31146 Federal Register / Vol. 66, No. 112 / Monday, June 11, 2001 / Rules and Regulations

correct ‘‘Amendment No. 61–107, 63–

30, 65–41, 108–18, 121–280 and 135–

78’’ to read ‘‘Amendment Nos. 61–107,

63–30, 65–41, 108–18, 121–280 and

135–79’’.

Issued in Washington, DC on June 6, 2001.

Donald Byrne,

Assistant Chief Counsel, Regulations

Division.

[FR Doc. 01–14656 Filed 6–8–01; 8:45 am]

BILLING CODE 4910–13–M

DEPARTMENT OF TRANSPORTATION

Federal Aviation Administration

14 CFR Part 121 and 135

[Docket No. FAA–2000–7119; Amendment

No. 121–281 and 135–80]

RIN 2120–AG89

Emergency Medical Equipment;

Correction

AGENCY: Federal Aviation

Administration (FAA), DOT.

ACTION: Final rule; correction.

SUMMARY: This document contains a

correction to the final rule, published in

the Federal Register on April 12, 2001

(66 FR 19028). That final rule responds

to the Aviation Medical Assistance Act

of 1998 by requiring that air carrier

operators carry automated external

defibrillators on large, passengercarrying aircraft and augment currently

required emergency medical kits.

FOR FURTHER INFORMATION CONTACT: Judi

citrenbaum, (202) 267–9689.

Correction of Publication

In the final rule FR Doc. 01–8923,

beginning on page 19028 in the Federal

Register issue of April 12, 2001, make

the following corrections:

1. On page 19028, in column 1, in the

heading section, beginning on line 5,

correct ‘‘Amendment No. 121–280 and

135–78’’ to read ‘‘Amendment Nos.

121–281 and 135–80’’.

Issued in Washington, DC, on June 6, 2001.

Donald Byrne,

Assistant Chief Counsel, Regulations

Division.

[FR Doc. 01–14657 Filed 6–8–01; 8:45 am]

BILLING CODE 4910–13–M

DEPARTMENT OF HEALTH AND

HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 606, 607, 610, 640, 660,

and 809

[Docket No. 98N–0581]

Requirements for Testing Human

Blood Donors for Evidence of Infection

Due to Communicable Disease Agents

AGENCY: Food and Drug Administration,

HHS.

ACTION: Final rule.

SUMMARY: The Food and Drug

Administration (FDA) is revising the

general biological product standards

applicable to human blood and blood

components 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

supplemental (i.e., additional, more

specific) testing approved for such use

by FDA when a donation is found to be

reactive for any of the required

screening tests for evidence of infection

due to communicable disease agents.

The agency also is requiring

manufacturers of certain test kits to use

reference panels, when available, to

verify the acceptable sensitivity and

specificity of each lot. This final rule is

intended to help protect the safety and

ensure the quality of the Nation’s blood

supply, to enhance the safety of medical

devices containing blood or blood

components, to provide FDA with clear

enforcement authority, and to promote

consistency in the industry. Elsewhere

in this issue of the Federal Register,

FDA is publishing a rule requiring blood

and plasma establishments to notify

donors, including autologous donors,

whenever the donor is deferred or

determined not to be suitable for current

or future donations of blood and blood

components.

DATES: This rule is effective December

10, 2001.

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. Background

Requirements for testing blood donors

for hepatitis B surface antigen (HBsAg)

and antibody to human

immunodeficiency virus (anti-HIV) are

currently codified in part 610 (21 CFR

part 610), and requirements for

performing a serological test for syphilis

are codified in part 640 (21 CFR part

640). The agency has issued various

guidance documents to registered blood

and plasma establishments providing

recommendations for testing for

antibody to hepatitis B core antigen

(anti-HBc), antibody to human Tlymphotropic virus types I and II (antiHTLV I/II), antibody to hepatitis C virus

(anti-HCV), and HIV–1 p 24 antigen.

The purposes of the guidance

documents are to assist blood and

plasma 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, we (FDA)

determined that blood and plasma

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, we

proposed a regulation requiring testing

consistent with our current

recommendations and industry practice.

In the Federal Register of August 19,

1999 (64 FR 45340), we published a

proposed rule to revise the testing

requirements codified in part 610. The

proposed rule would require:

• Each donation of human blood or

blood component, including autologous

donations, to 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 reactive for

any of the required screening tests for

evidence of infection due to

communicable disease agents, to be

further tested using a supplemental

(additional, more specific) test that has

been approved for such use by FDA;

• The required testing to be performed

by a laboratory certified under the

Clinical Laboratory Improvement

Amendments of 1988 (CLIA) or meeting

equivalent requirements as described by

Health Care Financing Administration

(HCFA), and registered with FDA in

accordance with part 607 (21 CFR part

607);

• Deferral from future donations of

donors who test reactive;

• Criteria for release or shipment of

human blood or blood components prior

to completion of testing under limited

circumstances;

Federal Register / Vol. 66, No. 112 / Monday, June 11, 2001 / Rules and Regulations 31147

• Restrictions on shipment or use of

human blood or blood components that

test reactive when screened for evidence

of infection; and

• Manufacturers of approved test kits

used for testing donations of human

blood and blood components for

evidence of infection due to

communicable disease agents, or for use

in the diagnosis, or monitoring of HIV,

to verify an acceptable sensitivity and

specificity of each lot of test kit using a

reference panel obtained from FDA, or

an FDA designated source, when

available.

We provided 90 days for comments

on the proposed rule.

In the same Federal Register issue (64

FR 45355), we proposed new § 630.6 to

require blood and plasma

establishments to notify donors of

deferral based on evidence of infection

due to communicable disease agents or

failure to satisfy donor suitability

criteria. We intended to finalize the

donor notification rule and issue it

simultaneously with this document.

On November 9, 1999, we announced

a public workshop held on November

22, 1999, and extended to December 22,

1999, the comment period on both

proposed rules, entitled ‘‘Requirements

for Testing Human Blood Donors for

Evidence of Infection Due to

Communicable Disease Agents,’’ and

‘‘General Requirements for Blood, Blood

Components, and Blood Derivatives;

Notification of Deferred Donors.’’ The

purpose of the public meeting was to

provide a public forum for gathering

information and views regarding the

proposed rules.

II. Highlights and Summary of the Final

Rule

A. Plain Language

We have written the final rule using

plain language consistent with the

presidential memorandum on plain

language in government writing, dated

June 1, 1998. We have adopted the plain

language approach to make the rule

more accessible and understandable to

the public. As a result, we have used

pronouns in describing who must

comply, e.g., ‘‘you’’ refers, in the

appropriate context, to an establishment

that collects blood or blood components

or to an establishment that is a

consignee of a collecting establishment.

We also have used ‘‘must’’ instead of

‘‘shall,’’ and are using charts to clarify

provisions.

B. Test Requirements (§ 610.40)

In § 610.40(a) of the final rule, we

require the use of screening tests for

evidence of infection due to

communicable disease agents, i.e., HIV,

types 1 and 2; HBV; HCV; and HTLV,

types I and II, for each donation of

human blood and blood component. In

§ 610.40(b), we are requiring testing

using one or more tests to reduce

adequately and appropriately the risk of

disease transmission. We are allowing

for future advancements in testing

methodologies by not specifying the test

marker(s) for each disease agent. Further

testing is required of all donations,

including autologous (some exceptions

apply) that are reactive when screened

for evidence of infection due to any of

the communicable disease agents, using

supplemental (additional, more specific)

tests approved for such use by FDA in

§ 610.40(e). (See section IV of this

document.) We have eliminated the use

of the term ‘‘repeatedly reactive’’ and

replaced it with ‘‘reactive.’’ The

terminology was revised to allow for

future technology in testing, where the

process of repeating an initial reactive

result in duplicate would no longer be

appropriate. However, for the test

technologies recommended in current

guidance, ‘‘reactive’’ means ‘‘repeatedly

reactive,’’ because the manufacturers’

instructions for current tests require

duplicate retesting after an initial

reactive result.

Specified exceptions to the testing

requirements in § 610.40(c) are

described as they apply to a dedicated

donor (a donor whose collections are

used by an identified recipient, see

section V.B of this document), a donor

of Source Plasma, a donor of blood or

blood components intended as a

component of, or used to prepare, a

medical device (see section II.D of this

document), and samples used or

distributed for clinical laboratory testing

or research purposes and not intended

for administration to humans or in the

manufacture of a product.

In § 610.40(d) of the final rule, we

have created a separate paragraph for

autologous donations. Testing of

autologous donations is not required

under this section unless an autologous

donation of blood or blood components

potentially could be used for allogeneic

transfusion or shipped to another

establishment. If shipped to an

establishment that does not permit the

use of autologous donations for

allogeneic use, only the first donation in

each 30 day period must be tested as

discussed in section V of this document.

In § 610.40(f), testing required under

§ 610.40(a), (b), and (e) must be

performed by a laboratory registered

under part 607 and either certified to

perform testing on human specimens

under the Clinical Laboratory

Improvement Amendments of 1988 (42

U.S.C. 263a) under 42 CFR part 493 or

has met equivalent requirements as

determined by HCFA under those

provisions. Therefore, § 607.65(g) is

removed, formerly exempting from

registration clinical laboratories that are

approved for Medicare reimbursement

and are engaged in the testing of blood

products in support of other registered

blood establishments.

Release or shipment prior to

completion of testing in § 610.40(g) may

occur in appropriately documented

emergency medical situations, or when

approved in writing by FDA, provided

that the shipping establishment notifies

the consignee that test results are not yet

available, that the tests for

communicable disease agents are

completed as soon as possible, and that

the results are provided promptly to the

consignee.

Under § 610.40(h), an establishment

must not ship or use blood or blood

components that have a reactive

screening test for a communicable

disease agent(s) or reactive serological

test for syphilis, or that were collected

from a donor with a previous record of

a reactive screening test for a

communicable disease agent(s) or

reactive serological test for syphilis.

Exceptions to this requirement are:

• For blood and blood components

from autologous donors when labeled as

required in § 610.40(d);

• When approval in writing is

obtained from FDA and the blood or

blood component is labeled as required

under § 610.40(h)(2)(ii);

• Samples for use or distribution, if

intended for clinical laboratory testing

or research and not intended for

administration in humans or for further

manufacturing use;

• When a collection from a donor with

a record of a reactive screening test

result tests negative and the donor is

shown, or previously was shown, to be

suitable by an acceptable requalification

method; and

• When a collection from a donor,

who tests reactive for anti-HBc and

otherwise is determined to be suitable,

may be used for further manufacturing

into plasma derivatives without prior

FDA approval or the ‘‘BIOHAZARD’’

legend.

C. Donor Deferral (§ 610.41)

Under § 610.41(a), any donor of blood

and blood components, including an

autologous donor, who tests reactive for

a communicable disease agent(s)

described under § 610.40(a) or reactive

with a serological test for syphilis must

be deferred from future donations.

Exceptions apply as follows:

31148 Federal Register / Vol. 66, No. 112 / Monday, June 11, 2001 / Rules and Regulations

• A donor who tests reactive for antiHTLV I/II or anti-HBc only once is

permitted to donate again without being

deferred from further donation unless

there is further testing using an

approved supplemental (additional,

more specific) test;

• A deferred donor who tests reactive

for HIV, types 1 and 2, HBV, HCV,

HTLV types I and II, or syphilis may

donate blood or blood components to be

shipped or used under the provisions

described in § 610.40(h)(2)(ii);

• A deferred donor who showed

evidence of infection due to HBsAg

when previously tested may donate

blood or blood components to be used

in the preparation of Hepatitis B

Immune Globulin (Human) provided the

donor’s current donation tests

nonreactive for HBsAg and the donor

otherwise is determined to be suitable;

• A deferred donor who tests reactive

for anti-HBc or for evidence of infection

due to HTLV, types I and II, may serve

as a donor of Source Plasma collected

for further manufacturing use;

• A deferred donor who tests reactive

by a screening test for syphilis may

serve as a donor of human blood and

blood components, if the donation is

further tested by an adequate and

appropriate test demonstrating that the

reactive screening test is a biological

false positive; and

• A deferred donor who tests reactive

for a communicable disease agent(s)

described under § 610.40(a) or reactive

with a serological test for syphilis may

serve as an autologous donor.

Under new § 630.6 in the donor

notification rule found elsewhere in this

issue of the Federal Register, all

deferred donors, including those

deferred donors who may serve as

donors under specified conditions

described in § 610.41, must be notified

of their deferral.

Under § 610.41(b) the regulations

permit the reentry of a deferred donor

into the donor pool when the donor is

requalified by a process or method

(algorithm) approved by FDA for such

purpose.

D. Medical Devices (§§ 610.42 and

610.44)

In the proposed rule, we discussed

the need for labeling of medical devices

manufactured from reactive blood or

blood components. In the final rule, we

have changed the text of § 610.42 to

require labeling for all medical devices

that contain blood or a blood

component as a medical device

component, and not just in vitro

diagnostic products. Under § 610.42(a),

when a medical device contains human

blood or a human blood component as

a component of the final device and the

human blood or blood component was

found to be reactive by a screening test

for a communicable disease agent(s) or

reactive by a serological test for syphilis

then the device labeling requires a

warning statement indicating that the

product was manufactured from a

donation found to be reactive by a

screening test for evidence of infection

due to the identified communicable

disease agent(s). Other labeling

requirements in subchapter H (Medical

Devices) of chapter I would also apply.

