnote 1] However, it remains possible, despite the best practices of a blood establishment, that a person might donate blood early in infection, during the "window" period, when the HIV antibody test remains negative but HIV is present in the person's blood. Accordingly, a recipient of such a donation may not know that he or she may have become infected with HIV. If the same donor attempts to donate blood at a later date, the test for antibody to HIV then may be repeatably reactive. FDA and the Health Care Financing Administration (HCFA) are proposing steps designed to further protect the blood supply and to notify recipients of the possibility that they may have received blood products contaminated with HIV. FDA's proposal, along with HCFA's proposal published elsewhere in this Federal Register, would require facilities involved in the collection, processing, and administration of blood to quarantine certain blood and blood components and to inform the consignee, and, as appropriate, the recipient's attending physician or the recipient, of the possibility that blood previously used for transfusion was obtained from a donor who subsequently tested repeatably reactive for antibody to HIV. These rules would result in transfusion recipients receiving information so they can be tested for evidence of HIV infection, receive early treatment, if indicated, and take appropriate precautions to prevent the further spread of the virus.
Under certain circumstances, PHS has already encouraged direct notification of transfusion recipients at increased risk for HIV Infection. In the MMWR of March 20, 1987, PHS recommended testing and counseling for individuals who received multiple transfusions of unscreened blood in areas with a high incidence of AIDS. A number of blood centers and transfusion services have attempted direct notification by letter of all patients who received transfusions between 1977 and 1985. Data collected from these efforts indicate that sweeping notification of a group of recipients is extremely resource-intensive, and particularly where recipients are unaware of donors' risk factors, recipients are not motivated to respond and the effort is not very effective. [footnote 2] A 1988 PHS mailing of AIDS information to all the nation's households included a notification of the need for testing for antibody to HIV for patients who received a transfusion between the years 1977 and 1986. MMWR. 37:261-269, 1988. FDA believes that these proposed rules, in conjunction with those being proposed by HCFA elsewhere in this Federal Register, will provide a more efficient means of notification.[footnote 3]
II. Coordination Between HHS Agencies
A. Memorandum of Understanding
In a memorandum of understanding (MOU), FDA and HCFA agreed to coordinate the Inspections of blood banks and transfusion services to minimize duplication of effort and to reduce the burden on affected facilities. In the MOU, it was estimated that HCFA would be responsible for inspecting and surveying approximately 3,000 transfusion services. FDA continues to conduct the inspections of establishments where activities include more than the performance of compatibility testing. (See 49 FR 34448 (August 31,1984), 21 CFR 607.65.)
B. Locating Blood Donors
The Social Security Administration operates a Blood Donor Locater Service (BDLS) to enable States and authorized blood donation facilities to notify blood donors whose donations indicate that they are or may be infected with HIV. Section 205(c)(2)(D) of the Social Security Act (42 U.S.C. 405(c)(2)(D)) permits states to require a blood donor to furnish his or her social security number (SSN) to a State agency or to an authorized blood donation facility. With the SSN, an authorized blood donation facility may request the State to contact the BDLS to obtain the donor's mailing address. The State agency may also make a request on its own behalf for this information to the BDLS.
C. Summary of the Proposed Rules of HCFA and FDA
Under proposed 606.100(b)(19) and 610.46(a), an establishment would be required to quarantine, and to notify the consignees regarding the need to quarantine, certain blood and blood components previously collected from a donor who subsequently tests repeatably reactive for antibody to HIV. The proposed rule, would also require consignees to quarantine such products. Under proposed 610.46(b), in situations in which blood establishments distributed such units, blood establishments would be required to test by a licensed, more specific test, the donor's blood sample from the current donation that tested repeatably reactive. Blood establishments would be required to notify the consignees of the results of the licensed, more specific test. If the licensed, more specific test result is negative, the units from prior collections are regarded as negative for antibody to HIV, and the prior collections, which previously tested negative, may be released from quarantine under proposed 610.46(c). If the licensed, more specific test result is positive or indeterminate, the units from prior collections may not be released from quarantine. The blood establishment would be required to dispose of extant products located at the establishment and to notify the consignees of the test result and of the need for the appropriate disposal of extant products. The general requirements for disposal of unsuitable products would apply to the specific situation where a product does not qualify for release from quarantine under this proposal. FDA has provided guidance to establishments for disposal of unsuitable products (ref. 3). If the licensed, more specific test result is positive, the blood establishment would be required to report the positive result to consignees that received units from prior collection, so that steps are taken to initiate notification of the attending physicians of transfusion recipients.
Under proposed 606.160 (b) (1) (vii) FDA would amend its biologics regulations to require blood establishments to prepare and maintain records so that previous donations from a donor could be identified, and to keep records of the look-back process. As with other records related to recipient health and donor suitability, the confidentiality of such donor and recipient records should be protected, consistent with evolved practices, standard operating procedures (SOP's), generally-recognized policies and expectations, and local, State, and Federal requirements.
