[Federal Register Volume 72, Number 164 (Friday, August 24, 2007)]
[Rules and Regulations]
[Pages 48766-48801]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: E7-16607]
[[Page 48765]]
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Part III
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 Hepatitis C
Virus Infection (``Lookback''); Final Rule
Federal Register / Vol. 72, No. 164 / Friday, August 24, 2007 / Rules
and Regulations
[[Page 48766]]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Parts 606 and 610
[Docket No. 1999N-2337 (formerly 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
Hepatitis C Virus Infection (``Lookback'')
AGENCY: Food and Drug Administration, HHS.
ACTION: Final rule.
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SUMMARY: The Food and Drug Administration (FDA) is requiring
establishments collecting Whole Blood or blood components, including
Source Plasma and Source Leukocytes, to establish, maintain, and follow
an appropriate system for identifying blood and blood components
previously donated by a donor who tests reactive for evidence of
hepatitis C virus (HCV) infection on a subsequent donation identified
either by current testing or after a review of historical testing
records, or when the collecting establishment is made aware of other
reliable test results or information indicating evidence of HCV
infection. Such collections may be at increased risk of transmitting
HCV infection. FDA is requiring collecting establishments to quarantine
prior in-date blood and blood components from such a donor, to notify
consignees of prior in-date blood and blood components from such a
donor for quarantine purposes, and to perform further testing on the
donor. FDA is also requiring consignees to notify transfusion
recipients of blood and blood components from such a donor, as
appropriate. In addition, FDA is revising the human immunodeficiency
virus (HIV) ``lookback'' requirements for greater consistency with the
HCV ``lookback'' requirements, and extending the record retention
period to 10 years. FDA is taking this action to help ensure the
continued safety of the blood supply and to help ensure that
information is provided to recipients of blood and blood components
that may have been at increased risk of transmitting HIV or HCV
infection. Elsewhere in this issue of the Federal Register, FDA is
announcing the availability of a guidance document entitled ``Guidance
for Industry: `Lookback' for Hepatitis C Virus (HCV): Product
Quarantine, Consignee Notification, Further Testing, Product
Disposition, and Notification of Transfusion Recipients Based on Donor
Test Results Indicating Infection with HCV'' (the ``lookback''
guidance). We are also issuing this final rule in conjunction with a
companion interim final rule published by the Centers for Medicare and
Medicaid Services (CMS) elsewhere in this issue of the Federal
Register.
DATES: This rule is effective February 20, 2008.
FOR FURTHER INFORMATION CONTACT: Stephen M. Ripley, 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:
Table of Contents
I. Introduction
A. Background
B. Legal Authority
II. Highlights and Summary of the Final Rule
A. Restructuring of the Proposed Rule
B. Summary of the Final Rule
C. Changes to Related Regulations
III. Comments on the Proposed Rule and FDA's Responses
A. General Comments
B. Records
C. HIV and HCV ``Lookback''
IV. Analysis of Impacts
A. Economic Impact\3\
B. Benefits of the Final Rule
C. Impact on Small Entities
V. The Paperwork Reduction Act of 1995
A. Annual Reporting Burden
B. Estimated One-Time Reporting Burden
C. Estimated Annual and One-Time Recordkeeping Burden
VI. Environmental Impact
VII. Federalism
VIII. References
I. Introduction
A. Background
As a result of extensive screening and testing procedures and other
layers of safety used to help ensure a safe blood supply, the risk of
transmitting infection through blood transfusion is very low. Despite
the best practices of blood establishments\1\, however, a person may
donate blood and blood components early in an 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). Such products are considered as having an increased risk of
transmitting infection. We are issuing this final rule to help ensure
the continued safety of the blood supply and to help ensure that
information is provided to recipients of blood and blood components
possibly donated during a ``window'' period, which therefore may be at
increased risk of transmitting infection.
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\1\ The term ``establishment'' is defined in FDA's blood
regulations at 21 CFR 607.3(c).
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Chronic hepatitis due to HCV is a major health problem in the
United States. The infection is usually asymptomatic for decades
despite possible progression. Thus, individuals with chronic, active
hepatitis C can remain unaware that they have a serious infection until
symptoms develop late in the course of the disease. Five to twenty
percent of infected persons might develop cirrhosis of the liver over a
period of 20 to 30 years and one to five percent might die from the
consequences of long term infection (liver cancer or cirrhosis). As a
result, infected people typically are unaware of their disease.
Although transfusion-transmitted infections account for only a small
proportion of HCV infections, it is possible to identify and
``lookback'' at prior donations collected during the ``window'' period
from donors later identified as reactive on a test for evidence of HCV
infection. Further information on existing donor screening and testing
requirements and a history of HCV testing is provided in the proposed
rule entitled ``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')'' (the HCV ``lookback'' proposed rule)
(November 16, 2000, 65 FR 69378 at 69379).
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),'' we did not recommend a
``lookback'' program, pending the outcome of discussions on the issue
at the December 1993 Blood Product Advisory Committee (BPAC) meeting.
Following the discussions on HCV at the meeting in December 1993, the
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 (additional, more
specific) test.
[[Page 48767]]
However, BPAC only marginally endorsed consignee\2\ 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. We issued in July 1996 a
memorandum to all registered blood establishments 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). 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.
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\2\ We use the term ``consignee'' to refer to the person or
entity to whom the blood is shipped.
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The Department of Health and Human Services Advisory Committee on
Blood Safety and Availability (the HHS 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 DHHS Advisory
Committee discussed the public health benefits of notification of
transfusion recipients receiving prior collections from a donor who
subsequently tests reactive for evidence of HCV infection and made
recommendations for HCV ``lookback.'' Following acceptance by the
Department of Health and Human Services (DHHS) of the DHHS Advisory
Committee's recommendations for HCV ``lookback,'' we 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 we recommended that blood establishments implement
HCV ``lookback'' procedures. In the March 1998 guidance, we recommended
that donors currently testing repeatedly reactive for antibody to HCV
by a licensed test be further tested for antibody to HCV using a
licensed, multi-antigen supplemental test. Additionally, we 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 by a
licensed multiantigen-based antibody screening test and reactive by a
licensed or investigational supplemental test. This notification would
enable consignees to inform recipients that they were transfused with
units that may have contained HCV, so that they might obtain further
medical counseling and treatment. The March 1998 guidance provided our
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 we issued a revised guidance dated
September 1998, on October 21, 1998 (63 FR 56198), 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 Test for
Antibody to Hepatitis C Virus (Anti-HCV); (2) Supplemental Testing, and
the Notification of Consignees and Blood Recipients of Donor Test
Results for Anti-HCV,'' (the September 1998 guidance). The September
1998 guidance 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 addressed several significant comments
and requests from industry:
We revised several time periods for ``lookback'' actions
in response to concerns about the impact on industry and the need for
additional time for testing due to availability problems with certain
test kits, and to allow time for the completion of physician education
(ensuring that counseling messages would be available for use in
notification of recipients);
We clarified options for further testing with an HCV
enzyme linked immunosorbent assay 3.0 (HCV EIA 3.0 screening test);
We clarified our recommendations on labeling of the blood
and blood components released from quarantine and for consistency with
existing regulations on product labeling;
We provided flow chart diagrams to assist industry in
implementing procedures contained in the guidance; and
We recommended the option of transfusion services
notifying the transfusion recipient directly as an alternative to
notifying the transfusion recipient's physician of record, to permit
easier, more rapid notification of the recipient.
At public meetings on November 24, 1998, and January 28, 1999, the
DHHS Advisory Committee reconsidered the issue of recipient
notification related to repeatedly reactive results by the single
antigen-based antibody screening test. The DHHS Advisory Committee
recommended that targeted ``lookback'' be initiated based on a
repeatedly reactive HCV EIA 1.0 screening test result on a repeat donor
except in the following conditions: (1) A supplemental (additional,
more specific) test was performed and the result did not indicate
increased risk of HCV infection; (2) in the absence of a supplemental
test result, the signal to cut-off (S[sol]CO) value of the repeatedly
reactive HCV EIA 1.0 screening test was less than 2.5; or (3) followup
testing of the donor was negative. We published a notice in the Federal
Register of June 22, 1999 (64 FR 33309), announcing the availability of
a draft guidance entitled ``Draft 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)'' (the June 1999
draft guidance). Consistent with the recommendations of the DHHS
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 test 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 records exist. In addition, we revised the flowchart
diagrams to reflect the changes to the guidance. We added specific
recommendations for prior collections from a repeatedly reactive
autologous donor and clarified recommendations on implementing
``lookback'' for repeatedly reactive plasma donations.
On November 16, 2000, FDA and the Health Care Financing
Administration, now known as the Centers for Medicare and Medicaid
Services (CMS), issued proposed rules that would further
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protect the blood supply and notify recipients of the possibility that
they may have received blood or blood components with an increased risk
of transmitting HCV. FDA's HCV ``lookback'' proposed rule, along with
CMS's companion proposed rule (November 16, 2000, 65 FR 69416),
proposed to require establishments involved in the collection,
processing, and distribution of blood and blood components to
quarantine certain blood and blood components and to inform the
consignee. The consignee, as appropriate, would inform the recipient's
physician of record or the recipient of the possibility that blood used
for transfusion was obtained from a donor who subsequently tested
repeatedly reactive for antibody to HCV.
Elsewhere in this issue of the Federal Register, we are announcing
the availability of a guidance document entitled ``Guidance for
Industry: `Lookback' for Hepatitis C Virus (HCV): Product Quarantine,
Consignee Notification, Further Testing, Product Disposition, and
Notification of Transfusion Recipients Based on Donor Test Results
Indicating Infection with HCV'' (the ``lookback'' guidance). We
prepared the ``lookback'' guidance based on comments received on the
June 1999 draft guidance and comments received on the HCV ``lookback''
proposed rule and issued the guidance document for implementation by
the agency. The guidance document does not create or impose any legal
rights or requirements, rather, it represents our current thinking on
methods for satisfying the requirements now imposed by this rule and
addresses actions that could be taken based on results of screening and
supplemental testing. It supercedes the September 1998 guidance and the
HCV sections of the July 1996 memorandum.
B. Legal Authority
We are issuing this final 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) and the provisions of the Federal Food, Drug, and Cosmetic Act
(the act), which apply to drugs (section 201 of the act et seq. (21
U.S.C. 321 et seq.)). Under section 361 of the PHS Act, by delegation
from the Secretary of Health and Human Services, we 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. Intrastate transactions may
also be regulated under section 361 of the PHS Act. (See Louisiana v.
Mathew, 427 F. Supp. 174, 176 (E. D. La. 1977).) Because a major
purpose of the HCV ``lookback'' final rule is to prevent the
introduction, transmission, and spread of HCV, a communicable disease,
section 361 of the PHS Act provides the primary legal authority for
this final rule, including the rule's provisions on standard operating
procedures, records, donor deferral, and ``lookback'' requirements, for
manufacturers, including collecting establishments, and consignees.
All blood and blood components introduced or delivered for
introduction into interstate commerce also are subject to section 351
of the PHS Act. Section 351(a) requires that manufacturers of
biological products, which include blood and blood components intended
for further manufacture into injectable products, have a license,
issued upon a demonstration that the product is safe, pure, and potent
and that the manufacturing establishment meets all applicable
standards, including those prescribed in the FDA regulations, designed
to ensure the continued safety, purity, and potency of the blood.
Moreover, section 351(a)(2)(A) of the PHS Act gives us, by delegation
from the Secretary of Health and Human Services, authority to
establish, by regulation, requirements for the approval, suspension,
and revocation of biologics licenses. This final rule establishes such
requirements for blood and blood components intended for further
manufacture into injectable products.
Our license revocation regulations provide that we may initiate
revocation proceedings, among other reasons, if an establishment or
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 (21 CFR 601.5). The requirements of this final
rule are designed to ensure the continued safety, purity and potency of
donated blood and blood products. Section 351 of the PHS Act also
provides for civil and criminal penalties for violation of the laws
governing biological products. Violations can be punishable by fines,
imprisonment, or both.
Section 351(j) of the PHS Act states that the Federal, Food, Drug,
and Cosmetic Act also applies to biological products. Blood and blood
components for transfusion or for further manufacture into injectable
products are drugs, as that term is defined in section 201(g)(1) of the
act. (See United States v. Calise, 217 F. Supp. 705, 709 (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. For example, 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 to current good manufacturing
practice (CGMP). Under this final rule, the CGMP regulations for
manufacturers of blood and blood components are amended to require
those establishments to develop standard operating procedures (SOPs)
for HCV ``lookback,'' identification, quarantine of affected blood and
blood components, and consignee and transfusion recipient notification.
A blood or plasma establishment that fails to comply with HCV
``lookback'' procedures would not be in compliance with CGMP
requirements and, therefore, would be subject to the act's enforcement
provisions.
II. Highlights and Summary of the Final Rule
We are issuing this final rule in conjunction with a companion
interim final rule published by CMS elsewhere in this issue of the
Federal Register. This final rule and the CMS interim final rule
provide steps designed to further protect the blood supply and to
notify recipients of the possibility that they may have received blood
or blood components at increased risk of transmitting HIV or HCV. The
phrase ``blood and blood components,'' as used in this rulemaking,
includes Source Plasma and Source Leukocytes.
A. Restructuring of the Proposed Rule
After careful review of the proposed rule, and in response to
comments submitted to the docket, we have revised the codified section
of the proposed rule as follows:
We combined proposed Sec. Sec. 610.46 and 610.47 into
requirements under new Sec. 610.46 for prospective HIV ``lookback.''
We combined proposed Sec. Sec. 610.48 and 610.49 into
requirements under new Sec. 610.47 for prospective HCV ``lookback.''
We removed the requirements for retrospective HCV
``lookback'' from proposed Sec. Sec. 610.48 and 610.49 and placed them
under new Sec. 610.48.
Each section separates provisions for collecting
establishments and for consignees.
The codified section lists objective actions and
eliminates the prescriptive language in the proposed rule.
The sections for prospective HIV and HCV ``lookback''
(Sec. Sec. 610.46 and 610.47) are analogous in their requirements.
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The final rule establishes a ``cut-off'' date for
retrospective HCV ``lookback.''
B. Summary of the Final Rule
1. HIV and HCV ``Lookback'' (Sec. Sec. 610.46 and 610.47,
respectively)
a. Responsibilities of the collecting establishment. In Sec. Sec.
610.46 and 610.47, respectively, the final rule requires collecting
establishments to establish, maintain, and follow an appropriate system
for performing HIV and HCV prospective ``lookback'' when a donor tests
reactive for evidence of HIV or HCV infection (see Sec. 610.40(a) and
(b) (21 CFR 610.40(a) and (b))), or when the collecting establishment
becomes aware of other reliable test results or information indicating
evidence of HIV or HCV infection (``prospective lookback'') (Sec. Sec.
610.46(a)(1) and 610.47(a)(1)). The requirement for ``an appropriate
system'' states the intention of the requirement and replaces the more
prescriptive language of the proposed rule. This provision requires the
collecting establishment to design SOPs to identify and quarantine all
blood and blood components previously collected from a donor who later
tests reactive for evidence of HIV or HCV infection, or when the
collecting establishment is made aware of other reliable test results
or information indicating evidence of HIV or HCV infection (see section
II.C.4 of this document for further discussion of the term
``reactive''). Within 3 calendar days of the donor testing reactive by
an HIV or HCV screening test or the collecting establishment becoming
aware of other reliable test results or information, the collecting
establishment must take the following actions:
Review all records, required to be maintained under Sec.
606.160(d), to identify blood and blood components previously donated
by such a donor. For those blood and blood components collected 12
months and less before the donor's most recent nonreactive screening
tests for HIV or HCV, or 12 months and less before the donor's reactive
direct viral detection test, e.g., nucleic acid test (NAT) (HIV and
HCV) or HIV p24 antigen test (HIV), and a nonreactive antibody
screening test for HIV or HCV, whichever is a lesser period (Sec. Sec.
610.46(a)(1)(i) and (a)(1)(ii), and 610.47(a)(1)(i) and (a)(1)(ii)),
the collecting establishment must do the following:
Quarantine all identified previously collected in-date
blood and blood components if intended for use in another person or for
further manufacturing into injectable products (Sec. Sec.
610.46(a)(1)(ii)(A) and 610.47(a)(1)(ii)(A)). Pooled blood components
solely intended for further manufacturing into products that are
manufactured using validated clearance (i.e., inactivation and removal)
procedures are not subject to quarantine; and
Notify consignees to quarantine all identified previously
collected in-date blood and blood components (Sec. Sec.
610.46(a)(1)(ii)(B) and 610.47(a)(1)(ii)(B)). The consignee's pooled
blood components solely intended for further manufacturing into
products that are manufactured using validated viral clearance (i.e.,
inactivation and removal) procedures also are not subject to
quarantine.
Within 45 calendar days of the reactive screening test, the
collecting establishment must perform a supplemental additional, more
specific) test on the reactive donation (Sec. 610.40(e)) for HIV
(Sec. 610.46(a)(2)) or HCV (Sec. 610.47(a)(2)), and must notify the
consignees of the supplemental test results, or the results of a
reactive screening test if there is no available supplemental test that
is approved for such use by FDA (Sec. Sec. 610.46(a)(3) and
610.47(a)(3)). Thus, if we have not approved a supplemental test for a
required screening test, you must notify consignees of the results of
the reactive screening test. Similarly, if there is a shortage of an
approved supplemental test such that they are not available for
commercial purchase, you must notify consignees of the results of the
reactive screening test. By adding the term ``available'' to the
codified language, we are not authorizing blood establishments to
simply choose to notify consignees of the result of a reactive
screening test if the establishment has simply run out of the approved
supplemental test. Rather, the test must be unavailable commercially.
We are also adding ``or if under an IND or IDE, is exempted for such
use by FDA'' so that we have the ability to authorize the use of a
supplemental test under an investigational new drug application (IND)
or an investigational device exemption (IDE) under certain
circumstances. In such cases, we will issue guidance on alternative
product use under conditions where approved supplemental tests are
unavailable, or when a product under IND or IDE is exempted for such
use. Currently, there are FDA-approved supplemental tests for all
antibody and antigen screening tests for HIV and HCV, except NAT.
Therefore, if a donor tests reactive by NAT and nonreactive by an
antibody screening test, the results would be reported to the consignee
without further testing. Notification must include the supplemental
test results for all identified blood and blood components previously
collected from donors who later test reactive for evidence of HIV or
HCV infection.
Once the collecting establishment receives the supplemental test
results and notifies the consignees, then the collecting establishments
must release, destroy, or relabel quarantined in-date blood and blood
components consistent with the supplemental test results or a reactive
screening test if there is no available supplemental test that is
approved for such use by FDA, or if under an IND or IDE, is exempted
for such use by FDA (Sec. Sec. 610.46(a)(4) and 610.47(a)(4)). Our
current thinking on the appropriate actions of releasing, destroying,
and relabeling is discussed in the ``lookback'' guidance.
b. Responsibilities of the consignees. The consignee must also
establish, maintain, and follow an appropriate system (as described in
section II.B.1.a of this document) for performing HIV and HCV
``lookback'' when notified by the collecting establishment that they
have received blood and blood components previously collected from
donors who later tested reactive for evidence of HIV or HCV infection,
or when the collecting establishment is made aware of other reliable
test results or information indicating evidence of HIV or HCV infection
in a donor (Sec. Sec. 610.46(b) and 610.47(b)). This provision for a
system requires the consignee to establish SOPs for the following
actions:
Quarantining consigned in-date blood and blood components
when notified by the collecting establishment (Sec. Sec. 610.46(b)(1)
and 610.47(b)(1)).
Releasing, destroying, or relabeling quarantined in-date
blood and blood components consistent with the supplemental test
results or a reactive screening test if there is no available
supplemental test that is approved for such use by FDA or exempted for
such use by FDA (Sec. Sec. 610.46(b)(2) and 610.47(b)(2)).
Notifying transfusion recipients of blood and blood
components, or the recipient's physician of record or legal
representative, when such action is indicated by the results of the
supplemental (additional, more specific) tests or a reactive screening
test if there is no available supplemental test that is approved for
such use by FDA, or if under an IND or IDE, is exempted for such use by
FDA. The consignee must make reasonable attempts to perform the
notification within 12 weeks of receipt of the supplemental test result
or receipt of a reactive screening test result when
[[Page 48770]]
there is no available supplemental test that is approved for such use
by FDA, or if under an IND or IDE, is exempted for such use by FDA.
Notification of the recipient is necessary in order to permit testing,
counseling, and (if necessary) treatment for recipients who received
blood or blood components potentially at risk of transmitting HIV or
HCV (Sec. Sec. 610.46(b)(3) and 610.47(b)(3)).
c. No recall action. We have added a statement in Sec. Sec.
610.46(c), 610.47(c), and 610.48(d) that ``lookback'' does not
constitute a recall as defined in 21 CFR 7.3. Discussion of the
differences between a recall action and a ``lookback'' action may be
found in the HCV ``lookback'' proposed rule (65 FR 69378 at 69391). FDA
recognizes that a ``lookback'' action does not mean that an
establishment has erred or that it did not meet its obligations under
the regulations and the statute in assuring the safety of the blood
supply. However, failure to comply with the ``lookback'' regulations is
a regulatory violation and may merit enforcement action.
2. HCV ``Lookback'' Requirements Based on Review of Historical Testing
Records (Sec. 610.48)
As previously described, we have removed the requirements for the
review of historical testing records from proposed Sec. Sec. 610.48
and 610.49 and placed them under final Sec. 610.48 Hepatitis C virus
(HCV) ``lookback'' requirements based on review of historical testing
records. It is important to identify and notify recipients previously
transfused with blood or blood components at increased risk of
transmitting HCV infection because HCV is a chronic, often asymptomatic
disease that may ultimately have serious consequences. Therefore, we
are requiring the review of historical HCV testing records of donors so
that blood and blood components previously collected from donors who
later test reactive for evidence of HCV infection are identified, and
recipients of such blood and blood components are notified of the
possibility of being infected with HCV. With this information, the
recipients can be tested and, if infected, pursue treatment and
counseling, and take preventive measures to avoid transmitting HCV to
others. The requirements for historical review of HCV testing records
or ``retrospective review'' are the same as the requirements for the
prospective review of HCV testing records, except for variations in the
required time for completion of the actions, the extent of record
review, and a distinction regarding the specimen that may be used for
further testing (either a frozen sample from the same reactive donation
or a fresh sample from the same donor).
a. Completion of required actions. To permit adequate time to
perform the requirement for the review of historical HCV testing
records, Sec. 610.48(a) requires that the collecting establishments
complete the actions prescribed in Sec. 610.48(b) within 1 year of the
effective date of this final rule. Consignees must complete the actions
prescribed in Sec. 610.48(c) within 1 year of the date of notification
by the collecting establishment.
We have also established a date for the conclusion of historical
record review of HCV testing in Sec. 610.48(b)(1)(i). The historical
record review must include all HCV testing performed before February
20, 2008, the effective date of this rule. The requirements under Sec.
610.48 will remain in effect for 8 years after the date of publication
in the Federal Register.
b. Extent of record review. When performing the historical record
review, under Sec. 610.48(b)(1)(i), the establishment must review all
HCV testing from February 20, 2008 back indefinitely for computerized
electronic records, and to January 1, 1988, for all other records. Once
a reactive screening test is found, you must identify for further
action blood and blood components collected 12 months and less before
the donor's most recent nonreactive screening tests, or 12 months and
less before the donor's reactive direct viral detection test and
nonreactive antibody screening test, whichever is the lesser period
(Sec. 610.48(b)(1)(ii) and (b)(1)(iii)).
To prevent unnecessary repetition of already completed ``lookback''
actions, we have added an exemption stating that any ``lookback''
action performed before the effective date of the final rule that
otherwise satisfies the requirements for prospective ``lookback'' in
final Sec. 610.47, is exempt from the retrospective ``lookback''
requirements in final Sec. 610.48. We recognize that, without this
exemption, when this final rule becomes effective, collecting
establishments that already performed prospective ``lookback'' actions
that comport with the recommendations set forth in the ``lookback''
guidance could face a situation in which they would be compelled under
the final rule to repeat these already completed ``lookback'' actions
under the retrospective ``lookback'' provisions. As this would mandate
an obvious waste of effort and would penalize establishments that
conducted expeditious prospective ``lookback'' actions guided by our
recommendations in the ``lookback'' guidance, we have added the
exemption for completed adequate ``lookback.''
c. Further testing. Under Sec. 610.48(b)(1)(ii), quarantine and
consignee notification are not required when donors, who tested
reactive by a screening test, test negative on the same donation by an
appropriate supplemental (additional, more specific) test for evidence
of HCV infection. In the context of this rule, an appropriate
supplemental test for a reactive antibody screening test is a test for
antibody, i.e., the recombinant immuno-blot assay (RIBA). At this time,
an appropriate supplemental test for NAT does not exist. However, when
a supplemental test becomes appropriate for NAT, we will notify the
public on its use through guidance.