We also are allowing for an exemption

approved by FDA to the statement of

warning in circumstances where the

reactivity of the human blood or blood

component in the device presents no

significant health risk through the use of

the device.

In proposed § 610.44, manufacturers

of test kits would be required to use,

when available, a reference panel

obtained from FDA or from a FDA

designated source to verify the

sensitivity and specificity of kits

approved for use in testing donations of

blood and blood components for

communicable disease agents listed in

§ 610.40(a) and for an HIV test approved

for use in the diagnosis and monitoring

of HIV.

In the final rule, we are amending the

requirements to clarify that when

available and appropriate, a

manufacturer must use panels that have

been provided or identified by FDA to

verify acceptable sensitivity and

specificity of kits used to test donations

of human blood and blood components,

including licensed supplemental

(additional, more specific) tests. The

agency is making this change after

reviewing 21 CFR 660.46. That

regulation recognizes that official lot

release may not be required after a

manufacturer consistently produces a

product that meets specifications.

Consistent with this policy, the agency

has recognized that less strict reference

standard testing requirements may be

appropriate in some situations.

Accordingly, FDA has revised 1§ 610.44

to require use of reference panels only

when such use is appropriate and

panels are available. Moreover, FDA

may determine that reference panel

testing of each lot is not appropriate,

based on a manufacturer’s consistent

prior production of products of

acceptable sensitivity and specificity. In

that situation, intermittent testing of lots

may be appropriate.

FDA also is clarifying that

§ 610.44(a)(2) requires manufacturers of

an HIV test kit approved for use in

diagnosis, prognosis, or monitoring to

use an FDA provided or designated

reference panel, when available and

appropriate to assure acceptable

sensitivity and specificity of each lot of

test kit. When available and appropriate,

FDA expects the manufacturer to

perform testing using the panel to assure

that each lot meets acceptable

sensitivity and specificity.

The agency also is making a

conforming amendment to § 809.20(b)

(21 CFR 809.20(b)), to make clear that

§ 610.44 applies to all HIV test kits that

are biological products, and are

approved for diagnosis, prognosis, or

monitoring, including any such kits

reviewed under the medical device

authorities.

In the proposed rule, we stated that as

technology and scientific knowledge

advance, and the demands placed on

the blood industry change, there will

continue to be instances when a

regulation will become outdated or

where unanticipated circumstances may

warrant a departure from a regulation.

To allow for flexibility in such cases, we

discussed the availability of approval

for exemption upon written request

from a manufacturer to FDA. We also

noted that, under § 640.120, applicants

may submit requests for exceptions or

alternatives to regulations regarding

blood, blood components, or blood

products. Consistent with this policy,

we created a similar provision in the

final rule that is applicable to the

labeling of medical devices in § 610.42,

and distribution of lots found not to be

acceptable for sensitivity and specificity

in § 610.44. We would approve an

exception or alternative under these

sections only if we concluded that the

safety, purity, potency, and

effectiveness of the final product were

adequately assured. Manufacturers may

submit, in writing to FDA, a request for

an exception or alternative to

§§ 610.42(a) and 610.44(b). In limited

circumstances, a request and approval

may be made orally followed by a

written request and written approval.

E. Technical Amendments

We also made technical changes to

existing regulations, consistent with this

rulemaking. We removed §§ 606.121(g),

607.65(g), 610.45, 640.2(d), and 660.42.

We revised §§ 640.5(f) and 640.67 for

consistency with § 610.40, and in

§§ 606.121(h)(2) and (h)(3), 640.14,

640.23(a), 640.33(a), and 640.53(a) we

deleted ‘‘§ 610.45.’’ We have amended

§§ 606.121(e)(5)(ii) and 640.70(a)(2) to

conform with the labeling requirement

in § 610.40(h)(2)(ii)(E), and amended

§ 809.20(b) to conform with § 610.44.

Federal Register / Vol. 66, No. 112 / Monday, June 11, 2001 / Rules and Regulations 31149

III. Testing for Syphilis

In the proposed rule, we solicited

comments, with supporting data, from

the public in regard to the value of such

a test as a marker of high risk behavior,

as a surrogate test for other

communicable diseases, and as a screen

for syphilis in blood and blood

components to prevent transfusionrelated transmission. We recognized

that many scientists, including some

members of the blood banking

community, continue to advocate the

elimination of the serological test for

syphilis as a testing requirement.

Comments were received and are

discussed in comment 28 of this

document. We have concluded that

there are insufficient data to justify

eliminating the requirement for a

serological test for syphilis. Therefore,

§§ 640.5(a) and 640.65(b) remain in

effect at this time. The agency remains

interested in receiving scientific data to

clarify the value of performing serologic

tests for syphilis on donations of blood

and plasma.

IV. Relevant Guidance

Over time, we have issued guidance

representing the agency’s current

thinking on the adequate and

appropriate testing of blood and blood

component donations for evidence of

infection due to various communicable

disease agents. Because we are not

specifying the test or tests to be used in

this regulation, we are listing in the

following table the test or tests we

currently believe reduce adequately and

appropriately the risk for transmission

of communicable disease agents.

TABLE 1.—SCREENING TESTS

Tests

Whole Blood and

Blood Components

Including Recovered Plasma

Components of, or

Used to Prepare,

Medical Devices

Containing Viable

Leukocytes

Components of, or

Used to Prepare,

Medical Devices

Not Containing

Viable Leukocytes

Source Plasma

Serological Test for Syphilis (STS) X X X X

Antibodies to HIV, types 1 and 2 (anti-HIV) X X X X

HIV–1 Antigen (HIV–1 Ag) X X X X

Hepatitis B Surface Antigen (HBsAg) X X X X

Antibody to Hepatitis B Core Antigen (anti-HBc) X X1 X1

Antibody to Hepatitis C Virus Encoded Antigen (antiHCV)X XX X

Antibodies to HTLV, types I and II (anti-HTLV I/II) X X

1Anti-HBc testing not recommended for donations intended solely for further manufacturing into in vitro medical devices.

TABLE 2.—ADDITIONAL MORE SPECIFIC TESTS

Tests STS anti-HIV HIV–1Ag HBsAg anti-HBc anti-HCV anti-HTLV I/II

Approved Supplemental

Tests X X X1 X1 X

1A neutralization assay is performed as part of the screening test procedure for a reactive sample.

As technology advances, we intend to

regularly issue guidance describing

those tests that we believe would

adequately and appropriately reduce the

risk of transmission of communicable

disease agents. Unless we determine

that prior public participation is not

feasible or appropriate, we intend to

issue such guidance in draft, giving the

opportunity for public comment and for

manufacturers to prepare to use any

appropriate new testing technologies.

When prior public participation is not

feasible or appropriate, for example,

when immediate action is necessary to

protect the public health, we may

immediately implement the guidance.

We have prepared a list of guidance

documents that currently are applicable

to these regulations. They are listed in

order by date of issuance.

• Recommendations for the

Management of Donors and Units that

are Initially Reactive for Hepatitis B

Surface Antigen (HBsAg); December 2,

1987

• HTLV–I Antibody Testing;

November 29, 1988

• FDA Recommendations Concerning

Testing for Antibody to Hepatitis B Core

Antigen (Anti-HBc); September 10, 1991

• Clarification of FDA

Recommendations for Donor Deferral

and Product Distribution Based on the

Results of Syphilis Testing; December

12, 1991

• Revised Recommendations for

Testing Whole Blood, Blood

Components, Source Plasma and Source

Leukocytes for Antibody to Hepatitis C

Encoded Antigen (Anti-HCV); April 23,

1992

• Revised Recommendations for the

Prevention of Human

Immunodeficiency Virus (HIV)

Transmission by Blood and Blood

Products; April 23, 1992

• Revised Recommendations for

Testing Whole Blood, Blood

Components, Source Plasma and Source

Leukocytes for Antibody to Hepatitis C

Virus Encoded Antigen (Anti-HCV)

[Supplements previous guidance April

23, 1992]; August 5, 1993

• Donor Suitability Related to

Laboratory Testing for Viral Hepatitis

and a History of Viral Hepatitis;

December 22, 1993

• Recommendations for Donor

Screening with a Licensed Test for HIV–

1 Antigen; August 8, 1995

• Additional Recommendations for

Donor Screening with a Licensed Test

Kit for HIV–1 Antigen [Supplements

previous guidance August 8, 1995];

March 14, 1996

• Additional Recommendations for

Testing Whole Blood, Blood

Components, Source Plasma, and

Source Leukocytes for Antibody to

Hepatitis C Virus Encoded Antigen

(Anti-HCV) [Supplements previous HCV

guidance—April 23, 1992 and August 5,

1993]; May 16, 1996

• Guidance for Industry: Donor

Screening for Antibodies to HTLV–II;

August 15, 1997

• Guidance for Industry: Errors and

Accidents Regarding Saline Dilution of

31150 Federal Register / Vol. 66, No. 112 / Monday, June 11, 2001 / Rules and Regulations

Samples Used for Viral Marker Testing;

June 11, 1998

The guidance documents referenced

in this document or otherwise

applicable to the testing of donors of

blood and blood components 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 connect to CBER at http:/

/www.fda.gov/cber/publications.htm.

V. Comments on the Proposed Rule

We received 24 letters of comment on

the proposed rule, most of which raised

multiple issues. The comments were

submitted by blood centers, hospitals,

transfusion services, trade associations,

and professional associations. A number

of comments expressly supported our

revision of communicable disease

testing requirements to incorporate the

agency’s guidance and industry practice

into one comprehensive regulatory

framework to help ensure the safety of

the blood supply. A summary of the

comments and the agency’s responses

follow.

A. Testing of Autologous Donations

In the proposed rule, each donation of

autologous blood and blood component

would be tested for evidence of

infection due to the following

communicable disease agents: HIV,

types 1 and 2; HBV; HCV; and HTLV,

types I and II. The testing would be

performed using screening tests

approved for such use by FDA. One or

more such tests would be performed as

necessary to reduce adequately and

appropriately the risk of transmission of

communicable disease. Restrictions on

shipment or use would not apply to

autologous blood and blood components

provided the autologous blood and

blood components are labeled

appropriately. We requested comments

on alternatives (including the rationale)

to testing each autologous donation,

such as procedural or labeling

improvements. A majority of comments

submitted to us responded to this issue.

(Comment 1) Six comments support

testing autologous donations in the

same manner as allogeneic donations.

The comments argue that a significant

error rate in the use of autologous blood

for allogeneic use or use in preparing a

product, makes the current risks to

recipients of blood and blood

components unacceptable. They further

argue that testing will reduce these

risks, as well as the risk to healthcare

workers from inadvertent exposure.

Several of these comments recommend

that autologous donations testing

reactive for a communicable disease

agent(s) should not be exempt from the

restrictions on shipment and use in the

proposed rule. They argue that positive

donations of autologous blood should be

discarded to protect the health of

healthcare workers and to prevent

inadvertent use of such autologous

blood for allogeneic transfusions.

Eleven comments oppose testing of

autologous donations for evidence of

infection due to communicable disease

agents. These comments argue that

testing would not significantly reduce

the risk of inadvertent allogeneic

transfusions with autologous blood and

blood components because testing alone

does not address the process errors that

cause inadvertent allogeneic

transfusions. Errors in labeling and

handling autologous blood will occur

regardless of whether donations are

tested. Several comments argue that we

presented no data to suggest testing will

reduce inadvertent allogeneic

transfusion. One comment points out

that inadvertent allogeneic transfusion

errors occur despite the fact that an

estimated 60 to 70 percent of autologous

donations currently are tested. The

comments that argue against testing

instead support regulation that focuses

on improving quality assurance systems.

These comments recommend

optimizing labeling, separating

processing paths and segregating storage

for autologous donations, as well as

requiring multiple identifications of

recipients to address directly all

(autologous and allogeneic) transfusion

errors. Finally, comments opposed to

testing autologous donations argue that

the significant costs of testing are

unwarranted given the lack of clinical

utility. They argue that in many cases,

particularly in small, rural hospitals

where patients will have few

alternatives, the costs of testing will be

prohibitive and will result in reduced

availability of autologous services.

Several comments also suggest that

reduced availability of autologous

donations will result in an increase in

allogeneic use with its attenuated risks

outweighing any minor increase in

safety from testing autologous

donations.