Under HOFA's proposed rule, issued elsewhere in this Federal Register, transfusion services or other blood establishments inspected by HOFA that are notified by a blood establishment that a donor of blood products shipped to them for transfusion subsequently has tested positive by a licensed, more specific test for antibody to HIV would be required to notify the recipient's attending physician, the recipient, or other authorized person, as appropriate. HCFA has proposed to require the transfusion service to have a written agreement with each blood supplier documenting these procedures. We are especially interested in receiving comments on whether this proposed requirement would be more appropriately implemented as part of the FDA requirements applicable to blood banks or in the manner proposed, as part of a medicare hospital standard. Under FDA's proposed rule, transfusion services inspected by FDA that are so notified also would be required to notify the recipient's attending physician, the recipient, or other authorized person as appropriate.
The agencies are taking these actions to address blood safety issues affecting transfusion recipients who may be at increased risk for HIV infection, and to restrict the use of potentially infectious blood and blood components in the manufacture of injectable and noninjectable blood products.
III. FDA'S proposed Rule
Under the biologics licensing and quarantine provisions of the Public Health Service Act (42 U.S.C. 262-264) and the drug, device, and the general administrative provisions of the Federal Food, Drug, and Cosmetic Act (the act) (21 U.S.C. 351-353, 355360, 371-374), FDA has the authority to promulgate regulations to protect the public from unsafe or ineffective biological products and to promulgate regulations necessary to prevent the transmission of communicable diseases into the United States or from one State to another.
Under these statutory authorities, FDA currently requires that each donation of blood intended for transfusion, or for use in preparing a product, be tested and found negative or antibody to HIV under 810.45 (21 CFR 610.45). Existing regulations already restrict the use, for transfusion or for manufacture, of a donation testing repeatably reactive. Although current screening tests for antibody to HIV are very sensitive, antibody testing may not identify all blood units capable of transmitting infection. For this reason, many blood establishments have instituted special precautions when blood has been collected and the donor later tests repeatably reactive for antibody to HIV. These procedures involve determining the suitability of prior collections of blood and blood components from that donor. These procedures also may involve notifying consignees that have received prior collections from the donor so consignees may arrange to determine the suitability of such units, and, if appropriate, may take steps so that recipients of transfusions of those units are notified. These procedures are generally referred to as "look-back."
This proposal would require blood establishments, including consignees, to take certain actions when donors subsequently show evidence of antibody to HIV. These actions include quarantining units from prior collections pending a determination of the suitability of the units, notifying consignees of such units of the need for quarantine, and maintaining records regarding the quarantine and notification. Below is a discussion of the specific provisions of the proposed rules, beginning with a discussion of certain terms used in the rules.
A. The Term "HIV"
Throughout the proposed rule, FDA uses the term "HIV" to refer to HIV-1, the principal virus associated with AIDS in the United States, and HIV-2, a closely related virus, also associated with AIDS. HIV-2 has been found in other parts of the world, but is found only very rarely in the United States. A licensed test is also available that can detect antibody to HIV-1. The licensed test for antibody to HIV-1 may give repeatably reactive results based on cross-reactivity from antibody to HIV-2, but the current HIV-1 tests do not distinguish between antibody to HIV-1 and antibody to HIV-2. FDA is using the more general term "HIV" to require quarantine and notification regardless of whether the establishment has determined that the antibody detected is to HIV-1 or HIV-2.
B. The Term "Repeatably Reactive for Antibody to HIV" Based on FDA's extensive experience with blood establishments, including annual inspections, FDA believes that the current practice of blood establishments Is to screen blood donations with licensed Enzyme Immunoassay (EIA) tests, which detect antibody to HIV. The preamble describes how look-back is to be implemented when an establishment uses licensed EIA tests for donor screening. EIA test results are either negative or repeatably reactive. If the results are negative. the blood and blood components are suitable for use. If the EIA test result is repeatably reactive, then the product is not suitable for use. Establishments then perform licensed Western Blot testing for the purpose of determining the suitability of previously collected units, or for the purpose of counseling the donor. Although establishments currently use licensed Eia tests in accordance with 21 CFR 610.45(a)(1), other tests may be-approved for use under 21 CFR 610.45(a)(2). It Is possible that as - technology advances, and if other tests become practical for use as screening tests, establishments may seek FDA approval of other tests for donor screening purposes. This proposed rule, like 21 CFR 610.45, is flexible enough to provide for the use of other approved screening tests whether or not they detect HIV antibody. As other tests are approved for screening purposes. FDA will provide guidance on the look-back program using those test technologies.