Under Sec. 610.48(b)(2), if a supplemental (additional, more
specific) test for HCV is not performed on the same donation at the
time of the reactive screening test, the collecting establishment may
choose to perform the supplemental test or a licensed screening test
(e.g., an EIA 3.0) with known greater sensitivity than the test of
record (e.g., an EIA 2.0) on a frozen sample from the same reactive
donation, or may collect and test a fresh sample from the same donor,
if obtainable. If a supplemental test for a reactive screening test is
not approved for such use by FDA, or if under an IND or IDE, is
exempted for such use by FDA, a suitable test is unavailable, or the
collecting establishment does not perform further testing due to the
unavailability of a sample, then the collecting establishment must
proceed with quarantine and consignee notification under Sec.
610.48(b)(3), (b)(4), and (b)(5).
A variation between Sec. Sec. 610.47(a)(3) (prospective review)
and 610.48(b)(4) (retrospective review) is the event initiating the
notification of the consignee of the test results within 45 calendar
days. Under Sec. 610.47(a)(3), the collecting establishment must
notify the consignee of the supplemental test results within 45
calendar days after the donor tests reactive for evidence of HCV
infection. Under Sec. 610.48(b)(4), the collecting establishment must
notify the consignee of the supplemental test results within 45
calendar days of completing the supplemental tests.
d. Notification of transfusion recipients. Under Sec.
610.48(c)(3), the consignee is required to notify the transfusion
recipient under any of the following conditions:
The supplemental (additional, more specific) test for HCV
is positive; or
The supplemental test is indeterminate, but the
supplemental test
[[Page 48771]]
is know to be less sensitive than the screening test; or
The screening test is reactive and there is no available
supplemental test that is approved for such use by FDA, or if under an
IND or IDE, is exempted for such use by FDA; or
The supplemental testing is not performed.
Transfusion recipients do not need to be notified if there
is a negative result by an alternative licensed screening test with
known greater sensitivity than the test of record, and that the
alternative screening test was performed on the original reactive donor
sample or a fresh sample from the same donor.
C. Changes to Related Regulations
1. Standard Operating Procedures (Sec. 606.100(b)(19))
We are requiring that collecting establishments and consignees
establish, maintain, and follow procedures:
For identifying previously donated blood and blood
components from a donor who later tests reactive for evidence of
infection with HIV or HCV, or when the collecting establishment becomes
aware of other reliable test results or information indicating evidence
of infection;
For quarantining such in-date blood and blood components,
intended for use in another person or for further manufacture into
injectable products, except pooled components intended solely for
further manufacturing into products that are manufactured using
validated viral clearance (i.e., inactivation and removal) procedures;
For notifying consignees to quarantine such in-date blood
and blood components, except pooled components intended solely for
further manufacturing into products that are manufactured using
validated viral clearance (i.e., inactivation and removal) procedures;
For determining the suitability of the quarantined blood
or blood components for release, destruction, or relabeling;
For notifying the consignees of the test results for HIV
or HCV performed on donors of such blood and blood components; and
For notifying the recipient of such blood or blood
components, the recipient's physician of record, or the recipient's
legal representative by the consignee that the recipient received blood
or blood components which may have been at increased risk of
transmitting HIV or HCV, respectively.
2. Recordkeeping (Sec. 606.160(b)(1)(viii))
Collecting establishments and consignees must keep records
concerning the requirements of this final rule. This includes any
records relating to quarantine; notification of consignees; testing;
notification of the transfusion recipient, the recipient's physician of
record, or the recipient's legal representative; and disposition of the
identified blood and blood components.
3. Retention of Records (Sec. 606.160(d))
Current Sec. 606.160(d) requires the retention of records no less
than 5 years after the records of processing are completed or 6 months
after the latest expiration date for the individual product, whichever
is the latest date. In Sec. 606.160(d), we are changing the
requirement for record retention from 5 years to 10 years. There can be
a prolonged time between exposure to an agent and development of
symptoms, as is the case for HIV and HCV. A longer record retention
time will allow establishments to trace recipients of blood from donors
who had not been regular donors. This change is also consistent with
industry standards for record retention by blood establishments for
``lookback'' to identify recipients who may have been infected with HIV
or HCV (AABB Standards for Blood Banks and Transfusion Services; 23rd
edition). Because of the widespread use of electronic recordkeeping, it
is now practical to search records for up to 10 years.
This change accommodates the advances in medical diagnosis and
therapy that have created opportunities for disease prevention or
treatment many years after recipient exposure to a donor later
determined to be at increased risk of transmitting disease by
transfusion.
4. Donor Deferral (Sec. 610.41(c))
In the Federal Register of June 11, 2001 (66 FR 31146), we
published a final rule entitled ``Requirements for Testing Human Blood
Donors for Evidence of Infection Due to Communicable Disease Agents''
(the June 2001 final rule). Under Sec. 610.41(a), any donor of blood
and blood components who tests reactive for a communicable disease
agent described in Sec. 610.40(a) or reactive with a serological test
for syphilis must be deferred from donation. Section 610.41(b) permits
the reentry of a deferred donor into the donor pool when the donor is
requalified by a process or method approved for such use by FDA.
We have moved proposed Sec. 610.40(g) to Sec. 610.41(c) in this
final rule. Section 610.41(c) requires collecting establishments to
perform ``lookback'' when a donor tests reactive by a screening test
for HIV or HCV, or when the establishment becomes aware of other
reliable tests results or information indicating evidence of infection
with HIV or HCV.
To be consistent with the language used in the June 2001 final
rule, we refer in this final rule to screening tests as ``reactive''
instead of ``repeatedly reactive,'' to accommodate the different
testing algorithms established for NAT and other screening tests. In
cases where the testing algorithm requires initial and repeat testing
as part of a single screening procedure, we would interpret the term
``reactive'' to mean ``repeatedly reactive.''
III. Comments on the Proposed Rule and FDA's Responses
Twelve blood establishments, i.e., blood banks, blood centers, and
blood industry trade associations, submitted comments raising multiple
issues with the proposed rule. The following comments and responses are
grouped by subject matter rather than by sections of the proposed rule
because many comments generally relate to both HIV and HCV prospective
review (Sec. Sec. 610.46 and 610.47, respectively), and HCV
retrospective review (Sec. 610.48). When the comment or response is
particular to HIV, HCV, prospective review, or retrospective review, we
specify it when we describe the comment.
Five comments expressed general approval of the proposed rule.
Another comment noted that the proposed rule was in keeping with the
commenter's mission to provide the best possible health care. One
comment stated that the proposed rule goes beyond the current guidance
issued in September 1998, i.e., to include the prior donations from
individuals identified as HCV-infected through their reactivity on the
HCV screening test by EIA 1.0, and extending multi-antigen ``lookback''
further back in time. Another comment supported extending the
requirement for HCV ``lookback'' beyond the September 1998 guidance.
We also received comments on the specific prescriptive language of
the proposed rule for quarantining, releasing from quarantine,
relabeling, appropriate algorithms for proceeding with HCV ``lookback''
resulting from the historical record review, the interpretation of the
signal to cutoff values used in interpreting the results of
[[Page 48772]]
the EIA 1.0 test, and the use of unlicensed tests in the algorithms.
However, because in preparing this final rule, we opted to set forth
requirements rather than specific procedures for achieving those
requirements, we have not responded specifically to comments on
prescriptive language that is not in the final rule. We reviewed and
considered all comments in preparing the ``lookback'' guidance.
Although the ``lookback'' guidance does not prescribe the sole means to
comply with this final rule, it does discuss measures that would
satisfy the final rule's requirements. A summary of the comments and
our responses follows.
A. General Comments
(Comment 1) Several comments stated that the proposed rule is too
long and complex, making it difficult to find cross-referenced relevant
provisions within the proposed rule, and that a flowchart or table
would make the requirements easier to follow and understand. Many
comments pointed out that certain testing outcomes are not adequately
addressed in the proposed rule's prescriptive language. One comment
urged FDA to create an appropriate mechanism, allowing blood
establishments to modify ``lookback'' timeframes and procedures as new
tests or new generations of viral tests become available. One comment
suggested that FDA modify the proposed rule by issuing requirements
that would apply to donors who test reactive by screening tests for HCV
(prospective ``lookback'') as of the effective date of the final rule,
and that the September 1998 guidance would apply to all other
``lookback'' actions (retrospective ``lookback'').
(Response) We agree that the proposed rule was long, complex, and
difficult to understand. When we issued the proposed rule, we provided
reference tables to help readers understand the proposed requirements
due to the complexity of the codified section. The tables showed the
various tests performed for HCV, steps of the ``lookback'' process, and
applicable provisions of proposed Sec. Sec. 610.48 and 610.49. As
described in section II.A of this document, and in response to the
comments, we have restructured the codified section of the final rule
to make it easier to understand and follow. We have constructed the
requirements by listing the objective actions that must be performed
and by eliminating the prescriptive language in the final rule. In
other words, the regulation now tells you what to do, not how to do it.
We considered the comments on testing outcomes in the proposed rule
when revising the September 1998 guidance document. We are issuing the
``lookback'' guidance, which represents our current thinking on how to
conduct HCV ``lookback.'' We have not prescribed specifically how you
must comply with the final rule's requirements, though the guidance
discusses the agency's current thinking and offers an explanation of
some satisfactory approaches. We provide flowcharts and tables in the
guidance document to assist you in performing the ``lookback'' actions.
As new tests or new generations of viral tests become available, we can
revise or modify the companion guidance to assist you in complying with
the required ``lookback'' actions.
As requested, we have provided a date in Sec. 610.48(b)(1)(i),
which defines the period of record review under Sec. 610.48.
Consistent with the ``lookback'' guidance, establishments could already
be performing the review now required under Sec. Sec. 610.47 and
610.48 by the time this final rule becomes effective. However, we want
to reiterate that, whereas the ``lookback'' guidance offers only our
current thinking on some satisfactory approaches, it is this final rule
that imposes a date to define record review and creates an enforceable
requirement.
(Comment 2) Another comment expressed concern regarding the adverse
consequences of informing donors of potential HCV infected status when
such a donor tests reactive by a screening test for HCV. The comment
pointed out the scientific uncertainty in treating HCV-infected
individuals and asked FDA to be mindful of these facts when issuing the
final rule. The comment further explained that treatment protocols are
ambiguous for many infected individuals and response rates are
variable. The comment was concerned that the donor's infectious status
may not result in high risk behavior change, especially where no
clinical symptoms are present, and that there may be personal
ramifications of informing a donor of an infectious status, i.e.,
personal disruption or trauma and potential for discrimination against
the donor.
(Response) Although this rulemaking does not address notification
of donors at increased risk of transmitting HCV, we are very aware of
the consequences of informing donors (required under 21 CFR 630.6), as
well as recipients, of their increased risk of being infected with HCV.
However, in the interest of protecting individual and public health, we
believe it is imperative that such individuals be informed so that they
may pursue further testing and counseling. Through such means the
recipient can monitor the disease process, if infected, and can take
precautions to prevent infecting others. Notification of the individual
also is necessary because some infected individuals with a progressive,
but treatable liver disease, remain asymptomatic for many years and are
not being treated because of a lack of awareness of their condition.
The agency cannot regulate the behavior of the individual if infected,
nor eliminate the trauma of notification, but notifying the individual,
recommending further testing, and permitting an opportunity for
counseling and treatment can help minimize any adverse outcome and is
necessary to protect the health of others.
B. Records
Proposed Sec. 606.160(d) would require that blood establishments
keep records no less than 10 years after the completion of the
processing of records or 6 months after the latest expiration date for
the individual product, whichever is later.
(Comment 3) One comment agreed with the proposed requirement. The
comment further suggested that prospective ``lookback'' be confined to
a ``rolling'' 10-year period, which would be consistent with the CMS
companion interim final rule requiring transfusion services to maintain
records of disposition for 10 years. The comment also requested that
FDA establish an expiration date for recovered plasma to prevent the
retention of records indefinitely as required for such products in
current Sec. 606.160(d).
(Response) We agree that the 10-year recordkeeping period should be
a ``rolling'' 10-year period. The final rule requires collecting
establishments to retain records for 10 years from the date of
completion of the processing records or 6 months after the latest
expiration date for the individual product, whichever is later (Sec.
606.160(d)). A ``rolling'' 10-year record retention period is described
as the establishment increasing the record retention period yearly
until 10 years of records from the date of disposition have accrued.
For example, if you currently have records dating back 5 years, then
the first year after the effective date of this regulation you must
have 6 years of records, the second year after the effective date, you
must have 7 years of records, etc., until 10 years have been reached.
However, if you already retain 10 years of records, then the 10-year
record retention period is immediately satisfied.
As for the comment's suggestion regarding an expiration date for
recovered plasma, the comment raises significant issues beyond the
scope of
[[Page 48773]]
this rulemaking. We decline to establish an expiration date for
recovered plasma at this time, but we will take the comment's
suggestion under consideration.
C. HIV and HCV ``Lookback''
1. Initiation of Record Review
Proposed Sec. Sec. 610.46(a) and 610.48(a) would require that the
collecting establishment initiate HIV or HCV ``lookback,''
respectively, when a donor tests reactive by a screening test for
evidence of HIV or HCV infection. Collecting establishments would also
initiate record review when the establishment becomes aware of other
test results indicating evidence of HIV or HCV infection, provided that
the testing was performed by a laboratory certified under the Clinical
Laboratories Improvement Amendments of 1988 (CLIA), using a test
approved by FDA.
(Comment 4) One comment suggested deleting from proposed Sec. Sec.
610.46(a) and 610.48(a), the requirement to conduct prospective record
review when a blood establishment is ``made aware of other test
results'' indicating evidence of HIV or HCV infection. The comment
explained that the language is too vague as to the nature, source, and
reliability of the information, and requested clarification of what
constitutes ``made aware'' and ``evidence.'' The comment also
considered determining a lab's CLIA certification status as problematic
because there is no available database for searching such information.
(Response) We decline to delete the requirement. In the preamble of
the proposed rule (65 FR 69378 at 69383), we explained that this
provision clarifies the existing language in Sec. 610.46, which
requires HIV ``lookback'' when the donor is determined otherwise to be
unsuitable when tested under 21 CFR 610.45.
However, we added the term ``reliable'' as describing other test
results that initiate record review. We consider other ``reliable''
test results to be information that, if known to the collecting
establishment, would indicate that the donor is unsuitable or should be
deferred from donation.
A collecting establishment does not routinely receive information
that a donor is unsuitable for donation unless the screening and
testing occurs in the same collecting establishment. However, we are
aware that donors may inform collecting establishments when they test
reactive for evidence of HIV or HCV as a result of a physical
examination or if they donate at another collecting establishment. In
the final rule, therefore, we have removed the provision from proposed
Sec. Sec. 610.46(a) and 610.48(a) for the testing laboratory to be
certified under CLIA and for the other information to be based on a
test approved by FDA, and have described our thoughts about the
relevant laboratory qualification information in the ``lookback''
guidance. These qualifications are already required under Sec.
610.40(f). Such qualifying information can be obtained by asking if the
laboratory is a Medicare participant.
2. Extent of Record Review
Proposed Sec. Sec. 610.46(a) and 610.48(a) would require that the
collecting establishment review HIV or HCV testing records and identify
blood and blood components previously collected from a donor who
subsequently tests reactive for evidence of infection with HIV or HCV.
Record review would include all available records.
Proposed Sec. 610.48(c) would require collecting establishments to
perform a review of records for HCV testing prior to the effective date
of the final rule. These records would date back indefinitely for
computerized electronic records, and to January 1, 1988, for all other
readily retrievable records, or to the date 12 months before the most
recent negative screening test for HCV, whichever is the lesser period.
(Comment 5) Several comments asked for revisions to the codified
section to clarify the extent of prospective record review. One comment
requested a fixed date for ``lookback'' regardless of the
establishment's method of recordkeeping. The comment stated that the
proposed rule penalizes establishments that keep records longer and
agreed that the rule is a deterrent for keeping good computerized
records. The other comment interpreted the language of the proposed
prospective HIV and HCV record review, i.e., ``whenever records are
available,'' as resulting in an open-ended, continuous search. The
comments preferred the description of the retrospective HCV record
review and suggested modifying the prospective HIV and HCV record
review language to reflect similar language, or, as one comment
suggested, changing the record review period to 10 years for
transfusable products and 6 months for recovered plasma intended for
further manufacturing use. The comment reasoned that, because recovered
plasma does not have an expiration date, the blood establishment would
have to search records that are 20 to 30 years old. Another comment
recommended limiting the record review to computerized electronic
records.
For retrospective review, one comment recommended that we base the
``lookback'' on a record review that extends as far back as
computerized records exist for donation and distribution, or back to
January 1, 1988, whichever is longer.
(Response) In regards to the extent of record review required under
final Sec. Sec. 610.46(a)(1) and 610.47(a)(1) (prospective review), we
recognize the difficulty in interpretation and we have eliminated the
phrase ``whenever records are available.'' In its place, we have
inserted a reference to the requirements under Sec. 606.160(d) for the
record retention period (10 years). Any affected blood or blood
components collected before the required record retention period will
most likely be outdated; or collected more than 12 months before the
donor's most recent nonreactive screening tests for HIV or HCV, or more
than 12 months before the donor's reactive direct viral detection test,
e.g., NAT (HIV and HCV) or HIV p24 antigen test (HIV), and nonreactive
antibody screening test for HIV or HCV, and will not need to be
quarantined. If the establishment retains records beyond the required
retention period, we suggest that the establishment search such records
as appropriate in the ``lookback'' requirements to identify blood and
blood components previously collected from a donor who later tests
reactive for evidence of HIV or HCV infection. Our intention is not to
penalize those establishments that keep records longer than required,
but to help ensure that recipients are notified that they may have
received blood or blood components at increased risk of transmitting
infection so that they may seek testing, counseling, and (if necessary)
treatment.
We decline to make the suggested change for retrospective record
review because not all establishments' records are computerized.
(Comment 6) Three comments requested clarification of certain terms
used in the proposed rule. One comment requested that the prospective
and retrospective ``lookback'' be consistent with regard to the form
and content of the reviewed records, i.e., ``computerized electronic
records'' and ``readily retrievable records.'' The comment also
suggested defining ``available'' in the prospective ``lookback'' as
synonymous with ``computerized electronic'' in the retrospective
``lookback.'' Another comment contended that nonconformity in such
language might lead to different interpretations between the blood
establishments and FDA investigators. A
[[Page 48774]]
third comment requested clarification of the term ``readily.''
(Response) We acknowledge that the descriptive terminology used in
the proposed codified section relating to the extent of record review
could lead to differences in interpretation. However, we decline to use
the same terms for prospective review and retrospective review due to
the different events initiating the review, i.e., a donor's reactive
screening test for HIV or HCV in prospective review or the final rule's
requirement for historical HCV testing record review. However, to
lessen confusion, we are changing the description of the prospective
record review in Sec. Sec. 610.46(a)(1)(i) and 610.47(a)(1)(i) from
``whenever records are available'' to ``records required under Sec.
606.160(d).'' In this final rule, records must be available for 10
years after the records of processing are completed or 6 months after
the latest expiration date for the individual product, whichever is
later. Because the current regulation requires a 5-year record
retention period, the 10-year record retention period is a ``rolling''
10 years, as previously discussed in comment 3 of this document.
Prospective record review must include all records required under Sec.
606.160(d), including computerized electronic records. We have removed
the term ``readily retrievable'' from the final rule.
3. Quarantine
Proposed Sec. Sec. 610.46(a) and 610.48(a) and (c) would require
the collecting establishment to quarantine in-date blood and blood
components identified during the record review. Because the identified
in-date blood and blood components are considered at risk for
transmitting HIV or HCV infection and are still in inventory, they
would be required to be removed from inventory and isolated in
quarantine so that they may not be transfused or used for further
manufacture into injectable products. The proposal would require
collecting establishments to notify consignees to quarantine such blood
and blood components, removing the possibility of infecting others. The
proposed rule would require the collecting establishment to complete
these actions within 3 calendar days of the donor testing reactive for
evidence of HIV or HCV infection. We specifically requested comments on
the appropriateness of 3 calendar days to complete quarantine and
notification of consignees.
(Comment 7) Several comments requested that FDA revise Sec.
610.46(a) to be consistent with Sec. 610.48(a) by limiting quarantine
and notification of consignees to in-date products, and that the
retrospective review in proposed Sec. 610.48(e) be limited to in-date
products only. Another comment suggested eliminating the action of
quarantine for outdated products for both prospective and retrospective
record review. The same comment asked whether in-date and outdated
products are to be treated identically.
(Response) We agree with the comment that the requirements for HIV
``lookback'' in proposed Sec. 610.46(a) and the requirements for HCV
``lookback'' in proposed Sec. 610.48(a) should be consistent and have
made the change. The action of quarantining identified blood and blood
components by the collecting establishment and the initial notification
of the consignees to quarantine such products is limited to in-date
blood and blood components because they are available for transfusion
or use for further manufacturing into injectable products if they
remain in inventory. Quarantine by the collecting establishment or
consignee does not apply to outdated blood and blood components because
they should no longer be in the establishment's releasable inventory.
However, we want to clarify that the prospective HIV and HCV
``lookback'' (final Sec. Sec. 610.46 and 610.47) must identify both
in-date and outdated blood and blood components previously donated by a
donor with a reactive screening test for HIV or HCV. This
identification is necessary so that recipients of such blood and blood
components can be notified for the purpose of testing, counseling, and
treatment if indicated by the supplemental (additional, more specific)
test results. These actions also apply to the requirements of
historical HCV testing record review under final Sec. 610.48.
(Comment 8) One comment urged FDA to modify the time period of 12
months for the quarantine of identified prior collections of blood and
blood components from the most recent reactive screening test for
evidence of HIV infection in proposed Sec. 610.46(c). The comment
suggested changing the time period from 12 to 3 months to remain
consistent with current guidance for donors testing reactive for HIV-1
antigen in a Blood Memorandum to All Registered Blood and Plasma
Establishments entitled ``Recommendations for Donor Screening with a
Licensed Test for HIV-1 Antigen'' (August 1995 memorandum).
(Response) We understand the comment's request for consistency with
existing guidance. However, we decline to make the change for the
following reason. Since 1995, industry has collected additional
scientific information showing that donors infected with HIV may
experience intermittent viremias for a variable period of time prior to
a persistently detectable viremia or an antibody response. Because
these episodes of transient viremia may extend over a longer window
period than previously estimated, we are requiring a record review
period of 12 months before the donor's reactive direct viral detection
test with a nonreactive antibody screening test or 12 months prior to
the most recent nonreactive screening tests, whichever is the lesser
period. A 12-month timeframe is necessary to encompass with sufficient
confidence the window period for HIV prior to the detection of
antibody. We have elected not to address an alternative (possibly
shorter) ``lookback'' period based on the last negative direct viral
test in order to minimize operational complexity and because the
appropriate period has not been well established scientifically. This
requirement supersedes the 3-month ``lookback'' recommendation for
donors testing reactive for HIV p24 antigen in the August 1995
memorandum and is for prospective application. However, we recommend
that collecting establishments ``lookback'' 12 months before the few
previously identified reactive HIV p24 antigen tests with a nonreactive
antibody screening test that were confirmed as infected with HIV.
(Comment 9) One comment interpreted ``quarantine'' as gaining
control of distributed prior collections of blood and blood components
from a donor who subsequently tests reactive by a screening test for
evidence of HIV or HCV infection.
(Response) We disagree with the comment's interpretation of
``quarantine.'' The requirement for ``quarantine'' simply means the
removal of the identified in-date blood and blood components from the
collecting establishment's or consignee's inventory and their placement
into isolation to prevent transfusion or use for further manufacture
into injectable products. It is not intended to require the collecting
establishment to physically retrieve the identified blood and blood
components from the consignee, though such action is permissible. It
also is permissible for the consignee to return to the collecting
establishment any in-date blood and blood components identified for
quarantine.