A number of comments recommend

an intermediate position between

testing all autologous donations and

testing none. Three comments support

testing only one in a series of autologous

donations, noting that many autologous

donors donate multiple donations in a

short timeframe, therefore, testing each

donation would result in significant

costs without any appreciable increase

in safety to the blood supply. One

comment calls for testing autologous

donations once in 30 days if the

autologous donation is to be shipped

from the collection establishment before

transfusion. If the donation is collected

and transfused in the same facility, the

comment recommends no testing be

required. The same comment supports

labeling all autologous donations with a

unique label stating ‘‘FOR

AUTOLOGOUS USE ONLY’’ and all

reactive or untested donations with a

‘‘BIOHAZARD’’ legend. Further, the

comment calls for prohibiting

establishments from using autologous

donations as allogeneic donations. The

comment argues that requiring testing

every 30 days for shipped autologous

donations, labeling changes, and

preventing the use of autologous blood

and blood components for allogeneic

transfusion are better, more costefficient methods of protecting patients

and health care personnel.

Based on the comments submitted

and our own evaluation, the agency has

concluded that its proposal to test all

autologous donations in the same

manner as allogeneic donations should

be amended. While communicable

disease testing plays a major role in

improving the safety of the allogeneic

blood supply, we are not convinced that

the testing of all autologous donations is

necessary to improve the safety of the

general blood supply. It is the

inadvertent improper use of autologous

donations, rather than the product itself,

which poses risk to the public health.

Many of the incidents involving

autologous donations that compromise

transfusion safety are caused by process

or clerical error. As one comment points

out, these errors occur regardless of

whether the autologous donation is

tested and its communicable disease

status is known. We are persuaded that

such errors involving autologous

donations can be better addressed by

changes in labeling and processing of

autologous donations. We believe that

clearly marking autologous donations as

‘‘DONOR UNTESTED,’’ as well as with

the autologous label (§ 606.121(i) (21

CFR 606.121(i))), will alert healthcare

workers that they could be handling

potentially infectious products and

Federal Register / Vol. 66, No. 112 / Monday, June 11, 2001 / Rules and Regulations 31151

should take appropriate precautions. We

believe that not requiring testing of

autologous donations will help assure

continued autologous services at certain

small, rural blood establishments,

which do not use autologous donations

for allogeneic use. We believe that these

labeling changes will sufficiently

increase the safety of autologous

transfusions without compromising the

availability of these services.

However, we have concluded that

under certain circumstances there is a

potential risk to blood safety from

autologous donations, and under those

circumstances labeling changes alone

are insufficient to protect the public

health. First, blood establishments that

permit autologous donations to be used

for allogeneic transfusions run a

potentially greater risk of erroneous

transfusion of an autologous donation to

an unintended recipient. We are

requiring that establishments that

maintain a program permitting

allogeneic use of autologous donations

test each autologous donation collected

regardless of whether the particular

blood or blood component is ‘‘crossedover’’ for allogeneic use. Positive and

reactive donations must be labeled with

a ‘‘BIOHAZARD’’ legend as well as with

the label ‘‘FOR AUTOLOGOUS USE

ONLY’’ as required under § 606.121(i).

Autologous donations that test negative

for evidence of infection due to

communicable disease agents must be

labeled ‘‘FOR AUTOLOGOUS USE

ONLY’’ as further specified under

§ 606.121(i). The agency believes that

blood establishments that use

autologous donations for allogeneic uses

should be subject to these additional

safety measures to prevent erroneous

allogeneic uses. The agency believes

that for such establishments the

additional margin of safety achieved by

testing all donations in the

establishment’s inventory and labeling

reactive donations with a

‘‘BIOHAZARD’’ legend is necessary to

protect the public health.

The second area in autologous

transfusion services that presents

additional safety concerns is the

shipment of autologous products from

the collection facility to another

establishment. Errors, including clerical

errors in inventory management and

breakage of autologous donations, may

occur when the product is handled by

a variety of individuals and facilities

throughout collection, transport,

storage, and transfusion. We are

requiring that blood establishments that

ship autologous products to other

establishments that do not use

autologous donations for allogeneic use

must test the first autologous donation

collected at the beginning of each 30-

day period for evidence of infection due

to communicable disease agents. We

believe a minimum requirement of

testing the autologous donor’s blood at

least once in 30 days is sufficient

because autologous donations are

usually given in a series over a short

timeframe. Because these donations are

not intended to be transfused into any

other recipient than the donor, testing

once in 30 days for evidence of infection

due to communicable disease agents

will give an added measure of safety to

those handling the blood without the

costs of testing each autologous

donation. Thus, if an autologous donor

donated three times over a 30-day

period and the establishment ships the

autologous donations to another

establishment that does not allow use of

autologous donations for allogeneic

transfusion, the rule requires, at a

minimum, that the establishment test

the first collection only. If the donor

donated a fourth time on the 31st day

or later, the establishment must test the

fourth collection.

(Comment 2) One comment raises

several additional arguments against

testing autologous donations including:

Testing may give a false sense of

increased protection resulting in

decreased attention and more errors;

testing may result in denial of services

to patients or loss of autologous donor

programs; and testing of autologous

donations constitutes the practice of

medicine since autologous donors are

patients under a doctor’s care.

We do not believe that testing of

autologous donations will result in

decreased attention and more errors.

Communicable disease testing of

allogeneic blood and blood components

has been an important and effective tool

to ensure the safety of the blood supply.

Testing of autologous donations, which

are shipped to or collected in an

establishment that maintains a program

that uses autologous blood and blood

components for allogeneic transfusion

will provide an additional margin of

safety against a potentially greater risk

of error. We do not believe that

communicable disease testing of

autologous donations will result in a

denial of such services to patients or in

the loss of such programs. We are not

requiring testing of autologous blood

and blood components except when an

establishment has a program allowing

the use of autologous donations for

allogeneic transfusion, or ships the

autologous donations from the

collecting facility. We believe this

approach allows services and programs

for autologous collections to continue

while protecting potential allogeneic

recipients and healthcare workers who

may be exposed to biohazardous blood

or blood components.

The comment views the testing of

autologous donations as practice of

medicine. However, we do not consider

testing of autologous donations to be

practice of medicine, but to be a

safeguard in protecting the public health

when autologous donations are made

available for allogeneic use or when

others may be exposed to potentially

hazardous donations during shipment of

autologous donations by the collecting

establishment. This policy responds to a

recommendation in the February 1997

report issued by the General Accounting

Office entitled ‘‘Blood Supply: FDA

Oversight and Remaining Issues of

Safety.’’

(Comment 3) Two comments argue

that testing and labeling autologous

blood and blood components can

seriously jeopardize the confidentiality

of the donor’s communicable disease

status.

We do not believe the required testing

and labeling of autologous donations

will seriously compromise the donor’s

confidentiality. The final rule does not

require most autologous donors to be

tested, and labeling on untested

autologous donations will not raise

confidentiality issues. In addition, the

label will not identify in any manner the

donor’s particular communicable

disease status. The ‘‘BIOHAZARD’’

legend on donations from autologous

donors who test positive or reactive will

serve as a necessary alert for blood

healthcare workers and help prevent

transfusion errors. We recommend that

autologous donors be informed

beforehand if their donations will be

tested for evidence of infection due to

communicable disease agents. Thus,

autologous donors may choose not to

donate in a setting where testing is

required.

(Comment 4) Seven comments raise

the issue of what to do with autologous

blood or blood components that test

reactive by one or more of the

communicable disease agents identified

in § 610.40(a). Several of these

comments point out that blood

establishments are under ethical and

legal constraints that would prevent

them from discarding test positive

autologous donations. Several

comments suggest that under a recent

Supreme Court decision it may be a

violation of the American with

Disabilities Act (‘‘ADA’’) to deny HIVinfected patients the right to use their

own blood. Two comments strongly

support discarding autologous

donations testing reactive. These

comments argue that the risks from

31152 Federal Register / Vol. 66, No. 112 / Monday, June 11, 2001 / Rules and Regulations

keeping these positive donations in

blood inventories are too great. The

comments argue these donations should

be treated similarly to blood from a

positive allogeneic donor and discarded.

We are not prohibiting blood

establishments from transfusing positive

donors with their own blood. These

donations, however, if made available

for autologous use must be labeled

‘‘FOR AUTOLOGOUS USE ONLY’’ and

also with a ‘‘BIOHAZARD’’ legend.

(Comment 5) Several comments call

for prohibiting the use of autologous

donations for allogeneic transfusion for

all blood collection establishments. The

comments argue that the benefit of

testing would be negated if test positive

autologous donations remain in the

system subject to the processing errors

that can occur when use of autologous

donations for allogeneic transfusions is

permitted.

The agency has determined that this

final rulemaking is not the appropriate

venue to institute a requirement

prohibiting use of autologous donations

for allogeneic use. However, we believe

that this issue should be considered

further in the more general context of

medical errors. In the interim, we

believe that requiring blood

establishments that continue the

practice of using autologous donations

for allogeneic transfusions to test and

appropriately label all their autologous

donations will help control errors

involving autologous donations testing

reactive for a communicable disease

agent(s).

(Comment 6) Four comments point

out that the proposed rule does not

address perioperative autologous blood

collections. Two comments suggest that

requiring testing of perioperative

collections would effectively eliminate

them because testing would not be

completed in time for donations to be

used. One comment suggests the final

rule should contain an exception for

intraoperatively salvaged blood.

We are not proposing testing of

perioperative blood collections. These

blood or blood components are

collected and used within the same

facility where the operation is being

performed, and are not intended for

allogeneic use. They also do not become

part of the transfusion center’s or blood

collection establishment’s inventories.

Therefore, we do not consider

perioperative blood or blood component

donations subject to testing for evidence

of infections under the purview of the

final rule.

(Comment 7) Four comments suggest

that we deal with the issue of the

inappropriate use of recovered plasma

for further manufacture from untested or

communicable disease marker reactive

autologous blood by banning the use of

untested or reactive recovered plasma or

by requiring testing of autologous blood

to be used for salvage.

Under 21 CFR 606.100(b)(18), blood

establishments are required to establish

and maintain standard operating

procedures (SOP’s) for recovered

plasma. If a blood establishment intends

to use recovered plasma from an

untested donation for further

manufacturing use, the donation would

then be considered an allogeneic

donation subject to the testing

requirements for allogeneic donations

under the final rule. The use of untested

or reactive autologous blood for further

manufacturing is prohibited unless

exempted under § 610.40(h)(2).

B. Exception for Dedicated Apheresis

Donations

We requested comments on whether

to exempt from testing for evidence of

infection due to communicable disease

agents each donation from a dedicated

apheresis donor (defined in section I.B

of this document) and instead test such

donors only once in each 30-day period.

(Comment 8) Eight comments

responded to this request. One comment

opposes a once in each 30-day period

testing exception for dedicated

apheresis donors, arguing that recipients

of these donations are entitled to the

same protection as other recipients of

blood components. The remaining seven

comments support allowing testing of

dedicated apheresis donors only once

every 30 days. These comments cite the

fact that dedicated apheresis donations

are often used for patients in dire

situations who are unable to wait for

each donation to be tested. They argue

that dedicated apheresis donations

tested only once in each 30-day period

would not present a safety concern

because new tests have substantially

increased the reliability of the first

donation’s test results; because

subsequent donations during the 30-day

period would create little additional risk

to the recipient, since the first donation

would expose the recipient to any

undetected infection; and because new

risk of exposure could be caught by

taking the donor’s medical history

(including health and social history

screening) on the day of each

subsequent collection. (See 21 CFR

640.3(a).)

Based on the comments submitted

and the agency’s own evaluation, we

have concluded that donations from

dedicated apheresis donors must be

tested for evidence of infection due to

communicable disease agents at the first

donation and at a minimum of once at

the beginning of each successive 30-day

period. This exception from universal

testing will provide the recipient of

dedicated apheresis donations with

adequate protection against disease

transfer since the test results would be

unlikely to change within the 30-day

period. We also believe this exception

will limit donor exposure when the

patient needs frequent transfusions and

will help avoid delaying treatment of

patients in need of emergency

transfusions.

(Comment 9) One comment suggests

that the communicable disease agent

testing should be allowed near the time

of the first collection to facilitate

expedited release of dedicated apheresis

donations to patients in need.

We have reviewed the comment and

will consider permitting communicable

disease agent testing prior to collection

of the first dedicated donation in the

context of creating specific standards for

dedicated donations in future

rulemaking.

(Comment 10) Two comments call for

use of an abbreviated donor screening

questionnaire for dedicated apheresis

donors.

Since we are limiting testing for

evidence of infection due to

communicable disease agents to the first

donation in each 30-day period, we

believe that the screening process plays

an even more important role in

evaluating the safety of the blood or

blood component being collected from

the dedicated donor. The possible

implications of an abbreviated screening

are not in the scope of this rulemaking,

and are under study for future

rulemaking.

(Comment 11) Two comments suggest

extending this exception from universal

testing to other dedicated blood

components (e.g. dedicated granulocyte

donors; parent to child donations of

plasma or red blood cells).

We agree with this comment. We

believe that donations from dedicated

donors should be treated alike in

regards to communicable disease

testing. Accordingly, the agency has

extended the exception allowing testing

for evidence of infection due to

communicable disease agents to the first

donation in each 30-day period for all

donations of blood and blood

components from dedicated donors to a

single, identified recipient. Syphilis

testing is required, at a minimum, for

the first donation in each 30-day period

in addition to the other communicable

disease agents listed in § 610.40(a).

