Requirements for Testing Human Blood Donors for Evidence of Infection Due to Communicable Disease Agents

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

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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.

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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