(Comment 10) Five comments considered the timeframe of 3 calendar
days in proposed Sec. Sec. 610.46 and 610.48 to be inadequate for the
quarantine of all
[[Page 48775]]
prior collections of blood and blood components from donors testing
reactive by a screening test for evidence of HIV or HCV infection, and
for consignee notification, especially if the quarantine action is
initiated by information from an outside source (prospective record
review). Another comment stated that 3 calendar days is appropriate for
quarantining in-date blood and blood components, but that additional
time is needed for consignee notification. Several comments suggested 7
calendar days, 3 working days, or 5 business days as alternative
timeframes for quarantine and consignee notification. Two comments
suggested that the time period start once the prior collections of the
donor with the reactive screening test are identified, not when the
reactive screening test occurs.
(Response) We decline to change the timeframe. Our objective is to
minimize the possibility of transmitting an HIV or HCV infection to an
individual due to his or her exposure to blood and blood components at
risk of transmitting HIV or HCV. It is important that consignee
notification and quarantine of such blood and blood components be
performed expeditiously within a reasonable timeframe and we believe
that 3 calendar days is reasonable. We define ``3 calendar days'' as
the period ending at the close of business 3 full days after a donor
tests reactive. So, for example, if a donor testing reactive by a
screening test for HIV or HCV on the first day (e.g., Friday), then
quarantine by the collecting establishment and notification of
consignees to quarantine must occur by close of business on the fourth
day (e.g., Monday).
(Comment 11) Several comments suggested adjusting the time period
for quarantine and notification for the HCV retrospective review
requirements in proposed Sec. 610.48(e) and (f). Suggested changes
ranged from 3 working days, to 7 calendar or 5 business days, to 1 year
for quarantine of prior collections and consignee notification. Another
comment requested a change from 3 calendar days to 3 working days for
outdated products. One comment suggested deleting proposed Sec.
610.48(f)(2), which addresses the review of historical records based on
screening performed using a single antigen-base antibody screening test
during 1990 to 1992. The comment said that there would be few in-date
products that would necessitate immediate quarantine and notification
of the consignee.
(Response) We decline to make the suggested changes for the reason
stated in response to comment 10 of this document. We want to clarify
that these actions are initiated by the identification of a reactive
screening test on a donor upon review of historical records. The 3-
calendar day timeframe is required only when in-date blood and blood
components are identified. If the review does not identify in-date
blood and blood components, then the quarantine and notification of
consignees to quarantine is unnecessary.
We agree with the comment to delete proposed Sec. 610.48(f)(2)
based on the reason that there would be few in-date products that would
necessitate quarantine and notification of consignees. This revision is
not necessary because of our restructuring of the codified section.
4. Exemptions From Quarantine
Proposed Sec. Sec. 610.46(c) and 610.48(g) would permit exemption
from quarantine of blood and blood components collected more than 12
months before the donor's most recent negative screening test for HIV
or HCV infection.
(Comment 12) One comment suggested that FDA make an exception to
HIV and HCV ``lookback'' for autologous donations that have a reactive
screening test for HIV or HCV if the donor did not make any prior
donations for allogeneic use, and if the blood establishment receiving
those prior autologous donations from the donor did not have a
crossover program, i.e., unused autologous donations put into inventory
for allogeneic use.
(Response) We agree that such autologous donations should be exempt
from ``lookback'' because the risk of transmitting HIV and HCV
infection to a recipient does not exist because the autologous donor
has not donated blood or blood components that will be used by others.
We have clarified in the final rule that ``lookback'' applies to blood
and blood components ``intended for use in another person.''
(Comment 13) One comment requests that we exempt products
previously quarantined under FDA guidance and other existing
regulations for ``lookback'' from new quarantine requirements. The
comment suggested that we consider previous ``lookback'' actions as
prospective and not impose further review requirements on these cases
that would make the same reviews retrospective. The comment also
claimed that retrospective record review is a one-time process and that
it is too cumbersome to have retrospective requirements intertwined
with the continuous process of prospective records review requirements.
(Response) If actions performed pursuant to the ``lookback''
guidance or requirements for quarantine fulfill the requirements of
this final rule, then they are considered completed. As discussed in
section II.B.2.b and comment 1 of this document, we established a date
distinguishing the end of the retrospective review period and an
exemption in certain circumstances, thereby eliminating any overlap of
retrospective review and prospective review.
(Comment 14) Four comments asked us to include blood and blood
components already pooled for further manufacturing use in the
exception to quarantine in proposed Sec. Sec. 610.46 and 610.48. The
comments also asked if these sections include historical or
retrospective record review in addition to the prospective record
review.
(Response) We agree with the comment and have added the exemption
from quarantine for pooled blood components intended solely for further
manufacturing into products that are manufactured using validated viral
clearance (i.e., inactivation and removal) procedures in the
requirements for prospective review, in final Sec. Sec.
610.46(a)(1)(ii), 610.47(a)(1)(ii), and in the requirement for
retrospective record review in final Sec. 610.48(b)(3)(i) and (c)(1).
Pooled components intended solely for further manufacturing are
exempted because it is impractical to retrieve such pools and,
additionally, the manufacturing process is designed to remove or
inactivate HIV and HCV.
5. Notification of Consignee
Proposed Sec. Sec. 610.46(a)(1)(ii), 610.48(a)(1)(ii), and
610.48(e)(2) and (f)(2) would require the collecting establishment to
notify the consignee to quarantine in-date blood and blood components
previously collected from a donor who later tested reactive for
evidence of HIV or HCV infection. Notification would be required to
occur within 3 calendar days after the date a donor tests reactive by a
screening test for HIV or HCV, or after the date of identification of
the donor's reactive screening test for HCV.
In proposed Sec. Sec. 610.46(b) and 610.48(b) (prospective
review), the collecting establishment would notify the consignee of the
results of further testing within 45 days after the donor tested
reactive by a screening test for HIV or HCV. Under proposed Sec.
610.48(h)(3) (retrospective review), the collecting establishment would
notify the consignee of the results of further testing within 45 days
following completion of further testing and prior
[[Page 48776]]
to 1 year after the effective date of the final rule.
(Comment 15) Two comments requested clarification of the
notification responsibilities in general. One comment suggested listing
all the conditions that trigger quarantine and consignee notification
in one section of the codified section of the final rule. The comment
also requested clarification of the different criteria that trigger
consignee notification versus recipient notification. The second
comment recommended that the consignee be notified after the
confirmatory test is completed to make the notification more effective
by supplying all the necessary information and to reduce the number of
contacts.
(Response) We agree with the comment to group separately the
requirements specific to consignee notification and recipient
notification. Consequently, we have restructured the final rule into
specific actions for the collecting establishment, which is responsible
for consignee notification, and the consignee, who is responsible for
the recipient notification. However, we do not agree with the
recommendation that the collecting establishment limit notifying the
consignee until after all the testing is completed. We clarified that
the collecting establishment must notify the consignee when in-date
blood and blood components distributed to the consignee are identified
for the purpose of quarantine, and notify the consignee again with the
results of the completed further testing. The consignee must notify the
transfusion recipient if indicated by the results of the supplemental
tests for HIV or HCV infection or when the donor's screening test is
reactive and there is no available supplemental test that is approved
for such use by FDA, or if under an IND or IDE, is exempted for such
use by FDA.
(Comment 16) One comment suggested that we create an exemption for
notifying the consignee when the consignee gives documentation to the
blood establishment showing that records no longer exist for products
during a specified time period. The comment said that if the blood
establishment knows that records do not exist, then it would be
ineffective to notify the consignee to quarantine the products.
(Response) We agree that it would be ineffective to notify the
consignee to quarantine blood and blood components if records do not
exist. However, initial notification of the consignee is for the
purpose of quarantining in-date blood and blood components. Such
consignees of blood and blood components must have existing records
under Sec. 606.160(d). The final rule requires the collecting
establishment to notify the consignee of further testing results for
both in-date and outdated blood and blood components identified as at
increased risk of transmitting HIV or HCV infection for the purpose of
recipient notification.
(Comment 17) A few comments asked that we clarify, in proposed
Sec. 610.48(g), that it is not necessary to notify the consignee when
prior collections from a donor with a reactive screening test for HCV
are exempt due to the supplemental test results.
(Response) In the preamble to the proposed rule (65 FR 69378 at
69387), we explained that when an appropriate supplemental (additional,
more specific) test for HCV is negative and is completed within the 3
calendar days provided for the completion of quarantine and consignee
notification, consignee notification is not necessary. In the final
rule, if the supplemental test is negative within the provided 3
calendar days, then the reactive screening test result is interpreted
as a ``false reactive,'' HCV infection is not indicated, and the
identified blood and blood components are considered not at increased
risk of transmitting HCV. If, however, the supplemental test is
completed more than the provided 3 calendar days after the date of the
reactive screening test for HCV infection, the collecting establishment
must quarantine identified in-date blood and blood components, and
notify consignees to quarantine identified in-date blood and blood
components, but may release the blood and blood components from
quarantine if the supplemental test is negative. This applies to a
donor testing reactive by a screening test for HIV infection as well.
For retrospective record review, when a collecting establishment
identifies a donor testing reactive by a HCV screening test, and if an
appropriate supplemental test is negative, then quarantine and
consignee notification is unnecessary. However, if additional
supplemental testing or testing with a licensed screening test with
known greater sensitivity than the test of record is necessary to
establish the infectious status of the identified blood and blood
components, then quarantine and consignee notification of in-date blood
and blood components must occur within the provided 3 calendar days
until further testing is completed.
6. Further Testing and Consignee Notification of Test Results
In the case of prospective record review, proposed Sec. Sec.
610.46(b) and 610.48(b) would require that the collecting establishment
perform further testing on the donor's blood and notify the consignee
of the results within 45 calendar days after the date on which the
donor tested reactive by a screening test for evidence of HIV or HCV
infection.
While performing retrospective record review, proposed Sec.
610.48(h) and (i) would require the collecting establishment to perform
further testing, if not previously performed. The collecting
establishment would perform the further testing either on a frozen
sample from the reactive donation, if available, or on a fresh specimen
from the donor, if obtainable. The collecting establishments would then
notify the consignees of the results within 45 calendar days following
the completion of further testing and prior to 1 year after the
effective date of the final rule.
(Comment 18) One comment suggested changing ``shall'' to ``may'' in
proposed Sec. 610.48(h)(1) and (i)(1) to give the establishment the
option of immediately performing quarantine and notification rather
than locating the donor for further testing.
(Response) We agree with the comment and have revised final Sec.
610.48(b)(2) by changing ``shall'' to ``may'' to permit the collecting
establishment to choose between either immediate quarantine and
consignee notification, or obtaining a sample for further testing from
the donor. However, we emphasize the benefit of further testing when
recipient notification is indicated, and reiterate that every effort
should be made to complete further testing.
(Comment 19) One comment suggested alternatives for the 45-calendar
day time period for notifying consignees of the results of further
testing in both prospective and retrospective review. For proposed
Sec. Sec. 610.46(b) and 610.48(h)(3)(i), the comment suggested
exempting completely the requirement of notifying the consignee of
further HIV or HCV testing results within 45 days when prior
collections are returned to the blood establishment or destroyed. The
comment suggested extending the time period to 90 days in proposed
Sec. 610.48(b) for notifying consignees of further HCV testing results
when the products from prior collections of the donor are outdated. The
90-day time period would permit the blood establishment to retrieve
records that are stored offsite and in varying forms, or to give
additional search and review efforts to records not as readily
accessible for in-date products. The comment further suggested that
[[Page 48777]]
notification for outdated products made from prior collections should
occur within 1 year of the effective date of the final rule and only if
the test results indicate that consignees must take action to notify
the recipients.
(Response) We agree that it is not necessary to notify the
consignee of the results of further testing within 45 calendar days if
the blood and blood components previously collected from a donor who
later tests reactive for evidence of HIV or HCV infection are returned
to the collecting establishment or destroyed by the consignee.
We decline to extend the time period of 45 calendar days to 90
calendar days in final Sec. 610.48(b) as suggested by the comment.
Although the comment reasoned that a longer time period would enable
the collecting establishment to retrieve records that are stored
offsite and in varying forms or enhance additional search and review
efforts to records not as readily accessible as those for in-date
products, we believe that 45 calendar days is adequate for such
purposes and that it is imperative that consignees obtain such
information, which may necessitate recipient notification, in a
reasonable time period.
7. Notification of Transfusion Recipient
Proposed Sec. Sec. 610.47 and 610.49 would require consignees
(transfusion services) to notify recipients that they received blood
and blood components previously collected from a donor later determined
to be unsuitable when tested for evidence of infection with HIV or HCV.
The transfusion service would notify the recipient's physician of
record (i.e., physician of record or physician who ordered the blood or
blood component) and ask the physician to inform the recipient of the
need for HIV or HCV testing and counseling. If the physician is not
available or declines to notify the recipient, the transfusion service
would be required to notify the recipient and inform the recipient of
the need for HIV or HCV testing and counseling. The notification
process would include a minimum of three attempts within a maximum of
12 weeks of receipt of the result of the supplemental test. If the
recipient is adjudged incompetent by a State court, or the recipient is
competent but State law permits notification of a legal representative
or relative, or if the recipient is a minor, then the transfusion
service would notify the legal representative, relative, or recipient's
physician of record. If the recipient is deceased, proposed Sec.
610.47(c) for HIV would have the notification process continue, and the
transfusion service or the recipient's physician of record would notify
the legal representative or relative. Under proposed Sec. 610.49(c)
for HCV, if the recipient were deceased, then the notification process
would be terminated.
(Comment 20) One comment urged FDA to remove the exceptions for
recipient notification by the transfusion service/consignee in proposed
Sec. 610.49(a) and place them in the section that pertains to the
blood establishment. The comment stated that the requirement, as
proposed, would require the blood establishment to notify the consignee
even when the further testing results show that the donor is not at
increased risk of transmitting HCV. The comment said that the suggested
change would allow blood establishments to avoid notification of the
consignees in cases that require no recipient notification, would
streamline the final rule, and would have no ill effect on public
health.
(Response) We have accommodated the comment's request by
restructuring the codified section, requiring objective actions for
collecting establishments and consignees, and removing the prescriptive
language. In this process, we removed proposed Sec. 610.49.
(Comment 21) Several comments sought changes to proposed Sec.
610.49(b). One comment interpreted the proposed section as requiring
concurrent notification of the recipient's physician of record and the
recipient. Some comments stated that the recipient's physician of
record at a transfusion service often does not have an ongoing
relationship with the recipient and that the most common reason for
notifying the recipient directly is because the physician of record
refuses to notify the recipient. The comments would revise proposed
Sec. 610.49(b) to require the recipient's physician of record, not the
transfusion service, to notify the recipient and would make the
transfusion service responsible for notification only if the
recipient's physician requests it or is unavailable. One comment said
that the transfusion services are not in the position to provide
patient counseling and further testing of the recipient for diagnostic
purposes, and that the physician's decision should not be overridden by
the transfusion service.
(Response) The comments misread the proposed rule. Proposed Sec.
610.49(b) stated that ``[T]he transfusion service shall either notify
the recipient directly or notify the recipient's physician of record *
* * and ask him or her to inform the recipient of the need for HCV
testing and counseling.'' The proposal, therefore, did not propose
concurrent notification of the recipient's physician and the recipient.
In the final rule we require that the transfusion service notify the
transfusion recipient of blood and blood components at increased risk
of transmitting HCV, or the recipient's physician of record (Sec.
610.47(b)(3)). Whether the transfusion service or the recipient's
physician of record notifies the recipient, the recipient must be
informed of the need for testing and counseling. At a minimum, the
notifying party should inform the recipient of his or her increased
risk of HCV infection and advise the recipient to seek testing,
counseling, and treatment if necessary.
(Comment 22) Several comments expressed concern regarding the
requirement in proposed Sec. 610.49(b) that would require a minimum of
3 attempts to notify the recipient. The comments asked for the
flexibility to discontinue the attempts once the transfusion service
has obtained solid information indicating that further attempts are not
necessary or would not be fruitful, and documentation is kept. Two
comments would revise proposed Sec. 610.49(b) to require only one
attempt at notification using a traceable method, i.e., certified mail,
return receipt. The comments asserted that there is a tremendous cost
associated with more than one attempt and that we should permit the
transfusion services to show good faith effort at notification if they
use the information available in the patient record.
(Response) The final rule clarifies, in Sec. 610.47(b)(3), that a
consignee must make reasonable attempts to notify the recipient or the
recipient's physician of record. We eliminated the requirement for
three attempts; however, we emphasize that a consignee should continue
attempting to notify the recipient or the recipient's physician of
record until it is clear that further attempts would not be successful.
If the initial attempt or attempts are unsuccessful, a consignee may
need to try other methods to contact the recipient or the recipient's
physician of record. If a consignee is successful in notifying a
recipient or physician of record, then, obviously, no other attempts
are necessary. We have also clarified this requirement in Sec. Sec.
610.46(b)(3) and 610.48(c)(3). Consignees, under Sec.
606.160(b)(1)(viii), must document their attempts to notify recipients
or physicians of record and maintain a record of these attempts,
whether successful or not.
(Comment 23) Two comments requested consistency in proposed
Sec. Sec. 610.47(c) (HIV ``lookback'') and
[[Page 48778]]
610.49(c) (HCV prospective ``lookback'') regarding the notification of
the legal representative or relative when a transfusion recipient is
deceased. Proposed Sec. 610.47(c) for HIV would require notification
to continue if the transfusion recipient is deceased, and proposed
Sec. 610.49(c) for HCV would discontinue the process if the
transfusion recipient were deceased. Another comment requested that we
eliminate the requirement in proposed Sec. 610.49(c) to notify the
legal representative or relative of a recipient who is incompetent or
deceased. The comment said the risk of secondary transmission under
such circumstances is slim and such notification wastes resources.
(Response) The final rule, in Sec. 610.46(b)(3), continues to
require the consignee to notify the legal representative or relative of
a deceased recipient who received blood and blood components determined
to be at risk of transmitting HIV infection. Requiring notification of
the legal representative or relative when the recipient is deceased may
help prevent the further spread of HIV, which the donor may have spread
to a spouse or significant other before death. With this information,
the spouse or significant other may be tested for the communicable
disease, receive counseling, and take precautions not to spread it to
others, if infected. We do not believe that the notification
requirement is necessary in Sec. Sec. 610.47(b)(3) and 610.48(c)(3)
for HCV ``lookback'' because 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.
IV. Analysis of Impacts
FDA has examined the impacts of the final rule under Executive
Order 12866 and the Regulatory Flexibility Act (5 U.S.C. 601-612), and
the Unfunded Mandates Reform Act of 1995 (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, environmental, public health and safety, and other
advantages; distributive impacts; and equity). The agency believes that
this final rule is an economically significant regulatory action under
section 3(f)(1) of the Executive order, since it may lead to impacts of
greater than $100 million in any one year.
The Regulatory Flexibility Act requires agencies to analyze
regulatory options that would minimize any significant impact of a rule
on small entities. Because the average annualized costs for small
entities will be less than 0.3 percent of average annual revenues, the
final rule will not have a significant economic impact on a substantial
number of small entities.
Section 202(a) of the Unfunded Mandates Reform Act of 1995 requires
that agencies prepare a written statement, which includes an assessment
of anticipated costs and benefits, before proposing ``any rule that
includes any Federal mandate that may result in the expenditure by
State, local, and tribal governments, in the aggregate, or by the
private sector, of $100,000,000 or more (adjusted annually for
inflation) in any one year.'' The current threshold after adjustment
for inflation is $122 million, using the most current (2005) Implicit
Price Deflator for the Gross Domestic Product. FDA does not expect this
final rule to result in any 1-year expenditure that would meet or
exceed this amount.
The final rule will provide information to consignees and
recipients of blood and blood components that may be at increased risk
of transmitting HCV infection. Based on the following analysis, FDA
projects that one-time costs will total approximately $73.5 million and
annual costs will be approximately $1.7 million. Benefits of the final
rule are measured as the gains in quality-adjusted life years (QALYs)
of blood transfusion recipients who receive treatment for newly-
identified post-transfusion hepatitis C virus infections that would
otherwise go untreated in the absence of ``lookback.'' The value of
this potential one-time gain in quality-adjusted life years ranges from
$264 million to $1,228 million depending on the societal value of a
quality-adjusted life year, or from $30.9 million to $143.9 million
when annualized over 10 years with a 3 percent discount rate. Benefits
could not be estimated with a 7 percent discount rate. With total
annualized costs of $10.3 million, the net annualized benefits of the
final rule are between $20.6 million and $133.6 million with a 3
percent discount rate over 10 years. Thus, FDA has determined that the
final rule will be economically significant as defined by the Executive
Order, because the final rule might generate benefits that exceed $100
million in a single year.
A. Economic Impact\3\
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\3\ The final rule revises the HIV ``lookback'' requirements to
make them consistent with the HCV ``lookback'' requirements. Because
these revisions do not change the level of effort required for HIV
``lookback,'' an economic impact for the HIV ``lookback'' is not
provided. The economic analysis for the HIV ``lookback''
requirements is addressed in the Federal Register issued September
9, 1996 (61 FR 47420).
---------------------------------------------------------------------------
The purpose of the final rule is to ensure the continued safety of
the Nation's blood supply by removing blood previously donated by
individuals who test reactive for evidence of the HCV infection and by
notifying recipients that these blood and blood components are at
increased risk of transmitting the infection. Although blood is
screened for several infectious diseases, including HCV, it is possible
for a donor to give blood in the early stages of an infection before a
screening test can detect its presence. Blood given during this window
period has an increased risk of transmitting disease. The need for this
final rule stems from the information failure caused by the inability
of screening tests to identify infections in the early stages. HCV
``lookback'' will ensure that blood transfusion recipients be notified
in the rare event that they receive at-risk blood.
In addition to the proposed rule, the agency has issued several
draft guidances on HCV ``lookback.'' The final rule, however, outlines
the set of actions blood collection establishments and consignees
(i.e., transfusion service establishments) must follow when tests show
that an allogeneic blood donation from a repeat donor may be at
increased risk for HCV infection. Because industry guidance can be
updated more quickly as technologies advance, much of the prescriptive
language in the proposed rule has been removed from the final rule. In
response to the agency's guidance documents, much of the blood industry
has voluntarily adopted HCV ``lookback'' as a standard business
practice. Nevertheless, some establishments have not implemented all
elements of ``lookback,'' specifically recipient notification. Without
the final rule, partial implementation of ``lookback'' would likely
persist with some blood transfusion recipients not being notified that
they received blood components at increased risk for HCV infection. The
agency further notes that the costs and benefits of the FDA and CMS
interim final rule are not additive, as the impacts considered in the
CMS interim final rule are also accounted for in the FDA final rule.
[[Page 48779]]
1. Annual Number of Blood Donations and Blood Components Affected
a. Number of donations from repeat donors confirmed HCV positive.
At a May 2, 2003, meeting of the DHHS Advisory Committee, the agency
reported that previously unpublished American Red Cross (ARC) data show
the HCV prevalence rate for repeat donors was 0.007 percent in 2000
(Ref. 1). This estimate implies that with approximately 11.2 million
donations annually from repeat donors (14 million donations x 80
percent of donations from repeat donors), blood banks will find an
estimated 780 donations from HCV-infected donors (11.2 million
donations x 0.007 percent infected with HCV) per year. We note the
reported prevalence rate has declined since 1997 when the ARC reported
an HCV prevalence rate of 0.03 percent for repeat donors (Ref. 2). If
prevalence rates continue to decline, we would expect even fewer
donations from HCV-infected donors in the future.
b. Number of previously donated components. A blood donation is
normally separated into multiple components. Based on 1999 Center for
Disease Control and Prevention (CDC) survey findings, we initially
estimated that an average of 1.1 previously donated components would be
found for each donor triggering ``lookback'' (Ref. 3). Several comments
from blood banks affiliated with the America's Blood Centers (ABC)
disagreed with the CDC survey findings and cited their experience that
a review of donation records for a donor testing reactive to evidence
of HCV infection can uncover up to 10 previously donated components.
The wording of some survey questions may partially explain why CDC
found fewer components. Blood banks reported the number of repeat
donors who triggered ``lookback'' according to the type of screening
test used, and the total number of blood components for these donors
that had been previously shipped to transfusion services. However, some
blood banks may have held or destroyed donations with abnormal
surrogate markers for HCV even though the blood screened negative for
HCV. These blood banks would report fewer components previously shipped
to transfusion services (Ref. 3, p. 1180).
The agency accepts that some collecting establishments may have
more previously donated components than suggested by the CDC data.
However, ABC establishments receive only about half of the annual
donations in the United States. We assume that the CDC survey findings
are representative of the remaining blood donations. Taking the average
of the midpoint of the range reported in comments on the proposed rule
(i.e., 5 components) and the CDC survey findings (i.e., 1.112
components), we increase the estimated average number of previously
donated components for each donation from 1.1 to 3.1 (3.06 = (5 +
1.112) / 2).
2. The Number and Type of Entities Affected
The final 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. In the United States, there are 981
registered blood collection establishments and 60 licensed plasma
collection establishments listed with FDA's Office of Blood Research
and Review (OBRR) (i.e., a total of 1,041 establishments). CMS has
records of another 4,980 establishments that transfuse blood and blood
components.
With the exception of hospitals that both collect and transfuse
blood products, establishments affected by the final rule will either
act as a blood collection establishment or as a consignee (i.e., a
transfusion service), but not both. To distinguish the impact of the
requirements on blood collection establishments and consignees, the
final rule provisions affecting each type of establishment will be
treated separately in the analysis that follows.
3. Estimated Impact on Blood and Plasma Collection Establishments
First, we present the costs that are the same for all collection
establishments, regardless of the number of ``lookbacks'' performed.
Second, we discuss the costs that vary according to how many
``lookbacks'' occur.
a. Fixed costs--Standard operating procedures and record retention.
Each blood or plasma collection establishment must perform a one-time
review and reconcile its current SOPs with the requirements of the
final rule. In the analysis for the proposed rule, FDA estimated a
staff medical technologist will need an additional 40 hours to review
and update SOPs for the following actions: (1) Record review; (2)
product quarantine; (3) consignee notification to quarantine identified
products; (4) consignee notification of supplemental (additional, more
specific) test results; (5) release, destruction, or relabeling of
quarantined products; and (6) donor and blood product recordkeeping. No
comments on this estimate were submitted to the agency. Using the
original time burden and the revised loaded hourly wage of $33.84 (Ref.
4), each establishment will incur one-time costs of $1,354, resulting
in an industry-wide cost of approximately $1.4 million (40 hours x
$33.84 per hour x 1,041 establishments).
The final rule requires that blood and plasma collection
establishments extend the length of time they keep individual product
records from 5 to 10 years after the records of processing have been
completed, or 6 months after the expiration date for the individual
product, whichever is the later date. According to the AABB (formerly
known as the American Association of Blood Banks), all establishments
collecting blood in the United States, including the American Red Cross
and America's Blood Centers, are accredited by their organization and
comply with their standards. Current AABB standards require that
establishments retain records 10 years. Because the final rule will not
affect current industry practices, the blood collection industry will
incur no additional compliance costs for this provision.
b. Variable costs--HCV ``lookback.'' The agency has issued several
draft guidances describing the specific actions blood collection
establishments should take when a donor's screening test is reactive
for HCV or if the blood collection establishment becomes aware of other
reliable test results or information indicating evidence of HCV
infection. When these activities are initiated by a current blood
donation, the current donation is destroyed and the set of actions
required of the collection establishment is called a prospective
``lookback.'' However, when ``lookback'' is triggered by an historical
review of blood donor testing records, the set of actions is called an
historical or retrospective ``lookback.''
Although the actions required by the prospective and retrospective
``lookback'' provisions of the final rule are similar, the timing of
these actions differs between the two ``lookbacks.'' In general, for
donors with reactive test results for HCV, the collection establishment
must take the following actions: (1) Review records to identify any
other blood donations from these donors, (2) quarantine all previously
collected in-date components from the donors that were intended for use
in another person or for further manufacture into injectable products,
and (3) notify consignees to quarantine all previously collected in-
date
[[Page 48780]]
components at increased risk of transmitting the virus.
A collection establishment must perform a supplemental test (i.e.,
a test more specific than the screening test as described in the
current industry guidance) for HCV on the current reactive blood
sample. For reactive donations identified by an historical review of
donor testing records, if no supplemental test was performed when the
donation was collected, a collection establishment may perform a
supplemental test on a frozen sample from the same reactive donation or
a fresh sample from the same donor. If no further supplemental testing
is possible for the retrospective ``lookback'', a blood collection
establishment must send the reactive test results to the consignee.
Once supplemental or other required test results are received, both
types of ``lookback'' require that the collecting establishment do the
following: (1) Notify consignees of these test results for both in-date
and outdated previously collected components, (2) identify quarantined
in-date components, and (3) take the appropriate action (i.e., release
from quarantine, destroy the quarantined components, or relabel the
components) indicated by the test results. However, collections taken
more than 12 months before the donor's most recent nonreactive
screening tests, or 12 months before the donor's reactive direct viral
detection test and nonreactive antibody screening test for HCV are
exempt from the required record review.
Some comments requested that FDA specify how the final rule will
affect plasma establishments because HCV is inactivated when pooled
plasma is further manufactured. The ``lookback'' requirements of the
final rule will only affect plasma establishments that store and
distribute unpooled units to consignees. The number of firms in this
category is expected to be small. Comments from a plasma industry trade
organization support the agency's initial analysis that plasma
establishments will only be minimally affected by these requirements.
i. Prospective HCV ``lookbacks.'' At the May 2003 DHHS Advisory
Committee meeting, the agency reported that FDA-inspected blood
collection establishments voluntarily follow the agency's draft
guidance and perform prospective ``lookback'' as part of their standard
business practices (Ref. 1). No parties present at the meeting
dissented from this statement. Because these provisions of the final
rule will not require blood collection establishments to change their
current practices, the blood collection industry will not incur any
additional compliance costs for prospective ``lookback.''
ii. Retrospective HCV ``lookback.'' The final rule requires a
review of historical testing records for donations collected prior to
the effective date of the final rule. Within 1 year of the effective
date of the final rule, blood establishments must complete the
retrospective ``lookback'' as described previously in this document.
Because industry did not comment on the agency's initial estimate of
the compliance costs for the retrospective ``lookback,'' the cost per
consignee notification remains unchanged from the initial analysis (65
FR 69378 at 69396).
Published and unpublished data from CDC suggest that 188,448
components from donors screened with single-antigen screening tests and
105,706 components from donors screened with multi-antigen screening
tests require retrospective ``lookback'' by blood collection
establishments (Ref. 3). In their survey of the blood industry, CDC
found that by 1999, blood collection establishments had completed about
85 percent of the retrospective ``lookback'' based on reactive multi-
antigen tests or approximately 30 percent of the entire retrospective
``lookback'' (Ref. 3). Adjusting our initial estimate to account for
completion of 85 percent of blood collection establishments'
``lookbacks'' based on reactive multi-antigen test results, blood
collection establishments must conduct no more than 204,000
``lookbacks'' [188,448 components screened with single-antigen tests +
((100 percent - 85 percent) x 105,706 components screened with multi-
antigen tests)]. At the estimated cost of $113 per notification, blood
collection establishments will spend about $23 million (i.e., $22.9
million = 203,775 components x $112.50) to comply with the
retrospective ``lookback'' provisions of the final rule, or $2.7
million per year when annualized for 10 years at a 3 percent discount
rate and $3.3 million when annualized at 7 percent. Furthermore,
``lookback'' efforts have continued since the CDC survey was conducted.
Although CDC has not conducted a follow-up survey, informal contacts
with the blood collection industry have indicated that a substantial
portion of the retrospective ``lookback'' has already been completed.
Thus, $23 million represents an upper bound for the compliance costs of
the retrospective ``lookback.'' If, for example, ``lookback'' based on
multi-antigen screening tests has been completed, the one-time cost for
``lookback'' based on the older single-antigen screening test will be
$21 million (188,448 components x $112.50 per component), or $2.5
million annualized for 10 years at a 3 percent discount rate and $3.0
million annualized at 7 percent.
c. Total costs for blood collection establishments. The costs of
the final rule for blood collection establishments are shown in table 1
of this document. FDA estimates that the blood collection industry will
incur total one-time costs to revise SOPs and complete the
retrospective ``lookback'' of up to $24.3 million. Over 10 years, the
annualized costs equal about $2.9 million at a 3 percent discount rate
and $3.5 million at a 7 percent discount rate.
Table 1.--Costs of the Final Rule for Blood Collection Establishments\1\
----------------------------------------------------------------------------------------------------------------
Annualized Costs ($ million)
Number Affected Current Compliance One-Time Costs ($ -------------------------------------
Rate (percent) million) 3 percent 7 percent
----------------------------------------------------------------------------------------------------------------
Review and 1,041 0 1.4 0.2 0.2
revise
SOPs
----------------------------------------------------------------------------------------------------------------
Retain 1,041 100 -- -- --
records
for 10
years
----------------------------------------------------------------------------------------------------------------
Prospectiv 981 100 -- -- --
e
``lookbac
k''
----------------------------------------------------------------------------------------------------------------
Retrospect 981 30+ 22.9 2.7 3.3
ive
``lookbac
k''\2\
----------------------------------------------------------------------------------------------------------------
Total 24.3 2.9 3.5
----------------------------------------------------------------------------------------------------------------
\1\ Numbers may not sum due to rounding.
[[Page 48781]]
\2\ This upper bound estimate assumes that at least 30 percent of the retrospective ``lookback'' has been
completed, including 85 percent of the ``lookback'' based on the multi-antigen screening test and no
``lookbacks'' based on the single-antigen screening test.
4. Estimated Impact on Blood Product Consignees (Transfusion Services)
Similar to the analysis for blood and plasma collection
establishments, we focus first on the costs that are independent of the
number of ``lookbacks'' conducted and then on the costs that vary
according to how many ``lookbacks`` consignees perform.
a. Fixed costs--Standard operating procedures and record retention.
Similar to blood collection establishments, consignees must also review
and adapt their current SOPs to the requirements of the final rule.
Specifically, consignees must have procedures for the required set of
actions to take when notified by a blood collection establishment that
the consignee received blood products at increased risk of transmitting
HCV infection. These actions include the following: (1) Identifying and
quarantining affected in-date unpooled blood components, and (2)
processing quarantined in-date unpooled blood components according to
the results of a supplemental test. Moreover, when the supplemental
test for HCV is positive or there is no available supplemental test for
a reactive screening test, the consignee must notify blood transfusion
recipients that they received blood products at increased risk of
transmitting the HCV infection. Because consignees already have SOPs in
place for HIV ``lookback,'' FDA estimated that an average of 16
additional hours would be needed by each consignee to adapt or modify
current procedures. We did not receive any comments on the estimate of
this time burden; therefore it remains unchanged for the final
analysis. At the revised hourly wage of $33.84 with benefits for a
staff medical technologist (Ref. 4), each consignee will incur one-time
costs of $541, or about $2.7 million for the entire industry ($33.84
per hour x 16 hours x 4,980 consignees).
The final rule requires that consignees increase the time they keep
records from 5 to 10 years. Although the agency did not include the
annual cost of keeping records for a longer period in the analysis for
the proposed rule, it may take 40 hours for a computer programmer to
perform routine maintenance of these additional records. At a wage of
$34.00 per hour including benefits (Ref. 5), a consignee would spend an
additional $1,360 annually to conform to this provision of the final
rule. However, according to the AABB, 80 percent of the consignees are
accredited by the AABB and already comply with their standards,
including retaining records for 10 years. Taking AABB compliance into
account, the final economic analysis includes additional costs of
maintaining records for 20 percent of the consignees, a total annual
cost of $1.4 million ($34.00 per hour x 40 hours x 4,980 consignees x
20 percent).
b. Variable costs--HCV ``lookback.'' The prospective and
retrospective provisions of the final rule require a similar set of
actions by the consignee, although the amount of time a consignee may
take to complete an action varies. The HCV ``lookback'' provisions of
the final rule require that upon notification that a consignee was
shipped blood or blood components at increased risk of transmitting HCV
infection, the consignee must quarantine all identified in-date
unpooled blood components, and make a reasonable effort to notify any
recipients of blood components from donors confirmed HCV positive of
the increased risk posed by these products. The consignees may notify
the recipient's physician of record or notify the recipient directly.
If the transfusion recipient is a minor or adjudged incompetent by a
State court, the consignees would be required to notify the recipient's
legal representative or the recipient's physician of record. Once
supplemental test results on quarantined in-date unpooled products are
received, the consignee must take the appropriate action indicated by
those results (i.e., release from quarantine, destruction, or
relabeling of affected blood products).
Consignee costs can be separated into product quarantine costs and
recipient notification costs. Based on the amount of time required to
complete the different actions, the agency estimates that the product
quarantine accounts for about 40 percent of the unit cost ($66 = 40
percent x $165) while the recipient notification accounts for the other
60 percent of the unit cost ($99 = 60 percent x $165). Although
consignees did not comment on the agency's initial estimate that it
would cost $165 to comply with all of the ``lookback'' provisions for
each affected component, Los Angeles County recently reported that a
vendor was paid $118 per patient to abstract health records, locate and
notify transfusion recipients, and give pretest counseling (Ref. 6).
Without other data, for both the prospective and retrospective
``lookbacks,'' we continue to use $66 as the cost of product
quarantine, but increase the cost of recipient notification from $99 to
$118, based on the experience of the Los Angeles County.
i. Prospective HCV ``lookback.'' According to agency inspectors,
FDA-inspected consignees voluntarily follow the agency's draft guidance
and currently comply with all requirements of prospective ``lookback.''
Although we have no data that directly measure the number of
``lookbacks'' FDA-inspected establishments conduct, we expect the
number will be proportional to the number of transfusions given in
these establishments. Using data from the American Hospital
Association, Healthcare Cost and Utilization Project, and FDA's Center
for Biologics Evaluation and Research's registration list, we estimate
that FDA-inspected establishments give between 25 percent and 35
percent of all transfusions (Refs. 7 and 8). We assume for this
analysis that CMS-inspected establishments account for between 65
percent and 75 percent of all transfusions. Some CMS-inspected
establishments currently conduct prospective ``lookback;'' in the
absence of data on the actual number, we assume for this analysis that
all CMS-inspected establishments will need to comply with the
requirements of prospective ``lookback.'' This assumption may overstate
the actual costs of prospective ``lookback'' by no more than $120,000
annually.
Consignees will quarantine blood components when notified that they
received components from a donor who subsequently tested reactive on a
screening test for HCV. All other ``lookback'' actions would be
triggered when the consignee receives supplemental test results for the
donor. When notified that they received blood components from donors
who are confirmed HCV positive with a supplemental test, consignees
must attempt to notify recipients of those blood components. The
proposed rule would have required consignees make at least three
attempts to notify a transfusion recipient. Several comments expressed
concern that it would be costly to continue attempts to contact an
individual who no longer resides at the last known address in the
recipient's medical records. In response to these comments, the final
rule removes the prescriptive language concerning the number of
notification attempts. Under the final rule, consignees must make a
reasonable attempt to contact any affected transfusion recipient within
12
[[Page 48782]]
weeks of receipt from the collecting establishment of the donor's
supplemental test results indicating evidence of HCV infection, or
receipt of the reactive screening test if a supplemental test result is
not available.
Based on the HCV prevalence levels reported by the American Red
Cross for 2000, about 2,400 components could trigger ``lookback'' (780
donations from HCV-infected donors x 3.1 components per donation) (Ref.
1). The CDC survey found that on average about 85 percent of the at-
risk components sent to consignees were transfused (Ref. 3). For the
analysis of the proposed rule, we assumed that no patient would receive
more than one affected component. This assumption suggests that
consignees will quarantine about 2,400 components and attempt about
2,050 recipient notifications (780 HCV positive donors x 3.1 components
per donor x 85 percent transfused).
Because CMS-inspected consignees account for about 65 percent to 75
percent of the number of transfusions, the annual costs for consignees
to conduct the prospective ``lookback'' actions range from $260,000 to
$300,000 [65 percent by CMS-inspected establishments x (2,400
components annually triggering quarantine x $66 per component
quarantine + 2,050 components annually triggering recipient
notification x $118 per recipient notification) to 75 percent by CMS-
inspected establishments x (2,400 components annually triggering
quarantine x $66 per component quarantine + 2,050 components annually
triggering recipient notification x $118 per recipient
notification)].\4\
---------------------------------------------------------------------------
\4\ With 10 components, we estimate that consignees attempt from
4,350 to 5,020 recipient notifications at an annual ``lookback''
cost from $800,000 to $925,000.
---------------------------------------------------------------------------
ii. Retrospective HCV ``lookback.'' Retrospective ``lookback'' will
be triggered when a blood collecting establishment notifies a consignee
that a review of historical records for blood donations screened with
multi-antigen or single-antigen tests shows that an at-risk blood
component may have been sent to the consignee. For consignees that also
collect blood, it is likely that these consignees will identify
additional at-risk components among their historical donor testing
records. Once the consignee becomes aware that it received an at-risk
blood component, it must complete the required ``lookback'' actions
within 1 year.
From their interim survey findings published in 1999, CDC estimated
that 115,228 components screened with multi-antigen tests will trigger
retrospective ``lookback'' by consignees. However, CDC also estimated
that consignees had completed 80 percent of retrospective ``lookback,''
including recipient notification, for these components\5\ (Ref. 3).
According to unpublished CDC data, an additional 188,448 components
from donors screened with the single-antigen tests could trigger
``lookback'' by consignees. We lack information to estimate the total
number of ``lookbacks'' that will be based on single-antigen tests and
thus retain the number of components screened with single-antigen tests
(i.e., 188,448 components) used in the analysis of the proposed rule.
Adjusting our initial estimate of the number of components screened
with multi-antigen tests by 80 percent to account for ``lookbacks''
completed by 1999, consignees have no more than 212,000 components
[188,448 components screened with single-antigen tests + ((100 percent
- 80 percent completion rate) x 115,228 components screened with multi-
antigen tests)] requiring action. At a total unit cost of $184 ($66 +
$118) per component triggering ``lookback'', the estimated one-time
cost associated with the review of historical testing records is about
$39 million (211,494 components x $184 / component). If all
retrospective ``lookbacks'' based on the multi-antigen screening test
have been completed, consignees will only incur additional one-time
costs of $35 million (188,448 components x $184 / component).
---------------------------------------------------------------------------
\5\ This differs from the 105,706 components that CDC estimated
for collection establishments because some consignees identified,
among their own collections, additional at-risk components that had
been screened with multi-antigen tests. Moreover, CDC found that
completion rates for retrospective ``lookback'' based on multi-
antigen tests varied for blood collection establishments (i.e., 85
percent completion rate) and consignees (i.e., 80 percent completion
rate).
---------------------------------------------------------------------------
c. Total costs for consignees. Table 2 of this document shows the
costs of the final rule for blood product consignees. Industry will
incur up to $1.7 million in annual costs for the prospective
``lookback'' provisions and to retain records for 10 years, and up to
$42 million in one-time costs for SOPs and the retrospective
``lookback'' based on historical review of records. The annualized
costs of the final rule over 10 years at 3 and 7 percent interest rates
will be $6.5 and $7.6 million.
Table 2.--Costs of the Final Rule for Consignees (Transfusion Services)\1\
----------------------------------------------------------------------------------------------------------------
Annualized Costs ($ million)
Current Compliance One-Time Costs Annual Costs -------------------------------
Rate (percent) ($ million) ($ million) 3 percent 7 percent
----------------------------------------------------------------------------------------------------------------
Review and revise SOPs 0 2.7 .............. 0.3 0.4
----------------------------------------------------------------------------------------------------------------
Retain records for 10 80 ................ 1.4 1.4 1.4
years
----------------------------------------------------------------------------------------------------------------
Prospective 25 to 35 ................ 0.3 - 0.3 0.3 - 0.3 0.3 - 0.3
``lookback''
----------------------------------------------------------------------------------------------------------------
Retrospective 30+ 38.9 .............. 4.6 5.5
``lookback''\2\
----------------------------------------------------------------------------------------------------------------
Total ..................... 41.6 1.6 - 1.7 6.5 - 6.5 7.5 - 7.6
----------------------------------------------------------------------------------------------------------------
\1\ Numbers may not add due to rounding.
\2\ This upper bound estimate assumes that at least 30 percent of the retrospective ``lookback'' has been
completed, including 80 percent of the ``lookbacks'' based on the multi-antigen screening test and no
``lookbacks'' based on the single antigen screening test.
5. Summary of SOP, Record Retention and ``Lookback'' Costs
Table 3 of this document summarizes the estimated costs of the
final rule for blood collection establishments and consignees. The one-
time costs for retrospective ``lookback'' and to revise procedures will
be $65.9 million. Because blood collecting establishments have 1 year
after the effective date of the final rule to complete their review of
historical records and consignees have 1 year after being notified by
collecting establishments to complete their recipient notifications, we
expect that
[[Page 48783]]
the one-time costs will be incurred over a 2 year period. Over 10
years, the total annualized costs of these activities will range from
$9.3 million to $9.4 million for a 3 percent discount rate and $11.0
million for a 7 percent discount rate. We estimate the testing and
treatment costs for transfusion recipients in the benefits section.
Table 3.--SOP, Record Retention and ``Lookback'' Costs of the Final Rule\1\
----------------------------------------------------------------------------------------------------------------
Annualized Costs ($ million)
One-Time Costs ($ Annual Costs ($ ---------------------------------
million) million) 3 percent 7 percent
----------------------------------------------------------------------------------------------------------------
Review and revise SOPs 4.1 ............... 0.5 0.6
----------------------------------------------------------------------------------------------------------------
Retain records for 10 years .................. 1.4 1.4 1.4
----------------------------------------------------------------------------------------------------------------
Prospective ``lookback'' .................. 0.3 - 0.3 0.3 - 0.3 0.3 - 0.3
----------------------------------------------------------------------------------------------------------------
Retrospective ``lookback'' 61.8 ............... 7.2 8.8
----------------------------------------------------------------------------------------------------------------
Total 65.9 1.6 - 1.7 9.3 - 9.4 11.0 - 11.0
----------------------------------------------------------------------------------------------------------------
\1\ Numbers may not add due to rounding.
B. Benefits of the Final Rule
1. Overview
The final rule will help ensure the continued safety of the blood
supply. FDA is requiring specific blood safety procedures designed to
minimize risk to the blood supply and, in the rare cases that patients
receive at-risk blood or blood components, to inform those recipients.
Prior to 1990, with no reliable test licensed to screen blood
donations for HCV, the risk of transmission from blood transfusion was
1:200 according to CDC. Improvements in test accuracy have reduced
these risks dramatically so that current repeat donor screening tests
based on nucleic acid amplification technology are associated with a
less than a 1:1.6 million risk of transfusion-related transmission of
HCV (Ref. 9). Even though transfusion of HCV-infected blood components
is no longer one of the primary ways people acquire the infection, HCV
can still go undetected in blood collected from donors during the
window period before screening tests can detect the presence of the
virus. Because 70 to 75 percent of HCV infections are asymptomatic, if
recipients of blood products at increased risk of HCV transmission
become infected, most would not show any symptoms of the infection for
several years and would not know to seek treatment in the early stages
of the infection.
Once information becomes available that blood from an infected
donor may have entered the blood supply, it is medically ethical to
inform identified transfusion recipients of their HCV risk. Timely
notification of possible HCV infection gives recipients the chance to
be tested and, if infected, obtain treatment and counseling, and take
preventive measures to avoid transmitting HCV to others. When treatment
is initiated early in an infection, the best and most cost effective
outcomes are achieved. For example, Bennett and others showed that the
years of life gained and cost effectiveness of interferon-alpha2b
treatment decreased as the age of the patient increased, from 3.1 years
at $500 per year of life extended (YLE) for 20-year-old patients to 22
days at $62,000 per YLE for 70-year-old patients (Ref. 10). Moreover,
because HCV infection may be associated with chronic liver disease,
cirrhosis and hepatocellular carcinoma, an informed recipient can take
steps to protect his or her liver function, such as decreasing or
eliminating alcohol consumption and carefully monitoring the hepatic
effects of any prescription or over-the-counter drugs and herbal
supplements.
Notification will cause some recipients to seek testing and medical
advice. Once diagnosed with HCV infection, some people will obtain
treatment that would otherwise not have been received in the absence of
``lookback.'' These treatments lead to the health benefits from this
final rule. In what follows, we have estimated these benefits, and the
medical and other health-care costs.
2. Estimate of Improved Patient Outcomes: Gains in Quality-Adjusted
Life Years
Newly identified recipients who test positive for HCV may receive
drug therapy for the previously unknown HCV infection. Markov models
based on the results of clinical trials suggest that, in many cases,
drug therapy will improve patient outcomes, measured as a gain in
quality-adjusted life years.\6\ However, drug therapy is not
recommended for all patients with chronic HCV infection. Most clinical
trials exclude up to two-thirds of the patients with an HCV infection
(Ref. 11). We expect that newly identified recipients infected with HCV
would not differ from HCV-infected individuals in the general
population. Therefore, in contrast to the initial estimate, this
analysis assumes that only 33 percent of the newly identified
recipients would receive drug therapy.
---------------------------------------------------------------------------
\6\ A cost-effectiveness model (i.e., Markov model) of a drug
therapy begins at a defined health state and follows how a drug
therapy affects patient outcomes and lifetime health care costs.
Models use transitional probabilities between health states to
simulate the timing of patient outcomes. Each health state is
assigned a (1) health care cost per unit of time and (2) quality of
life utility between 0 and 1. The quality-adjusted life years are
defined as the number of years that a patient remains in a
particular health state, adjusted by the quality of life utility for
that health state. Summing the quality-adjusted life years for all
health states totals the quality-adjusted life years for a
particular drug therapy. The health care costs for a particular
health state are the product of the health care costs per unit time
and the amount of time the patient remains in the health state.
Summing the health care costs for all health states totals the
health care costs for a particular drug therapy. The cost per
quality-adjusted life year is the total health care costs divided by
the number of quality-adjusted life years. Treatment costs and
changes in quality-adjusted life years associated with different
therapies can be used to compare the cost-effectiveness of different
drug therapies for the same condition.
---------------------------------------------------------------------------
For the proposed rule we used the Markov model from Kim and others
that predicted a gain of 0.25 quality-adjusted life years with 6 months
of interferon monotherapy (Ref. 12).\7\ No comments
[[Page 48784]]
were received on the method we used to estimate the gain in quality-
adjusted life years. However, newer studies have found that treatment
with interferon and ribavirin yield better outcomes than treatment with
interferon alone. Because the Kim model only examines gains from
treatment with now-obsolete therapies, our initial analysis predicts
lower benefits than would be achieved with current treatment regimes.
---------------------------------------------------------------------------
\7\ Kim and others developed a Markov model that compares the
long-term outcomes for treatment of HCV between: (1) No treatment
and (2) treatment with interferon-alpha for 6 months. Beginning with
a state of chronic HCV infection, patients may be cured or
transition to other health states including compensated cirrhosis,
decompensated cirrhosis, hepatocellular carcinoma, orthotopic liver
transplantation, and death. Each simulation run includes 4,000
patients, stratified by age (30, 40, 50 and 60 years old). Age
cohorts were further divided equally by: (1) Gender, and (2)
virulence of the infection. Quality of life utilities for each
health state were elicited from medical professionals with a generic
instrument.
---------------------------------------------------------------------------
Models on the effects of combination therapy predict gains ranging
from 0.3 to 2.8 quality-adjusted life years per person treated (Ref.
13). Differences in how models simulate the progression of chronic HCV
infection make comparison of published models difficult. For this
analysis, we have selected the model by Younossi and others (Ref. 14)
because it estimates a disease progression similar to that used by Kim
and others (Ref. 12).\8\
---------------------------------------------------------------------------
\8\ Although the Younossi model simulates long-term outcomes of
six drug treatment regimes compared with the no treatment option,
for this analysis we only compare the results of: (1) No treatment,
and (2) combination treatment with interferon and ribavirin
following virus genotyping. Similar to the Kim model, the Younossi
model begins with chronic HCV infection. Some transitional
probabilities differ between the two models, because Younossi and
others based their probabilities on different published findings.
The Younossi model simulates outcomes for cohorts of identical
patients, using a 45-year-old man as the reference patient.
Sensitivity analyses using two alternate ages for the reference
patient (30 and 60 years of age) had relatively little effect on the
outcomes of the model. Similar to Kim's parameter for infection
virulence, genotyping of the hepatitis C virus introduces a
variation in treatment response into the model. When possible,
Younossi and others used quality of life utilities elicited directly
from patients using the Health Utility Index Mark III, a multi-
attribute health status classification system (Ref. 18). Costs and
health states of the model were discounted at 3 percent. Our
assumption about the proportion of newly identified recipients who
would seek treatment accounts for potential gender differences
between the Kim and Younossi models. Moreover, since ``lookback''
will only identify living recipients, presumably those healthy or
young enough to survive the medical condition requiring the
transfusion, the Younossi model is likely to be representative of
those newly identified recipients with asymptomatic chronic
hepatitis C.
---------------------------------------------------------------------------
3. Costs of Diagnostic Testing
a. Cost of screening tests. Screening recipients for HCV infection
would cost about $49 for the screening test, including $30 for the
laboratory test (Ref. 15), and $19 for 15 minutes of a physician's time
at hourly wages plus benefits of $77 ($30 + (0.25 hours x $59.04 per
hour x 1.3)). Although it is uncertain how much time consumers will
lose taking this test, we estimate about 1 hour with an average value
of $22.61.
b. Cost of supplemental tests. Because about 35 percent of reactive
screening results are false positives, the cost of the supplemental
test will vary depending on whether medical counseling is provided.
When a test result is positive, supplemental testing costs about $158,
including $81 for the laboratory test (Ref. 15), and about $77 for 1
hour of a physician's time ($81+ (1 hour x $59.04 per hour x 1.3)).
With the additional time for counseling, a patient might lose up to 2
hours valued at $45.22 (2 hours x $22.61 per hour). With a negative
supplemental test result (i.e., a false positive reactive screening
result), medical counseling is unnecessary, reducing the cost to about
$100, including $81 for the laboratory test and $19 for 15 minutes of a
physician's time ($81 + (0.25 hours x $59.04 per hour x 1.3)).
Moreover, patients would lose about 1 hour for a cost of about $22.61.
c. Cost of HCV genotype testing. Accounting for about 75 percent of
all chronic HCV infections, genotype 1 HCV is more difficult to treat
than other genotypes and requires a longer course of drugs. Viral
genotyping will cost about $486 for the laboratory test. Similar to
other diagnostic blood work, patients can lose up to $22.61 for 1 hour
of time.
d. Cost of liver biopsy. A liver biopsy can measure whether an HCV
infection has progressed to liver disease. Needle biopsies account for
about 95 percent of the diagnostic liver biopsies associated with HCV
infection. In about 5 percent of cases, a more invasive procedure such
as a wedge biopsy may be required. The needle biopsy costs about $560,
including $455 for the facilities and $105 for the physician's time (82
minutes / 60 minutes per hour x $59.04 per hour x 1.3). In addition,
patients might lose up to 2.5 hours with a value of $56.50 ($22.61 per
hour x 2.5 hours). In contrast to the needle biopsy, the wedge biopsy
requires a median stay of 4 days in the hospital and can cost about
$10,280, including $9,858 for hospital charges (Ref. 16) and about $422
for a physician to follow-up after the biopsy (5.5 hours x $59.04 per
hour x 1.3) (Ref. 17). Moreover, because some mortality risk exists
with this procedure, patients and their families may experience anxiety
before the surgery. However, we have no data quantifying the value to
avoid this anxiety or any pain associated with the biopsy.
e. Summary of testing costs. Table 4 of this document summarizes
the costs of the diagnostic tests used in the benefits analysis. The
table also includes the average number of hours that patients lose for
each test.
Table 4.--Costs of Diagnostic Tests and Lost Time\1\
----------------------------------------------------------------------------------------------------------------
Laboratory Physician Time Cost of Lost Patient Value of Lost
Type of Test Cost (minutes) Physician Time\2\ Time Time\3\ Total Cost
----------------------------------------------------------------------------------------------------------------
HCV screening $30 15 $19 1 hr $23 $72
test
----------------------------------------------------------------------------------------------------------------
Supplemental .............. .............. ................. .............. .............. ..............
test:
Negative $81 15 $19 1 hr $23 $123
results
Positive $81 60 $77 2 hr $45 $203
results
----------------------------------------------------------------------------------------------------------------
HCV $486 0 0 1 hr $23 $509
genotyping
----------------------------------------------------------------------------------------------------------------
Liver biopsy: .............. .............. ................. .............. .............. ..............
Needle $455 82 $105 2.5 hr $57 $616
biopsy
Wedge $9,858 330 $422 4 days $2,224\4\ $12,504
biopsy
----------------------------------------------------------------------------------------------------------------
\1\ Numbers may not sum or multiply due to rounding.
\2\ Valued at a loaded hourly wage of $76.75 ($59.04 per hour with 30 percent benefits).
\3\ Valued at $22.61 per hour.
\4\ This includes the willingness to pay to avoid a 0.03 percent mortality risk, using $5 million as the value
of a statistical life.
[[Page 48785]]
4. Benefits of Prospective ``Lookback''
The economic benefit of a public health action normally relates to
the risk reduction associated with that action. Because the current
risk of transfusion-transmitted HCV infection is already very low
(i.e., less than 1:1.6 million), we anticipate that prospective
``lookback'' will occur infrequently. However, in the rare case when
``lookback'' is necessary, this action will be relatively cost-
effective. To assess the cost-effectiveness of prospective
``lookback,'' we first estimate the number of transfusion recipients
that would be newly identified, then estimate the testing costs
associated with ``lookback.''
a. The number of HCV positive transfusion recipients identified by
``lookback.'' FDA cannot precisely determine the number of HCV positive
individuals who could be newly identified by ``lookback,'' although
this analysis suggests that it would vary from one-half dozen to two
dozen per year. As discussed in the section on the costs of prospective
``lookback'' (i.e., section IV.A.4.b.i of this document), about 2,050
affected components may trigger recipient ``lookback'' each year.
Taking into account notifications already being made by FDA-inspected
consignees, the final rule will require that consignees attempt from
approximately 1,330 (2,050 x 65 percent noncompliance) to 1,540 (2,050
x 75 percent noncompliance) recipient notifications.\9\
---------------------------------------------------------------------------
\9\ We note that if there are 10 affected components for each
donor triggering ``lookback,'' consignees would attempt from 4,350
to 5,020 recipient notifications and might newly identify from 14 to
59 HCV positive recipients, of which from 4 to 20 could seek
treatment and potentially gain from 3 QALYs to 56 QALYs.
---------------------------------------------------------------------------
For the analysis of the proposed rule, we based the probability of
finding a newly infected transfusion recipient on the CDC survey
findings for recipients transfused within 3 years of the survey (i.e.,
1996 to 1999) (Ref. 3). Therefore, using these CDC findings, we
estimate that from 568 recipients (1,330 x 48 percent living x 89
percent successfully notified) to 656 recipients (1,540 x 48 percent
living x 89 percent successfully notified) will be successfully
notified by ``lookback.'' Once recipients are successfully notified
that they received at-risk blood, about 307 (568 recipients x 54
percent tested) to 354 (656 recipients x 54 percent tested) will decide
to seek testing to determine if they are infected with HCV. We predict
that about 35 percent of the reactive screening tests will have false
positive results. As shown in table 5 of this document, the estimated
number of negative supplemental test results varies from 107 (307 x 35
percent) to 124 (354 x 35 percent), depending on the current
noncompliance rate.
Because NAT pooled testing has reduced the risk of transfusion-
related HCV infection, the HCV positive rate of recipients notified by
``lookback'' may be lower than the 10 percent suggested by the CDC
survey findings for 1996--1999 (table 2 in Ref. 3). In table 5 of this
document, therefore, we present upper and lower bound estimates of the
number of individuals that would potentially test HCV positive. As
discussed earlier, the CDC survey found that about one-third of the HCV
positive recipients will already know about their infection (Ref. 3).
Therefore, fewer infected individuals will be newly identified by
``lookback'' than test positive for HCV. The possible range of newly
identified recipients that would be expected from prospective
``lookback'' each year extends from 6 to 24, depending on the
noncompliance rate and the HCV positive rate.
Table 5.--Estimated Annual Number of Diagnostic Tests and Newly Identified Recipients With Prospective
``Lookback''\1\
----------------------------------------------------------------------------------------------------------------
65 Percent CMS-Inspected
75 Percent CMS-Inspected
----------------------------------------------------------------------------------------------------------------
HCV screening tests 307
354
----------------------------------------------------------------------------------------------------------------
Negative supplemental tests (i.e., false positive
screening result) 107
124
----------------------------------------------------------------------------------------------------------------
HCV Positive Rate
-------------------------------------------------------
2.7 10 2.7 10
percent\2\ percent\3\ percent\2\ percent\3\
����������������������������������������������������������������������������������������������������������������
Positive supplemental tests 8 31 10 35
----------------------------------------------------------------------------------------------------------------
Newly identified HCV infected recipients\4\ 6 21 7 24
----------------------------------------------------------------------------------------------------------------
\1\ Recipient estimates are rounded to the nearest integer; numbers may not sum or multiply due to rounding.
\2\ Derived as the ratio of the ``window'' period and the inter-donation period. For this example we assume a 10-
day window period with NAT screening and a 365-day median inter-donation interval (0.027 = 10/365).
\3\ Based on the CDC survey findings that 10 percent of the newly identified blood recipients transfused in 1996-
1999, were confirmed HCV antibody-positive with the third generation serological tests (see table 2 in Ref.
3).
\4\ Sixty-eight percent of the recipients that test HCV positive do not already know about their infection.
b. Testing costs of prospective ``lookback.'' Even though some
individuals contacted by ``lookback'' will already know about their HCV
positive status, for this analysis we assume that all recipients
successfully contacted will receive diagnostic testing. Because
Younossi and others found negative incremental treatment costs (i.e., a
lifetime cost savings over the no treatment option), we exclude all
treatment costs from this analysis (Ref. 14). Table 6 of this document
summarizes the total testing costs of prospective ``lookback'' for all
recipients.
[[Page 48786]]
Table 6.--Total Costs of Testing and Lost Patient Time of Prospective ``Lookback''\1,2\
----------------------------------------------------------------------------------------------------------------
65 Percent CMS-Inspected
75 Percent CMS-Inspected
----------------------------------------------------------------------------------------------------------------
HCV screening tests $22,049
$25,442
----------------------------------------------------------------------------------------------------------------
Negative supplemental tests (i.e., false positive
screening result) $13,199
$15,230
----------------------------------------------------------------------------------------------------------------
HCV Positive Rate
-------------------------------------------------------
2.7 percent 10 percent 2.7 percent 10 percent
����������������������������������������������������������������������������������������������������������������
Positive supplemental tests $1,708 $6,233 $1,970 $7,192
----------------------------------------------------------------------------------------------------------------
Total testing costs $36,956 $41,482 $42,642 $47,864
----------------------------------------------------------------------------------------------------------------
\1\ Numbers may not sum due to rounding.
\2\ Derived from tables 4 and 5 of this document.
c. Cost-effectiveness of prospective ``lookback.'' Because the
costs of ``lookback'' and the number of newly identified infected
recipients are essentially proportional, the cost-effectiveness of
recipient notification does not vary with changes in the number of
prospective ``lookbacks.'' Total annual ``lookback'' and testing costs
for the prospective ``lookback'' range from $300,000 to $350,000 (see
sections IV.A.4.b.i and IV.B.4.b) of this document), depending on the
proportion of CMS-inspected consignees already performing prospective
``lookback'' (i.e., 65 to 75 percent). As shown in table 7 of this
document, the cost per newly identified transfusion recipient infected
with HCV ranges from about $14,400, if the HCV positive rate is 10
percent and to about $51,900, if the HCV positive rate is 2.7 percent.
We note again that these cost-effectiveness ratios hold regardless of
the number of donations from repeat donors that trigger prospective
``lookback.''
Table 7.--Cost-Effectiveness of Recipient Notification for Prospective ``Lookback''\1\
----------------------------------------------------------------------------------------------------------------
65 Percent CMS-Inspected
75 Percent CMS-Inspected
-------------------------------------------------------
HCV Positive Rate
-------------------------------------------------------
2.7 percent 10 percent 2.7 percent 10 percent
����������������������������������������������������������������������������������������������������������������
Costs of Testing & Lost Patient Time $36,956 $41,482 $42,642 $47,864
----------------------------------------------------------------------------------------------------------------
``Lookback'' costs $260,006 $260,006 $300,007 $300,007
----------------------------------------------------------------------------------------------------------------
Total costs $296,963 $301,488 $342,649 $347,871
----------------------------------------------------------------------------------------------------------------
Newly identified HCV infected recipients\2\ 6 21 7 24
----------------------------------------------------------------------------------------------------------------
Cost per newly identified recipient\3\ $51,897 $14,435 $51,897 $14,435
----------------------------------------------------------------------------------------------------------------
\1\ Numbers may not sum or multiply due to rounding.
\2\ Recipient estimates are rounded to the nearest integer.
\3\ Calculated with the non-rounded number of newly identified recipients (i.e., 5.7, 20.9, 6.6, and 24.1).
5. Benefits of Retrospective ``Lookback''
Because the one-time retrospective ``lookback'' has the potential
to newly identify thousands of infected transfusion recipients, the key
benefit of ``lookback'' is the health improvement that newly identified
individuals would enjoy as a result of timely treatment. We estimate
this benefit by looking first at the number of newly identified
recipients chronically infected with the hepatitis C virus. Using the
published Younossi model of disease progression, we then estimate the
number of quality-adjusted life years that each person could gain from
interferon and ribavirin treatment of their HCV infection. Then we
estimate the value that society might place on this health improvement.
Next we quantify the potential costs of diagnostic testing and
treatment. Finally we report the cost-effectiveness of this one-time
public health initiative.
a. The number of HCV positive transfusion recipients identified by
``lookback.'' For the analysis of the proposed rule, we estimated that
about 2 percent (30 percent living x 74 percent successfully notified x
51 percent tested x 25 percent positive for HCV x 68 percent unknown
infection) of the 258,125 recipient notifications\10\ performed under
retrospective ``lookback'' (i.e., about 5,000 recipients) would newly
identify individuals who test positive for the hepatitis C virus. As
discussed previously, consignees completed at least 80 percent of the
retrospective ``lookback'' based on multi-antigen screening by 1999.
Subtracting the recipient notifications
[[Page 48787]]
that have been completed (i.e., 80 percent), table 8 of this document
shows the potential number of HCV-positive recipients that
retrospective ``lookback'' might newly identify, and the corresponding
number of diagnostic tests that might be performed.
---------------------------------------------------------------------------
\10\ ``Lookback'' actions for consignees include product
quarantine and recipient notification. Based on their interim survey
findings, CDC estimated that only about 85 percent of the components
received by consignees are transfused. Based on this CDC data,
consignees will perform product quarantine for about 269,100
components and perform about 258,100 recipient notifications.
Table 8.--Estimated One-Time Number of Diagnostic Tests and Newly Identified Recipients With Retrospective
``Lookback''\1\
----------------------------------------------------------------------------------------------------------------
Multi-Antigen Screening Single-Antigen
Results\2\ Screening Results\3\ Total
----------------------------------------------------------------------------------------------------------------
HCV screening tests 2,353 17,819 20,172
----------------------------------------------------------------------------------------------------------------
Negative supplemental tests (i.e., false positive 824 6,237 7,060
screening result)\4\
----------------------------------------------------------------------------------------------------------------
Positive supplemental tests 447 5,168 5,615
----------------------------------------------------------------------------------------------------------------
Newly identified HCV-positive recipients\5\ 304 3,514 3,818
----------------------------------------------------------------------------------------------------------------
\1\ Recipient estimates are rounded to the nearest integer; numbers may not sum or multiply due to rounding.
\2\ Adjusting the number of components triggering ``lookback'' based on multi-antigen tests (i.e., 115,228
components) by the transfusion rate (i.e., 85 percent transfused) and the completion rate (80 percent of
completed), consignees will attempt about 19,674 transfusion recipient notifications. Estimates were derived
using the findings in table 3 of Ref. 3: 31 percent would be living, 78 percent would be successfully
notified, 50 percent would be tested, and a 19 percent HCV positive rate.
\3\ Adjusting the number of components triggering ``lookback'' based on single-antigen tests (i.e., 188,448) by
the transfusion rate (i.e., 85 percent transfused), consignees will attempt about 160,879 transfusion
recipient notifications. Estimates were derived using the findings in table 2 for transfusions in 1988-1989 of
Ref. 3: 30 percent would be living, 72 percent would be successfully notified, 52 percent would be tested, 29
percent HCV positive rate.
\4\ Based on 35 percent false positive rate for screening tests.
\5\ Based on CDC survey findings that 68 percent of the HCV positive recipients did not already know about their
infection.
b. Number of Quality-Adjusted Life Years gained. Benefits of the
retrospective ``lookback'' come from treating post-transfusion
hepatitis C virus infections, and in doing so, delaying or reducing
adverse health outcomes from illnesses that would be caused by
untreated hepatitis C virus infections. We use a quality-adjusted life
year as the measure of this gain in health outcomes and estimate the
number of quality-adjusted life years that newly identified infected
recipients can gain from treatment of their chronic HCV infections.
Adjusting for the 75 percent chronic infection rate, about 2,865
chronically infected recipients would be newly identified by
retrospective ``lookback'' (3,818 newly identified recipients x 75
percent chronic infection rate).
As noted previously, to estimate the gain in quality-adjusted life
years, we selected the Markov model of Younossi and others (Ref. 14).
Their findings predict that patients receiving combination therapy with
standard interferon could gain 2.8 quality-adjusted life years,
compared with receiving no treatment for the infection. For this
analysis, we assume that newly identified transfusion recipients are
similar to the general population in terms of genotype of the hepatitis
C virus (i.e., 75 percent are infected by genotype 1 HCV) and
suitability for treatment (33 percent of HCV positive individuals would
receive drug therapy). Accounting for these factors, an estimated 945
individuals (2,864 patients x 33 percent treated) would gain 2,640
quality-adjusted life years (2.79 quality-adjusted life years/patient x
945 patients).
c. The societal value of ``lookback''. The preferred measure of the
value of the benefit of retrospective ``lookback'' is the average
willingness to pay to reduce the probability of adverse health outcomes
from untreated post-transfusion HCV infections. Such measures are not
readily available for most illnesses, including those caused by
hepatitis C virus infection. In the absence of the direct measures
recommended in the literature (Ref. 18), we assign a monetary value to
a quality-adjusted life year as a proxy for willingness to pay. We
recognize, however, that there is no unique, accepted societal monetary
value for a quality-adjusted life year gained, and some economists are
skeptical that this measure of public health improvement is even
sufficiently consistent with consumer preferences to permit systematic
estimates of its monetary value. To reflect the uncertainty about the
value of a quality-adjusted life year, FDA uses a range of dollar
amounts.
As a lower bound, FDA uses $100,000 per quality-adjusted life year,
an amount similar to that used by Cutler and Richardson (Ref. 19). We
derive other values for a quality-adjusted life year from estimates of
the value of a statistical life. A number of empirical studies indicate
a societal willingness to pay from $1.6 million to $11.6 million to
avoid a statistical death. Although there is not necessarily a direct
link between the willingness to pay to reduce the probability of a
particular illness (or set of symptoms) and the willingness to pay to
reduce the probability of death, the value of a statistical life--the
sum of individual willingness to pay to avoid small risks of premature
death that together add up to one expected life saved--bounds the value
of a quality-adjusted life year, which is used in this analysis as a
proxy for the sum of individual willingness to pay to avoid small risks
of being undiagnosed as HCV positive and suffering additional morbidity
impacts.
Current estimates of the value of a statistical life run from $1
million to $11 million (Ref. 20). In recent regulatory analyses, we
have used values of $5 million and $6.5 million, which fall within that
range. Because the Younossi model was developed with a 3 percent
discount rate, we use this discount rate to estimate the value of a
statistical life year. Annualizing $6.5 million over 35 years at 3
percent implies a value of $300,000 for an additional statistical life
year and to develop an upper bound, annualizing $10 million over 35
years at 3 percent discount rates implies a value of $465,000 for an
additional statistical life year.\11\ We therefore calculate estimated
benefits from this final rule with three possible values of a quality-
adjusted life year: $100,000, $300,000 and $465,000. This range of
values is consistent with a reasonable interpretation of studies of
willingness
[[Page 48788]]
to pay to reduce mortality risks (Ref. 20).
---------------------------------------------------------------------------
\11\ We could, however, generate these same two values with many
different combinations of values of a statistical life, discount
rates, and years.
---------------------------------------------------------------------------
At $100,000 per quality-adjusted life year gained, the
retrospective ``lookback'' would yield one-time benefits to society of
$264 million (2,640 quality-adjusted life years x $100,000 per quality-
adjusted life year). At $300,000 per quality-adjusted life year gained,
the retrospective ``lookback'' would yield one-time benefits to society
of $792 million (2,640 quality-adjusted life years x $300,000 per
quality-adjusted life year). At $465,000 per quality-adjusted life year
gained, the retrospective ``lookback'' would yield one-time benefits to
society of $1,228 million (2,640 quality-adjusted life years x $465,000
per quality-adjusted life year).
d. Testing costs of retrospective ``lookback.'' Table 9 of this
document summarizes the potential diagnostic testing costs associated
with retrospective ``lookback.'' Diagnostic costs are based on the
number of newly identified recipients with a hepatitis C virus
infection, the related testing frequencies, and the unit costs for
diagnostic tests and lost time for patients. As noted previously, we
selected the Markov model of Younossi and others for our analysis (Ref.