C. The Term "Promptly"
In proposed 010.46(a), FDA is proposing that specified actions be performed "promptly" rather than specifying time limits for performing the various steps of the look-back program. For an establishment with existing records on a computerized database, checking records of previous donations to identify the date products were collected, the date the last negative screening test was performed, and to whom the products were distributed often can be performed concurrently with the recording of the donor's repeatably reactive test results. However, for an establishment without this capability. the determination may take longer. Likewise, for a facility that performs licensed, more specific tests on site, the test results may be available more quickly than for a facility that sends samples for testing to an outside laboratory. FDA Is using the general term "promptly" in order to recognize that differences will exist. However, within 2 weeks after the donors repeatably reactive test, the establishment should have the results of the more specific testing. and FDA is proposing a 2-week limit in which the establishment would be required to perform the test and notify consignees of the results. As discussed later in this preamble, the written SOP's of each blood establishment should address the time limits for performing each significant step of its look-back program If the blood establishment is unable to meet the time limits prescribed in the SOP's for a specific task, the reasons for that deviation should be described in the establishment's records. It is within the blood establishment's customary practices to perform testing. to arrange or appropriate action based on test results, and to maintain contact with consignees regarding. among other things. the quality of the product and services. The agency can estimate reasonable time limits based on this experience, and such time limits can be imposed for these activities. However, FDA is not proposing time limits for the notification of recipients but is relying on HCFA's expertise in the area of hospital practice. Consistent with HCFA's proposed rule, published elsewhere In this issue of the Federal Register. FDA believes that the hospital's notification effort should consist of, at the minimum, several attempts by phone or in writing to reach the attending physician or the recipient. The hospital's notification effort should begin Immediately after receiving word from the blood hank. and should be completed 8 weeks later. FDA would require that the hospital document the attempts to notify the recipient and indicate whether the recipient was located. FDA specifically invites public comment on the sufficiency of this level of effort. The agency believes that the chain of notification about the potentially infectious blood and/or
blood products should be from the hospital to the recipient's attending physician (physician of record), and that only in rare situations would the reciient receive this notification from the hospital. FDA invites comment as to whether a regulation describing the mechanics of this notification is necessary and whether additional explanation is necessary to identify when the hospital should directly notify the recipient. The agency believes this proposed rule is self-explanatory, but that a stated timeframe may be necessary to determine when the recipient should be notified by the hospital if the attending physician cannot be reached by telephone.
D. Amendments to Part 66 -- Current Good Manufacturing Practice for Blood and Blood Components
Under 21 CFR part 606, FDA provides CGMP regulations for licensed and unlicensed blood establishments to help ensure the continued safety, purity, potency, and efficacy of blood and blood components. To Implement the look-back program, FDA proposes to amend the CGMP regulations regarding written SOP's and records.
1. Standard Operating Procedures
FDA proposes adding new paragraph (b) (19) to 606.100. Proposed 606.100(b)(19) would require that establishments have written procedures to look-back at prior donations of blood and blood products from a donor who has previously donated blood and subsequently tests repeatably reactive for antibody to HIV when tested in accordance with 610.45. The written procedures would be required to describe in detail how obligations under this section would be met. The written SOP's would be required to include procedures to quarantine in-house blood and blood components, including Source Plasma and Recovered Plasma, and products intended for research, whether intended for transfusion or further manufacture, that were obtained from such donors. Consignees are blood establishments, and for clarity the proposed rule provides a separate, express provision requiring consignees to quarantine such products. The written SOP's also would be required to include procedures to notify consignees regarding the need to quarantine such products; procedures to determine the suitability for release of such products held in quarantine; procedures to notify consignees of blood and blood components from such donors of the results of the suitability determination; and procedures to determine the proper disposition of the products as approriate. The written procedures should include timeframes for meeting each obligation; they should also include a list of persons authorized to provide and receive notification.
2. Records
FDA proposes adding new paragraphs (b)(1)(vii) and (b)(1)(viii) to 606.160. Proposed 606.160(b)(1)(vii) would require that an establishment's records be organized in a manner to readily relate a donor with the unit number of each donation from that donor. Many establishments already organize records in this manner to implement existing programs regarding look-back, donor deferrals, recruitment of previous donors, record transfer to computer data banks, and recordkeeping efficiency. FDA is aware, however, that some blood establishments, using their current recordkeeping systems, are unable to readily determine the complete history of donations, including the unit numbers of the blood collected, from a specific donor. Some blood establishments, particularly small blood establishments, have organized information on blood donors by other systems, such as by the date of donation, which would not readily accommodate the proposed look-back procedures. FDA does not propose to require that blood establishments reorder and rerecord all previous information, but proposes that new information be entered on recordkeeping systems that are suitably modified by the proposed effective date. Upon the effective date of the final rule, to the extent that prior recordkeeping systems exist that relate a donor with each previous donation, FDA proposes that an establishment would be required to review its records to identify units for quarantine and consignee notification under proposed 606.160(b)(1)(vii). Beginning with the effective date of the final rule, FDA proposes to require that donor information be recorded in a manner to readily relate a donor with the unit number of each donation from that donor.
