HIV AIDS Resource Guide/HIV-AIDS Resource Guide.iso/STAT/PROP_FED/CFR-2ABC.ASC

Text File | 1993-01-14 | 57KB | 1,061 lines

/* This contains the proposed amendments to federally mandated
"Current Good Manufacturing Practices" in handling blood, as of
Autumn 1993. */


DEPARTMENT OF HEALTH AND  HUMAN SERVICES
Food and Drug Administration
21 CFR PARTS 606 AND 610
[DOCKET No. 91N-0152]
RIN 0905-AC90

Current Good Manufacturing Practices  for Blood and Blood
Components;  Notification of Consignees Receiving  Blood and
Blood Components at  increased Risk for Transmitting HIV
infection

AGENCY:   Food and Drug Administration,  HHS
ACTION:   Proposed rule.

SUMMARY: The Food and Drug Administration (FDA) is proposing to
amend the biologics regulations to require that blood
establishments prepare and follow written procedures when the
blood establishments have collected blood and blood components
that are potentially contaminated with human immunodeficiency
virus (HIV). This proposal would require that when a donor who
previously donated blood subsequently is tested for HIV in
accordance with 21 CFR 610.45, and tests repeatably reactive for
antibody to HIV, a blood establishment shall perform more
specific testing using a licensed test, and notify consignees who
received such blood so that appropriate action is taken. Blood
establishments and consignees would also be required to
quarantine previously collected blood and blood components from
such donors. FDA is also proposing that certain transfusion
services take steps to notify transfusion recipients. FDA is
proposing these rules to help ensure the continued safety of the
blood supply, to help ensure that information is provided to
users of blood and blood components and to help ensure that
transfusion recipients of potentially contaminated blood and
blood components may be notified as appropriate. These procedures
are commonly referred to as "look-back" rules.

DATES: Written comments by August 30, 1993. FDA proposes that any
final rule based on this proposal be effective 60 days after date
of publication of the final rule.

ADDRESSES: Written comments to the Dockets Management Branch (HFA
-205). Food and Drug Administration, rm 1-23, 12420 Parklawn Dr.,
Rockville, MD 20857.

FOR FURTHER INFORMATION CONTACT: Paula McKeevor, Food and Drug
Administration, Center for Biologics Evaluation and Research (HFM-
6 35), 1401 Rockville Pike, Rockville, MD 20859-1448, 301-295-
9074.

SUPPLEMENTARY INFORMATION:

I.   Introduction  Part 606 (21 CFR part 606) contains current
good manufacturing practices (CGMP's) for blood establishments
designed to help ensure the continued safety, purity, potency,
and efficacy of blood and blood components. The regulations in
this part apply to both licensed and unlicensed blood
establishments. Blood establishments include human blood and
plasma donor centers, blood banks, transfusion services, other
blood product manufacturers and independent laboratories that
engage in quality control and testing for registered blood
product establishments (21 CFR 607.3(c)). Consignees are included
in the definition of blood establishments. In addition, part 610
(21 CFR part 610) provides rules and testing standards generally
applicable to biological products, including blood and blood
components.
HIV is the virus that causes acquired immunodeficiency syndrome
(AIDS) a communicable disease that can be transmitted through
blood and blood components contaminated with HIV. FDA has
implemented an extensive system of additional testing and donor-
screening procedures, performed before, during, and after
donation takes place, to help prevent the transfusion of blood
components that are potentially contaminated with HIV. Beginning
in 1983, the Public Health Service (PHS) issued recommendations
that individuals who engaged in high risk practices for AIDS
voluntarily refrain from donating blood or plasma. See Morbidity
and Mortality Weekly Report (MMWR), 32:101-103, 1983. Beginning
in 1985, FDA licensed kits to test for antibody to HIV, and blood
banks began testing units of blood and blood components for
antibody to HIV (ref. 1). Since 1988, FDA has required that units
of blood and blood components be tested for antibody to HIV using
licensed tests (21 CFR 610.45). Since 1986, confidential unit
exclusion and donor history interviews have become a routine part
of the donation procedure, so that donors may indicate
confidentially if their units should be excluded from the blood
supply. FDA's recommendations regarding these procedures have
been revised periodically as additional information regarding the
epidemiology of HIV has become available. The most recent
recommendation was issued to all registered blood establishments
on December 5, 1990 (ref. 2). These procedures are designed to
help ensure the continued safety of the blood supply.
As a result of this effort, the possibility of transmitting HIV
through blood transfusion has decreased significantly. Within the
last 3 years, the risk of HIV transmission via blood transfusion
has been estimated to be between 1 in 38,000 and 1 in 153,000.
[footnote 1] However, it remains possible, despite the best
practices of a blood establishment, that a person might donate
blood early in infection, during the "window" period, when the
HIV antibody test remains negative but HIV is present in the
person's blood. Accordingly, a recipient of such a donation may
not know that he or she may have become infected with HIV. If the
same donor attempts to donate blood at a later date, the test for
antibody to HIV then may be repeatably reactive. FDA and the
Health Care Financing Administration (HCFA) are proposing steps
designed to further protect the blood supply and to notify
recipients of the possibility that they may have received blood
products contaminated with HIV. FDA's proposal, along with HCFA's
proposal published elsewhere in this Federal Register, would
require facilities involved in the collection, processing, and
administration of blood to quarantine certain blood and blood
components and to inform the consignee, and, as appropriate, the
recipient's attending physician or the recipient, of the
possibility that blood previously used for transfusion was
obtained from a donor who subsequently tested repeatably reactive
for antibody to HIV. These rules would result in transfusion
recipients receiving information so they can be tested for
evidence of HIV infection, receive early treatment, if indicated,
and take appropriate precautions to prevent the further spread of
the virus.
Under certain circumstances, PHS has already encouraged direct
notification of transfusion recipients at increased risk for HIV
Infection. In the MMWR of March 20, 1987, PHS recommended testing
and counseling for individuals who received multiple transfusions
of unscreened blood in areas with a high incidence of AIDS. A
number of blood centers and transfusion services have attempted
direct notification by letter of all patients who received
transfusions between 1977 and 1985. Data collected from these
efforts indicate that sweeping notification of a group of
recipients is extremely resource-intensive, and particularly
where recipients are unaware of donors' risk factors, recipients
are not motivated to respond and the effort is not very
effective. [footnote 2] A 1988 PHS mailing of AIDS information to
all the nation's households included a notification of the need
for testing for antibody to HIV for patients who received a
transfusion between the years 1977 and 1986. MMWR. 37:261-269,
1988. FDA believes that these proposed rules, in conjunction with
those being proposed by HCFA elsewhere in this Federal Register,
will provide a more efficient means of notification.[footnote 3]
II.  Coordination Between HHS Agencies
A.   Memorandum of Understanding
In a memorandum of understanding (MOU), FDA and HCFA agreed to
coordinate the Inspections of blood banks and transfusion
services to minimize duplication of effort and to reduce the
burden on affected facilities. In the MOU, it was estimated that
HCFA would be responsible for inspecting and surveying
approximately 3,000 transfusion services. FDA continues to
conduct the inspections of establishments where activities
include more than the performance of compatibility testing. (See
49 FR 34448 (August 31,1984), 21 CFR 607.65.)
B.   Locating Blood Donors
The Social Security Administration operates a Blood Donor Locater
Service (BDLS) to enable States and authorized blood donation
facilities to notify blood donors whose donations indicate that
they are or may be infected with HIV. Section 205(c)(2)(D) of the
Social Security Act (42 U.S.C. 405(c)(2)(D)) permits states to
require a blood donor to furnish his or her social security
number (SSN) to a State agency or to an authorized blood donation
facility. With the SSN, an authorized blood donation facility may
request the State to contact the BDLS to obtain the donor's
mailing address. The State agency may also make a request on its
own behalf for this information to the BDLS.
C.   Summary of the Proposed Rules of HCFA and FDA
Under proposed 606.100(b)(19) and 610.46(a), an establishment
would be required to quarantine, and to notify the consignees
regarding the need to quarantine, certain blood and blood
components previously collected from a donor who subsequently
tests repeatably reactive for antibody to HIV. The proposed rule,
would also require consignees to quarantine such products. Under
proposed 610.46(b), in situations in which blood establishments
distributed such units, blood establishments would be required to
test by a licensed, more specific test, the donor's blood sample
from the current donation that tested repeatably reactive. Blood
establishments would be required to notify the consignees of the
results of the licensed, more specific test. If the licensed,
more specific test result is negative, the units from prior
collections are regarded as negative for antibody to HIV, and the
prior collections, which previously tested negative, may be
released from quarantine under proposed 610.46(c). If the
licensed, more specific test result is positive or indeterminate,
the units from prior collections may not be released from
quarantine. The blood establishment would be required to dispose
of extant products located at the establishment and to notify the
consignees of the test result and of the need for the appropriate
disposal of extant products. The general requirements for
disposal of unsuitable products would apply to the specific
situation where a product does not qualify for release from
quarantine under this proposal. FDA has provided guidance to
establishments for disposal of unsuitable products (ref. 3). If
the licensed, more specific test result is positive, the blood
establishment would be required to report the positive result to
consignees that received units from prior collection, so that
steps are taken to initiate notification of the attending
physicians of transfusion recipients.
Under proposed 606.160 (b) (1) (vii) FDA would amend its
biologics regulations to require blood establishments to prepare
and maintain records so that previous donations from a donor
could be identified, and to keep records of the look-back
process. As with other records related to recipient health and
donor suitability, the confidentiality of such donor and
recipient records should be protected, consistent with evolved
practices, standard operating procedures (SOP's), generally-
recognized policies and expectations, and local, State, and
Federal requirements.
Under HOFA's proposed rule, issued elsewhere in this Federal
Register, transfusion services or other blood establishments
inspected by HOFA that are notified by a blood establishment that
a donor of blood products shipped to them for transfusion
subsequently has tested positive by a licensed, more specific