14). Because Younossi's simulation begins after a patient has received
a liver biopsy and uses HCV genotype to determine the duration of
therapy, we also estimate these costs. All recipients infected with the
hepatitis C virus would receive genotyping, however, only those
infected with the genotype 1 virus (i.e., 75 percent) would undergo a
liver biopsy. We exclude all treatment costs from this analysis because
Younossi and others found negative incremental treatment costs (i.e., a
lifetime cost savings over the no treatment option) (Ref. 14).
Table 9.--Total Costs of Diagnostic Testing and Lost Patient Time of
Retrospective ``Lookback''\1\
------------------------------------------------------------------------
Cost of
Diagnostic
Type Diagnostic Tests Tests\2\ ($
mil)
------------------------------------------------------------------------
HCV screening tests\3\ 1.4
------------------------------------------------------------------------
Negative supplemental tests (i.e., false positive 0.9
screening result)\3\
------------------------------------------------------------------------
Positive supplemental tests\3\ 1.1
------------------------------------------------------------------------
Hepatitis C virus genotype tests\4\ 1.5
------------------------------------------------------------------------
Liver biopsy\5\ 2.6
------------------------------------------------------------------------
Total 7.5
------------------------------------------------------------------------
\1\ Numbers may not sum or multiply due to rounding.
\2\ Unit costs for diagnostic tests are from table 4 of this document.
\3\ Number of diagnostic tests are from table 8 of this document.
\4\ We assume that seventy-five percent of the recipients with positive
supplemental tests are chronically infected with the hepatitis C virus
and have HCV genotype testing.
\5\ The prevalence rate for hepatitis C virus genotype 1 is
approximately 75 percent; ninety-five percent of recipients infected
with genotype 1 have a needle biopsy, and 5 percent of recipients
infected with genotype 1 have a wedge biopsy.
e. Cost-effectiveness of retrospective ``lookback.'' The cost-
effectiveness of retrospective ``lookback'' can be expressed as the
cost per newly identified transfusion recipient or as the cost per
quality-adjusted life year gained. Compliance with the retrospective
``lookback'' will cost about $61.8 million (see table 3 of this
document). Accounting for these compliance costs and the screening and
supplemental test costs in table 9 of this document, the one-time
retrospective ``lookback'' will cost about $17,100 per newly identified
HCV positive person (($1.4 million screening tests + $0.9 million
negative supplemental tests + $1.1 million positive supplemental tests
+ $61.8 million compliance costs) / 3,818 recipients).
Including all testing costs, the retrospective ``lookback''
provisions of the final rule would cost approximately $69.4 million
($61.8 million ``lookback'' costs + $7.5 million total testing costs)
with a cost-effectiveness of $26,300 per quality-adjusted life year
gained ($69.4 million/2,640 quality-adjusted life years). Younossi's
article reports an incremental treatment cost savings, but we do not
have sufficient information to include these savings in the cost per
quality-adjusted life year (Ref. 14) and therefore ignore all treatment
costs in our analysis. To the extent that we exclude these cost
savings, the cost-effectiveness ratio is overstated.
6. Summary of Benefits and Costs of the Final Rule
Recent public reviews of blood supply issues have recognized the
importance of ensuring safety. Although the current risk of
transfusion-transmitted HCV infection is already very low (i.e., less
than 1:1.6 million), one-time retrospective ``lookback'' has the
potential to newly identify thousands of infected transfusion
recipients. In contrast, because we anticipate that prospective
``lookback'' will occur infrequently, in most years, between 0 and 5
newly identified recipients might seek treatment and benefit from a
gain in quality-adjusted life years. The size of this gain is so small,
however, that it is captured in the rounding for the retrospective
``lookback'' analysis. Therefore, we exclude these gains from this
analysis of the final rule and quantify only the benefits of gains in
quality-adjusted life years from the retrospective ``lookback.'' The
final rule can be expected to gain a one-time total of 2,640 quality-
adjusted life years with an estimated discounted value that ranges from
$264 million to $1,228 million. As presented in table 10, over 10 years
the annualized net benefits of all provisions of the final rule,
including direct and diagnostic costs for both retrospective
``lookback'' and prospective ``lookback,'' will range from about $20.6
million ($31.0 million annualized benefits-$10.3 million annualized
costs) to $133.6 million ($143.9 million annualized benefits-$10.3
million annualized costs). For all provisions of the final rule, the
present value of all costs equals $87.6 million and is the sum of (1)
The one-time ``lookback'' costs ($65.9 million) and one-time diagnostic
costs ($7.5 million) for the retrospective ``lookback'', and (2) the
present value of the annual direct and diagnostic costs for the
prospective ``lookback'' over 10 years at a 3 percent discount rate
($13.8 million in direct costs + $0.4 million in diagnostic costs). The
cost-effectiveness of the entire final rule equals $33,200 per quality-
adjusted life year ($87.6 million / 2,640 quality-adjusted life years)
as shown in table 10.
Table 10.--Summary of Net Benefits and Cost Per QALY\1\
----------------------------------------------------------------------------------------------------------------
Annualized Costs\2\:
Prospective and Retrospective ``Lookback'' $9.4
Testing and Lost Patient Time $0.9
----------------------------------------------------------------------------------------------------------------
Total Annualized Costs $10.3
----------------------------------------------------------------------------------------------------------------
[[Page 48789]]
Low value of QALY Medium value of High value of
QALY QALY
--------------------------------------------------------
Annualized Benefits\3\: $31.0 $92.9 $143.9
Value of QALYs gained
----------------------------------------------------------------------------------------------------------------
Total Annualized Net Benefits $20.6 $82.5 $133.6
----------------------------------------------------------------------------------------------------------------
Cost-Effectiveness:
Present Value of Total Costs\4\ $87.6
Number of QALYs gained\5\ 2,640
----------------------------------------------------------------------------------------------------------------
Cost per QALY ($) $33,200
----------------------------------------------------------------------------------------------------------------
\1\ Some numbers are rounded. Unless noted, all dollar amounts are $ million. Costs and benefits annualized over
10 years at 3 percent discount rate.
\2\ Includes costs to comply with all provisions of the final rule, all costs associated with the gain in QALYs
from the retrospective ``lookback,'' and the costs of screening and confirmatory tests to newly identify HCV
positive recipients with prospective ``lookback.''
\3\ Includes only quantifiable benefits of retrospective ``lookback.'' QALYs are valued at $100,000, $300,000
and $465,000.
\4\ Includes one-time costs and the present value of annual costs over 10 years at 3 percent.
\5\ Because so few individuals would be newly identified from prospective ``lookback,'' the summary benefits
equal the gains through retrospective ``lookback.'' Note that prospective effects, should they exist,
unambiguously increase benefits but the size of this gain would be so small that it is captured in the
rounding for the retrospective ``lookback'' analysis.
7. Alternatives Considered for HCV ``Lookback''
FDA finds that the targeted ``lookback'' approach is the most
effective alternative when evaluated in terms of ethical, cost, and
effectiveness criteria. The following provides a discussion of the
baseline for the analysis and the alternatives that have been
considered.
a. Baseline: No regulatory action. FDA has already issued an
industry guidance concerning HCV ``lookback.'' Because FDA can only
recommend a process and timeframe with a guidance, with no means of
enforcing it, some establishments might decide not to perform
``lookback'' or to adopt a more extended timeframe to perform the
``lookback'' based on the review of historical testing records to
spread the costs of this effort. Such delay, however, would increase
each recipient's risk of serious disease complications.
b. Alternative: Use of general ``lookback.'' General ``lookback''
is an alternative approach that has the potential to reach all patients
who received transfusions during the period covered by ``lookback.''
The cost and ultimate effectiveness of general ``lookback'' would vary
depending on the program structure and the risk message. Because
general ``lookback'' would not be based on identification of at-risk
donations, the risk message would communicate the average risk of HCV
infection from a blood transfusion. To be effective, the risk message
should reach those recipients who would have been contacted by targeted
``lookback'' and motivate them to seek testing, but not to
unnecessarily alarm and burden the majority of recipients who would
never be contacted by targeted ``lookback'' and who face an extremely
low risk of being infected by HCV from a transfusion. Compared with
targeted ``lookback,'' general ``lookback'' programs shift costs from
blood collection establishments and consignees to: (1) The entity
conducting the general ``lookback'' program; and (2) recipients,
health-care providers and payers.
No nationwide general ``lookback'' campaign has been conducted in
the United States, although some limited programs have been initiated.
For example, a CDC Web site offers educational materials about
hepatitis C (www.cdc.gov/hepatitis). In 1999, CDC pilot-tested an HCV
general ``lookback'' with public service announcement posters in the
public transit systems of two cities, and also distributed an audio-
and videotaped general ``lookback'' message by the surgeon general to
radio and television stations in 2000. The effectiveness of these
programs is unknown.
In the United States, few articles have been published on the
outcomes of general ``lookback'' programs. Although several general and
targeted ``lookback'' programs have been conducted in Canada, there has
been no standardization of outcomes or cost estimates in that country.
The authors of an article reviewing general ``lookback'' programs in
Canada concluded that without standardized data, it is impossible to
compare the cost-effectiveness of Canadian targeted and general
``lookback'' programs (Ref. 21). Moreover, it is uncertain whether the
Canadian experience would be comparable to what would happen in the
United States. Nevertheless, in Canada, general ``lookback'' programs
missed some recipients that were identified by targeted ``lookback.''
For example, a 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'' (Ref. 22). As a result, targeted ``lookback''
raised the number of HCV-positive recipients tested at that hospital by
at least 9 percent over general ``lookback.''
In 2000, the Alaska Native Medical Center--a hospital providing
services to Alaska Natives--began a general ``lookback'' program to
contact adults and children who had received transfusions between
January 1980 and July 1992 (Ref. 23). Patients identified by the record
review were sent letters notifying them of their transfusion history
and encouraged them to seek testing for HCV infection. In a study of
that program, the study's authors estimate that the entire program cost
$129,000, a total that includes $56 for each patient notification. They
note that a similar program in a private sector health care setting
would cost substantially more than their results suggest.
Another general ``lookback'' program conducted in Alaska notified
patients who had received transfusions in a neonatal intensive care
unit between January 1975 and July 1992. These patients may have been
unaware of the previous transfusion event. As a regional referral
center located in Anchorage, the neonatal intensive care unit provided
care for patients from the Alaska Native Medical Center (i.e.,
integrated health-care setting) and for
[[Page 48790]]
patients of private sector health-care providers.
Results of general ``lookback'' varied significantly between the
two health-care settings, with a higher percentage of patients
identified and screened in the integrated health care setting than in
the private sector setting (Ref. 24). As shown in table 11 of this
document, 63 percent of the patients in the integrated health-care
setting sought testing for hepatitis C virus infection, compared with
17 percent of the patients in the private sector health-care setting.
This difference illustrates the uncertainty about the yield of a
general ``lookback'' program in the United States. Characteristics of
each health-care setting might explain some of the differences in
yields between health-care settings. For example, patient records in
the integrated health-care setting contain the results of hepatitis C
tests. In contrast, private sector patients had to report the results
of their hepatitis C tests on an anonymous questionnaire.
With the results of the two Alaskan programs we provide a rough
estimate of the potential costs and outcomes of a nationwide general
``lookback'' program for patients who received transfusions between
1988 and mid-1992 (i.e., a similar timeframe to the retrospective
targeted ``lookback'' based on single-antigen tests). Published data
suggests that about 15.2 million patients received red blood cell or
whole blood transfusions during this period (Refs. 25, 26, and 27). We
apply the transitional probabilities from the two Alaskan ``lookback''
programs, shown in table 11 of this document, to the total number of
patients transfused, to estimate the number of patients that might be
identified at each stage of the general ``lookback'' program. With this
information, we estimate a type of general ``lookback'' program similar
to the recipient notification programs conducted in Canada and
calculate an estimate of the total potential ``lookback'' and
diagnostic costs.
Table 11.--Yields of Three ``Lookback'' Programs\1\
------------------------------------------------------------------------
Percentage of Published Results of General
Patients from ``Lookback'' Programs
the Prior Stage -------------------------------------- Targeted
of ``Lookback'' Private Sector ``Lookback''\4\
(number of Integrated Health Health Care
patients) Care Setting\2\ Setting\3\
------------------------------------------------------------------------
Transfused 100%............. 100%............. 100%
(3,169).......... (1,396).......... (160,879)
------------------------------------------------------------------------
Sent notice 38%.............. 27%.............. 21%
(1,213).......... (374)............ (34,267)
------------------------------------------------------------------------
Notified who 63%.............. 17%.............. 52%
were screened (764)............ (64)............. (17,819)
------------------------------------------------------------------------
Screened who 2%............... 2%............... 29%
tested HCV+ (19)............. (1).............. (5,168)
------------------------------------------------------------------------
\1\ Numbers may not sum or multiply due to rounding.
\2\ Based on the results from Ref. 23.
\3\ Based on the results from Ref. 24.
\4\ Based on the CDC interim survey results for transfusions from 1988
to 1989 (Ref. 3).
Comparing the yield of a nationwide general ``lookback'' program in
a private sector health care setting to the yield of a nationwide
general ``lookback'' program in an integrated health care setting gives
us a range of potential outcomes for a general ``lookback'' program for
recipients who received transfusions between 1988 and mid-1992. It
should be noted that the Alaskan programs include some recipients who
received blood transfusions prior to 1988, before blood donations were
routinely screened for HCV. In addition, applying the transitional
probabilities from the Alaskan programs to recipients transfused
between 1988 and mid-1992, when the risk of transfusion-related HCV
infection was falling, overestimates the potential yield of general
``lookback.''
A general ``lookback'' program with recipient notification requires
far more resources than targeted ``lookback.'' As shown in Table 12 of
this document our analysis suggests that a general transfusion
recipient notification program could cost more than $500 million and
newly identify between 3,600 and 30,000 recipients of tranfusions who
are infected with the hepatitis C virus and who choose to receive
treatment. However, these results should be interpreted with caution.
CDC estimated that about 300,000 people might have been infected by
blood transfusions in the 20 years prior to donor screening for HCV
(Ref. 3). Our analysis suggests that general ``lookback'' might newly
identify from 1.2 percent to 10 percent of those people who were
infected with HCV from a blood transfusion even though we only include
transfusion recipients between 1988 and mid-1992. However, in the
United States, about 3.9 million people are infected with the hepatitis
C virus (Ref. 28). Because general ``lookback'' contacts more persons
than targeted ``lookback,'' the program might identify persons who were
infected with the hepatitis C virus by other routes than transfusions.
Thus, general ``lookback'' is likely to generate benefits not directly
related to at-risk transfusions.
``Lookback'' programs can take many forms and target different at-
risk populations. General ``lookback'' activities, such as those tested
by CDC, can play an important role in efforts to reach the population
at risk due to parental drug use or other risk behaviors not involving
blood transfusion (Ref. 3). We have considered an Alaskan-type general
``lookback'' here as a potential alternative to a targeted
``lookback.'' If further evidence or analysis shows that the yield of
the Alaskan-type program is representative of the potential yield of a
nationwide general ``lookback'' program, then a general ``lookback''
program might be a cost-effective public health initiative to
complement a targeted ``lookback'' and notify a subset of transfusion
recipients who might be missed by the targeted ``lookback'' (e.g.
patients who received transfusions before blood donations were screened
for HCV; patients who were transfused as infants but who are unaware of
the transfusion event and who respond only after receiving the second
``lookback'' notification).
[[Page 48791]]
To understand the potential yield of a general ``lookback'' that
complements targeted ``lookback,'' we use the numbers shown in table 12
to adjust our estimate of the total costs and number of quality-
adjusted life years gained. This approach assumes that the targeted
``lookback'' program is completed before the general ``lookback''
program begins. We also assume that all of the infected persons
identified by the targeted ``lookback'' would be included within the
set of infected persons identified by general ``lookback'' programs. To
adjust the yields, we subtract the diagnostic costs and quality-
adjusted life years gained from targeted ``lookback'' from the
diagnostic costs and quality-adjusted life years gained from general
``lookback.'' The adjusted total costs for a general recipient
notification ``lookback'' that complements the targeted ``lookback''
range from $487.3 million (= $494.1 million - $6.8 million) to $735.1
million (= $741.9 million - $6.8 million), and the adjusted gain in
quality-adjusted life years range from 7,567 quality-adjusted life
years (= 9,992 quality-adjusted life years - 2,425 quality-adjusted
life years) to 81,205 quality-adjusted life years (= 83,630 quality-
adjusted life years - 2,425 quality-adjusted life years). Thus, the
potential cost per quality-adjusted life year for a general
``lookback'' program that complements targeted ``lookback'' range from
$9,050 to $64,400. We therefore conclude that the targeted ``lookback''
analyzed here is the preferred alternative for this final rule, but an
Alaskan-type general ``lookback'' could be a cost-effective HCV policy.
c. Final: Use of targeted ``lookback.'' The ``lookback'' provisions
of the final 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 send out
notifications to the most recent address. Ideally, the recipient will
still be alive and be able to receive testing and treatment, if
appropriate.
Despite the difficulties of implementing targeted ``lookback,'' FDA
concludes that this alternative remains the most reliable means of
reaching people at increased risk of HCV infection from a transfusion.
However, in response to comments on the proposed rule, some of the more
prescriptive language was moved from the codified section to the
accompanying guidance for industry. Therefore, the final rule lists the
objective actions required of industry, and the timeframe in which they
must be taken to give individual establishments the flexibility to
accomplish these actions in the most cost effective manner.
d. Limited comparison of regulatory alternatives. The purpose of
this final rule is to contact recipients who received transfusions of
blood or blood components that were at risk of transmitting the
hepatitis C virus. Table 12 of this document presents a comparison of
the retrospective targeted ``lookback'' based on single-antigen tests
and possible general ``lookback'' programs for recipients of
transfusions between 1988 and mid-1992. The two general ``lookback''
estimates illustrate the uncertainty of general ``lookback'' and the
likelihood that this program would identify people who were infected by
other routes than transfusion events. The cost-effectiveness of the
targeted ``lookback'' program falls in between the cost-effectiveness
of the two general programs. The estimated effectiveness of targeted
``lookback'' is less uncertain than the estimated effectiveness of
general ``lookback'', and is therefore more likely to achieve the goals
of this final rule.
Table 12.--Comparison of the Targeted ``Lookback'' Program Based on
Single-Antigen Screening Tests and Two General ``Lookback'' Programs for
Recipients Who Received Transfusions Between 1988 and mid-1992\1\
------------------------------------------------------------------------
Estimate of a Nationwide General
``Lookback'' Program for
Targeted Recipients Transfused Between
``Lookback'' for 1988 and mid-1992
donations screened ----------------------------------
with single antigen Private sector Integrated
test health care health care
setting setting
------------------------------------------------------------------------
Number of 160,879 15.2 million.... 15.2 million
patients
transfused
Number of 34,267 4,058,811....... 5,798,974
``lookback''
notifications
Number of 17,819 694,556......... 3,652,446
screening tests
Number of 11,405 10,852.......... 181,666
supplemental
tests
Number of HCV+ 5,168 10,852.......... 90,833
patients
Number of HCV+ 869 3,581........... 29,975
patients
treated
------------------------------------------------------------------------
``Lookback'' $55.9\2\$426.2\3\....... $324.7\4\
costs ($ mil)
Diagnostic $6.8 $67.9........... $417.2
costs\5\ ($
mil)
Total costs ($ $62.7 $494.1.......... $741.9
mil)
------------------------------------------------------------------------
Number of QALYs 2,425 9,992........... 83,630
gained
------------------------------------------------------------------------
Cost per QALY $25,862\6\ $49,449......... $8,871
gained ($)
------------------------------------------------------------------------
Incremental cost -- $57,011......... $8,364
per QALY gained
between
targeted and
the upper and
lower bounds of
general
``lookback''
------------------------------------------------------------------------
\1\ Unless noted, all dollar amounts are $ million.
\2\ ``Lookback'' costs of $113 for blood collection establishments and
$184 for transfusion establishments.
\3\ ``Lookback'' costs of $105 based on Ref. 24.
\4\ ``Lookback'' costs of $56 based on Ref. 23.
\5\ Unit costs for diagnostic tests are shown in table 4 of this
document.
\6\ For this example, we report the cost-effectiveness of the
retrospective ``lookback'' based on single-antigen tests. This differs
from the cost-effectiveness of the entire retrospective ``lookback''
reported in section 6.e. of this document.
[[Page 48792]]
C. Impact on Small Entities
No comments were received on the initial regulatory flexibility
analysis or the agency's request for specific information essential to
estimate the final rule's impact on small entities. Because information
on the affected industries is limited, the agency cannot predict the
extent of the economic impact of the final rule on small entities and,
therefore, performed a final regulatory flexibility analysis.
The final rule will help ensure the continued safety of the blood
supply and will help ensure that consignees and recipients who received
blood and blood components at increased risk of transmitting HCV are
informed. Affected entities include commercial plasma centers,
community and hospital blood banks, and hospital transfusion services
that collect or receive blood and blood components. For the regulatory
flexibility analysis affected firms are considered small if they are:
(1) A for-profit firm with annual receipts or revenue less than the
current Small Business Administration (SBA) industry size standards;
(2) an independently owned and operated, not-for-profit enterprise
which is not dominant in its field; or (3) operated by a small
governmental jurisdiction with a population of less than 50,000
individuals. Aggregate information about hospitals and blood banks are
available under SIC (Standard Industrial Classification) group 80 for
health services. However, the North American Industry Classification
System (NAICS) reports information at the blood and organ banks level.
Similarly, more detailed general medical and surgical hospital
information is available with NAICS than with the SIC system. To
estimate the economic impact of the final rule on these different types
of small entities, the costs per firm shown in table 13 of this
document are expressed as a percentage of average annual revenue in
tables 14, 15, and 16 of this document.
Table 13.--Estimated Per Firm Regulatory Costs by Type of Small Entity\1\
----------------------------------------------------------------------------------------------------------------
Share of Total Annualized Costs
Type of Small Entity ``Lookback'' Annual One-Time -------------------------------
Costs Costs\2\ Costs\3\ 3 percent 7 percent
----------------------------------------------------------------------------------------------------------------
Plasma collection N/A -- $1,350 $160 $190
----------------------------------------------------------------------------------------------------------------
Blood collection 0.04% -- $10,210 $1,200 $1,450
----------------------------------------------------------------------------------------------------------------
For-profit hospital 0.02% $1,410 $7,370 $2,270 $2,460
----------------------------------------------------------------------------------------------------------------
Not-for-profit hospital 0.02% $1,410 $7,060 $2,240 $2,420
----------------------------------------------------------------------------------------------------------------
Government hospital 0.00% $1,370 $1,420 $1,540 $1,570
----------------------------------------------------------------------------------------------------------------
\1\ Numbers may not add due to rounding.
\2\ Although 80 percent of hospitals already retain records for 10 years, this analysis assumes small hospitals
are not in compliance with this provision of the final rule. Blood collection establishments currently comply
with these provisions of the final rule.
\3\ Includes one-time cost for SOPs and historical ``lookback'' actions.
In the United States, most plasma establishments are owned by
large, for-profit companies, whereas almost all blood collection
establishments are not-for-profit organizations. The SBA size standards
in effect since December 6, 2005, define as small any blood and organ
bank (NAICS 621991) with an annual income of less than $9 million.
Although the 1997 Economic Census lists 449 blood and organ banks
(including plasma collection establishments) owned by 173 for-profit
firms and 721 blood and organ banks owned by 300 not-for-profit firms
(NAICS 621991), this data has limited use because it includes organ
banks, excludes any blood collection establishment operating as part of
a hospital, and uses different receipt sizes than the SBA.
FDA estimates the final rule will affect 60 commercial plasma
collection establishments and 981 blood collection establishments. The
FDA registry of blood establishments does not provide an indication of
the size of the registered entities. However, previously the agency
estimated that 37 small plasma establishments collect approximately 8
percent of the plasma and 906 small blood banks collect 35 percent of
the donated blood (66 FR 31146 at 31159).
Each affected establishment will incur the one-time cost to revise
SOPs. Blood and plasma collection establishments have had procedures in
place for HIV ``lookback'' for years. Thus, no additional skills are
required because each establishment has existing personnel experienced
in preparation of SOPs and the establishment would update existing SOPs
by including HCV into the ``lookback'' procedures. Using 1997 Economic
Census data on for-profit firms included in NAICS 621991, table 14 of
this document illustrates that the annualized costs of the SOPs will be
less than 0.5 percent of average receipts for all small plasma
entities, illustrating that the average impact of the final rule will
not be significant for small plasma entities.
Table 14.--One-Time and Annualized Costs of the Final Rule on For-Profit Plasma Centers Operating All Year\1\
----------------------------------------------------------------------------------------------------------------
Per Firm One- Per Firm Annualized Costs as
Average Time Costs as Percent of Average Receipts\2\
Receipts Size of Number of Receipts\1\ Receipt per Percent of ---------------------------------
Firm\1\ Firms\1\ ($1,000) Firm\1\ Average
($1,000) Receipts\2\ 3 percent 7 percent
----------------------------------------------------------------------------------------------------------------
< $100,000 28 1,714 61.2 2.2% 0.3% 0.3%
----------------------------------------------------------------------------------------------------------------
$100,000 to 21 3,257 155.1 0.9% 0.1% 0.1%
$249,999
----------------------------------------------------------------------------------------------------------------
[[Page 48793]]
$250,000 to 16 5,737 358.6 0.4% 0.0% 0.1%
$499,999
----------------------------------------------------------------------------------------------------------------
$500,000 to 30 21,626 720.9 0.2% 0.0% 0.0%
$999,999
----------------------------------------------------------------------------------------------------------------
$1,000,000 to 37 56,837 1,536.1 0.1% 0.0% 0.0%
$2,499,999
----------------------------------------------------------------------------------------------------------------
$2,500,000 to 16 55,677 3,479.8 0.0% 0.0% 0.0%
$4,999,999
----------------------------------------------------------------------------------------------------------------
$5,000,000 to 5 37,124 7,424.8 0.0% 0.0% 0.0%
$9,999,999
----------------------------------------------------------------------------------------------------------------
$10,000,000 + 20 804,559 NA NA ............... NA
----------------------------------------------------------------------------------------------------------------
Total 173 986,531 ............. ............... ............... ...............
----------------------------------------------------------------------------------------------------------------
\1\ Source: U.S. Department of Commerce, Economics and Statistics Administration, U.S. Census Bureau, ``1997
Economic Census, Health Care and Social Assistance, Subject Series: Establishment and Firm Size,'' EC97S62S-
SZ, October 2000, table 4a, NAICS 621991 (blood and organ banks).
\2\ Per firm costs from table 13 of this document.
In addition to the cost of revising SOPs, the one-time costs of the
retrospective ``lookback'' will be proportional to the volume of blood
collected by blood establishments. Therefore, small entities collecting
few donations will incur the lowest ``lookback'' costs. Because 906
small entities collect about 35 percent of the blood, the proportion of
``lookback'' costs for each entity will be small. For example, if blood
donations are distributed evenly among small blood collection
establishments, each small organization would incur only 0.04 percent
(0.04 percent = 35 percent / 906) of the ``lookback'' costs and collect
approximately 5,400 donations each year (5,408 donations /
establishment = 14 million donations x 35 percent / 906
establishments). Using $96 as the price for a unit of red blood cells,
small blood collection establishments average a minimum annual revenue
of approximately $520,000 (Ref. 29). Table 15 of this document
summarizes the one-time and annualized costs of the final rule as a
percentage of this minimum average revenue for small blood collection
organizations.
Table 15.--One-Time and Annualized Costs of the Final Rule on Not-For-Profit Blood Collection Organizations
----------------------------------------------------------------------------------------------------------------
Per Firm Annualized Costs as
Average Annual Per Firm One-Time Percent of Average Revenue\2\
Number of Small Organizations Revenue\1\ Costs as Percent of -------------------------------
Average Revenue\2\ 3 percent 7 percent
----------------------------------------------------------------------------------------------------------------
906 $519,200 2.0% 0.2% 0.3%
----------------------------------------------------------------------------------------------------------------
\1\ 5,370 units x $96/unit of red blood cells = $515,520. A unit of whole blood can be separated into non-red
blood cell components that yield additional revenues in excess of $135.
\2\ Per firm costs from table 13 of this document.
An estimated 4,980 hospitals perform transfusion services in the
United States. The SBA defines as small any general medical and
surgical hospital (NAICS 622110) with annual receipts less than $31.5
million. Similar to blood banks, the census uses receipt sizes that
differ from those of the SBA. Therefore, in this analysis, for-profit
hospitals with annual receipts less than $25 million are treated as
small businesses. Furthermore, not-for-profit, non-government hospitals
that have no more than one establishment are treated as small
organizations. Similarly, the number of government hospitals (NAICS
6221101) classified as single-unit firms, or firms with one
establishment, provides an estimate of the number of small government
hospitals. This approach most likely overestimates the number of
hospitals operated by small government jurisdictions, because many
urban county hospitals (i.e., with populations greater than 50,000) may
have only one establishment.
In contrast to blood banks, the 1997 Economic Census reports data
separately on 774 for-profit hospitals (NAICS 622110), 1,571 government
hospitals (NAICS 6221101), and 3,076 non-government, not-for-profit
hospitals (NAICS 6221102). Each hospital transfusion service will incur
the cost of preparing SOPs and 20 percent will spend more to retain
records an additional 5 years. Hospitals have experience preparing SOPs
and have already been performing an historical ``lookback'' under an
agency guidance to industry. Thus compliance with the final rule
requires no new skills.
Similar to blood banks, ``lookback'' costs are proportional to
transfusion volume. Unlike blood banks, however, data from several
sources provides sufficient information to distribute transfusion
volume to different types of small entities. National statistics from
the Healthcare Cost and Utilization Project (HCUP) on in-hospital blood
transfusions in 1997 (i.e., clinical classifications software procedure
category 222) give a reasonable estimate of the volume of blood
transfused by hospitals categorized by ownership (i.e., government;
private, not-for-profit; and private, for-profit) (Ref. 8).
Furthermore, HCUP provides data on the number of transfusions by
ownership category and
[[Page 48794]]
bed size. In 1997, HCUP defined bed size category based on location and
teaching status of the hospital. Thus small bed size refers to the
following: (1) 1 to 49 beds for rural hospitals; (2) 1 to 99 beds for
urban, non-teaching hospitals; and (3) 1 to 299 beds for urban,
teaching hospitals. However, most teaching hospitals are affiliated
with public or private, not-for-profit colleges or universities which
would be considered organizations. Using the HCUP definition, small
for-profit hospitals are assumed to have no more than 99 beds. Data
from a 1998 American Hospital Association (AHA) survey on hospitals in
the United States shows that hospitals with less than 100 beds had
average revenues of $27.7 million or less (Ref. 7). The HCUP data on
the number of transfusions given in small, for-profit hospitals is
used, therefore, to estimate the share of total transfusion for small
businesses. In contrast, small not-for-profit or government hospitals
may not necessarily be classified as small based on HCUP bed size. Thus
for these small entities, revenue shares calculated from the 1997
Economic Census data serve as proxies for transfusion volume.
Table 16 of this document shows the average one-time and annual
costs incurred by small hospitals as a percentage of annual receipts or
revenue. In all cases, one-time costs are less than one percent of
average revenue or receipts and annualized costs are less than 0.2
percent of average revenue or receipts. Therefore, the final rule does
not have a significant economic impact on these small entities.
Table 16.--Hospital Industry One-Time and Annual Costs as a Percentage of Average Annual Revenue by Size and
Type of Firm\1,2\
----------------------------------------------------------------------------------------------------------------
Per Firm One- Per Firm Annualized Costs as
Average Time Costs as Percent of Average Receipts
Receipt Size of Number of Receipts Receipt Per Percent of -------------------------------
Firm Firms ($1,000) Firm ($1,000) Average
Receipts 3 percent 7 percent
----------------------------------------------------------------------------------------------------------------
For-Profit Hospitals Operating All Year:\3\
$0 to $999,999 0 .............. .............. .............. .............. ..............
$1,000,000 to 6 9,737 1,622.8 0.5% 0.1% 0.2%
$2,499,999
$2,500,000 to 21 73,777 3,513.2 0.2% 0.1% 0.1%
$4,999,999
$5,000,000 to 43 316,631 7,363.5 0.1% 0.0% 0.0%
$9,999,999
$10,000,000 to 38 630,189 16,583.9 0.0% 0.0% 0.0%
$24,999,999
$25,000,000 + 66 NA NA .............. .............. NA
Total 174 33,782,805 .............. .............. .............. ..............
����������������������������������������������������������������������������������������������������������������
Size Category Number of Revenue Average Per Firm One-
(share of total Firms ($1,000) Revenue Per Time Costs as
revenue) Firm ($1,000) Percent of
Average
Revenue Per Firm Annualized Costs as
Percent of Average Revenue
-------------------------------
.............. .............. .............. .............. 3 percent 7 percent
����������������������������������������������������������������������������������������������������������������
Not-For-Profit Hospitals Operating All Year:\4\
Single-unit 918 44,832,121 48,836.7 0.0% 0.0% 0.0%
firm (14%)
One 813 74,651,556 91,822.3 0.0% 0.0% 0.0%
establishment
(23%)
Total 2,034 242,896,322 .............. .............. .............. ..............
----------------------------------------------------------------------------------------------------------------
Government Hospitals Operating All Year:\5\
Single-unit 994 23,175,491 23,315.4 0.0% 0.0% 0.0%
firm (7%)
One 515 43,739,763 84,931.6 0.0% 0.0% 0.0%
establishment
(14%)
Total 1,537 77,024,061 .............. .............. .............. ..............
----------------------------------------------------------------------------------------------------------------
\1\ Source: U.S. Department of Commerce, Economics and Statistics Administration, U.S. Census Bureau, ``1997
Economic Census, Health Care and Social Assistance, Subject Series: Establishment and Firm Size,'' EC97S62S-
SZ, October 2000.
\2\ Per firm costs from table 13 of this document.
\3\ 1997 Economic Census, table 4a, NAICS 622110. Based on 1997 HCUP data, small private for-profit hospitals
account for approximately 2 percent of the annual transfusion volume (1.8% = 23,182 / 1,296,723).
\4\ 1997 Economic Census, table 3b, NAICS 6221102. HCUP data shows private, not-for-profit hospitals account for
71% of all transfusions (= 924,730 / 1,296,723). According to 1997 Economic Census data, hospitals with less
than two establishments account for 37% of total revenues for all private, not-for-profit hospitals. Therefore
small, private, not-for-profit hospitals will incur about 27% (27% = 71% x 37%) of the consignee ``lookback''
costs. Costs as a percent of revenue less than 0.05 percent are rounded to 0.0 percent.
\5\ 1997 Economic Census, table 3b, NAICS 6221101, HCUP data shows government hospitals account for 15% of all
transfusions (= 193,679 / 1,296,723). According to 1997 Economic Census data, government hospitals with less
than two establishments account for 21% of total revenues for all government hospitals. Therefore, small
government hospitals will incur about 3% (3% = 15% x 21%) of the consignee ``lookback'' costs. Costs as a
percent of revenue less than 0.05 percent are rounded to 0.0 percent.
As described earlier, FDA has considered several alternatives, and
considers that a targeted ``lookback'' will be the most effective
approach to inform recipients of HCV-infected blood products. Because
``lookback'' costs are proportional to blood collection or transfusion
volume, the smallest entities will incur the lowest costs. Furthermore,
the agency allows for flexibility in an establishment's individual
approach to compliance by moving the prescriptive language of the
proposed rule to an industry guidance document and specifying only the
objective actions required by an establishment in the final rule. This
will enable each entity to develop procedures that are most appropriate
and cost-effective given the particular situation and the resources
available. In addition, the agency has specified a limited time frame
for notification to provide a clear endpoint to facilitate efforts
related to the historical ``lookback.'' The agency concludes that this
final rule will ensure the safety of
[[Page 48795]]
the blood supply and meet public health goals in the least intrusive
and most cost-effective way. Therefore, the agency certifies that the
final rule will not have a significant economic impact on a substantial
number of small entities.
V. The Paperwork Reduction Act of 1995
This final 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). A
description of these provisions, with an estimate of the annual
reporting and recordkeeping burden, follows. Included in the estimate
is the time for reviewing the instructions, searching existing data
sources, gathering and maintaining the data needed, and completing and
reviewing each collection of information.
Title: Current Good Manufacturing Practices for Blood and Blood
Components; Notification of Consignees and Transfusion Recipients
Receiving Blood and Blood Components at Increased Risk of Transmitting
Hepatitis C Virus Infection (``Lookback'').
Description: This final rule requires collecting establishments and
consignees to prepare and follow written procedures when a donor who
tests reactive for evidence of HIV or HCV infection either on a repeat
donation or after a review of historical testing records (recordkeeping
burden in Sec. 606.100(b)(19)). Such collections may be at increased
risk of transmitting HIV or HCV infection. We are requiring collecting
establishments to review testing records, to quarantine prior in-date
blood and blood components from such a donor, to perform further
testing on the donor, and to notify consignees of prior in-date blood
and blood components from such a donor for quarantine purposes
(reporting burden in Sec. Sec. 610.46(a)(1)(ii)(B),
610.47(a)(1)(ii)(B), and 610.48(b)(3)(ii) and (b)(3)(iii)) and to
notify consignees of further testing results (reporting burden in
Sec. Sec. 610.46(a)(3), 610.47(a)(3), and 610.48(b)(4)). We also are
requiring consignees to notify transfusion recipients, the recipients'
physicians of record, or the recipients' legal representatives that the
recipient received blood and blood components at increased risk of
transmitting HIV or HCV (reporting burden in Sec. Sec. 610.46(b)(3),
610.47(b)(3), and 610.48(c)(3)). Records of these actions must be kept
(recordkeeping burden in Sec. 606.160(b)(1)(viii)). We also are
extending record retention under Sec. 606.160(d) from 5 to 10 years.
Description of Respondents: Collecting establishments (business and
not-for-profit) and consignees of collecting establishments, including
hospitals, transfusion services, and physicians.
As required by section 3506(c)(2)(B) of the PRA, we provided an
opportunity for public comment on the information collection
requirements of the HCV ``lookback'' proposed rule (65 FR 69378). In
accordance with the PRA, OMB reserved approval of the information
collection burden in the proposed rule, stating it will make an
assessment in light of public comments received on the proposed rule.
No comments on the information collection requirements were submitted
to OMB or the docket.
The total reporting and recordkeeping burden for the first year is
estimated to be 495,309.5 hours. However, of this total approximately
456,280 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, 39,029.5 hours is estimated
as the ongoing annual burden related to these regulations. The total
ongoing annual burden for collecting establishments under Sec. Sec.
610.46(a)(1)(ii)(B), 610.46(a)(3), 610.46(b)(3), and
606.160(b)(1)(viii) for HIV ``lookback'' is estimated to be 12,763
hours. The total ongoing annual burden for collecting establishments
under Sec. Sec. 610.47(a)(1)(ii)(B), 610.47(a)(3), 610.47(b)(3), and
606.160(b)(1)(viii) for HCV ``lookback'' is estimated to be 26,266.5
hours.
Based on information retrieved from FDA's registration database and
as discussed in section IV of this document, there are approximately
1,041 FDA registered establishments (60 licensed plasma establishments
and 981 registered collecting establishments) in the United States that
collect approximately 27 million donations annually: 13 million
donations of Source Plasma and 14 million donations of Whole Blood,
including approximately 695,000 autologous units. As calculated in
section IV of this document, there are approximately 11.2 million
donations of Whole Blood from repeat donors per year. As previously
discussed in section IV.A.3.b of this document, the Source Plasma
industry will only be minimally affected by these requirements.
Therefore, we are only estimating burden for Source Plasma collecting
establishments in regards to Sec. 606.100(b)(19). The following
reporting and recordkeeping estimates are based on information provided
by industry and FDA experience.
A. Annual Reporting Burden
1. HIV Reporting Burden
In table 17 of this document, we estimate that approximately 3,500
repeat donors will test reactive on a screening test for HIV. We
estimate that an average of three components were made from each
donation. Under Sec. 610.46(a)(1)(ii)(B) and 610.46(a)(3), this
estimate results in 10,500 (3,500 x 3) notifications of the HIV
screening test results to consignees by collecting establishments for
the purpose of quarantining affected blood and blood components, and
another 10,500 (3,500 x 3) notifications to consignees of subsequent
test results. We estimate an average of 10 minutes per notification of
consignees. The estimate for consignee notifications in the final rule
is higher than the estimate in the proposed rule because we based our
calculations in the final rule on the number of components at risk of
transmitting HCV infection rather than the number of reactive donors.
We also have increased the number of components per donation from two
to three.
In addition, we estimate that Sec. 610.46(b)(3) will require 4,980
consignees to notify transfusion recipients or physicians of record an
average of 0.35 times per year resulting in a total number of 1,755
(585 confirmed positive repeat donors x 3) notifications. In the
proposed rule, we estimated 0.5 hours as the average time for a
reasonable attempt to notify recipients by consignees. However, under
Sec. 610.46(b)(3), we are increasing the estimate to 1 hour to
accommodate the time to gather test results and the recipient's records
and to accommodate multiple attempts to contact the recipient.
2. HCV Reporting Burden
We estimate that approximately 7,800 repeat donors per year would
test reactive for antibody to HCV (780 repeat donors confirmed HCV
positive / 0.1 rate for repeat donors confirmed HCV positive / repeat
donors with reactive tests = 7,800 repeat donors with reactive tests).
Under Sec. Sec. 610.47(a)(1)(ii)(B) and 610.47(a)(3), collecting
establishments would notify the consignee two times for each of the
23,400 (7,800 x 3 components) components prepared from these donations,
once for quarantine purposes and again with additional HCV test results
for a total of 46,800 notifications as an annual ongoing burden. Under
Sec. 610.47(b)(3), we estimate that approximately 4,980 consignees
would notify approximately 2,050 recipients (calculated in section
IV.A.4.b.i of this document) or their
[[Page 48796]]
physicians of record annually. The estimated average 1 hour to complete
notification is based on the criteria discussed in the previous section
on HIV Reporting Burden.
B. Estimated One-Time Reporting Burden
Based on estimates from CDC, we expect that for the one-time
retrospective review of historical testing records, as many as
approximately 212,000 blood components (calculated in section
IV.A.4.b.ii of this document) would be at increased risk for
transmitting HCV. For each of these products, under Sec. Sec.
610.48(b)(3)(ii) and (b)(3)(iii), and 610.48(b)(4) collecting
establishments would notify consignees to quarantine these products and
report additional HCV test results to consignees, and, under Sec.
610.48(c)(3), consignees would notify transfusion recipients or
recipients' physicians of record. CDC estimated that there could be
approximately 212,000 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 of
table 18 of this document are the same as the burden for table 7 of
this document.
C. Estimated Annual and One-Time Recordkeeping Burden
In the recordkeeping tables (tables 19 and 20 of this document),
the numbers in the ``Hours per Record'' column are based on our
estimate of the time to complete one record. We also estimate that each
documentation of consignee and recipient notification takes
approximately 5 minutes. In table 20 of this document, we estimate that
it will take collecting establishments approximately 40 hours to
establish the written procedures required under Sec. 606.100(b)(19)
and consignees approximately 16 hours to establish written procedures
under Sec. 606.100(b)(19). In table 19 of this document, the estimate
for annual recordkeeping is based on the estimate that it takes
approximately 10 minutes to document and maintain the records to relate
the donor with the unit number of each previous donation for both the
collecting establishment and the consignee. The time required for
recordkeeping under Sec. 606.160(b)(1)(viii) is estimated to be
approximately 10 minutes for each HIV or HCV reactive donation record
and approximately 10 minutes per transfusion recipient record required
under Sec. Sec. 610.46(b)(3), 610.47(b)(3), and 610.48(c)(3).
Because the final rule will not affect current industry practice of
retaining ``lookback'' records for 10 years, no burden is calculated
for Sec. 606.160(d). We estimate the burden for this collection of
information as follows:
Table 17.--Estimated Annual Reporting Burden\1\
----------------------------------------------------------------------------------------------------------------
No. of Annual Frequency Total Annual Hours per
21 CFR Section Respondents per Response Responses Response Total Hours
----------------------------------------------------------------------------------------------------------------
610.46(a)(1)(ii)(B) 981 10.7 10,500 0.17 1,785
----------------------------------------------------------------------------------------------------------------
610.46(a)(3) 981 10.7 10,500 0.17 1,785
----------------------------------------------------------------------------------------------------------------
610.46(b)(3) 4,980 0.35 1,755 1.0 1,755
----------------------------------------------------------------------------------------------------------------
610.47(a)(1)(ii)(B) 981 23.85 23,400 0.17 3,978
----------------------------------------------------------------------------------------------------------------
610.47(a)(3) 981 23.85 23,400 0.17 3,978
----------------------------------------------------------------------------------------------------------------
610.47(b)(3) 4,980 0.41 42,050 1.0 2,050
----------------------------------------------------------------------------------------------------------------
Total 15,331
----------------------------------------------------------------------------------------------------------------
\1\ There are no capital or operating and maintenance costs associated with this collection of information.
Table 18.--Estimated One-Time Reporting Burden\1\
----------------------------------------------------------------------------------------------------------------
No. of Annual Frequency Total Annual Hours per
21 CFR Section Respondents per Response Responses Response Total Hours
----------------------------------------------------------------------------------------------------------------
610.48(b)(3)(ii) and 981 216.1 212,000 0.17 36,040
(b)(3)(iii)
----------------------------------------------------------------------------------------------------------------
610.48(b)(4) 981 216.1 212,000 0.17 36,040
----------------------------------------------------------------------------------------------------------------
610.48(c)(3) 4,980 42.57 212,000 1.0 212,000
----------------------------------------------------------------------------------------------------------------
Total 284,080
----------------------------------------------------------------------------------------------------------------
\1\ There are no capital or operating and maintenance costs associated with this collection of information.
Table 19.--Estimated Annual Recordkeeping Burden\1\
----------------------------------------------------------------------------------------------------------------
No. of Annual Frequency of Total Annual Hours per
21 CFR Section Recordkeepers Recordkeeping Records Record Total Hours
----------------------------------------------------------------------------------------------------------------
606.160(b)(1)(viii)
----------------------------------------------------------------------------------------------------------------
HIV consignee 981 21.4 21,000 .17 3,570
notification
--------------------------------------------------------------------------------------
4,980 4.2 21,000 .17 3,570
----------------------------------------------------------------------------------------------------------------
HCV consignee 981 47.71 46,800 .17 7,956
notification
--------------------------------------------------------------------------------------
[[Page 48797]]
4,980 9.4 46,800 .17 7,956
----------------------------------------------------------------------------------------------------------------
HIV recipient 4,980 0.35 1,755 .17 298
notification
----------------------------------------------------------------------------------------------------------------
HCV recipient 4,980 0.41 2,050 .17 348.5
notification
----------------------------------------------------------------------------------------------------------------
Total 23,698.5
----------------------------------------------------------------------------------------------------------------
\1\ There are no capital or operating and maintenance costs associated with this collection of information.
Table 20.--Estimated One-Time Recordkeeping Burden\1\
----------------------------------------------------------------------------------------------------------------
No. of Annual Frequency Total Annual Hours per
21 CFR Section Recordkeepers of Recordkeeping Records Record Total Hours
----------------------------------------------------------------------------------------------------------------
606.100(b)(19) 1,041 1 1,041 40 41,640
----------------------------------------------------------------------------------------------------------------
606.100(b)(19) 4,980 1 4,980 16 79,680
----------------------------------------------------------------------------------------------------------------
606.160(b)(1)(viii) 1,041 203.65 212,000 .08 16,960
----------------------------------------------------------------------------------------------------------------
606.160(b)(1)(viii) 4,980 42.57 212,000 .08 16,960
----------------------------------------------------------------------------------------------------------------
610.48(c)(3) 4,980 42.57 212,000 .08 16,960
----------------------------------------------------------------------------------------------------------------
Total 172,200
----------------------------------------------------------------------------------------------------------------
\1\ There are no capital or operating and maintenance costs associated with this collection of information.
The information collection provisions of this final rule have been
submitted to OMB for review.
Before the final rule becomes effective, we will publish a notice
in the Federal Register announcing OMB's decision to approve, modify,
or disapprove the information collection provisions in this final rule.
An agency may not conduct or sponsor, and a person is not required to
respond to, a collection of information unless it displays a currently
valid OMB number.