(Comment 12) One comment also

calls for extending the exemption to

other non-infectious tests required for

donations from dedicated apheresis

Federal Register / Vol. 66, No. 112 / Monday, June 11, 2001 / Rules and Regulations 31153

donors, such as ABO, Rh, red cell

antibody screening.

We disagree with this comment. Tests

such as ABO, Rh, and red cell antibody

screening are part of matching the

donation to the donor and, therefore,

part of quality assurance processes.

(Comment 13) One comment suggests

that subsequent donations from

dedicated apheresis donors should not

be labeled as untested since the test

results from the first donation should

apply to subsequent donations.

We agree with this comment. We are

requiring that donations subsequent to

the first tested donation in each 30-day

period from dedicated donors, including

apheresis donors, be labeled ‘‘DONOR

TESTED WITHIN THE LAST 30 DAYS.’’

We are aware that there may be

occasions where the dedicated

donations are no longer needed by the

identified recipient. When an untested

donation is to be used for transfusion to

another recipient or for further

manufacturing, the establishment must

assure that all suitability criteria under

§ 640.3 are met and that testing required

under § 610.40 is completed and that

the donation tests nonreactive before

use.

C. Supplemental Testing

In proposed § 610.40(c), we would

require that each donation found to be

reactive by a screening test for evidence

of infection due to communicable

disease agents be further tested

whenever a supplemental (additional,

more specific) test has been approved

for such use by FDA.

(Comment 14) Three comments

support our proposal to further test

reactive donations whenever a

supplemental (additional, more specific)

test has been approved for such use by

FDA. These comments point out that

this information is relevant to the donor

and part of the usual and customary

business practice for blood centers to

provide. One of these comments also

suggests that requiring such testing will

provide test kit manufacturers with the

economic incentive to develop

supplemental tests for less common

viruses for which donors are screened.

Four comments oppose our

mandating supplemental testing. These

comments argue that there is not a

sufficient public health concern and

that the costs are too burdensome. The

comments suggest that our regulatory

concerns should be limited to deferring

reactive donors and labeling positive

donations. Several of these comments

argue that supplemental testing has no

impact on blood safety and is a medical

decision to be made by the donor’s

physician. Others suggest that blood

centers do supplemental testing

voluntarily if they intend to reenter

donors; so supplemental testing should

not be required.

Historically, we have recommended

in guidance supplemental testing of

reactive samples and, for HIV, we have

required supplemental testing in

§ 610.46(b). We consider supplemental

testing as part of communicable disease

control, necessary in protecting public

health. Screening tests are designed to

be highly specific for the tested marker.

Nevertheless, false positives occur due

to sample contamination, crossreactivity, or nonspecific causes. In

§ 610.40(e), we are requiring that

reactive samples be further tested by a

supplemental (additional, more specific)

test, when available, that has been

approved for such use by FDA.

Although a donor must be deferred

based on a reactive screening test, the

blood and plasma establishment should

use the information obtained through

supplemental testing to notify and

counsel the deferred donor. Providing

donors with accurate information about

their communicable disease status and

deferral as soon as possible helps ensure

a healthy donor population. Blood and

plasma establishments also can use

information from supplemental testing

to evaluate the donor for possible

reentry into the donor pool.

Requalification of donors contributes to

blood availability, which also is a public

health concern. Therefore, FDA believes

supplemental testing has a direct impact

on blood safety in preventing

communicable disease transmission and

in optimizing blood availability.

(Comment 15) Several comments

object to HCV supplemental testing in

particular because there is currently no

requirement for lookback or product

retrieval and there is no reentry

algorithm in place.

We disagree with the comments. We

consider supplemental testing part of

blood safety by providing deferred

donors with accurate, timely

information regarding their deferred

status and possible transmission of

communicable disease. Currently, we

allow reentry of donors who test

reactive by a multiantigen screening test

for HCV. Reentry into the donor

population must follow a method or

process approved by FDA. This process

includes the use of a supplemental test,

e.g., recombinant immunoblot assay 3.0

(RIBA 3.0). We have issued draft

guidance on our current thinking on

HCV ‘‘lookback’’ (see section IV of this

document for description on how to

access the draft guidance document); we

intend to finalize this guidance and to

propose new regulations in a future

rulemaking for ‘‘lookback’’ when donors

test reactive for HCV.

(Comment 16) One comment objects

to supplemental testing of autologous

donations. The comment objected, in

part, because of the costs associated

with testing each donation from

autologous donors.

Under the final rule, we require

testing of autologous donations only

where there is a public health risk, i.e.,

where an establishment has a program

allowing the use of autologous

donations for allogeneic transfusion, or

where a collecting establishment ships

autologous donations. For those

donations of autologous blood and

blood components that are required to

be tested, we also are requiring blood

establishments to further test such

donations using supplemental tests. If

an autologous donation is reactive in

screening tests, blood establishments are

required to defer the autologous donor

from future allogeneic donations. The

deferred autologous donor has the same

need as the deferred allogeneic donor

for accurate information regarding his or

her possible infectious status, and the

information from supplemental testing

may prevent the donor from spreading

the infection. Thus, we believe that

supplemental testing of autologous

donations is just as necessary to blood

safety and public health as

supplemental testing of allogeneic

donations. For those autologous donors

with a record of a positive supplemental

test for a specific communicable disease

agent, the establishment is not required

to perform the supplemental test again.

(Comment 17) Two comments argue

that the approved supplemental tests are

not always the best method of

confirmatory testing, pointing to

nucleic-acid-based testing (NAT) for

HCV and HIV. The comments also

suggest allowing blood establishments

to use NAT testing and leave the

decision to the donor’s physician

whether other supplemental tests are

warranted medically.

In structuring the proposed rule, we

intended to allow for advancements in

testing technology without further

rulemaking. We built into the

requirement for supplemental testing of

reactive donations the ability for blood

and plasma establishments to use

different testing methods as long as

those tests have been approved by the

agency. NAT is not yet available as a

supplemental testing method and

cannot now be used in lieu of licensed

or approved tests. However, we expect

further development in NAT, both as a

screening and supplemental test, and

intend to issue guidance on the use of

such testing in the future.

31154 Federal Register / Vol. 66, No. 112 / Monday, June 11, 2001 / Rules and Regulations

(Comment 18) Three comments

suggest that to reduce costs and delays

supplemental tests need be performed

only on the first reactive donation in a

series of donations.

Supplemental testing, when available,

is required for each donation that tests

reactive for evidence of infection due to

a communicable disease agent(s) listed

in § 610.40. We agree with the

comments in part, and applied the

suggestion to autologous donors. We are

making two exceptions to performing

supplemental testing on each reactive

donation. The first exception requires,

at a minimum, that supplemental testing

be performed on the first reactive

autologous donation in each 30-day

period. The second exception is when

an autologous donor has a positive

supplemental test of record. In that

instance, the supplemental test is not

required to be performed on subsequent

autologous donations.

D. Release or Shipment Prior To Testing

In proposed § 610.40(e), we would

allow the use or shipment prior to test

results of human blood or blood

components under two circumstances:

Appropriately documented medical

emergency situations; or when approved

in writing by FDA. Use or shipment

prior to test results may occur, provided

the consignee is notified that test results

are not available, the tests for evidence

of infection due to communicable

disease agents are performed as soon as

possible after release or shipment, and

the results are provided promptly to the

consignee.

(Comment 19) Several comments

support allowing use or shipment of

donations prior to testing in medical

emergencies and routine shipment for

further manufacturing use. One

comment opposes any use or shipment

prior to testing.

We believe these exceptions are

necessary to ensure the continued

availability of blood products in

emergency situations and when

products require rapid preparation, e.g.,

Source Leukocytes. In either instance,

the completion of testing prior to

shipment or use may not be feasible.

The regulations require the blood or

plasma establishment to document the

emergency release or shipment of blood

or blood components prior to

completion of testing. If the blood or

plasma establishment ships blood or

blood components for further

manufacturing use prior to completion

of testing, the blood establishment must

obtain prior approval from FDA. In

either instance, the blood or plasma

establishment must complete testing as

soon as possible thereafter, and must

notify the consignee of test results as

soon as they are available.

(Comment 20) One comment argues

that a blood establishment should not be

required to obtain approval from FDA

before shipping untested blood or blood

components for further manufacturing

use. The comment contends that there is

no public health concern since the

blood or blood components are not

released yet. The comment asserts that

a request for FDA approval would delay

manufacture of the biological product.

The comment asks that any such

requests be automatically approved 30

days after submission to FDA.

We believe it is essential as a public

health safeguard that blood or plasma

establishments shipping blood and

blood components for further

manufacturing use prior to completion

of testing obtain prior approval from

FDA and submit their SOP’s for review.

However, the blood or plasma

establishment must submit its SOP’s

and obtain prior approval only before its

first shipment—not, as some comments

seem to suggest, before each shipment.

This requirement of a single submission

will not delay the manufacture of a

biological product. We believe that this

provision will expedite the

manufacturing process by allowing

communicable disease testing to be

completed after shipment, but before

further manufacturing use. Prior

approval is necessary to help ensure

that a blood or plasma establishment is

following proper procedures in shipping

potentially infectious blood and blood

components for further manufacturing

use.

(Comment 21) One comment asks

FDA to clarify whether proposed

§ 610.40(e)(2) addresses the transfer of

untested donations within a

multifacility manufacturer for labeling

purposes.

Requests to ship blood and blood

components prior to testing between

facilities within a multifacility

manufacturer for labeling purposes

should be submitted through the license

application for that product. FDA will

review those applications on a case-bycase basis.

E. Donor Deferral

In proposed § 610.41, we would

require donors testing reactive for

evidence of infection due to a

communicable disease agent or reactive

for a serological test for syphilis be

deferred from future donations of blood

and blood components. Proposed

exceptions to this requirement are: (1)

Autologous donors; (2) plasmapheresis

donors with a reactive serological test

for syphilis under § 640.65; (3) donors

who test reactive for anti-HTLV, types I

or II, or anti-Hepatitis B core (anti-HBc)

on only one occasion; (4) donors who

test reactive for anti-HTLV, types I or II,

or anti-HBc may serve as donors of

Source Plasma; (5) deferred donors

testing reactive for evidence of infection

due to a communicable disease agent

may serve as donors for blood or blood

components when used following the

requirements for restriction on shipment

or use; (6) deferred donors showing

evidence of infection due to hepatitis B

virus when previously tested, may

donate blood or blood components in

the preparation of Hepatitis B Immune

Globulin (Human) provided their

current donations test negative for

HBsAg and the donor is determined

otherwise to be suitable; (7) donors

testing reactive with a serological test

for syphilis and found negative by an

approved specific treponemal test; and

(8) previously deferred donors later

found to be suitable as donors of blood

or blood components by a method or

process acceptable for such purposes by

FDA.

(Comment 22) One comment supports

and one comment opposes allowing

donors testing reactive for anti-HTLV,

type I or type II, or anti-HBc to serve as

donors of Source Plasma.

In the proposed rule, we explained

that the communicable disease agents

HTLV, types I and II, are highly cellassociated. It is well established that

HTLV, types I and II infection may be

transmitted to recipients by the

transfusion of cellular blood

components from infected donors.

Conversely, HTLV transmission has not

been demonstrated by the transfusion of

Plasma or Cryoprecipitate or by the use

of products made from Source Plasma.

Donors testing reactive for anti-HBc also

do not present a risk of transmitting

hepatitis B to recipients of plasma

derivatives made from Source Plasma.

Although blood that is reactive for antiHBc, even when negative for hepatitis B

surface antigen (HBsAg), has a low risk

of infectivity for HBV and would not be

suitable for transfusion, the plasma from

such blood 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-hepatitis B surface

antigen (anti-HB’s), which is hepatitis B

neutralizing antibody. This neutralizing

antibody is thought to contribute to the

safety of immune globulin products.

Additionally, all licensed human

plasma derivatives undergo procedures

Federal Register / Vol. 66, No. 112 / Monday, June 11, 2001 / Rules and Regulations 31155

that will inactivate HBV and HTLV. In

the final rule, therefore, we continue to

allow donors testing reactive for antiHTLV, type I or type II, or anti-HBc to

serve as donors of Source Plasma,

consistent with the exemption that

donors of Source Plasma need not be

tested for anti-HTLV, types I and II, and

anti-HBc.

(Comment 23) One comment suggests

creating a temporary deferral category

for donors found reactive with earlier

generation EIA/screening test, but

negative by more specific tests and

reenter those donors if they test negative

two times 6 months apart by a later

more specific/sensitive test for the same

marker.

We disagree with this comment on the

basis that it is too specific for a

regulation. The final rule contains a

provision in § 610.41(b), which allows

donors deferred based on reactive

screening tests to be reentered into the

donor pool if their blood subsequently

tests negative for the same

communicable disease agent and the

donor is shown to be suitable to donate

by a method or process approved by

FDA. We have identified such donor

reentry algorithms in guidance

documents for some of the

communicable disease agents listed in

§ 610.40 of the final rule. We expect, in

the future, that blood and plasma

establishments will submit for approval

other reentry algorithms for the listed

communicable disease agents.

