[Federal Register: November 16, 2000 (Volume 65, Number 222)]
[Proposed Rules]
[Page 69377-69416]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr16no00-14]
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Part II
Department of Health and Human Services
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Food and Drug Administration
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21 CFR Parts 606 and 610
Current Good Manufacturing Practice for Blood and Blood Components;
Notification of Consignees and Transfusion Recipients Receiving Blood
and Blood Components at Increased Risk of Transmitting HCV Infection
(``Lookback''); Proposed Rule
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Health Care Financing Administration
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42 CFR Part 482
Medicare and Medicaid Programs; Hospital Conditions of Participation:
Laboratory Services; Proposed Rule
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Parts 606 and 610
[Docket No. 99N-2337]
RIN 0910-AB76
Current Good Manufacturing Practice for Blood and Blood
Components; Notification of Consignees and Transfusion Recipients
Receiving Blood and Blood Components at Increased Risk of Transmitting
HCV Infection (``Lookback'')
AGENCY: Food and Drug Administration, HHS.
ACTION: Proposed rule.
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SUMMARY: The Food and Drug Administration (FDA) is proposing to amend
the biologics regulations to require that blood establishments
(including plasma establishments) prepare and follow written procedures
for appropriate action when it is determined that blood and blood
components at increased risk of transmitting hepatitis C virus (HCV)
infection have been collected from a donor who tested repeatedly
reactive for evidence of HCV infection at a later date. This proposed
rule would require blood establishments to quarantine prior collections
from such a donor, perform further testing on the donor, and notify
transfusion recipients, as appropriate, when such a donor is identified
at the time of a repeat donation or after performing a review of
historical testing records to identify donations at increased risk of
transmitting HCV. In addition, FDA is proposing to extend the record
retention period to 10 years to create opportunities for disease
prevention many years after recipient exposure to such a donor. This
action is taken as part of FDA's ``Blood Initiative'' to
comprehensively review and, as necessary, revise its regulations,
policies, guidances, and procedures related to the licensing and
regulation of blood products. This proposed rule is intended to help
ensure the continued safety of the blood supply and to help ensure that
information is provided to consignees and to prior recipients of blood
and blood components from a donor whose subsequent donation tests
positive for antibody to HCV or otherwise is determined to have been at
increased risk of transmitting HCV.
DATES: Submit written comments on the proposed rule by February 14,
2001. Submit written comments on the information collection provisions
by December 18, 2000. See section VII of this document for the proposed
effective date of a final rule based on this document.
ADDRESSES: Submit written comments to the Dockets Management Branch
(HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061,
Rockville, MD 20852. Submit written comments on the information
collection provisions to the Office of Information and Regulatory
Affairs, OMB, New Executive Office Bldg., 725 17th St. NW., Washington,
DC 20503, Attn: Wendy Taylor, Desk Officer for FDA.
FOR FURTHER INFORMATION CONTACT: Sharon A. Carayiannis, Center for
Biologics Evaluation and Research (HFM-17), Food and Drug
Administration, 1401 Rockville Pike, suite 200N, Rockville, MD 20852-
1448, 301-827-6210.
SUPPLEMENTARY INFORMATION:
I. Background
A. Blood Initiative
For a variety of reasons FDA has decided to comprehensively review
and, as necessary, revise its regulations, policies, guidance, and
procedures related to the licensing and regulation of blood products.
In the Federal Register of June 3, 1994 (59 FR 28821 and 59 FR 28822,
respectively), FDA issued two documents entitled ``Review of General
Biologics and Licensing Regulations'' (Docket No. 94N-0066) and
``Review of Regulations for Blood Establishments and Blood Products''
(Docket No. 94N-0080). These two documents announced the agency's
intent to review biologics regulations in 21 CFR parts 600, 601, 606,
607, 610, 640, and 660 (21 CFR 600, 601, 606, 607, 610, 640, and 660)
and requested written comments from the public. Interested persons were
given until August 17, 1994, to respond to the documents. In response
to requests for additional time, FDA twice extended the comment period,
as announced in the Federal Register of August 17, 1994 (59 FR 42193),
and November 14, 1995 (59 FR 56448). In addition, FDA responded to
requests for a public meeting to allow for the presentation of comments
regarding the agency's intent to review the biologics regulations. On
January 26, 1995, FDA held a public meeting to provide an opportunity
for all interested individuals to present their comments and to assist
the agency in determining whether the regulations should be revised,
rescinded, or continued without change. Since the time of the
regulation review, FDA has implemented a number of changes to its
regulations and policies applicable to the general biologics and
licensing regulations, some of which applied to blood products as well
as other biological products. (See, e.g., the final rules issued on May
14, 1996 (61 FR 24313); August 1, 1996 (61 FR 40153); November 6, 1996
(61 FR 57328); July 24, 1997 (62 FR 39890); and October 15, 1997 (62 FR
53536)).
Because of the importance of a safe national blood supply, the U.S.
House of Representatives Committee on Government Reform and Oversight,
Subcommittee on Human Resources and Intergovernmental Relations (the
Subcommittee) and other groups such as the General Accounting Office
(GAO), and the Institute of Medicine (IOM) have reviewed the agency's
policies, practices, and regulations. Reports issued following the
respective reviews made a number of recommendations as to how FDA might
improve the biologics regulations, particularly as they apply to the
continued safety of blood products. The relevant reports are: (1)
``Protecting the Nation's Blood Supply From Infectious Agents: The Need
for New Standards to Meet New Threats,'' by the Subcommittee (August 2,
1996); (2) ``Blood Supply: FDA Oversight and Remaining Issues of
Safety,'' by GAO (February 25, 1997); (3) ``Blood Supply: Transfusion-
Associated Risks,'' by GAO (February 25, 1997); and (4) ``HIV and the
Blood Supply: An Analysis of Crisis Decisionmaking,'' by IOM ( July 13,
1995). These reports are on file with the Dockets Management Branch
(address above) under the docket number given in the heading of this
document.
FDA has reviewed these reports and agrees with the majority of the
recommendations contained within them. However, rather than only
responding specifically to the recommendations from the Subcommittee,
GAO, IOM, and the public, FDA convened a number of internal task forces
to review a variety of issues related to the regulation of blood and
blood products, including how to most appropriately update the existing
regulations applicable to blood and blood products. In the future, FDA
intends to issue a number of blood-related rulemakings that various FDA
task groups are currently preparing. FDA is not describing the specific
recommendations it has received and the numerous objectives of the
Blood Initiative in this document. Future rulemaking and other notices
will describe and discuss specific recommendations and regulatory
objectives.
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B. Existing Donor Screening and Testing Requirements
FDA has developed five ``layers of safety'' to help ensure a safe
blood supply: Donor screening, donor deferral registries, testing
blood, blood quarantining, and monitoring and investigating problems.
The five layers of safety are designed to overlap so that they will
prevent the distribution of blood and blood products that are at
increased risk of transmitting communicable disease agents such as
human immunodeficiency virus (HIV) and hepatitis B virus (HBV). With
regard to screening donors and testing blood, FDA has defined an
extensive system of donor screening and testing procedures, two of the
five layers of safety, performed by blood establishments. These
procedures include the initial screening of individuals that volunteer
to donate blood using a questionnaire, interview, and physical
examination. This initial screening process is designed to protect the
donor and to establish whether the donor is in good health, to rule out
possible exposure to disease, such as through travel to an area endemic
for malaria, or through close contact with an infected individual, and
to identify whether the donor has engaged in behavior that would
indicate increased risk of a communicable disease. Individuals who
satisfactorily answer the questionnaire, pass the physical examination,
and then donate blood are further screened by laboratory testing for
evidence of infection due to communicable disease agents such as HIV
and HBV. In the Federal Register of August 19, 1999 (64 FR 45340), FDA
issued a proposed rule entitled ``Requirements for Testing Human Blood
Donors for Evidence of Infection Due to Communicable Disease Agents''
(hereinafter referred to as the testing proposed rule), to update,
revise, and redesignate the testing requirements of Sec. 610.45. The
relevance of the testing proposed rule to this proposed rule is
discussed in section III of this document.
As a result of the extensive screening and testing procedures and
the other layers of safety, the risk of transmitting infection through
blood transfusion is very low. Despite the best practices of blood
establishments, however, a person may donate blood early in infection,
during the period when the testable marker is not detectable by a
screening test, but the infectious agent is present in the donor's
blood (a ``window'' period). For example, if a donor donates blood on a
number of occasions and each donation tests negative for antibody to
HIV, but the donor returns and tests repeatedly reactive for antibody
to HIV at a later date, prior collections from such a donor would be at
increased risk of transmitting HIV. In addition, a recipient of a
transfusion of blood or blood components collected during the
``window'' period would not know that he or she may have become
infected with HIV through the transfusion unless notified.
Under such circumstances, FDA requires clarification of the donor's
status and procedures to ``lookback'' at prior collections, as
specified in Secs. 610.46 and 610.47 (the HIV ``lookback''
regulations). (See the final rule issued in the Federal Register of
September 9, 1996 (61 FR 47413).) The HIV ``lookback'' regulations
require facilities involved in the collection, processing, and
administration of blood to quarantine blood and blood components which
were collected from a donor who tested negative at the time of previous
donations but subsequently tests repeatedly reactive for antibody to
HIV. The regulations require blood establishments to inform consignees
(e.g., hospital transfusion services and manufacturers of plasma
derivatives) of the collection and distribution of such previously
donated blood and blood components, to perform further testing on the
donor, and to notify transfusion recipients, as appropriate.
C. History of HCV Testing
HCV frequently causes a clinically inapparent, but chronic
infection of the liver. Approximately 4 million individuals in the
United States are believed to be chronically infected with HCV. Despite
progression of disease, HCV infection is usually asymptomatic for about
20 years, but in many cases causes serious liver injury that is thought
to be the leading cause of late stage cirrhosis and liver failure in
the United States and to play a significant role in the development of
liver cancer. Therapy with licensed interferon produces long-term
benefit in only about 15 percent of cases, but a newly available
therapeutic modality, combination therapy using interferon plus
ribavirin, may improve this outcome.
The greatest risk for transmission of HCV is through direct
percutaneous exposure to infectious blood, such as through transfusion
of infectious blood or blood products, sharing of contaminated
equipment among injection drug users, or transplantation of organs or
tissues from infectious donors. Hemodialysis patients and health-care
workers exposed to needle sticks in the occupational setting are also
at risk for exposure to infectious blood. Direct percutaneous exposures
to infectious blood, particularly in the setting of drug abuse, account
for the majority of HCV infections acquired in the United States (Ref.
1). The incidence of transfusion transmitted HCV infection has
decreased markedly since the implementation of donor screening for HCV
and viral inactivation of clotting factors and intravenous immune
globulins. However, approximately 7 percent of the 3.9 million
Americans believed to be chronically infected with HCV were infected as
a result of transfusion of blood components prior to the availability
of donor screening tests or due to past use of nonviral-inactivated
plasma derivative products (Ref. 2).
HCV was established as a causative agent of transfusion associated
hepatitis only since its discovery in the late 1980's. In October 1989,
FDA's Blood Products Advisory Committee (BPAC) first discussed
``lookback'' for HCV, prior to the availability of donor screening
tests for HCV. BPAC advised that there was insufficient information
available concerning HCV infection to propose either product quarantine
or notification of recipients transfused with products prepared from
prior collections from donors later determined to be at increased risk
for transmitting HCV. Blood establishments implemented donor screening
tests after a single antigen, enzyme linked immunosorbent assay (EIA)
for antibody to HCV (HCV EIA 1.0 screening test) was licensed in May
1990. FDA issued a memorandum to all registered blood establishments in
November 1990, entitled ``Testing for Antibody to Hepatitis C Virus
Encoded Antigen (Anti-HCV),'' recommending use of approved donor
screening tests for antibody to HCV. A ``lookback'' program was not
recommended because: (1) Screening tests available at the time could
not distinguish between ongoing infection and recovery, and thus, the
meaning of a reactive test result for any one individual was not clear;
(2) donor screening for antibody to HCV did not include confirmatory
testing and most notifications would have been based on false-positive
donor test results; (3) there was limited knowledge of routes of
transmission for HCV other than parenteral; and (4) no potential long-
term benefits of therapy were known.
A significantly more sensitive multiantigen screening test (HCV EIA
2.0 screening test) was licensed in March 1992. In June 1993, FDA
licensed an HCV 2.0 strip immunoblot assay (HCV RIBA 2.0), a
supplemental (additional, more specific) test for antibody to HCV.
Supplemental tests for
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antibody to HCV are used to distinguish false positive from true
positive repeatedly reactive screening test results. Except for tests
available for investigational use, supplemental tests for antibody to
HCV have only been available since the HCV RIBA 2.0 supplemental test
was licensed in June 1993.
In an August 1993 memorandum to all registered blood establishments
entitled ``Revised Recommendations for Testing Whole Blood, Blood
Components, Source Plasma and Source Leukocytes for Antibody to
Hepatitis C Virus Encoded Antigen (Anti-HCV),'' FDA did not recommend a
``lookback'' program pending the outcome of discussions on the issue at
the December 1993 BPAC meeting. Following the discussions on HCV at the
meeting in December 1993, BPAC unanimously recommended product
quarantine of prior collections from a donor who later tests repeatedly
reactive for antibody to HCV and tests positive or indeterminate on a
supplemental test, but only marginally endorsed consignee notification
for the purpose of transfusion recipient notification, and reiterated
many of the reservations regarding the lack of an established public
health benefit in performing this activity. FDA issued a memorandum to
all registered blood establishments in July 1996 entitled
``Recommendations for the Quarantine and Disposition of Units from
Prior Collections from Donors with Repeatedly Reactive Screening Tests
for Hepatitis B Virus (HBV), Hepatitis C Virus (HCV), and Human T-
Lymphotropic Virus Type I (HTLV-I).'' The July 1996 memorandum
recommended testing, consignee notification, and quarantine of affected
products but did not provide recommendations for the notification of
recipients of such donations because the public health benefit of such
notification was not clear.
The Public Health Service Advisory Committee on Blood Safety and
Availability (the PHS Advisory Committee) discussed improvements in the
treatment and management of HCV infection and improvements in testing
for antibody to HCV at public meetings held on April 24 and 25, 1997,
and August 11 and 12, 1997. The PHS Advisory Committee also discussed
the public health benefits of notification of transfusion recipients
receiving prior collections from a donor who subsequently tests
repeatedly reactive for evidence of HCV infection. Following acceptance
by the Department of Health and Human Services (DHHS) of
recommendations for HCV ``lookback'' made in August of 1997 by the PHS
Advisory Committee, FDA issued a notice in the Federal Register of
March 20, 1998 (63 FR 13675), announcing the availability of a document
entitled ``Guidance for Industry: Supplemental Testing and the
Notification of Consignees of Donor Test Results for Antibody to
Hepatitis C Virus (Anti-HCV)'' (the March 1998 guidance) in which FDA
recommended that blood establishments implement HCV ``lookback''
procedures. In the March 1998 guidance, FDA recommended that donors
currently testing repeatedly reactive for antibody to HCV in a licensed
test be further tested for antibody to HCV using a licensed,
multiantigen supplemental test. Additionally, FDA recommended that
consignees of certain blood and blood components collected since
January 1, 1988, which were anti-HCV negative or untested, be notified
when donors subsequently test repeatedly reactive for anti-HCV in a
licensed multiantigen screening test and reactive in a licensed or
investigational supplemental test. This notification would enable
recipients to be informed that they had been transfused with units that
may have contained HCV so that they may obtain further medical
counseling. The March 1998 guidance provided FDA's recommendations for
donor screening, a review of past testing records, further testing for
antibody to HCV, notification of consignees, and transfusion recipient
notification and counseling by physicians regarding transfusion with
blood or blood components at increased risk of transmitting HCV. The
March 1998 guidance was intended to supplement the July 1996
memorandum.
In response to comments received, the March 1998 guidance was
withdrawn on September 8, 1998, and FDA issued a revised guidance on
October 21, 1998 (63 FR 56198, October 23, 1998) entitled ``Guidance
For Industry: Current Good Manufacturing Practice for Blood and Blood
Components: (1) Quarantine and Disposition of Units from Prior
Collections from Donors with Repeatedly Reactive Screening Tests for
Hepatitis C Virus (HCV); (2) Supplemental Testing, and the Notification
of Consignees and Blood Recipients of Donor Test Results for Antibody
to HCV (Anti-HCV),'' (the September 1998 guidance). The September 1998
guidance replaced the March 1998 guidance, and provided recommendations
to enable quarantine and disposition of blood and blood components from
prior collections from donors with repeatedly reactive screening test
results. The September 1998 guidance was provided on the CBER Home Page
for comment and implementation on September 23, 1999. Additionally, the
guidance document was mailed to all blood establishments on November
20, 1998.
The September guidance addressed several significant comments and
requests from industry: (1) FDA revised several time periods for
``lookback'' actions in response to concerns about impact on industry,
the need for additional time for testing due to availability problems
with certain test kits, and to allow time for the physician education
to be completed (ensuring that counseling messages would be available
for use in notification of recipients); (2) FDA clarified options for
further testing with an HCV enzyme linked immunosorbent assay 3.0 (HCV
EIA 3.0 screening test); (3) FDA made revisions to clarify
recommendations on labeling of products released from quarantine and
for consistency with existing regulations on product labeling; (4) FDA
provided flow chart diagrams to assist industry in implementing
procedures contained in the guidance; and (5) To permit easier, more
rapid notification of the recipient, FDA recommended the option of
transfusion services notifying the transfusion recipient directly as an
alternative to notifying the transfusion recipient's physician of
record.
At public meetings on November 24, 1998, and January 28, 1999, the
PHS Advisory Committee reconsidered the issue of recipient notification
related to repeatedly reactive results on the single antigen screening
test. The PHS Advisory Committee recommended that targeted ``lookback''
should be initiated based on a repeatedly reactive HCV EIA 1.0
screening test result on a repeat donor unless a supplemental test was
performed and the result did not indicate increased risk of HCV
infection, or, in the absence of a supplemental test result, the signal
to cut off (S/CO) value of the repeatedly reactive HCV EIA 1.0
screening test was less than 2.5, or follow-up testing of the donor was
negative. FDA published a notice in the Federal Register of June 22,
1999 (64 FR 33309), announcing the availability of a draft guidance
entitled, ``Guidance For Industry: Current Good Manufacturing Practice
for Blood and Blood Components: (1) Quarantine and Disposition of Prior
Collections from Donors with Repeatedly Reactive Screening Tests for
Hepatitis C Virus (HCV); (2) Supplemental Testing, and the Notification
of Consignees and Transfusion Recipients of Donor Test Results for
Antibody to HCV (Anti-HCV).'' Consistent with the
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recommendations of the PHS Advisory Committee, this revised draft
guidance addressed ``lookback'' actions related to donor screening by
HCV EIA 1.0 and also recommended that the search of historical testing
records of prior donations from donors with repeatedly reactive EIA
1.0, EIA 2.0, or EIA 3.0 screening tests for HCV should extend back
indefinitely to the extent that electronic or other readily retrievable
records exist. In addition, FDA revised the flow chart diagrams to
reflect the changes to the guidance. FDA added specific recommendations
for prior collections from a repeatedly reactive autologous donor and
clarified recommendations on implementing ``lookback'' for repeatedly
reactive plasma donations.
Based on comments submitted to the docket, FDA will revise the June
1999 draft guidance and issue a final guidance document for
implementation. These comments and comments submitted on any additional
guidance issued by the agency in the future will be considered in the
preparation of the final rule for HVC ``lookback.''
In addition to these recommendations, FDA is proposing in
Sec. 610.40(c) of the testing proposed rule to require ``Each donation
found to be repeatedly reactive by a screening test shall be further
tested whenever a supplemental (additional, more specific) test has
been approved for such use by FDA.''
II. Legal Authority
FDA is proposing to issue this new rule under the authority of
sections 351 and 361 of the Public Health Service Act (the PHS Act) (42
U.S.C. 262 and 264 et seq.) and the provisions of the Federal Food,
Drug, and Cosmetic Act (the act) which apply to drugs (21 U.S.C. 201 et
seq.). Under section 361 of the PHS Act, FDA may make and enforce
regulations necessary to prevent the introduction, transmission, and
spread of communicable disease between the States or from foreign
countries into the States. (See Sec. I, 1966 Reorg. Plan No. 3 at 42
U.S.C. 202 for delegation of section 361 authority from the Surgeon
General to the Secretary, Health and Human Services; see 21 CFR
510(a)(4) for delegation from the Secretary to the Food and Drug
Administration.) Intrastate transactions may also be regulated under
section 361. (See Louisiana v. Mathew, 427 F.Supp. 174, 176 (E.D.La.
1977).) A major purpose of the HCV ``lookback'' proposed rule is to
prevent the introduction, transmission, and spread of HCV.
All blood and blood components introduced or delivered for
introduction into interstate commerce also are subject to section 351
of the PHS Act (42 U.S.C. 262). Section 351(a) requires that
manufacturers must have a license which has been issued upon a showing
that the manufacturing establishment meets all applicable standards,
prescribed in the biologics regulations, designed to insure the
continued safety, purity, and potency of the blood and that the product
is safe, pure, and potent.
FDA's license revocation regulations provide for the initiation of
revocation proceedings, among other reasons, if the establishment or
the product fails to conform to the standards in the license
application or in the regulations designed to ensure the continued
safety, purity, or potency of the product (Sec. 601.5). Section 351 of
the PHS Act also provides for criminal penalties for violation of the
laws governing biologics. Violations can be punishable by fines or
imprisonment, or both.
The act also applies to biological products (42 U.S.C. 262(d), as
amended). Blood and blood components are considered drugs, as that term
is defined in section 201(g)(1) of the act (21 U.S.C. 321(g)(1)). (See
United States v. Calise, 217 F.Supp. 705 (S.D.N.Y. 1962)). Because
blood and blood components are drugs under the act, blood and plasma
establishments must comply with the substantive provisions and related
regulatory scheme of the act. Under section 501 of the act (21 U.S.C.
351), drugs are deemed ``adulterated'' if the methods used in their
manufacturing, processing, packing or holding do not conform with
current good manufacturing practices (CGMP's). Under the proposed HCV
``lookback'' rule, blood and plasma establishments would be required to
develop standard operating procedures (SOP's) for HCV ``lookback''
quarantine of affected blood and blood components and consignee and
transfusion recipient notification. A blood or plasma establishment
that failed to comply with HCV ``lookback'' procedures would violate
CGMP's and, therefore, would be subject to the act's enforcement
provisions.
III. Highlights of the Proposed Rule
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
or blood components contaminated with HCV. FDA's proposed rule, along
with HCFA's companion proposed rule 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. The consignee, as
appropriate, would inform 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
repeatedly reactive for antibody to HCV. FDA believes that this
proposed rule, in conjunction with HCFA's companion proposed rule will
provide a more efficient means of notification.
As previously discussed in section I.C of this document, chronic
hepatitis due to HCV is a major health problem in the United States
because the infection is usually clinically silent, and infected people
usually are unaware of their disease until serious damage has been
caused to the liver. Although transfusion transmitted HCV infection
accounts for only a small proportion of those infected with HCV, it is
possible to identify and quarantine affected blood and blood
components, perform further testing, and notify some transfusion
recipients who have received blood from a donor later determined to be
at increased risk of transmission of HCV. This process is commonly
referred to as ``lookback.''
FDA is issuing this proposed rule for HCV ``lookback'' as a
consequence of numerous public discussions, and extensive discussion
within DHHS, of the benefits of notifying recipients of blood at
increased risk of transmitting HCV. In parallel to this proposed rule,
there will be a major PHS educational campaign on HCV aimed at both the
medical community and the public. This proposed rule would establish
requirements, similar to those now in effect for HIV ``lookback,'' to
identify and quarantine prior collections later suspected as possible
window period donations because they were collected from a donor who
returned to donate and tested repeatedly reactive for evidence of HCV
infection, and to notify transfusion recipients based on further
testing of such a donor, as appropriate. In addition to HCV
``lookback'' requirements based on current testing that are similar to
those for HIV and that are triggered when a donor returns to donate and
tests repeatedly reactive on a screening test, this proposed rule would
require a review of historical testing records to identify prior
collections from donors at increased risk of transmitting HCV.
The review of historical testing records would extend back
indefinitely for computerized electronic records, and to January 1,
1998, for other readily retrievable records.
[[Page 69382]]
The requirements for ``lookback'' activity based on multiantigen
screening test results are handled in separate sections from those
based on single antigen screening test results because the proposed
requirements differ. For the purpose of this proposed rule, any
reference to ``blood or blood components'' will include Source
Leukocytes and Source Plasma unless specifically addressed. The
proposal would not require quarantine of products that have already
been pooled for further processing because the process of fractionation
inactivates or removes the HCV. For the purpose of this proposed rule,
any reference to blood establishments will include plasma
establishments.
FDA is also proposing conforming amendments to certain provisions
of Secs. 610.46 and 610.47, the HIV ``lookback'' regulations. The
proposed revisions to Secs. 610.46 and 610.47 are discussed under the
corresponding sections of this proposal and are intended to clarify and
provide consistency between the HIV and HCV ``lookback'' requirements.
The proposed HCV ``lookback'' regulations are particular to the
testing methodologies currently used. As testing technology continues
to develop, the ``window'' period might vary with the testing
methodology and FDA may determine that it is necessary to amend the
final rule that results from this proposal. In this section III, FDA
discusses each of the proposed requirements, the redesignation of
certain regulations and revisions to existing requirements.
A. Related Rulemaking
As previously stated, in the Federal Register of August 19, 1999
(64 FR 45340), FDA issued, as part of the Blood Initiative, a proposed
rule entitled ``Requirements for Testing Human Blood Donors for
Evidence of Infection Due to Communicable Disease Agents'' (the testing
proposed rule). In the testing proposed rule, FDA proposed to revise
the general biological product standards by adding testing requirements
for HCV, and by adding requirements for performing a licensed,
supplemental test when a donation is found to be repeatedly reactive
for any of the required screening tests for evidence of infection due
to communicable disease agents. The testing proposed rule would delete
Sec. 610.45, ``Human Immunodeficiency Virus (HIV) requirements,''
because its requirements would be included in the revision of proposed
Sec. 610.40. The use of the term ``repeatedly reactive'' in this
rulemaking is consistent with the testing proposed rule, which states
that ``according to the manufacturer's instructions, initially reactive
samples are to be tested again, generally in duplicate, and a sample
that is found to be reactive on any single retest (i.e., on one or more
of the duplicate retests), is considered to be repeatedly reactive.''
Refer to the testing proposed rule for additional discussion of
repeatedly reactive test results in section D., Further Testing. In
Sec. 610.40(a) and (c) of the testing proposed rule, FDA would revise
the requirements for performance of donor screening tests and for
supplemental testing of a donor who tests repeatedly reactive for
evidence of infection due to a communicable disease agent, including
HCV. As discussed in section III.D, this rule proposes that
Sec. 610.40(g), include the proposed requirements to initiate HCV
``lookback'' and requirements to initiate HIV ``lookback'' (currently
in Sec. 610.45(d), which would be deleted as part of the testing
proposed rule). Initiation of the ``lookback'' processes would be based
on results of HIV and HCV testing proposed in Sec. 610.40(a) and (c) of
the testing proposed rule. (Refer to section III.D of this document for
discussion of the proposed changes to Sec. 610.45(d).)