test for antibody to HIV would be required to notify the
recipient's attending physician, the recipient, or other
authorized person, as appropriate. HCFA has proposed to require
the transfusion service to have a written agreement with each
blood supplier documenting these procedures. We are especially
interested in receiving comments on whether this proposed
requirement would be more appropriately implemented as part of
the FDA requirements applicable to blood banks or in the manner
proposed, as part of a medicare hospital standard. Under FDA's
proposed rule, transfusion services inspected by FDA that are so
notified also would be required to notify the recipient's
attending physician, the recipient, or other authorized person as
appropriate.
The agencies are taking these actions to address blood safety
issues affecting transfusion recipients who may be at increased
risk for HIV infection, and to restrict the use of potentially
infectious blood and blood components in the manufacture of
injectable and noninjectable blood products.
III. FDA'S proposed Rule
Under the biologics licensing and quarantine provisions of the
Public Health Service Act (42 U.S.C. 262-264)  and the drug,
device, and the general administrative provisions of the Federal
Food, Drug, and Cosmetic Act (the act) (21 U.S.C. 351-353,
355360, 371-374), FDA has the authority to promulgate regulations
to protect the public from unsafe or ineffective biological
products and to promulgate regulations necessary to prevent the
transmission of communicable diseases into the United States or
from one State to another.
Under these statutory authorities, FDA currently requires that
each donation of blood intended for transfusion, or for use in
preparing a product, be tested and found negative or antibody to
HIV under 810.45 (21 CFR 610.45). Existing regulations already
restrict the use, for transfusion or for manufacture, of a
donation testing repeatably reactive. Although current screening
tests for antibody to HIV are very sensitive, antibody testing
may not identify all blood units capable of transmitting
infection. For this reason, many blood establishments have
instituted special precautions when blood has been collected and
the donor later tests repeatably reactive for antibody to HIV.
These procedures involve determining the suitability of prior
collections of blood and blood components from that donor. These
procedures also may involve notifying consignees that have
received prior collections from the donor so consignees may
arrange to determine the suitability of such units, and, if
appropriate, may take steps so that recipients of transfusions of
those units are notified. These procedures are generally referred
to as "look-back."
This proposal would require blood establishments, including
consignees, to take certain actions when donors subsequently show
evidence of antibody to HIV. These actions include quarantining
units from prior collections pending a determination of the
suitability of the units, notifying consignees of such units of
the need for quarantine, and maintaining records regarding the
quarantine and notification. Below is a discussion of the
specific provisions of the proposed rules, beginning with a
discussion of certain terms used in the rules.
A.   The Term "HIV"
Throughout the proposed rule, FDA uses the term "HIV" to refer to
HIV-1, the principal virus associated with AIDS in the United
States, and HIV-2, a closely related virus, also associated with
AIDS. HIV-2 has been found in other parts of the world, but is
found only very rarely in the United States. A licensed test is
also available that can detect antibody to HIV-1. The licensed
test for antibody to HIV-1 may give repeatably reactive results
based on cross-reactivity from antibody to HIV-2, but the current
HIV-1 tests do not distinguish between antibody to HIV-1 and
antibody to HIV-2. FDA is using the more general term "HIV" to
require quarantine and notification regardless of whether the
establishment has determined that the antibody detected is to HIV-
1 or HIV-2.
B.   The Term "Repeatably Reactive for Antibody to HIV"  Based on
FDA's extensive experience with blood establishments, including
annual inspections, FDA believes that the current practice of
blood establishments Is to screen blood donations with licensed
Enzyme Immunoassay (EIA) tests, which detect antibody to HIV. The
preamble describes how look-back is to be implemented when an
establishment uses licensed EIA tests for donor screening. EIA
test results are either negative or repeatably reactive. If the
results are negative. the blood and blood components are suitable
for use. If the EIA test result is repeatably reactive, then the
product is not suitable for use. Establishments then perform
licensed Western Blot testing for the purpose of determining the
suitability of previously collected units, or for the purpose of
counseling the donor.  Although  establishments currently use
licensed Eia tests in accordance with 21 CFR 610.45(a)(1), other
tests may be-approved for use under 21 CFR 610.45(a)(2). It Is
possible that as - technology advances, and if other tests become
practical for use as screening tests, establishments may seek FDA
approval of other tests for donor screening purposes. This
proposed rule, like 21 CFR 610.45, is flexible enough to provide
for the use of other approved screening tests whether or not they
detect HIV antibody. As other tests are approved for screening
purposes. FDA will provide guidance on the look-back program
using those test technologies.
C.   The Term "Promptly"
In proposed  010.46(a), FDA is proposing that specified actions
be performed "promptly" rather than specifying time limits for
performing the various steps of the look-back program.  For an
establishment with existing records on a computerized database,
checking records of previous donations to identify the date
products were collected, the date the last negative screening
test was performed, and to whom the products were distributed
often can be performed concurrently with the recording of the
donor's repeatably reactive test results. However, for an
establishment without this capability. the determination may take
longer. Likewise, for a facility that performs licensed, more
specific tests on site, the test results may be available more
quickly than for a facility that sends samples for testing to an
outside laboratory. FDA Is using the general term "promptly" in
order to recognize that differences will exist. However, within 2
weeks after the donor's repeatably reactive test, the
establishment should have the results of the more specific
testing. and FDA is proposing a 2-week limit in which the
establishment would be required to perform the test and notify
consignees of the results. As discussed later in this preamble,
the written SOP's of each blood establishment should address the
time limits for performing each significant step of its look-back
program If the blood establishment is unable to meet the time
limits prescribed in the SOP's for a specific task, the reasons
for that deviation should be described in the establishment's
records. It is within the blood establishment's  customary
practices to perform testing. to arrange or appropriate action
based on test results, and to maintain contact with consignees
regarding. among other things. the quality of the product and
services. The agency can estimate reasonable time limits based on
this experience, and such time limits can be imposed for these
activities. However, FDA is not proposing time limits for the
notification of recipients but is relying on HCFA's expertise in
the area of hospital practice. Consistent with HCFA's proposed
rule, published elsewhere In this issue of the Federal Register.
FDA believes that the hospital's notification effort should
consist of, at the minimum, several attempts by phone or in
writing to reach the attending physician or the recipient. The
hospital's notification effort should begin Immediately after
receiving word from the blood hank. and should be completed 8
weeks later. FDA would require that the hospital document the
attempts to notify the recipient and indicate whether the
recipient was located. FDA specifically invites public comment on
the sufficiency of this level of effort. The agency believes that
the chain of notification about the potentially infectious blood
and/or  blood products should be from the hospital to the
recipient's attending physician (physician of record), and that
only in rare situations would the reciient receive this
notification from the hospital. FDA invites comment as to whether
a regulation describing the mechanics of this notification is
necessary and whether additional explanation is necessary to
identify when the hospital should directly notify the recipient.
The agency believes this proposed rule is self-explanatory, but
that a stated timeframe may be necessary to determine when the
recipient should be notified by the hospital if the attending
physician cannot be reached by telephone.
D. Amendments to Part 66 -- Current Good Manufacturing Practice
for Blood and Blood Components
Under 21 CFR part 606, FDA provides CGMP regulations for licensed
and unlicensed blood establishments to help ensure the continued
safety, purity, potency, and efficacy of blood and blood
components. To Implement the look-back program, FDA proposes to
amend the CGMP regulations regarding written SOP's and records.