(Comment 24) One comment requests

that FDA explicitly allow the use of

newly developed technologies to reenter

donors under proposed § 610.40(f)(3).

We are allowing for further

advancements in testing methodologies

by not identifying specific tests to be

performed within this rulemaking. We

will continue evaluating new

technologies related to reentry of

deferred donors. We intend to issue

guidance concerning our views on the

use of those new technologies in

screening and confirmatory

communicable disease testing and as

part of reentry algorithms for donors

deferred based on results of screening

tests for infection due to communicable

disease agents.

(Comment 25) One comment stated

that the exception to deferral in

proposed § 610.41(a) should apply to

donors who test reactive for anti-HTLV,

types I and II, or anti-HBc on only one

occasion, unless further testing under

proposed § 610.40(c) is positive.

We agree in part with this comment.

Once a supplemental test for anti-HTLV,

types I and II, or for anti-HBc is

approved, deferral will occur after a

reactive screening test on one occasion

regardless of the outcome of the

supplemental (additional, more specific)

testing. When a supplemental test is

approved, we intend to issue guidance

on when donor requalification is

appropriate. Until such time, deferral

will be based on reactive test results on

two occasions.

(Comment 26) One comment requests

clarification of the rule’s impact on antiHBc testing of blood and blood

components for further manufacturing

use.

The final rule does not require blood

and plasma establishments to test blood

and blood components for further

manufacturing use (including Source

Plasma) for anti-HBc. The rule does not

prohibit establishments that choose to

test such products for anti-HBc from

using reactive blood or blood

components in fractionation products

and in in-vitro diagnostic products. A

guidance issued to all registered blood

establishments addresses labeling for

injectable and non-injectable products

using anti-HBc reactive blood

components. (See the list of documents

in section IV of this document (dated

September 9, 1991).)

(Comment 27) For the manufacture of

Hepatitis B Immune Globulin (Human)

(HBIG), one comment supports the use

of donors immunized to hepatitis B

virus, as an alternative to using donors

previously showing evidence of

infection due to hepatitis B virus. The

comment contends that this change

would expand the possible supply.

Another comment opposes the sole use

of blood from donors immunized to

hepatitis B virus in manufacture of

HBIG for reasons related to protecting

the public health.

We disagree with the first comment,

and accept the second. In the final rule,

we have permitted deferred donors

previously showing evidence of

infection due to hepatitis B virus to

donate blood or blood components for

use in the preparation of HBIG,

provided that the current donations test

nonreactive for HBsAg and that the

donor is otherwise suitable. The agency

has concluded that donors with

antibodies to HBsAg should not be

excluded. Donors having detectable

antibodies to HBsAg have a spectrum of

antibodies to different epitopes of the

hepatitis B virus and, therefore, are

acceptable or even desirable as donors

for HBIG. Blood or blood components

from such donors also may provide

better protection against future

mutations of the hepatitis B virus. We

believe that HBIG prepared from the

blood and blood components of donors

previously showing evidence of

infection would produce a more

effective product.

F. Syphilis

In the proposed rule, we requested

comments on continuing the

requirement for testing each donation of

blood and blood components for

syphilis. We also requested data

supporting their conclusion.

(Comment 28) The majority of

comments that responded to the issue of

testing for syphilis support eliminating

such testing. These comments argue that

there has been no reported case of

transfusion transmitted syphilis in 30

years; that studies show treponemes

don’t survive in blood stored at 4 1

⁄2C

and positive treponenemal DNA/RNA is

not present in test positive donations

based on studies using polymerase

chain reaction (PCR ) (ARCNET study);

that there are no relevant case reports of

platelet transfusion transmission; and

that recent studies indicate testing for

syphilis has limited value as a surrogate

marker for other communicable disease

agents or high risk behavior. The

comments also point out that syphilis

testing has unnecessarily constricted the

blood supply and eroded donor trust as

otherwise qualified donors are deferred

based on what turns out to be treated

previous infection. Those comments

that oppose eliminating the syphilis

requirements criticize the recent

ARCNET study’s methodology and

conclusions and argue that there is not

sufficient information to eliminate

testing requirements.

After reviewing the comments and

submitted study in addition to other

scientific data, we have determined that

the comments did not provide sufficient

supporting data to justify eliminating

the requirements to test blood and blood

components with a serological test for

syphilis. Preliminary results from

ongoing studies indicate that the

infectivity of seroreactive donors

remains the subject of scientific debate.

(See the transcript of the 67th Blood

Product Advisory Committee Meeting,

September 15, 2000). We will continue

to consider this issue including any

further studies that address the issues of

transfusion related syphilis infection or

testing for syphilis as a surrogate marker

for other communicable diseases. We

remain interested in receiving data

supporting the elimination of the

requirement for syphilis testing. Blood

and plasma establishments must

continue to test donations of blood and

blood components for syphilis under

§§ 640.5(a), 640.14, 640.23(a), 640.33(a),

640.53(a), and 640.65(b)(2) and

references to these sections are inserted

into the codified language in §§ 610.40

31156 Federal Register / Vol. 66, No. 112 / Monday, June 11, 2001 / Rules and Regulations

and 610.41. The final rule requires that

blood and plasma establishments defer

donors who test reactive for a serologic

test for syphilis unless a specific

treponemal antibody test is negative or

the donation is used for further

manufacturing into control serum for a

serological test for syphilis.

In § 610.40(h)(2)(vi) and (vii), we

added language describing current

requirements for the use of human

blood, blood components, and Source

Plasma with a reactive screening test for

syphilis that is determined to be a

biological false positive. Human blood

and blood components may be used if

the reactive screening test is further

tested by an adequate and appropriate

test demonstrating that the reactive

screening test is a biological false

positive. (See the list of documents in

section IV of this document (dated

December 12, 1991)). Such donations

must be labeled with both test results.

Source Plasma may be used from a

donor with a reactive screening test for

syphilis if the donor meets the

requirements of § 640.65(b)(2).

VI. Effective Date

This final rule becomes effective

December 10, 2001. All blood and blood

components collected on and after the

effective date must be in compliance

with the new requirements. Labeling

required by §§ 610.40(c)(3)(ii) and

(h)(2)(ii), and 610.42 must be submitted

to FDA as part of a supplement

submission requesting FDA approval

prior to distribution of a product under

§ 601.12(f)(1) (21 601.12(f)(1)). All other

labeling changes must be submitted in

an annual report under § 601.12(f)(3).

VII. Analysis of Impacts

FDA has examined the impacts of the

rule under Executive Order 12866,

under the Regulatory Flexibility Act (5

U.S.C. 601–612), and under the

Unfunded Mandates Reform Act(2

U.S.C. 1501 et seq.). 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).

The Office of Management and Budget

(OMB) has determined that the 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 Mandates

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

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 a Regulatory

Flexibility Analysis.

A. Objectives and Basis of the Action

The basis for this rule is to help

protect the safety and ensure the quality

of the Nation’s blood supply, and to

promote consistency in the industry.

The safety of the Nation’s blood supply

is enhanced when donors whose test

results indicate evidence of infection

due to communicable disease agents are

excluded from donating blood and

blood components. Under the biologics

licensing and quarantine provisions of

sections 351–361 of the Public Health

Service Act (PHS Act) (42 U.S.C. 262–

264) and the drug, device, and the

general administrative provisions of

sections 501–503, 505–519, and 701–

704 of the Federal Food, Drug, and

Cosmetic Act (the act) (21 U.S.C. 351–

353, 355–360i, 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 transmission of

communicable diseases into the United

States or from one State to another.

Under these statutory authorities, the

agency is: (1) Requiring supplemental

(additional, more specific) testing of all

donations that are reactive by screening

tests for which there are supplementary

tests; and (2) codifying 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 rule requires that each donation

of human blood or blood component,

including those intended for use as a

component of, or used to prepare, a

medical device, but not including those

intended for autologous use, unless

shipped or used for allogeneic

transfusion, be tested for evidence of

infection due to HIV, types 1 and 2;

HBV; HCV; and HTLV, types I and II.

Each donation that is reactive when

tested for evidence of infection due to

any of the disease agents would be

required to be further tested whenever

a supplemental (additional, more

specific) test has been approved for such

use by FDA. FDA is requiring that the

testing be done by a laboratory that is

registered with FDA and CLIA-certified

or meeting equivalent requirements as

determined by HCFA. The 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. Under the

rule, allogeneic donations that test

reactive shall not be shipped except in

situations specifically approved by

FDA. Autologous donations may be

shipped as long as they are properly

labeled.

This rule also requires manufacturers

of tests 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 testing of donations from

allogeneic and certain 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 registration database has record

of 981 registered blood establishments

that collect blood and blood

components and 60 licensed plasma

centers with approximately 370

locations that collect Source Plasma.

Whole Blood donors in the United

States are volunteers. By contrast, most

Source Plasma centers are commercial

establishments with paid donors. Based

on information published by the

American Association of Blood Banks

(AABB) regarding allogeneic donations

(Ref. 1), and communications with

experts in the blood banking industry

Federal Register / Vol. 66, No. 112 / Monday, June 11, 2001 / Rules and Regulations 31157

regarding the testing of autologous

donations, FDA believes that all of the

12 million blood donations (not

including 643,000 autologous

donations) currently collected annually

by the regional and community blood

centers and hospitals are already being

tested for the specific disease agents as

usual and customary business practice.

FDA further estimates that autologous

donations that are shipped are already

being tested for HIV, types 1 and 2,

HBV, HCV, HTLV, types I and II, and

syphilis as usual and customary

business practice. It is also usual and

customary business practice for

hospitals to solely use autologous

donations for autologous use and not

allow autologous donations to be used

for allogeneic transfusion. Therefore, we

estimate that since industry practices

are currently the same as FDA

requirements for testing shipped

autologous donations, and are more

stringent than FDA requirements for use

of autologous donations for allogeneic

transfusion, then additional costs to

blood establishments collecting

autologous blood and blood components

will be minimal, if any.

In 1997, the Government Accounting

Office (GAO) estimated that

approximately 12 million donations of

Source Plasma were collected by plasma

centers (Ref. 2). 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 rule.

However, based on GAO reported

variations in the plasma industry’s

confirmatory testing of repeat reactive

donations, it is also assumed that

supplemental testing for HCV is not

widely practiced at present.

The requirements for lot testing of

approved test kits by manufacturers will

entail use of CBER regulatory reference

panels to provide verification of the

specificity and sensitivity of each lot of

test kits 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 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

rule are already performing the tests to

comply with their own quality

assurance standards. The rule is

therefore expected to introduce no

substantial impact on these

establishments.

2. Estimated Impact of Requirements for

Donor Testing

The rule provisions for donation

testing, appropriate handling, labeling,

and distribution will involve a one-time

effort by all blood and plasma

establishments to review and modify

current blood and plasma donor testing,

handling, and recordkeeping protocols

to comply with the rule. While the rule

does establish test requirements, these

are not expected to increase the yearly

cost of donor screening testing.

The one-time effort to review and

modify current SOP’s is expected to take

approximately 8 hours of staff time to

reconcile the regulations against the

facility’s current standards. This process

could be performed by a technical

specialist who works 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 and plasma collecting

establishments. Because this final rule

does not require that all blood centers

test all autologous donations, it is a

lesser burden that what was in the

proposed rule. FDA assumes that the

cost will be the same for all facilities,

whether or not they currently test all

autologous donations. It is also assumed

that all facilities already perform careful

labeling and keep records of test results

for evidence of infection due to

communicable disease agents. Thus, the

total one-time cost for the industry is

estimated to be $276,955 ((370 + 981

establishments) x $205).

(Comment 29) Ten comments asserted

that testing of autologous donations is

costly to facilities and patients.

We have considered these comments

and we are limiting the requirement to

test autologous donations to two

occasions when risk of exposure is

increased, i.e., when autologous

donations are used for allogeneic

transfusion or when they are shipped. It

is assumed that there will be very little

testing that was not already being done,

and that the requirement to test

autologous donations when used for

allogeneic transfusion or shipped will

not impose additional cost.

The rule also allows that multiple

donations of blood and blood

components from single donors

dedicated to a single identified recipient

be tested once at the beginning of a 30-

day period. These dedicated donations,

however, are relatively uncommon and

are believed to generally undergo testing

by all facilities that is at least as frequent

as the rule requires.

(Comment 30) Two comments

contend that supplemental testing

should be required only for HIV and

HBsAg. Four additional comments

noted that supplemental testing is

expensive.

The agency believes that while there

are costs to supplemental testing, the

costs imposed by this rule are mitigated

because a substantial fraction of

facilities already perform supplemental

testing. In addition, the ability to obtain

more precise information on donors

testing reactive will improve public

health by providing these donors with

accurate health information.

Currently, blood and plasma

establishments are required under

§ 610.46(b) to further test donations that

test reactive by a screening test for HIV.