B. Proposed Revisions to Sec. 606.100(b)(19)
FDA is proposing to amend Sec. 606.100(b)(19), which currently
prescribes requirements for SOP's, in accordance with Secs. 610.46 and
610.47, to look at in-date prior collections from a donor who later
tests repeatedly reactive on a required test for HIV, or is otherwise
determined to be unsuitable when tested for HIV, and to notify
transfusion recipients. FDA is proposing to amend Sec. 606.100(b)(19)
to include requirements for blood establishments to have SOP's, in
accordance with proposed Secs. 610.48 and 610.49, for HCV ``lookback,''
including procedures for quarantine and testing, and notification of
transfusion recipients. The revised regulations would require SOP's to
look at prior collections from a donor who has donated blood and later
tests repeatedly reactive on a required test for HIV or HCV, or when
the blood establishment has been made aware of other test results
indicating evidence of HIV or HCV infection, and to notify transfusion
recipients, if appropriate.
C. Proposed Revisions to Sec. 606.160
FDA is proposing to amend Sec. 606.160. Section 606.160(b)(1)(viii)
currently prescribes requirements for maintaining records of
quarantine, notification, testing, and disposition performed under
Secs. 610.46 and 610.47, whenever a donor subsequently tests repeatedly
reactive for evidence of HIV infection. FDA is proposing to revise
Sec. 606.160(b)(1)(viii), to include requirements for maintaining
records of quarantine, notification, testing, and disposition performed
under proposed Secs. 610.48 and 610.49, whenever a donor subsequently
tests repeatedly reactive for evidence of HCV infection.
Section 606.160(d) currently prescribes that the retention period
for required processing records shall be no less than 5 years after
completion of the record or 6 months after the latest expiration date
for the individual product, whichever is a later date. FDA is proposing
to revise Sec. 606.160(d) by increasing the required retention period
to no less than 10 years after the records of processing have been
completed, or 6 months after the latest expiration date for the
individual product, whichever is a later date. FDA is proposing this
change in the retention period because advances in medical diagnosis
and therapy have created opportunities for disease prevention or
treatment many years after recipient exposure to a donor later
determined to be at increased risk of transfusion transmitted disease.
Additionally, methods of recordkeeping have advanced, improving the
ability of blood establishments to more easily maintain and retrieve
records.
D. Proposed Revisions to Sec. 610.45
As previously discussed, in the Federal Register of August 19, 1999
(64 FR 45340), FDA issued a proposed rule to revise Sec. 610.40, and to
delete Sec. 610.45, ``Human Immunodeficiency Virus (HIV)
requirements,'' because, except as discussed below, the requirements of
Sec. 610.45 would be included in proposed Sec. 610.40.
Section 610.45(d) currently requires blood establishments to comply
with Secs. 610.46 and 610.47, the HIV ``lookback'' requirements for
quarantine, consignee notification, further testing and transfusion
recipient notification, when applicable, whenever a donor's ``test
results for antibody to HIV are repeatedly reactive or otherwise
determined to be unsuitable when tested in accordance with paragraph
(a) of this section * * *.'' As previously discussed in section III.A
of this document, the testing proposed rule would delete Sec. 610.45.
This proposed rule would include the requirements of current
Sec. 610.45(d) into proposed Sec. 610.40(g). Proposed Sec. 610.40(g)
would require blood establishments to comply with Secs. 610.46 and
610.47, and with proposed Secs. 610.48 and 610.49, thereby requiring
compliance with the HIV and
[[Page 69383]]
HCV ``lookback'' regulations, respectively.
E. Proposed Revisions to Headings of Secs. 610.46 and 610.47
As a result of the addition of HCV ``lookback'' requirements, FDA
is proposing to revise the headings of the sections applicable to the
``lookback'' requirements for HIV. FDA is proposing to revise the
heading of Sec. 610.46 to read ``Human Immunodeficiency Virus (HIV)
`Lookback;' quarantine, consignee notification and further testing'' to
distinguish it from the new Sec. 610.48, ``Hepatitis C Virus (HCV)
```lookback;''' quarantine, consignee notification and further
testing.'' Likewise, FDA is proposing to amend the heading of
Sec. 610.47, ``Lookback'' Notification requirements for transfusion
services,'' to read ``Human Immunodeficiency Virus (HIV) ``Lookback;''
notification of transfusion recipients'' to distinguish it from the new
Sec. 610.49, ``Hepatitis C Virus (HCV) ``Lookback;'' notification of
transfusion recipients.'' As previously noted, FDA is proposing to
amend Sec. 610.46 for consistency with proposed Sec. 610.48 of this
proposed rule, and to amend Sec. 610.47 for consistency with
Sec. 610.49 of this proposed rule. The corresponding revisions to
Sec. 610.46 and to Sec. 610.47 are noted in the discussion of proposed
Sec. 610.48 and proposed Sec. 610.49.
F. Proposed Sec. 610.48(a), Quarantine and Consignee Notification
Proposed Sec. 610.48(a) identifies the circumstances that would
trigger the ``lookback'' process when a donor returns to donate and
tests repeatedly reactive on a screening test, and states the
requirements for quarantine of blood and blood components, notification
of consignees, and quarantine of blood and blood components by
consignees. Under proposed Sec. 610.48(a)(1), blood establishments
would be required to take appropriate action within 3-calendar days
after the date on which a donor returns to donate blood or blood
components and tests repeatedly reactive for evidence of HCV infection
on a required test, performed in accordance with proposed
Sec. 610.40(a), or the date on which the blood establishment was made
aware of other test results indicating evidence of HCV infection,
provided the testing was performed by a laboratory certified under the
Clinical Laboratory Improvement Amendments of 1988 (CLIA), using a test
approved by FDA. In the testing proposed rule (64 FR 45340, August 19,
1999) proposed Sec. 610.40(a) requires tests for specified communicable
disease agents, including for HCV, and requirements for further testing
of repeatedly reactive samples. For example, a blood establishment
completing a screening test on Tuesday afternoon with a repeatedly
reactive test result would have until the end of the day on Friday to
complete the requirements for quarantine and consignee notification.
FDA is specifically requesting comments on the appropriateness of 3
calendar days proposed for exemptions of the quarantine of prior
collections and consignee notification under proposed Secs. 10.48(a),
(e), and (f) and the conforming amendment to 610.46(a). FDA is also
proposing that the ``lookback'' measures specified in Sec. 610.48(a) be
initiated by a blood establishment upon receipt of information that a
person who has been a donor at that establishment has other test
results indicating evidence of HCV infection and that the test was
performed by a CLIA-certified laboratory, using a test approved by FDA,
regardless of the purpose of the testing. FDA recognizes that blood
establishments do not routinely receive such information, but should a
blood establishment become aware of such reliable test results, the
proposal would require appropriate ``lookback'' measures. State laws
and public health practices vary widely, making it impossible to
specify all circumstances under which test results may be provided to
the blood establishment. However, FDA believes that the blood
establishment has the obligation, upon the receipt of such reliable
test results, to initiate appropriate action to protect the blood and
plasma supply. In addition, the reliability of test results may vary,
depending on the quality of the test method used and on the
qualifications of the testing facility to perform the test.
Accordingly, FDA is proposing to require the initiation of ``lookback''
procedures when the test results originate from a laboratory certified
under CLIA and when the laboratory has used FDA-approved tests.
Proposed Sec. 610.48(a) would require blood establishments and
their consignees to identify and quarantine all affected blood and
blood components collected prior to the donor's repeatedly reactive
screening test for HCV. Under proposed Sec. 606.160(d), blood
establishments would retain records for ``* * * no less than 10 years *
* *'' or, for products that remain in inventory, for 6 months after the
latest expiration date of the product, whichever is the later date, and
under proposed Sec. 610.48(a) blood establishments would quarantine any
in-date prior collections that remain in inventory. If the blood
establishment has information to assure that there are no in-date prior
collections, there is no need to trace those products.
Proposed Sec. 610.48(a)(1)(i) would require blood establishments to
quarantine all in-date prior collections from a donor testing
repeatedly reactive for evidence of HCV infection. Proposed
Sec. 610.48(a)(1)(ii) would require blood establishments to notify
consignees of the repeatedly reactive HCV screening test result so that
the consignee may quarantine all in-date prior collections of blood and
blood components. Proposed Sec. 610.48(a)(2) would require consignees
to quarantine all in-date prior collections of blood and blood
components that remain in inventory.
For consistency, FDA is also proposing conforming amendments to the
corresponding HIV ``lookback'' requirements of Sec. 610.46(a). FDA is
proposing to amend Sec. 610.46(a) by changing the title of the
paragraph to ``Quarantine and consignee notification'' and to clarify
that blood establishments would be required to complete the quarantine
and consignee notification requirements within 3-calendar days after
the date on which the donor tests repeatedly reactive for evidence of
HIV infection. FDA is proposing to replace the phrase ``or otherwise
determined to be unsuitable when tested in accordance with
Sec. 610.45'' with ``or when the blood establishment has been made
aware of other test results indicating evidence of HIV infection,
provided the testing was performed by a laboratory certified under the
Clinical Laboratory Improvement Amendments of 1988, using a test
approved by FDA'' to eliminate any confusion that might be caused by
different wording. Likewise, for clarity and consistency, FDA is
proposing to replace ``For Whole Blood, blood components, Source Plasma
and Source Leukocytes collected from that donor within the 5 years
prior to the repeatedly reactive test, if intended for transfusion, or
collected within the 6 months prior to the repeatedly reactive test, if
intended for further manufacture into injectable products, * * *.''
with ``For in-date blood and blood components collected from that donor
at any time prior to the repeatedly reactive test, whenever records are
available, if intended for transfusion or for further manufacture into
injectable products, * * *.'' Also, FDA recognizes that it is not
necessary for ``lookback'' requirements to distinguish collections
intended for transfusion from those intended for further manufacturing.
FDA is clarifying that ``lookback'' requirements should be followed for
any
[[Page 69384]]
prior collection that has not expired because records are held for 6
months after the latest expiration date of the individual product.
G. Proposed Sec. 610.48(b), Further Testing and Consignee Notification
of Results
Proposed Sec. 610.48(b) would require further testing whenever a
donor returns to donate and tests repeatedly reactive for evidence of
HCV infection, as described in Sec. 610.48(a), and notification of
consignees of the results of the further testing. Proposed
Sec. 610.48(b) would require blood establishments to perform further
testing, in accordance with proposed Sec. 610.40(c) of the testing
proposed rule (as previously discussed), after a donor with a record of
prior collections tests repeatedly reactive for evidence of HCV
infection when tested in accordance with proposed Sec. 610.40(a) of the
testing proposed rule. Blood establishments would be required to notify
consignees of the results of the further testing within 45-calendar
days after the day on which the donor tests repeatedly reactive on a
screening test for evidence of HCV infection.
FDA is proposing a conforming amendment to Sec. 610.46(b) for HIV
``lookback'' by changing the maximum time provided for a blood
establishment to notify consignees of the results of the further
testing from 30 to 45 days. This change is proposed for consistency
between the HIV and HCV ``lookback'' regulations and in response to
comments that although further testing for HIV and HCV can be completed
within 30 days, additional time is needed to notify consignees
following completion of the further testing.
H. Proposed Sec. 610.48(c), Review of Historical Testing Records and
Identification of Donors Tested Using a Multiantigen Screening Test
Prior to the Effective Date of this Regulation
As discussed in section I.C of this document in this preamble,
blood establishments routinely have been testing blood donations for
antibody to HCV since 1990. In the guidance documents issued in March
1998, September 1998 and June 1999, FDA issued recommendations (draft
guidance was issued in June 1999) for blood establishments to initiate
``lookback'' procedures consistent with those now being proposed,
including when, through a review of historical testing records,
previous instances are identified when a donor had tested repeatedly
reactive on a multiantigen screening test for evidence of HCV
infection. FDA believes that since 1990, many blood establishments have
routinely initiated ``lookback'' procedures consistent with the
regulations now being proposed, and with the issuance of the
recommendations in 1998 and 1999, many additional establishments have
undertaken the review of historical testing records and have initiated
appropriate ``lookback'' procedures. However, because HCV is a chronic,
often asymptomatic disease that may ultimately have serious
consequences, FDA believes that it is imperative to identify and notify
recipients who have been transfused with blood or blood components for
which there is an increased risk of transmission of HCV as determined
by subsequent donor testing. Such transfusion recipients should be made
aware that they should seek further testing to see if they are infected
and, if so, to receive appropriate counseling and medical care.
The requirements of proposed Sec. 610.48(c) and (d) are based on
the agency's understanding of current research in hepatitis testing.
FDA specifically invites comments on these provisions and requests
individuals to submit data in support of the comments. To the extent
the data do not support these provisions, FDA would revise the rule
accordingly. FDA recognizes that the review of historical testing
records (performed in accordance with proposed Sec. 610.48(c) and (d))
will identify tests performed using both licensed and unlicensed tests,
HCV EIA 1.0, 2.0, and 3.0, as well as, HCV RIBA 2.0 and 3.0
supplemental tests. For that reason, the proposed requirements for
testing performed prior to the effective date of any final rule
resulting from this proposal (that is, test results identified in the
review of historical testing records) would take into account the use
of unlicensed tests, under specific circumstances. In addition, testing
performed following the effective date of any final rule resulting from
this proposal (such as further testing performed in accordance with
proposed Sec. 610.48(h) or (i)) would require use of a currently
licensed test, as specified.
The purpose of Sec. 610.48(c) is to identify, through a search of
available historical testing records, those prior collections that
might have been collected during the window period, that is, a donation
that may have been made after the donor became infected with HCV but
before it was possible for a screening test to detect antibody to HCV.
The identification of prior collections would be based on the
multiantigen screening test result and would be followed by appropriate
steps to perform quarantine, further testing and notification of
consignees and transfusion recipients, as discussed in detail in this
and other sections of this proposed rule. Blood establishments would be
required to perform a review of historical testing records to identify,
within 1 year of the effective date of any final rule resulting from
this proposal, prior collections at increased risk of transmitting HCV
infection because they are from a donor who later tested repeatedly
reactive for evidence of HCV infection on a multiantigen screening test
and who either: (1) Has no record of further testing for HCV performed
on the repeatedly reactive sample and no record of a negative licensed,
multiantigen screening test performed at a later date (as specified in
Sec. 610.48(c)(4) and (c)(5); or (2) has a record of further testing
(as specified in Sec. 610.48(c)(1), (c)(2), and (c)(3)) that
potentially indicates evidence of HCV infection, as discussed in detail
later in this proposed rule. As discussed in the following paragraph,
after the review of historical testing records, ``lookback'' actions
would be triggered for certain prior collections. Blood establishments
would be required to quarantine any in-date prior collections still in
inventory where records show that they were collected from donors later
found to have a repeatedly reactive multiantigen screening test for
evidence of HCV infection (unless exempt from quarantine under
Sec. 610.48(g)(2)), and to notify consignees to quarantine such prior
collections, as specified under proposed Sec. 610.48(e)(2); to perform
further testing, as specified in proposed Sec. 610.48(h)(1), on donors
identified in accordance with proposed Sec. 610.48(c)(4) and (c)(5); or
optionally to perform further testing in accordance with
Sec. 610.48(h)(2) on donors identified in accordance with
Sec. 610.48(c)(2) and (c)(3); and to notify consignees of the test
result, in accordance with proposed Sec. 610.48(h)(3), as described in
the following paragraph. Transfusion services notified by blood
establishments of prior receipt of blood or blood components at
increased risk of transmitting HCV would either notify the transfusion
recipients directly or notify the recipient's physician of record
(i.e., physician of record or physician who ordered the blood or blood
component), as specified in proposed Sec. 610.49(b).
Under proposed Sec. 610.48(c), the review would include records, if
available, dating back indefinitely for computerized electronic
records, and to January 1988 for other readily retrievable records, or
12 months prior to the donor's most recent negative
[[Page 69385]]
multiantigen screening test for antibody to HCV, whichever is the
lesser period. This 12-month time period requirement is intended to
identify any potential ``window period'' donation. Review of historical
testing records dating back indefinitely would not be necessary for
prior collections from many donors (i.e., prior collections from donors
who have a record of a prior negative multiantigen screening test
result because the prior collections would not be considered to be
window period donations.) Examples are provided in the following
paragraph. In addition, many donors who test repeatedly reactive for
evidence of HCV infection are first-time donors with no previous
history of donation. Thus, no ``lookback'' action is needed for such a
first-time donor because ``lookback'' activity targets prior
collections and no prior collections exist for a first time donor.
Proposed Sec. 610.48(c) would limit the review of records to the
identification of prior collections dating back to ``the date 12 months
prior to the donor's most recent negative multiantigen screening test
for HCV.'' FDA believes that this 12-month period prior to the last
negative multiantigen screening test for HCV establishes with high
confidence that, prior to that date, possible HCV infection would have
been detected by a screening test; if any ``window period'' donation
was collected, it would have occurred after that date. For example, it
would not be necessary to identify collections dating back indefinitely
for a donor who has donated every 6 months from January 1983 until
testing repeatedly reactive on a screening test for evidence of HCV
infection in January 1998, with the last negative multiantigen
screening test on July 1, 1997. In this example, the last negative
multiantigen screening test for antibody to HCV is July 1, 1997, and 12
months prior to that would be July 2, 1996. Under the proposal, the
blood establishment would use the later date of July 2, 1996 (rather
than the maximum time period back to January 1983), and the blood
establishment would identify donations made on or after July 2, 1996,
to July 1, 1997, as possible ``window period'' donations. In this
example, donations made prior to July 2, 1996, would not be suspected
to be ``window period'' donations, capable of transmitting HCV
infection to a transfusion recipient. Note that a negative test result
on a single antigen EIA screening test for HCV may not be used as the
``most recent negative multiantigen screening test'' and is not a basis
to limit the ``lookback'' activity, as described previously, due to the
limited sensitivity of the single antigen HCV EIA test.
FDA is proposing the review of historical testing records to
identify five specific instances following a repeatedly reactive
multiantigen screening test that should be used to identify increased
risk of transmitting HCV from the donor's prior collections. Under
Sec. 610.48(c), blood establishments would identify prior collections
from donors who tested repeatedly reactive for evidence of HCV
infection on a licensed, multiantigen screening test and who: (1)
Tested positive on a supplemental test for HCV performed on the
repeatedly reactive sample (as specified in Sec. 610.48(c)(1)); or
(c)(2) tested indeterminate on a supplemental test for HCV (as
specified in Sec. 610.48(c)(2)); or (c)(3) testing repeatedly reactive
on licensed HCV EIA 3.0 screening test and negative on a licensed HCV
RIBA 2.0 supplemental test but with no records of a negative licensed
HCV RIBA 3.0 supplemental test performed on the repeatedly reactive
sample or a later sample from the same donor; or (4) tested repeatedly
reactive for evidence of HCV infection on an HCV EIA 2.0 screening test
with no record of a supplemental test for HCV performed on the
repeatedly reactive sample or on a later sample from the donor and no
record of a negative licensed HCV EIA 3.0 screening test performed on
the repeatedly reactive sample or later on the same donor; or (5)
tested repeatedly reactive for evidence of HCV infection on a licensed,
HCV EIA 3.0 screening test with no record of a supplemental test for
HCV performed on the repeatedly reactive sample or on a later sample
from the same donor. As discussed previously, the requirements of
proposed Sec. 610.48(c) for review of historical testing records to
identify prior collections from affected donors are particular to the
testing methods used and exceptions are specified in Sec. 610.48(g),
Exemption from Quarantine. Prior collections that would not be
identified as possible ``window period'' donations and would not
require further action are exempted from quarantine as described in
Sec. 610.48(g)(2). For donors identified in accordance with
Sec. 610.48(c)(4) and (c)(5) for whom no records of further testing
exist to clarify the status of prior collections determined to be at
increased risk of transmitting HCV infection, blood establishments
would be required, as described under proposed Sec. 610.48(e), to
perform quarantine and consignee notification for any in-date prior
collections that remain in inventory and to perform further testing, as
described under proposed Sec. 610.48(h)(1).
I. Proposed Sec. 610.48(d), Review of Records and Identification of
Donors Testing Repeatedly Reactive on a Single Antigen Screening Test
Prior to the Effective Date of this Regulation
The purpose of Sec. 610.48(d), which parallels the requirements of
Sec. 610.48(c), is to identify, through a review of historical testing
records, those prior collections that might have been collected during
the window period of HCV infection, based on a single antigen screening
test result. Similar to the requirements of Sec. 610.48(c), which is
based on the multiantigen screening test, proposed Sec. 610.48(d)
would: (1) Require blood establishments to review available historical
records of donor testing that occurred prior to the effective date of
this regulation to identify prior collections that are potential window
period donations; (2) require the review of available historical
testing records dating back indefinitely for computerized electronic
records and to January 1988 for other readily retrievable records; and
(3) require that blood establishments complete the review or historical
testing records within 1 year of the effective date of any final rule
that results from this proposal.
Under Sec. 610.48(d), blood establishments would identify
previously distributed blood and blood components in any of the
following four instances: (1) As proposed in Sec. 610.48(d)(1), where
the donor tested repeatedly reactive for evidence of HCV infection on
the single antigen screening test and repeatedly reactive on an HCV EIA
2.0 or HCV EIA 3.0 screening test for HCV performed on the repeatedly
reactive sample or a fresh sample from the same donor; (2) as proposed
in Sec. 610.48(d)(2), where the donor tested repeatedly reactive for
evidence of HCV infection on the single antigen screening test and
either positive or indeterminate on an HCV 2.0 or HCV 3.0 strip
immunoblot assay (HCV RIBA 2.0 or HCV RIBA 3.0 supplemental test,
respectively) supplemental test for HCV; or (3) as proposed in
Sec. 610.48(d)(3), where the donor tested repeatedly reactive for
evidence of HCV infection on an HCV EIA 1.0 screening test, with a
signal to cut off (S/CO) value less than 2.5 for at least two out of
the three EIA tests (i.e., the initial EIA screening test and the
duplicate retests) with no record of a supplemental test or
multiantigen screening test for HCV performed on the repeatedly
reactive sample or on a later sample from the same donor ; or (4) as
proposed in Sec. 610.48(d)(4), where the donor tested repeatedly
reactive for
[[Page 69386]]
evidence of HCV infection on an HCV EIA 1.0 screening test, with a S/CO
value equal to or greater than 2.5 for at least two out of the three
EIA tests or with no determination of S/CO value for all three EIA
tests, and with no record of a supplemental test or multiantigen
screening test for HCV performed on the repeatedly reactive sample or
on a later sample from the same donor. (The S/CO value for each test
result is calculated as the ratio of the absorbency value obtained for
the donor sample divided by the absorbency value for the cutoff in that
assay run.)
As previously discussed in section I.C of this document, the PHS
Advisory Committee met on January 28, 1999, to consider options for
expanding the targeted HCV ``lookback'' program to include recipients
of blood from donors subsequently identified as repeatedly reactive by
the single antigen HCV EIA 1.0 screening test. Approximately 80 percent
of the HCV EIA 1.0 repeatedly reactive donations were identified before
the first confirmatory test became available. The PHS Advisory
Committee concluded that it would be reasonable to limit the
``lookback'' for EIA 1.0 based on the S/CO value of the screening tests
in cases where supplemental testing had not been done and further
testing of the original repeatedly reactive sample or a later sample
from the same donor was impractical. The PHS Advisory Committee
concluded that it would be appropriate to perform HCV ``lookback'' on a
subset of the donors testing repeatedly reactive on EIA 1.0 screening
tests to capture the vast majority of the true positives and minimize
the unnecessary false recipient notifications. The requirements
proposed in Sec. 610.48(d) and (i) reflect the PHS Advisory Committee's
recommendations for use of the S/CO value based on a critical ratio of
2.5 in evaluating risk of HCV transmission under ``lookback''
circumstances identified in the review of historical testing records.
As discussed previously, the requirements of proposed
Sec. 610.48(d) for review of historical testing records to identify
prior collections from affected donors are particular to the testing
methods used and exceptions are specified in Sec. 610.48(g), Exemption
from quarantine. Prior collections that would not be identified as
possible ``window period'' donations and would not require further
action are exempted from quarantine as described in Sec. 610.48(g)(3).
J. Proposed Sec. 610.48(e), Quarantine and Consignee Notification
Following the Review of Historical Testing Records Based on Screening
Performed Using a Multiantigen Screening Test
The purpose of proposed Sec. 610.48(e) is to require quarantine of
prior collections that were identified in the review of historical
testing records, based on a multiantigen screening test in accordance
with proposed Sec. 610.48(c), until further testing is completed, if
necessary, and the blood establishment can make a determination to
release the prior collections from quarantine (under proposed
Sec. 610.48(j)(2)), or to destroy or relabel them (under proposed
Sec. 610.48(k)). Proposed Sec. 610.48(e) would require blood
establishments to quarantine certain prior collections until further
testing is completed to clarify the status of the prior collections,
and to notify consignees so that prior collections they hold can be
quarantined. This requirement is intended to prevent the transfusion of
a prior collection from a donor identified in the review of records as
being at increased risk of transmitting HCV infection while further
testing is performed.
Proposed Sec. 610.48(e)(1) would require blood establishments to
quarantine in-date prior collections of blood and blood components
collected from donors identified in the review of records, under
proposed Sec. 610.48(c), while further testing is performed, as
required in proposed Sec. 610.48(h)(1) or as optional testing is
performed in accordance with Sec. 610.48(h)(2).
As previously mentioned, some exceptions to quarantine are
specified in proposed Sec. 610.48(g)(2). Prior collections that meet
the criteria under proposed Sec. 610.48(g)(2) would not be suspected as
``window period'' donations and would be exempt from quarantine, as
discussed in following sections. If no exemption to quarantine applies,
blood establishments would be required to perform quarantine within 3
days of the date on which the establishment identifies a donor's
repeatedly reactive multiantigen screening test. All identification
performed in accordance with Sec. 610.48(c) and the resulting
quarantine and notification must be completed within a maximum of 1
year from the effective date of any final rule resulting from this
proposal.
Proposed Sec. 610.48(e)(2) would require blood establishments,
within 3-calendar days of the date on which the donor's repeatedly
reactive multiantigen screening test is identified, to notify
consignees of the donor's test results, including supplemental test
results, if available, so that consignees may quarantine all in-date
prior collections of blood and blood components subject to quarantine
under proposed Sec. 610.48(e)(1). FDA is specifically requesting
comments on the appropriateness of the 1-year timeframe to complete all
quarantine and notification.
