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

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 606 and 610

[Docket No. 91N-0152]

RIN 0910-AA05

Current Good Manufacturing Practices for Blood and Blood

Components: Notification of Consignees Receiving Blood and Blood

Components at Increased Risk for Transmitting HIV Infection

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule.

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SUMMARY: The Food and Drug Administration (FDA) is amending the

biologics regulations to require that blood establishments (including

plasma establishments) prepare and follow written procedures for

appropriate action when it is determined that Whole Blood, blood

components (including recovered plasma), Source Plasma and Source

Leukocytes at increased risk for transmitting human immunodeficiency

virus (HIV) infection have been collected. This final rule requires

that when a donor who previously donated blood is tested on a later

donation in accordance with the regulations, and tests repeatedly

reactive for antibody to HIV, the blood establishment shall perform

more specific testing using a licensed test, if available, and notify

consignees who received Whole Blood, blood components, Source Plasma or

Source Leukocytes from prior collections so that appropriate action is

taken. Blood establishments and consignees are required to quarantine

previously collected Whole Blood, blood components, Source Plasma and

Source Leukocytes from such donors, and if appropriate, notify

transfusion recipients.

The Health Care Financing Administration (HCFA) is also issuing a

final rule, published elsewhere in this Federal Register, which

requires all transfusion services subject to HCFA's conditions of

Medicare participation for hospitals to notify transfusion recipients

who have received Whole Blood or blood components from a donor whose

subsequent donation test results are positive for antibody to HIV

(hereinafter referred to as HCFA's final rule). FDA is requiring

transfusion services that do not participate in Medicare and are,

therefore, not subject to HCFA's final rule, to take steps to notify

transfusion recipients.

FDA is taking this action to help ensure the continued safety of

the blood supply, and to help ensure that information is provided to

consignees of Whole Blood, blood components, Source Plasma and Source

Leukocytes and to recipients of Whole Blood and blood components from a

donor whose subsequent donation tests positive for antibody to HIV.

DATES: This regulation is effective November 8, 1996. Written comments

on the information colelction requirements should be submitted by

February 7, 1997.

ADDRESSES: Submit written comments on the information collection

requirements to the Dockets Management Branch (HFA-305), Food and Drug

Administration, 12420 Parklawn Dr., rm. 1-23, Rockville, MD 20857.

FOR FURTHER INFORMATION CONTACT:

Sharon Carayiannis, Center for Biologics Evaluation and Research (HFM-

630), Food and Drug Administration, 1401 Rockville Pike, suite 200N,

Rockville, MD 20852-1448, 301-594-3074.

SUPPLEMENTARY INFORMATION:

I. Introduction

FDA has implemented an extensive system of donor screening and

testing procedures performed by blood establishments before, during,

and after donation, to help prevent the transfusion of blood products

that are at increased risk for transmitting HIV. HIV is the virus that

causes acquired immune deficiency syndrome (AIDS), a

[[Page 47414]]

communicable disease that can be transmitted through transfusion.

As a result of the screening and testing procedures, the risk of

transmitting HIV infection through blood transfusion is very low.

Despite the best practices of blood establishments, however, a person

may donate blood early in infection, during the period when the

antibody to HIV is not detectable by a screening test, but HIV is

present in the donor's blood (a so-called ``window'' period). If the

donor attempts to donate blood at a later date, the test for antibody

to HIV may, at that time, be repeatedly reactive. Therefore, FDA

believes such circumstances require clarification of the donor's status

through testing with a more specific antibody test and procedures to

``lookback'' at prior collections. Previously collected Whole Blood and

blood components would be at increased risk for transmitting HIV and a

recipient of a transfusion of Whole Blood and blood components

collected during the ``window'' period would not know that he or she

may have become infected with HIV through the transfusion unless

notified.

In the Federal Register of June 30, 1993 (58 FR 34962), FDA issued

a proposed rule to require appropriate action when it is later

determined that blood and blood components might have been collected

during the ``window'' period. FDA has reviewed comments submitted on

the proposed rule and is now issuing this final rule to require

facilities involved in the collection, processing, and administration

of blood to quarantine Whole Blood, blood components, Source Plasma and

Source Leukocytes which were collected from a donor who tested negative

at the time of previous donations but subsequently tests repeatedly

reactive for antibody to HIV. The final rule requires blood

establishments to inform consignees (e.g., hospital transfusion

services and manufacturers of plasma derivatives) of the collection and

distribution of such previously donated Whole Blood, blood components,

Source Plasma and Source Leukocytes.