Anti-HBc and anti-HTLV, types I and II,

do not have supplemental (additional,

more specific) tests approved for such

use by FDA at this time. Therefore, the

yearly increase in cost imposed by this

final rule is based on the assumption

that blood and plasma collecting

establishments will need to begin

supplemental (additional, more specific)

testing on donations that test reactive

for HCV and HBsAg. Assuming: (1) An

average 0.18 percent (0.0018) rate of

HCV reactive donations; (2) an average

0.05 percent (0.0005) rate of HBsAg

reactive donations; and (3) an annual

volume of approximately 24 million

blood and plasma donations, and the

cost for a supplemental (additional,

more specific) test for HCV and HbsAg

is approximately $144.50 and $8.00

respectively (Ref. 3), then the annual

cost is estimated to be no greater than

$5,946,400 ((24,000,000 x 0.0018) x

$114.50 + (24,000,000 x 0.0005) x

$8.00).

In summary, the rule would result in

an estimated one-time cost of $276,955,

and a total annual cost of $5,042,400 to

the blood and plasma industries.

31158 Federal Register / Vol. 66, No. 112 / Monday, June 11, 2001 / Rules and Regulations

3. Expected Benefits of the Rule

The 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 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. 4). 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 the

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. 5). HCV

and HBV transfusion risks have also

declined. In 1990, prior to specific

testing, HCV was transmitted by 0.2 to

0.5 percent of transfusions, compared

with the current rate of approximately

0.0005 percent. The risk of HBV

transfusion transmission is currently

estimated to be 1 in 500,000 transfused

units.

The gravity of the disease risks

addressed by the rule is 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

transmitted by sexual contact and

intravenous drug abuse, 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 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. 6). 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

will have a risk of liver cancer that is

12 to 300 times higher than the risk to

non-carriers. An estimated 4,000

persons die each year from hepatitis Brelated 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. 7).

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. 8). Of patients with

transfusion-associated chronic non-A,

non-B hepatitis who undergo biopsy

within 5 years after onset, at least 40

percent have histological evidence of

chronic active hepatitis and 10 to 20

percent have evidence of cirrhosis (Ref.

9). An estimated 30 percent of those

infected will eventually die of liverrelated 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 qualityadjusted life years (Ref. 10). As

described previously, the requirement of

HIV, types 1 and 2; HBV; HCV; HTLV,

types I and II; and syphilis testing for

blood and blood component 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 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. FDA has

therefore prepared a Regulatory

Flexibility Analysis. The blood and

plasma establishments affected by the

rule are included under the major

Standard Industry 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.’’ ‘‘Small governmental

jurisdiction’’ generally means

governments of cities, counties, towns,

townships, villages, school districts, or

special districts with a population of

less than 50,000.

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. 11) 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 Small

Business Association (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. (Note

that while there are over 5,000

community hospitals in this small entity

impact analysis, not all 5,000 hospitals

are collecting facilities. Therefore, this

does not invalidate the estimate of 60

licensed plasma centers with 370

locations and 981 registered blood

establishments affected by the rule.)

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

Federal Register / Vol. 66, No. 112 / Monday, June 11, 2001 / Rules and Regulations 31159

might be excluded from that definition

because they are reported to be hospitals

in a system. According to the AHA

survey definition, ‘‘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

nonFederal 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] nonfederal, nonprofit hospitals may qualify

as small entities. Although, a total of

2,794 [2,783 + 11] hospitals might

qualify as small entities, not all such

hospitals collect blood and blood

components, and some would be

transfusion services only.

Approximately 75 of the 981

registered blood establishments that

collect blood and blood components are

responsible for collecting 65 percent of

the blood supply (7.8 million

donations). The remaining 906

registered blood establishments

assumed to operate as small entities

would collect 45 percent of the blood

supply (5.4 million donations). If the

estimated 5.4 million donations of blood

and blood components were evenly

distributed over the 906 registered blood

collection establishments, each

establishment would average 5,960

donations annually, of which

approximately 11 (0.0018 x 5,960) might

test reactive for HCV and approximately

3 (0.0005 x 5,960) of which might test

reactive for HBsAg, and require

supplemental testing. The expected cost

of the additional testing would then be

$1,283.50 (($114.50 x 11) + ($8.00 x 3))

per establishment per year.

The number of plasma facilities that

would qualify as small entities is also

uncertain. According to the General

Accounting Office (Ref. 12)

approximately 370 paid plasma

collection locations annually collect

about 12 million plasma donations, the

vast majority of which is processed by

8 companies. FDA estimates that

approximately 90 percent of these

plasma collection locations are owned

by companies that operate multiple

facilities. 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 locations (37 locations) may

qualify as small business

establishments. The potential impact on

these facilities will be a function of the

number of donors and the HCV and

HBsAg reactive findings among donors

at their facility. If the estimated 12

million plasma donations were evenly

distributed over the collection centers,

each center would average 25,000

donations. Assuming approximately 8

units per plasma donor per year (Ref.

12), each center would average 3,125

donors, approximately 6 (0.0018 x

3,125) of whom might test reactive for

HCV and approximately 2 (0.0005 x

3,125) of whom might test reactive for

HBsAg, and require supplemental

testing. The expected cost of the

additional testing would then be $703

(($114.50 x 6) + ($8.00 x 2)) per center

per year.

In addition to these for-profit

establishments, the remaining plasma

collection centers function within blood

collection centers that are operated by

the American National 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 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 alternatives for

lessening the burden on small entities.

The proposed rule proposed that all

autologous blood be tested. By choosing

this less costly alternative that does not

require autologous blood testing, FDA is

lessening the burden on small entities.

VIII. The Paperwork Reduction Act of

1995

This final rule contains information

collection requirements that are subject

to review by OMB under the Paperwork

Reduction Act of 1995 (the 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 the estimate is the

time for reviewing instructions,

searching existing data sources,

gathering and maintaining the data

needed, and completing and reviewing

each collection of information.

Title: Recordkeeping and Reporting

Requirements for Testing Human Blood

Donors for Evidence of Infection Due to

Communicable Disease Agents.

Description: FDA is revising the test

requirements in part 610 subpart E

issued under the authorities of the act

and the PHS Act. Section 610.40 of the

final rule requires screening tests for

evidence of infection due to

communicable disease agents, HIV,

types 1 and 2; HBV; HCV; HTLV, types

I and II, be performed on each donation

of human blood and blood component.

Certain exceptions to performing

screening tests are described elsewhere

in this rule.

In § 610.40(c)(1)(ii), each dedicated

donation must be labeled as required

under § 606.121 and with a label

entitled ‘‘INTENDED RECIPIENT

INFORMATION LABEL’’ containing the

name and identifying information of the

recipient. Each donation that is untested

in the 30-day period must be labeled

‘‘DONOR TESTED WITHIN THE LAST

30 DAYS.’’

In § 610.40(d)(4), each autologous

donation must be labeled as required

under § 606.121 and with the following

label, as appropriate. If the donation is:

(1) Untested, label with ‘‘UNTESTED;’’

(2) negative, label as required under

§ 606.121; (3) reactive on the current

collection or in the last 30 days, label

with ‘‘BIOHAZARD’’ legend; and (4)

tested negative within the last 30 days,

label with ‘‘DONOR TESTED WITHIN

THE LAST 30 DAYS.’’

Under § 610.40(g), each donation that

may be released or shipped prior to

testing must be labeled as required

under § 606.121(h) and the test results

must be provided promptly to the

consignee. Section 610.40(g)(1) permits

release or shipment prior to completion

of testing in documented medical

emergencies, and § 610.40(g)(2) permits

release or shipment prior to completion

of testing when FDA provides written

approval for the shipment or use.

In § 610.40(h)(2)(ii), human blood or

blood components intended for further

manufacturing use may be shipped or

used under the following conditions.

• When FDA provides written

approval for the shipment or use;

• When such human blood and blood

components are labeled as required

under § 606.121 or § 640.70 and with

the ‘‘BIOHAZARD’’ legend;

• When such human blood and blood

components are labeled reactive for the

appropriate screening test for evidence

of infection due to the identified

communicable disease agent(s);

• When such human blood and blood

components are intended for further

manufacturing use into injectable

products, and a statement indicating the

exempted use specifically approved by

FDA is included on the container label;

• When such human blood and blood

components are intended solely as a

component of, or used to prepare, a

medical device and the statement

‘‘Caution: For Further Manufacturing

Use As a Component of a Medical

Device For Which There Are No

Alternative Sources;’’ and

31160 Federal Register / Vol. 66, No. 112 / Monday, June 11, 2001 / Rules and Regulations

• When such human blood and blood

components are intended for in vitro

use and the statement ‘‘Caution: For

Further Manufacturing Into In Vitro

Diagnostic Reagents For Which There

Are No Alternative Sources’’ is

included.

In § 610.40(h)(2)(vi) and (h)(2)(vii), we

added language describing current

practice on the use of human blood and

blood components, and Source Plasma,

with a reactive screening test for

syphilis that is determined to be a

biological false positive.

In § 610.42(a), medical devices

containing or used to prepare human

blood or blood components that are

reactive for syphilis or by a screening

test for evidence of infection due to a

communicable disease agent(s) must

include, in addition to appropriate

labeling requirements in subchapter H

(Medical Devices), a statement of

warning that the product was

manufactured from a donation testing

reactive for the identified

communicable disease agent(s).

Description of Respondents:

Establishments that collect blood and

blood components.

As required by section 3506(c)(2)(B)

of the PRA, FDA provided an

opportunity for public comment on the

information collection requirements of

the proposed rule (64 FR 67207). In

accordance with the PRA, OMB

reserved approval of the information

collection burden in the proposed rule

stating they will make an assessment in

light of public comments received on

the proposed rule. No letters of

comment on the information collection

requirements were submitted to OMB or

the docket.

Based on current information

retrieved from FDA’s registration data

base, there are approximately 60

licensed plasma collection facilities and

approximately 981 registered blood

collection facilities for a total of 1,041

establishments. These facilities collect

annually an estimated 24.6 million

donations: 12 million donations of

Source Plasma and 12.6 million

donations of Whole Blood, including

643,000 autologous.

Annual Reporting Burden (Table 3)

Section 610.40(c)(1)(ii) requires that

each dedicated donation be labeled as

required under § 606.121 (OMB No.

0910–0116) and with a label containing

the name and identifying information of

the recipient. FDA estimates that

approximately 5 percent (10,250) of the

205,000 donations that are donated

specifically for the use of an identified

recipient would be tested under the

dedicated donors testing provisions in

§ 610.40(c). FDA estimates that the

remaining 95 percent would be tested as

allogeneic donations in accordance with

§ 610.40(a), (b), and (e) because most

such donors do not donate more often

than once in a 30-day period, and

because most establishments choose to

test every donation. We estimate that

each establishment expends

approximately 5 minutes to insert the

name of the recipient and identifying

information on each label.

In § 610.40(g)(2) and (h)(2)(ii)(A), a

manufacturer must obtain written

approval from FDA when a

manufacturer seeks to: (1) Ship human

blood or blood components for further

manufacturing use prior to completion

of testing; or (2) ship human blood or

blood components found to be reactive

by a screening test for evidence of a

communicable disease agent(s) or

collect from a donor with a record of a

reactive screening test, respectively. The

only product currently shipped prior to

completion of 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 each shipment does not

have to be reported to the agency. To

obtain approval from FDA as described

in § 610.40(g)(2), we expect the

manufacturer(s) to submit specific

procedures for collection, shipment, and

quarantine of a product before testing is

completed, and the completion of

testing as soon as possible after

shipping. In addition, the manufacturer

must promptly communicate the test

results to the consignee. FDA has

received two applications from the

manufacturers of Source Leukocytes

during fiscal year (FY) 95, FY 96, and

FY 97. Therefore, we estimate receiving

an average of two 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. The information that a

manufacturer would need to put

together for the request is typically part

of an Biologics License Application

(BLA) submission. Therefore, we

estimate 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.

Under § 610.40(h)(2)(ii)(C) and

(h)(2)(ii)(D), industry estimates that each

manufacturer would ship an estimated

10 blood or blood components per

month that would require 2 labels; one

as reactive for the appropriate screening

test under paragraph (C), and the other

stating the exempted use specifically

approved by FDA under paragraph (D).

According to FDA’s database, there are

approximately 300 licensed

manufacturers that ship known reactive

blood or blood components. Industry

also estimates that it would take

approximately 10 minutes per blood or

blood component to affix the labels.

In § 610.40(h)(2)(vi), each donation of

human blood or blood component that

tests reactive by a screening test for

syphilis and is determined to be a

biological false positive, must be labeled

with both test results. After reviewing

information from industry, we estimate

that approximately 15,120 donations

annually test reactive by a screening test

for syphilis, and are determined to be

biological false positives by additional

testing. We also estimate that the

establishment would expend

approximately 5 minutes to label the

blood or blood component with the

results of both tests.