K. Proposed Sec. 610.48(f), Quarantine and Consignee Notification
Following the Review of Records Based on Screening Performed Using a
Single Antigen Screening Test
The purpose of Sec. 610.48(f), which parallels the requirements of
Sec. 610.48(e), is to require quarantine of prior collections that were
identified in the review of historical testing records based on single
antigen testing, in accordance with proposed Sec. 610.48(d), until
further testing is completed, if necessary, and a determination can be
made to release the prior collections from quarantine (under proposed
Sec. 610.48(j)(3)), or to destroy or relabel them (under proposed
Sec. 610.48(k)). Proposed Sec. 610.48(f) would require blood
establishments to quarantine certain prior collections until further
testing is completed to clarify the status of the prior collections,
and to notify consignees so that prior collections they hold can be
quarantined. This requirement is intended to prevent the transfusion of
a prior collection from a donor identified in the review of records as
being at increased risk of transmitting HCV infection while further
testing is performed.
Proposed Sec. 610.48(f)(1) would require blood establishments to
quarantine in-date prior collections of blood and blood components from
donors identified in the review of historical testing records, under
proposed Sec. 610.48(d), while further testing is performed, as
required in proposed Sec. 610.48(i)(1) or as optional testing is
performed in accordance with Sec. 610.48(i)(2).
Under this proposal, blood establishments would be required to
perform quarantine within 3 calendar days of the date on which the
blood establishment identifies a donor's repeatedly reactive single
antigen screening test. All identification performed in accordance with
Sec. 610.48(d) and the resulting quarantine and notification must be
completed within a maximum of 1 year from the effective date of any
final rule resulting from this proposal. As previously mentioned, some
exceptions to quarantine are specified in proposed Sec. 610.48(g)(3).
Prior collections that
[[Page 69387]]
meet the criteria under proposed Sec. 610.48(g)(3) would not be
suspected as ``window period'' donations and would, therefore, be
exempt from quarantine, as discussed in following sections.
Proposed Sec. 610.48(f)(2) would require blood establishments,
within 3-calendar days of the date on which the donor's repeatedly
reactive single antigen screening test is identified, to notify
consignees of the donor's test results, including supplemental test
results, if available, so that consignees may quarantine all in-date
prior collections of blood and blood components subject to quarantine
under proposed Sec. 610.48(f)(1). FDA is specifically requesting
comments on the appropriateness of 3-calendar days proposed for
completion of the quarantine of prior collections and consignee
notification under Sec. 610.48(f) and the appropriateness of the 1-year
timeframe to complete all quarantine and notification.
Proposed Sec. 610.48(f)(3) would require consignees notified in
accordance with proposed Sec. 610.48(f)(2) to quarantine all prior
collections of blood and blood components subject to quarantine under
proposed Sec. 610.48(f)(1), except as provided in proposed
Sec. 610.48(g)(3).
L. Proposed Sec. 610.48(g), Exemption From Quarantine
Proposed Sec. 610.48(g) specifies which prior collections are not
suspected as being window period donations and, therefore, are not
subject to quarantine under proposed Sec. 610.48(a), (e), and (f).
Proposed Sec. 610.48(g)(1) would exempt from quarantine certain prior
collections otherwise subject to quarantine under proposed
Sec. 610.48(a) when a donor tests repeatedly reactive on a multiantigen
screening test for evidence of HCV infection. Proposed
Sec. 610.48(g)(1)(i) is intended to identify certain donations that are
not suspected of being collected during the ``window period'' because
they were collected prior to the time a possible window period could
have existed, and would not be subject to quarantine under proposed
Sec. 610.48(a). Under proposed Sec. 610.48(g)(1)(i), for donations
collected more than 12 months prior to the donor's most recent negative
multiantigen screening test, a high confidence level exists that no
infection could have existed at the time of donation and remain
undetected by a screening test, and, therefore, blood establishments
would not be required to quarantine blood or blood components
``collected more than 12 months prior to the donor's most recent
negative multiantigen screening test when tested for HCV in accordance
with Sec. 610.40(a). An explanation of ``window period'' donations and
a corresponding example are provided previously in the description of
proposed Sec. 610.48(c).
In addition, proposed Sec. 610.48(g)(1)(ii) would provide that when
an appropriate licensed supplemental test for HCV (discussed in this
section III.L) is found to be negative and is completed within the 3-
day time period provided for completion of quarantine and consignee
notification, quarantining of prior collections of blood and blood
components from that donor would not be required. Thus, if the
supplemental test is found negative within 3-calendar days after the
date on which the donor tested repeatedly reactive for evidence of HCV
infection (the time provided for completion of quarantine and consignee
notification), then the repeatedly reactive screening test result would
be interpreted as a ``false positive,'' would not indicate HCV
infection, and prior collections from that donor would not be
considered to be at increased risk of transmitting HCV. If, however,
the supplemental testing is completed more than 3 days after the date
of the repeatedly reactive screening test result (the time provided for
completion of quarantine and consignee notification), the blood and
blood components would be quarantined but could then be released from
quarantine if the supplemental test is negative, as provided in
proposed Sec. 610.48(j).
As specified in proposed Sec. 610.48(g), the supplemental test must
be appropriately chosen, i.e., the appropriately chosen supplemental
test should contain all the antigens of the screening test that was
performed. Under proposed Sec. 610.48(g)(1)(ii), if the repeatedly
reactive screening test was obtained using an HCV EIA 2.0 screening
test, then an appropriate supplemental test would be either an HCV RIBA
2.0 or an HCV RIBA 3.0. However, if the repeatedly reactive screening
test result was obtained using an HCV EIA 3.0 screening test, then the
appropriate supplemental test would be an HCV RIBA 3.0. The HCV RIBA
2.0 supplemental test would not be an appropriately chosen supplemental
test following an HCV EIA 3.0 screening test because the HCV RIBA 2.0
supplemental test does not include all antigens contained in the HCV
EIA 3.0 screening test.
Proposed Sec. 610.48(g)(2) provides for exceptions from quarantine
performed in accordance with proposed Sec. 610.48(e) following the
review of historical testing records based on screening performed using
a multiantigen screening test. Similar to the provisions of proposed
Sec. 610.48(g)(1), proposed Sec. 610.48(g)(2) is intended to exempt
from quarantine those prior collections that are not suspected as being
collected during the ``window period.'' Under proposed
Sec. 610.48(g)(2), prior collections of blood and blood components
would not be subject to quarantine under proposed Sec. 610.48(e) if
they meet any of the following criteria: (1) The prior collection was
donated more than 12 months prior to the donor's most recent negative
multiantigen screening test for evidence of HCV infection that preceded
the repeatedly reactive screening test; or (2) records show that the
repeatedly reactive screening test result was obtained using an HCV EIA
2.0 screening test, and either the original sample or a later sample
from the same donor was tested and found negative using an HCV RIBA
2.0, or an HCV RIBA 3.0 supplemental test or an HCV EIA 3.0 screening
test. (As previously discussed, a negative test result on a single
antigen EIA screening test for HCV may not be used as the ``most recent
negative multiantigen screening test'' and is not a basis to limit the
``lookback'' activity, as described previously, due to the limited
sensitivity of the HCV EIA 1.0 screening test); or (3) records show
that the repeatedly reactive screening test result was obtained using
an HCV EIA 3.0 screening test, and either the original sample or a
later sample from the same donor was tested and found negative using an
HCV RIBA 3.0 supplemental test.
Proposed Sec. 610.48(g)(3) provides for exceptions from quarantine
(performed in accordance with proposed Sec. 610.48(f)) following the
review of records based on screening performed using a single antigen
screening test. Similar to the provisions of proposed Sec. 610.48(g)(1)
and (g)(2), proposed Sec. 610.48(g)(3) is intended to exempt from
quarantine those prior collections that are not suspected as being
collected during the ``window period.'' Under proposed
Sec. 610.48(g)(3), prior collections of blood and blood components
would not be subject to quarantine under proposed Sec. 610.48(f) if
they meet any of the following four criteria: (1) Records show that the
repeatedly reactive screening test result was obtained using an HCV EIA
1.0 screening test, and either the original sample or a later sample
from the same donor was tested and found negative using an HCV EIA 2.0
or an HCV EIA 3.0 screening test (exempted under proposed
Sec. 610.48(g)(3)(i)); or (2) records show that the repeatedly reactive
screening test result was obtained using an HCV EIA 1.0
[[Page 69388]]
screening test, and either the original sample or a later sample from
the same donor was tested and found negative using a HCV RIBA 2.0 or a
HCV RIBA 3.0 supplemental test (exempted under proposed
Sec. 610.48(g)(3)(ii)); or (3) the donor identified in accordance with
proposed Sec. 610.48(d)(1), as testing repeatedly reactive on an HCV
EIA 2.0 or 3.0 screening test, was further tested using an HCV RIBA 2.0
or HCV RIBA 3.0 supplemental test, using a fresh sample, or frozen
sample from the repeatedly reactive donation and the result was
negative (exempted under Sec. 610.48(g)(3)(iii)); or (4) the donor
identified in accordance with proposed Sec. 610.48(d)(2), as testing
indeterminate on an HCV RIBA 2.0 supplemental test, was further tested
using either an HCV EIA 3.0 or a HCV RIBA 3.0 supplemental test using a
fresh sample, or frozen sample from the repeatedly reactive donation
and the result was negative (exempted under proposed
Sec. 610.48(g)(3)(iv)).
FDA is also proposing a conforming amendment to Sec. 610.46(c),
which specifies requirements for exemption from quarantine for HIV
``lookback,'' for consistency with the HCV ``lookback'' requirements by
changing ``Whole Blood, blood components, Source Plasma and Source
Leukocytes'' to ``blood and blood components.''
M. Proposed Sec. 610.48(h), Further Testing Following Review of
Historical Testing Records and Consignee Notification Based on
Screening Performed Using a Multiantigen Screening Test
Proposed Sec. 610.48(h) is intended to require that prior
collections identified in accordance with Sec. 610.48(c)(4) and (c)(5),
based on multiantigen screening test results, either be further tested
and consignees notified so that blood establishments can determine if
the prior collection should be released from quarantine (under
Sec. 610.48(j)), or destroyed or relabeled (under Sec. 610.48(k)), and
if notification of transfusion recipients is necessary (under
Sec. 610.49(a)). In addition, blood establishments would have the
option to perform further testing for prior collections identified in
accordance with Sec. 610.48(c)(2) and (c)(3). Proposed
Sec. 610.48(h)(1) would require blood establishments, by 1 year from
the effective date of any final rule resulting from this proposal, to
perform further testing to clarify the status of prior collections
collected from a donor identified, in accordance with Sec. 610.48(c)(4)
and (c)(5), as being at increased risk of transmitting HCV. Proposed
Sec. 610.48(h)(1) would require that further testing be performed as
follows: (1) As proposed in Sec. 610.48(h)(1)(i)(A), if the repeatedly
reactive test result was obtained using a licensed HCV EIA 2.0
screening test, blood establishments would perform a licensed
supplemental test for HCV on a frozen sample from the repeatedly
reactive donation, if it is available. If such a frozen sample is not
available, blood establishments would obtain a fresh sample from the
donor and perform a licensed supplemental test for HCV; or
alternatively, (2) as proposed in Sec. 610.48(h)(1)(i)(B), if the
repeatedly reactive test result was obtained using a licensed HCV EIA
2.0 screening test, blood establishments would perform a licensed HCV
EIA 3.0 screening test on a frozen sample, if it is available. If such
a frozen sample is not available, blood establishments would obtain a
fresh sample from the donor and perform a licensed HCV EIA 3.0
screening test and a licensed supplemental test if the HCV EIA 3.0
screening test is repeatedly reactive; or (3) as proposed in
Sec. 610.48(h)(1)(ii), if the repeatedly reactive test result was
obtained using a licensed HCV EIA 3.0 screening test, blood
establishments would perform a licensed supplemental test for HCV on a
frozen sample, if available. If such a frozen sample is not available,
blood establishments would obtain a fresh sample from the donor and
perform a licensed supplemental test for HCV; or (4) as proposed in
Sec. 610.48(h)(1)(iii), blood establishments would make a determination
that neither a frozen sample from the repeatedly reactive donation nor
a fresh sample from the donor is available for further testing. For
example, the blood establishment might make a determination that
additional testing is not possible because the sample was not stored
properly, or the donor could not be located or the donor declined
further testing.
Under proposed Sec. 610.48(h)(2), blood establishments would have
the option to perform further testing on prior collections identified
in accordance with Sec. 610.48(c)(2) and (c)(3). This provision would
make it possible to clarify the status of the prior collections and, in
some instances, based on further testing, it might not be necessary to
destroy the prior collections or notify transfusion recipients. Under
proposed Sec. 610.48(h)(2), blood establishments that have performed
the review of records and identified prior collections in accordance
with proposed Sec. 610.48(c)(2) or (c)(3) of this section may further
test a frozen sample from the repeatedly reactive donations or a fresh
sample from the same donor by 1 year from the effective date of any
final rule resulting from this proposal, as follows: (1) As proposed in
Sec. 610.48(h)(2)(i), if the donor was identified in accordance with
proposed Sec. 610.48(c)(2) of this section as testing repeatedly
reactive using an HCV EIA 2.0 screening test, and indeterminate on a
HCV RIBA 2.0 supplemental test, blood establishments have the option to
perform further testing using either an HCV EIA 3.0 screening test or a
currently available licensed supplemental test for HCV; or (2) as
proposed in Sec. 610.48(h)(2)(ii), if the donor was identified in
accordance with proposed Sec. 610.48 (c)(2) of this section as testing
repeatedly reactive using an HCV EIA 2.0 screening test, indeterminate
on a HCV RIBA 2.0 supplemental test, and repeatedly reactive on an HCV
EIA 3.0 screening test, blood establishments have the option to perform
further testing using an appropriately chosen licensed supplemental
test for HCV (refer to section L of this document that discusses
proposed Sec. 610.48(g) for more information regarding use of ``an
appropriately chosen supplemental test''); or (3) as proposed in
Sec. 610.48(h)(2)(iii), if the donor was identified in accordance with
(c)(2) of this section as testing repeatedly reactive using an HCV EIA
3.0 screening test, and indeterminate on a HCV RIBA 2.0 supplemental
test, blood establishments have the option to perform further testing
using an appropriately chosen licensed supplemental test for HCV; or
(4) as proposed in Sec. 610.48(h)(2)(iv), if the donor was identified
in accordance with proposed Sec. 610.48 (c)(3) of this section as
testing repeatedly reactive using an HCV EIA 3.0 screening test, and
negative on a HCV RIBA 2.0 supplemental test, blood establishments have
the option to perform further testing using an appropriately chosen
licensed supplemental test for HCV. Based on the results of the further
testing, the blood establishment can make a decision regarding the next
appropriate step under proposed Sec. 610.48(j), to release from
quarantine, or under proposed Sec. 610.48(k), to destroy or
appropriately label prior collections, or under proposed
Sec. 610.49(a), to notify any transfusion recipients.
Under proposed Sec. 610.48(h)(3), blood establishments would be
required to notify consignees of the results of the additional testing,
performed in accordance with proposed Sec. 610.48(h)(1) or (h)(2), upon
completing the additional testing and prior to 1 year from the
effective date of any final rule resulting from this proposal. Blood
[[Page 69389]]
establishments would be required to notify the consignee of any risk of
HCV transmission that exists for such prior collections, based on the
results of the additional testing. If the prior collection was from a
donor identified in the review of historical testing records in
accordance with proposed Sec. 610.48(c)(1) through (c)(5), and no
additional testing was performed, or if no sample was available for
further testing, as provided in proposed Sec. 610.48(h)(1)(iii), the
blood establishment would be required, within 1 year from the effective
date of a final rule that results from this proposal, to notify
consignees of any risk of HCV transmission for such prior collections.
The review of historical testing records identifies those donors
whose test results indicate some degree of risk of HCV transmission for
prior collections. If the testing records do not include supplemental
testing, further testing of the original repeatedly reactive sample or
a fresh sample from the donor is needed. The purpose of further testing
is to provide the opportunity for blood establishments to evaluate the
test results and determine the next appropriate step in the
``lookback'' process. Blood establishments must consider several
significant issues when evaluating HCV screening and supplemental
tests. Prior collections from donors who subsequently test positive or
indeterminate on a supplemental test for HCV (except donors testing
indeterminate on a RIBA 3.0 supplemental test as described below), are
at increased risk of transmitting HCV. Prior collections from such
donors would be destroyed or relabeled as proposed in Sec. 610.48(k),
or, if transfused, would trigger notification of recipients because of
the increased risk of transmission of HCV infection.
However, in the case of a donor whose screening test was repeatedly
reactive by HCV EIA 2.0, if an indeterminate RIBA 2.0 supplemental test
result is followed by a negative result on an HCV EIA 3.0 screening
test or an HCV RIBA 3.0 supplemental test, prior collections may be
released from quarantine, as proposed in Sec. 610.48(j), and
transfusion recipients need not be notified. This release from
quarantine is based on current research that indicates absence of
polymerase chain reaction (PCR) reactivity for HCV RNA in HCV RIBA 2.0
indeterminate/HCV EIA 3.0 negative samples or in HCV RIBA 2.0
indeterminate/HCV RIBA 3.0 negative samples. Conversely, prior
collections from donors who subsequently test repeatedly reactive on an
EIA screening test and indeterminate on an HCV RIBA 3.0 supplemental
test must also be destroyed or relabeled because they represent an
increased risk of HCV transmission (under proposed Sec. 610.48(k)).
However, if these prior collections have been transfused, consignee
notification for the purpose of recipient notification need not be
performed (as noted in relevant sections of proposed Sec. 610.49(a))
due to infrequent PCR positivity (only 1.6 percent) in HCV EIA 3.0
repeatedly reactive/HCV RIBA 3.0 indeterminate samples and infrequent
(0.5 percent to 4 percent) PCR reactivity in HCV RIBA 2.0
indeterminate/HCV RIBA 3.0 indeterminate samples.
N. Proposed Sec. 610.48(i), Further Testing and Consignee Notification
Following Review of Records Based on Screening Performed Using a Single
Antigen Screening Test
The purpose of proposed Sec. 610.48(i), which parallels the
requirements of proposed Sec. 610.48(h), is to require that prior
collections, identified in the review of historical testing records and
based on single antigen testing in accordance with Sec. 610.48(d)(4),
be further tested and consignees notified so that blood establishments
can determine if the prior collections should be released from
quarantine (under Sec. 610.48(j)), or destroyed or relabeled (under
Sec. 610.48(k)), and if notification of transfusion recipients is
necessary (under Sec. 610.49(a)). In addition, blood establishments
would have the option to perform further testing for prior collections
identified in accordance with Sec. 610.48(d)(1), (d)(2), and (d)(3).
Proposed Sec. 610.48(i)(1) would require blood establishments, within 1
year of the effective date of any final rule resulting from this
proposal, to perform further testing to clarify the status of prior
collections collected from a donor identified, in accordance with
Sec. 610.48(d)(4), as being at increased risk of transmitting HCV.
Proposed Sec. 610.48(i)(1) would require that further testing for
donors identified in accordance with proposed Sec. 610.48(d)(4) be
performed as follows: (1) As proposed in Sec. 610.48(i)(1)(i), blood
establishments would be required to perform a licensed supplemental
test for HCV on a frozen sample from the repeatedly reactive donation,
if available. If such a frozen sample is not available, blood
establishments would be required to obtain a fresh sample from the
donor and perform a licensed RIBA 3.0 supplemental test for HCV; or (2)
as proposed under Sec. 610.48(i)(1)(ii), blood establishments would be
required to make a determination that neither a frozen sample from the
repeatedly reactive donation nor a fresh sample from the donor is
available for further testing. For example, under certain
circumstances, the blood establishment could make a determination that
additional testing is not possible because the sample was not stored
properly, or the donor could not be located or the donor declined
further testing.
Under proposed Sec. 610.48(i)(2), blood establishments would have
the option to perform further testing on prior collections identified
in accordance with Sec. 610.48(d)(1) and (d)(2). This provision would
make it possible to clarify the status of the prior collections and, in
some instances, based on further testing, it might not be necessary to
destroy the prior collections or notify transfusion recipients. Under
proposed Sec. 610.48(i), blood establishments that have performed the
review of historical testing records and identified prior collections
in accordance with proposed Sec. 610.48 (d)(1) or (d)(2) of this
section may further test a frozen sample from the repeatedly reactive
donation or a fresh sample from the same donor by 1 year from the
effective date of any final rule resulting from this proposal, as
follows: (1) As proposed under Sec. 610.48(i)(2)(i), if the donor was
identified in accordance with proposed Sec. 610.48 (d)(1) of this
section as testing repeatedly reactive on an HCV EIA 1.0 screening test
and repeatedly reactive on either an HCV EIA 2.0 or HCV EIA 3.0
screening test, blood establishments have the option to perform further
testing using an appropriate licensed supplemental test for HCV; or (2)
as proposed under Sec. 610.48(i)(2)(ii), if the donor was identified in
accordance with paragraph (d)(2) of this section as testing repeatedly
reactive on an HCV EIA 1.0 screening test with an indeterminate test
result obtained using a HCV RIBA 2.0 supplemental test, blood
establishments have the option to perform further testing using a
currently available licensed supplemental test for HCV or an HCV EIA
3.0 screening test. If such optional further testing is performed using
an HCV EIA 3.0 screening test and the result is repeatedly reactive,
blood establishments have the additional option to perform further
testing using an appropriately chosen licensed supplemental test for
HCV; or (3) as proposed under Sec. 610.48(i)(2)(iii), if the donor was
identified in accordance with paragraph (d)(3) of this section as
testing repeatedly reactive on an HCV EIA 1.0 screening test with a S/
CO value less than 2.5 for at least two out of the three EIA tests, and
with no record of a supplemental test or multiantigen
[[Page 69390]]
screening test for HCV performed on the repeatedly reactive sample or
on a later sample from the same donor, blood establishments have the
option to perform further testing using a licensed multiantigen
screening test for HCV or a licensed supplemental test for HCV.
Under proposed Sec. 610.48(i)(3), blood establishments would be
required to notify consignees of the results of the additional testing,
performed in accordance with proposed Sec. 610.48(i)(1) or (i)(2), upon
completing the additional testing and prior to 1 year from the
effective date of any final rule resulting from this proposal. Blood
establishments would be required to notify the consignee of any risk of
HCV transmission that exists for such prior collections, based on the
results of the additional testing. If the prior collection was from a
donor identified in the review of historical testing records in
accordance with proposed Sec. 610.48(d)(1) through (d)(4), and no
additional testing was performed, or if no sample was available for
further testing, as provided in proposed Sec. 610.48(i)(1)(ii), the
blood establishment would be required to notify consignees, within 1
year from the effective date of a final rule that results from this
proposal, of any risk of HCV transmission for such prior collections.
O. Proposed Sec. 610.48(j), Release From Quarantine
The purpose of proposed Sec. 610.48(j) is to identify those prior
collections of blood and blood components intended for transfusion or
for manufacture into injectable products that have been quarantined and
further tested that may be released from quarantine, based on the
results of the additional testing. Under proposed Sec. 610.48(j)(1),
those prior collections subject to quarantine under proposed
Sec. 610.48(a) would be released for use only if the donor's current,
repeatedly reactive sample is further tested using a licensed,
supplemental test for HCV, as required in proposed Sec. 610.48(b), and
the result of the supplemental test is negative. Because the negative
supplemental test result indicates that the repeatedly reactive
screening test result was a ``false positive,'' prior collections from
the donor are not suspected as being a possible window period donation,
are not at increased risk of transmitting HCV and therefore, may be
released from quarantine.
Under proposed Sec. 610.48(j)(2), prior collections subject to
quarantine under proposed Sec. 610.48(e)(1) (as a result of the review
of historical testing records and based on a multiantigen screening
test) would be released from quarantine only if such prior collections
were not suspected as being ``window'' period donations. Such prior
collections, if not exempt from quarantine under proposed
Sec. 610.48(g)(2), would be released from quarantine if certain
conditions are met as follows: (1) As proposed in
Sec. 610.48(j)(2)(i)(A), if the donor's testing records meet the
conditions specified in proposed Sec. 610.48(c)(4) (repeatedly reactive
HCV EIA 2.0 screening test without additional test results) and further
testing was performed in accordance with Sec. 610.48(h)(1)(i)(A) on a
frozen sample from the repeatedly reactive donation or a fresh sample
from the same donor, and the result of the licensed supplemental test
for HCV is negative; or (2) as proposed in Sec. 610.48(j)(2)(i)(B), if
the donor's testing records meet the conditions specified in proposed
Sec. 610.48(c)(4) and the blood establishment performed further testing
in accordance with proposed Sec. 610.48(h)(1)(i)(B) on a frozen sample
from the repeatedly reactive donation or a fresh sample from the same
donor, using either a licensed HCV EIA 3.0 screening test and the
result is negative, or the result of the licensed HCV EIA 3.0 screening
test is repeatedly reactive and further testing is performed using a
licensed supplemental test for HCV and the result is negative; or (3)
as proposed in Sec. 610.48(j)(2)(ii), if the donor's testing records
meet the conditions specified in proposed Sec. 610.48(c)(5) (repeatedly
reactive HCV EIA 3.0 screening test without additional test results)
and the blood establishment performed further testing in accordance
with proposed Sec. 610.48(h)(1)(ii) of this section on a frozen sample
or a fresh sample from the same donor using a licensed, supplemental
test for HCV and the result is negative; or (4) as proposed in
Sec. 610.48(j)(2)(iii), if the donor's testing records meet the
conditions specified in proposed Sec. 610.48(c)(2) (repeatedly reactive
multiantigen screening test and indeterminate supplemental test) and
the blood establishment performed further testing in accordance with
proposed Sec. 610.48(h)(2), and one of three conditions specified in
proposed Sec. 610.48(j)(2)(iii)(A), (j)(2)(iii)(B) or (j)(2)(iii)(C)
applies. (Proposed Sec. 610.48(j)(2)(iii)(A) addresses repeatedly
reactive sample that was tested using an HCV EIA 2.0 screening test, or
a later sample from the same donor that was further tested in
accordance with proposed Sec. 610.48(h)(2)(i) of this section using
either an HCV EIA 3.0 screening test or a licensed supplemental test
for HCV and the result is negative. Proposed Sec. 610.48(j)(2)(iii)(B)
addresses the repeatedly reactive sample that was tested using an HCV
EIA 2.0 screening test or a later sample from the donor that was
further tested in accordance with proposed Sec. 610.48(h)(2)(ii) of
this section using a HCV RIBA 3.0 and the result is negative. Proposed
Sec. 610.48(j)(2)(iii)(C) addresses the repeatedly reactive sample that
was tested using an HCV EIA 3.0 screening test or a later sample from
the same donor that was further tested in accordance with proposed
Sec. 610.48(h)(2)(iii) of this section using a licensed supplemental
test for HCV and the result is negative) or; (5) under proposed
Sec. 610.48(j)(2)(iv), if the donor's testing records meet the
conditions specified in proposed Sec. 610.48(c)(3) (repeatedly reactive
HCV EIA 3.0 screening test and indeterminate HCV RIBA 2.0 supplemental
test) and further testing was performed in accordance with proposed
Sec. 610.48(h)(2)(iv) of this section on a frozen sample or a fresh
sample from the same donor using a licensed supplemental test for HCV
and the result is negative.