1.   Standard Operating Procedures
FDA proposes  adding new paragraph (b) (19) to 606.100.  Proposed
606.100(b)(19) would require that establishments have written
procedures to look-back at prior donations of blood and blood
products from a donor who has previously donated blood and
subsequently tests repeatably reactive for antibody to HIV when
tested in accordance with 610.45. The written procedures would be
required to describe in detail how obligations under this section
would be met. The written SOP's would be required to include
procedures to quarantine in-house blood and blood components,
including Source Plasma and Recovered Plasma, and products
intended for research, whether intended for transfusion or
further manufacture, that were obtained from such donors.
Consignees are blood establishments, and for clarity the proposed
rule provides a separate, express provision requiring consignees
to quarantine such products. The written SOP's also would be
required to include procedures to notify consignees regarding the
need to quarantine such products; procedures to determine the
suitability for release of such products held in quarantine;
procedures to notify consignees of blood and blood components
from such donors of the results of the suitability determination;
and procedures to determine the proper disposition of the
products as approriate. The written procedures should include
timeframes for meeting each obligation; they should also include
a list of persons authorized to provide and receive notification.

2.   Records

FDA proposes adding new paragraphs (b)(1)(vii) and (b)(1)(viii)
to  606.160. Proposed  606.160(b)(1)(vii) would require that an
establishment's records be organized in a manner to readily
relate a donor with the unit number of each donation from that
donor. Many establishments already organize records in this
manner to implement existing programs regarding look-back, donor
deferrals, recruitment of previous donors, record transfer to
computer data banks, and recordkeeping efficiency. FDA is aware,
however, that some blood establishments, using their current
recordkeeping systems, are unable to readily determine the
complete history of donations, including the unit numbers of the
blood collected, from a specific donor. Some blood
establishments, particularly small blood establishments, have
organized information on blood donors by other systems, such as
by the date of donation, which would not readily accommodate the
proposed look-back procedures. FDA does not propose to require
that blood establishments reorder and rerecord all previous
information, but proposes that new information be entered on
recordkeeping systems that are suitably modified by the proposed
effective date. Upon the effective date of the final rule, to the
extent that prior recordkeeping systems exist that relate a donor
with each previous donation, FDA proposes that an establishment
would be required to review its records to identify units for
quarantine and consignee notification under proposed
606.160(b)(1)(vii). Beginning with the effective date of the
final rule, FDA proposes to require that donor information be
recorded in a manner to readily relate a donor with the unit
number of each donation from that donor.
Under proposed  606.160(b)(1)(viii), FDA would require that
records be kept documenting  the quarantine, consignee
notification, testing, and disposition of products requred under
proposed 610.46(a) and (b). FDA is not proposing at this time
specific requirements regarding methods for notification, such as
whether notification must be performed in writing by facsimile or
overnight mail, certified mail, regular mail, or orally by
telephone. The means of notification should be set under each
blood establishment's written SOP. However, regarding the
information included about the notification, for both initial and
followup contacts, the proposed notification records should
identify all persons who gave and received the notification, the
dates and times of notification, the types and unit numbers of
all blood and blood components which are the subject of the
notification, the dates that the donor tested repeatably
reactive, the dates and results of more specific testing, and
other information regarding the notification event. As with
similar records related to recipient health and donor
suitability, strict confidentiality of these records should be
maintained.

E. Amendments to Part 610 - General Biological Products Standards

Under proposed  610.46(a), when a blood donor tests repeatably
reactive for antibody to HIV, an establishment would be required
to quarantine units collected from this donor within the past 5
years if intended for transfusion, and to quarantine units
collected within the past 6 months if intended for further
manufacture. The blood establishment would be required to
promptly notify consignees who would also be required to
quarantine such products.

Under proposed  610.46(b), if a blood establishment  distributed
such units, the blood establishment would be required to perform
a licensed, more specific test for antibody to HIV. Within 2
weeks after the donor's repeatably reactive test, the blood
establishment would be reguired to notify the consignees of the
results of the licensed, more specific test: Whether positive,
indeterminate, negative, or unavailable. Proposed  610.46(c)
provides specific circumstances for the release of products from
quarantine based on the evaluation of the test result. FDA
intends that these proposed requirements apply to blood and blood
components intended for transfusion or further manufacture,
including blood and blood components intended for research use.
Thus, establishments would be required to meet the standards for
all blood and blood components intended for transfusion or for
further manufacture, as applicable.

Under existing  610.45, blood and blood components, including
plasma, that are repeatably reactive to a test for antibody to
HIV are subject tc restrictions on use, regardless of the results
of subsequent testing. FDA does not propose that the units
testing repeatably reactive would be releasable if the results of
more specific testing are negative. The units that would be
releasable under this proposed rule are only those blood and
blood components from revious donations that have been tested and
found negative for antibody to HIV; FDA does not propose to amend
the restrictions in  610.45. Products collected at the time the
donor tests repeatably reactive must not be reissued for any
purpose, except as provided in  610.45(c). Additionally, FDA does
not propose to change the recommendations restricting the reentry
of donors whose screening test results are repeatably reactive.
The current procedures for donor reentry were provided by FDA in
its memorandum to all blood establishments of December 5, 1990
(Ref. 2). FDA proposes to amend  610.45 for clarity, to refer to
the requirements of  610.46 and 610.47. HCFA regulations
expressly reference  610.45, therefore, an express referral in
610.45 to 610.46 and 610.47 will facilitate HCFA-regulated
facilities in recognizing all requirements related to the test
for antibody to HIV.