Section 610.42(a) requires a warning

statement, including the identity of the

communicable disease agent, on

medical devices containing human

blood or blood components found to be

reactive by a screening test for evidence

of infection due to a communicable

disease agent(s) or syphilis. Human

blood or a blood component with a

reactive screening test, as a component

of a medical device, is an integral part

of the medical device, e.g., a positive

control for an in vitro diagnostic testing

kit. It is usual and customary business

practice for manufacturers to include on

the container label a warning statement

that identifies the communicable

disease agent. In addition, on the rare

occasion when a human blood or blood

component with a reactive screening

test is the only component available for

a medical device that does not require

a reactive component, then a statement

of warning is required to be affixed to

the medical device. To account for this

rare occasion we estimate that the

warning statement would be necessary

no more than once a year and we

estimate the manufacturer would need

to expend 1 hour to complete the

labeling requirement.

Annual Recordkeeping Burden (Table 4)

Under § 610.40(g)(1), we are

permitting in rare emergency

circumstances, the release or shipment

of human blood or blood components

prior to the completion of testing for

evidence of infection due to

communicable disease agents. Such

emergencies include, e.g., where a

patient’s need for blood is so acute as to

preclude any communicable disease

Federal Register / Vol. 66, No. 112 / Monday, June 11, 2001 / Rules and Regulations 31161

testing of the blood. We have concluded

that the use of untested or incompletely

tested blood in such medical

emergencies should not be prohibited.

Release of blood or blood components

due to a medical emergency prior to

completion of required testing must be

appropriately documented. We estimate

the recordkeeping to be minimal with

one or less occurrence per year.

Documentation of the medical

emergency should take a half-hour or

less. The reporting of test results to the

consignee in § 610.40(g) does not create

a new burden for respondents because

it is the usual and customary business

practice or procedure to finish the

testing and provide the results to the

manufacturer responsible for labeling

the blood products.

TABLE 3.—ESTIMATED ANNUAL REPORTING BURDEN1

21 CFR Section No. of Respondents Annual Frequency

per Response

Total Annual

Responses

Hours per

Response Total Hours

610.40(c)(1)(ii) 1,041 9 10,250 .08 820

610.40(g)(2) 2 1 2 1 2

610.40(h)(2)(ii)(A) 2 1 2 1 2

610.40(h)(2)(ii)(C) and

(h)(2)(ii)(D) 300 10 3,000 0.2 600

610.40(h)(2)(vi) 1,041 15 15,120 0.08 1,210

610.42(a) 1 1 1 1 1

Total 2,635

1There are no capital costs or operating and maintenance costs associated with this collection of information.

TABLE 4.—ESTIMATED ANNUAL RECORDKEEPING BURDEN1

21 CFR Section No. of

Recordkeepers

Annual Frequency

per Recordkeeping

Total Annual

Records

Hours per

Recordkeeper Total Hours

610.40(g)(1) 981 1 981 0.5 490.5

1There 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

§ 610.40(c)(3)(ii), (d)(4), and (h)(2)(ii)(B)

and (h)(2)(ii)(E) 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

the blood supply safe and protect public

health.

The information collection provisions

of this final rule have been submitted to

OMB for review.

Prior to the effective date of this final

rule, FDA will publish a notice in the

Federal Register announcing OMB’s

decision to approve, modify, or

disapprove the information collection

provisions in this final rule. An agency

may not conduct or sponsor, and a

person is not required to respond to, a

collection of information unless it

displays a currently valid OMB number.

IX. Environmental Impact

The agency has determined under 21

CFR 25.30(j) that this action is of a type

that does not individually or

cumulatively have a significant effect on

the human environment. Therefore,

neither an environmental assessment

nor an environmental impact statement

is required.

X. Federalism

FDA has analyzed this final rule in

accordance with the principles set forth

in Executive Order 13132. FDA has

determined that the rule does not

contain policies that have substantial

direct effects on the States, on the

relationship between the National

Government and the States, or on the

distribution of power and

responsibilities among the various

levels of government. Accordingly, the

agency has concluded that the rule does

not contain policies that have

federalism implications as defined in

the order and, consequently, a

federalism summary impact statement is

not required.

XI. 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. American Association of Blood

Banks, Facts About Blood and Blood

Banking, ‘‘http://www.aabb.org’’.

2. General Accounting Office, ‘‘Blood

Safety: Enhancing Safeguards Would

Strengthen the Nation’s Blood Supply,’’

GAO–HEHS–97–143, June 1997.

3. 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, no. 4, pp. 591–596, 1998.

4. American Association of Blood

Banks (AABB) Association Bulletin No.

95–4: AABB Position on Testing of

Autologous Units. Attachment 1: AABB

Anonymous Autologous Survey Request,

May 9, 1999.

5. Podnos, Y. D. and R. A. Williams,

Current Risks for Blood Borne Viral

Illness in Blood Transfusion, Western

Journal of Medicine, vol. 168, no. 1, pp.

36–37, January 1998.

6. 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.

7. 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.

8. U.S. Centers for Disease Control

and Prevention, 1997, ‘‘www.cdc.gov/

ncidod/diseases/hepatitis’’.

9. Morbidity and Mortality Weekly

Report, 40 (RR–4) April 19, 1991.

10. Kim, W. R., J. J. Peterucha, J. E.

Hermans, T. M. Therneau, E. R.

Dickson, R. W. Evans, and J. B. Gross,

31162 Federal Register / Vol. 66, No. 112 / Monday, June 11, 2001 / Rules and Regulations

‘‘Cost-Effectiveness of 6 and 12 Months

of Interferon Therapy for Chronic

Hepatitis C,’’ Annals of Internal

Medicine, vol. 127, no. 10, November

1997.

11. Healthcare InfoSource, Inc., a

subsidiary of the American Hospital

Association, Hospital Statistics, 1998

ed., Chicago, IL.

12. General Accounting Office,

‘‘Blood Plasma Safety: Plasma Product

Risks Are Low if Good Manufacturing

Practices Are Followed.’’ GAO–HEHS–

98–205, September 1998.

List of Subjects

21 CFR Part 606

Blood, Labeling, Laboratories,

Reporting and recordkeeping

requirements.

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.

21 CFR Part 809

Labeling, Medical devices.

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, 21 CFR parts 606,

607, 610, 640, 660, and 809 are

amended as follows:

PART 606—CURRENT GOOD

MANUFACTURING PRACTICE FOR

BLOOD AND BLOOD COMPONENTS

1. The authority citation for 21 CFR

part 606 continues to read as follows:

Authority: 21 U.S.C. 321, 331, 351, 352,

355, 360, 360j, 371, 374; 42 U.S.C. 216, 262,

263a, 264.

2. Section 606.121 is amended by

revising paragraph (e)(5)(ii), by

removing and reserving paragraph (g),

and in paragraphs (h)(2) and (h)(3) by

removing ‘‘610.45,’’ to read as follows:

§ 606.121 Container label.

* * * * *

(e) * * *

(5) * * *

(ii) The statement as applicable:

‘‘Caution: For Manufacturing Use

Only’’; or ‘‘Caution: For Use in

Manufacturing Noninjectable Products

Only.’’ If the recovered plasma has a

reactive screening test for evidence of

infection due to a communicable

disease agent(s) under § 610.40 of this

chapter, or is collected from a donor

with a previous record of a reactive

screening test for evidence of infection

due to a communicable disease agent(s)

under § 610.40 of this chapter, the

recovered plasma must be labeled as

required under § 610.40(h)(2)(ii)(E) of

this chapter.

* * * * *

PART 607—ESTABLISHMENT

REGISTRATION AND PRODUCT

LISTING FOR MANUFACTURERS OF

HUMAN BLOOD AND BLOOD

PRODUCTS

3. 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.

§ 607.65 [Amended]

4. Section 607.65 Exemption for blood

product establishments is amended by

removing paragraph (g).

PART 610—GENERAL BIOLOGICAL

PRODUCTS STANDARDS

5. The authority citation for 21 CFR

part 610 is revised to read as follows:

Authority: 21 U.S.C. 321, 331, 351, 352,

353, 355, 360, 360c, 360d, 360h, 360i, 371,

372, 374, 381; 42 U.S.C. 216, 262, 263, 263a,

264.

6.–7. The heading of subpart E is

revised to read as follows:

Subpart E—Testing Requirements for

Communicable Disease Agents

8. Section 610.40 is revised to read as

follows:

§ 610.40 Test requirements.

(a) Human blood and blood

components. Except as specified in

paragraphs (c) and (d) of this section,

you, an establishment that collects

blood or blood components, must test

each donation of human blood or blood

component intended for use in

preparing a product, including

donations intended as a component of,

or used to prepare, a medical device, for

evidence of infection due to the

following communicable disease agents:

(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; and

(6) Human T-lymphotropic virus, type

II.

(b) Testing using one or more

approved screening tests. To test for

evidence of infection due to

communicable disease agents

designated in paragraph (a) of this

section, you must use screening tests

that the Food and Drug Administration

(FDA) has approved for such use, in

accordance with the manufacturer’s

instructions. You must perform one or

more such tests as necessary to reduce

adequately and appropriately the risk of

transmission of communicable disease.

(c) Exceptions to testing for allogeneic

transfusion or further manufacturing

use.

(1) Dedicated donations. (i) You must

test donations of human blood and

blood components from a donor whose

donations are dedicated to and used

solely by a single identified recipient

under paragraphs (a), (b), and (e) of this

section; except that, if the donor makes

multiple donations for a single

identified recipient, you may perform

such testing only on the first donation

in each 30-day period. If an untested

dedicated donation is made available for

any use other than transfusion to the

single, identified recipient, then this

exemption from the testing required

under this section no longer applies.

(ii) Each donation must be labeled as

required under § 606.121 of this chapter

and with a label entitled ‘‘INTENDED

RECIPIENT INFORMATION LABEL’’

containing the name and identifying

information of the recipient. Each

donation must also have the following

label, as appropriate:

Donor Testing Status Label

Tests negative Label as required under § 606.121

Tested negative within the last 30 days ‘‘DONOR TESTED WITHIN THE LAST 30 DAYS’’

Federal Register / Vol. 66, No. 112 / Monday, June 11, 2001 / Rules and Regulations 31163

(2) Source Plasma. You are not

required to test donations of Source

Plasma for evidence of infection due to

the communicable disease agents listed

in paragraphs (a)(5) and (a)(6) of this

section.

(3) Medical device. (i) You are not

required to test donations of human

blood or blood components intended

solely as a component of, or used to

prepare, a medical device for evidence

of infection due to the communicable

disease agents listed in paragraphs (a)(5)

and (a)(6) of this section unless the final

device contains viable leukocytes.

(ii) Donations of human blood and

blood components intended solely as a

component of, or used to prepare, a

medical device must be labeled

‘‘Caution: For Further Manufacturing

Use as a Component of, or to Prepare,

a Medical Device.’’

(4) Samples. You are not required to

test samples of blood, blood

components, plasma, or sera if used or

distributed for clinical laboratory testing

or research purposes and not intended

for administration to humans or in the

manufacture of a product.

(d) Autologous donations. You, an

establishment that collects human blood

or blood components from autologous

donors, or you, an establishment that is

a consignee of a collecting

establishment, are not required to test

donations of human blood or blood

components from autologous donors for

evidence of infection due to

communicable disease agents listed in

paragraph (a) of this section or by a

serological test for syphilis under

paragraph (i) of this section, except:

(1) If you allow any autologous

donation to be used for allogeneic

transfusion, you must assure that all

autologous donations are tested under

this section.

(2) If you ship autologous donations

to another establishment that allows

autologous donations to be used for

allogeneic transfusion, you must assure

that all autologous donations shipped to

that establishment are tested under this

section.

(3) If you ship autologous donations

to another establishment that does not

allow autologous donations to be used

for allogeneic transfusion, you must

assure that, at a minimum, the first

donation in each 30-day period is tested

under this section.

(4) Each autologous donation must be

labeled as required under § 606.121 of

this chapter and with the following

label, as appropriate:

Donor Testing Status Label

Untested ‘‘DONOR UNTESTED’’

Tests negative Label as required under § 606.121

Reactive on current collection/reactive in the last 30 days ‘‘BIOHAZARD’’ legend in § 610.40(h)(2)(ii)(B)

Tested negative within the last 30 days ‘‘DONOR TESTED WITHIN THE LAST 30 DAYS’’

(e) Further testing. You must further

test each donation, including autologous

donations, found to be reactive by a

screening test performed under

paragraphs (a) and (b) of this section,

whenever a supplemental (additional,

more specific) test has been approved

for such use by FDA, except:

(1) For autologous donations, you

must further test under this paragraph,

at a minimum, the first reactive

donation in each 30-day period; or

(2) If you have a record for that donor

of a positive result on a supplemental

(additional, more specific) test approved

for such use by FDA, you do not have

to further test an autologous donation.

(f) Testing responsibility. Required

testing under this section, must be

performed by a laboratory registered in

accordance with part 607 of this chapter

and either certified to perform such

testing on human specimens under the

Clinical Laboratory Improvement

Amendments of 1988 (42 U.S.C. 263a)

under 42 CFR part 493 or has met

equivalent requirements as determined

by the Health Care Financing

Administration in accordance with

those provisions.