In the Federal Register of June 30, 1993 (58 FR 34977), HCFA also

issued a proposed rule which would require certain transfusion services

to notify recipients of transfusions determined to be from a donor

whose subsequent donation tests positive for antibody to HIV

(hereinafter referred to as HCFA's proposed rule). The final rules

issued by both FDA and HCFA require transfusion services to perform

such notifications.

In a memorandum of understanding (MOU), FDA and HCFA agreed to

coordinate the inspections of transfusion services in medicare

participating hospitals to minimize duplication of effort and to reduce

the burden on affected facilities. Blood establishments, including

those hospital transfusion services not subject to HCFA's regulations

on the conditions of Medicare participation for hospitals, such as

Indian Health Service and Veteran's Administration Hospitals, are

subject to FDA's final rule. Thus, all transfusion services are subject

to the requirements for quarantine and transfusion recipient

notification under either the FDA or HCFA rule.

II. Highlights of the Final Rule

Under the biologics licensing and quarantine provisions of the

Public Health Service Act (42 U.S.C. 262-264) and the drug, device, and

the general administrative provisions of the Federal Food, Drug, and

Cosmetic Act (the act) (21 U.S.C. 351-353, 355-360, and 371-374), FDA

has the authority to promulgate 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, FDA currently requires that each

donation be tested and found negative for antibody to HIV under

Sec. 610.45 (21 CFR 610.45). Existing regulations already restrict the

use, for transfusion or further manufacture, of a donation testing

repeatedly reactive for antibody to HIV. Even though current licensed

screening tests for antibody to HIV are very sensitive, testing may not

identify all units capable of transmitting HIV infection. For this

reason, many blood establishments have instituted special procedures

when blood or plasma has been collected from a donor testing positive

for antibody to HIV at a later date. These procedures, commonly

referred to as ``lookback'' procedures, involve determining the

suitability of prior collections of Whole Blood, blood components,

Source Plasma and Source Leukocytes from such a donor. These existing

procedures may also involve notifying consignees that have received

prior collections from the donor so consignees can quarantine such

products and, as appropriate, take steps to notify the transfusion

recipients of such Whole Blood and blood components.

While many blood establishments have voluntarily developed written

``lookback'' procedures, these existing procedures vary significantly

among blood establishments. As proposed in the Federal Register of June

30, 1993, FDA is amending the biologics regulations to require blood

establishments to prepare and follow written standard operating

procedures (SOP's), defining steps to be taken when ``lookback''

circumstances arise.

The final rule requires blood establishments to perform more

specific testing of the donor's blood using a licensed test, and to

notify consignees who received Whole Blood, blood components, Source

Plasma and Source Leukocytes from prior collections so that appropriate

action is taken. Blood establishments and consignees shall quarantine,

as described later in this document, previously collected Whole Blood,

blood components, Source Plasma and Source Leukocytes from such donors

until the donor's status is clarified through further testing. FDA is

requiring that other informative test results, if available, be

considered when determining the status of the donor and the suitability

of prior collections.

Upon completion of more specific testing, the final rule also

requires hospital transfusion services that do not participate in

Medicare and are, therefore, not subject to HCFA's final rule, to take

steps to notify transfusion recipients, as appropriate. Such

transfusion recipients shall receive notification for the purpose of

testing for evidence of HIV infection, early treatment, if indicated,

and counseling to take appropriate precautions to prevent the further

spread of the virus such as to sexual partners.

III. HCFA's Companion Rule

Under HCFA's proposed rule, transfusion services operated by

hospitals participating in Medicare and inspected by HCFA that receive

notification of previously collected Whole Blood and blood components

at increased risk for transmitting HIV, would be required to quarantine

such prior collections and notify the transfusion recipient's attending

physician, the transfusion recipient, or other authorized person, as

appropriate. HCFA's final rule requires the hospital transfusion

service to have a written agreement with each blood supplier

documenting these procedures.

As referenced in section I. of this document, FDA and HCFA

coordinate the inspections of transfusion services in medicare

participating hospitals to minimize duplication of effort and to reduce

the burden on affected facilities. In the MOU, it was estimated that

HCFA would be responsible for inspecting and surveying approximately

3,000 transfusion services. FDA continues to conduct the inspections of

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establishments were activities include more than the performance of

compatibility testing. (See 49 FR 34448, August 31, 1984, and 21 CFR

607.65.)