1. Quarantine and Notification Procedure

Proposed  610.46 would require quarantine of previously collected
products and notification of consignees in specified
circumstances. FDA proposes that blood establishments be required
to follow, at a minimum, the precautions listed below, and that
they are performed promptly when a previous donor of blood and
blood components subsequently tests repeatably reactive for
antibody to HIV:
a.   Quarantine and notification of consignees for blood and
blood components intended for transfusion. Under  610.46 (a), FDA
proposes to require blood establishments to quarantine previously
collected blood and blood components intended for transfusion
that have been collected during the time period from the present
extending back 5 years, or, if there is a record of the donor's
last licensed negative test for antibody to HIV which had been
performed in accordance with 610.45, then back to the time 12
months before such test. Proposed  610.46(a) would also require
blood establishments to notify consignees so that such products
are appropriately quarantined.

b.   Quarantine and notification of consignees for blood and
blood components intended for further manufacture. Also under
610.46(a), FDA proposes to require blood establishments to
identify and quarantine all units in inventory intended for
further manufacture, including Source Plasma and Recovered
Plasma, that have been collected during the time period from the
present extending back to the time 6 months prior to the
repeatably reactive test. Proposed  610.46(a) would also require
blood establishments to notify consignees regarding the need to
quarantine unpooled units that were collected within the past 6
months.

Blood, blood components, and Source Plasma intended for further
manufacture are pooled quickly and are unlikely to be available
after 6 months. In addition, they are subjected to further
manufacturing steps in making various final products. The
proposed rule would require collecting establishments to
quarantine products intended for further manufacture that have
been pooled by the establishment but not yet shipped to a
consignee. These pools are more often small and their quarantine
provides an additional margin of safety without negatively
affecting the availability of the blood product. FDA also
proposes a requirement to notify consignees so they may
quarantine products intended for manufacture. FDA is not
proposing to require consignees to quarantine products pooled by
the consignee as a preliminary step for further manufacture,
because these are often large pools, comprising a thousand units
or more, and their diversion could have serious consequences on
the availability of blood products.

In addition, products manufactured from blood and blood
components, including plasma, undergo further manufacturing steps
so the final products are treated in such a manner to prevent the
transmission of HIV. Some method to inactivate viral contaminants
is used in the manufacture of all such products. The most common
practice for treating blood and blood products is heat
inactivation treatment. FDA thoroughly reviews the methods
proposed by manufacturers in establishment and product license
applications and amendments and evaluates the effectiveness of
these methods before approving any methods. FDA also reviews
epidemiologic evidence, which has also established that these
treatment processes reduce the risk of HIV Infection from these
products.

2. Testing and Notification of Consignees
Proposed  610.46(b) would apply in situations involving a donor
who subsequently tests repeatedly reactive, and would require
that for blood and blood components intended for transfusion or
for further manufacture which have been distributed, a blood
establishment must test the donor's blood for HIV by a licensed,
more specific test. This more specific test would be performed on
blood that is collected at the time the donor first tests
repeatably reactive for antibody to HIV; FDA is not proposing to
require more specific testing on each unit in quarantine. Blood
establishments that have distributed prior units would be
required to notify the consignees of the results of the more
specific test within 2 weeks from tha date of the repeatably
reactive test. The consignee would rely on the results of the
licensed, more specific test to determine whether to notify
physicians of the recipients of prior transfusions, in accordance
with HCFA's and FDA's proposed rules, as well as to determine the
disposition of the products in quarantine.

3.   Release From Quarantine

Under proposed  610.46(c), units from previous donations would be
unsuitable for release from quarantine unless the result of the
licensed, more specific test for antibody to HIV is negative. If
the result of the licensed, more specific test is positive,
indeterminate, or not available within 2 weeks, then the units
must not be released from quarantine. Instead, the blood
establishment is responsible for notifying the consignee of the
results so that the units may be appropriately disclosed.

FDA notes that the procedures deecribed above have two related
but distinct objectives. First, the proposed procedures will help
ensure that blood and blood components that may be contaminated
with HIV are quarantined. This objective would be met by
following FDA's proposed requirements. The second objective
involves a joint effort between FDA and HCFA. FDA is proposing
regulations so that users of blood and blood components intended
for transfusion are provided with adequate information so that,
in compliance with HCFA's and FDA's proposed regulations, they
may notify the transfusion recipient's attending physician that
the blood or blood components may have been contaminated with
HIV.

4. Transfusion Services; Quarantine and Notification Requirements

Elsewhere In this issue of the Federal Register, HCFA has
proposed to require recipient notification for all hospitals that
participate in the Medicare program. HCFA's proposal does not
extend to hospitals and transfusion services that do not
participate in the Medicare program, so nonparticipating
establishments will not be subject to HCFA's proposed rule.
Because of the significant public health issue associated with
the look-back program,  including the need to notify transfusion
recipients so they can be tested, obtain early treatment if
needed, and prevent the further spread of this disease, FDA is
proposing  610.47, which would require all registered
establishments that do not participate in the Medicare program to
take steps to notify transfusion recipients. Proposed  610.47
would also require such facilities to take steps to quarantine
units collected from a donor who subsequently tests repeatably
reactive for antibody to HIV.

F. Other Reliable Indications That Donors Have Evidence of HIV
As proposed. the look-back procedures would be required only when
indicated by the results of testing performed by a blood
establishment. A blood establishment may receive information from
other sources, such as a State health department, a physician,
friends or relatives of a donor, or other blood establishments,
which indicate that a donor may be infected with HIV. The
availability of this information varies from State to State
because of differing State laws regarding the type, detail, and
restrictions on the use of this information, and because of
confidentiality issues. Because a blood establishment may not
receive such information consistently, nor may it be able to
readily evaluate the reliability of all types of information, at
this time FDA is not proposing additional circumstances under
which look-back would be required. FDA invites comment on whether
there are additional circumstances when a blood establishment can
reliably and consistently receive information that should result
in the required initiation of the look-back procedures included
in this proposed rule. FDA encourages blood establishments to
initiate look-back procedures whenever they have received
reliable information that a donor is infected with HIV.

G. Limitations on Temporal Requirements for look-back
FDA is proposing temporal limitations on the requirement for look-
back. If at the time the donor's blood Is first identified as
being repeatably reactive, it is known when the most recent
negative screening test was performed in accordance with 610.45,
units collected more than 12 months prior to the date of the last
negative screening test need not be quarantined. If the date of
the most recent negative screening test is not known, units
collected previously would be quarantined until the date can be
determined. As discussed in subparagraph 2 below, units collected
more than 5 years prior to the date of the repeatably reactive
test need not be quarantined. FDA is proposing that units
intended for further manufacture need not be held in quarantine
if collected more than 6 months prior to the donor's current
repeatably reactive test. The blood establishment would also
quarantine these previously collected units until the dates of
collection and previous negative test are determined.

1. Twelve Months Before the Date of the Repeatably Reactive Test
Previous donors of blood and blood components intended for
transfusion or further manufacture who have donated since
licensed testing became available, approximately in mid-1985,
should have tested negative for anti-HIV by a licensed test at
the prior donation. In rare cases, the donor may have tested
negative by that previous test while in the "window" period, a
time period usually less than 6 months during which time the
donor tests negative for HIV but may be infectious for the virus.
Based on experience, current estimates predict with approximately
95 percent confidence that in all cases of HIV infection, the
person will test positive for anti-HIV by a licensed test within
6 months from the date of infection (ref. 2). To provide an
additional margin of safety, FDA has extended the period for look-
back to 12 months, to more closely approximate a 99 percent
confidence interval. [footnote 4] Accordingly, FDA has
constructed the proposed look-back procedures so that  virtually
all donations collected during the "window" period are
appropriately included.
2. Five Years From the Date of the Repeatably Reactive Test
In accordance with Federal requirements, most records related to
blood donors and transfusion recipients are kept for 5 years. In
rare cases, the donor 's last negative screening test may have
occurred more than 4 years before the repeatably reactive test
result, so that the period 12 months prior to the donor's last
negative screening test would cover a time period for which
records may no longer be available. Under this proposal, look-
back will not be required to continue beyond 5 years prior to the
date of the donor's repeatably reactive test for anti-HIV for
several reasons:
(1) After 5 years. hospitals are not required to keep records
identifying transfusion recipients. so such transfusions may not
be traceable;
(2) High mortality exists among transfusion recipients for
reasons not directly related to the blood transfusion (because
transfusion recipients are often elderly and conditions requiring
transfusion are often life-threatening); the majority of
recipients will not survive beyond 5 years so attempts to notify
these recipients would be inefficient and ineffective;
(3) If HIV infection were present in a recipient's blood for 5
years, the recipient may be aware of the condition independently
without need for notification; and
(4) The program described in the MMWR of March 20, 1987, and in
the PHS mailing to every household in 1988, included a
notification of the need for followup testing for recipients of
transfusion before mid-1985.
3. Six Months After Collection of Products Intended for Further
Manufacture
Past experience has shown that blood, blood components, and
Source Plasma intended for further manufacture are pooled quickly
and subjected to further manufacturing steps in making various
final products. Accordingly, 6 months after collection, such
units are rarely, if ever, recoverable as single units or small
pools of units. Because the final products intended for
administration to humans and treated in such a manner to prevent
the transmission of HIV, as discussed above, and because after 6
months products from individual donors cannot be readily isolated
and quarantined, a 6 month-period is appropriate to help ensure
the continued safety of the blood supply while helping to ensure
the availability of safe and effective products.

IV.  Environmental Impact
The agency has determined under 21 CFR 25.24(c)(10) that this
proposed action is of a type that does not individually or
cumulatively have a significant effect on the human environment.
Therefore, neither an environmental assessment nor an
environmental impact statement is required.

V. Economic Assesement
The agency has examined the economic impact of this proposed rule
and has determined that it does not require either a regulatory
impact analysis, as specified in Executive Order  12291, or a
regulatory flexibility analysis, as specified in the Regulatory
Flexibility Act (Pub; L. 96354). The benefits of this rule to the
public are twofold. The primary purpose of the look-back
requirement is to reduce the risk of HIV infection through
transfusion of blood and blood components during the window
period, at wich time antibodies to the HIV virus in the donor are
not detectable through normal screening procedure. Notification
of consignees to quarantine potentially infected components,
until confirmatory testing is completed, will prevent any further
infection of the public. Once a donor has converted to HIV
positive, all recipients of previously donated components during
the potential window period can be notified, tested, and treated
before they begin to exhibit symptoms of infection. Spreading of
the virus can be retarded through early detection made possible
by this rule.