Under proposed 606.160(b)(1)(viii), FDA would require that records be kept documenting the quarantine, consignee notification, testing, and disposition of products requred under proposed 610.46(a) and (b). FDA is not proposing at this time specific requirements regarding methods for notification, such as whether notification must be performed in writing by facsimile or overnight mail, certified mail, regular mail, or orally by telephone. The means of notification should be set under each blood establishment's written SOP. However, regarding the information included about the notification, for both initial and followup contacts, the proposed notification records should identify all persons who gave and received the notification, the dates and times of notification, the types and unit numbers of all blood and blood components which are the subject of the notification, the dates that the donor tested repeatably reactive, the dates and results of more specific testing, and other information regarding the notification event. As with similar records related to recipient health and donor suitability, strict confidentiality of these records should be maintained.
E. Amendments to Part 610 - General Biological Products Standards
Under proposed 610.46(a), when a blood donor tests repeatably reactive for antibody to HIV, an establishment would be required to quarantine units collected from this donor within the past 5 years if intended for transfusion, and to quarantine units collected within the past 6 months if intended for further manufacture. The blood establishment would be required to promptly notify consignees who would also be required to quarantine such products.
Under proposed 610.46(b), if a blood establishment distributed such units, the blood establishment would be required to perform a licensed, more specific test for antibody to HIV. Within 2 weeks after the donor's repeatably reactive test, the blood establishment would be reguired to notify the consignees of the results of the licensed, more specific test: Whether positive, indeterminate, negative, or unavailable. Proposed 610.46(c) provides specific circumstances for the release of products from quarantine based on the evaluation of the test result. FDA intends that these proposed requirements apply to blood and blood components intended for transfusion or further manufacture, including blood and blood components intended for research use. Thus, establishments would be required to meet the standards for all blood and blood components intended for transfusion or for further manufacture, as applicable.
Under existing 610.45, blood and blood components, including plasma, that are repeatably reactive to a test for antibody to HIV are subject tc restrictions on use, regardless of the results of subsequent testing. FDA does not propose that the units testing repeatably reactive would be releasable if the results of more specific testing are negative. The units that would be releasable under this proposed rule are only those blood and blood components from revious donations that have been tested and found negative for antibody to HIV; FDA does not propose to amend the restrictions in 610.45. Products collected at the time the donor tests repeatably reactive must not be reissued for any purpose, except as provided in 610.45(c). Additionally, FDA does not propose to change the recommendations restricting the reentry of donors whose screening test results are repeatably reactive. The current procedures for donor reentry were provided by FDA in its memorandum to all blood establishments of December 5, 1990 (Ref. 2). FDA proposes to amend 610.45 for clarity, to refer to the requirements of 610.46 and 610.47. HCFA regulations expressly reference 610.45, therefore, an express referral in 610.45 to 610.46 and 610.47 will facilitate HCFA-regulated facilities in recognizing all requirements related to the test for antibody to HIV.
1. Quarantine and Notification Procedure
Proposed 610.46 would require quarantine of previously collected products and notification of consignees in specified circumstances. FDA proposes that blood establishments be required to follow, at a minimum, the precautions listed below, and that they are performed promptly when a previous donor of blood and blood components subsequently tests repeatably reactive for antibody to HIV:
a. Quarantine and notification of consignees for blood and blood components intended for transfusion. Under 610.46 (a), FDA proposes to require blood establishments to quarantine previously collected blood and blood components intended for transfusion that have been collected during the time period from the present extending back 5 years, or, if there is a record of the donor's last licensed negative test for antibody to HIV which had been performed in accordance with 610.45, then back to the time 12 months before such test. Proposed 610.46(a) would also require blood establishments to notify consignees so that such products are appropriately quarantined.
b. Quarantine and notification of consignees for blood and blood components intended for further manufacture. Also under 610.46(a), FDA proposes to require blood establishments to identify and quarantine all units in inventory intended for further manufacture, including Source Plasma and Recovered Plasma, that have been collected during the time period from the present extending back to the time 6 months prior to the repeatably reactive test. Proposed 610.46(a) would also require blood establishments to notify consignees regarding the need to quarantine unpooled units that were collected within the past 6 months.
Blood, blood components, and Source Plasma intended for further manufacture are pooled quickly and are unlikely to be available after 6 months. In addition, they are subjected to further manufacturing steps in making various final products. The proposed rule would require collecting establishments to quarantine products intended for further manufacture that have been pooled by the establishment but not yet shipped to a consignee. These pools are more often small and their quarantine provides an additional margin of safety without negatively affecting the availability of the blood product. FDA also proposes a requirement to notify consignees so they may quarantine products intended for manufacture. FDA is not proposing to require consignees to quarantine products pooled by the consignee as a preliminary step for further manufacture, because these are often large pools, comprising a thousand units or more, and their diversion could have serious consequences on the availability of blood products.
In addition, products manufactured from blood and blood components, including plasma, undergo further manufacturing steps so the final products are treated in such a manner to prevent the transmission of HIV. Some method to inactivate viral contaminants is used in the manufacture of all such products. The most common practice for treating blood and blood products is heat inactivation treatment. FDA thoroughly reviews the methods proposed by manufacturers in establishment and product license applications and amendments and evaluates the effectiveness of these methods before approving any methods. FDA also reviews epidemiologic evidence, which has also established that these treatment processes reduce the risk of HIV Infection from these products.
2. Testing and Notification of Consignees
Proposed 610.46(b) would apply in situations involving a donor who subsequently tests repeatedly reactive, and would require that for blood and blood components intended for transfusion or for further manufacture which have been distributed, a blood establishment must test the donor's blood for HIV by a licensed, more specific test. This more specific test would be performed on blood that is collected at the time the donor first tests repeatably reactive for antibody to HIV; FDA is not proposing to require more specific testing on each unit in quarantine. Blood establishments that have distributed prior units would be required to notify the consignees of the results of the more specific test within 2 weeks from tha date of the repeatably reactive test. The consignee would rely on the results of the licensed, more specific test to determine whether to notify physicians of the recipients of prior transfusions, in accordance with HCFA's and FDA's proposed rules, as well as to determine the disposition of the products in quarantine.
3. Release From Quarantine
Under proposed 610.46(c), units from previous donations would be unsuitable for release from quarantine unless the result of the licensed, more specific test for antibody to HIV is negative. If the result of the licensed, more specific test is positive, indeterminate, or not available within 2 weeks, then the units must not be released from quarantine. Instead, the blood establishment is responsible for notifying the consignee of the results so that the units may be appropriately disclosed.
FDA notes that the procedures deecribed above have two related but distinct objectives. First, the proposed procedures will help ensure that blood and blood components that may be contaminated with HIV are quarantined. This objective would be met by following FDA's proposed requirements. The second objective involves a joint effort between FDA and HCFA. FDA is proposing regulations so that users of blood and blood components intended for transfusion are provided with adequate information so that, in compliance with HCFA's and FDA's proposed regulations, they may notify the transfusion recipient's attending physician that the blood or blood components may have been contaminated with HIV.
4. Transfusion Services; Quarantine and Notification Requirements
Elsewhere In this issue of the Federal Register, HCFA has proposed to require recipient notification for all hospitals that participate in the Medicare program. HCFA's proposal does not extend to hospitals and transfusion services that do not participate in the Medicare program, so nonparticipating establishments will not be subject to HCFA's proposed rule. Because of the significant public health issue associated with the look-back program, including the need to notify transfusion recipients so they can be tested, obtain early treatment if needed, and prevent the further spread of this disease, FDA is proposing 610.47, which would require all registered establishments that do not participate in the Medicare program to take steps to notify transfusion recipients. Proposed 610.47 would also require such facilities to take steps to quarantine units collected from a donor who subsequently tests repeatably reactive for antibody to HIV.
F. Other Reliable Indications That Donors Have Evidence of HIV
As proposed. the look-back procedures would be required only when indicated by the results of testing performed by a blood establishment. A blood establishment may receive information from other sources, such as a State health department, a physician, friends or relatives of a donor, or other blood establishments, which indicate that a donor may be infected with HIV. The availability of this information varies from State to State because of differing State laws regarding the type, detail, and restrictions on the use of this information, and because of confidentiality issues. Because a blood establishment may not receive such information consistently, nor may it be able to readily evaluate the reliability of all types of information, at this time FDA is not proposing additional circumstances under which look-back would be required. FDA invites comment on whether there are additional circumstances when a blood establishment can reliably and consistently receive information that should result in the required initiation of the look-back procedures included in this proposed rule. FDA encourages blood establishments to initiate look-back procedures whenever they have received reliable information that a donor is infected with HIV.
G. Limitations on Temporal Requirements for look-back
FDA is proposing temporal limitations on the requirement for look-back. If at the time the donor's blood Is first identified as being repeatably reactive, it is known when the most recent negative screening test was performed in accordance with 610.45, units collected more than 12 months prior to the date of the last negative screening test need not be quarantined. If the date of the most recent negative screening test is not known, units collected previously would be quarantined until the date can be determined. As discussed in subparagraph 2 below, units collected more than 5 years prior to the date of the repeatably reactive test need not be quarantined. FDA is proposing that units intended for further manufacture need not be held in quarantine if collected more than 6 months prior to the donor's current repeatably reactive test. The blood establishment would also quarantine these previously collected units until the dates of collection and previous negative test are determined.
1. Twelve Months Before the Date of the Repeatably Reactive Test
Previous donors of blood and blood components intended for transfusion or further manufacture who have donated since licensed testing became available, approximately in mid-1985, should have tested negative for anti-HIV by a licensed test at the prior donation. In rare cases, the donor may have tested negative by that previous test while in the "window" period, a time period usually less than 6 months during which time the donor tests negative for HIV but may be infectious for the virus. Based on experience, current estimates predict with approximately 95 percent confidence that in all cases of HIV infection, the person will test positive for anti-HIV by a licensed test within 6 months from the date of infection (ref. 2). To provide an additional margin of safety, FDA has extended the period for look-back to 12 months, to more closely approximate a 99 percent confidence interval. [footnote 4] Accordingly, FDA has constructed the proposed look-back procedures so that virtually all donations collected during the "window" period are appropriately included.
2. Five Years From the Date of the Repeatably Reactive Test
In accordance with Federal requirements, most records related to blood donors and transfusion recipients are kept for 5 years. In rare cases, the donor 's last negative screening test may have occurred more than 4 years before the repeatably reactive test result, so that the period 12 months prior to the donor's last negative screening test would cover a time period for which records may no longer be available. Under this proposal, look-back will not be required to continue beyond 5 years prior to the date of the donor's repeatably reactive test for anti-HIV for several reasons:
(1) After 5 years. hospitals are not required to keep records identifying transfusion recipients. so such transfusions may not be traceable;
(2) High mortality exists among transfusion recipients for reasons not directly related to the blood transfusion (because transfusion recipients are often elderly and conditions requiring transfusion are often life-threatening); the majority of recipients will not survive beyond 5 years so attempts to notify these recipients would be inefficient and ineffective;
(3) If HIV infection were present in a recipient's blood for 5 years, the recipient may be aware of the condition independently without need for notification; and
(4) The program described in the MMWR of March 20, 1987, and in the PHS mailing to every household in 1988, included a notification of the need for followup testing for recipients of transfusion before mid-1985.
3. Six Months After Collection of Products Intended for Further Manufacture
Past experience has shown that blood, blood components, and Source Plasma intended for further manufacture are pooled quickly and subjected to further manufacturing steps in making various final products. Accordingly, 6 months after collection, such units are rarely, if ever, recoverable as single units or small pools of units. Because the final products intended for administration to humans and treated in such a manner to prevent the transmission of HIV, as discussed above, and because after 6 months products from individual donors cannot be readily isolated and quarantined, a 6 month-period is appropriate to help ensure the continued safety of the blood supply while helping to ensure the availability of safe and effective products.
IV. Environmental Impact
The agency has determined under 21 CFR 25.24(c)(10) that this proposed action is of a type that does not individually or cumulatively have a significant effect on the human environment. Therefore, neither an environmental assessment nor an environmental impact statement is required.
V. Economic Assesement
The agency has examined the economic impact of this proposed rule and has determined that it does not require either a regulatory impact analysis, as specified in Executive Order 12291, or a regulatory flexibility analysis, as specified in the Regulatory Flexibility Act (Pub; L. 96354). The benefits of this rule to the public are twofold. The primary purpose of the look-back requirement is to reduce the risk of HIV infection through transfusion of blood and blood components during the window period, at wich time antibodies to the HIV virus in the donor are not detectable through normal screening procedure. Notification of consignees to quarantine potentially infected components, until confirmatory testing is completed, will prevent any further infection of the public. Once a donor has converted to HIV positive, all recipients of previously donated components during the potential window period can be notified, tested, and treated before they begin to exhibit symptoms of infection. Spreading of the virus can be retarded through early detection made possible by this rule.
Most blood establishments already participate in a look-back program. Ninety-five percent of blood establishments, collecting 98 percent of the nation's blood supply, already participate in a look-back notification of their customers concerning units of blood previously shipped that may be at increased risk of transmitting HIV because the donor was later found to be repeatably reactive. Thus, requirements for written procedures and records of notification that apply to blood establishments regulated by FDA, and that relate only to blood units taken from donors who later were found to be repeatably reactive, would effect about 5 percent of blood establishments; the remaining 95 percent of blood establishments may need to make minor adjustments in their procedures which FDA believes should only have a minimal impact. FDA expects the total annualized cost of this proposed rule on blood establishments to be $2,469,950. FDA anticipates only a small number of cases per year which can be traced to potentially infectious blood and therefore the need to notify transfusion recipients will arise infrequently. FDA has determined that the proposed rule is not a major rule as defined in Executive Order 12291. Further, FDA certifies that the proposed rule will not have a significant impact on a substantial number of small business entities, as defined in the Regulatory Flexibility Act.
V. Paperwork Reduction Act of 1980
This proposed rule contains information collections which are subject to review by the Office of Management and Budget (OMB) under the Paperwork Reduction Act of 1980. The title, description, and respondent description of the information collection are shown below with an estimate of the annual reporting and recordkeeping burden. Included in the estimate is the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing the collection of information.