Under proposed Sec. 610.48(j)(3), prior collections subject to
quarantine under proposed Sec. 610.48(f)(1) (as a result of the review
of historical testing records and based on a single antigen screening
test) would be released from quarantine only if such prior collections
were not suspected as being ``window'' period donations. Such prior
collections, if not exempt from quarantine under proposed
Sec. 610.48(g)(3), would be released from quarantine if certain
conditions are met as follows: (1) Under proposed Sec. 610.48(j)(3)(i),
if the donor's testing records meet the conditions specified in
proposed Sec. 610.48(d)(4) (repeatedly reactive HCV EIA 1.0 screening
test with an S/CO value greater than or equal to 2.5) and further
testing was performed in accordance with proposed Sec. 610.48(i)(1)(i)
on a fresh sample, or frozen sample from the repeatedly reactive
donation using a licensed supplemental test for HCV and the result is
negative; or (2) under proposed Sec. 610.48(j)(3)(ii), if the donor's
testing records meet the conditions specified in proposed Sec. 610.48
(d)(1) (repeatedly reactive HCV EIA 1.0 screening test and repeatedly
reactive HCV EIA 2.0 or 3.0 screening test) and further testing was
performed in accordance with proposed Sec. 610.48(i)(2)(i) on a fresh
sample, or frozen sample from the repeatedly reactive donation and the
result of the appropriate supplemental test for HCV is negative; or (3)
under proposed Sec. 610.48(j)(3)(iii), if the donor's testing records
meet the conditions specified in
[[Page 69391]]
proposed Sec. 610.48 (d)(2) and further testing (in the case of a
repeatedly reactive HCV EIA 1.0 and indeterminate HCV RIBA 2.0
supplemental test) was performed in accordance with proposed
Sec. 610.48 (i)(2)(ii) on a fresh sample, or frozen sample from the
repeatedly reactive donation and the result when further tested using
either an HCV EIA 3.0 screening test or a licensed supplemental test
for HCV is negative; or (4) under proposed Sec. 610.48(j)(3)(iv), if
the donor's testing records meet the conditions specified in proposed
Sec. 610.48 (d)(3) (repeatedly reactive HCV EIA 1.0 with an S/CO less
than 2.5) and further testing was performed in accordance with proposed
Sec. 610.48(i)(2)(iii) on a fresh sample, or frozen sample from the
repeatedly reactive donation and the result when further tested using a
licensed multiantigen screening test for HCV or a licensed supplemental
test for HCV is negative.
FDA is proposing a conforming amendment to Sec. 610.46(d), which
specifies requirements for release from quarantine for HIV
``lookback,'' for consistency with the HCV ``lookback'' requirements by
changing ``Whole Blood, blood components, Source Plasma and Source
Leukocytes'' to ``blood and blood components.''
P. Proposed Sec. 610.48(k), Destruction or Labeling of Prior
Collections Held in Quarantine
The purpose of proposed Sec. 610.48(k) is to identify prior
collections that must be destroyed or appropriately labeled, that is,
those prior collections that are not exempt from quarantine under
proposed Sec. 610.48(g) and do not meet the conditions for release from
quarantine in accordance with proposed Sec. 610.48(j). Proposed
Sec. 610.48(k) would require that blood establishments and consignees
take appropriate action for prior collections subject to quarantine
under proposed Sec. 610.48(a), (e), and (f). Blood establishments would
be required to either destroy the quarantined prior collections or
appropriately label the collections for in vitro use unless: (1) The
prior collection was determined to be exempt from quarantine in
accordance with proposed Sec. 610.48(g), or (2) the prior collection
was subject to release from quarantine under proposed Sec. 610.48(j).
FDA recognizes there may be some limited uses for quarantined prior
collections which are not suitable for release from quarantine for the
product's original intended use. Such prior collections should not be
used for transfusion or for further manufacturing into injectable
products. FDA recommends that these prior collections be destroyed as a
general practice; however, in limited situations, release for research
or manufacture into in-vitro diagnostic reagents may be acceptable. If
released for these uses, prior collections should be relabeled
consistent with Secs. 606.121 and 640.70. In addition, these prior
collections must be relabeled as ``Biohazard'' with the cautionary
statements as follows:
Collected from a donor who subsequently tested reactive for anti-
HCV. An increased risk of transmission of hepatitis C is present.''; in
addition, the label must contain one of the following cautionary
statements, as appropriate: ``Caution: For Further Manufacturing Into
In-Vitro Diagnostic Reagents For Which There Are No Alternative
Sources.'' or ``For Laboratory Research Use Only.
FDA is proposing a conforming amendment to Sec. 610.46, the HIV
``lookback'' requirements, for consistency and to clarify the actions
to be taken for prior collections subject to quarantine under
Sec. 610.46(a). FDA is proposing to redesignate Sec. 610.46(e) as
Sec. 610.46(f) and to add new Sec. 610.46(e) Destruction or labeling of
prior collections held in quarantine, consistent with this proposal.
Q. Proposed Sec. 610.48(l)
Proposed Sec. 610.48(l) specifies that actions taken under proposed
Sec. 610.48 do not constitute a recall. This regulation is consistent
with current Sec. 610.46(e) applicable to the HIV ``lookback''
requirements (as noted previously, FDA is proposing to redesignate
paragraph (e) as paragraph (f)). While there are similarities between
the product recall process and ``lookback,'' there are several
important differences: (1) The recall procedures described in part 7
(21 CFR part 7) are intended as a guideline while ``lookback'' would be
a regulatory requirement; (2) additional steps are required in
``lookback'' which are not ordinarily performed in a product recall;
(3) because each ``lookback'' would be initiated due to similar
circumstances, a health hazard evaluation and recall classification by
the agency (see Sec. 7.41) is unnecessary; and (4) the products being
quarantined may not be in violation of applicable laws (see Sec. 7.40).
FDA recognizes that a ``lookback'' action does not mean that an
establishment has erred or did not meet its obligations under the
regulations and the law in assuring the safety of the blood supply.
Failure to take appropriate action in accordance with the proposed
``lookback'' regulations, however, would be a violation and FDA would
take enforcement action, when appropriate, in such situations.
R. Proposed Sec. 610.49(a), Hepatitis C Virus (HCV) ``Lookback;''
Notification of Transfusion Recipients
The purpose of proposed Sec. 610.49 is to identify the
circumstances under which it is necessary to notify transfusion
recipients; who is responsible for performing the notification; and the
timeframes for completing the notification process. The notification
process is intended to result in the notification of transfusion
recipients who have received prior collections of blood and blood
components from a donor later determined to be at increased risk of
transmitting HCV infection because they are possible ``window period''
donations. Refer to the discussion in the description of proposed
Sec. 610.48(c) for more information on ``window period'' donations. As
previously discussed, there are two sets of circumstances which trigger
``lookback'' activity. The notification of transfusion recipients would
be performed as a result of: (1) The identification of a donor who
returns to donate again and tests repeatedly reactive for evidence of
HCV infection on a licensed multiantigen screening test (as specified
in Sec. 610.48(a)) and further testing (performed as specified in
proposed Sec. 610.48(b)) indicates an increased risk of transmitting
HCV; or (2) the identification of a donor, as a result of the review of
historical testing records (in accordance with proposed Sec. 610.48(c)
or (d)), and further testing (as shown in historical records or as
performed under proposed Sec. 610.48(h) or (i)) indicates an increased
risk of transmitting HCV. Under the proposal, transfusion recipient
notification need not be performed for prior collections of Source
Plasma and Source Leukocytes, because they are intended for further
manufacture and not for transfusion. Proposed Sec. 610.49(a), would
require transfusion services to take appropriate actions, in accordance
with Sec. 610.49(b) and (c), when a transfusion recipient has received
blood or blood components, from a donor later determined to be at
increased risk of transmitting HCV infection as follows: (1) The donor
was identified in accordance with proposed Sec. 610.48(a) and the
result of the licensed, supplemental test performed in accordance with
proposed Sec. 610.48(b) is positive; or (2) the donor was identified in
accordance with proposed Sec. 610.48(c)(1), and the result of the
supplemental test identified in the review of records is positive; or
(3) the
[[Page 69392]]
donor was identified in accordance with proposed Sec. 610.48(c)(2), and
the result of the supplemental test identified in the review of records
is indeterminate, unless either the historical testing records or
further testing (in accordance with proposed Sec. 610.48(h)) show the
indeterminate supplemental test result was obtained using a licensed
supplemental test, and the initial test result was determined to be a
false positive because any of the conditions for exemption from
quarantine or release from quarantine have been met ; or (4) the donor
was identified in accordance with proposed Sec. 610.48(c)(4) or (c)(5)
as testing repeatedly reactive on a multiantigen screening test with no
record of further testing and the result of the licensed, supplemental
test performed, in accordance with proposed Sec. 610.48(h)(1)(i)(A),
(h)(1)(i)(B), or (h)(1)(ii) is positive; or (5) the donor was
identified in accordance with proposed Sec. 610.48(c)(4) or (c)(5) as
having no record of further testing and no fresh or frozen sample is
available for further testing, as specified in proposed
Sec. 610.48(h)(1)(iii); or (6) the donor was identified in accordance
with proposed Sec. 610.48(d)(1) unless the initial test result was
determined to be a false positive because any of the conditions for
exemption from quarantine (under proposed Sec. 610.48(g)(3)) or release
from quarantine (under proposed Sec. 610.48(j)(3)) have been met, or
the donor was further tested in accordance with Sec. 610.48(i)(2)(i)
using an appropriately chosen supplemental test for HCV and the result
is negative or indeterminate; or (7) the donor was identified in
accordance with proposed Sec. 610.48(d)(2) and the result of the
supplemental test performed using an HCV RIBA 2.0 or HCV RIBA 3.0
supplemental test is positive as identified in the review of historical
testing records; or (8) the donor was identified in accordance with
proposed Sec. 610.48(d)(2), and the result of the supplemental test
performed using HCV RIBA 2.0 is indeterminate, unless any of the
conditions for exemption from quarantine (under proposed
Sec. 610.48(g)(3)), or release from quarantine (under proposed
Sec. 610.48(j)(3)) have been met, or the donor was further tested in
accordance with proposed Sec. 610.48(i)(2)(ii) using a licensed
supplemental test for HCV and the result is indeterminate; or (9) the
donor was identified in the review of historical testing records in
accordance with proposed Sec. 610.48(d)(3) (repeatedly reactive HCV EIA
1.0 with an S/CO value less than 2.5) and the result of the licensed,
supplemental test for HCV performed in accordance with proposed
Sec. 610.48(i)(2)(iii) is positive; or (10) the donor was identified in
the review of historical testing records in accordance with proposed
Sec. 610.48(d)(4) (as testing repeatedly reactive on a single antigen
screening test with a S/CO value equal to or greater than 2.5 for at
least two of the three EIA tests, or the S/CO value can not be
calculated, and with no record of further testing) and the result of
the licensed, supplemental test for HCV performed in accordance with
Sec. 610.48(i)(1) is positive; or (11) the donor was identified in the
review of historical testing records, in accordance with
Sec. 610.48(d)(4), and no record of further testing is available and no
fresh or frozen sample is available for further testing, as specified
in Sec. 610.48(i)(1)(ii).
FDA is proposing conforming amendments to HIV ``lookback''
requirements of Sec. 610.47(a) for consistency with the HCV
``lookback'' requirements of proposed Sec. 610.49(a). FDA is proposing
to amend Sec. 610.47(a) to clarify that transfusion services shall
notify recipients of prior collections of blood and blood components
from a donor later determined to be at increased risk of transmitting
HIV infection when tested for evidence of HIV infection and the result
of the additional tests required in Sec. 610.46(b) are positive.
S. Proposed Sec. 610.49(b), Notification of Recipients of Prior
Transfusion
Proposed Sec. 610.49(b) describes the requirements for the process
of notification of transfusion recipients. Under proposed
Sec. 610.49(b), consistent with requirements for notification in the
HIV ``lookback'' regulations in Sec. 610.47, the transfusion service
would either notify the physician of record (i.e., the physician of
record or physician who ordered the blood) and ask him or her to inform
the recipient, or would notify the recipient directly. FDA recognizes
that, under certain circumstances, the physician may have developed an
ongoing relationship with the patient and may agree to take
responsibility for notification and counseling. The transfusion service
is ultimately responsible for ensuring that the notification takes
place. The transfusion service might seek assistance in the
notification process. For example, the transfusion service might
determine that such notification and counseling would be best conducted
by staff in another department in the hospital, who may be better
trained and experienced in counseling patients. Under proposed
Sec. 610.49(b) and under the proposed conforming amendment to
Sec. 610.47(b), a transfusion service may elect to notify the
transfusion recipient directly, without the assistance of the patient's
physician of record. FDA specifically requests comment whether the
transfusion service should be required to perform concurrent
notification of the physician of record whenever the transfusion
service notifies the transfusion recipient directly.
Proposed Sec. 610.49(b) would require the transfusion service to
make a minimum of three attempts to notify the transfusion recipient or
the recipient's physician of record. The time period provided for
completion of the recipient notification would be based on the date of
donor testing and the date of receipt of the supplemental test result
from the blood establishment. Recipient notification based on donor
testing completed after the effective date of the regulation, as
specified in the final rule resulting from this proposal, would be
required to be completed within a maximum of 12 weeks of receipt of the
results of the donor's supplemental test for HCV from the blood
establishment. Recipient notification based on donor testing completed
prior to the effective date of the regulation, as specified in the
final rule resulting from this proposal (historical records of donor
testing), would be required to be completed within 1 year of receipt of
notification of test results from the blood establishment. FDA is
proposing a longer period of time for completion of transfusion
recipient notification based on donor testing completed prior to the
effective date of the regulation because such notification would be
made as a result of the review of historical testing records performed
in accordance with proposed Sec. 610.48(c) and (d), and it is possible
that a transfusion service could have a large number of notifications
to complete. However, FDA believes that the transfusion recipient
notification process should begin and be completed as soon as feasible
because such a notification will not require a year to complete in all
cases. FDA recognizes that many blood establishments may be performing
such transfusion recipient notifications consistent with the
recommendations of the June 1999 draft guidance. Therefore, FDA
believes that if a blood establishment has a limited number of
transfusion recipient notifications to perform as a result of this
regulation, then the notifications could be completed in less than the
1-year period that would be provided under this proposal. In addition,
donors identified in accordance with proposed Sec. 610.48(c)(2) through
(c)(5), and proposed Sec. 610.48(d)(1) through (d)(4) generally will be
further tested by the
[[Page 69393]]
blood establishment in accordance with Sec. 610.48(h) and (i),
respectively. In those instances, FDA would require that the
notification of recipients based on such a licensed supplemental test,
performed after the effective date of the regulation, be completed
within 12 weeks of the date of receipt of the supplemental test result
from the blood establishment.
Under proposed Sec. 610.49(b), the transfusion service would be
responsible for the basic explanation to the recipient, referral for
counseling and further testing, and documentation of the notification
or attempts to notify the physician of record or the recipient, under
Sec. 606.160 of this chapter. Under this proposal, each establishment
should have a well-designed system for notification, and would need to
develop SOP's that describe each step in the notification system, as
well as the required documentation. The SOP would address the need for
documentation of person(s) contacted, by whom, when and whether the
transfusion recipient was notified directly, or the physician of record
agreed to notify the recipient, and the outcome of the notification
efforts, including the reasons for inability to notify.
FDA is requesting comment on the appropriateness of requiring a
minimum of three attempts to notify affected transfusion recipients as
proposed for HIV and HCV ``lookback.'' FDA is proposing to increase the
record retention requirement to 10 years (proposed Sec. 606.160(d)) and
to increase the length of time for which HIV and HCV ``lookback'' must
be initiated, from a maximum of 5 years as currently required in
Sec. 610.46(a) for HIV ``lookback'' (for HCV ``lookback'' in proposed
Sec. 610.48(a)). In addition, FDA is proposing to require HCV
``lookback'' based on the review of available historical testing
records (proposed Sec. 610.48(c) and (d)) for those prior collections``
* * * dating back indefinitely for computerized electronic records and
to January 1, 1988, for other readily retrievable records.'' FDA
specifically requests comment on the minimum number of attempts which
should be required to notify affected transfusion recipients identified
in the records that are more than 5 years old and who, therefore, might
be more difficult to locate. FDA also requests the submission of data
which support a specific number of attempts to notify affected
transfusion recipients.
FDA is proposing conforming amendments to HIV ``lookback''
requirements of Sec. 610.47(b) for consistency with the HCV
``lookback'' requirements of proposed Sec. 610.49(b). FDA is proposing
to amend Sec. 610.47(b) to clarify that transfusion services have the
option of either notifying the transfusion recipient directly or
notifying the recipient's physician of record and asking him or her to
notify the recipient and that notification (based on donor testing
completed after the effective date of the regulation) must be completed
within a maximum of 12 weeks.
T. Proposed Sec. 610.49(c), Notification of Legal Representative or
Relative
Proposed Sec. 610.49(c) would require the transfusion service or
physician to notify a legal representative, designated in accordance
with State law, if the transfusion recipient has been adjudged
incompetent by a State court. In addition, if the transfusion recipient
is competent, but State law permits a legal representative or relative
to receive the information on the recipient's behalf, proposed
Sec. 610.49(c) would require the transfusion service or physician to
notify the recipient, or his or her legal representative or relative.
If the transfusion recipient is a minor at the time of notification,
the transfusion service would be required to notify the recipient's
legal representative. Under proposed Sec. 610.49(c), reasons for
notifying the recipient's relative or legal representative on his or
her behalf would be documented, as required in the recordkeeping
provisions of Sec. 606.160. Proposed Sec. 610.49(c) would not require
notification efforts to continue if the recipient is deceased because,
as previously discussed, direct percutaneous exposure to infectious
blood, particularly in the setting of drug abuse, accounts for the
majority of HCV infections acquired in the United States. Secondary
transmission of HCV to sexual partners, care providers or others with
close contact is very unlikely.
FDA is proposing conforming amendments to HIV ``lookback''
requirements of Sec. 610.47(c) for consistency with the HCV
``lookback'' requirements of proposed Sec. 610.49(c). FDA is proposing
to amend Sec. 610.47(c) to clarify that transfusion service or
physician would be required to notify the legal representative if the
transfusion recipient is a minor at the time of notification and to
document the result of the notification or the attempts to complete the
notification.
U. Proposed Sec. 610.49(d), Reference Tables
Proposed Sec. 610.49(d) includes four tables intended to assist in
identifying the applicable paragraphs of proposed Secs. 610.48 and
610.49 and the corresponding ''lookback'' actions. In particular, the
requirements of proposed Secs. 610.48 and 610.49 that are based on the
review of historical testing records require that many different
testing sequences be addressed. These tables are intended to clarify
the applicable sections and the corresponding steps of the ``lookback''
process that must be considered for a particular sequence of tests.
Table 1 identifies applicable sections for the ``lookback'' process
based on current donor testing, for donors identified in accordance
with proposed Sec. 610.48(a). For example, a donor that tests
repeatedly reactive for HCV upon returning to donate again, would be
identified by the blood establishment in accordance with proposed
Sec. 610.48(a). Table 1 of proposed Sec. 610.49 lists the subsequent
``lookback'' actions that must be taken and the applicable regulations.
Continuing with this example, in addition to other ``lookback''
actions, table 1 shows that such a donor would be further tested in
accordance with proposed Sec. 610.48(b), and prior collections could be
released from quarantine if the conditions of proposed
Sec. 610.48(j)(1) were met.
Tables 2, 3, and 4 of proposed Sec. 610.49 identify applicable
sections for the ``lookback'' process based on the review of historical
testing records. A different table applies based on the specific
screening test that was performed. Table 2 identifies applicable
sections based on the review of historical testing records for donors
identified in accordance with proposed Sec. 610.48(c) as testing
repeatedly reactive using an HCV EIA 3.0 screening test. Table 3
identifies applicable sections based on the review of historical
testing records for donors identified in accordance with proposed
Sec. 610.48(c) as testing repeatedly reactive using an HCV EIA 2.0
screening test. Table 4 of proposed Sec. 610.49 identifies applicable
sections based on the review of historical testing records for donors
identified in accordance with proposed Sec. 610.48(d) and tested using
a single antigen screening test, HCV EIA 1.0.
IV. Analysis of Impacts and Initial Regulatory Flexibility Analysis
FDA has examined the impacts of the proposed rule under Executive
Order 12866, under the Regulatory Flexibility Act (5 U.S.C. 601-612),
and under the Unfunded Mandates Reform Act (Public Law 104-4).
Executive Order 12866 directs agencies to assess all costs and benefits
of available regulatory alternatives and, when regulation is necessary,
to select regulatory approaches that maximize net benefits (including
potential economic,
[[Page 69394]]
environmental, public health and safety, and other advantages;
distributive impacts; and equity). The Regulatory Flexibility Act
requires agencies to analyze whether a rule may have a significant
impact on a substantial number of small entities and, if it does, to
analyze regulatory options that would minimize the impact. Section
202(a) of the Unfunded Mandates Reform Act requires that agencies
prepare a written statement of anticipated costs and benefits before
proposing any rule that may result in an expenditure by State, local,
and tribal governments, in the aggregate, or by the private sector, of
$100 million in any one year (adjusted annually for inflation).
The agency has determined that the proposed rule may be a
significant action as defined by the Executive Order. The analysis
below details FDA's estimate of the potential costs and benefits of the
rule. As described in the analysis that follows, the rule is likely to
have a significant economic effect on a substantial number of small
entities. FDA has therefore prepared an Initial Regulatory Flexibility
Analysis. The Unfunded Mandates Reform Act does not require FDA to
prepare a statement of costs and benefits for the proposed rule,
because the proposed rule is not expected to result in any 1-year
expenditure that would exceed $100 million adjusted for inflation. The
current inflation adjusted statutory threshold is about $110 million.
A. Economic Impact
The purpose of the proposed rule is to help ensure the continued
safety of the blood supply and to help ensure that information is
provided to consignees and recipients of blood products in the event of
a repeat donor's seroconversion to positivity for hepatitis C. The
proposed action is considered necessary to interdict prior in-date
collections at increased risk for transmitting HCV and to help assure
that blood product recipients receive counseling and treatment if
necessary, as effective therapies become available for hepatitis C. The
proposed rule will further support public confidence in safety of the
U.S. blood supply, recognizing priorities for the reduction of
infectious disease risks to transfusion recipients. The agency further
notes that the costs and benefits of the FDA and the Health Care
Finance Administration (HCFA) rule are not additive, as the impacts
considered in the HCFA rule are also accounted for in the FDA rule.
1. The Number and Type of Entities Affected
The proposed rule will affect establishments that collect, process,
and ship blood and blood components, and establishments that transfuse
those products. The affected entities include commercial plasma
centers, regional and community blood collection or donation centers,
hospitals that operate blood collection centers, and facilities that
transfuse blood products. The HCFA estimates that there are
approximately 6,200 transfusing facilities. FDA's Office of Blood
Research and Review (OBRR) has a record of 2,801 registered blood and
plasma establishments.
According to a 1992 survey (Ref. 3), U.S. blood establishments
collect an annual total of 13,794,000 units of blood. Allogeneic
donations (not directed for a specific recipient) accounted for 87.2
percent (12,035,000 units). Approximately 79 percent of allogeneic
donations are provided by repeat donors. (This percentage is based on
American Red Cross estimates based on donations between January 1996
and June 1997.) FDA's analysis of the HCV ''lookback'' rule focuses on
allogeneic donations by repeat donors, and the subset of those donors
expected to test repeatedly reactive in a screening test for evidence
of HCV infection. As outlined in preceding sections of this document,
the proposed rule includes a set of provisions for processes to be
performed by blood establishments. In general terms, these provisions
concern donor recordkeeping, record review, identification and
quarantine of affected units for repeat reactive donors, notification
of consignees of unpooled products concerning the HCV status of
affected units, and further testing to confirm HCV positivity. The
proposed rule also specifies requirements for blood product consignees
that relate to quarantine of in-date unpooled products based on blood
establishment notifications, and recipient notification when
appropriate.
Plasma centers will be affected by the proposed rule only to the
extent that these establishments store and distribute unpooled units to
consignees that also retain unpooled units in their inventories. FDA
currently has little information about the volume of unpooled units
retained by plasma centers that would be affected by this proposal.
Because this information is essential for the estimation of economic
impact, FDA requests detailed industry comment on current practices for
recordkeeping and retention of unpooled units of plasma (including
estimated numbers of unpooled units), both at collection centers and
the facilities to which these units are subsequently shipped. For the
purpose of this analysis, FDA has assumed that most units will be
pooled prior to the initiation of any ``lookback'' activity and,
therefore, that plasma establishments will be minimally affected by the
proposed rule. Plasma establishments similarly will not be affected by
the proposed requirements for review of historical testing records.
FDA, therefore, assumes that the primary impact on plasma
establishments will involve the review of the proposed regulation by
each establishment to determine how current facility SOP's would be
affected.
With the exception of hospitals that both collect and transfuse
blood products, most establishments affected by the rule will either
act as a blood collection establishment or as a consignee (transfusion
service), not as both. To distinguish the impact of the requirements
for blood establishments and for consignees, the rule provisions
affecting each type of entity will be treated separately in the
analysis that follows. Table 1 of this document provides a summary of
the estimated one-time versus the yearly costs for blood establishments
and blood product consignees. The basis for these estimates are
explained in sections IV.A.2 and IV.A.3 of this document.
Table 1.--Summary of Estimated One-Time Yearly Costs for Blood
Establishment and Blood Product Consignees
------------------------------------------------------------------------
Affected
Entities One-Time Cost Yearly Cost
(number)
------------------------------------------------------------------------
Blood Establishments (2,800)
------------------------------------------------------------------------
Hepatitis C $2,875,040
Virus (HCV)
``Lookback''
Standard
Operating
Procedures
(SOP's)
------------------------------------------------------------------------
Prospective $4,558,442
review
------------------------------------------------------------------------
[[Page 69395]]
Historical $33,239,402
review
------------------------------------------------------------------------
Subtotal $36,114,442 $4,558,442
------------------------------------------------------------------------
Consignees (6,200)
------------------------------------------------------------------------
HCV $2,546,464
``Lookback''
SOP's
------------------------------------------------------------------------
Prospective $2,114,632
review
------------------------------------------------------------------------
Historical $50,106,540
Review
------------------------------------------------------------------------
Subtotal $52,653,004 $2,114,632
------------------------------------------------------------------------
Total $88,767,446 $6,673,074
------------------------------------------------------------------------
2. Estimated Impact on Blood and Plasma Establishments
Many of the provisions of the proposed rule will affect blood
establishments. Each establishment will need to review the provisions
of the rule in order to reconcile current facility practices for record
review, sample quarantine, consignee notification and other related
processes, and donor and blood product recordkeeping, with the
requirements of the rule. FDA estimates the cost of performing such a
one-time review and reconciliation of blood establishment SOP's to be
approximately $1,027 per establishment, assuming that the review will
require approximately 40 hours per facility and be performed by a staff
medical technologist (Ref. 4). This yields a total one-time cost of
$2,875,040.
The proposed rule requires that blood establishments extend the
retention period for required processing records for blood donors from
5 to 10 years after the records of processing have been completed or 6
months after the latest expiration date for the individual product,
whichever is a later date. FDA estimates that this provision will cost
approximately $3,110,240 per year, assuming that routine maintenance of
donor files for the additional period of time will require
approximately 40 hours of additional programming support time per
facility per year, at a cost of $27.77 per hour of programmer time,
based on 1997 Bureau of Labor Statistics estimates (40 x $27.77 x
2,800).
The proposed rule requires that blood and plasma establishments act
within 3-calendar days of receiving the results of an FDA-licensed HCV
test performed by a blood establishment or a CLIA-certified laboratory,
with repeatedly reactive HCV results for a repeat blood donor. The
establishment would retain the records for all in-date products and
quarantine any in-date unpooled product that remain in inventory,
quarantine all in-date unpooled prior collections, and notify
consignees of the repeatedly reactive test result so that they may also
quarantine any in-date unpooled prior collections. However, prior
collections made more than 12 months prior to the last negative
multiantigen HCV screening test are exempt from the required
quarantine. Following the repeatedly reactive results of the initial
screening tests, the blood establishment would be required to notify
consignees of the result of the more specific supplemental HCV test
within 45-calendar days after the day on which the donor tests
repeatedly reactive in a screening test for evidence of HCV infection.
If the result of further testing with a licensed supplemental test is
negative, then the initial screening test result can be considered a
``false positive'' and the in-date prior collections can be released
from quarantine.
FDA's estimated cost of these provisions is based on an estimated
number of consignee notifications multiplied by the unit cost of each
notification. First, the number of annual affected blood donations was
calculated as the product of 12 million donations, an 80 percent repeat
donor rate, and a 0.12 percent HCV positive donor rate. The resulting
11,520 figure was then adjusted upward to 12,816 to reflect the
difference found between the number of donors triggering ``lookback''
and the component notifications reported as interim results from a
recent survey conducted by the Centers for Disease Control and
Prevention (CDC) (Ref. 4). Assuming a cost of $113 per notification
based on remarks from a representative of the nation's blood banks
(Ref. 5) yields a consignee notification cost to blood banks of
$1,448,202 per year (12,816 x $113). Thus, the prospective review in
the proposed rule results in a yearly total cost of $4,558,442
($3,110,240 + $1,448,202) for blood establishments. These costs may be
slightly understated, because the CDC survey-based projections extend
back only to 1988 records. Nevertheless, because the proposed rule
requires pre-1988 searches only for ``computerized electronic
records,'' this underestimate would be small.
The proposed rule would also require a review of historical testing
records of donations collected prior to the effective date of the rule.
Blood establishments will be required to review records from prior
collections to identify donors that tested repeatedly reactive in a
screening test for evidence of HCV infection, for whom either: (1)
There is no record of further testing, (2) the donor tested
indeterminate on a supplemental test for HCV (with some exceptions), or
(3) the donor tested positive on a supplemental test. The purpose of
the record review is to identify prior collections from donors who are
likely to be infected in order to notify recipients of such donations,
and quarantine affected products that remain in inventory.
Following their review of historical testing records, blood
establishments would be required to do the following tasks. If the
records show that the repeat donation, testing repeatedly reactive in a
screening test for evidence of HCV infection, was followed by an
appropriate licensed supplemental test with confirmed negative results,
no further action is needed. If the repeat donation, testing repeatedly
reactive in a screening test for evidence of HCV infection, was
followed by a supplemental test with confirmed positive results, the
blood establishment
[[Page 69396]]
would notify consignees of blood products from the donor's prior
donations and quarantine affected products that remain in inventory. If
the records show that the donation, testing repeatedly reactive in a
screening test for evidence of HCV infection, was followed by a
supplemental test with indeterminate result, or there is no record of
supplemental testing to determine the donor's HCV status, the blood
establishment would try to perform supplemental testing to clarify the
status of prior collections. If a frozen sample from the donation
testing repeatedly reactive in a screening test for evidence of HCV
infection is available, that sample would be used in supplemental
testing; otherwise, the blood establishment would attempt to contact
the donor to obtain a fresh sample for testing. If further testing with
fresh or frozen samples is accomplished, the blood establishment would
be required to notify consignees of the test result. If no frozen
sample is available and a fresh sample cannot be retrieved from the
donor, the blood establishment would be required to notify consignees
of the results of the repeatedly reactive screening test and the
inability to clarify the donor's HCV status. Within 1 year of the
effective date of the final rule, blood establishments would be
required to perform the testing needed to clarify the status of prior
collections. Blood establishments would be required to notify
consignees of HCV positive test results within 45 days of completion of
further testing performed as a result of the review of historical
testing records. If no further testing could be performed, consignees
would be notified within 1 year.
FDA's estimate of the cost of performing the specified review of
historical testing records is based on the CDC estimate of 294,154
attempted notifications (188,448 during the period 1990 to mid-1992 and
105,706 during the period from mid-1992 to 1998) and the estimated cost
of $113 per notification (Ref. 5). This yields a one-time review cost
of $33,239,402. Again, this estimate does not account for pre-1988
computerized electronic records, but the agency believes there are
relatively few.
In total, as shown in table 1, FDA's estimates that blood
collection agencies will incur ``lookback'' related one-time costs of
about $36.1 million and annual costs of about $4.6 million. As the
industry has already initiated this program, it is likely that the
greater part of these costs have already been incurred.
3. Estimated Impact on Blood Product Consignees
The proposed rule would require that transfusion services (i.e.,
consignees) notify transfusion recipients who received prior
collections from a donor at increased risk of transmitting HCV.
Recipient notification is included in both the prospective ``lookback''
and the review of historical testing records to identify prior
collections. The transfusion service may notify the physician of record
or notify the recipient directly. If the transfusion recipient is a
minor or adjudged incompetent by a State court, the transfusion service
or physician would be required to notify the recipient's legal
representative. The proposed rule is expected to generate one-time
costs and some additional annual costs for blood product consignees.
One-time costs include the development of facility SOP's for recipient
notification. FDA assumes that these tasks will involve the review of
current SOP's (e.g., for HIV ``lookback'') and the adaptation or
modification of current procedures to address the provisions of this
rule and estimates that they will require an average of 16 hours per
facility for facilities that act as consignees. The review would be
performed by a staff medical technologist at an estimated cost of
$25.67 per hour. Thus, FDA estimates the total one-time cost for the
6,200 transfusing facilities to be $2,546,464.
For notifications resulting from prospective donor testing and
required quarantine, the required notification effort would include a
minimum of three attempts to notify the transfusion recipient and would
be completed within a maximum of 12 weeks of receipt from the blood
establishment of the results of the donor's supplemental test for HCV.
The agency's estimated cost of compliance with provisions concerning
the prospective review and recipient notification is based on the
previously described estimate of 11,520 annual affected donations. This
figure was adjusted to 12,816 to reflect the CDC survey finding that
the number of components sent to transfusion facilities exceeded the
number of donors triggering ``lookback'' at blood centers by 11.2
percent. The cost per attempted notification is estimated at $165 which
reflects the average cost quoted by a third party contractor for
matching, notifying, testing, counciling, and documenting ``lookback''
efforts for over 100 hospitals (Ref. 6). Although the proposed rule
does not specifically require hospitals to perform testing and
counciling services, many do. These assumptions yield an annual cost of
$2,114,632 (12,816 x $165) for blood consignees to conduct prospective
``lookback'' activities.
Notifications resulting from the review of historical testing
records and the identification of prior collections are to be completed
by the transfusion service within 1 year of receipt of notification
from the blood establishment. The recipient notification provided by
the transfusion service would include a basic explanation to the
recipient, referral for counseling and further testing and
documentation of the notification or attempts to notify the physician
of record or recipient. The estimated one-time cost of recipient
notification associated with the review of historical testing records
is $50,106,540. This is based on the CDC estimate of about 303,676
recipients identified for notification (188,448 from 1990 to mid-1992
and 115,228 from 1990 to mid-1992), and the average cost of $165 of
staff time per component for recipient notification. Thus, FDA
estimates the total one-time cost to blood transfusion facilities to be
$52,653,004 ($2,546,464 + $50,106,540) for conducting retrospective
``lookback''.
The cost of targeted HCV ``lookback'' notification in the United
States is expected to compare favorably with the experiences reported
in earlier efforts, e.g., in Canada (Ref. 7), which were likely based
on less automated approaches to recordkeeping. Table 2 of this document
shows the cost of the HCV ``lookback'' per recipient notified, using
CDC data to project various outcomes of the ``lookback'' effort. As
shown in table 2, the assumption that a total of 258,551 transfusion
recipients will be identified for notification through the historical
``lookback'' effort translates to an estimated one-time cost of about
$642 per recipient identified. CDC further estimates that approximately
57,885 will still be living and notified through the retrospective
review. This estimate implies a one-time cost of $1,440 per notified
living recipient.
[[Page 69397]]
Table 2.--Estimated Cost Per Recipient Notification
------------------------------------------------------------------------
Cost of Cost Per Cost Per
``Lookback'' and Recipient Recipient
Notification\1\ Transfused Notified
------------------------------------------------------------------------
Prospective $6,673,074\2\ $658 $1,541
Historial $83,345,942 $642 $1,440
------------------------------------------------------------------------
\1\ Excludes cost of developing SOP's.
\2\ Annual cost.
B. Benefits of the Proposed Rule
The proposed rule is intended to help ensure the continued safety
and adequacy of the national blood supply. Threats to the safety of the
blood supply and the importance of a timely regulatory response to
assure public safety have been the focus of numerous review efforts in
recent years, by the U.S. House of Representatives Committee on
Government Reform and Oversight, Subcommittee on Human Resources and
Intergovernment Relations, the General Accounting Office, IOM, and
private organizations including the American Liver Foundation and the
DHHS Advisory Committee on Blood Safety and Availability. The proposed
``lookback'' effort provides benefits both at the individual level of
blood recipients and at a societal level, in terms of both the safety
and continued adequacy of the national blood supply. The discussion
that follows first addresses individual level benefits and then
considers societal benefits.
1. Individual Benefits of HCV ``lookback''
Over the past several years, the improved accuracy of HCV testing,
the increased understanding of hepatitis C outcomes, the value of
counseling against risk behaviors that worsen outcomes, and the
advances in treatment of HCV have collectively created a medical and
ethical imperative to inform identified transfusion recipients of their
HCV risk. Prior to the widespread use of HCV screening of blood donors,
transfusion was one of the most common modes of transmission. Although
patients with chronic hepatitis C may remain asymptomatic for a number
of years, the consequences of their disease are extremely serious. For
example, CDC population-based studies indicate that 40 percent of
chronic liver disease is HCV-related, resulting in an estimated 8,000
to 10,000 deaths each year (Ref. 8). Current CDC estimates of medical
and work-loss costs of all HCV-related acute and chronic liver disease
(including cases resulting from blood transfusion) are in excess of
$600 million annually, and HCV-associated end-stage liver disease is
the most frequent indication for liver transplantation among adults.
The cost of liver transplantation is estimated to be approximately
$200,000 in the first year and $20,000 per year for subsequent years;
and the cost of treatment for hepatocellular carcinoma, another
sequelae of chronic liver disease, is estimated to be $10,000 per year
(Ref. 9).
Timely notification of HCV infection benefits the infected blood
recipient in several important ways. First, although factors predicting
severity of liver disease due to HCV have not been well-defined, recent
data indicate that increased alcohol intake is associated with more
severe liver disease. According to CDC, even moderate amounts of
alcohol in patients with chronic hepatitis C might enhance liver
disease. Consequently, an HCV-infected patient identified by the
proposed ``lookback'' program could minimize liver damage associated
with alcohol consumption by restricting his or her intake.
Next, while other percutaneous exposures currently represent the
most common means of infection, some case-control studies have also
reported a positive association with sexual contact with a person with
a history of hepatitis and acquiring hepatitis C. In fact, 15 to 20
percent of the acute hepatitis C patients reported to CDC's sentinel
counties surveillance system have a history of sexual exposure in the
absence of other risk factors. Infected patients identified through the
proposed ``lookback'' procedures could take steps to protect sexual
partners from the risk of infection.
Next, it is important to note that identified infected patients
would benefit from treatment with available therapies. Studies of
patient characteristics and responsiveness to therapy indicate that
best results are achieved if treatment is initiated earlier in the
disease, when patients are younger and have not yet developed cirrhosis
(Ref. 10). For example, Bennett et al. estimated the cost effectiveness
of a single course (6 months) of treatment with alfa interferon and
found that patients at age 20 experience an average of 3.1 years of
life gained at $500 per year of life extended (YLE); 30-year-old
patients have an average gain of 1.9 years of life, at $7,100/YLE;
patients starting treatment at age 50 have 6 months of life gained at
$7,100/YLE; and 70-year-old patients gain an average of 22 days at
$62,000/YLE (Ref. 11).
Next, care providers for the identified infected patient would be
aware of the infection and could use additional precautions to avoid
the risk of exposure to blood or wounds when providing care to the
patient. Finally, identified infected patients would be informed that
they must not donate blood.
Currently, the primary treatment for chronic hepatitis C is alfa
interferon therapy (Ref. 12). On average, of those patients who undergo
interferon treatment, a reported 10 to 20 percent show a sustained
response after 6 months of therapy, and 20 to 30 percent a sustained
response if therapy is continued for 12 months. Although alfa
interferon produces a wide array of adverse side effects (Ref. 13), and
some patients experience a relapse of HCV infection despite therapy,
the benefits for patients identified for treatment through HCV
``lookback'' are likely to continue to increase as improved therapies
are developed. In particular, combination therapy using alfa interferon
plus ribavirin has been reported to result in an improved outcome (Ref.
13).
In addition to the ``lookback'' costs discussed previously, the
overall cost-effectiveness of the proposed regulation will vary with
the cost and effectiveness (i.e., cure rate) of therapy for hepatitis
C, and the cost of treatment for chronic liver disease and its sequelae
in the absence of, or with failure of treatment for hepatitis C. A
single course of alfa interferon therapy has been estimated to cost
$2,300 (Ref. 9), but hepatitis C therapy is a rapidly changing area of
clinical practice and the cost-effectiveness of treatment can shift
dramatically with the introduction of new drugs and the age
distribution and the comorbidities of the population receiving
treatment. An illustrative example, however, can demonstrate the
potential benefits of the increased therapies that might result from
this
[[Page 69398]]
regulation. Although FDA cannot precisely determine the number of HCV
positive individuals that would respond to the notification and seek
medical consultation, a projection derived largely from interim
findings of the CDC survey indicates that retrospective notification
activities might identify about 3,764 cases of previously unidentified
chronic HCV. This projection assumes that about 22.4 percent of 258,551
potential recipients are notified, about 13 percent of those notified
test positive for HCV, 66.7 percent of the HCV cases are not currently
known, and 75 percent of the HCV cases are chronic. Kim et al. (Ref. 9)
found that, on average, patients with chronic HCV gain 0.25 discounted
(3 percent) quality adjusted life-years (QALY's) from 6 months of
interferon- 2b treatment. (The authors do not provide estimates for any
other discount rates.) On this basis, the above assumptions imply that
retrospective ``lookback'' would gain a total of 941 QALY's, at a cost
of about $88,573 per QALY.
There is no generally accepted means of valuing life-years saved,
although a number of empirical studies indicate a societal willingness-
to-pay of from $1.6 million to $11.6 million to avoid a statistical
death. Assuming a mid-range estimate of $5 million and annualizing over
a 35-year period at 3 percent yields an annual value of $233,000. The
above assumptions imply that providing 6 months of interferon- 2b
therapy to an additional 3,764 HCV-positive individuals could produce
societal willingness-to-pay benefits of $219 million. The additional
discounted (3 percent) incremental cost of providing such therapy was
estimated by Kim et al. to be about $1,000 per patient, which implies
an additional treatment cost of only $3,764,000 (3,764 patients x
$1,000). Thus, by this measure, the individual benefits of
retrospective HCV ``lookback'' easily exceed their incremental costs.
The benefits of the prospective ``lookback'' provisions can be
similarly analyzed. Based on the CDC interim findings, FDA assumed that
prospective ``lookback'' notifications would be initiated for 10,894
transfused recipients, of which 48 percent would be successful, 5.4
percent of those who are notified would test positive for HCV, 66.7
percent would be previously unknown, and 75 percent chronic. Thus, 123
patients could potentially gain 0.25 QALY's per year at a cost of
roughly $217,011 per QALY. According to the monetization values
described above, these health gains could generate annual benefits of
$7.2 million, or roughly the level of the prospective ``lookback''
costs.
The agency recognizes the substantial uncertainty that surrounds
such estimates. For example, medical cost-effectiveness studies
sometimes assume a maximum societal value of about $50,000 per QALY.
This modification would imply one-time retrospective ``lookback''
benefits of about $47 million and annual prospective ``lookback''
benefits of about $1.5 million, which would cover over half of the
estimated initial costs of compliance. In addition, the figures assume
that the distribution of recipient ages would reasonably match those of
the Kim et al. study. Other studies of HCV treatment outcomes may
project differently. FDA seeks public comment on the above assumptions
and estimates.
2. Societal Benefits of HCV ``lookback''
In addition to the direct benefits of medical treatment, the
proposed ``lookback'' program will help to boost confidence and trust
in the national blood supply. Thus, HCV ``lookback'' will generate
societal benefits that are incremental to the health benefits discussed
above. Recent public reviews of blood supply issues have recognized the
importance of assuring both safety and the perception of safety. For
example, reviews suggest that the public trust in the blood supply
system was severely shaken by the transmission of HIV by blood
products. This effect was exacerbated by the perceived failure of blood
collection centers, public health agencies, and health care providers
to take timely action to prevent or minimize patient risk. The failure
to institute an HIV ``lookback'' program at an early date resulted in a
number of cases in which transfusion recipients were unaware of their
infection, failed to seek treatment and subsequently infected others
(Refs. 13 and 14).
Now that information is available to identify and to offer
counseling and treatment options for those confirmed HCV-positive, FDA
believes that the public trust demands the timely communication of
relevant risk information. Although the agency cannot accurately assess
the dollar value of this public trust or the potential impact of its
loss, the following discussion, considers the cost of unfavorable
shifts in public perception to be a potential indicator of the value of
stabilizing public trust in the U.S. blood system. The purpose of the
discussion is to provide an order-of-magnitude value assessment to
which the estimated costs of HCV ``lookback'' can be compared.
Potential indicator of yearly cost: Changes in the blood donation
patterns. The impact of the AIDS epidemic on the perceived safety of
the nation's blood supply is believed to have contributed to the
reduction in volunteer blood donations and to the dramatic increase in
autologous and directed blood donation in subsequent years. The IOM
discussion of bioethical issues in risk communication regarding the
blood supply describes blood services as special because ``Trust is
perhaps uniquely important. You know pretty fast if you have lost the
public trust because people stop showing up to donate'' (Ref. 17). This
comment suggests two measures of the loss of public trust in the blood
supply in the wake of the HIV/AIDS transfusions of the 1980's: The
reduction in the volume of allogeneic blood donations and the
substantial increase in the volume of autologous blood collections.
These shifts have associated opportunity costs and inefficiency costs.
Part of the observed changes in blood donation reflect tighter donor
screening and more efficient use of the patient's own blood in
scheduled surgery. But some of the shift is believed to reflect a
distrust of the blood supply not warranted based on objective measures
of disease risk. FDA reviewed the extent of the blood donation decline
that might be attributable to AIDS-related public mistrust and asked
whether a similar round of impacts might result if risk communication
about known HCV exposures were perceived as inadequate by the general
public.
CDC estimates that the number of donations per donor has dropped
from five as recently as 1992 to 1993, to two donations per donor in
the period 1996 to 1998. This trend was already apparent in the survey
findings of Wallace et al. published in 1995. Their survey compared
blood collections in 1989 with collections in 1992, and found that
904,000 fewer allogeneic units and 462,000 more autologous units of
blood were collected in 1992 compared with 1989. At an estimated
average price of $103 per unit\1\, the reduction in (allogeneic)
donations represents an annual loss to the nation's blood supply valued
at $93.11 million. If the allogeneic donations yielded more than one
product per unit donation, the loss of potential supply would be
greater.
---------------------------------------------------------------------------
\1\ The estimates of $103 per allogeneic unit and $137 per
autologous unit represent midpoint values in the range of blood
costs reported by S. L. Lee in ``Patients' Willingness to pay for
Autologous Blood Donation'' in Risk in Perspective, Harvard Center
for Risk Analysis, vol. 6, No. 6, June 1988.
---------------------------------------------------------------------------
[[Page 69399]]
Autologous blood collection presents less risk of infectious
disease, but it is not generally considered to be cost-effective, since
much of the collected product is ultimately discarded because the
patient does not require it. Of the estimated 1,117,000 autologous
units collected in 1992, a total of 546,000 was reported as discarded.
At an estimated average cost of $137 per unit, this represents an
annual loss valued at $74.80 million. These discarded autologous units
represent a real cost incurred by either the hospital or other blood
establishment (if unrecoverable), by the third-party payer, or by the
patient for a product that provided no therapeutic value. The most
recent data suggest that the volume of unnecessary autologous
collections is starting to decline, with clinical practice changes and
regained public trust in the blood supply. Although the shifting
patterns of blood collections may largely reflect appropriate responses
to actual blood safety risks, if even a fraction of the shifts result
from misperceptions, due to perceived failures in government and
industry risk communication, then avoidable opportunity and
inefficiency costs will be incurred.
FDA cannot assume that the failure to require notification of known
exposures to hepatitis C among transfusion recipients would produce a
similar second round of blood supply shifts and costs. However,
hepatitis C has been characterized in the media, which influences
public perception, as being as lethal as AIDS (Ref. 18) and its
prevalence is much greater. If timely communication and support for
patients, after inadvertent exposure to hepatitis C, were to eliminate
as little as 15 percent of the yearly costs associated with the supply
shifts described previously, this annual saving of over $25 million
would exceed the $19 million in total annualized compliance costs
estimated to be imposed by this regulation (calculated over 10 years at
7 percent).
3. Alternatives Considered for HCV ``Lookback''
FDA finds that the targeted ``lookback'' approach proposed is the
most effective of several alternatives when evaluated in terms of
ethical, cost, and effectiveness criteria. The following provides a
discussion of the alternatives that have been considered.
a. Alternative: Publication of FDA guidance but no regulatory
requirement for ``lookback''. One alternative to regulation involves
FDA taking no further action, as the agency has already issued industry
guidance concerning HCV ``lookback''. The principle advantage of this
approach would be the elimination of FDA expenses related to issuing
and later enforcing the rule. However, although the ``lookback''
process described in the guidance is much the same as that required
under the proposed rule, the approach would be less effective in
achieving the desired benefits. Because FDA would only recommend a
process and timeframe, but have no basis for enforcing it, some in
industry may elect a more extended timeframe for performing the
``lookback'' based on the review of historical testing records in order
to spread the costs of this effort. Such delay, however, would increase
each recipient's risk of serious disease complications and speed the
spread of infection.
For blood establishments, a potential cost of such delay would be
the risk of litigation by blood recipients who discover through other
means that they have contracted hepatitis C through transfusion. The
risk of litigation, however, appears relatively small. Blood-product
related injuries have been removed from the scope of strict liability
law by blood shield laws in 47 of the 51 jurisdictions in this country.
Although these laws may protect society's interest in assuring an
adequate blood supply by shielding providers and manufacturers from
liability claims in instances where due care is taken, they have also
made it difficult and often impossible for individuals to obtain
compensation for infections acquired from blood or blood products. A
review of transfusion associated AIDS litigation for the period 1984
through 1993 (Ref. 20) reports only a handful of cases based on failure
of a blood establishment to perform ``lookback'' and none were reported
won by a plaintiff on this basis. The adoption of an approach involving
agency informal action based on the expectation of industry self-
regulation to solve problems has been strongly criticized in the IOM
review as inadequate to protect the public in the context of HIV/AIDS.
FDA believes this view is similiarly applicable to HCV.
b. Alternative: Use of general ``lookback.''. An alternative to
targeted ``lookback'' is an approach referred to as ``general
lookback.'' This approach would be implemented through the general
broadcast and other public media and regional medical organizations.
The program would be aimed at all patients who received blood before
the onset of screening, with the recommendation that they be tested for
evidence of infection. Physicians participate in the program by
recommending that previously transfused patients be tested for HCV. The
program often includes a letter campaign to all previously transfused
patients (regardless of the HCV status of the blood donors) from
hospitals and other blood consignees who performed the transfusion
service.
The cost and ultimate effectiveness of general ``lookback'' would
vary depending on the program structure. All of the general
``lookback'' approaches involve reduced costs for blood collection
centers, because the identification of infected donors would no longer
be required. Nevertheless, if the general ``lookback'' involves a
consignee letter campaign, the record review needed to identify current
addresses for all transfusion recipients could be as great or greater
than that required to identify only those recipients of blood products
who are at higher risk of HCV.
A recent Canadian effort involving general letter ``lookback'' is
estimated to have cost $1,654 per identified and confirmed positive
recipient ($2,123 including HCV testing) (Ref. 7). Another Canadian
hospital had completed a general letter ``lookback'' for HCV when the
Canadian Red Cross Society began targeted ``lookback'' in 1995. By
April of 1998, at least 13 new seropositive recipients had been
identified by targeted ``lookback'' who were missed by general
``lookback.'' As a result, targeted ``lookback'' raised the number of
HCV-positive recipients tested at that hospital by at least 9 percent
over general ``lookback.''
A general approach without letter notification can be less costly.
A 1990 electronic media program in Cincinnati, for example, was
estimated to have cost the blood center only $13,370, or $209 per
identified positive recipient; although the authors note that ``costs
to the notified recipients may far exceed those of the Center'' (Ref.
19). Despite the vigorous public information campaign, less than 5
percent of these recipients sought testing (Ref. 24). The CDC also is
undertaking a program of general ``lookback'' media activities, but
evidence of effectiveness is not yet available.
At this time, FDA believes that although general ``lookback'' may
be less costly, it is unlikely to communicate the relevant risk message
to the majority of affected transfusion recipients. The effectiveness
of a general ``lookback'' program requires that patients: (1) Be
reached by the program, (2) be aware of the transfusion episode, and
(3) seek testing even though the average risk per recipient is small.
Experience suggests that a substantial share of patients and families
are not
[[Page 69400]]
aware of earlier transfusions. A review of general ``lookback'' efforts
in Canada, for example, found that 25 to 32 percent of pediatric
patients and their families were unaware of an earlier transfusion. FDA
agrees that general ``lookback'' activities can be important,
particularly by reaching the population at risk due to parenteral drug
use or other risk behaviors not involving blood transfusion. General
``lookback'' activities can also reinforce the effectiveness of
targeted ``lookback.'' The agency believes, however, that by itself,
general ``lookback'' does not adequately inform all affected recipients
of blood transfusions.
c. Proposed: Use of targeted ``lookback.'' The ``lookback''
provisions of the proposed rule can be characterized as a ``targeted
lookback'' program, meaning that the notification of infection risk is
limited to or targeted at individuals identified as recipients of blood
from donors subsequently found to be infected with HCV. Targeted
``lookback'' requires that the transfusion service be aware that the
donor subsequently tested positive, donor and product disposition
records be available to link blood components with the identified
donors, and the physician or transfusion service know the recipient's
current whereabouts. Blood consignees would locate recipient records
for all transfused units from an affected donor, and have current
recipient or physician address information available so that
notifications can be delivered. Ideally, the recipient will still be
alive and be able to receive testing and treatment, if appropriate.
Recent experiences among Canadian facilities implementing HCV
``lookback'' suggest that the effectiveness of targeted ``lookback''
may vary, depending on the extent to which these conditions for success
hold true within a community. For example, a Canadian Red Cross Center
in Toronto reported that although able to identify 5,301 affected
components, trace 3,209 of those to hospitals, obtain responses for
2,807 (87 percent) of the units, and identify 2,437 as having been
transfused, the establishment found that 45 percent of the transfused
patients had already died. Of those remaining, only 184 patients (8
percent of the transfused) were finally tested as a result of the
``lookback'' effort, although as many as 68 percent of those tested
were found to be HCV positive (Ref. 21).
Despite the difficulties of implementing targeted ``lookback,'' FDA
concludes that it remains a valuable means of reaching patients at high
risk for HCV. As noted previously, a comparison of Canadian efforts in
targeted ``lookback'' versus general ``lookback'' through physician and
public education found that a large number of targeted patients and
families were unaware of the transfusion episode. These recipients
would not have been reached through the general ``lookback'' effort
(Ref. 7). Similar experiences have occurred with HIV ``lookback''
efforts (Ref. 22).
C. Small Business Impact
Because of the lack of information to characterize the relevant
volumes of affected blood and plasma products, the impact on those
establishments and consignees that might qualify as small entities is
uncertain. The FDA has therefore prepared an Initial Regulatory
Flexibility Analysis. The blood establishments and blood product
consignees affected by the proposed rule are included under the major
SIC (standard industrialization classification) group 80 for providers
of Health Services. According to Section 601 of the Regulatory
Flexibility Act of 1980, the term ``small entity'' encompasses the
terms ``small business,'' ``small organization'' and ``small
governmental jurisdiction.'' According to the Small Business
Administration (SBA), a small business within the blood industry is an
enterprise with less than $5 million in annual receipts. A small
organization is a not-for-profit enterprise which is independently
owned and operated and is not dominant in its field. A ``small
governmental jurisdiction'' generally means governments of cities,
counties, towns, townships, villages, school districts, or special
districts, with a population of less than 50,000.
The FDA registry of blood establishments does not provide an
indication of the size of the registered entities. Although uncertain,
it is likely that some smaller facilities may experience significant
costs as a result of compliance with the proposed rule. According to
the 1996 directory of the American Association of Blood Banks (AABB),
only 34 regional and community blood centers have annual revenues of
less than $5 million and each collect no more than 30,000 donations per
year. Based on their survey of the blood industry in 1992, Wallace et
al. (Ref. 3) estimate an annual total of 12,035,000 units of allogeneic
blood were collected by blood establishments. Each small blood center
would therefore account for approximately 0.2 percent (30,000/
12,035,000) of all collections. Assuming that the one-time and annual
costs of HCV ``lookback'' for blood collection facilities (see table 1
of section IV of this document) will be proportionate to the volume of
collections, this implies that the small centers would each experience
a one-time cost of approximately $72,229 ($36,114,442 x 0.002) and
yearly costs of approximately $9,117 ($4,558,442 x 0.002). Based on an
estimated average price of $103 per allogeneic unit (see footnote 1)
this one-time cost would represent approximately 2 percent ($72,229/
($103 x 30,000)) of annual average revenues. The yearly costs of on-
going prospective ``lookback'' would represent approximately 0.3
percent of average annual revenues ($9,117/($103 x 30,000)).
Hospitals are expected to be the primary entity affected by the
proposed requirements for transfusion services, but the extent of the
small business impact is uncertain. Although the details of transfusion
activities at hospitals are not available, FDA examined other data to
develop a preliminary assessment of small business impact. The size of
U.S. hospitals varies substantially. The 1998 American Hospital
Association (AHA) survey data indicate a total of 5,134 U.S. registered
community hospitals grouped into eight bed size categories. The average
annual revenues for facilities in these bed size categories range from
approximately $5.5 million to $513 million. However, since many
hospitals are not-for-profit or are operated by state and local
governments, the SBA annual receipts criteria for small businesses
would not apply to these facilities. Of the 5,134 U.S. community
hospitals included in the AHA report 1,330 are under the control of
State and local government, 3,045 are nonprofit institutions and the
remaining 759 are reported to be investor-owned.
The number of hospitals that would meet at least one of the various
SBA definitions for small entities is uncertain. According to the AHA
statistics for 1998, the smallest reported hospital size category
includes 262 hospitals with 6 to 24 beds, and total gross revenues of
$1.43 billion, yielding average revenues of $5.46 million. FDA assumes
that the 11 facilities reported to be investor-owned within this bed
size category could qualify as small entities. Although it is possible
that all nonprofit hospitals may qualify as small entities, it appears
that a number of facilities might be excluded from that definition
because they are reported to be hospitals in a system. According to the
AHA survey definition, ``hospitals in a system'' refer to those
``hospitals belonging to a corporate body that owns and/or manages
health provider facilities or health-related subsidiaries;
[[Page 69401]]
the system may also own non-health-related facilities'' (Ref. 23). The
AHA currently has record of 1,592 hospitals that are non-Federal and
nonprofit (including State and local government controlled) that are
hospitals in a system. If these facilities were excluded, FDA estimates
that 2,783 (1,330 State and local + 3,045 nonprofit - 1,592 in-a-
system) non-Federal, nonprofit hospitals may qualify as small entities.
Thus, a total of 2,794 (2,783 + 11) hospitals might qualify as small
entities.
The agency does not know how many of the estimated affected
transfusion recipients received their transfusion as part of care
provided at a hospital qualifying as a ``small entity.'' The following
analysis of potential impact by size of hospital suggests that,
regardless of hospital size, the cost impact may be limited if the
number of affected transfusion recipients is proportionate to the
number of inpatient surgeries performed by hospitals in different size
categories. Table 3 of this document estimates the percentage of all
inpatient hospital surgeries, based on the number of inpatient
surgeries reported to AHA as performed by hospitals in different bed
size categories. This percentage is used to estimate a share of the
total 303,676 retrospective recipient notification activities initiated
by hospitals in each category. The number of transfusion recipients to
be contacted per hospital within a bed size category is based on the
total estimated recipients per bed size category divided by the number
of hospitals reported for each category. These estimates are presented
in the right-most column of table 3. (Note that estimated values are
rounded).
Table 3.--Estimated Number of Affected Blood Recipients Per Hospital, Based on Estimated Number of Facilities
and Distribution of Important Surgeries By Hospital Size Category (Retrospective Review)
----------------------------------------------------------------------------------------------------------------
Non-Federal Estimated Percent Estimated Share of Estimated Recipients
Bed Size Category Hospitals Inpatient Surgeries Recipients per Hospital
----------------------------------------------------------------------------------------------------------------
6 to 24 262 0.21 627 2
25 to 49 906 2.02 6,121 7
50 to 99 1,128 6.03 18,315 16
----------------------------------------------------------------------------------------------------------------
Table 4 presents estimates of the cost per hospital, which are
derived from estimates of the number of transfusion recipients per
hospital (as shown in table 3) and the estimated notification cost of
$165 per recipient. To provide additional perspective on relative
impact, table 4 includes the notification cost shown as a percentage of
average annual gross revenues per hospital. The notification cost is
estimated to be approximately 0.01 percent of the average annual gross
revenues for every size category.
Table 4.--Estimated Notification Cost as a Percent of Gross Annual Revenue, Based on Estimates of Average Annual
Hospital Revenue
----------------------------------------------------------------------------------------------------------------
Cost per Hospital Notification Cost as
Bed Size Category for Retrospective Gross Annual Revenue Percent of Gross
Notification per Hospital Annual Revenue
----------------------------------------------------------------------------------------------------------------
6 to 24 $395 $5.459 million 0.01 percent
25 to 49 $1,115 $12.606 million 0.01 percent
50 to 99 $2,679 $27.711 million 0.01 percent
100 to 199 $7,256 $74.803 million 0.01 percent
----------------------------------------------------------------------------------------------------------------
A similar analysis of the yearly cost impact of prospective on-
going notification, that would involve an estimated 12,816 affected
components distributed across all hospitals, produces costs per
hospital per year ranging from $17 per facility for the smallest
hospital size category, to approximately $1,936 per facility for
hospitals in the 500 + bed size category. For all bed size categories,
the estimated yearly costs represent less than one-thousandth of a
percent of average annual revenues.
These findings of the Initial Regulatory Flexibility Analysis
suggests that the relative cost impact may be fairly consistent across
hospitals of different sizes, if the number of affected transfusion
recipients per hospital is proportionate to the number of inpatient
surgeries performed by hospitals in different size categories. However,
the distribution of affected transfusion recipients across hospitals of
different size and types of ownership is currently unknown. Because
this information is essential for the estimation of the economic impact
on small entities, FDA requests industry comment on the anticipated
numbers of affected transfusion recipients, the ability to trace
transfused products, and the volume of transfused products handled by
consignees, particularly those that can be classified as small
entities.
In general, it is expected that the regulatory costs for blood
establishments will be a function of the volume of donors, the number
of donations testing repeatedly reactive in a screening test for
evidence of HCV infection, the volume of donor blood components that
must be traced, the quality of facility recordkeeping and the number of
different consignees to which the collection facility distributes blood
products. These factors are likely to be larger and generate higher
potential costs for larger blood establishments. Yet careful screening
is already in place in most facilities, which will minimize the number
of affected units over time. It is similarly expected that transfusing
facilities will already have recordkeeping systems and SOP's in place
that can be readily adapted to HCV ``lookback.'' Also, recordkeeping
and procedures to support targeted ``lookback'' for HIV are expected to
provide a ready capability to trace donations and components affected
by the proposed rule. FDA anticipates therefore that most of the
information infrastructure needed for HCV ``lookback'' will already be
in place for both blood establishments and blood transfusion services.
For both types of establishments, the cost of compliance will primarily
involve additional staff time.
[[Page 69402]]
As described earlier, FDA has considered several alternatives, and
considers that a targeted ``lookback'' will be the most effective
approach to contacting affected recipients of HCV-infected blood
products. However, within that approach the agency allows for
flexibility in the facility's individual approach to compliance, to
help minimize the resource impact. For example, the particular design
and systems for record-keeping and standard operating procedures
developed in response to the proposed rule are under the control of the
facility, as is the approach taken to notification. This will enable
each facility to develop procedures that are most appropriate and cost-
effective given the resources available. In addition, the agency has
specified a limited time frame for notification, and a maximum required
number of attempts, in order to provide a clear endpoint to facility
efforts related to the ``lookback.''
Although FDA has obtained initial estimates of the number of blood
centers that would be classified as small entities, the agency
currently does not have data on the distribution of repeat donors,
donations testing repeatedly reactive in a screening test for evidence
of HCV infection, and affected blood components, for those
establishments that would qualify as small business entities. Because
this information is essential for the estimation of the economic impact
on small businesses, FDA requests industry comment on the current
recordkeeping, the ability to trace products, and the volumes of
donation units and components handled by these facilities.
V. The Paperwork Reduction Act of 1995
This proposed rule contains information collection provisions that
are subject to review by the Office of Management and Budget (OMB)
under the Paperwork Reduction Act of 1995 (the PRA) (44 U.S.C. 3501-
3520). The title, description, and respondent description of the
information collection provisions are shown in section V of this
document with an estimate of the annual reporting and recordkeeping
burden. Included in this estimate is the time for reviewing the
procedures, searching existing data sources, gathering and maintaining
the data needed, and completing and reviewing each collection of
information.
FDA invites comments on: (1) Whether the proposed collection of
information is necessary for the proper performance of FDA's functions,
including whether the information will have practical utility; (2) the
accuracy of FDA's estimate of the burden of the proposed collection of
information, including the validity of the methodology and assumptions
used; (3) ways to enhance the quality, utility, and clarity of the
information to be collected; and (4) ways to minimize the burden of the
collection of information on respondents, including through the use of
automated collection techniques, when appropriate, and other forms of
information technology.
Title: Reporting and recordkeeping requirements within Current Good
Manufacturing Practices for Blood and Blood Components: Notification of
Consignees and Transfusion Recipients Receiving Blood and Blood
Components at Increased Risk for Transmitting HCV Infection
(``lookback'').
Description: This proposed rule would require that blood
establishments prepare and follow written procedures when the blood
establishments have collected Whole Blood, blood components, Source
Plasma, and Source Leukocytes later determined to be at risk for
transmitting HCV infections. Under the proposed rule, blood
establishments would be required to include procedures that are similar
to procedures now in effect for HIV ``lookback'' (Secs. 610.46 and
610.47), for clarifying the status of the donor who later tests
repeatedly reactive in a licensed screening test for HCV, quarantining
prior collections from such donors, and notifying transfusion
recipients, as appropriate, based on further testing of the donor. When
a donor who previously donated blood is tested in accordance with
Sec. 610.40 on a later donation, and tests repeatedly reactive for
antibody to HCV, the blood establishment would be required to perform a
supplemental test using a licensed test, and notify consignees who
received Whole Blood, blood components, Source Plasma, and Source
Leukocytes from prior collections so that appropriate action is taken.
Blood establishments and consignees would be required to quarantine
previously collected Whole Blood, blood components, Source Plasma and
Source Leukocytes from such donors (some exemptions apply), and where
appropriate, consignees would notify transfusion recipients.
Under the proposed rule, blood establishments additionally would be
required to perform a one-time retrospective review of historical HCV
testing records that will identify prior collections from donors at
increased risk for transmitting HCV. The retrospective review of HCV
testing records would be limited to a period of time that is 12 months
prior to the last negative licensed multiantigen screening test,
whenever there is a record of such a prior test. Blood establishments
would be required to notify consignees of the risk of HCV transmission
that exists for prior collections based on the retrospective review of
HCV testing records and the results of the supplemental HCV testing
performed before or as a result of the retrospective review of testing
records. Blood establishments would notify consignees of the risk of
HCV transmission that exists for prior collections from a donor who
tested repeatedly reactive on a screening test for HCV and for whom the
blood establishment has no record of further testing and further
testing is impractical or infeasible (an exception may apply). Under
this proposal, consignees would notify the transfusion recipients.
FDA is also proposing conforming amendments to certain provisions
of Secs. 610.46 and 610.47, the HIV ``lookback'' regulations (61 FR
47413, September 9, 1996). The proposed revisions to Secs. 610.46 and
610.47, discussed under the corresponding sections of this proposal,
are intended to clarify and provide consistency between the HIV and HCV
``lookback'' requirements but do not include a requirement for the
retrospective review of historical HIV testing records. The agency is
issuing this proposed rule to help ensure that the blood supply
continues to be safe, that information is provided to users of blood
and blood components, and that transfusion recipients of blood and
blood components at risk for transmitting HCV will be notified, as
appropriate.
Description of Respondents: Blood establishments (Business and Not-
for-Profit) and consignees of blood establishments, including
hospitals, transfusion services and physicians.
The total reporting and recordkeeping burden for the first year is
estimated to be 492,148 hours. However, of this total approximately
470,237 hours would be expended on a one-time basis for establishing
the written procedures and doing the one-time retrospective review of
historical HCV testing records. Therefore, 21,911 hours is estimated as
the ongoing annual burden related to this proposed regulation. The
total ongoing annual burden for blood collection facilities under
Secs. 610.46(a), 610.46(b), 610.47(b) and 606.160(b)(1)(viii) for HIV
``lookback'' is estimated to be 1,843 hours. The total ongoing annual
burden for blood collection facilities under Secs. 610.48(a)(1)(ii),
610.48(b), 610.49(b), 610.49(c) and 606.160(b)(1)(viii) for
[[Page 69403]]
HCV ``lookback'' is estimated to be 20,698 hours.
Based on information previously discussed in section IV of this
document, there are approximately 2,800 FDA registered blood
establishments in the United States that collect approximately 12
million allogeneic donations annually. The CDC estimates there are
approximately 9,628,000 donations from repeat donors per year. The
following reporting and recordkeeping estimates are based on
information provided by industry, and FDA experience.
1. HIV Reporting Burden
In table 5, it is estimated that approximately 3,500 repeat donors
(an annual average of 1.25 repeat donors per establishment) will test
repeatedly reactive on a screening test for HIV. Under proposed
Secs. 610.46(a) and (b), this estimate results in 3,500 notifications
of the HIV screening test results to consignees by blood establishments
for the purpose of quarantine of affected units, and another 3,500
notifications to consignees of subsequent test results. FDA estimates
an average of 10 minutes per notification of consignees.
In addition, it is estimated that 180 transfusion services not
subject to HCFA regulations will be required under Sec. 610.47(b) to
notify physicians, or in some cases recipients, an average of 0.14
times per year resulting in a total number of 25 notifications. The
estimate of one-half hour for notifications under Sec. 610.47(b) is
based on the minimum requirement of three attempts to notify recipients
by transfusion services. FDA estimates that each repeat donor has
donated two previous times and two components were made from each
donation. The estimates for HIV ``lookback'' provided in the tables
differ from the estimates for HIV ``lookback'' provided in a notice
published in the Federal Register of November 4, 1999 (64 FR 60212)
because FDA has new, updated information from industry representatives
from which to base its estimates.
2. HCV Reporting Burden
Based on the interim results from a recent CDC survey (ref. 4), CDC
estimates that 11,520 repeat donors per year would test repeatedly
reactive for antibody to HCV. Under proposed Secs. 610.48(a)(1)(ii) and
610.48(b), blood establishments would notify the consignee two times
for each of the 12,816 components prepared from these donations, once
for quarantine purposes and again with additional HCV test results for
a total 25,632 notifications as an annual ongoing burden. Under
proposed Sec. 610.49(b) and (c), FDA estimates that approximately 6,200
transfusion services would notify two recipients annually.
A. HCV One-time Reporting Burden
Based on estimates from CDC, FDA expects that for the one-time
retrospective review of historical testing records, as many as 303,676
blood components would be at increased risk for transmitting HCV. For
each of these products, under Secs. 610.48(e)(2), 610.48(f)(2),
610.48(h)(3)(i) and (ii), and 610.48(i)(3)(i) and (ii), blood
establishments would notify consignees to quarantine these products and
report additional HCV test results to consignees, and, under
Sec. 610.49(b) and (c), consignees would notify transfusion recipients
or recipients' physicians of record. CDC estimated that there could be
approximately 258,125 transfusion recipients that would be notified
after a one-time retrospective review of historical test results for
HCV screening. The numbers in the hours per response column are based
on FDA's knowledge and experience regarding notification.
B. HCV Ongoing Annual Reporting Burden
Under Sec. 610.49(b) and (c), it is estimated that transfusion
services may be expected to notify approximately 10,894 transfusion
recipients per year, as previously discussed. The estimated average 0.5
hours to complete notification under Secs. 610.47(b), 610.49(b) and (c)
is based on FDA's knowledge and experience. The estimates of 13 hours,
5,447 hours, and 129,063 hours, respectively, allow for a consignee to
make up to three attempts to complete the notification process.
3. HIV and HCV Recordkeeping Burden
In the recordkeeping charts, the numbers in the hours per record
column are based on FDA's estimate of the time to complete one record.
FDA estimates that it will take blood collection facilities
approximately 40 hours to establish the written procedures proposed
under Sec. 606.100(b)(19) and consignees approximately 16 hours to
establish written procedures in accordance with proposed Sec. 610.49(b)
and (c). In table 7, the estimate of 154 recordkeepers and 175 total
annual records are based on the estimate that the HIV ``lookback''
requirements of Sec. 610.47(b) are already implemented voluntarily by
more than 95 percent of the facilities, which collect 98 percent of the
Nation's blood supply. FDA estimates that it takes transfusion services
approximately 10 minutes to document and maintain the records to relate
the donor with the unit number of each previous donation. The time
required for recordkeeping under Sec. 606.160(b)(1)(viii) is estimated
to be approximately 10 minutes for each HIV or HCV repeatedly reactive
donation record and approximately 10 minutes per transfusion recipient
record required under Secs. 610.47(b) and 610.49(b) and (c).
FDA estimates the burden for this collection of information as
follows:
Table 5.--Estimated Annual Reporting Burden\1\
----------------------------------------------------------------------------------------------------------------
21 CFR Annual Frequency Total Annual
Section No. of Respondents per Response Responses Hours per Response Total Hours
----------------------------------------------------------------------------------------------------------------
610.46(a) 2,800 1.25 3,500 .17 600
610.46(b) 2,800 1.25 3,500 .17 600
610.47(b) 180 0.14 25 .50 13
610.48(a)(i) 2,800 4.6 12,816 .17 2,179
(ii)
610.48(b) 2,800 4.6 12,816 .17 2,179
610.49(b)and 6,200 2 10,894 .50 5,447
(c)
Total 11,018
----------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of
information.
[[Page 69404]]
Table 6.--Estimated One-Time Reporting Burden\1\
----------------------------------------------------------------------------------------------------------------
21 CFR Annual Frequency Total Annual
Section No. of Respondents per Response Respondents Hours per Response Total Hours
----------------------------------------------------------------------------------------------------------------
610.48(e)(2) 2,800 41 115,228 .1 11,523
610.48(f)(2) 2,800 67 188,448 .1 18,845
610.48(h)(3) 2,800 41 115,228 .1 11,523
(i) and
(h)(3)(ii)
610.48(i)(3) 2,800 67 188,448 .1 18,845
(i) and
(i)(3)(ii)
610.49(b) 6,200 42 258,125 .5 129,063
and (c)
Total 189,799
----------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of
information.
Table 7.--Estimated Annual Recordkeeping Burden\1\
----------------------------------------------------------------------------------------------------------------
21 CFR No. of Annual Frequency Total Annual
Section Recordkeepers of Recordkeeping Records Hours per Record Total Hours
----------------------------------------------------------------------------------------------------------------
606.160(b)(1
)(viii)
HIV 154 1.14 175 .17 30
HIV 2,800 1.25 3,500 .17 600
HCV 2,800 9 25,632 .17 4,357
606.160(b)(1 6,200 4 25,632 .17 4,357
)(viii)
610.49(b) 6,200 2 12,816 .17 2,179
and (c)
Total 11,523
----------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of
information.
Table 8.--Estimated One-Time Recordkeeping Burden\1\
----------------------------------------------------------------------------------------------------------------
21 CFR No. of Frequency of
Section Recordkeepers Recordkeeping Total Records Hours per Record Total Hours
----------------------------------------------------------------------------------------------------------------
606.100(b)(1 2,800 1 2,800 40 112,000
9)
606.100(b)(1 6,200 1 6,200 16 99,200
9)
606.160(b)(1 2,800 108 303,676 0.08 24,294
)(viii)
606.160(b)(1 6,200 49 303,676 0.08 24,294
)(viii)
610.49(b) 6,200 42 258,125 0.08 20,650
and (c)
Total 280,438
----------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of
information.
There are no capital costs or operating and maintenance costs
associated with this collection of information.
In compliance with the Paperwork Reduction Act of 1995 (44 U.S.C.
3507(d)), the agency has submitted the information collection
provisions of this proposed rule to OMB for review. Interested persons
are requested to submit written comments regarding information
collection by December 18, 2000, to the Office of Information and
Regulatory Affairs, OMB (address above), Attention: Wendy Taylor, Desk
Officer for FDA.
VI. Request for Comments
Interested persons may submit to the Dockets Management Branch
(address above) written comments regarding this proposed rule by
February 14, 2001. 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
this document. Received comments may be seen in the office above
between 9 a.m. and 4 p.m., Monday through Friday.
VII. Proposed Effective Date
The agency is proposing that any final rule that may issue based
upon this proposed rule become effective 180 days after its date of
publication in the Federal Register.
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. Alter, M., ``Epidemiology of Hepatitis C,'' Hepatology,
26:62S-65S, 1997.
2. Alter, M., ``Epidemiology of Hepatitis C,'' Hepatology,
26:62S-65S, 1997.
3. Wallace, E. L., W. H. Churchill, D. M. Surgenor, J. An, G.
Cho, S. McGurk, and L. Murphy, ``Collection and Transfusion of Blood
and Blood Components in the United States, 1992,'' Transfusion, 35:
802-812, 1995.
4. Alter, M., CDC Survey Interim Results.
5. MacPherson, J., America's Blood Centers, ``Advisory Committee
on Blood Safety and Availability'' Tenth Meeting, vol. II, p. 7.
6. Quattrocchi, R., Home Access Health Corp.
7. Goldman, M., S. Juodvalkis, P. Gill, and G. Spurll,
``Hepatitis C Lookback,'' Transfusion Medicine Review, vol. 12, No.
2: 84-93, 1998.
8. U.S. Department of Health and Human Services, Center for
Disease Control and Prevention, ``Recommendations for Prevention and
Control of Hepatitis C Virus (HCV) Infection and HCV-Related Chronic
Disease,'' Morbidity and Mortality Weekly Report, vol. 47, No. RR-
19, October 16, 1998.
9. Kim, W. R., J. J. Poterucha, J. E. Hermans, T. M. Therneau,
E. R. Dickson, R. W. Evans, and J. B. Gross, ``Cost-Effectiveness of
6 and 12 Months of Interferon-alfa Therapy for Chronic Hepatitis
C,'' Annals of Internal Medicine, vol. 127, No. 10, November 1997.
10. Davis, G. L., and J. Y. N. Lau, ``Factors Predictive of a
Beneficial Response to Therapy of Hepatitis C,'' Hepatology, vol.
26, No. 3, Suppl.1: 122s-126s.
11. Bennett, W. G., Y. Inoue, J. R. Beck, J. B Wong, S. G.
Pauker, and G. L. Davis, ``Estimates of the Cost-Effectiveness of a
Single Course of Interferon-alfa2b in Patients with Histologically
Mild Chronic Hepatitis C,'' Annals of Internal Medicine, vol. 127,
No. 10, November 1997.
12. National Institutes of Health (NIH) Consensus Development
Conference Panel Statement: Management of Hepatitis C,
[[Page 69405]]
Hepatology, vol. 26, No. 3, Suppl. 1:2s-10s, 1997.
13. Dusheiko, G., ``Side Effects of Alpha Interferon in Chronic
Hepatitis C,'' Hepatology, vol. 26, No. 3, Suppl. 1:112s-119s, 1997.
14. J. G. McHutchison et al., New England Journal of Medicine,
339: 1485, 1998.
15. Leveton, L. B., H. C. Sox, Jr., and M. A. Stoto, editors,
HIV and the Blood Supply: An Analysis of Crisis Decisionmaking,
Chapter 7, Institute of Medicine, National Academy Press,
Washington, DC, 1995.
16. Ottosen, J. S., The Blood Conspiracy: How to Avoid Getting
AIDS and Hepatitis in a Transfusion, Aspen Leaf Press, Woodland
Park, CO, 1993.
17. Moreno, J. D., ``Attitudes Toward Risk: The Right to Know
and the Right to Give Informed Consent'' in Blood and Blood
Products: Safety and Risk, Institute of Medicine, National Academy
Press, Washington, DC, 1996.
18. Groopman, J., ``The Shadow Epidemic'' The New Yorker, May
11, 1998.
19. Zuck, T. F., G. A. Rose, U. J. Dumaswala, N. J. Geer,
``Experience with a Transfusion Recipient Education Program about
Hepatitis C,'' Transfusion, vol. 30, No. 8, 761, 1990.
20. Kern, J. M., and B. B. Croy, ``A Review of Transfusion-
Associated AIDS Litigation: 1984 Through 1993,'' Transfusion, vol.
34, No. 6, 1994.
21. Wall, A., W. Lau, J. Lewis, J. A. Chiavetta, S. Mohammad,
and R. Herst, ``Hepatitis C Virus (HCV) Targeted Lookback Program,''
Transfusion, vol. 37 Suppl. s392, 1997.
22. Gill, M. J., D. Towns, S. Allaire, and G. Meyers,
``Transmission of Human Immunodeficiency Virus Through Blood
Transfusion: The Use of Lookback and Traceback Approaches to
Optimize Recipient Identification in a Regional Population,''
Transfusion, vol. 37, 513-516, 1997.
23. Healthcare InfoSource, Inc., a subsidiary of the American
Hospital Association, Hospital Statistics, 1998 ed., Chicago IL.
24. AuBuchon, J., ``Public Health, Public Trust, and Public
Decision Making: Making Hepatitis C Virus Lookback Work,''
Transfusion, vol. 39, p. 124, 1999.
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 and the
Public Health Service Act, and under authority delegated to the
Commissioner of Food and Drugs, it is proposed that 21 CFR parts 606
and 610 be amended as follows:
PART 606--CURRENT GOOD MANUFACTURING PRACTICE FOR BLOOD AND BLOOD
COMPONENTS
1. The authority citation for 21 CFR part 606 continues to read as
follows:
Authority: 21 U.S.C. 321, 331, 351, 352, 355, 360, 360j, 371,
374; 42 U.S.C. 216, 262, 263a, 264.
2. Section 606.100 is amended by revising paragraph (b)(19) to read
as follows:
Sec. 606.100 Standard operating procedures.
* * * * *
(b) * * *
(19) Procedures in accordance with Secs. 610.46 and 610.48 of this
chapter to look at prior donations of blood and blood components from a
donor who has donated blood and subsequently tests repeatedly reactive
for evidence of human immunodeficiency virus (HIV) infection or
hepatitis C virus (HCV) infection when tested in accordance with
Sec. 610.40 of this chapter or when a blood establishment has been made
aware of other test results indicating evidence of HIV or HCV
infection. Procedures to quarantine in-date blood and blood components,
intended for further manufacture into injectable products 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; procedures to notify
consignees of blood and blood components from such donors of the
results of the HIV and HCV testing performed on such donors; procedures
in accordance with Secs. 610.47 and 610.49 of this chapter to notify
physician of record so that recipients of transfusion with blood or
blood components are informed that they may have received blood or
blood components at increased risk of transmitting HIV and HCV,
respectively.
* * * * *
3. Section 606.160 is amended by revising paragraph (b)(1)(viii)
and the second sentence of paragraph (d) to read as follows:
Sec. 606.160 Records.
* * * * *
(b) * * *
(1) * * *
(viii) Records of quarantine, consignee notification, further
testing, transfusion recipient notification, and disposition performed
under Secs. 610.46, 610.47, 610.48, and 610.49 of this chapter.
* * * * *
(d) * * * The retention period shall be no less than 10 years after
the records of processing have been completed or 6 months after the
latest expiration date for the individual product, whichever is the
later date. * * *
* * * * *
PART 610--GENERAL BIOLOGICAL PRODUCTS STANDARDS
4. The authority citation for 21 CFR part 610 continues to read as
follows:
Authority: 21 U.S.C. 321, 351, 352, 353, 355, 360, 371; 42
U.S.C. 216, 262, 263, 263a, 264.
5. Section 610.40 is amended by adding paragraph (g) to read as
follows:
Sec. 610.40 Test for hepatitis B surface antigen.
* * * * *
(g) For a donor whose test result for HIV or HCV is repeatedly
reactive when tested in accordance with paragraphs (a), (c), and (d) of
this section, or when a blood establishment has been made aware of
other test results indicating evidence of HIV or HCV infection, the
blood establishment shall comply, as applicable, with Secs. 610.46,
610.47, 610.48, and 610.49.
6. Section 610.46 is amended by revising the section heading and
paragraph (a), the heading for paragraph (b), the first sentence of
paragraphs (b) and (c), and paragraph (d); by redesignating paragraph
(e) as paragraph (f); by revising newly redesignated paragraph (f); and
by adding new paragraph (e) to read as follows:
Sec. 610.46 Human Immunodeficiency Virus (HIV) ``Lookback;''
quarantine, consignee notification and further testing.
(a) Quarantine and consignee notification. (1) All blood and plasma
establishments shall take appropriate action when a donor of blood or
blood components tests repeatedly reactive for evidence of HIV
infection on a screening test in accordance with Sec. 610.40(a), or
when the blood establishment has been made aware of other test results
indicating evidence of HIV infection, provided the testing was
performed by a laboratory certified under the Clinical Laboratory
Improvement Amendments of 1988, using a test approved by FDA. For blood
and blood components collected from that donor at any time prior to the
repeatedly reactive test, whenever records are available, if intended
for transfusion or for further manufacture into injectable products,
except those products exempt from quarantine in accordance with
paragraph (c) of this section, the blood establishment shall, within 3-
calendar days after the date on which the donor tested repeatedly
reactive for evidence of HIV infection or after the date on which the
blood establishment was made aware of other test results
[[Page 69406]]
indicating evidence of HIV infections, identify the prior collections
from that donor and:
(i) Quarantine all such prior collections of blood and blood
components; and
(ii) Notify consignees of the repeatedly reactive HIV screening
test result so that the consignee may quarantine all such prior
collections of blood and blood components.
(2) Consignees notified in accordance with paragraph (a)(1)(ii) of
this section shall quarantine all such prior collections of blood and
blood components held at that establishment, except as provided in
paragraph (c) of this section.
(b) Further testing and consignee notification of results. Blood
establishments shall perform further testing on the donor's blood, as
specified in Sec. 610.40(c), and shall notify the consignee(s) of the
results of this test within 45-calendar days after the date on which
the donor tested repeatedly reactive for evidence of HIV infection on a
screening test. * * *
(c) Exemption from quarantine. Prior collections otherwise subject
to quarantine under paragraph (a) of this section 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 for HIV in accordance with
Sec. 610.40(a). * * *
(d) Release from quarantine. Prior collections of blood and blood
components intended for transfusion or further manufacture into
injectable products which have been quarantined under paragraph (a) of
this section may be released if the donor's current repeatedly reactive
sample is subsequently tested for antibody to HIV as provided in
paragraph (b) of this section and the test result is negative, absent
other informative test results.
(e) Destruction or labeling of prior collections held in
quarantine. Blood establishments and consignees shall destroy or
appropriately label for in vitro use prior collections of blood and
blood components otherwise subject to quarantine in accordance with
paragraphs (a) and (d) of this section, unless such prior collections
are determined to be exempt from quarantine in accordance with
paragraph (c) of this section or subject to release from quarantine in
accordance with paragraph (d) of this section. Quarantined prior
collections made available for in vitro use shall be appropriately
relabeled consistent with Secs. 606.121 and 640.70 of this chapter. In
addition, these units must be relabeled as ``Biohazard'' with the
cautionary statement as follows:
``Collected from a donor who subsequently tested positive for anti-HIV.
An increased risk for transmission of human immunodeficiency virus is
present;'' in addition, the label must contain one of the following
cautionary statements, as appropriate: ``Caution: For Further
Manufacturing Into In Vitro Diagnostic Reagents For Which There Are No
Alternative Sources.'' or ``For Laboratory Research Use Only.''
(f) Actions under this section. Actions under this section do not
constitute a recall as defined in Sec. 7.3 of this chapter.
7. Section 610.47 is revised to read as follows:
Sec. 610.47 Human Immunodeficiency Virus (HIV) ``Lookback;''
notification of transfusion recipients.
(a) Appropriate actions following further testing. Transfusion
services that are not subject to the Health Care Financing
Administration's regulations on conditions of Medicare participation
for hospitals (42 CFR part 482) are required to take appropriate action
in accordance with paragraphs (b) and (c) of this section when a
recipient has received prior collections of blood or blood components
from a donor later determined to be unsuitable when tested for evidence
of infection due to HIV and the result of the additional tests as
provided for in Sec. 610.46(b) are positive.
(b) Notification of recipients of prior transfusion. If the
transfusion service has administered blood or blood components as
described in paragraph (a) of this section, the transfusion service
shall either notify the recipient directly or notify the recipient's
physician of record (i.e., physician of record or physician who ordered
the blood or blood component) and ask him or her to inform the
recipient of the need for HIV testing and counseling. If the physician
is not available 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 notification process shall include
a minimum of three attempts to notify the recipient, or the recipient's
physician, and be completed within a maximum of 12 weeks of receipt of
the result of the licensed, more specific test for HIV from the blood
establishment. The transfusion service is responsible for notification,
including basic explanations to the recipient and referral for
counseling and further testing, and shall document the notification and
the result of attempts to notify the recipient and the recipient's
physician of record, if contacted, under Sec. 606.160 of this chapter.
(c) Notification of legal representative or relative. If the
transfusion recipient has been adjudged incompetent by a State court,
the legal representative, designated in accordance with State law,
shall be notified. If the transfusion recipient is competent, but State
law permits a legal representative or relative to receive the
information on the recipient's behalf, the transfusion service or the
physician who agreed to perform the notification on behalf of the
transfusion service shall notify the recipient or his or her legal
representative or relative. If the transfusion recipient is a minor at
the time of notification, the transfusion service or physician, as
described in this paragraph, shall notify the recipient's legal
representative or relative. If the transfusion recipient is deceased,
the transfusion service or physician, as described in this paragraph,
shall continue the notification process and inform the deceased
recipient's legal representative or relative. The transfusion service
is responsible for notification, including basic explanations to the
recipient's legal representative or relative and referral for
counseling and further testing of the recipient, and shall document the
notification and the result of attempts to notify the recipient's legal
representative or relative and the recipient's physician of record, if
contacted, under Sec. 606.160 of this chapter. Reasons for notifying
the recipient's relative or legal representative on his or her behalf
shall be documented under Sec. 606.160 of this chapter.
8. Section 610.48 is added to subpart E to read as follows:
Sec. 610.48 Hepatitis C Virus (HCV) ``Lookback;'' quarantine,
consignee notification and further testing.
(a) Quarantine and consignee notification. (1) Repeatedly reactive
screening test. All blood and plasma establishments shall take
appropriate action when a donor of blood or blood components tests
repeatedly reactive for evidence of HCV infection on a screening test,
in accordance with Sec. 610.40(a), or when the blood establishment has
been made aware of other test results indicating evidence of HCV
infection, provided the testing was performed by a laboratory certified
under the Clinical Laboratory Improvement Amendments of 1988, using a
test approved by FDA. For in-date blood and blood components collected
from that donor at any time prior to the repeatedly reactive test,
[[Page 69407]]
whenever records are available, if intended for transfusion, or if
intended for further manufacture into injectable products, except those
products exempt from quarantine in accordance with paragraph (g)(1) of
this section, the blood establishment shall, within 3-calendar days
after the date on which the donor tested repeatedly reactive for
evidence of HCV infection or after the date on which the blood
establishment was made aware of other test results indicating evidence
of HCV infection, identify the prior collections from that donor and:
(i) Quarantine all such prior collections of blood and blood
components; and
(ii) Notify consignees of the repeatedly reactive HCV screening
test result so that the consignee may quarantine all such prior
collections of blood and blood components.
(2) Quarantine by consignee. Consignees notified in accordance with
paragraph (a)(1)(ii) of this section shall quarantine all such prior
collections of blood and blood components held at that establishment,
except as provided in paragraph (g)(1) of this section.
(b) Further testing and consignee notification of results. In the
case of a donor with a repeatedly reactive screening test for HCV,
blood establishments shall perform further testing on the donor's
blood, as specified in Sec. 610.40(c). Where prior collections from the
same donor were distributed, blood establishments shall notify the
consignee(s) of the results of this test within 45-calendar days after
the date on which the donor tested repeatedly reactive for evidence of
HCV infection on a screening test.
(c) Review of historical testing records and identification of
donors tested using a multiantigen screening test prior to [the
effective date of the final rule]. Blood establishments shall review
records of donor testing completed prior to [the effective date of the
final rule] in order to identify donors who tested repeatedly reactive
for evidence of HCV infection on a multiantigen screening test for HCV
and to identify prior collections from such donors. Blood
establishments shall, by (date 1 year from the effective date of the
final rule), identify previously distributed blood and blood components
from such donors, based on available required records maintained in
accordance with Sec. 606.160 of this chapter, dating back indefinitely
for computerized electronic records and to January 1, 1988, for other
readily retrievable records, or to the date 12 months prior to the
donor's most recent negative multiantigen screening test for antibody
to HCV, whichever is the lesser period. Blood establishments shall
identify previously distributed blood and blood components from such
donors in any of the following instances:
(1) First instance. Where the donor tested repeatedly reactive for
evidence of HCV infection on the multiantigen screening test and
positive on a supplemental test for HCV performed on the repeatedly
reactive sample;
(2) Second instance. Where the donor tested repeatedly reactive for
evidence of HCV infection on the multiantigen screening test and
indeterminate on a supplemental test for HCV performed on the
repeatedly reactive sample;
(3) Third instance. Where the donor tested repeatedly reactive for
evidence of HCV infection on an HCV EIA 3.0 multiantigen screening test
and negative on a HCV 2.0 strip immunoblot assay (HCV RIBA 2.0
supplemental test) with no record of a negative licensed HCV 3.0 strip
immunoblot assay (RIBA 3.0 supplemental test) performed on the
repeatedly reactive sample or a later sample from the same donor.
(4) Fourth instance. Where the donor tested repeatedly reactive for
evidence of HCV infection on a licensed HCV EIA 2.0 screening test with
no record of a supplemental test for HCV performed on the repeatedly
reactive sample or on a later sample from the same donor and no record
of a negative licensed HCV EIA 3.0 screening test performed on the
repeatedly reactive sample or a later sample from the same donor; or
(5) Fifth instance. Where the donor tested repeatedly reactive for
evidence of HCV infection on a licensed HCV EIA 3.0 screening test with
no record of a supplemental test for HCV performed on the repeatedly
reactive sample or on a later sample from the same donor.
(d) Review of historical testing records and identification of
donors tested using a single antigen screening test prior to [the
effective date of the final rule]. Blood establishments shall review
records of donor testing completed prior to [the effective date of the
final rule] in order to identify donors who tested repeatedly reactive
for evidence of HCV infection on a single antigen screening test for
HCV and to identify prior collections from such donors. Blood
establishments shall, by (date 1 year from the effective date of the
final rule), identify previously distributed blood and blood components
from such donors, based on available required records maintained in
accordance with Sec. 606.160 of this chapter, dating back indefinitely
for computerized electronic records and to January 1, 1988, for other
readily retrievable records, or to the date 12 months prior to the
donor's most recent negative multiantigen screening test for antibody
to HCV, whichever is the lesser period, in any of the following
instances:
(1) First instance. Where the donor tested repeatedly reactive for
evidence of HCV infection on the single antigen screening test and
repeatedly reactive on an HCV EIA 2.0 or HCV EIA 3.0 screening test
performed on the repeatedly reactive sample or a fresh sample from the
same donor;
(2) Second instance. Where the donor tested repeatedly reactive for
evidence of HCV infection on the single antigen screening test and
either positive or indeterminate on an HCV 2.0 or HCV 3.0 strip
immunoblot assay (HCV RIBA 2.0 or HCV RIBA 3.0, respectively)
supplemental test for HCV performed on the repeatedly reactive sample
or a fresh sample from the same donor;
(3) Third instance. Where the donor tested repeatedly reactive for
evidence of HCV infection on an HCV EIA 1.0 screening test, with a
signal to cutoff (S/CO) value less than 2.5 for at least two out of the
three EIA tests (i.e., the initial EIA screening test and the duplicate
retests), with no record of a supplemental test or multiantigen
screening test for HCV performed on the repeatedly reactive sample or
on a later sample from the same donor; or
(4) Fourth instance. Where the donor tested repeatedly reactive for
evidence of HCV infection on an HCV EIA 1.0 screening test, with a S/CO
value equal to or greater than 2.5 for at least two out of the three
EIA tests (i.e., the initial EIA screening test and the duplicate
retests) or with no determination of S/CO value for all three EIA
tests, and with no record of a supplemental test or multiantigen
screening test for HCV performed on the repeatedly reactive sample or
on a later sample from the same donor.
(e) Quarantine and consignee notification following the review of
historical testing records based on screening performed using a
multiantigen screening test. Blood establishments shall, by (date 1
year from the effective date of the final rule), complete all
quarantine and consignee notification requirements for prior
collections from donors identified in the review of historical testing
records in accordance with paragraph (c) of this section as follows:
(1) Quarantine. Blood establishments shall, within 3-calendar days
of the date of the identification of the donor's repeatedly reactive
multiantigen screening test for HCV, quarantine all in-date prior
collections of blood and blood components collected from such a donor
at any time prior to the
[[Page 69408]]
repeatedly reactive multiantigen screening test and identified in
accordance with paragraph (c) of this section, if intended for
transfusion, or if intended for further manufacture into injectable
products, except those products exempt from quarantine in accordance
with paragraph (g)(2) of this section.
(2) Consignee notification. Blood establishments shall, within 3-
calendar days of the date of identification of the donor's repeatedly
reactive multiantigen screening test for HCV, notify consignees of the
donor's test results, including the supplemental test results, if
available, so that consignees may quarantine all in-date prior
collections of blood and blood components subject to quarantine under
paragraph (e)(1) of this section.
(3) Quarantine by consignees. Consignees notified in accordance
with paragraph (e)(2) of this section shall quarantine all in-date
prior collections of blood and blood components subject to quarantine
under paragraph (e)(1) of this section, except as provided in paragraph
(g)(2) of this section.
(f) Quarantine and consignee notification following the review of
historical testing records based on screening performed using a single
antigen screening test. (1) Quarantine. Blood establishments shall, by
(date 1 year from the effective date of the final rule) and within 3-
calendar days of the date of the identification of the donor's
repeatedly reactive single antigen screening test for HCV, quarantine
all in-date prior collections of blood and blood components collected
from such a donor at any time prior to the repeatedly reactive single
antigen screening test and identified in accordance with paragraph (d)
of this section, if intended for transfusion, or if intended for
further manufacture into injectable products, except those products
exempt from quarantine in accordance with paragraph (g)(3) of this
section.
(2) Consignee notification. Blood establishments shall, within 3-
calendar days of the date of identification of the donor's repeatedly
reactive single antigen screening test for HCV, notify consignees of
the donor's test results, including the supplemental test results, if
available, so that consignees may quarantine all in-date prior
collections of blood and blood components subject to quarantine under
paragraph (f)(1) of this section.
(3) Quarantine by consignees. Consignees notified in accordance
with paragraph (f)(2) of this section shall quarantine all in-date
prior collections of blood and blood components subject to quarantine
under paragraph (f)(1) of this section, except as provided in paragraph
(g)(3) of this section.
(g) Exemption from quarantine. As used in Sec. 610.48, an
appropriately chosen licensed supplemental test is one which includes
all antigens contained in the screening test that was performed.
(1) Prior collections subject to quarantine under paragraph (a) of
this section. Prior collections otherwise subject to quarantine under
paragraph (a) of this section need not be placed in quarantine if a
determination has been made that:
(i) The blood or blood component was collected more than 12 months
prior to the donor's most recent negative multiantigen screening test
when tested for HCV in accordance with Sec. 610.40(a); or
(ii) An appropriately chosen licensed supplemental test for HCV,
performed in accordance with paragraph (b) of this section has been
completed within 3-calendar days of the date of the donor's repeatedly
reactive screening test and the result is negative.
(2) Prior collections subject to quarantine under paragraph (e)(1)
of this section. Prior collections otherwise subject to quarantine
under paragraph (e)(1) of this section need not be placed in quarantine
if a determination has been made that:
(i) The blood or blood component was collected more than 12 months
prior to the donor's most recent negative multiantigen screening test
for HCV that preceded the repeatedly reactive screening test; or
(ii)(A) The repeatedly reactive screening test result was obtained
using an HCV EIA 2.0 screening test, and either the original sample or
a later sample from the same donor was tested and found negative using
an HCV RIBA 2.0 or HCV RIBA 3.0 supplemental test or an HCV EIA 3.0
screening test; or
(B) The repeatedly reactive screening test result was obtained
using an HCV EIA 3.0 screening test, and either the original sample or
a later sample from the same donor was tested and found negative using
an HCV RIBA 3.0 supplemental test;
(3) Prior collections subject to quarantine under paragraph (f)(1)
of this section. Prior collections otherwise subject to quarantine
under paragraph (f)(1) of this section need not be placed in quarantine
if the donor's testing records show that:
(i) The repeatedly reactive screening test result was obtained
using an HCV EIA 1.0 screening test, and either the original sample or
a later sample from the same donor was further tested and found
negative using an HCV EIA 2.0 or 3.0; or
(ii) The repeatedly reactive screening test result was obtained
using an HCV EIA 1.0 screening test, and either the original sample or
a later sample from the same donor was tested and found negative using
an HCV RIBA 2.0 or HCV RIBA 3.0 supplemental test ; or
(iii)(A) The donor, identified in accordance with paragraph (d)(1)
of this section, as testing repeatedly reactive on an HCV EIA 2.0, was
further tested using a HCV RIBA 2.0 or HCV RIBA 3.0 supplemental test,
on a fresh sample, or frozen sample from the repeatedly reactive
donation and the result was negative; or
(B) The donor, identified in accordance with paragraph (d)(1) of
this section, as testing repeatedly reactive on an HCV EIA 3.0, was
further tested using an HCV RIBA 3.0 supplemental test, on a fresh
sample, or frozen sample from the repeatedly reactive donation and the
result was negative; or
(iv) The donor identified in accordance with paragraph (d)(2) of
this section, as testing indeterminate on a HCV RIBA 2.0 supplemental
test, was further tested using either an HCV EIA 3.0 or a HCV RIBA 3.0
supplemental test on a fresh sample, or frozen sample from the
repeatedly reactive donation and the result was negative.
(h) Further testing following review of historical testing records
and consignee notification based on screening performed using a
multiantigen screening test. (1) Further testing. Blood establishments
that have performed the review of records and identified prior
collections in accordance with paragraphs (c)(4) and (c)(5) of this
section shall, by (date 1 year from the effective date of the final
rule):
(i)(A) If the repeatedly reactive test result was obtained using a
HCV EIA 2.0 screening test, perform a licensed supplemental test for
HCV on a frozen sample from the repeatedly reactive donation, if
available; or if such a frozen sample is not available, obtain a fresh
sample from such a donor and perform a licensed supplemental test for
HCV; or
(B) If the repeatedly reactive test result was obtained using a HCV
EIA 2.0 screening test, perform a licensed HCV EIA 3.0 screening test
on a frozen sample, if available, or on a fresh sample from such a
donor and perform a licensed supplemental test if the HCV EIA 3.0
screening test is repeatedly reactive; or
(ii) If the repeatedly reactive test result was obtained using a
HCV EIA 3.0 screening test, perform a licensed supplemental test for
HCV on a frozen
[[Page 69409]]
sample, if available, or on a fresh sample from such a donor; or
(iii) Make a determination that neither a frozen sample from the
repeatedly reactive donation nor a fresh sample from the donor is
available for further testing.
(2) Options for further testing. Blood establishments that have
performed the review of records and identified certain prior
collections in accordance with paragraphs (c)(2) or (c)(3) of this
section, and as described in paragraphs (h)(2)(i) through (h)(2)(iv) of
this section may further test a frozen sample from the repeatedly
reactive donation or a fresh sample from the same donor by (date 1 year
from the effective date of the final rule), as follows:
(i) Donors identified in accordance with paragraph (c)(2) of this
section as testing repeatedly reactive using an HCV EIA 2.0 screening
test, and indeterminate on an HCV RIBA 2.0 supplemental test, may be
further tested using either a licensed HCV EIA 3.0 screening test or a
currently available licensed supplemental test for HCV;
(ii) Donors identified in accordance with paragraph (c)(2) of this
section as testing repeatedly reactive using an HCV EIA 2.0 screening
test, indeterminate on a HCV RIBA 2.0 supplemental test, and repeatedly
reactive on an HCV EIA 3.0 screening test, performed in accordance with
paragraph (h)(2)(i) of this section, may be further tested using an
appropriately chosen licensed supplemental test for HCV;
(iii) Donors identified in accordance with paragraph (c)(2) of this
section as testing repeatedly reactive using an HCV EIA 3.0 screening
test, and indeterminate on a HCV RIBA 2.0 supplemental test, may be
further tested using an appropriately chosen licensed supplemental test
for HCV;
(iv) Donors identified in accordance with paragraph (c)(3) of this
section as testing repeatedly reactive using an HCV EIA 3.0 screening
test, and negative on a HCV RIBA 2.0 supplemental test with no record
of a negative HCV RIBA 3.0 supplemental test, may be further tested
using an appropriately chosen licensed supplemental test for HCV.
(3) Consignee notification. Except for blood and blood components
exempt from quarantine in accordance with paragraph (g)(2) of this
section, blood establishments shall:
(i) Within 45 days following completion of additional testing and
prior to (date 1 year from the effective date of the final rule),
notify consignees of the results of the additional licensed screening
test and/or the licensed, supplemental test performed in accordance
with paragraphs (h)(1) and (h)(2) of this section; or
(ii) Prior to (date 1 year from the effective date of the final
rule), notify consignees of the test results for a donor who was
identified in the review of historical testing records, in accordance
with paragraphs (c)(1) through (c)(5) of this section.
(i) Further testing following review of historical testing records
and consignee notification based on screening performed using a single
antigen screening test. (1) Further testing. Blood establishments that
have performed the review of records and identified prior collections
in accordance with paragraph (d)(4) of this section shall, by (date 1
year from the effective date of the final rule):
(i) Perform a licensed, supplemental test for HCV on a frozen
sample from the repeatedly reactive donation, if available; or if such
a frozen sample is not available, obtain a fresh sample from such a
donor and perform a licensed supplemental test for HCV; or
(ii) Make a determination that neither a frozen sample from the
repeatedly reactive donation nor a fresh sample from the donor is
available for further testing.
(2) Options for further testing. Blood establishments that have
performed the review of records and identified certain prior
collections in accordance with paragraphs (d)(1) or (d)(2) of this
section and described in paragraphs (i)(2)(i) through (i)(2)(iii) of
this section may further test a frozen sample from the repeatedly
reactive donation or a fresh sample from the same donor, by (date 1
year from the effective date of the final rule), as follows:
(i) Donors identified in accordance with paragraph (d)(1) of this
section as testing repeatedly reactive on an HCV EIA 1.0 screening test
and repeatedly reactive on either an HCV EIA 2.0 or HCV EIA 3.0
screening test may be further tested using an appropriately chosen
licensed supplemental test for HCV; or
(ii) Donors identified in accordance with paragraph (d)(2) of this
section as testing repeatedly reactive on an HCV EIA 1.0 screening test
with an indeterminate test result obtained using an HCV RIBA 2.0
supplemental test, may be further tested using a currently available
licensed supplemental test for HCV or an HCV EIA 3.0. If such optional
further testing is performed using an HCV EIA 3.0 and the result is
repeatedly reactive, blood establishments may perform further testing
using an appropriately chosen licensed supplemental test for HCV.
(iii) Donors identified in accordance with paragraph (d)(3) of this
section as testing repeatedly reactive on an HCV EIA 1.0 screening test
with a S/CO value less than 2.5 for at least two out of the three EIA
tests, and with no record of a supplemental test or multiantigen
screening test for HCV performed on the repeatedly reactive sample or
on a later sample from the same donor, may be further tested using a
licensed multiantigen screening test for HCV or a licensed supplemental
test for HCV.
(3) Consignee notification. Except for blood and blood components
exempt from quarantine in accordance with paragraph (g)(3) of this
section, blood establishments shall:
(i) Within 45 days following completion of additional testing and
prior to (date 1 year from the effective date of the final rule),
notify consignees of the results of the additional licensed screening
test and/or the licensed, supplemental test performed in accordance
with paragraphs (i)(1) and (i)(2) of this section; or
(ii) Prior to (date 1 year from the effective date of the final
rule), notify consignees of the test results for a donor who was
identified in the review of historical testing records in accordance
with paragraphs (d)(1) through (d)(4) of this section.
(j) Release from quarantine. (1) Prior collections subject to
quarantine under paragraph (a) of this section. Prior collections of
blood and blood components intended for transfusion or further
manufacture into injectable products which are subject to quarantined
under paragraph (a) of this section may be released if the donor's
current, repeatedly reactive sample is subsequently tested using a
licensed, supplemental test for HCV as provided in paragraph (b) of
this section and the result is negative.
(2) Prior collections subject to quarantine under paragraph (e)(1)
of this section. Prior collections of blood and blood components, which
are not exempt from quarantine under paragraph (g)(2) of this section,
and are otherwise subject to quarantine under paragraph (e)(1) of this
section may be released from quarantine if:
(i)(A) The donor's testing records meet the conditions specified in
paragraph (c)(4) of this section and further testing was performed in
accordance with paragraph (h)(1)(i)(A) of this section on a frozen
sample from the repeatedly reactive donation or a fresh sample from the
same donor using a licensed supplemental test for HCV, and the result
of the licensed supplemental test for HCV is negative; or
[[Page 69410]]
(B) The donor's testing records meet the conditions specified in
paragraph (c)(4) of this section and further testing was performed in
accordance with paragraph (h)(1)(i)(B) of this section on a frozen
sample from the repeatedly reactive donation or a fresh sample from the
same donor using a licensed, HCV EIA 3.0 screening test and the result
is negative, or using a licensed, supplemental test if the HCV EIA 3.0
screening test is repeatedly reactive and the result of the licensed,
supplemental test is negative; or
(ii) The donor's testing records meet the conditions specified in
paragraph (c)(5) of this section and further testing was performed in
accordance with paragraph (h)(1)(ii) of this section on a frozen sample
or a fresh sample from the same donor using a licensed, supplemental
test for HCV and the result is negative; or
(iii) The donor's testing records meet the conditions specified in
paragraph (c)(2) of this section and further testing was performed, in
accordance with paragraph (h)(2) of this section, as follows:
(A) The repeatedly reactive sample (test performed using an HCV EIA
2.0 screening test), or a later sample from the donor was further
tested in accordance with paragraph (h)(2)(i) of this section using
either a licensed HCV EIA 3.0 screening test or a licensed supplemental
test for HCV and the result is negative; or
(B) The repeatedly reactive sample (test performed using an HCV EIA
2.0 screening test) or a later sample from the donor was further tested
in accordance with paragraph (h)(2)(ii) of this section using an
licensed supplemental test for HCV and the result is negative; or
(C) The repeatedly reactive sample (test performed using an HCV EIA
3.0 screening test) or a later sample from the donor was further tested
in accordance with paragraph (h)(2)(iii) of this section using a
licensed supplemental test for HCV and the result is negative; or
(iv) The donor's testing records meet the conditions specified in
paragraph (c)(3) of this section and further testing was performed in
accordance with paragraph (h)(2)(iv) of this section on a frozen sample
or a fresh sample from the same donor using a licensed supplemental
test for HCV and the result is negative.
(3) Prior collections subject to quarantine under paragraph (f)(1)
of this section. Prior collections of blood and blood components, which
are not exempt from quarantine under paragraph (g)(3) of this section,
and are otherwise subject to quarantine under paragraph (f)(1) of this
section may be released from quarantine if:
(i) The donor's testing records meet the conditions specified in
paragraph (d)(4) of this section and further testing was performed in
accordance with paragraph (i)(1)(i) of this section on a fresh sample,
or frozen sample from the repeatedly reactive donation using a licensed
supplemental test for HCV and the result is negative; or
(ii) The donor's testing records meet the conditions specified in
paragraph (d)(1) of this section and further testing was performed in
accordance with paragraph (i)(2)(i) of this section on a fresh sample,
or frozen sample from the repeatedly reactive donation and the result
of the an appropriately chosen licensed supplemental test for HCV is
negative; or
(iii) The donor's testing records meet the conditions specified in
paragraph (d)(2) of this section and further testing was performed in
accordance with paragraph (i)(2)(ii) of this section on a fresh sample,
or frozen sample from the repeatedly reactive donation and the result
when further tested using either a licensed HCV EIA 3.0 screening test
or a licensed supplemental test for HCV is negative;
(iv) The donor's testing records meet the conditions specified in
paragraph (d)(3) of this section and further testing was performed in
accordance with paragraph (i)(2)(iii) of this section on a fresh
sample, or frozen sample from the repeatedly reactive donation and the
result when further tested using a licensed multiantigen screening test
for HCV or a licensed supplemental test for HCV is negative.
(k) Destruction or labeling of prior collections held in
quarantine. Blood establishments and consignees shall destroy or
appropriately label for in vitro use prior collections of blood and
blood components otherwise subject to quarantine in accordance with
paragraphs (a), (e), and (f) of this section, unless such prior
collections are determined to be exempt from quarantine in accordance
with paragraph (g) of this section or subject to release from
quarantine in accordance with paragraph (j) of this section.
Quarantined prior collections made available for in vitro use shall be
appropriately relabeled consistent with Secs. 606.121 and 640.70 of
this chapter. In addition, these units must be relabeled as
``Biohazard'' with the cautionary statement as follows:
``Collected from a donor who subsequently tested reactive for anti-
HCV. An increased risk of transmission of hepatitis C virus is
present.''; in addition, the label must contain one of the following
cautionary statements as appropriate: ``Caution: For Further
Manufacturing Into In-Vitro Diagnostic Reagents For Which There Are No
Alternative Sources'' or ``For Laboratory Research Use Only.''
(l) Recalls. Actions under this section do not constitute a recall
as defined in Sec. 7.3 of this chapter.
9. Section 610.49 is added to subpart E to read as follows:
Sec. 610.49 Hepatitis C Virus (HCV) ``Lookback;'' notification of
transfusion recipients.
(a) Appropriate actions following further testing. Transfusion
services are required to take appropriate action in accordance with
paragraphs (b) and (c) of this section when a recipient has received
prior collections of blood or blood components from a donor later
determined to be at increased risk of transmitting HCV infection when
tested for evidence of infection due to HCV and:
(1) The result of the licensed, supplemental test, performed as
prescribed in Sec. 610.48(b) and in accordance with the testing
requirements specified in Sec. 610.40(c), is positive;
(2) The result of the supplemental test identified in the review of
historical testing records is positive, as specified in
Sec. 610.48(c)(1);
(3) The result of the supplemental test identified in the review of
historical testing records in accordance with Sec. 610.48(c)(2) is
indeterminate, unless:
(i) The review of historical testing records shows the supplemental
test was performed using an HCV RIBA 3.0 supplemental test; or
(ii) Any of the conditions for exemption from quarantine specified
in Sec. 610.48(g)(2) have been met; or
(iii) The donor was further tested in accordance with
Sec. 610.48(h)(2)(i), (h)(2)(ii), or (h)(2)(iii) and any of the
conditions for release from quarantine specified in
Sec. 610.48(j)(2)(iii) have been met; or
(iv) The donor was further tested in accordance with
Sec. 610.48(h)(2)(ii) or (h)(2)(iii) using a supplemental test for HCV
and the result is indeterminate;
(4) The result of the licensed supplemental test performed in
accordance with Sec. 610.48(h)(1)(i)(A), (h)(1)(i)(B), or (h)(1)(ii) is
positive for a donor identified in the review of historical testing
records in accordance with Sec. 610.48(c)(4) and (c)(5), as testing
repeatedly reactive on a multiantigen screening test in the past with
no record of further testing;
(5) No record of further testing is available for a donor
identified in the
[[Page 69411]]
review of historical testing records, in accordance with
Sec. 610.48(c)(4) and (c)(5), and no fresh or frozen sample is
available for further testing, as specified in Sec. 610.48(h)(1)(iii);
(6) The result of the additional test using HCV EIA 2.0 or 3.0
identified in the review of historical testing records is repeatedly
reactive, as specified in Sec. 610.48(d)(1), unless:
(i) Any of the conditions for exemption from quarantine specified
in Sec. 610.48(g)(3) have been met; or
(ii) The donor was further tested in accordance with
Sec. 610.48(i)(2)(i) and any of the conditions for release from
quarantine specified in Sec. 610.48(j)(3) have been met; or
(iii) The donor was further tested in accordance with
Sec. 610.48(i)(2)(i) using an appropriately chosen licensed
supplemental test for HCV and the result is indeterminate; or
(7) The result of the supplemental test performed using an HCV RIBA
2.0 or HCV RIBA 3.0 is positive for a donor identified in the review of
historical testing records in accordance with Sec. 610.48(d)(2);
(8) The result of the supplemental test performed using an HCV RIBA
2.0 is indeterminate, for a donor identified in the review of
historical testing records in accordance with Sec. 610.48(d)(2),
unless:
(i) Any of the conditions for exemption from quarantine specified
in Sec. 610.48(g)(3) have been met; or
(ii) The donor was further tested in accordance with
Sec. 610.48(i)(2)(ii) and any of the conditions for release from
quarantine specified in Sec. 610.48(j)(3) have been met; or
(iii) The donor was further tested in accordance with
Sec. 610.48(i)(2)(ii) using a licensed supplemental test for HCV and
the result is indeterminate; or
(9) The result of the licensed, supplemental test for HCV or a
licensed multiantigen screening test performed in accordance with
Sec. 610.48(i)(2)(iii) is positive for a donor identified in the review
of historical testing records, in accordance with Sec. 610.48(d)(3); or
(10) The result of the licensed, supplemental test for HCV
performed in accordance with Sec. 610.48(i)(1) is positive for a donor
identified in the review of historical testing records, in accordance
with Sec. 610.48(d)(4), as testing repeatedly reactive on a single
antigen screening test with a S/CO value equal to or greater than 2.5
for at least two of the three EIA tests, or the S/CO value can not be
calculated, and with no record of further testing; or
(11) No record of further testing is available for a donor
identified in the review of historical testing records, in accordance
with Sec. 610.48(d)(4), and no fresh or frozen sample is available for
further testing, as specified in Sec. 610.48(i)(1)(ii).
(b) Notification of recipients of prior transfusion. If the
transfusion service has administered blood or blood components later
determined to be at increased risk of transmitting HCV infection, as
described in paragraph (a) of this section, the transfusion service
shall either notify the recipient directly or notify the recipient's
physician of record (i.e., physician of record or physician who ordered
the blood or blood component) and ask him or her to inform the
recipient of the need for HCV testing and counseling. If the physician
is not available or declines to notify the recipient, the transfusion
service shall notify the recipient and inform the recipient of the need
for HCV testing and counseling. The notification of transfusion
recipients based on donor testing completed after (the effective date
of the final rule) shall include a minimum of three attempts to notify
the recipient or the recipient's physician of record and be completed
within a maximum of 12 weeks of receipt of the result of the
supplemental test for HCV from the blood establishment. The
notification of transfusion recipients based on donor testing completed
prior to (the effective date of the final rule) shall include a minimum
of three attempts to notify the recipient or the recipient's physician
of record and be completed within 1 year of the date on which the
transfusion service received notification from the blood establishment.
The transfusion service is responsible for notification, including
basic explanations to the recipient and referral for counseling and
further testing, and shall document the notification and the result of
attempts to notify the recipient and the recipient's physician of
record, if contacted, under Sec. 606.160 of this chapter.
(c) Notification of legal representative or relative. If the
transfusion recipient has been adjudged incompetent by a State court,
the legal representative, designated in accordance with State law,
shall be notified. If the transfusion recipient is competent, but State
law permits a legal representative or relative to receive the
information on the recipient's behalf, the transfusion service or the
physician who agreed to perform the notification on behalf of the
transfusion service shall notify the recipient or his or her legal
representative or relative. If the transfusion recipient is a minor at
the time of notification, the transfusion service or physician, as
described in this paragraph, shall notify the recipient's legal
representative or relative. If the transfusion recipient is deceased,
the transfusion service or physician, as described in this paragraph,
may discontinue the notification process. The transfusion service is
responsible for notification, including basic explanations to the
recipient's legal representative or relative and referral for
counseling and further testing of the recipient, and shall document the
notification and the result of attempts to notify the recipient's legal
representative or relative and the recipient's physician of record, if
contacted, under Sec. 606.160 of this chapter. Reasons for notifying
the recipient's relative or legal representative on his or her behalf
shall be documented under Sec. 606.160 of this chapter.
(d) Reference tables. Tables 1 through 4 of this paragraph show the
various tests performed for HCV (including both current donor testing
shown in table 1 of this paragraph and tests identified in the review
of historical testing records in tables 2 through 4 of this paragraph),
steps of the ``lookback'' process, and applicable provisions of
Secs. 610.48 and 610.49. Based on the initial screening test select the
appropriate table from the following:
[[Page 69412]]
Table 1.--Outline of Provisions of Sec. 610.48 for Hepatitis C Virus (HCV) ``Lookback'' Based on Current Donor
Testing
----------------------------------------------------------------------------------------------------------------
Actions to be taken Applicable section(s):
----------------------------------------------------------------------------------------------------------------
Identify prior collections 610.48(a)(1)
Quarantine prior in-date collections 610.48(a)(1)(i)
Notify consignees to quarantine 610.48(a)(1)(ii)
Consignees perform quarantine of prior collections 610.48(a)(2)
Exemptions from quarantine 610.48(g)(1)(i)
610.48(g)(1)(ii)
Perform further testing 610.48(b)
Notify consignees of test results 610.48(b)
Release prior collections from quarantine 610.48(j)(1)\1\
Destroy or label prior collections 610.48(k)
Notify transfusion recipients 610.49(a)(1)\2\
----------------------------------------------------------------------------------------------------------------
\1\ If the licensed supplemental test for HCV is negative.
\2\ If the licensed supplemental test for HCV is positive.
[[Page 69413]]
Table 2.--Outline of Provisions of Sec. 610.48 for Hepatitis C Virus (HCV) ``Lookback'' Based on Review of Historical Testing Records and Identification of Donors Testing Repeatedly Reactive Using an HCV EIA\1\ 3.0 Screening Test
----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Results of Further Testing: RIBA 2.0\2\ Positive or RIBA RIBA 2.0 Negative RIBA 2.0 Indeterminate RIBA 3.0 Negative RIBA 3.0 Indeterminate No Supplemental Test Done
3.0\3\ Positive
----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Actions To Be Taken: Applicable Sections
----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Identify prior collections 610.48(c)(1) 610.48(c)(3) 610.48(c)(2) 610.48(c)(2) 610.48(c)(5)
----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Quarantine prior in-date
collections
----------------------------------
Notify consignees to quarantine 610.48(e)(1), (e)(2), (e)(3) 610.48(e)(1), (e)(2), (e)(3) 610.48(e)(1), (e)(2), (e)(3) 610.48(e)(1), (e)(2), (e)(3) 610.48(e)(1), (e)(2), (e)(3)
----------------------------------
Consignees perform quarantine of
prior collections
----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Exemptions from quarantine 610.48(g)(2)(i) 610.48(g)(2)(i) 610.48(g)(2)(i) 610.48(g)(2)(ii)(B) 610.48(g)(2)(i) 610.48(g)(2)(i)
----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Perform further testing 610.48(h)(1)(ii)\4\ 610.48(h)(1)(iii)\6\
----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Perform optional further testing 610.48(h)(2)(iv)\4\ 610.48(h)(2)(iii)\4\
----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Notify consignees of test results 610.48(h)(3)(ii) 610.48(h)(3)(i) 610.48(h)(3)(i) 610.48(h)(3)(ii) 610.48(h)(3)(i) 610.48(h)(3)(i)
610.48(h)(3)(ii) 610.48(h)(3)(ii) 610.48(h)(3)(ii) 610.48(h)(3)(ii)
----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Release prior collections from 610.48(j)(2)(iv)\5\ 610.48(j)(2)(iii)(C)\5\ 610.48(j)(2)(ii)\5\
quarantine
----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Destroy or label prior 610.48(k) 610.48(k) 610.48(k) 610.48(k) 610.48(k) 610.48(k)
collections
----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Notify transfusion recipients 610.49(a)(2) 610.49(a)(3) 610.49(a)(4)\7\ 610.49(a)(5)
----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ ``EIA'' means enzyme linked immunosorbant assay.
\2\ ``RIBA 2.0'' means HCV 2.0 strip immunoblot assay.
\3\ ``RIBA 3.0'' means HCV 3.0 strip immunoblot assay.
\4\ Using a licensed supplemental test for HCV.
\5\ If the licensed supplemental test for HCV is negative.
\6\ No frozen or fresh sample is available for further testing.
\7\ If the licensed supplemental test for HCV is positive.
[[Page 69414]]
Table 3.--Outline of Provisions of Sec. 610.48 for Hepatitis C Virus (HCV) ``Lookback'' Based on Review of Historical Testing Records and Identification of Donors Testing Repeatedly Reactive
Using an HCV EIA\1\ 2.0 Screening Test
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Results of Further Testing: RIBA 2.0\2\ RIBA 2.0 RIBA 2.0 Indeterminate RIBA 3.0 RIBA 3.0 No Supplemental Test Done
Positive or Negative Negative Indeterminate
RIBA 3.0 \3\
Positive
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Actions to be Taken: Applicable Sections
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Identify prior collections 610.48(c)(1) 610.48(c)(2) 610.48(c)(2) 610.48(c)(4)
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Quarantine prior in-date collections ............... ...............
-------------------------------------------
Notify consignees to quarantine 610.48(e)(1), 610.48(e)(1), (e)(2), (e)(3) 610.48(e)(1), 610.48(e)(1), (e)(2), (e)(3)
(e)(2), (e)(3) (e)(2), (e)(3)
-------------------------------------------
Consignees perform quarantine of prior ............... ...............
collections
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Exemptions from quarantine 610.48(g)(2)(i) 610.48(g)(2)(ii 610.48(g)(2)(i) 610.48(g)(2)(ii 610.48(g)(2)(i) 610.48(g)(2)(i)
)(A) )(A)
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Perform further testing 610.48(h)(1)(i 610.48(h) 610.48(h)
)(A)\9\ (1)(i)(B) \10 (1)(iii) \11\
\
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Perform optional further testing 610.48(h) 610.48(h)
(2)(i)\4\ (2)(i)\6\
610.48(h)(2)(ii
)\5\
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Notify consignees of test results 610.48(h)(3)(ii 610.48(h)(3)(i) 610.48(h)(3)(i) 610.48(h) 610.48(h)(3)(i 610.48(h)(3)(i 610.48(h)(3)(i
) 610.48(h) 610.48(h) (3)(ii) ) ) )
(3)(ii) (3)(ii) 610.48(h)(3)(i 610.48(h)(3)(i 610.48(h)(3)(i
i) i) i)
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Release prior collections from quarantine 610.48(j)(2)(ii 610.48(j) 610.48(j)(2)(i 610.48(j)(2)
i)(A)\7\ (2)(iii)(A)\8\ )(A)\12\ (i)(B)\13\
610.48(j)(2)(ii
i)(B)\8\
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Destroy or label prior collections 610.48(k) 610.48(k) 610.48(k) 610.48(k) 610.48(k) 610.48(k) 610.48(k)
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Notify transfusion recipients 610.49(a)(2) 610.49(a)(3) 610.49(a)(3) 610.49(a)(4)\1 610.49(a)(4)\1 610.49(a)(5)
4\ 4\
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ ``EIA'' means enzyme linked immunosorbant assay.
\2\ ``RIBA 2.0'' means HCV 2.0 strip immunoblot assay.
\3\ ``RIBA 3.0'' means HCV 3.0 strip immunoblot assay.
\4\ Using an HCV EIA 3.0 screening test.
\5\ If the HCV EIA 3.0 screening test is repeatedly reactive, may perform a licensed supplemental test for HCV.
\6\ Using a licensed supplemental test for HCV.
\7\ If the HCV EIA 3.0 screening test is negative.
\8\ If the licensed supplemental test for HCV is negative.
\9\ Perform a licensed supplemental test for HCV.
\10\ Perform an HCV EIA 3.0 screening test and perform a licensed supplemental test for HCV if the HCV EIA 3.0 screening test is repeatedly reactive.
\11\ No frozen or fresh sample is available for further testing.
\12\ If the licensed supplemental test for HCV is negative.
\13\ If the HCV EIA 3.0 screening is negative; or, if it is repeatedly reactive, the licensed supplemental test for HCV is negative.
\14\ If the licensed supplemental test for HCV is positive.
[[Page 69415]]
Table 4.--Outline of Provisions of Sec. 610.48 for Hepatitis C Virus (HCV) ``Lookback'' Based on Review of Historical Testing Records and Identification of Donors Testing Repeatedly Reactive
Using an HCV EIA \1\ 1.0 Screening Test
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
RESULTS OF FURTHER TESTING: EIA 2.0\2\ EIA 3.0\3\ EIA 2.0 RIBA 2.0 RIBA 2.0 RIBA 3.0 RIBA 2.0 S/CO\4\ 2.5 S/CO >2.5 or No
Repeatedly Repeatedly Negative or Positive or Indeterminate Indeterminat Negative or Determination of S/
Reactive Reactive EIA 3.0 RIBA 3.0 e RIBA 3.0 CO
Negative Positive Negative
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
ACTIONS TO BE TAKEN: Applicable Sections
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Identify prior collections 610.48(d)(1) 610.48(d)(1) 610.48(d)(2) 610.48(d)(2) 610.48(d)(2) 610.48(d)(3) 610.48(d)(4)
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Quarantine prior in-date ................. ................. ............. ............. ............... ............. ............. .............
collections
---------------------------------
Notify consignees to quarantine 610.48(f)(1), 610.48(f)(1), 610.48(f)(1), 610.48(f)(1), 610.48(f)(1), ............. 610.48(f)(1), 610.48(f)(1), (f)(2), (f)(3)
(f)(2), (f)(3) (f)(2), (f)(3) (f)(2), (f)(2), (f)(3) (f)(2), (f)(2),
(f)(3) (f)(3) (f)(3)
---------------------------------
Consignees perform quarantine of ................. ................. ............. ............. ............... ............. ............. .............
prior collections
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Exemptions from quarantine 610.48(g)(3)(iii) 610.48(g)(3)(iii) 610.48(g)(3)( 610.48(g)(3)(iv 610.48(g)(3)( .............
\5\ \5\ i) )\7\ ii)
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Perform further testing 610.48(i)(1)( 610.48(i)(1)(
i)\13\ ii)\14\
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Perform optional further testing 610.48(i)(2)(i)\6 610.48(i)(2)(i)\6 ............. ............. 610.48(i)(2)(ii ............. ............. 610.48(i) ............. .............
\ \ )\8\ (2)(iii)\10\
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Notify consignees of test 610.48(i)(3)(i) 610.48(i)(3)(i) ............. 610.48(i)(3)( 610.48(i)(3)(i) 610.48(i)(3)( ............. 610.48(i)(3)( 610.48(i)(3)( 610.48(i)(3)(
results 610.48(i)(3)(ii) 610.48(i)(3)(ii) ii) 610.48(i)(3)(ii ii) i) i) i)
) 610.48(i)(3)( 610.48(i)(3)( 610.48(i)(3)(
ii) ii) ii)
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Release prior collections from 610.48(j)(3)(ii)\ 610.48(j)(3)(ii)\ ............. ............. 610.48(j)(3)(ii ............. ............. 610.48(j)(3)( 610.48(j)(3)(
quarantine 5\ 5\ i)\9\ iv)\11\ i)\15\
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Destroy or label prior 610.48(k) 610.48(k) ............. 610.48(k) 610.48(k) 610.48(k) ............. 610.48(k) 610.48(k) 610.48(k)
collections
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Notify transfusion recipients 610.49(a)(6) 610.49(a)(6) ............. 610.49(a)(7) 610.49(a)(8) ............. ............. 610.49(a)(9)\ 610.49(a)(10) 610.49(a)(11)
12\ \16\
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ ``EIA'' means enzyme linked immunosorbant assay.
\2\ ``RIBA 2.0'' means HCV 2.0 strip immunoblot assay.
\3\ ``RIBA 3.0'' means HCV 3.0 strip immunoblot assay.
\4\ ``S/CO'' means ``Signal to cut off.''
\5\ If further testing using an appropriately chosen supplemental test for HCV was performed and the result was negative.
\6\ May perform further testing using an appropriately chosen licensed supplemental test for HCV.
\7\ If further testing using an HCV EIA 3.0 screening test or an HCV RIBA 3.0 supplemental test was performed and the result was negative.
\8\ May perform further testing using an HCV EIA 3.0 screening test or a licensed supplemental test for HCV. If an HCV EIA 3.0 screening test is performed and is repeatedly reactive, may
perform further testing using a licensed supplemental test for HCV.
\9\ If further testing using an HCV EIA 3.0 screening test or a licensed supplemental test for HCV was performed and the result was negative.
\10\ May perform further testing using a licensed multiantigen screening test for HCV or a licensed supplemental test for HCV.
\11\ If further testing using a licensed multiantigen screening test for HCV or a licensed supplemental test for HCV was performed and the result was negative.
\12\ If further testing using a licensed multiantigen screening test for HCV or a licensed supplemental test for HCV was performed and the result was positive.
\13\ Using a licensed supplemental test for HCV.
\14\ No frozen or fresh sample is available for further testing.
\15\ If the licensed supplemental test for HCV is negative.
\16\ If the licensed supplemental test for HCV is positive.
[[Page 69416]]
Dated: December 3, 1999.
Jane E. Henney,
Commissioner of Food and Drugs.
Donna E. Shalala,
Secretary of Health and Human Services.
[FR Doc. 00-28907 Filed 11-15-00; 8:45 am]
BILLING CODE 4160-01-F