IV. Other Sources of Information

As FDA recognized in the preamble to the proposed rule, blood

establishments may receive information from other sources which

indicate that a donor may be infected with HIV. FDA encourages blood

establishments to initiate ``lookback'' procedures whenever they have

information that a donor has become infected with HIV. FDA recognizes

the existence of diagnostic modalities for HIV infection, other than

antibody testing, such as virus culture or direct viral assays. FDA

encourages blood establishments to consider such test results, when

available and reliable, and to voluntarily initiate the ``lookback''

process as described in this final rule. Additionally, the final rule

requires that such results be considered prior to release of units

quarantined in a ``lookback'' procedure.

In particular, FDA recommends that blood establishments voluntarily

initiate ``lookback'' procedures based on HIV antigen testing, as

indicated in the August 8, 1995, Memorandum to All Registered Blood

Establishments, Regarding Recommendations for Donor Screening with a

Licensed Test for HIV-1 Antigen. In the August 8, 1995, memorandum FDA

provided recommendations for the implementation of donor screening

tests for HIV type 1 (HIV-1) antigen(s) within 3 months of the

commercial availability of the first test for HIV-1 antigen(s). The

August 8, 1995, memorandum stated that the average infectious

``window'' period, when HIV antibody is not detectable by the screening

test, is estimated to be approximately 22 to 25 days for screening with

combination assays for antibodies to HIV-1 and HIV-2. The memorandum

further stated that HIV antigen screening could reduce the ``window''

period by an estimated 6 days and could be expected to prevent up to 25

percent of the current ``window'' period donations or about 5 to 10

cases of transfusion associated HIV per year. Because HIV-1 antigen

screening will reduce but not eliminate the residual risk for HIV-1

from transfusion, FDA regards such screening as an interim measure

pending the availability of improved technology for this purpose. FDA

encourages continued development of new methods no further reduce the

risk of HIV transmission due to ``window'' period donations.

V. Responses to Letters of Comment

FDA provided interested individuals 60 days to submit written

comments on the proposed rule. FDA received a total of 25 letters of

comment, which included 10 from blood collection facilities or blood

banks, 8 from pathologists or pathology associations, 6 from blood

banking associations, and 1 from a parent of children with hemophilia.

Twenty-one comments agreed with the concept of ``lookback''. There

were differences of opinion as to how the ``lookback'' process should

be conducted and concerns regarding liability of various individuals

involved in the process. Three comments indicated support for the

strengthening of the ``lookback'' requirements, while eight comments

suggested that the proposed rule's cost to industry would pose a

significant burden with little benefit to public health.

After review and consideration of all comments, FDA continues to

believe that the new requirements for the handling of prior collections

of Whole Blood, blood components, Source Plasma and Source Leukocytes

later found to be at increased risk for transmitting HIV infection are

important public health measures. Below, FDA provides responses to the

comments received.

A. General Comments

1. Terminology Used by FDA and HCFA

Two comments expressed some confusion over specific terminology and

the differences in terminology used by FDA and HCFA. One comment

suggested the use of ``transfusion service'' instead of ``consignee.''

One comment suggested the use of a more specific term for

``recipient.''

FDA's use of the term consignee includes any facility to which the

Whole Blood, blood components, Source Plasma and Source Leukocytes have

been shipped (e.g., a transfusion service, a manufacturer of blood

products, or another blood banking establishment). As written, when the

rule uses the term consignee, it refers to more than a transfusion

service. The FDA and HCFA rules refer to ``transfusion services'' when

the rules are specific to transfusion services. To interchange these

terms would cause more confusion and would not achieve the goals

sought.

As suggested by one comment, FDA has amended the rule to use the

terms transfusion recipient or transfused patient in a number of places

to make it clear that FDA is referring to the recipient of the

transfusion. Where the term ``recipient'' is used alone, FDA believes

that the context makes it clear that the term refers to patients and

not to consignees.

FDA believes that the terminology used in the rules is appropriate

and understood by the entities subject to FDA regulation. FDA also

believes that the terminology used by HCFA is understood by the

entities regulated by HCFA.

2. Blood Donor Locator Service

Three comments stated an interest in using the Blood Donor Locator

Service (BDLS) as a part of the ``lookback'' process. One request was

to expand this service to locate recipients also.

The BDLS final rule which was published in the Federal Register of

December 24, 1991 (56 FR 66561), addressed similar comments calling for

the expanded use of the service. The statutory authority to conduct the

BDLS, as defined by section 8008 of the Technical and Miscellaneous

Revenue Act of 1988 (Pub. L. 100-647), only authorizes the Social

Security Administration to provide address information for blood donors

whose test results for antibody to HIV show that they are, or may be,

infected with HIV. The legislation authorizing the BDLS does not extend

to transfusion recipients or to any other individual. Participation in

the BDLS by State agencies and blood donation facilities is voluntary,

but participants must agree to comply with the provisions of the

statute and the regulations as defined in the BDLS final rule.

3. Organization of Information in the Final Rule

One comment suggested that the organization of information in the

regulations was confusing, and asked for clarification of the intent of

the regulations.

The rule is divided into subsections that provide specific

direction on each aspect of the ``lookback'' process. Each subsection

of the rule must be reviewed for a complete understanding of all

aspects of this important information. The following description serves

as a brief overview of the regulations. Section 606.100 (21 CFR

606.100) states the requirements for SOP's, and Sec. 606.160 (21 CFR

606.160) states the requirements for recordkeeping. Section 610.45(d)

identifies the circumstances under which the ``lookback'' process shall

be initiated. Section 610.46(a) (21 CFR 610.46(a)) states the

requirements for the initial steps of the ``lookback'' process. Section

610.46(a)(1) establishes the circumstances for quarantine and requires

notification of consignees to

[[Page 47416]]

quarantine such products. Section 610.46(a)(2) discusses quarantine of

products held by consignees.

Section 610.46(b) specifies the time limit for completion of the

licensed, more specific test and the notification of the consignee of

those test results. Section 610.46(c) addresses products that are

exempt from quarantine and Sec. 610.46(d) discusses requirements for

release from quarantine. Section 610.46(e) makes clear that these

actions are not considered to be product recalls. Section 610.47(a) (21

CFR 610.47(a)) covers those transfusion services not subject to HCFA's

regulations. Section 610.47(b) contains requirements for notification

of recipients and Sec. 610.47(c) addresses the notification of a legal

representative or relative acting on behalf of the recipient.

B. Comments on Sec. 606.100

Four comments requested more specific direction regarding the

content of SOP's.

It is intention of FDA to allow appropriate flexibility to blood

establishments in the development of their procedures. For example, as

mentioned in one comment, a blood establishment could identify by title

or name the individuals authorized to provide and receive consignee

notification in the ``lookback'' process. FDA further discusses the

content of SOP's in the responses to comments on specific subsections

of the rule.

C. Comments on Sec. 610.45(d)

1. Use of Information from Other Sources to Initiate ``Lookback''

Process

One comment stated that there will be additional circumstances when

a blood establishment can reliably and consistently receive information

that should result in the initiation of a ``lookback'' process. The

sources of this information may include the U.S. military, health

departments or physicians of former donors now found to be HIV-infected

or diagnosed as having AIDS.

FDA agrees that there will be circumstances when the initiation of

``lookback'' may be based on reliable information provided by the U.S.

military, health departments, and other sources and recommends

appropriate action in those instances. However, a blood establishment

generally has no control over whether they will be appropriately

contacted by these outside sources. In addition, the laws and

procedures governing such notifications will vary from State to State.

Therefore, FDA's final rule does not contain specific additional

circumstances under which ``lookback'' is required because the ability

for each establishment to meet the requirements will vary so widely,

based upon varying State laws, local practices, and confidentiality

issues.

2. Initiation of ``Lookback'' Process Based on Repeatedly Reactive

Screening Results

Three comments objected to the initiation of the ``lookback''

process based on the repeatedly reactive antibody screening test

results before the completion of the licensed, more specific test. One

comment stated that any ``lookback'' action, beyond the quarantine of

product, based on the antibody screening test results would be

inappropriate because those tests have a high rate of false positive

results and were not intended to be diagnostic without further

confirmatory testing.

One comment stated that there is a very high cost associated with

preventing the transfusion of very few infectious units based on: (1)

The estimate that of all donations made each year, most blood and blood

components will be transfused before a donor is permitted to donate

again 56 days later; (2) the estimate that only one half of donors will

return to donate again; and (3) the very low number of units expected

to be infectious despite proper testing.

One comment in support of the rule stated that the rule did not

place undue hardship on the blood banking industry. One comment

objected to the more stringent requirements for notification due to the

current burden of escalating demands and diminishing resources,

including increased workload due to more complicated patient illnesses,

vacant technical positions that cannot be filled due to the declining

numbers of skilled, qualified medical technologists, and hospital costs

rising faster than revenues. One comment stated concern that patient

needs would not be met because the increased regulation would force

hospital based donor centers to close as a result of economic

pressures.