Title: Current Good Manufacturing Practices for Blood and Blood. Components; Notification of Consignees Receiving Blood and Blood Components at Increased Risk for Transmitting HIV Infection.
Description: This proposed rule would require that blood establishments prepare and follow written procedures when the blood establishments have collected blood and blood components that are potentially contaminated with HIV. This proposal would require that when a previous donor subsequently tests positive for antibody to HIV, a blood establishment shall quarantine previously collected blood, blood components, and plasma collected from such donor, and notify consignees of such blood so that appropriate action is taken. The agency is proposing these rules to help ensure the continued safety of the blood supply, to help ensure that information is provided to users of blood and blood components, and to help ensure that transfusion recipients of potentially contaminated blood and blood components may be notified as appropriate.
Description of Respondents: Blood establishments (Business and Not-for-Profit).
/* CHART PCX HERE*/
These estimates are an approximation of the average time expected to be necessary for a collection of information. They are based on such information as is available to FDA. The agency seeks comment on these estimates, particularly the industries' view of the number of firms and products affected by the collections of information contained in this proposed rule.
The agency will submit a copy of this proposed rule to OMB for its review of these information collections. Interested persons are requested to send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden, to FDA's Dockets Management Branch (address above), and to the Office of Information and Regulatory Affairs, OMB, rm. 3208, New Executive Office Bldg., Washington, DC 20503, Attn: Desk Officer for FDA.
VII. Comments
Interested persons may, on or before August 30, 1993 submit to the Dockets Management Branch (address above) written comments regarding this proposal. Two copies of any comments are to be submitted, except that individuals may submit one copy. Comments are to be identified with the docket number found in brackets in the heading of the document. Received comments may be Seen in the office above between 9 a.m. and 4 p.m.. Monday through Friday.
VIII. References
The following references have been placed on display in the Dockets Management Branch (address above) and may be seen by interested persons between 9 a.m. and 4 p.m., Monday through Friday.
1. Memorandum to Registered Blood Establishments from the Director, Office of Biologics Research and Review, July 22, 1985.
2. Memorandum to Blood Establishments from the Director. Center for Biologics Evaluation and Research, December 5, 1990.
3. Memorandum to All Registered Blood Establishments from the Director. Center for Biologics Evaluation and Research, April 6, 1988.
List of subjects
21 CFR Part 606
Blood, Labeling, Laboratories, Reporting and recordkeeping requirements.
21 CFR Part 610
Biologics, Labeling, Reporting and recordkeeping requirements.
Therefore, under the Federal Food, Drug, and Cosmetic Act, the Public Health Service Act, and the Administrative Procedure Act, it is proposed that 21 CFR parts 606 and 610 be amended as follows:
PART 6O6-CURRENT GOOD MANUFACTURING PRACTICE FOR BLOOD AND BLOOD COMPONENTS
1. The authority citation for 21 CFR part 606 continues to read as follows:
Authority: Secs. 201, 301, 501, 502, 505, 510, 520, 701, 704 of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321, 331, 351, 352, 355, 360, 360j, 371, 374); secs. 215, 351, 353, 361 of the Public Health Service Act (42 U.S.C. 216, 262, 263a, 264).
2. Section 606.100 is amended by adding new paragraph (b)(19) to read as follows:
606.100 Standard operating procedures.
* * * * *
(b) *****
(19) Procedures in accordance with 610.46 of this chapter to look-back at prior donations of blood and blood products from a donor who has donated blood and subsequently tests repeatably reactive for infection with human immunodeficiency virus (HIV) or otherwise is determined to be unsuitable when tested in accordance with 610.45 of this diapter. Procedures to quarantine in-house blood and blood components intended for transfusion or further manufacture, including Source Plasma and Recovered Plasma, that were obtained from such donors; procedures to notify consignees regarding the need to quarantine such products; procedures to determine the suitability for release of such products from quarantine; procedures to notify consignees of blood and blood components from such donors of the results of the antibody testing of such donors; and procedures in accordance with 610.47 of this chapter to notify attending physicians so that transfusion recipients are informed that they may have received blood infected with the human immunodeficiency virus.
* * * * *
3. Section 606.160 is amended by adding new paragraphs (b)(1)(vii) and (b)(1)(viii) to read as follows:
606.160 Records.
* * * * *
(b) * * *
(1) * * *
(vii) Records to relate the donor with the unit number of each previous donation from that donor.
(viii) Records of quarantine, notification, testing, and disposition performed pursuant to 610.46 and 610.47 of this chapter.
* * * *
PART 6l0--GENERAL BIOLOGICAL PRODUCTS STANDARDS
4. The authority citation for 21 CFR part 610 continues to read as follows:
Authority: Secc. 201, 501, 502, 503, 505, 510, 701 of the Federal Food, Drug and Cosmetic Act (21 U.S.& 321, 351, 352, 353, 355, 360, 371); secs. 215, 351, 352, 353, 361 of the Public Health Service Act (42 U.S.C. 216, 262, 263, 263a. 264).
5. Section 610.45 Is amended by adding new paragraph (d) to read as follows:
610-45 Human immunodeficiency virus (HIV) requirements.
* * * * *
(d) For a donor whose test results for antibody to HIV are repeatably reactive or otherwise determined to be unsuitable when tested in accordance with paragraph (a) of this section, the blood establishment shall comply, as applicable, with 610.46 and 610.47.
6. New 610.46 and 610.47 are added to subpart E to read as follows:
610.46 Look-back requirements.
(a) Quarantine and notification. (1) All blood establishments are required to take appropriate action when a donor of blood or blood components, including Source Plasma, tests repeatably reactive for antibody to human immunodefidency virus (HIV) or otherwise is determined to be unsuitable when tested in accordance with 610.45. For units collected from that donor within the 5 years prior to the repeatably reactive test if intended for transfusion, or collected within the 6 months prior to the repeatably reactive test if intended for further manufacture, the blood establishment shall promptly:
(i) Quarantine all such blood and blood components held at that establishment; and
(ii) Notify consignees so that such products they hold are quarantined.
(2) Consignees notified in accordance with paragraph (a)(1)(ii) of this section shall quarantine unpooled products held at that establishment
(b) Testing and notification of consignees of results. Blood establishments that have distributed blood or blood components from a donor described in paragraph (a) of this section shall perform a licensed, more secific test for HIV on the donor's blood, and further shall notify the consignees, within 2 weeks after the donor's repeatably reactive test, of the results of the test.
(c) Release and exemption from quarantine. Products intended for transfusion or futher manufacture which have been quarantined under this section may be released if the donor is subsequently
tested for antibody to HIV by a licensed, more specific test and the test result is negative. In addition, products intended for transfusion need not be held in quarantine if a determination has been made that the blood or blood component was collected more than 12 months prior to the donor's most recent negative screening test when tested in accordance with 610.45.
(d) Actions under this section do not constitute a product recall as defined in 7.3(g) of this chapter.
610.47 Look-back notification requirements for transfusion services.
(a) Transfusion services that are not subject to the Health Care Financing Administration's regulations on conditions of Medicare participation (42 CFR part 482) are required to take appropriate action in accordance with paragraph (b) of this section when a recipient has received blood from a donor determined to be unsuitable when tested for human immunodeficiency virus (HIV) infection in accordance with 610.45 and the results of the licensed more specific test are positive, or not available within 2 weeks as specified in 610.46.
(b)Notification of recipients of prior transfusions. If the transfusion service has administered any unit of blood as described in paragraph (a) of this section, the transfusion service shall notify the recipients' attending physician (physician of record) and ask him or her to inform the recipient of the need for HIV testing and counseling. The physician may notify another authorized person, such as a parent or guardian of the recipient, if the reasons to do so are documented pursuant to 606.160 of this chapter. If the physician is unavailable or declines to notify the recipient, the transfusion service shall notify the recipient and inform the recipient of the need for HIV testing and counseling. The transfusion service is responsible for notification, including basic explanations to the recipient and referral for counseling, and shall document the notification or attempts to notify the attending physician or the recipient, pursuant to 606.160 of this chapter.
Dated: March 26, 1993.
David A. Kessler, Commissioner of Food and Drugs.
Donna E. Shalala, Secretary of Health and Human Services.
[FR Doc. 93-15400 Filed 6-29-93; 8:45 am]
FOOTNOTES:
1. A 1988 Centers for-Disease Control report based on a theoretical model estimated the risk of transmission in a worst-case scenario at 1:38,000. A 1989 report by the American Red Cross, based on empirical data, estimated the risk at 1:153,000. Other studies estimated the risk between 1:50,000 and 1:68,000. Busch, M., et al.. New England Journal of Medicine, 1991, 325:1-5; Cohen, N. O. et al., New England Journal of Medicine, 1989, 320:1172-1178; Kleinman et al., Transfusion, 1988. 28:499-501.
2. See, e.g., Busch, et al., Risk of Human Immunodeficiency Virus (HIV) Transmission by Blood Transfusion Before the Implementation of HIV-1 Antibody Screening, Transfusion, 1991, 31:4-12.
3. Ibid. See also Busch, M.P. et al., Is Lookback Doing the Job? (letter), Transfusion, 27:503-504, 1987; Sampson, et al., Identification of HIV Infection in Transfusion Recipients: The utility of cross-referencing previous donor records with AIDS case reports, Transfusion, 30:214-218, 1990.
4. See Horsburg, C.R., Jr., et al., "Estimated Duration of HIV Infection Before Detection of Antibody," The Lancet, 16:637-40, 1989.
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