[Federal Register Volume 64, Number 160 (Thursday, August 19, 1999)]
[Proposed Rules]
[Pages 45340-45355]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 99-21296]
[[Page 45339]]
_______________________________________________________________________
Part IV
Department of Health and Human Services
_______________________________________________________________________
Food and Drug Administration
_______________________________________________________________________
21 CFR Parts 600 et al.
Requirements for Testing Human Blood Donors for Evidence of Infection
Due to Communicable Disease Agents and Requirements for Blood, Blood
Components, and Blood Derivatives; Rules and Proposed Rules
Federal Register / Vol. 64, No. 160 / Thursday, August 19, 1999 /
Proposed Rules
[[Page 45340]]
DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Parts 607, 610, 640, and 660
[Docket No. 98N-0581]
Requirements for Testing Human Blood Donors for Evidence of
Infection Due to Communicable Disease Agents
AGENCY: Food and Drug Administration, HHS.
ACTION: Proposed rule.
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SUMMARY: The Food and Drug Administration (FDA) is proposing to revise
the general biological product standards by updating the hepatitis B
virus (HBV) and human immunodeficiency virus (HIV) testing
requirements, by adding testing requirements for hepatitis C virus
(HCV), human T-lymphotropic virus (HTLV), and by adding requirements
for licensed supplemental (i.e., additional, more specific) testing
when a donation is found to be repeatedly reactive for any of the
required screening tests for evidence of infection due to communicable
disease agents. The agency is also proposing to require manufacturers
of test kits approved for use in testing donations of human blood and
blood components for evidence of infection due to communicable disease
agents to use reference panels, when available, to verify the
acceptable sensitivity and specificity of each lot. FDA is taking this
action as part of the agency's ``Blood Initiative'' in which FDA is
reviewing and revising, when appropriate, its regulations, policies,
guidance, and procedures related to blood and blood products, including
plasma derivatives. This proposed rule is intended to help protect the
safety and ensure the quality of the nation's blood supply and to
promote consistency in the industry.
DATES: Submit written comments on the proposed rule by November 17,
1999. Submit written comments on the information collection provisions
by September 20, 1999. The agency is proposing that any final rule that
may issue based upon this proposed rule become effective 180 days after
its date of publication in the Federal Register.
ADDRESSES: Submit written comments to the Dockets Management Branch
(HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061,
Rockville, MD 20852. Submit written comments on the information
collection provisions to the Office of Information and Regulatory
Affairs, OMB, New Executive Office Bldg., 725 17th St. NW., Washington,
DC 20503, Attn: Wendy Taylor, Desk Officer for FDA.
FOR FURTHER INFORMATION CONTACT: Paula S. McKeever, Center for
Biologics Evaluation and Research (HFM-17), Food and Drug
Administration, 1401 Rockville Pike, suite 200N, Rockville, MD 20852-
1448, 301-827-6210.
SUPPLEMENTARY INFORMATION:
I. Introduction
A. The Blood Initiative
For a variety of reasons, discussed as follows, FDA has decided to
comprehensively review and, as necessary, revise its regulations,
policies, guidance, and procedures related to the licensing and
regulation of blood products. In the Federal Register of June 3, 1994
(59 FR 28821 and 59 FR 28822, respectively), FDA issued two documents
entitled ``Review of General Biologics and Licensing Regulations''
(Docket No. 94N-0066) and ``Review of Regulations for Blood
Establishments and Blood Products'' (Docket No. 94N-0080). The
documents announced the agency's intent to review biologics regulations
in parts 600, 601, 606, 607, 610, 640, and 660 (21 CFR parts 600, 601,
606, 607, 610, 640, and 660) and requested written comments from the
public. Interested persons were given until August 17, 1994, to respond
to the documents. In response to requests for additional time, FDA
twice extended the comment period, as announced in the Federal Register
of August 17, 1994 (59 FR 42193), and November 14, 1994 (59 FR 56448).
In addition, FDA responded to requests for a public meeting to allow
for the presentation of comments regarding the agency's intent to
review the biologics regulations. On January 26, 1995, FDA held a
public meeting to provide an opportunity for all interested individuals
to present their comments and to assist the agency in determining
whether the regulations should be revised, rescinded, or continued
without change. Since the time of the regulation review, FDA has
implemented a number of changes to its regulations and policies
applicable to the general biologics and licensing regulations, some of
which applied to blood products as well as other biological products.
(See, e.g., the final rules issued on May 14, 1996 (61 FR 24313);
August 1, 1996 (61 FR 40153); November 6, 1996 (61 FR 57328); July 24,
1997 (62 FR 39890); and October 15, 1997 (62 FR 53536).)
Because of the importance of a safe national blood supply, the U.S.
House of Representatives Committee on Government Reform and Oversight,
Subcommittee on Human Resources and Intergovernmental Relations (the
Subcommittee) and other groups such as the General Accounting Office
(GAO), and the Institute of Medicine (IOM) have reviewed the agency's
policies, practices, and regulations. Reports issued following the
respective reviews made a number of recommendations as to how FDA might
improve the biologics regulations, particularly as they apply to the
continued safety of blood products. The relevant reports are: (1)
``Protecting the Nation's Blood Supply From Infectious Agents: The Need
for New Standards to Meet New Threats'' by the Subcommittee (August 2,
1996); (2) ``Blood Supply: FDA Oversight and Remaining Issues of
Safety'' by GAO (February 25, 1997); (3) ``Blood Supply: Transfusion-
Associated Risks'' by GAO (February 25, 1997); and (4) ``HIV and the
Blood Supply: An Analysis of Crisis Decisionmaking'' by IOM (July 13,
1995). These reports are on file with the Dockets Management Branch
(address above) under the docket number given in the heading of this
document.
FDA has reviewed these reports and agrees with the majority of the
recommendations contained within them. However, rather than to only
respond specifically to the recommendations from the Subcommittee, GAO,
IOM, and the public, FDA has convened a number of internal task forces
to review a variety of issues related to the regulation of blood and
blood products, including how to most appropriately update the existing
regulations applicable to blood and blood products. In the future, FDA
intends to issue a number of blood-related rulemakings that various FDA
task groups are currently preparing. FDA is not describing the specific
recommendations it has received and the numerous objectives of the
Blood Initiative in this document. Future rulemaking and other notices
will describe and discuss specific recommendations and regulatory
objectives.
B. Requirements and Recommendations for Testing Donors of Blood and
Blood Components
Requirements for testing blood donors for hepatitis B surface
antigen and antibody to HIV are currently codified in part 610. The
agency has issued various guidance documents to registered blood and
plasma establishments providing recommendations for testing for
antibody to hepatitis B core antigen, antibody to human T-lymphotropic
virus types I and II, antibody to hepatitis
[[Page 45341]]
C virus, and HIV-1 p24 antigen. The purposes of the guidance documents
are to assist blood establishments in protecting the safety of the
blood supply and to establish policies with the intent of promoting
consistency in the industry. These guidance documents represent the
agency's current thinking on the appropriate testing of human blood
donors for evidence of infection due to various communicable disease
agents. Through inspection, FDA has determined that blood
establishments generally have been following these recommendations.
However, there have been instances where there have been variations in
testing and in the determination of suitability of the blood based on
the testing results. Accordingly, FDA is proposing to require testing
consistent with its current recommendations and industry practice. This
will help ensure consistency in the blood industry's testing practices,
and provide FDA with clear enforcement authority if compliance problems
should occur.
The guidance documents referenced in this document or otherwise
applicable to the testing of blood donors may be obtained from the
Office of Communication, Training, and Manufacturers Assistance (HFM-
40), Center for Biologics Evaluation and Research (CBER), Food and Drug
Administration, 1401 Rockville Pike, suite 200N, Rockville, MD 20852-
1448. Send one self-addressed adhesive label to assist that office in
processing your requests. The guidance documents may also be obtained
by mail by calling the CBER Voice Information system at 1-800-835-4709
or 301-827-1800, or by FAX by calling the FAX Information System at 1-
888-CBER-FAX or 301-827-3844. Persons with access to the Internet may
obtain the documents by using the World Wide Web (WWW). For WWW access,
connect to CBER at ``http://www.fda.gov/cber/publications.htm''.
As part of the Blood Initiative, the agency is proposing to revise
part 610 subpart E. Currently, subpart E requires testing for HBV and
HIV and the development and administration of a product quarantine and
recipient notification (``Lookback'') program when donors test
repeatedly reactive for antibody to HIV, or otherwise are determined to
be unsuitable when tested in accordance with Sec. 610.45. In response
to the recommendations made in various reports addressing the safety of
the nation's blood supply mentioned previously, FDA is proposing to:
(1) Require screening tests for evidence of infection due to
communicable disease agents for autologous donations (blood donations
intended to be later reinfused into the donor) in order to reduce the
risk of transmission of communicable disease by untested units
inadvertently entering the blood supply; (2) require supplemental
(additional, more specific) testing of all donations that are
repeatedly reactive by screening tests for which there are supplemental
(additional, more specific) tests; and (3) codify as requirements those
recommendations that FDA has issued that are necessary to ensure blood
safety, including testing for evidence of infection due to HIV, HBV,
HCV, and HTLV. FDA is considering proposing a general testing
regulation for blood and blood components in the future that would
require blood establishments to test for additional relevant
communicable diseases. Such a rule could impose testing obligations as
additional relevant communicable disease agents are identified and FDA
approves tests for such agents.
II. Legal Authority
FDA is proposing to issue this new rule under the authority of
sections 351 and 361 of the Public Health Service Act (PHS Act) (42
U.S.C. 262 and 264 et seq.), and the provisions of the Federal Food,
Drug, and Cosmetic Act (the act) that apply to drugs (21 U.S.C. 201 et
seq.). Under section 361 of the PHS Act, FDA may make and enforce
regulations necessary to prevent the introduction, transmission, and
spread of communicable disease between the States or from foreign
countries into the States (see Sec. I, 1966 Reorg. Plan No. 3 at 42
U.S.C. 202 for delegation of section 361 authority from the Surgeon
General to the Secretary of the Department of Health and Human Services
(Secretary); see 21 CFR 5.10(a)(4) for delegation from the Secretary to
the Food and Drug Administration). 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)). Testing each donation for
evidence of infection due to communicable disease agents would help
prevent unsafe units of blood or blood components from entering the
blood supply. The focus of the proposed rule is preventing the
introduction and spread of communicable disease through transfusion.
All blood and blood components introduced or delivered for
introduction into interstate commerce also are subject to section 351
of the PHS Act (42 U.S.C. 262). Section 351(a) of the PHS Act requires
that manufacturers must have a license which has been issued upon
showing that the manufacturing establishment meets all applicable
standards, prescribed in the biologics regulations, designed to insure
the continued safety, purity, and potency of the blood and blood
components, and that the product is safe, pure, and potent. FDA's
license revocation regulations provide for the initiation of revocation
proceedings, if, among other reasons, the establishment or the product
fails to conform to the standards in the license application or in the
regulations designed to ensure the continued safety, purity, or potency
of the product (Sec. 601.5). Section 351 of the PHS Act provides for
criminal penalties for violation of the laws governing biologics.
Violations can be punishable by fines or imprisonment, or both.
The act also applies to biological products (42 U.S.C. 262(d), as
amended). Blood and blood components are considered drugs, as that term
is defined in section 201(g)(1) of the act (21 U.S.C. 321(g)(1)) (see
United States v. Calise, 217 F. Supp. 705 (S.D.N.Y. 1962)). Because
blood and blood components are drugs under the act, blood
establishments must comply with the substantive provisions and related
regulatory scheme. Under section 501 of the act (21 U.S.C. 351), drugs
are deemed ``adulterated'' if the methods used in their manufacturing,
processing, packing, or holding do not conform with current good
manufacturing practices (21 U.S.C. 351(a)(2)(B)). Under the proposed
rule, blood establishments would be required to test each donation of
blood and blood components for evidence of infection due to
communicable disease agents. Blood and blood components manufactured
from donations that are not tested in accordance with this proposed
rule would be considered adulterated under 21 U.S.C. 351(a)(2)(B), and
blood establishments, and blood and blood components would be subject
to the act's enforcement provisions for violations of the act.
III. Description of the Proposed Rule
This rule is proposed in order to reduce the risk of infection due
to communicable disease agents to blood product recipients and to
individuals handling blood or blood products including components of a
medical device. FDA proposes to require that each donation of human
blood or blood component, including those intended for autologous use
or as a component of a medical device, be tested for evidence of
infection due to HIV, types 1 and 2; HBV; HCV; and HTLV, types I and
II. Each donation that tests repeatedly reactive when screened for
evidence of infection due to any of the
[[Page 45342]]
communicable disease agents would be required to be further tested
whenever a supplemental (additional, more specific) test has been
approved for such use by FDA. Testing would be required to be performed
by a laboratory certified under the Clinical Laboratory Improvement
Amendments of 1988 (CLIA) and registered with FDA in accordance with
part 607. When donors test repeatedly reactive, the agency would
require deferral of such donors from future donations. Criteria are
proposed for release or shipment of human blood or blood components
prior to completion of testing, and restrictions on shipment or use of
human blood or blood components that test repeatedly reactive when
screened for evidence of infection. The proposed rule would also
require manufacturers of approved test kits to test human blood donors
for evidence of infection due to communicable disease agents to verify
an acceptable sensitivity and specificity of each lot of test kit using
a reference panel obtained from CBER, when available.
A. Required Testing for Communicable Disease Agents
Proposed Sec. 610.40(a) would require testing for evidence of
infection due to the communicable disease agents HIV, types 1 and 2;
HBV; HCV; and HTLV, types I and II using screening tests approved for
such use by FDA in accordance with the manufacturers' instructions. The
agency is not proposing to specify the marker(s) to be tested for, such
as a specific antigen or antibody. The purpose of testing is to
adequately and appropriately reduce the risk of transmission of
communicable disease agents. Thus, one or more tests that would fulfill
proposed Sec. 610.40 should be chosen for this purpose.
Historically, tests for new or different markers of infection due
to a communicable disease agent have changed as they become more
appropriate or the technology in testing has become more sensitive or
specific. Therefore, FDA is structuring the proposed regulations so
that manufacturers may adopt adequate and appropriate methodologies to
protect the safety of the nation's blood supply, without necessitating
rulemaking by the agency with the development or advancement of each
test method, e.g., FDA recognizes the possibility that nucleic-acid-
based screening could replace some current methods of testing. FDA
believes that such nucleic-acid-based screening, including ``in-house''
or ``home brew'' screening of blood or blood components for
communicable disease agents required under this regulation should be
regulated under section 351 of the PHS Act when the blood or blood
components are intended for use in preparing a product, including
donations for autologous use or as a component of a medical device.
Several manufacturers have begun to conduct nucleic-acid-based
screening of plasma pools for HIV and HCV under investigational new
drugs (IND). FDA considers such nucleic acid testing of plasma pools
used to manufacture blood products to be donor screening. FDA intends
to issue draft guidance and request public comment on nucleic acid
testing in the near future.
As technology advances, FDA intends to regularly issue guidance
describing those tests that it believes are adequate and appropriate in
reducing the risk of transmission of communicable disease agents. The
agency would issue such guidance in draft, giving the opportunity for
public comment and for manufacturers to prepare to use any appropriate
new testing technologies. In some circumstances, when it is necessary
to protect the public health, the agency may, as described under its
current Good Guidance Practices (62 FR 8961, February 27, 1997),
recommend immediate implementation of the guidance. Consistent with FDA
guidance, as discussed in section I.B of this document, it is current
practice by the blood industry to test blood donations intended for
transfusion or for further manufacture for antibody to HIV, types 1 and
2; HIV-1 p24 antigen; hepatitis B surface antigen (HBsAg); antibody to
hepatitis C; and by a serologic test for syphilis. Blood donations
intended for transfusion routinely are additionally tested for antibody
to HTLV, types I and II, and antibody to hepatitis B core antigen
(anti-HBc).
Although blood that is repeatedly reactive for anti-HBc would not
be suitable for transfusion even when negative for HBsAg, the plasma
from such blood (viz., recovered plasma) would be suitable for
manufacture into plasma derivatives. In most cases, blood that is
negative for HBsAg but is reactive for anti-HBc would be from a donor
who has cleared a hepatitis B infection. Such a donor would still have
circulating anti-HBc and presumably would also have circulating anti-
HBs, which is hepatitis B neutralizing antibody.
In a small percentage of ``window-period'' cases, the blood could
be from a donor who only recently became infected with hepatitis B
virus such that the number of viruses in the blood are below detectable
limits via antigen testing. While a unit of blood from a donor in
window period could be infectious, use of plasma from such a donor,
after pooling with plasma from many donors and manufacturing into
plasma derivatives, does not present a risk of transmitting hepatitis B
to recipients of the plasma derivatives. On the basis of our present
knowledge, this safety results from several factors. First, plasma that
is negative for HBsAg, even if it is reactive for anti-HBc, would have
only a low titer of hepatitis B virus. This titer is further lowered by
pooling with many ``true-negative'' units of plasma. Second, virtually
all plasma derivatives undergo validated virus removal and/or
inactivation procedures in the course of manufacture. Third, there is a
high probability that some units of plasma in the pool will be reactive
for anti-HBs. This can have the added benefit both of neutralizing any
hepatitis B virus present and potentially aiding in its removal during
the process of purifying plasma derivatives. For this last reason,
present knowledge suggests that excluding plasma that is negative for
HBsAg but reactive for anti-HBc could reduce the safety of plasma
derivatives because it would reduce the level of anti-HBs in pooled
plasma and thereby reduce protection against any contaminating
hepatitis B virus present in the pooled plasma.
For the same reasons, FDA does not currently believe that Source
Plasma (which is not obtained from Whole Blood donations and is used
only for further manufacture) that is negative for HBsAg needs to be
tested for anti-HBc.
In January 1995, as part of a National Institutes of Health
Consensus Development Conference, a panel of non-federal, nonadvocate
experts met to provide physicians and other transfusion medicine
professionals with a consensus on infectious disease testing for blood
transfusions. One of the issues reviewed was the value of testing for
syphilis in protecting the safety of the blood supply. The serologic
test for syphilis was introduced in 1938 to prevent the transmission of
syphilis through blood transfusions. In the early AIDS era it was
thought to have additional value as a marker of high risk behavior,
although this benefit has been challenged. The serologic test for
syphilis has a high rate of false positives, leading to further
supplemental (additional, more specific) testing using specific
treponemal confirmatory tests. After discussion, the panel agreed
``Because the contribution of serologic tests for syphilis in
preventing transfusion-transmitted syphilis is not understood, the
panel concludes that testing of donors for syphilis should continue.''
FDA regulations continue to require the
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serologic test for syphilis (see Secs. 640.5(a) and 640.65(b)).
However, the agency recognizes that many scientists, including some
members of the blood banking community, continue to advocate the
elimination of the serologic test for syphilis as a testing
requirement. The agency is soliciting comments, with supporting data,
from the public in regard to the value of donor testing for syphilis as
a marker of high risk behavior, as a surrogate test for other
infectious diseases, and in preventing the transmission of syphilis
through blood transfusion. If the agency receives comments with
adequate data supporting the removal of the requirement for a serologic
test for syphilis, FDA may proceed with rulemaking to remove the
requirements for a serologic test for syphilis, including treponemal
and nontreponemal based tests, from part 640.
B. Affected Products
Each donation of human blood or blood components, i.e., whole
blood, red blood cells, plasma, sera, platelets, and leukocytes,
intended for transfusion or for further manufacturing, would be
required to be tested for evidence of infection due to communicable
disease agents. For the purpose of this proposed rule, any reference to
``blood or blood components'' will include Source Leukocytes and Source
Plasma unless specifically addressed. This proposal includes testing
requirements for donations intended for autologous use or as a source
material or component of a medical device. Inclusion of testing
requirements for donations intended solely for use in a medical device
is a safeguard for persons who may be exposed to infectious blood
products used in such devices.
Despite the reduced risk of infection when using autologous blood,
FDA is concerned that the increased demand to use autologous donations
may compromise transfusion safety for both autologous and allogeneic
recipients. Recent data from an industry conducted survey show that
errors and accidents involving autologous blood occur with sufficient
frequency to compromise the safety of both autologous and allogeneic
transfusions. Examples of these errors and accidents include the
erroneous transfusion of an autologous unit to an unintended recipient;
the inappropriate salvage of plasma for further manufacture from
untested or infectious disease marker positive autologous units; the
breakage of autologous units during laboratory processing or product
transport; and clerical errors in inventory management, including
inadvertent crossover of autologous units to the allogeneic inventory.
Proposed Sec. 610.40 would require uniform testing for both autologous
and allogeneic donations, thus significantly reducing any risk to the
public health posed by the inadvertent improper use of potentially
infectious products.
Unlicensed blood and blood components are often used as components
or source material in the manufacture of certain medical devices,
including in vitro diagnostic test kits. To apply the current good
manufacturing practice (CGMP) for blood and blood components to such
products used in the manufacture of unlicensed blood products that are
device components or device raw materials, FDA issued a final rule on
June 9, 1989 (54 FR 24706), requiring manufacturers of such products to
follow the blood CGMP's in 21 CFR part 606. The preamble to that final
rule stated that blood products that are device components or device
raw materials excluded from the scope of the device CGMP's under
Sec. 820.1 (the quality system regulation) are subject to the blood
CGMP's in part 606. Violations of part 606 involving such device
components or raw materials are subject to enforcement action under
section 501(h) of the act.
Accordingly, FDA is proposing in this rule to clarify the
applicability of testing for evidence of infection due to communicable
disease agents to human blood or blood components used in the
manufacture of a medical device.
C. Exceptions
Proposed Sec. 610.40(b)(1) and (b)(2) would exempt Source Plasma,
and donations of human blood and blood components intended solely as a
component of an in vitro medical device unless they contain viable
leukocytes, from being tested for evidence of infection with HTLV,
types I and II. Donations of Source Plasma, i.e., the fluid portion of
human blood collected by plasmapheresis and intended as source material
for further manufacturing use, would not be required to be tested for
evidence of infection with HTLV, types I and II because HTLV is highly
cell-associated in humans and HTLV transmission has not been
demonstrated by the transfusion of plasma or by the use of products
made from Source Plasma. Currently, in FDA's existing guidance, testing
for antibodies to HTLV, types I and II is recommended for donors only
if blood components, including plasma, are intended for transfusion.
Under proposed Sec. 610.40(b)(3), FDA would not apply the
requirements under Sec. 610.40(a) to certain cases when the human blood
or blood components are not intended for commercial distribution or for
use in preparing a product. This proposal would be consistent with the
current requirements in Sec. 610.45 Human Immunodeficiency Virus (HIV)
requirements. Such cases include the in-house use (i.e., use within the
same establishment) or distribution of samples of blood, blood
components, plasma, or sera for: (1) Clinical laboratory testing ; and
(2) research purposes, provided that it is not intended for
administration to humans or use in manufacturing a product. FDA
believes that the proposed exceptions would help ensure the continued
public health while not impeding continuing research efforts and the
ability to ship blood samples for purposes of clinical laboratory
testing.