(g) Release or shipment prior to

testing. Human blood or blood

components that are required to be

tested for evidence of infection due to

communicable disease agents

designated in paragraphs (a) and (i) of

this section may be released or shipped

prior to completion of testing in the

following circumstances provided that

you label the blood or blood

components under § 606.121(h) of this

chapter, you complete the tests for

evidence of infection due to

communicable disease agents as soon as

possible after release or shipment, and

that you provide the results promptly to

the consignee:

(1) Only in appropriately documented

medical emergency situations; or

(2) For further manufacturing use as

approved in writing by FDA.

(h) Restrictions on shipment or use—

(1) Reactive screening test. You must

not ship or use human blood or blood

components that have a reactive

screening test for evidence of infection

due to a communicable disease agent(s)

designated in paragraphs (a) and (i) of

this section or that are collected from a

donor with a previous record of a

reactive screening test for evidence of

infection due to a communicable

disease agent(s) designated in

paragraphs (a) and (i) of this section,

except as provided in paragraphs

(h)(2)(i) through (h)(2)(vii) of this

section.

(2) Exceptions. (i) You may ship or

use blood or blood components

intended for autologous use, including

reactive donations, as described in

paragraph (d) of this section.

(ii) You must not ship or use human

blood or blood components that have a

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 deferred under § 610.41(a)

unless you meet the following

conditions:

(A) Except for autologous donations,

you must obtain from FDA written

approval for the shipment or use;

(B) You must appropriately label such

blood or blood components as required

under § 606.121, or § 640.70 of this

chapter, and with the ‘‘BIOHAZARD’’

legend;

(C) Except for autologous donations,

you must label such human blood and

blood components as reactive for the

appropriate screening test for evidence

of infection due to the identified

communicable disease agent(s);

(D) If the blood or blood components

are intended for further manufacturing

31164 Federal Register / Vol. 66, No. 112 / Monday, June 11, 2001 / Rules and Regulations

use into injectable products, you must

include a statement on the container

label indicating the exempted use

specifically approved by FDA.

(E) Each blood or blood component

with a reactive screening test and

intended solely as a component of, or

used to prepare a medical device, must

be labeled with the following label, as

appropriate:

Type of Medical Device Label

A medical device other than an in vitro diagnostic reagent ‘‘Caution: For Further Manufacturing Use as a Component of a Medical

Device For Which There Are No Alternative Sources’’

An in vitro diagnostic reagent ‘‘Caution: For Further Manufacturing Into In Vitro Diagnostic Reagents

For Which There Are No Alternative Sources’’

(iii) The restrictions on shipment or

use do not apply to samples of blood,

blood components, plasma, or sera if

used or distributed for clinical

laboratory testing or research purposes,

and not intended for administration in

humans or in the manufacture of a

product.

(iv) You may use human blood or

blood components from a donor with a

previous record of a reactive screening

test(s) for evidence of infection due to

a communicable disease agent(s)

designated in paragraph (a) of this

section, if:

(A) At the time of donation, the donor

is shown or was previously shown to be

suitable by a requalification method or

process found acceptable for such

purposes by FDA under § 610.41(b); and

(B) tests performed under paragraphs

(a) and (b) of this section are

nonreactive.

(v) Anti-HBc reactive donations,

otherwise nonreactive when tested as

required under this section, may be

used for further manufacturing into

plasma derivatives without prior FDA

approval or a ‘‘BIOHAZARD’’ legend as

required under paragraphs (h)(2)(ii)(A)

and (h)(2)(ii)(B) of this section.

(vi) You may use human blood or

blood components, excluding Source

Plasma, that test reactive by a screening

test for syphilis as required under

paragraph (i) of this section if,

consistent with § 640.5 of this chapter,

the donation is further tested by an

adequate and appropriate test which

demonstrates that the reactive screening

test is a biological false positive. You

must label the blood or blood

components with both test results.

(vii) You may use Source Plasma from

a donor who tests reactive by a

screening test for syphilis as required

under § 610.40(i) of this chapter, if the

donor meets the requirements of

§ 640.65(b)(2) of this chapter.

(i) Syphilis testing. In addition to the

testing otherwise required under this

section, you must test by a serological

test for syphilis under §§ 640.5(a),

640.14, 640.23(a), 640.33(a), 640.53(a),

and 640.65(b)(2) of this chapter.

9. Section 610.41 is revised to read as

follows:

§ 610.41 Donor deferral.

(a) You, an establishment that collects

human blood or blood components,

must defer donors testing reactive by a

screening test for evidence of infection

due to a communicable disease agent(s)

listed in § 610.40(a) or reactive for a

serological test for syphilis under

§ 610.40(i), from future donations of

human blood and blood components,

except:

(1) You are not required to defer a

donor who tests reactive for anti-HBc or

anti-HTLV, types I or II, on only one

occasion. When a supplemental

(additional, more specific) test for antiHBc or anti-HTLV, types I and II, has

been approved for use under § 610.40(e)

by FDA, such a donor must be deferred;

(2) A deferred donor who tests

reactive for evidence of infection due to

a communicable disease agent(s) listed

in § 610.40(a) may serve as a donor for

blood or blood components shipped or

used under § 610.40(h)(2)(ii);

(3) A deferred donor who showed

evidence of infection due to hepatitis B

surface antigen (HBsAg) when

previously tested under § 610.40(a), (b),

and (e) subsequently may donate Source

Plasma for use in the preparation of

Hepatitis B Immune Globulin (Human)

provided the current donation tests

nonreactive for HBsAg and the donor is

otherwise determined to be suitable;

(4) A deferred donor, who otherwise

is determined to be suitable for donation

and tests reactive for anti-HBc or for

evidence of infection due to HTLV,

types I and II, may serve as a donor of

Source Plasma;

(5) A deferred donor who tests

reactive for a communicable disease

agent(s) described under § 610.40(a) or

reactive with a serological test for

syphilis under § 610.40(i), may serve as

an autologous donor under § 610.40(d).

(b) A deferred donor subsequently

may be found to be suitable as a donor

of blood or blood components by a

requalification method or process found

acceptable for such purposes by FDA.

Such a donor is considered no longer

deferred.

10. Section 610.42 is added to subpart

E to read as follows:

§ 610.42 Restrictions on use for further

manufacture of medical devices.

(a) In addition to labeling

requirements in subchapter H of this

chapter, when a medical device

contains human blood or a blood

component as a component of the final

device, and the human blood or blood

component was found to be reactive by

a screening test performed under

§ 610.40(a) and (b) or reactive for

syphilis under § 610.40(i), then you

must include in the device labeling a

statement of warning indicating that the

product was manufactured from a

donation found to be reactive by a

screening test for evidence of infection

due to the identified communicable

disease agent(s).

(b) FDA may approve an exception or

alternative to the statement of warning

required in paragraph (a) of this section

based on evidence that the reactivity of

the human blood or blood component in

the medical device presents no

significant health risk through use of the

medical device.

11. Section 610.44 is added to subpart

E to read as follows:

§ 610.44 Use of reference panels by

manufacturers of test kits.

(a) When available and appropriate to

verify acceptable sensitivity and

specificity, you, a manufacturer of test

kits, must use a reference panel you

obtain from FDA or from an FDA

designated source to test lots of the

following products. You must test each

lot of the following products, unless

FDA informs you that less frequent

testing is appropriate, based on your

consistent prior production of products

of acceptable sensitivity and specificity:

(1) A test kit approved for use in

testing donations of human blood and

blood components for evidence of

Federal Register / Vol. 66, No. 112 / Monday, June 11, 2001 / Rules and Regulations 31165

infection due to communicable disease

agents listed in § 610.40(a); and

(2) Human immunodeficiency virus

(HIV) test kit approved for use in the

diagnosis, prognosis, or monitoring of

this communicable disease agent.

(b) You must not distribute a lot that

is found to be not acceptable for

sensitivity and specificity under

§ 610.44(a). FDA may approve an

exception or alternative to this

requirement. Applicants must submit

such requests in writing. However, in

limited circumstances, such requests

may be made orally and permission may

be given orally by FDA. Oral requests

and approvals must be promptly

followed by written requests and

written approvals.

§ 610.45 [Removed]

12. Section 610.45 Human

Immunodeficiency Virus (HIV)

requirements is removed.

PART 640—ADDITIONAL STANDARDS

FOR HUMAN BLOOD AND BLOOD

PRODUCTS

13. 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.

§ 640.2 [Amended]

14. Section 640.2 General

requirements is amended by removing

paragraph (d).

15. Section 640.5 is amended by

revising paragraph (f).

§ 640.5 Testing the blood.

* * * * *

(f) Test for communicable disease

agents. Whole Blood shall be tested for

evidence of infection due to

communicable disease agents as

required under § 610.40 of this chapter.

§ 640.14 [Amended]

16. Section 640.14 Testing the blood

is amended by removing ‘‘§§ 610.40 and

610.45’’ and by adding in its place ‘‘

§ 610.40’’.

§ 640.23 [Amended]

17. Section 640.23 Testing the blood

is amended in paragraph (a) by

removing ‘‘§§ 610.40 and 610.45’’ and

by adding in its place ‘‘§ 610.40’’.

§ 640.33 [Amended]

18. Section 640.33 Testing the blood

is amended in paragraph (a) by

removing ‘‘§§ 610.40 and 610.45’’ and

by adding in its place ‘‘§ 610.40’’.

§ 640.53 [Amended]

19. Section 640.53 Testing the blood

is amended in paragraph (a) by

removing ‘‘§§ 610.40 and 610.45’’ and

by adding in its place ‘‘§ 610.40’’.

20. Section 640.67 is revised to read

as follows:

§ 640.67 Laboratory tests.

Each unit of Source Plasma shall be

tested for evidence of infection due to

communicable disease agents as

required under § 610.40 of this chapter.

21. Section 640.70 is amended by

revising paragraph (a)(2).

§ 640.70 Labeling.

(a) * * *

(2) The statement ‘‘Caution: For

Manufacturing Use Only’’ for products

intended for further manufacturing into

injectable products, or the statement,

‘‘Caution: For Use In Manufacturing

Noninjectable Products Only’’, for

products intended for further

manufacturing into noninjectable

products. The statement shall follow the

proper name in the same size and type

of print as the proper name. If the

Source Plasma has a reactive screening

test for evidence of infection due to a

communicable disease agent(s) under

§ 610.40 of this chapter, or is collected

from a donor with a previous record of

a reactive screening test for evidence of

infection due to a communicable

disease agent(s) under § 610.40 of this

chapter, the Source Plasma must be

labeled under § 610.40(h)(2)(ii)(E) of this

chapter.

* * * * *

PART 660—ADDITIONAL STANDARDS

FOR DIAGNOSTIC SUBSTANCES FOR

LABORATORY TESTS

22. The authority citation for 21 CFR

part 660 continues to read as follows:

Authority: 21 U.S.C. 321, 331, 351, 352,

353, 355, 360, 360c, 360d, 360h, 360i, 371,

372; 42 U.S.C. 216, 262, 263, 263a, 264.

§ 660.42 [Removed]

23. Section 660.42 Reference panel is

removed.

PART 809—IN VITRO DIAGNOSTIC

PRODUCTS FOR HUMAN USE

24. The authority citation for 21 CFR

part 809 continues to read as follows:

Authority: 21 U.S.C. 331, 351, 352, 355,

360b, 360c, 360d, 360h, 360i, 360j, 371, 372,

374, 381.

25. Section 809.20 is amended by

revising paragraph (b).

§ 809.20 General requirements for

manufacturers and producers of in vitro

diagnostic products.

* * * * *

(b) Compliance with good

manufacturing practices. In vitro

diagnostic products shall be

manufactured in accordance with the

good manufacturing practices

requirements found in part 820 of this

chapter and, if applicable, with § 610.44

of this chapter.

Dated: June 1, 2001.

Bernard A. Schwetz,

Acting Principal Deputy Commissioner.

[FR Doc. 01–14408 Filed 6–8–01; 8:45 am]

BILLING CODE 4160–01–F

DEPARTMENT OF HEALTH AND

HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 606 and 630

[Docket No. 98N–0607]

General Requirements for Blood,

Blood Components, and Blood

Derivatives; Donor Notification

AGENCY: Food and Drug Administration,

HHS.

ACTION: Final rule.

SUMMARY: The Food and Drug

Administration (FDA) is amending the

biologics regulations to require blood

and plasma establishments to notify

donors, including autologous donors,

whenever the donor is deferred or

determined not to be suitable for current

or future donations of blood and blood

components. A donor is deferred based

on results of tests for communicable

disease agents or determined not to be

suitable for donation based on failure to

satisfy suitability criteria. Blood and

plasma establishments also are required

to notify the referring physician of an

autologous donor when the autologous

donor is deferred based on tests for

evidence of infection with a

communicable disease agent(s). A

standard operating procedure (SOP) and

recordkeeping also are required. This

final rule is intended to help protect

public health and to promote

consistency in the industry. Elsewhere

in this issue of the Federal Register,

FDA is publishing a final rule on the

requirements for testing human blood

donors for evidence of infection due to

communicable disease agents.

DATES: This rule is effective December

10, 2001.

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: