[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.

-----------------------------------------------------------------------

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

[[Page 45343]]

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