FDA is requesting comment on whether to exempt from testing for
evidence of infection due to communicable disease agents listed in
proposed Sec. 610.40(a) each donation of dedicated apheresis donors.
Specifically, FDA seeks comments on whether the proposed rule, when
finalized, should be revised to permit testing proposed in
Sec. 610.40(a) to be completed only once at the beginning of a 30-day
period of donation by a dedicated apheresis donor for a single
recipient. This procedure is currently practiced in specific clinical
situations such as a human leukocyte antigen (HLA) matched or family
donor donating as a dedicated donor for a patient being treated for
diseases such as aplastic anemia, bone marrow, transplant candidate, or
leukemia. The agency is requesting comments on the testing of dedicated
apheresis platelet donors, at a minimum, at the beginning of a 30-day
period during which other donations may continue without further
testing. The agency is also requesting comments on alternatives
(including the rationale) to testing each donation that may be applied
to autologous donations as well as dedicated apheresis donors for a
single recipient. For example, could the added safety resulting from
mandatory testing of autologous donations be similarly achieved by both
improving procedures or requirements for clearly and permanently
marking autologous units to distinguish them from allogeneic units and
requiring that they be labeled as untested for infectious disease
agents, and if so, what additional factors would favor the choice of
one approach over the other.
[[Page 45344]]
D. Further Testing
Under Sec. 610.40(a), each donor blood sample would be tested by a
screening test approved for such use by FDA, according to the
directions supplied by the manufacturer of the test kit. As described
in the directions, each tested sample would be determined to be
reactive or nonreactive. A reactive result on initial testing (initial
reactivity) indicates the possible presence of a marker in the sample.
According to the manufacturers' instructions, initially reactive
samples are to be tested again, generally in duplicate, and a sample
that is found to be reactive on any single retest (i.e., on one or more
of the duplicate retests), is considered to be repeatedly reactive.
Screening tests are designed to be highly sensitive for the marker
specific to the test kit. Because of this sensitivity, the possibility
of false positives due to sample contamination, cross reactivity or
nonspecific binding exists. In Sec. 610.40(c), the agency proposes to
require that repeatedly reactive samples be further tested by a
supplemental (additional, more specific) test, when available, that has
been approved for such use by FDA. In the past, FDA has issued
guidances, discussed previously, that recommend the supplemental
testing of repeatedly reactive samples. Although a donor may be
deferred from donating based on a repeatedly reactive screening test
alone, the supplemental testing would be required so that the following
information could be ascertained: (1) Medical information useful in
notification and counseling as soon as possible for the donor; and (2)
Additional information to be used in evaluating the donor for possible
reentry into the donor pool at a future time.
E. Testing Responsibility
Under the regulations, testing of donor blood samples is considered
a step in the manufacture of blood products (see Sec. 607.3(d)).
Appropriate testing is critical to the continued safety of the nation's
blood supply. FDA believes that it is important that FDA know which
laboratories are performing such testing and that such laboratories can
perform testing adequately. Accordingly, FDA is proposing in
Sec. 610.40(d) to require that testing for evidence of infection due to
the communicable disease agents designated in Sec. 610.40(a) be
performed by a laboratory registered with FDA in accordance with part
607, and certified to perform testing on human specimens under the CLIA
(see 42 CFR part 493). In addition, FDA is proposing to remove
Sec. 607.65(g), which exempts from registration clinical laboratories
that are approved for Medicare reimbursement and which are engaged in
the testing of blood products in support of other registered
establishments. As a result, such laboratories would need to register
with FDA.
F. Release or Shipment Prior to Testing
Under Sec. 610.40(e), FDA proposes to permit, in specified
situations, the release or shipment of human blood or blood components
before the completion of testing required under Sec. 610.40(a). Section
640.2(f) would be removed. The agency recognizes that there are rare
medical emergencies, e. g., where a patient's need for blood is so
acute that transfusion is necessary before knowing the results of any
communicable disease testing of the blood. FDA believes that the use of
untested or incompletely tested blood in such medical emergencies
should not be prohibited. Because products other than Whole Blood may
need to be released in medical emergency situations, FDA is proposing
to place the provision for medical emergency situations in
Sec. 610.40(e), which is applicable to all blood products, and to
remove Sec. 640.2(f), which is applicable to Whole Blood only.
FDA is proposing in Sec. 610.40(e) to permit, with FDA approval,
routine shipment of certain blood components for further manufacturing
before testing is completed and the tests results are received by the
collection facility. To obtain approval from FDA, the agency would
expect the collection facility and the manufacturing facility to whom
the blood product is being shipped, to submit with their request
specific procedures for collection, shipment, and quarantine of a
product before testing is completed. Once the procedures have been
approved, manufacturers may then begin to ship products prior to the
completion of testing. This proposal is intended to ensure the
continued availability of biological products, such as interferon, that
are important to the medical community and which require rapid
preparation from blood.
The provisions for emergency release and shipment prior to
completion of testing would require appropriate documentation, that
testing would be performed as soon as possible, and that the results
would be provided promptly to the consignee.
G. Restrictions on Shipment or Use
In Sec. 610.40(f)(1), FDA is proposing to require that blood and
blood components testing repeatedly reactive when screened for evidence
of infection due to a communicable disease agent designated in proposed
Sec. 610.40(a), or collected from a donor with a record of a repeatedly
reactive test result, shall not be shipped or used to prepare any
product, including products not subject to licensure, except as
described in section III of this document. FDA believes that
inappropriate handling, labeling, or use of such blood could be
hazardous to the public health. Therefore, FDA is proposing to restrict
the shipment or use of such blood and blood components.
Under proposed Sec. 610.40(f)(2)(i), the restriction on shipment or
use of blood or a blood component that tests repeatedly reactive when
screened for evidence of infection due to a communicable disease agent
listed in proposed Sec. 610.40(a) would not apply to units intended for
autologous use. Autologous blood or blood components would be required
to be appropriately labeled in accordance with Sec. 606.121(i) and with
the Biohazard legend demonstrated in the codified section. Under
proposed Sec. 610.40(f)(2)(ii), blood establishments intending to ship
or use human blood or blood components for further manufacture that
test repeatedly reactive when screened for evidence of infection due to
a communicable disease agent listed in proposed Sec. 610.40(a) would
apply for approval by FDA. Application for approval would be submitted
as part of the license application or a supplement to the approved
license. For unlicensed products, application for approval would be
submitted in accordance with Sec. 640.120 as discussed in section K of
this document. The written application would describe the intended use
of the blood or blood component, and the procedures for collecting,
handling, labeling, and shipping the blood. Blood and blood components
are required to be labeled in accordance with Secs. 606.121 and 640.70,
as appropriate. Repeatedly reactive blood or blood components would be
required to be labeled as repeatedly reactive for the applicable marker
for the identified communicable disease agent and display the Biohazard
legend. If repeatedly reactive blood or blood components are to be used
for further manufacturing into injectable products, the blood or blood
component would be required to be labeled with the exempted use
specifically approved by FDA. For manufacturing into noninjectable
products, such as in vitro diagnostic products when there is no
alternative source such as monoclonal antibody, repeatedly reactive
blood or blood components would be required to be labeled with the
statement ``Caution:
[[Page 45345]]
For Further Manufacturing Into Non-Injectable Products For Which There
Are No Alternative Sources''. Distribution may not commence until
approval is granted.
Under proposed Sec. 610.40(f)(3), FDA would permit the use of
blood or blood components from a donor who was deferred as a result of
testing repeatedly reactive on a screening test(s) for specified
communicable disease agent(s) if the blood or blood components test
negative for those same disease agent(s) and the donor has been shown
to be suitable to donate blood by a method or process described in a
supplement to the establishment's license and approved for that purpose
by FDA. (Such methods are called ``donor reentry'' algorithms.) FDA has
identified such methods or processes in the agency's guidance
documents, discussed previously, in the format of algorithms, or step-
by-step procedures designed to reenter the donor into the donor pool,
when appropriate.
There are occasions when human blood or blood components that test
repeatedly reactive when screened for evidence of infection due to a
communicable disease agent listed in proposed Sec. 610.40(a) are needed
for further manufacture, e.g., when used in the manufacture of certain
in vitro diagnostic products. The agency proposes in Sec. 610.42 to
require that a repeatedly reactive unit used for further manufacturing
into an in vitro diagnostic product be labeled as repeatedly reactive
for the applicable marker of infection due to the identified
communicable disease agent. For an in vitro diagnostic product
manufactured from a repeatedly reactive unit, the agency would require
in Sec. 610.42 that the manufacturer label the product in accordance
with 21 CFR 809.10 and that a warning be included stating that the
product was manufactured from a donation that tested repeatedly
reactive for the appropriate marker of infection for the identified
communicable disease agent. This would be required to help prevent the
spread of communicable disease in those handling the product, (i.e.,
such labeling should result in handlers taking appropriate precautions
for their and other's safety).
H. Compliance with Secs. 610.46 and 610.47 (``Lookback'' requirements
for HIV)
Current Sec. 610.45(d) requires the blood establishment to comply
with Secs. 610.46 and 610.47 and perform testing, quarantine, consignee
notification and recipient notification when a blood donor tests
repeatedly reactive for HIV or when the blood establishment has been
made aware of other test results indicating HIV infection. The agency
is not proposing to include this requirement in this proposed rule.
However, in future rulemaking, the agency will propose new regulations
for ``Lookback'' when donors test repeatedly reactive for HCV,
comparable to those requirements currently applicable for donors
testing repeatedly reactive for HIV. The new ``Lookback'' proposed
regulations will consolidate in one section the current requirements
for HIV ``Lookback'' and the proposed HCV ``Lookback'' requirements. In
the event that finalization of the new proposed ``Lookback'' rule is
delayed, the agency intends to issue the current language in
Sec. 610.45(d) as Sec. 610.40(g) with specific paragraph and section
cites revised.
I. Donor Deferral
Once the donor (except for autologous donors or other donors as
discussed in section III.I of this document), at the time of donation,
tests repeatedly reactive by a screening test(s) performed in
accordance with proposed Sec. 610.40(a), the blood or blood components
from that donation are to be quarantined and either destroyed or
excluded from use in transfusion; and, based on the particular marker
that tests repeatedly reactive, the donor will then be either deferred
from donating in the future or deferred if a similar result is obtained
on any subsequent donation. Similar provisions under Secs. 640.5 and
640.65 apply to donations reactive for syphilis, however, some
additional exceptions apply. Blood establishments are currently
required under Sec. 606.160 to maintain records of results and
interpretation of all tests and retests, and a record from which
unsuitable donors may be identified so that products from such
individuals will not be distributed. Proposed Sec. 610.41 explicitly
would require the deferral of donors based on testing. FDA is issuing
elsewhere in this issue of the Federal Register, notice and comment
rulemaking proposing to require the notification of donors of their
deferral from donating in the future and the reason for the deferral
(such as health history or test results). FDA also intends to issue
notice and comment rulemaking in the near future proposing donor
suitability criteria.
In proposed Sec. 610.41(a), donors who test repeatedly reactive for
HTLV, types I and II, or anti-HBc only once, would be permitted to
donate again without being deferred from further donation unless there
is further testing using an approved supplemental (additional, more
specific) test. This proposal is consistent with FDA's guidance to all
registered blood establishments dated August 19, 1997, entitled ``Donor
Screening for Antibodies to HTLV-II.'' Once supplemental tests for
HTLV, types I and II are approved, donors would be deferred after only
a single repeatedly reactive donation similar to most other screening
tests. It is FDA's expectation that donor reentry algorithms would
become feasible at that time. However, until such time, upon testing
repeatedly reactive a second time for HTLV, types I and II or anti-HBc,
the donor would be deferred.
FDA is proposing in Sec. 610.41(b) to permit donors testing
repeatedly reactive for HTLV, types I and II or anti-HBc to serve as
donors of Source Plasma (See section III.C of this document for
discussion on the risk of transmitting HTLV, types I and II through
Source Plasma; see section III.A of this document for discussion on the
use of plasma from donors who test repeatedly reactive for anti-HBc).
However, the agency is requesting comments on this proposal that
permits such donors to donate Source Plasma to be used in the
manufacture of plasma derivatives as it relates to exposure to other
possible risks, such as the association of HTLV infection with abuse of
intravenous drugs.
Proposed Sec. 610.41(c)(1) permits deferred donors to donate blood
and blood components when used in accordance with Sec. 610.40(f). In
proposed Sec. 610.40(f), the agency proposes that blood and blood
components that test repeatedly reactive when screened for evidence of
infection due to communicable disease agents listed in proposed
Sec. 610.40(a) would not be shipped or used except for autologous use
or for purposes or under conditions approved in writing by FDA. Such
approval may also be obtained under current Sec. 640.120.
The agency is proposing in Sec. 610.41(c)(2) to restrict the use of
blood or blood components from donors showing evidence of infection due
to hepatitis B virus when tested in accordance with Sec. 610.40(a) and
(c). Such blood and blood components may be approved for use only as a
source of antibody to hepatitis B surface antigen (anti-HBS, Hepatitis
B neutralizing antibody) for the preparation of Hepatitis B Immune
Globulin (Human) or as a component of a medical device. Use of such
blood or blood components would be prohibited in the manufacture of
other biological products. The agency requests comments on the use of
vaccinated donors for HBV as an alternative to using donors previously
showing evidence of infection due to
[[Page 45346]]
hepatitis B virus in the preparation of Hepatitis B Immune Globulin
(Human).
In proposed Sec. 610.41(d), the agency would not defer donors of
blood and blood components from further donations, if the donor was
found negative by an approved specific treponemal test (confirmatory
test for syphilis) despite a reactive screening test. Accordingly, if
the donor tests positive by the more specific test, then the donor
would be deferred and reentered into the donor pool only in accordance
with proposed Sec. 610.41(e). Donors of Source Plasma testing reactive
for the serologic test for syphilis, shall follow the procedure
provided in Sec. 640.65(b)(2)(ii), (b)(2)(iii), and (b)(2)(iv).
J. Use of Reference Panels by Manufacturers of Test Kits
For a number of years, FDA has made available reference panels
(also known as lot release panels) of known reactivity to a marker of
infection due to a communicable disease agent. These reference panels
are used by manufacturers in the qualitative and semi-quantitative
evaluations of their in vitro tests to detect a defined marker of
infection due to the identified communicable disease agent. FDA is
proposing to move the requirements for reference panels for hepatitis B
test kits to proposed Sec. 610.44 and add that reference panels be used
when available for all the test kits for communicable disease agents
identified in proposed Sec. 610.40(a) and for all approved HIV tests.
The agency would require the use of these regulatory reference panels
obtained from the Center for Biologics Evaluation and Research (CBER)
or from an FDA designated source, when available, to provide a
verification by the manufacturer of the sensitivity and specificity of
each lot of test kit approved for use in testing donations of human
blood and blood components. This release criterion would be applied to
lots of test kits produced by licensed manufacturers or lots produced
by manufacturers pursuing licensure of such tests. Once a reference
panel is assembled and available for use in lot release testing, the
Director, CBER, would send a letter informing all licensed
manufacturers of the appropriate test kit of the availability of the
reference panel and of the date the agency believes the new reference
panel should be put into use for lot release testing. This will usually
be followed by a notice in the Federal Register. Lots of test kits
found to be not acceptable for sensitivity and specificity would be
prohibited from release. By inserting the requirement in this section,
FDA is attempting to emphasize the need for reference panels to
manufacturers of blood and blood components so that they may use the
appropriately released lot of test kits. Accordingly, the agency is
proposing to remove Sec. 660.42, a requirement for a reference panel
for hepatitis B surface antigen, and include the use of reference
panels by manufacturers of test kits in proposed Sec. 610.44 for better
consolidation.
K. Use of Sec. 640.120-Alternative Procedures
FDA recognizes that as technology and scientific knowledge advance,
there will continue to be instances when a regulation will become
outdated or where unanticipated circumstances may warrant a departure
from an approach detailed in the regulations. In order to be more
responsive to improved technologies, increased scientific knowledge,
and concerns about the continued availability of blood and blood
products, the agency has issued a regulation at Sec. 640.120, which
allows the Director, CBER, to approve an exception or alternative to
any requirement in subchapter F of chapter I of title 21 of the Code of
Federal Regulations regarding blood, blood components, or blood
products. The Director, CBER, would approve such an exception or
alternative only if, in the judgment of the Director, CBER, the safety,
purity, potency, and effectiveness of the final product is adequately
ensured. The Director, CBER, may request additional data or information
from the person who has requested permission for an exception or
alternative before granting the request. Any exception or alternative
to the proposed rule, once finalized, would proceed under Sec. 640.120.
L. Removal of Sec. 610.45
With the reconstruction and streamlining of the regulations in
regard to testing requirements for communicable disease agents, the
agency is proposing to remove Sec. 610.45, human immunodeficiency virus
(HIV) requirements, because it has been incorporated into the revision
of proposedSec. 610.40.
IV. Analysis of Impacts and Initial Regulatory Flexibility Analysis
FDA has examined the impacts of the proposed rule under Executive
Order 12866, under the Regulatory Flexibility Act (5 U.S.C. 601-612),
and under the Unfunded Mandates Reform Act (Public Law 104-4).
Executive Order 12866 directs agencies to assess all costs and benefits
of available regulatory alternatives and, when regulation is necessary,
to select regulatory approaches that maximize net benefits (including
potential economic, environmental, public health and safety, and other
advantages; distributive impacts; and equity). The Regulatory
Flexibility Act requires agencies to analyze whether a rule may have a
significant impact on a substantial number of small entities and, if it
does, to analyze regulatory options that would minimize the impact.
Section 202(a) of the Unfunded Mandates Reform Act requires that
agencies prepare a written statement of anticipated costs and benefits
before proposing any rule that may result in an expenditure in any one
year by State, local, and tribal governments, in the aggregate, or by
the private sector, of $100 million (adjusted annually for inflation).
OMB has determined that the proposed rule is a significant
regulatory action as defined by the Executive Order and so is subject
to review. Because the rule does not impose any mandates on State,
local, or tribal governments, or the private sector, that will result
in any one year of $100 million or more, FDA is not required to perform
a cost-benefit analysis according to the Unfunded Mandate Reform Act.
The Regulatory Flexibility Act requires agencies to prepare a
Regulatory Flexibility Analysis for each rule unless the agency
certifies that the rule will not have a significant economic impact on
a substantial number of small entities. Although the proposed rule is
not expected to have a significant economic impact on a substantial
number of small business entities, a precise impact is uncertain.
Therefore, the agency has prepared an Initial Regulatory Flexibility
Analysis.
A. Objectives and Basis of the Proposed Action
FDA is taking this action as part of the agency's ``Blood
Initiative'' in which FDA is reviewing and revising, when appropriate,
its regulations, policies, guidance, and procedures related to blood
and blood products, including plasma derivatives. The basis for this
proposed rule is to help protect the safety and ensure the quality of
the nation's blood supply, and to promote consistency in the industry.
Under the biologics licensing and quarantine provisions of the PHS Act
(42 U.S.C. 262-264) and the drug, device, and the general
administrative provisions of the act (21 U.S.C. 351-353, 355-360, and
371-374), FDA has the authority to issue regulations designed to
protect the public from unsafe or ineffective biological products and
to issue regulations necessary to prevent the
[[Page 45347]]
transmission of communicable diseases into the United States or from
one State to another. Under these statutory authorities, the agency is
proposing to: (1) Require screening tests for evidence of infection due
to communicable disease agents for autologous donations in order to
reduce the risk of transmission of communicable disease by untested
units entering the blood supply inadvertently; (2) require supplemental
(additional, more specific) testing of all donations that are
repeatedly reactive by screening tests for which there are supplemental
tests; and (3) codify as requirements those recommendations that FDA
has issued that are necessary to ensure blood safety, including testing
for evidence of infection due to HIV, HBV, HCV, and HTLV.
B. Nature of the Impact
The proposed rule requires that each donation of human blood or
blood component, including those intended for autologous use or as a
component of a medical device, be tested for evidence of infection due
to HIV, types 1 and 2; HBV; HCV; and HTLV, types I and II. Each
donation that tests repeatedly reactive when tested for evidence of
infection due to any of the disease agents would be required to be
further tested whenever a supplemental, more specific test has been
approved for such use by FDA. FDA is proposing to require that the
testing be done by a laboratory that is registered with FDA and CLIA-
certified. The proposed rule also contains provisions for appropriate
deferral of donors based on test results, and exemptions for Source
Plasma from being tested for evidence of infection from HTLV, types I
and II. FDA is proposing to permit shipping of units prior to testing
if appropriate procedures are developed for collection, shipment and
quarantine to protect against unnecessary communicable disease risks
from use of shipped units later found to test repeatedly reactive.
Under the proposed rule, allogeneic donations that test repeatedly
reactive shall not be shipped except in situations specifically
approved by FDA; however, repeatedly reactive autologous units may be
shipped with labeling to indicate biohazard.
The rule would also require manufacturers of test kits, approved
for use in testing donations of human blood and blood components for
these disease agents, to verify an acceptable sensitivity and
specificity of each lot of test kit, using a reference panel obtained
from CBER or an FDA designated source, when available.
1. The Type and Number of Entities Affected
The proposed testing of donations from allogeneic and autologous
donors of blood and blood components will affect all blood and plasma
establishments that collect blood and blood components from such
donors. FDA's Office of Blood Research and Review (OBRR) has record of
2,801 registered blood and plasma establishments, including 487 plasma
centers and 2,314 blood centers. Most Source Plasma centers are
commercial establishments with paid plasma donors. By contrast, whole
blood donors in the United States are volunteers. The most recently
published survey of the blood industry was conducted in 1992 (Ref. 1),
and the aggregate figures for blood collection reported in the 1992
survey are generally consistent with the aggregate numbers (i.e., 14
million blood donations) currently provided by the American Association
of Blood Banks (AABB) (Ref. 2), although the number of registered
facilities is now somewhat higher. The 1992 survey of U.S. blood
establishments reported on 2,093 entities, including 157 distinct
regional and community blood centers. Data on activities of the
regional and community blood centers were obtained as responses to the
AABB's 1993 Institutional Membership Questionnaire, directly from the
American Red Cross, or in the case of non-AABB centers, from responses
to questionnaires mailed from the Center for Blood Research. According
to the 1992 survey, 1,936 hospitals listed as members of the AABB, are
involved in blood collection. These hospitals are a subset of the
American Hospital Association (AHA) list of 5,288 hospitals presumed to
transfuse blood.
According to the 1992 survey, all U.S. blood establishments were
estimated to collect a total of 13,794,000 units of blood. Allogeneic
donations accounted for 87.2 percent (12,035,000 units), directed
donations accounted for 3.2 percent (436,000 units) and autologous
donations comprised 8.1 percent (1,117,000 units) of the total.
Regional and community blood centers report receiving 702,000 of the
total autologous units, and hospital blood centers collected an
estimated 415,000 units. Based on information published by the AABB and
the American Red Cross regarding allogeneic donations, and
communications with experts in the blood banking industry regarding the
testing of autologous donations, FDA believes that all blood donations
currently collected by the regional and community blood centers, and
all of the allogeneic donations collected by hospitals are already
being tested for the specified disease agents. FDA also estimates that
approximately one-third to one-half of the autologous donations
currently collected by hospitals are already being tested for HIV,
types 1 and 2, HBV, HCV, and HTLV, types I and II. In the following
analysis, an approximate midpoint of 40 percent is used as the assumed
percentage of hospital-collected autologous donations already being
tested for the specified disease agents.
In 1997, the Government Accounting Office (GAO) estimated that
approximately 12 million donations of Source Plasma were collected by
plasma centers (Ref. 3). Although the precise number of those donations
currently tested for HIV, types 1 and 2, HBV, and HCV is not reported,
FDA assumes that virtually all donations are currently being initially
screened for the communicable disease agents specified for plasma
donations in the proposed rule. However, based on GAO reported
variations in the plasma industry's confirmatory testing of repeat
reactive donations, it is also assumed that supplemental confirmatory
testing for HCV is not widely practiced at present.
The proposed requirements for manufacturer testing of approved test
kits will entail manufacturers' use of CBER regulatory reference panels
to provide verification of the specificity and sensitivity of each lot
of test kit approved for use in testing donations of human blood. This
release criterion would be applied to lots of test kits produced by
licensed manufacturers or lots produced by manufacturers pursuing
licensure of such tests. FDA estimates that the number of manufacturers
of kits for the four disease agents specified in the rule currently
ranges from six to seven establishments per disease agent. It is also
possible that some additional number of manufacturers may pursue
licensure of such kits in future years, although the total number is
likely to remain small because of the expected limits of demand for
such tests.
FDA currently has reference panels available for all of the disease
agents specified in the proposed rule, and has made the panels
available to all currently licensed manufacturers of test kits. To the
agency's knowledge, all currently licensed manufacturers covered by the
proposed rule are already performing the proposed tests to comply with
their own quality assurance standards. The proposed rule is therefore
expected to introduce no substantial impact on these establishments.
[[Page 45348]]
2. Estimated Impact of Proposed Requirements for Donor Testing
The proposed rule provisions for donation testing, appropriate
handling, labeling, and distribution will involve a one-time effort by
all blood establishments to review and modify current blood donor
testing, handling, and recordkeeping protocols to comply with the
proposed rule. The rule will also involve a yearly increase in donor
testing for establishments that currently do not test both allogeneic
and autologous blood and blood component donations.
The one-time effort to review and modify current standard operating
procedures (SOP's) is expected to vary among establishments, depending
on whether the establishment already engages in testing and labeling
both autologous and allogeneic blood donations for the specified set of
disease agents. For establishments that already perform testing and
labeling of both autologous and allogeneic donations (i.e., all plasma
centers collecting only for allogeneic use, regional and community
blood centers, and 40 percent of hospital collection sites), FDA
estimates that it would take approximately 8 hours of staff time to
reconcile the proposed regulations against the facility's current
standards. This process could be performed by a technical specialist
who acts as a regulatory reviewer or manager of quality assurance.
Based on the total average hourly compensation of $25.67 for
professional specialty and technical occupations in the health services
industry, as reported by Bureau of Labor Statistics for March 1997, the
cost would be approximately $205, for each of the blood centers and an
estimated 40 percent of the hospital blood centers. For establishments
that already perform the proposed testing on allogeneic, but do not
test autologous donations, FDA assumes that approximately 16 hours of
staff time would be required to reconcile and expand the current
facility standards to comply with the requirements of the proposed
regulation. The cost in this case would be $411 per facility. It is
also assumed that all facilities perform careful labeling and
recordkeeping on autologous units donations, and that recordkeeping
will include more infectious disease information but will not require
substantially more time than is already allocated. Thus, the total one-
time cost for the industry is estimated to be $813,554 (2,800
establishments - 1,936 hospital blood centers) x $205 + (1,936 x 0.40 x
$205) + (1,936 x 0.60 x $411).
The yearly increase in cost of testing for the 1,162 hospitals
assumed not to currently test all donations is based on a proportional
extrapolation (60 percent of donors) from the estimated number of
autologous donations collected in hospital blood centers, as reported
in the 1992 blood collection survey (415 units); the estimated cost per
required test; and an estimated rate of 0.19 percent HCV repeat-
reactive donations reported by the American Red Cross, based on
donations received between January 1996 and June 1997. The cost for
HIV, types 1 and 2 is estimated to be approximately $5 per test (Ref.
4); the cost per test for HBV, i.e., HBsAg and anti-HBc, are
respectively estimated to be $39.20 (Ref. 5) and $38.59; the cost of
HCV-EIA and supplemental assay are respectively estimated to be $49.90
and $114.50 (Ref. 6) per test; and the cost of HTLV, types I and II is
estimated to be $5.00 per test (Ref. 7). The total yearly increase in
cost for the industry, based on these factors, is estimated to be
$34,316,570 (415,000 x .60 x [($5.00 + $39.20 + $38.59 + $49.90 +
$5.00) + 0.0019 x $114.50)].
The yearly increase in cost for the plasma industry is based on the
assumption that potentially all plasma centers will need to begin
routine followup testing on donations that test repeatedly reactive for
hepatitis C. Assuming an average 0.18 percent (0.0018) rate of HCV
repeatedly reactive donations, an annual volume of 12 million donations
and the cost of $114.50 per supplemental HCV test, the annual cost is
estimated to be no greater than $2,514,420. FDA recognizes that the
cost may actually be less if a substantial fraction of HCV repeatedly
reactive donations collected by the plasma centers already undergo
confirmatory testing.
In summary, the proposed rule would result in an estimated one-time
cost of $813,554, and a total annual cost of $36,830,990 ($34,316,570 +
$2,514,420) to the blood and plasma industries.
3. Expected Benefits of the Proposed Rule
The proposed rule is intended to increase the safety of all blood
and blood component products by providing recipients with increased
protection against communicable disease transmission. The rule
addresses exposures that may occur through accidents and errors in
administration of autologous as well as allogeneic blood units. For
example, AABB Anonymous Survey Report included reports of erroneous
transfusions (1.2 percent of respondents), untested recovered plasma
salvaged (3.7 percent), units lost in transit (12.3 percent), units
broken in the lab (33.6 percent), and units broken outside the lab
(32.2 percent), as well as other errors (9.8 percent) (Ref. 17). The
reduction in communicable disease risk already achieved among
allogeneic blood transfusions as a result of infectious disease testing
of donors has been quite dramatic. For example, as a result of
expansion of blood donor screening and improved laboratory tests, it is
now estimated that the chances of transfusion-related HIV infection
have decreased to between 1 in 450,000 to 660,000 per unit of blood
(Ref. 8). HCV and HBV transfusion risks have also declined. In 1994,
4.3 percent of all HCV infections were transfusion-related, compared to
the current rate of 0.02 percent to 0.05 percent. Similarly, although
5.7 percent of the general population is estimated to be seropositive
for HBV, the risk of HBV transfusion transmission is currently
estimated to be 1 in 200,000 transfused units.
Although the impetus for autologous donation is often the donor's
desire to avoid risk of infection from other donors' blood, studies
comparing the prevalence of disease markers in autologous donations
compared to allogeneic donations have found the incidence of positive
disease markers for first time donations among autologous donors to be
similar to that among first-time allogeneic donors. Moreover, the rate
among first-time autologous donors was generally higher than that found
among repeat allogeneic donors (Ref. 9). The finding of positive
markers for an allogeneic donation, however, would result in a blood
bank's rejection of the donor unit. By contrast, the disease-positive
autologous unit would be retained and potentially stored in the same
freezer as the screened allogeneic units. Without the proposed
requirement for infectious disease testing and labeling, the label of a
disease-positive autologous unit may not indicate that the unit
presents a potentially infectious disease risk. The accidental and
inadvertent use of such units may expose unwitting recipients to a
higher than acceptable risk.
The gravity of the disease risks addressed by the proposed rule are
widely recognized. Transfusion of HIV, the virus that causes AIDS,
continues to cause great concern. Human T cell leukemia/lymphoma
viruses types I and II were identified in the early 1980's. Infection
with the virus is associated with tropical spastic paraparesis, adult
T-cell leukemia/lymphoma, and some inflammatory disorders (Lapane et
al.). Although the virus is primarily sexually
[[Page 45349]]
transmitted, it can also be transmitted through blood transfusion.
HBV is a major cause of acute and chronic hepatitis, cirrhosis and
primary hepatocellular carcinoma worldwide. The Centers for Disease
Control and Prevention (CDC) estimated that in 1985 approximately
300,000 persons became infected with HBV. Prior to the development of
hepatitis B screening tests, transfusion-related risks were
significant. A retrospective testing of blood donors using first
generation tests for the presence of HBsAg found that over half of
recipients of HBsAg-positive blood developed hepatitis (Ref. 10). Of
the current pool of 1 to 1.25 million HBV carriers, approximately 25
percent will develop chronic hepatitis which will progress to cirrhosis
and carriers have a risk of liver cancer that is 12 to 300 times higher
than noncarriers. An estimated 4,000 persons die each year from
hepatitis B-related cirrhosis, and more than 800 die from primary
hepatocellular carcinoma (PHC). The lifetime medical cost per case of
PHC and cirrhosis is estimated to be $96,500 (Ref. 11).
Epidemiologic and experimental studies indicate that HCV is
primarily transmitted by the parenteral route. Persons at increased
risk of acquiring hepatitis C include parenteral drug users; health-
care workers with occupational exposure to blood; hemodialysis
patients; and recipients of whole blood, blood cellular components or
plasma. Transfusion of blood or blood products, which accounted for a
substantial proportion of HCV infections acquired more than 10 years
ago, is now an uncommon means of transmission. CDC estimates that
150,000 to 170,000 new HCV infections occur annually in the United
States (Ref. 12). Of patients with transfusion-associated chronic non-
A, non-B hepatitis who undergo biopsy within 5 years after onset, at
least 40 percent have histologic evidence of chronic active hepatitis
and 10 to 20 percent have evidence of cirrhosis (Ref. 13). An estimated
30 percent of those infected will eventually die of liver-related
causes, an estimated 8,000 patients per year. Although some HCV
patients have been found to respond to interferon therapy, the average
cost of care per year for persons with liver disease from chronic
hepatitis C is estimated to range from $24,600 for patients without
interferon-alpha therapy to $26,500 per year for those receiving a 12-
month course of therapy. The latter has been estimated to provide
patients with an additional 0.37 quality-adjusted life years (Ref. 14).
As described previously, the requirement of HIV, types 1 and 2; HBV;
HCV; and HTLV, types I and II testing for all blood and blood component
donations, including those for autologous donations, significantly
reduces the U.S. population's exposure to the morbidity and mortality
risks associated with these diseases, and their attendant costs.
4. Small Entity Impact
The information available to characterize the relevant volumes of
affected blood and plasma products is limited. Although the proposed
rule is not expected to have a significant impact on a substantial
number of small entities, the impact on blood and plasma establishments
that might qualify as small entities is uncertain. The FDA has
therefore prepared an Initial Regulatory Flexibility Analysis. The
blood and plasma establishments affected by the proposed rule are
included under the major Standard Industrial Code (SIC) group 80 for
providers of health services. According to section 601 of the
Regulatory Flexibility Act of 1980, the term ``small entity''
encompasses the terms ``small business,'' ``small organization,'' and
``small governmental jurisdiction.'' According to the Small Business
Administration (SBA), a small business within the blood industry is an
enterprise with less than $5 million in annual receipts. A small
organization is a not-for-profit enterprise which is independently
owned and operated and is not dominant in its field. A ``small
governmental jurisdiction'' generally means governments of cities,
counties, towns, townships, villages, school districts, or special
districts with a population of less than fifty thousand.
As described in the foregoing analysis, hospitals that do not
currently test autologous donations for HIV types 1 and 2, HBV, HCV,
and HTLV types I and II are expected to be the primary entity affected
by the proposed rule. However, the extent of the small business impact
is uncertain. Although the details of blood collection at hospitals are
not available, FDA examined other data to develop a preliminary
assessment of small business impact. The size of U.S. hospitals varies
substantially. The 1998 American Hospital Association (AHA) survey data
(Ref. 15) indicate a total of 5,134 U.S. registered community hospitals
grouped into 8 bedsize categories. The average annual revenues for
facilities in these bedsize categories range from approximately $5.5
million to $513 million. However, since many hospitals are not-for-
profit or are operated by State and local governments, the SBA annual
receipts criteria for small businesses would not apply to these
facilities. Of the 5,134 U.S. community hospitals included in the AHA
report 1,330 are under the control of State and local government, 3,045
are nonprofit institutions, and the remaining 759 are reported to be
investor-owned.
The number of hospitals that would meet at least one of the various
SBA definitions for small entities is uncertain. According to the AHA
statistics for 1998, the smallest reported hospital size category
includes 262 hospitals with 6 to 24 beds, and total gross revenues of
$1.43 billion, yielding average revenues of $5.46 million. FDA assumes
that the 11 facilities reported to be investor-owned within this
bedsize category could qualify as small entities. Although it is
possible that all nonprofit hospitals may qualify as small entities, it
appears that a number of facilities might be excluded from that
definition because they are reported to be hospitals in a system.
According to the AHA survey definition, ``hospitals in a system'' refer
to those ``hospitals belonging to a corporate body that owns and/or
manages health provider facilities or health-related subsidiaries; the
system may also own non-health-related facilities.'' The AHA currently
has record of 1,592 hospitals that are non-federal and nonprofit
(including State and local government controlled) that are hospitals in
a system. If these facilities were excluded, FDA estimates that 2,783
[1,330 State and local + 3,045 nonprofit - 1,592 in-a-system] non-
federal, nonprofit hospitals may qualify as small entities. Thus, a
total of 2,794 [2,783 + 11] hospitals might qualify as small entities.
The agency does not know how many of the estimated total of 415,000
autologous units would be collected at hospitals qualifying as a
``small entity,'' nor how many of those establishments are already
performing the proposed testing for autologous donors (as noted in the
earlier cost analysis, an estimated 40 percent of all hospital-based
autologous collections already include blood testing). Some of the
hospitals that would be classified as small entities will already be
testing autologous donors as required by the proposed rule, and are
therefore expected to incur an estimated one-time cost of $205, as
described earlier. Other small establishments, that begin autologous
donor testing in compliance with the proposed rule, will incur an
estimated $411 one-time cost, and yearly costs of new testing based on
the number of autologous donors at their facility. The following
analysis of potential impact focuses on the annual blood testing costs,
which represent the largest
[[Page 45350]]
component of cost impact. The analysis assumes that the collections of
autologous units may be distributed across hospitals of different size
in proportion to the hospitals' share of all reported inpatient
surgeries. Table 1 estimates the percentage of all inpatient hospital
surgeries, based on the number of inpatient surgeries reported to AHA
as performed by hospitals in different bedsize categories. This
percentage is used to estimate a share of the total of 415,000
autologous units collected by hospitals in each bedsize category, for
which testing would be newly required under the proposed rule. The
number of autologous units per hospital within a bedsize category is
based on the total estimated autologous units per bedsize category
divided by the total number of hospitals reported for that size
category. These estimates (rounded to the nearest whole unit) are
presented in the rightmost column of the Table 1.
Table 1.--Estimated Autologous Blood Units Per Hospital Based on
Estimated Share of Inpatient Surgeries by Bedsize Category and Total
Hospital Collections of Autologous Units
------------------------------------------------------------------------
Estimated
Estimated share of Estimated
Bedsize Non-federal percent 415,000 autologous
Category Hospitals inpatient collected units per
surgeries autologous hospital
units
------------------------------------------------------------------------
6 to 24 262 0.21 857 3
25 to 49 906 2.02 8,364 9
50 to 99 1,128 6.03 25,029 22
100 to 1,338 19.38 80,407 60
199
200 to 692 20.99 87,095 126
299
300 to 361 16.24 67,398 187
399
400 to 196 12.17 50,506 258
499
500 + 251 22.97 95,343 380
------------------------------------------------------------------------
The cost impact of testing autologous blood collections is based on
the above estimates of autologous units per hospital, and the earlier
estimated average HIV, HCV, HTLV, and HBV testing cost per donation of
$137.82 [$5.00 + $49.90+ $5.00 $38.50 + $39.20] + [0.0019 x $114.50].
The estimated annual cost impact per hospital, by bedsize category, is
shown in the Table 2. To provide some perspective on relative impact,
the newly-incurred cost for autologous unit testing is also shown as a
percentage of average annual gross revenues per hospital. The
notification cost is estimated to be approximately 0.01 percent of the
average annual gross revenues for every size category.
Table 2.-- Estimated Dollar Cost Per Hospital for Autologous Blood Testing and Estimated Cost as a Percentage of
Average Annual Revenues
----------------------------------------------------------------------------------------------------------------
Estimated Cost per Hospital Autologous Blood Testing
Bedsize Category at $138 per Newly Tested Gross Annual Revenue per Cost as Percent of Gross
Unit Hospital (Millions) Annual Revenue
----------------------------------------------------------------------------------------------------------------
6 to 24 $451 $5.459 0.01
25 to 49 $1,272 $12.606 0.01
50 to 99 $3,058 $27.711 0.01
100 to 199 $8,282 $74.803 0.01
200 to 299 $17,346 $153.988 0.01
300 to 399 $25,731 $236.917 0.01
400 to 499 $35,514 $329.161 0.01
500 + $52,351 $513.066 0.01
----------------------------------------------------------------------------------------------------------------
These findings of this analysis suggest that the relative cost
impact may be fairly consistent across hospitals of different sizes, if
the number of affected autologous units per bedsize category is
proportionate to the number of inpatient surgeries performed by
hospitals in different size categories. However, the distribution of
affected autologous units across hospitals of different size and types
of ownership is currently unknown. Because this information is
essential for the estimation of the economic impact on small entities,
FDA requests industry comment on the anticipated numbers of affected
units of autologous blood and their distribution across hospitals in
the industry, particularly those units collected by hospitals that can
be classified as small entities.
Regardless of size, the net cost impact for hospitals that must
begin testing autologous units may be limited because the cost of the
require testing may generally be shifted to patients or to third-party
payers, including Medicare. For example, the cost of units or packed
red blood cells or blood components, including costs of processing and
administration, are covered under both Medicare Part A and Part B (Ref.
16). Currently, Medicare pays for all but the first 3 pints of blood
per calendar year. A Medicare beneficiary may choose to pay for or
replace the first three units of blood, the annual blood deductible.
The specific requirements and anticipated costs for changes in
SOP's for donation collection, testing, labeling, quarantine, and
distribution are described previously. All blood establishments are
already engaged in a substantial amount of donation testing,
recordkeeping, unit labeling, and control. For some hospital blood
centers, these activities may be expanded. However, as indicated
previously, it is not clear whether the establishments most affected
could be characterized as small business entities.
The number of plasma facilities that would qualify as small
entities is also uncertain. According to the General Accounting Office
(Ref. 16) approximately 370 paid plasma
[[Page 45351]]
collection centers annually collect about 11 million liters of plasma,
the vast majority of which is processed by four companies: Alpha
Therapeutic Corp., Baxter Healthcare Corp., Bayer Corp., and Centeon
LLC. FDA estimates that approximately 90 percent of these plasma
collection centers are owned by companies that operate a number of
centers. Although the agency is uncertain about the level of revenues
for these companies, it is considered likely that most would have
annual receipts of $5 million or more per year. The remaining 10
percent of paid plasma collection centers may qualify as small business
establishments. The potential impact on these facilities will be a
function of the number of donors and the HCV repeatedly reactive
findings among donors at their facility. If the estimated 12 million
plasma donations were evenly distributed over the 487 registered
facilities, each facility would average 25,000 donations. Assuming
approximately 8 units per plasma donor per year (Ref. 16) each facility
would average 3,125 donors, approximately 6 [0.0018 x 3,125] of whom
might test repeatedly reactive for HCV and require supplemental
testing. The expected cost of the additional testing would then be $687
[$114.50 x 6] per facility per year.
In addition to these for-profit entities, the remaining 100 or so
plasma collection facilities, of the total of 487 registered
facilities, function within blood collection centers that are operated
by the American Red Cross, or are independently operated. The
independently operated, not-for-profit blood collection centers would
likely qualify as small entities. The added impact of the proposed rule
on plasma collection performed at blood collection facilities is
expected to be small, however, because the required testing would
already be performed for whole blood donation.
FDA has considered several alternatives for lessening burden on
small entities. The first alternative would be to not issue additional
requirements for testing of allogeneic or autologous donations for
evidence of infection due to communicable disease agents and continue
with the recommendations for testing in addition to the required tests
for HIV and HBV. FDA considers this alternative to be ineffective
because it does not promote consistency in testing and related
procedures among entities, does not provide FDA with clear enforcement
authority, and is converse to the agency's and industry's mission,
i.e., the safety of the blood supply. A second alternative would be to
continue to specify in the regulations the marker to be tested for,
such as a specific antigen or antibody. Tests for new or different
markers of infection due to a communicable disease agent have changed
as they become more appropriate or the technology in testing has become
more sensitive or specific. FDA believes this alternative would not
provide for the continued improvement in the testing regimen and would
limit flexibility not only in testing, but in controlling cost to the
different entities performing testing. Finally, FDA has requested
industry comment and suggestions for alternatives to autologous unit
testing, as discussed earlier under section `` C . Exceptions.''
V. The Paperwork Reduction Act of 1995
This proposed rule contains information collection provisions that
are subject to review by the Office of Management and Budget (OMB)
under the Paperwork Reduction Act of 1995 (PRA) (44 U.S.C. 3501-3520).
The title, description, and respondent description of the information
collection provisions are shown below with an estimate of the annual
reporting and recordkeeping burden. Included in this 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.
FDA invites comments on: (1) Whether the proposed collection of
information is necessary for the proper performance of FDA's functions,
including whether the information will have practical utility; (2) the
accuracy of FDA's estimate of the burden of the proposed collection of
information, including the validity of the methodology and assumptions
used; (3) ways to enhance the quality, utility, and clarity of the
information to be collected; and (4) ways to minimize the burden of the
collection of information on respondents, including through the use of
automated collection techniques, when appropriate, and other forms of
information technology.
Title: Requirements for Testing Human Blood Donors for Evidence of
Infection due to Communicable Disease Agents.
Description: FDA is proposing to revise the testing requirements in
part 610 subpart E issued under the authorities of the act and the PHS
Act. Currently, subpart E in part 610 requires testing for HBV and HIV
and the development and administration of product quarantine and
recipient notification (``Lookback'') program when donors test
repeatedly reactive for antibody to HIV, or otherwise are determined to
be unsuitable when tested in accordance with Sec. 610.45. FDA is
proposing to: (1) Require screening tests for evidence of infection due
to communicable disease agents for autologous donations; (2) require
supplemental (additional, more specific) testing of all repeatedly
reactive screening test results for which there is a supplemental test;
and (3) codify as requirements those recommendations that FDA has
issued that are necessary to ensure blood safety, including testing for
evidence of infection due to HIV, HBV, HCV, and HTLV.
FDA proposes to require that each donation of human blood or blood
component, including those intended for autologous use or as a
component of a medical device, be tested for evidence of infection due
to HIV, types 1 and 2; HBV; HCV; and HTLV, types I and II. Each
donation that tests repeatedly reactive when screened for evidence of
infection due to any of the communicable disease agents would be
required to be further tested whenever a supplemental (additional, more
specific) test has been approved for such use by FDA. Testing would be
required to be performed by a laboratory certified under CLIA and
registered with FDA in accordance with part 607. Deferral of donors
testing repeatedly reactive from future donations would be required.
Criteria are proposed for release or shipment of human blood or blood
components prior to completion of testing, and restrictions on use of
human blood or blood components that test repeatedly reactive when
screened for evidence of infection. The proposed rule would also
require manufacturers of test kits approved to test human blood donors
for evidence of infection due to communicable disease agents to verify
an acceptable sensitivity and specificity of each lot of test kit using
a reference panel obtained from CBER of other FDA designated source,
when available.
Description of Respondents: Manufacturers of blood and blood
components and clinical testing laboratories.
Based on June 1998 registration records, there are approximately
2,801 FDA registered blood collection facilities in the United States
that collect approximately 27,000,000 units of Whole Blood and Source
Plasma annually. To ensure consistency in the blood industry's testing
practices, FDA is proposing to require testing consistent with its
current recommendations and industry practice. Laboratories that
perform testing of donor blood samples must be registered with FDA in
accordance with part 607. Currently,
[[Page 45352]]
Sec. 607.65(g) provides an exemption from FDA registration to clinical
laboratories that are approved for Medicare reimbursement and which are
engaged in the testing of blood products in support of other registered
establishments. FDA is proposing to remove this exemption and require
such clinical labs to register. Because laboratories that currently
perform testing of donor blood samples are already registered, FDA
anticipates that the number of new registrants from clinical labs that
will no longer be exempt from registration will be one or less per
year. Under part 607 the burden for registrants not previously exempt
is approved under OMB 0910-0052. Under that OMB package, FDA estimated
the time required to prepare and send in the information for a new
registration is approximately 1 hour.
FDA proposes to permit the emergency release or shipment of human
blood or blood components prior to the completion of testing for
evidence of infection due to communicable disease agents. The agency
recognizes that there are rare medical emergencies, e.g., where a
patient's need for blood is so acute as to preclude any communicable
disease testing of the blood. FDA believes that the use of untested or
incompletely tested blood in such medical emergencies should not be
prohibited. FDA is proposing to remove Sec. 640.2(f), which provides
for emergency release of Whole Blood prior to completion of required
testing and to place the provision for medical emergency situations in
Sec. 610.40(e), which will be applicable to all blood products,
including Whole Blood. Release of blood or blood components due to a
medical emergency prior to completion of required testing must be
appropriately documented and the results of required testing provided
to the consignees as soon as possible. Because such a medical emergency
is a rare occurrence, FDA expects the recordkeeping and reporting
burden to be very minimal with one or less occurrence per year.
Documentation of the medical emergency should take a half hour or less
and the reporting of test results to consignees is considered under
section 1320.3(b)(2) of the PRA to be part of usual and customary
practice or procedures to finish the testing and provide the results.
FDA is proposing in Sec. 610.40(e) to permit, with FDA approval,
shipment of certain blood components for further manufacturing before
testing is completed and the test results are received by the
collection facility. The only product currently shipped prior to
completion of hepatitis B testing is a licensed product, Source
Leukocytes, used in the manufacture of interferon, which requires rapid
preparation from blood. Shipment of Source Leukocytes are preapproved
under a product license application (and the shipment does not have to
be reported to the agency). To obtain approval from FDA, the agency
would expect the manufacturer(s) to submit specific procedures for
collection, shipment, and quarantine of a product before testing is
completed, completion of testing as soon as possible after shipping,
and prompt communication of test results to the consignee. Based on the
number of applications for the manufacture of Source Leukocytes
received during fiscal year (FY) 95, FY 96, and FY 97, the agency
anticipates two applications may be received annually. According to
information from industry, a license application of this type would
contain safety and effectiveness information and would take
approximately 1,600 hours to prepare. FDA estimates that approximately
1 hour of the estimated 1,600 hours would be used in preparing the
request for FDA's approval to ship a product prior to completion of
testing.
According to information retrieved from FDA's database on licensed
establishments, there are approximately 145 manufacturers producing
licensed Source Leukocytes. Under Sec. 610.40(e)(2), the agency
estimates, based on information provided by industry, that each
manufacturer would ship approximately three units of blood or blood
components prior to testing the donor and that it would take an
estimated 15 minutes to provide the completed test results to the
consignee.
Under Sec. 610.40(f)(2)(ii), according to FDA's database, there are
approximately 343 licensed manufacturers that would ship known
repeatedly reactive units. Industry estimates that each manufacturer
would ship an estimated 10 units per month that would require two
labels; one as repeatedly reactive for the appropriate screening test,
and the other stating the exempted use specifically approved by FDA.
Industry also estimates that it would take approximately 10 minutes per
unit to affix the labels.
FDA estimates the burden for this collection of information as
follows:
Table 3.--Estimated Annual Reporting Burden1
----------------------------------------------------------------------------------------------------------------
Annual
21 CFR Section No. of Frequency per Total Annual Hours per Total Hours
Respondents Response Responses Response
----------------------------------------------------------------------------------------------------------------
607.20 1 1 1 1 1
610.40(e)(2) 145 36 5,220 0.25 1,305
610.40(f)(2)(ii) 343 120 41,160 0.2 8,232
Total 9,538
----------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of
information.
Table 4.--Estimated Annual Recordkeeping Burden1
----------------------------------------------------------------------------------------------------------------
Annual
21 CFR Section No. of Frequency per Total Annual Hours per Total Hours
Recordkeepers Recordkeeping Records Recordkeeper
----------------------------------------------------------------------------------------------------------------
610.40 1 1 1 1 1
----------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of
information.
Under section 1320.3(c)(2) of the PRA, the labeling requirements in
21 CFR 610.40(f)(2) and 610.42 do not constitute collection of
information because information required to be on the labeling is
originally supplied by the Federal Government to the manufacturers for
the purpose of disclosure to the public in order to keep
[[Page 45353]]
the blood supply safe and protect public health.
The reporting of test results to the consignee in Sec. 610.40(e)
does not constitute collection of information burden because it is the
customary and usual practice or procedure to finish the testing and
provide the results to the manufacturer responsible for labeling the
blood products.
In compliance with section 3507(d) of the PRA of 1995 (44 U.S.C.
3507(d)), the agency has submitted a copy of this proposed rule to OMB
for review of the information collection provisions. Interested persons
are requested to submit written comments regarding information
collection by September 20, 1999 to the Office of Information and
Regulatory Affairs, OMB (address above).
VI. Environmental Impact
The agency has determined under 21 CFR 25.31(j) that this action is
of a type that does not individual or cumulatively have a significant
effect on the human environment. Therefore, neither an environmental
assessment nor an environmental impact statement is required.
VII. Request for Comments
Interested persons may, on or before November 17, 1999, submit to
the Dockets Management Branch (address above) written comments
regarding this proposal, except that comments regarding information
collection provisions should be submitted in accordance with the
instructions in section V. of this document. Two copies of any comments
on issues other than information collection are to be submitted, except
that individuals may submit one copy. Comments are to be identified
with the docket number found in brackets in the heading of this
document. Received comments may be seen in the office above between 9
a.m. and 4 p.m., Monday through Friday.
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. Wallace, E. L., W. H. Churchill, D. M. Surgenor, J. An, G.
Cho, S. McGurk, and L. Murphy, ``Collection and Transfusion of Blood
and Blood Components in the United States, 1992,'' Transfusion, 35,
802-812, 1995.
2. American Association of Blood Banks, Facts About Blood and
Blood Banking, ``http://www.aabb.org/docs/facts.html''.
3. General Accounting Office, ``Blood Safety: Enhancing
Safeguards Would Strengthen the Nation's Blood Supply,'' GAO-HEHS-
97-143, June 1997.
4. AuBuchon, J. P., J. D. Birkmeyer, and M. P. Busch, ``Cost-
effectiveness of Expanded Human Immunodeficiency Virus Testing
Protocols for Donated Blood,'' Transfusion, 37:45-51, 1997.
5. Kaur, S., L. Rybicki, B. R. Bacon, J. L. Gollan, V. K.
Rustgi, W. D. Carey, and the National Hepatitis Surveillance Group,
``Performance Characteristics and Results of a Large-scale Screening
program for Viral Hepatitis and Risk Factors Associated with
Exposure to Viral Hepatitis B and C: Results of the National
Hepatitis Screening Survey,'' Hepatology, vol. 24, 5:979-986, 1996.
6. Lapane, K. L., A. F. Jakiche, D. Sugano, C. S. Wayne Weng,
and W. D. Carey, ``Hepatitis C Infection Risk Analysis: Who Should
Be Screened? Comparison of Multiple Screening Strategies Based on
the National Hepatitis Surveillance Program,'' The American Journal
of Gastroenterology, vol. 93, 4:591-596, 1998.
7. Tynell, E., S. Andersson, E. Lithander, M. Arneborn, J.
Blomberg, H. Bertil Hansson, A. Krook, M. Nomberg, K. Ramstedt, A.
Shanwell, and A. Bjorkman, ``Screening for Human T-Cell Leukaemia/
Lymphoma Virus Among Blood Donors in Sweden: Cost Effectiveness
Analysis,'' British Medical Journal, vol. 316, 1417-1422, May 1998.
8. Podnos, Y. D., and R. A. Williams, Current Risks for Blood
Borne Viral Illness in Blood Transfusions, Western Journal of
Medicine, vol. 168, 1:36-37, January 1998.
9. Myhre, B. A., and P. I. Figueroa, ``Infectious Disease
Markers in Various Groups of Donors,'' Annals of Clinical and
Laboratory Science, vol. 25, 1:39-43, 1995.
10. Public Health Service Inter-Agency Guidelines for Screening
Donors of Blood, Plasma, Organs, Tissues, and Semen for Evidence of
Hepatitis B and Hepatitis C, Morbidity and Mortality Weekly Report
40 (RR-4) April 19, 1991.
11. Margolis, H. S., P. J. Coleman, R. E. Brown, E. E. Mast, S.
H. Sheingold, and J. A. Arevalo, ``Prevention of Hepatitis B Virus
Transmission by Immunization: An Economic Analysis of Current
Recommendations,'' Journal of the American Medical Association, vol.
274, No. 15, October 1995.
12. U.S. Centers for Disease Control and Prevention, 1997,
``www.cdc.gov/ncidod/diseases/hepatitis''.
13. Morbidity and Mortality Weekly Report, 40 (RR-4) April 19,
1991.
14. Kim, W. R., J. J. Poterucha, J. E. Hermans, T. M. Therneau,
E. R. Dickson, R. W. Evans, and J. B. Gross, ``Cost-Effectiveness of
6 and 12 Months of Interferon Therapy for Chronic Hepatitis C,''
Annals of Internal Medicine, vol. 127, No. 10, November 1997.
15. Healthcare InfoSource, Inc., a subsidiary of the American
Hospital Association, Hospital Statistics, 1998 Edition, Chicago,
IL.
16. General Accounting Office, ``Blood Plasma Safety: Plasma
Product Risks Are Low if Good Manufacturing Practices Are
Followed,'' GAO-HEHS-98-205, September 1998.
17. American Association of Blood Banks (AABB) Association
Bulletin No. 95-4: AABB Position on Testing of Autologous Units.
Attachment 1: AABA Anonymous Autologous Survey Request, May 9, 1999.
List of Subjects
21 CFR Part 607
Blood.
21 CFR Parts 610 and 660
Biologics, Labeling, Reporting and recordkeeping requirements.
21 CFR Part 640
Blood, Labeling, Reporting and recordkeeping requirements.
Therefore, under the Federal Food, Drug, and Cosmetic Act and the
Public Health Service Act, and under the authority delegated to the
Commissioner of Food and Drugs, it is proposed that 21 CFR parts 607,
610, 640, and 660 be amended as follows:
PART 607--ESTABLISHMENT REGISTRATION AND PRODUCT LISTING FOR
MANUFACTURERS OF HUMAN BLOOD AND BLOOD PRODUCTS
1. The authority citation for 21 CFR part 607 continues to read as
follows:
Authority: 21 U.S.C. 321, 331, 351, 352, 355, 360, 371, 374; 42
U.S.C. 216, 262.
Sec. 607.65 [Amended]
2. Section 607.65 Exemption for blood product establishments is
amended by removing paragraph (g).
PART 610--GENERAL BIOLOGICAL PRODUCTS STANDARDS
3. The authority citation for 21 CFR part 610 continues to read as
follows:
Authority: 21 U.S.C. 321, 351, 352, 353, 355, 360, 371; 42
U.S.C. 216, 262, 263, 263a, 264.
4. The Table of Contents for subpart E of part 610 is revised to
read as follows:
Subpart E--Testing Requirements for Communicable Disease Agents
Sec.
610.40 Test requirements.
610.41 Donor deferral.
610.42 Restrictions on use for further manufacture of in vitro
diagnostic products.
610.44 Use of reference panels by manufacturers of test kits.
610.46 ``Lookback'' requirements.
610.47 ``Lookback'' notification requirements for transfusion
services.
5. The heading of subpart E is revised to read as follows:
[[Page 45354]]
Subpart E--Testing Requirements for Communicable Disease Agents
6. Section 610.40 is revised to read as follows:
Sec. 610.40 Test requirements.
(a) Human blood and blood components. Except as specified in
paragraph (b) of this section, each donation of human blood or blood
components intended for use in preparing a product, including donations
intended for autologous use or as a component of a medical device,
shall be tested for evidence of infection due to the following
communicable disease agents by using screening tests approved for such
use by the Food and Drug Administration (FDA) in accordance with the
manufacturer's instructions. One or more such tests shall be performed
as necessary to adequately and appropriately reduce the risk of
transmission of communicable disease.
(1) Human immunodeficiency virus, type 1;
(2) Human immunodeficiency virus, type 2;
(3) Hepatitis B virus;
(4) Hepatitis C virus;
(5) Human T-lymphotropic virus, type I;
(6) Human T-lymphotropic virus, type II.
(b) Exceptions. (1) Donations of Source Plasma are not required to
be tested for evidence of infection due to the communicable disease
agents listed in paragraphs (a)(5) and (a)(6) of this section.
(2) Donations of human blood or blood components intended solely as
a component of an in vitro medical device are not required to be tested
for evidence of infection due to the communicable disease agents listed
in paragraphs (a)(5) and (a)(6) of this section unless they contain
viable leukocytes.
(3) Requirements in this subpart shall not apply to the in-house
use or distribution of samples of blood, blood components, plasma, or
sera if intended for clinical laboratory testing or research purposes,
and not for administration to humans or use in the manufacture of a
product.
(c) Further testing. Each donation found to be repeatedly reactive
by a screening test performed in accordance with paragraph (a) of this
section shall be further tested whenever a supplemental (additional,
more specific) test has been approved for such use by FDA.
(d) Testing responsibility. Testing for evidence of infection due
to the communicable disease agents designated in paragraph (a) of this
section shall be performed by a laboratory registered in accordance
with part 607 of this chapter and certified to perform testing on human
specimens under the Clinical Laboratory Improvement Amendments of 1988
(42 U.S.C. 263a) in accordance with 42 CFR part 493.
(e) Release or shipment prior to testing. Human blood or blood
components that are required to be tested for evidence of infection due
to the communicable disease agents designated in paragraph (a) of this
section may be:
(1) Released for shipment or use before test results are available
only in appropriately documented medical emergency situations; or
(2) Shipped for further manufacturing as approved in writing by
FDA, provided the tests for evidence of infection due to communicable
disease agents are performed as soon as possible after release or
shipment and the results provided promptly to the consignee.
(f) Restrictions on shipment or use. (1) Human blood or blood
components that have a repeatedly reactive screening test for evidence
of infection due to a communicable disease agent(s) designated in
paragraph (a) of this section or that are collected from a donor with a
record of a repeatedly reactive screening test for evidence of
infection due to a communicable disease agent designated in paragraph
(a) of this section shall not be shipped or used, except as provided in
paragraph (f)(2) or (f)(3) of this section.
(2) The restrictions shall not apply to:
(i) Blood or blood components intended for autologous use, provided
that such units shall be appropriately labeled in accordance with
Sec. 606.121(i) of this chapter and with the following Biohazard
legend:
[GRAPHIC] [TIFF OMITTED] TP19AU99.000
(ii) Blood or blood components may be shipped or used under
conditions specifically approved in writing by FDA, provided that such
blood or blood components are appropriately labeled in accordance with
Sec. 606.121 or Sec. 640.70 of this chapter and display the Biohazard
legend. Such blood or blood components shall be labeled as repeatedly
reactive for the appropriate screening test for evidence of infection
due to the identified communicable disease agent. For blood or blood
components intended for further manufacturing into injectable products,
labeling shall include a statement indicating the exempted use
specifically approved by FDA. For blood or blood components intended
for in vitro use, labeling shall include the statement ``Caution: For
Further Manufacturing Into Non-Injectable Products For Which There Are
No Alternative Sources''.
(iii) Samples for in-house use or distribution if intended for
clinical laboratory testing or research purposes, and not intended for
administration in humans or use in the manufacture of a product.
(3) Human blood or blood components testing negative for evidence
of infection due to a communicable disease agent(s) designated in
paragraph (a) of this section from a donor with a record of a
repeatedly reactive result for the same screening test for evidence of
infection due to a communicable disease agent(s) designated in
paragraph (a) of this section may be used if the donor has been
subsequently shown to be suitable by a requalification method or
process found acceptable for such purposes by FDA.
7. Section 610.41 is revised to read as follows:
Sec. 610.41 Donor deferral.
Except for autologous donors and as provided in
Sec. 640.65(b)(2)(ii), (b)(2)(iii), and (b)(2)(iv) of this chapter,
donors testing repeatedly reactive for evidence of infection due to a
communicable disease agent(s) listed in Sec. 610.40(a) or reactive for
a serologic test for syphilis shall be deferred from future donations
of blood and blood components except:
(a) Donors who test repeatedly reactive for HTLV, types I or II, or
anti-HBc on only one occasion, unless further tested under
Sec. 610.40(c).
(b) Donors testing repeatedly reactive for HTLV, types I and II or
anti-HBc may serve as donors of Source Plasma.
(c)(1) Deferred donors testing repeatedly reactive for evidence of
infection due to a communicable disease agent listed in Sec. 610.40(a)
may serve as donors for blood or blood components when used in
accordance with Sec. 610.40(f).
(2) Deferred donors previously showing evidence of infection due to
hepatitis B virus when tested in accordance with Sec. 610.40(a) and (c)
may
[[Page 45355]]
donate blood or blood components for use as a component of a medical
device or may donate blood or blood components in the preparation of
Hepatitis B Immune Globulin (Human) provided their current donations
test nonreactive when tested in accordance with Sec. 610.40(a) and the
donor is otherwise determined to be suitable.
(d) Donors with a reactive serologic test for syphilis need not be
deferred if found negative by an approved specific treponemal test
(confirmatory test for syphilis).
(e) Deferred donors may be found to be suitable as donors of blood
or blood components by a method or process found acceptable for such
purposes by the Food and Drug Administration.
8. Section 610.42 is added to subpart E to read as follows:
Sec. 610.42 Restrictions on use for further manufacture of in vitro
diagnostic products.
In vitro diagnostic products manufactured from human blood or
blood components found to be repeatedly reactive by a screening test
performed in accordance with Sec. 610.40(a) shall be labeled in
accordance with Sec. 809.10 of this chapter, and shall include a
statement of warnings in the label indicating that the product was
manufactured from a donation found to be repeatedly reactive by a
screening test for evidence of infection due to the identified
communicable disease agent.
9. Section 610.44 is added to subpart E to read as follows:
Sec. 610.44 Use of reference panels by manufacturers of test kits.
When available, a reference panel shall be obtained from the Center
for Biologics Evaluation and Research or from a Food and Drug
Administration designated source, and shall be used by the manufacturer
to verify acceptable sensitivity and specificity of:
(a) Each lot of a test kit approved for use in testing donations of
human blood and blood components for evidence of infection due to
communicable disease agents listed in Sec. 610.40(a); and
(b) Each lot of a human immunodeficiency virus (HIV) test approved
for use in the diagnosis or monitoring of this communicable disease
agent. A lot that is found to be not acceptable for sensitivity and
specificity under Sec. 610.44(a) and (b) shall not be released.
Sec. 610.45 [Removed]
10. Section 610.45 Human Immunodeficiency Virus (HIV) requirements
is removed.
PART 640--ADDITIONAL STANDARDS FOR HUMAN BLOOD AND BLOOD PRODUCTS
11. The authority citation for 21 CFR part 640 continues to read as
follows:
Authority: 21 U.S.C. 321, 351, 352, 353, 355, 360, 371; 42
U.S.C. 216, 262, 263, 263a, 264.
Sec. 640.2 [Amended]
12. Section 640.2 General requirements is amended by removing
paragraph (f).
PART 660--ADDITIONAL STANDARDS FOR DIAGNOSTIC SUBSTANCES FOR
LABORATORY TESTS
13. The authority citation for 21 CFR part 660 continues to read as
follows:
Authority: 21 U.S.C. 321, 351, 352, 353, 355, 360, 371; 42
U.S.C. 216, 262, 263, 263a, 264.
Sec. 660.42 [Removed]
14. Section 660.42 Reference panel is removed.
Dated: April 20, 1999.
Jane E. Henney,
Commissioner of Food and Drugs.
Donna E. Shalala,
Secretary of Health and Human Services.
[FR Doc. 99-21296 Filed 8-18-99; 8:45 am]
BILLING CODE 4160-01-F