VI. Environmental Impact
The agency has determined under 21 CFR 25.30(j) that this action is
of a type that does not individually or cumulatively have a significant
effect on the human environment. Therefore, neither an environmental
assessment, nor an environmental impact statement is required.
VII. Federalism
FDA has analyzed this final rule in accordance with the principles
set forth in Executive Order 13132. FDA has determined that the rule
does not contain policies that have substantial direct effects on the
States, on the relationship between the National Government and the
States, or on the distribution of power and responsibilities among the
various levels of government. Accordingly, the agency has concluded
that the rule does not contain policies that have federalism
implications as defined in the Executive Order and, consequently, a
federalism summary impact statement is not required.
VIII. References
The following references have been placed on display in the
Division of Dockets Management (HFA-305), Food and Drug Administration,
5630 Fishers Lane, rm. 1061, Rockville, MD 20852, and may be seen by
interested persons between 9 a.m. and 4 p.m., Monday through Friday.
(FDA has verified the Web site addresses, but we are not responsible
for subsequent changes to the Web sites after this document publishes
in the Federal Register.)
1. U.S. Department of Health and Human Services, Transcript of
DHHS Advisory Committee on Blood Safety and Availability, ``The
Economics of Blood and Where Blood Fits in the Overall Cost of
Healthcare,'' p. 78, May 2, 2003, http://www.hhs.gov/bloodsafety/transcripts/0502bloo.pdf.
2. Dodd, R.Y., S.L. Stramer, J. Aberle-Grasse, and E. Notari,
``Risk of Hepatitis and Retroviral Infections Among Blood Donors and
Introduction of Nucleic Acid Testing (NAT),'' Advances in
Transfusion Safety, International Symposium: Proceedings,
Developments in Biologicals, 102:19-27, 1999.
3. Culver, D.H., M.J. Alter, R.J. Mullan, and H.S. Margolis.
2000. ``Evaluation of the Effectiveness of Targeted Lookback for HCV
Infection in the United States-Interim Results,'' Transfusion,
40:1176-81.
4. U.S. Department of Labor, Bureau of Labor Statistics, ``Table
20. Private Industry Workers, Health Services, by Occupational
Group: Employer Costs per Hour Worked for Employee Compensation and
Costs as a Percent of Total Compensation, 1994-2001,'' p. 176, ftp://ftp.bls.gov/pub/special.requests/ocwc/ect/ecechist.pdf.
5. U.S. Department of Labor, Bureau of Labor Statistics, ``Table
13. Private Industry Workers, Service-Producing Industries, by
Occupational Group: Employer Costs per Hour Worked for Employee
Compensation and Costs as a Percent of Total Compensation, 1988-
2001,'' p. 112, ftp://ftp.bls.gov/pub/special.requests/ocwc/ect/ecechist.pdf.
6. Saxena, S, et al., ``Retrospective Targeted HCV Lookback
Using Centralized Contracted Notification Service,'' Transfusion,
43:799-806, 2003.
7. American Hospital Association, Healthcare InfoSource, Inc.,
Hospital Statistics, Chicago, IL, 1998.
8. U.S. Department of Health and Human Services, Agency for
Healthcare Research and Quality, ``HCUPnet, Healthcare Cost and
Utilization Project, 1997 National Statistics.''
9. Stramer, S.L., ``US NAT yield: Where Are We After 2 Years?''
Transfusion Medicine, 12:243-53, 2002.
10. Bennett, W.G., Y. Inoue, J.R. Beck, et al., ``Estimates of
the Cost-Effectiveness of a Single Course of Interferon-alpha-2b in
Patients with Histologically Mild Chronic Hepatitis C,'' Annals of
Internal Medicine, 127:855-65, November 15, 1997.
11. Strader, D.B., ``Understudied Populations with Hepatitis
C,'' Hepatology, 36:S226-36, 2002.
12. Kim, W.R., J.J. Poterucha, J.E. Hermans, et al., ``Cost-
Effectiveness of 6 and 12 Months of Interferon-alpha Therapy for
Chronic
[[Page 48798]]
Hepatitis C,'' Annals of Internal Medicine, 127:866-74, November 15,
1997.
13. Salomon, J.A., M.C. Weinstein, J.K. Hammitt and S.J. Goldie,
``Cost-effectiveness of Treatment for Chronic Hepatitis C Infection
in an Evolving Patient Population,'' Journal of the American Medical
Association, 290:228-37, July 9, 2003.
14. Younossi, Z.M., M. E. Singer, J.G. McHutchison and K.M.
Shermock, ``Cost Effectiveness of Interferon a2b Combined with
Ribavirin for the Treatment of Chronic Hepatitis C,'' Hepatology,
30:1318-24, 1999.
15. U.S. Department of Health and Human Services, Centers for
Medicare and Medicaid Services, ``Clinical Laboratory Fee Schedule
for CY2003.''
16. U.S. Department of Health and Human Services, Agency for
Healthcare Research and Quality, ``HCUPnet, Healthcare Cost and
Utilization Project, 2001 National Statistics--Cross-Classifying
Diagnoses or Procedures.''
17. U.S. Department of Health and Human Services, Centers for
Medicare and Medicaid Services, ``2003 Medicare Physician Fee
Schedule (MPFS).''
18. Institute of Medicine, 2006, Valuing Health for Regulatory
Cost-Effectiveness Analysis, Washington, DC: National Academies
Press.
19. Cutler, David M. and Elizabeth Richardson, 1997, ``Measuring
the Health of the U.S. Population,'' Brookings Papers on Economic
Activity, Microeconomics: 217-271.
20. Viscusi, W. Kip and Joseph E. Aldy, 2003, ``The Value of a
Statistical Life: A Critical Review of Market Estimates throughout
the World,'' Journal of Risk and Uncertainty, 27: 5-76.
21. Bowker, S.L., L.J. Smith, R.J. Rosychuk and J.K.
Preiksaitis, 2004, ``A Review of General Hepatitis C Virus Lookbacks
in Canada,'' Vox Sanguinis, 86: 21-7.
22. Goldman, Mindy, Sylvia Juodvalkis, Peter Gill and Gwendoline
Spurll, 1998, ``Hepatitis C Lookback,'' Transfusion Medicine
Reviews, 12: 84-93.
23. Williams, James L., Henry H. Cagle, Carol J. Christensen,
Leslie K. Fox-Leyva and Brian J. McMahon. 2005. ``Results of a
Hepatitis C General Transfusion Lookback Program for Patients Who
Received Blood Products Before July 1992,'' Transfusion, 45: 1020-6.
24. Cagle, Henry H., Jack Jacob, Chriss E. Homan, James L.
Williams, Carol J. Christensen and Brian J. McMahon, 2007, ``Results
of a General Hepatitis C Lookback Program for Persons Who Received
Blood Transfusions in a Neonatal Intensive Care Unit Between January
1975 and July 1992,'' Archives of Pediatric and Adolescent Medicine,
161: 125-30.
25. Surgenor, Douglas M., Edward L. Wallace, Steven H.S. Hao,
and Richard H. Chapman, 1990, ``Collection and Transfusion of Blood
in the United States, 1982-1988,'' The New England Journal of
Medicine, 322: 1646-51.
26. Wallace, E.L., D.M. Surgenor, H.S. Hao, R.H. Chapman and
W.H. Churchill. 1993. ``Collection and Transfusion of Blood and
Blood Components in the United States, 1989,'' Transfusion, 33: 139-
44.
27. Wallace, E.L., W.H. Churchill, D.M. Surgenor, J. An, G. Cho,
S. McGurk and L. Murphy. 1995. ``Collection and Transfusion of Blood
and Blood Components in the United States, 1992,'' Transfusion, 35:
802-12.
28. Alter, M.J., D. Kruszon-Moran, O.V. Nainan, G.M. McQuillan,
F. Gao, L.A. Moyer, R.A. Kaslow and H.S. Margolis, 1999, ``The
Prevalence of Hepatitis C Virus Infection in the United States, 1988
Through 1994,'' The New England Journal of Medicine, 341(8): 556-62.
29. America's Blood Centers, ``Financial Impact of Technologies
to Improve Blood Safety-Charts 1 and 2,'' October 19, 2001.
Lists of Subjects
21 CFR Part 606
Blood, Labeling, Laboratories, Reporting and recordkeeping
requirements.
21 CFR Part 610
Biologics, Labeling, Reporting and recordkeeping requirements.
0
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, 21 CFR parts 606 and 610 are amended as
follows:
PART 606--CURRENT GOOD MANUFACTURING PRACTICE FOR BLOOD AND BLOOD
COMPONENTS
0
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.
0
2. Section 606.100 is amended by revising paragraph (b)(19) to read as
follows:
Sec. 606.100 Standard operating procedures.
* * * * *
(b) * * *
(19) Procedures under Sec. Sec. 610.46, 610.47, and 610.48 of this
chapter:
(i) To identify previously donated blood and blood components from
a donor who later tests reactive for evidence of human immunodeficiency
virus (HIV) infection or hepatitis C virus (HCV) infection when tested
under Sec. 610.40 of this chapter, or when a blood establishment is
made aware of other reliable test results or information indicating
evidence of HIV or HCV infection;
(ii) To quarantine in-date blood and blood components previously
donated by such a donor that are intended for use in another person or
further manufacture into injectable products, except pooled components
intended solely for further manufacturing into products that are
manufactured using validated viral clearance procedures;
(iii) To notify consignees to quarantine in-date blood and blood
components previously donated by such a donor intended for use in
another person or for further manufacture into injectable products,
except pooled components intended solely for further manufacturing into
products that are manufactured using validated viral clearance
procedures;
(iv) To determine the suitability for release, destruction, or
relabeling of quarantined in-date blood and blood components;
(v) To notify consignees of the results of the HIV or HCV testing
performed on the donors of such blood and blood components;
(vi) To notify the transfusion recipient, the recipient's physician
of record, or the recipient's legal representative that the recipient
received blood or blood components at increased risk of transmitting
HIV or HCV, respectively.
* * * * *
0
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 concerning the following activities performed under
Sec. Sec. 610.46, 610.47, and 610.48 of this chapter: Quarantine;
consignee notification; testing; notification of a transfusion
recipient, the recipient's physician of record, or the recipient's
legal representative; and disposition.
* * * * *
(d) * * * You must retain individual product records no less than
10 years after the records of processing are completed or 6 months
after the latest expiration date for the individual product, whichever
is the later date. * * *
* * * * *
PART 610--GENERAL BIOLOGICAL PRODUCTS STANDARDS
0
4. The authority citation for 21 CFR part 610 continues to read as
follows:
Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 360, 360c,
360d, 360h, 360i, 371, 372, 374, 381; 42 U.S.C. 216, 262, 263, 263a,
264.
0
5. Section 610.41 is amended by adding paragraph (c) to read as
follows:
Sec. 610.41 Donor deferral.
* * * * *
(c) You must comply with the requirements under Sec. Sec. 610.46
and
[[Page 48799]]
610.47 when a donor tests reactive by a screening test for HIV or HCV
required under Sec. 610.40(a) and (b), or when you are aware of other
reliable test results or information indicating evidence of HIV or HCV
infection.
0
6. Section 610.46 is revised to read as follows:
Sec. 610.46 Human immunodeficiency virus (HIV) ``lookback''
requirements.
(a) If you are an establishment that collects Whole Blood or blood
components, including Source Plasma and Source Leukocytes, you must
establish, maintain, and follow an appropriate system for the following
actions:
(1) Within 3 calendar days after a donor tests reactive for
evidence of human immunodeficiency virus (HIV) infection when tested
under Sec. 610.40(a) and (b) or when you are made aware of other
reliable test results or information indicating evidence of HIV
infection, you must review all records required under Sec. 606.160(d)
of this chapter, to identify blood and blood components previously
donated by such a donor. For those identified blood and blood
components collected:
(i) Twelve months and less before the donor's most recent
nonreactive screening tests, or
(ii) Twelve months and less before the donor's reactive direct
viral detection test, e.g., nucleic acid test or HIV p24 antigen test,
and nonreactive antibody screening test, whichever is the lesser
period, you must:
(A) Quarantine all previously collected in-date blood and blood
components identified under paragraph (a)(1) of this section if
intended for use in another person or for further manufacture into
injectable products, except pooled blood components intended solely for
further manufacturing into products that are manufactured using
validated viral clearance procedures; and
(B) Notify consignees to quarantine all previously collected in-
date blood and blood components identified under paragraph (a)(1) of
this section if intended for use in another person or for further
manufacture into injectable products, except pooled blood components
intended solely for further manufacturing into products that are
manufactured using validated viral clearance procedures;
(2) You must perform a supplemental (additional, more specific)
test for HIV as required under Sec. 610.40(e) of this chapter on the
reactive donation.
(3) You must notify consignees of the supplemental (additional,
more specific) test results for HIV, or the results of the reactive
screening test if there is no available supplemental test that is
approved for such use by FDA, or if under an investigational new drug
application (IND) or investigational device exemption (IDE), is
exempted for such use by FDA, within 45 calendar days after the donor
tests reactive for evidence of HIV infection under Sec. 610.40(a) and
(b) of this chapter. Notification of consignees must include the test
results for blood and blood components identified under paragraph
(a)(1) of this section that were previously collected from donors who
later test reactive for evidence of HIV infection.
(4) You must release from quarantine, destroy, or relabel
quarantined in-date blood and blood components, consistent with the
results of the supplemental (additional, more specific) test performed
under paragraph (a)(2) of this section or the results of the reactive
screening test if there is no available supplemental test that is
approved for such use by FDA, or if under an IND or IDE, exempted for
such use by FDA.
(b) If you are a consignee of Whole Blood or blood components,
including Source Plasma and Source Leukocytes, you must establish,
maintain, and follow an appropriate system for the following actions:
(1) You must quarantine all previously collected in-date blood and
blood components identified under paragraph (a)(1) of this section,
except pooled blood components intended solely for further
manufacturing into products that are manufactured using validated viral
clearance procedures, when notified by the collecting establishment.
(2) You must release from quarantine, destroy, or relabel
quarantined in-date blood and blood components consistent with the
results of the supplemental (additional, more specific) test performed
under paragraph (a)(2) of this section, or the results of the reactive
screening test if there is no available supplemental test that is
approved for such use by FDA, or if under an IND or IDE, is exempted
for such use by FDA.
(3) When the supplemental (additional, more specific) test for HIV
is positive or when the screening test is reactive and there is no
available supplemental test that is approved for such use by FDA, or if
under an IND or IDE is exempted for such use by FDA, you must notify
transfusion recipients of previous collections of blood and blood
components at increased risk of transmitting HIV infection, or the
recipient's physician of record, of the need for recipient HIV testing
and counseling. You must notify the recipient's physician of record or
a legal representative or relative if the recipient is a minor,
deceased, adjudged incompetent by a State court, or, if the recipient
is competent but State law permits a legal representative or relative
to receive information on behalf of the recipient. You must make
reasonable attempts to perform the notification within 12 weeks after
receiving the supplemental (additional, more specific) test results for
evidence of HIV infection from the collecting establishment, or after
receiving the donor's reactive screening test result for HIV if there
is no available supplemental test that is approved for such use by FDA,
or if under an IND or IDE is exempted for such use by FDA.
(c) Actions under this section do not constitute a recall as
defined in Sec. 7.3 of this chapter.
0
7. Section 610.47 is revised to read as follows:
Sec. 610.47 Hepatitis C virus (HCV) ``lookback'' requirements.
(a) If you are an establishment that collects Whole Blood or blood
components, including Source Plasma and Source Leukocytes, you must
establish, maintain, and follow an appropriate system for the following
actions:
(1) Within 3 calendar days after a donor tests reactive for
evidence of hepatitis C virus (HCV) infection when tested under Sec.
610.40(a) and (b) of this chapter or when you are made aware of other
reliable test results or information indicating evidence of HCV
infection, you must review all records required under Sec. 606.160(d)
of this chapter, to identify blood and blood components previously
donated by such a donor. For those identified blood and blood
components collected:
(i) Twelve months and less before the donor's most recent
nonreactive screening tests, or
(ii) Twelve months and less before the donor's reactive direct
viral detection test, e.g., nucleic acid test and nonreactive antibody
screening test, whichever is the lesser period, you must:
(A) Quarantine all previously collected in-date blood and blood
components identified under paragraph (a)(1) of this section if
intended for use in another person or for further manufacture into
injectable products, except pooled blood components intended solely for
further manufacturing into products that are manufactured using
validated viral clearance procedures; and
(B) Notify consignees to quarantine all previously collected in-
date blood and
[[Page 48800]]
blood components identified under paragraph (a)(1) of this section if
intended for use in another person or for further manufacture into
injectable products, except pooled blood components intended solely for
further manufacturing into products that are manufactured using
validated viral clearance procedures;
(2) You must perform a supplemental (additional, more specific)
test for HCV as required under Sec. 610.40(e) on the reactive
donation.
(3) You must notify consignees of the supplemental (additional,
more specific) test results for HCV, or the results of the reactive
screening test if there is no available supplemental test that is
approved for such use by FDA, or if under an investigational new drug
application (IND) or investigational device exemption (IDE), is
exempted for such use by FDA, within 45 calendar days after the donor
tests reactive for evidence of HCV infection under Sec. 610.40(a) and
(b). Notification of consignees must include the test results for blood
and blood components identified under paragraph (a)(1) of this section
that were previously collected from donors who later test reactive for
evidence of HCV infection.
(4) You must release from quarantine, destroy, or relabel
quarantined in-date blood and blood components consistent with the
results of the supplemental (additional, more specific) test performed
under paragraph (a)(2) of this section, or the results of the reactive
screening test if there is no available supplemental test that is
approved for such use by FDA, or if under an IND or IDE, exempted for
such use by FDA.
(b) If you are a consignee of Whole Blood or blood components,
including Source Plasma or Source Leukocytes, you must establish,
maintain, and follow an appropriate system for the following actions:
(1) You must quarantine all previously collected in-date blood and
blood components identified under paragraph (a)(1) of this section,
except pooled blood components intended solely for further
manufacturing into products that are manufactured using validated viral
clearance procedures, when notified by the collecting establishment.
(2) You must release from quarantine, destroy, or relabel
quarantined in-date blood and blood components, consistent with the
results of the supplemental (additional, more specific) test performed
under paragraph (a)(2) of this section, or the results of the reactive
screening test if there is no available supplemental test that is
approved for such use by FDA, or if under an IND or IDE, is exempted
for such use by FDA.
(3) When the supplemental (additional, more specific) test for HCV
is positive or when the screening test is reactive and there is no
available supplemental test that is approved for such use by FDA, or if
under an IND or IDE, is exempted for such use by FDA, you must notify
transfusion recipients of previous collections of blood and blood
components at increased risk of transmitting HCV infection, or the
recipient's physician of record, of the need for recipient HCV testing
and counseling. You must notify the recipient's physician of record or
a legal representative or relative if the recipient is a minor,
adjudged incompetent by a State court, or if the recipient is competent
but State law permits a legal representative or relative to receive
information on behalf of the recipient. You must make reasonable
attempts to perform the notification within 12 weeks after receiving
the supplemental (additional, more specific) test results for evidence
of HCV infection from the collecting establishment, or after receiving
the donor's reactive screening test result for HCV if there is no
available supplemental test that is approved for such use by FDA, or if
under an IND or IDE, is exempted for such use by FDA.
(c) Actions under this section do not constitute a recall as
defined in Sec. 7.3 of this chapter.
0
8. Section 610.48 is added to subpart E to read as follows:
Sec. 610.48 Hepatitis C virus (HCV) ``lookback'' requirements based
on review of historical testing records.
(a) Establishments that collect Whole Blood or blood components,
including Source Plasma and Source Leukocytes, must complete the
following actions by February 19, 2009.
(b) If you are an establishment that collects Whole Blood or blood
components, including Source Plasma and Source Leukocytes, you must
establish, maintain, and follow an appropriate system for the following
actions:
(1) You must:
(i) Review all records of donor testing for hepatitis C virus (HCV)
performed before February 20, 2008. The review must include records
dating back indefinitely for computerized electronic records, and to
January 1, 1988, for all other records. Record review, quarantine,
testing, notification, and disposition performed before February 20,
2008 that otherwise satisfy the requirements under Sec. 610.47, are
exempt from this section.
(ii) Identify donors who tested reactive for evidence of HCV
infection. Donors who tested reactive by a screening test and negative
by an appropriate supplemental (additional, more specific) test under
Sec. 610.40(e) for evidence of HCV infection on the same donation are
not subject to further action.
(iii) Identify the blood and blood components previously collected
from such donors:
(A) Twelve months and less before the donor's most recent
nonreactive screening tests, or
(B) Twelve months and less before the donor's reactive direct viral
detection test, e.g., nucleic acid test and nonreactive antibody
screening test, whichever is the lesser period.
(2) If you did not perform a supplemental (additional, more
specific) test at the time of the reactive donation, you may perform a
supplemental test or a licensed screening test with known greater
sensitivity than the test of record using either a frozen sample from
the same reactive donation or a fresh sample from the same donor, if
obtainable. If neither is available, proceed with paragraphs (b)(3),
(b)(4), and (b)(5) of this section.
(3) You must, within 3 calendar days after identifying the blood
and blood components previously collected from donors who tested
reactive for evidence of HCV infection:
(i) Quarantine all previously collected in-date blood and blood
components identified under paragraph (b)(1)(iii) of this section if
intended for use in another person or for further manufacture into
injectable products, except pooled components solely intended for
further manufacturing into products that are manufactured using
validated viral clearance procedures.
(ii) Notify consignees to quarantine all previously collected in-
date blood and blood components identified under paragraph (b)(1)(iii)
of this section if intended for use in another person or for further
manufacture into injectable products, except pooled blood components
intended solely for further manufacturing into products that are
manufactured using validated viral clearance procedures; and
(iii) Notify consignees of the donor's test results, including the
results of a supplemental (additional, more specific) test or a
licensed screening test with known greater sensitivity than the test of
record, if available at that time.
(4) You must notify consignees of the results of the supplemental
(additional, more specific) test or the licensed screening test with
known greater sensitivity than the test of record for
[[Page 48801]]
HCV, if performed, within 45 calendar days of completing the further
testing. Notification of consignees must include the test results for
blood and blood components identified under paragraph (b)(1)(iii) of
this section that were previously collected from a donor who later
tests reactive for evidence of HCV infection.
(5) You must release from quarantine, destroy, or relabel
quarantined in-date blood and blood components consistent with the
results of the further testing performed under paragraph (b)(2) of this
section or the results of the reactive screening test if there is no
available supplemental test that is approved for such use by FDA, or if
under an investigational new drug application (IND) or investigational
device exemption (IDE), is exempted for such use by FDA.
(c) If you are a consignee of Whole Blood or blood components,
including Source Plasma and Source Leukocytes, you must establish,
maintain, and follow an appropriate system for the following actions,
which you must complete within 1 year of the date of notification by
the collecting establishment:
(1) You must quarantine all previously collected in-date blood and
blood components identified under paragraph (b)(1)(iii) of this
section, except pooled blood components solely intended for further
manufacturing into products that are manufactured using validated viral
clearance procedures, when notified by the collecting establishment.
(2) You must release from quarantine, destroy, or relabel
quarantined in-date blood and blood components, consistent with the
results of the further testing performed under paragraph (b)(2) of this
section, or the results of the reactive screening test if there is no
available supplemental test that is approved for such use by FDA, or if
under an IND or IDE is exempted for such use by FDA.
(3) When the supplemental (additional, more specific) test for HCV
is positive; or the supplemental test is indeterminate, but the
supplemental test is known to be less sensitive than the screening
test; or the screening test is reactive and there is no available
supplemental test that is approved for such use by FDA, or if under an
IND or IDE, is exempted for such use by FDA; or if supplemental testing
is not performed, you must make reasonable attempts to notify
transfusion recipients of previous collections of blood and blood
components at increased risk of transmitting HCV infection, or the
recipient's physician of record, of the need for recipient HCV testing
and counseling. You must notify the recipient's physician of record or
a legal representative or relative if the recipient is a minor,
adjudged incompetent by a State court, or if the recipient is competent
but State law permits a legal representative or relative to receive
information on behalf of the recipient.
(d) Actions under this section do not constitute a recall as
defined in Sec. 7.3 of this chapter.
(e) This section will expire on August 24, 2015.
Dated: July 5, 2007.
Jeffrey Shuren,
Assistant Commissioner for Policy.
[FR Doc. E7-16607 Filed 8-23-07; 8:45 am]
BILLING CODE 4160-01-S