Most blood establishments already participate in a look-back
program. Ninety-five percent of blood establishments, collecting
98 percent of the nation's blood supply, already participate in a
look-back notification of their customers concerning units of
blood previously shipped that may be at increased risk of
transmitting HIV because the donor was later found to be
repeatably reactive. Thus, requirements for written procedures
and records of notification that apply to blood establishments
regulated by FDA, and that  relate only to blood units taken from
donors who later were found to be repeatably reactive, would
effect about 5 percent of blood establishments; the remaining 95
percent of blood establishments may need to make minor
adjustments in their procedures which FDA believes should only
have a minimal impact. FDA expects the total annualized cost of
this proposed rule on blood establishments to be $2,469,950. FDA
anticipates only a small number of cases per year which can be
traced to potentially infectious blood and therefore the need to
notify transfusion recipients will arise infrequently. FDA has
determined that the proposed rule is not a major rule as defined
in Executive Order 12291. Further, FDA certifies that the
proposed rule will not have a significant impact on a substantial
number of small business entities, as defined in the Regulatory
Flexibility Act.

V. Paperwork Reduction Act of 1980
This proposed rule contains information collections which are
subject to review by the Office of Management and Budget (OMB)
under the Paperwork Reduction Act of 1980. The title,
description, and respondent description of the information
collection are shown below with an estimate of the annual
reporting and recordkeeping burden. Included in the estimate is
the time for reviewing instructions, searching existing data
sources, gathering and maintaining the data needed, and
completing and reviewing the collection of information.

Title: Current Good Manufacturing Practices for Blood and Blood.
Components; Notification of Consignees Receiving Blood and Blood
Components at Increased Risk for Transmitting HIV Infection.

Description: This proposed rule would require that blood
establishments prepare and follow written procedures when the
blood establishments have collected blood and blood components
that are potentially contaminated with HIV. This proposal would
require that when a previous donor subsequently tests positive
for antibody to HIV, a blood establishment shall quarantine
previously collected blood, blood components, and plasma
collected from such donor, and notify consignees of such blood so
that appropriate action is taken. The agency is proposing these
rules to help ensure the continued safety of the blood supply, to
help ensure  that information is provided to users of blood and
blood components, and to help ensure that transfusion recipients
of potentially contaminated blood and blood components may be
notified as appropriate.

Description of Respondents: Blood establishments (Business and
Not-for-Profit).

/* CHART PCX HERE*/

These estimates are an approximation of the average time expected
to be necessary for a collection of information. They are based
on such information as is available to FDA. The agency seeks
comment on these estimates, particularly the industries' view of
the number of firms and products affected by the collections of
information contained in this proposed rule.

The agency will submit a copy of this proposed rule to OMB for
its review of these information collections. Interested persons
are requested to send comments regarding this burden  estimate or
any other aspect of this collection of information, including
suggestions for reducing this burden, to FDA's Dockets Management
Branch (address above), and to the Office of Information and
Regulatory Affairs, OMB, rm. 3208, New Executive Office Bldg.,
Washington, DC 20503, Attn: Desk Officer for FDA.

VII. Comments
Interested persons may, on or before August 30, 1993 submit to
the Dockets Management Branch (address above) written comments
regarding this proposal. Two copies of any comments are to be
submitted, except that individuals may submit one copy. Comments
are to be identified with the docket number found in brackets in
the heading of the document. Received comments may be Seen in the
office above between 9 a.m. and 4 p.m.. Monday through Friday.

VIII. References
The following references have been placed on display in the
Dockets Management Branch (address above) and may be seen by
interested persons between 9 a.m. and 4 p.m., Monday through
Friday.

1.   Memorandum to Registered Blood Establishments from the
Director, Office of Biologics Research and Review, July 22, 1985.

2.   Memorandum to Blood Establishments from the Director. Center
for Biologics Evaluation and Research, December 5, 1990.

3.   Memorandum to All Registered Blood Establishments from the
Director. Center for Biologics Evaluation and Research, April 6,
1988.

List of subjects

21 CFR Part 606
Blood, Labeling, Laboratories, Reporting and recordkeeping
requirements.

21 CFR Part 610
Biologics, Labeling, Reporting and recordkeeping requirements.

Therefore, under the Federal Food, Drug, and Cosmetic Act, the
Public Health Service Act, and the Administrative Procedure Act,
it is proposed that 21 CFR parts 606 and 610 be amended as
follows:

PART 6O6-CURRENT GOOD MANUFACTURING PRACTICE FOR BLOOD AND BLOOD
COMPONENTS

1. The authority citation for 21 CFR part 606 continues to read
as follows:

Authority: Secs. 201, 301, 501, 502, 505, 510, 520, 701, 704 of
the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321, 331,
351, 352, 355, 360, 360j, 371, 374); secs. 215, 351, 353, 361 of
the Public Health Service Act (42 U.S.C. 216, 262, 263a, 264).

2. Section 606.100 is amended by adding new paragraph (b)(19) to
read as follows:

606.100 Standard operating procedures.

*    *  *  *  *

(b)  *****

(19) Procedures in accordance with  610.46 of this chapter to
look-back at prior donations of blood and blood products from a
donor who has donated blood and subsequently tests repeatably
reactive for infection with human immunodeficiency virus (HIV) or
otherwise is determined to be unsuitable when tested in
accordance with  610.45 of this diapter. Procedures to quarantine
in-house blood and blood components intended for transfusion or
further manufacture, including Source Plasma and Recovered
Plasma, that were obtained from such donors; procedures to notify
consignees regarding the need to quarantine such products;
procedures to determine the suitability for release of such
products from quarantine; procedures to notify consignees of
blood and blood components from such donors of the results of the
antibody testing of such donors; and procedures in accordance
with 610.47 of this chapter to notify attending physicians so
that transfusion recipients are informed that they may have
received blood infected with the human immunodeficiency virus.

*    *    *    *    *

3.   Section 606.160 is amended by adding new paragraphs
(b)(1)(vii) and (b)(1)(viii) to read as follows:

606.160 Records.

*    *  *  *  *

(b) * * *

(1) * * *

(vii) Records to relate the donor with the unit number of each
previous donation from that donor.

(viii) Records of quarantine, notification, testing, and
disposition performed pursuant to  610.46 and 610.47 of this
chapter.

*    *    *    *


PART 6l0--GENERAL BIOLOGICAL PRODUCTS STANDARDS

4. The authority citation for 21 CFR part 610 continues to read
as follows:

Authority: Secc. 201, 501, 502, 503, 505, 510, 701 of the Federal
Food, Drug and Cosmetic Act (21 U.S.& 321, 351, 352, 353, 355,
360, 371); secs. 215, 351, 352, 353, 361 of the Public Health
Service Act (42 U.S.C. 216, 262, 263, 263a. 264).

5. Section 610.45 Is amended by adding new paragraph (d) to read
as follows:

610-45 Human immunodeficiency virus (HIV) requirements.

*    *    *    *    *

(d) For a donor whose test results for antibody to HIV are
repeatably reactive or otherwise determined to be unsuitable when
tested in accordance with paragraph (a) of this section, the
blood establishment shall comply, as applicable, with  610.46 and
610.47.

6. New  610.46 and 610.47 are added to subpart E to read as
follows:

610.46 Look-back requirements.

(a)  Quarantine and notification. (1) All blood establishments
are required to take appropriate action when a donor of blood or
blood components, including Source Plasma, tests repeatably
reactive for antibody to human immunodefidency virus (HIV) or
otherwise is determined to be unsuitable when tested in
accordance with  610.45. For units collected from that donor
within the 5 years prior to the repeatably reactive test if
intended for transfusion, or collected within the 6 months prior
to the repeatably reactive test if intended for further
manufacture, the blood establishment shall promptly:

(i) Quarantine all such blood and blood components held at that
establishment; and

(ii) Notify consignees so that such products they hold are
quarantined.

(2) Consignees notified in accordance with paragraph (a)(1)(ii)
of this section shall quarantine unpooled products held at that
establishment

(b) Testing and notification of consignees of results. Blood
establishments that have distributed blood or blood components
from a donor described in paragraph (a) of this section shall
perform a licensed, more secific test for HIV on the donor's
blood, and further shall notify the consignees, within 2 weeks
after the donor's repeatably reactive test, of the results of the
test.

(c)  Release and exemption from quarantine. Products intended for
transfusion or futher manufacture which have been quarantined
under this section may be released if the donor is subsequently
tested for antibody to HIV by a licensed, more specific test and
the test result is negative. In addition, products intended for
transfusion need not be held in quarantine if a determination has
been made that the blood or blood component was collected more
than 12 months prior to the donor's most recent negative
screening test when tested in accordance with 610.45.

(d) Actions under this section do not constitute a product recall
as defined in  7.3(g) of this chapter.

610.47 Look-back notification requirements for transfusion
services.

(a) Transfusion services that are not subject to the Health Care
Financing Administration's regulations on conditions of Medicare
participation (42 CFR part 482) are required to take appropriate
action in accordance with paragraph (b) of this section when a
recipient has received blood from a donor determined to be
unsuitable when tested for human immunodeficiency virus (HIV)
infection in accordance with  610.45 and the results of the
licensed more specific test are positive, or not available within
2 weeks as specified in 610.46.

(b)Notification of recipients of prior transfusions. If the
transfusion service has administered any unit of blood as
described in paragraph (a) of this section, the transfusion
service shall notify the recipients' attending physician
(physician of record) and ask him or her to inform the recipient
of the need for HIV testing and counseling. The physician may
notify another authorized person, such as a parent or guardian of
the recipient, if the reasons to do so are documented pursuant to
606.160 of this chapter. If the physician is unavailable or
declines to notify the recipient, the transfusion service shall
notify the recipient and inform the recipient of the need for HIV
testing and counseling. The transfusion service is responsible
for notification, including basic explanations to the recipient
and referral for counseling, and shall document the notification
or attempts to notify the attending physician or the recipient,
pursuant to  606.160 of this chapter.

Dated: March 26, 1993.

David A. Kessler, Commissioner of Food and Drugs.
Donna E. Shalala, Secretary of Health and Human Services.
[FR Doc. 93-15400 Filed 6-29-93; 8:45 am]



FOOTNOTES:

1.   A 1988 Centers for-Disease Control report based on a
theoretical model estimated the risk of transmission in a worst-
case scenario at 1:38,000. A 1989 report by the American Red
Cross, based on empirical data, estimated the risk at 1:153,000.
Other studies estimated the risk between 1:50,000 and 1:68,000.
Busch, M., et al.. New England Journal of Medicine, 1991, 325:1-
5; Cohen, N. O. et al., New England Journal of Medicine, 1989,
320:1172-1178; Kleinman et al., Transfusion, 1988. 28:499-501.
2.   See, e.g., Busch, et al., Risk of Human Immunodeficiency
Virus (HIV) Transmission by Blood Transfusion Before the
Implementation of HIV-1 Antibody Screening, " Transfusion, 1991,
31:4-12.
3.   Ibid.  See also Busch, M.P. et al., "Is Lookback Doing the
Job?" (letter), Transfusion, 27:503-504, 1987; Sampson, et al.,
"Identification of HIV Infection in Transfusion Recipients:  The
utility of cross-referencing previous donor records with AIDS
case reports," Transfusion, 30:214-218, 1990.
4.   See Horsburg, C.R., Jr., et al., "Estimated Duration of HIV
Infection Before Detection of Antibody," The Lancet, 16:637-40,
1989.