One comment cited a threefold increase in the rate of repeatedly

reactive screening tests for antibody to HIV with none of those

confirmed by Western Blot in the past year, which would result in much

higher expected total annualized costs than projected by FDA. Two

comments stated that the actual costs would be twice that estimated by

FDA. Three comments stated that the goals of the proposed rule are

laudable but also estimated that most HIV infections are spread through

other modes of transmission and, therefore, our limited health care

dollars are better spent in other ways.

FDA is charged with the responsibility of protecting the public

from unsafe biological products and has the authority to promulgate

regulations to accomplish its public health mission. Comments on the

proposed rule indicate that SOP's for the ``lookback'' process are

already in place in a large percentage of blood establishments. Based

on comments received, FDA believes that the modification of existing

SOP's to meet the requirements of this rule would not impose an

unreasonable burden or expense to the large number of establishments

with an existing system for handling ``lookback'' circumstances.

FDA believes the prevention of a small number of transmissions of

HIV per year that will result from the initiation of the ``lookback''

process based on the repeatedly reactive antibody screening test

results or other informative test results is a clear benefit. FDA

believes that steps must be taken to avoid transfusion of potentially

unsuitable Whole Blood and blood components while waiting for the

completion of further testing, especially since the time limit for such

testing has been extended to 30 days, as described later in this

document. FDA recognizes that the requirement for the initiation of

this process at the time of the repeatedly reactive HIV antibody test

will result in some additional costs to blood establishments that

currently do not begin the process at this point. However, FDA believes

these steps are warranted to increase the safety of the nation's blood

supply.

D. Comments on Sec. 610.46(a)

1. Notification of Consignees

One comment stated concern regarding the notification of consignees

of the results of the licensed, more specific test and the potential

for confusion if the product in question had already been returned to

the blood donor center.

The final rule requires that blood establishments notify consignees

to quarantine Whole Blood, blood components, Source Plasma and Source

Leukocytes that are at increased risk for transmitting HIV infection.

Upon notification by the blood establishment, the consignee is to

promptly, within 72 hours, quarantine the affected products until

notified of the negative results of a licensed, more specific test.

Return of such products to the blood establishment is not a requirement

of this rule, and, therefore, should not create confusion. However, if

the

[[Page 47417]]

consignee does return the blood or blood components to the blood

establishment, no further consignee notification would be required. FDA

has amended the final rule to clarify the requirement to promptly

notify consignees, within 72 hours, for the purpose of identifying

those products that remain in inventory and require quarantine.

2. Products for Further Manufacture

One comment concerned Sec. 610.46(a)(2), which requires that

unpooled products held by the consignee shall be quarantined. The

comment stated that while it appears that the proposed rule is

structured to exclude large pools of plasma from some requirements, the

rule might be interpreted to have a different result when the

collecting facility and the manufacturing facility hold the same

license. The comment stated further that in this situation, both large

and small pools would be quarantined since the products were not

shipped to a consignee to be pooled.

The comment also asked that small pools of plasma intended for

further manufacture into noninjectable products also be exempt from

quarantine because they are sometimes pooled at the collection facility

and may include plasma considered to be in short supply. The comment

stated that small pools of plasma intended for the manufacture of

noninjectable products should be exempt from quarantine because they

are sufficiently safe as noninjectable products.

A collection facility would be required to quarantine all in-house

or ``on-site'' Whole Blood, blood components, Source Plasma and Source

Leukocytes. A manufacturing facility that shares an establishment

license with the collecting facility is not required to quarantine

pooled products. To avoid a shortage of injectable and noninjectable

products the final rule exempts from quarantine pooled Source Plasma

and Source Leukocytes intended for further manufacture into injectable

and noninjectable products, as described in Sec. 610.46(c). FDA

believes this requirement will better identify those affected products

to be quarantine while ensuring the availability of blood products for

further manufacture.

Additionally, FDA agrees that pools intended for further

manufacture into noninjectable products are sufficiently safe due to

their intended use as noninjectable products and are, therefore, exempt

from quarantine. The rule has been amended to clarify that Pooled

Source Plasma and Pooled Source Leukocytes are exempt from quarantine.

Appropriate safeguards must be used to prevent such products intended

for further manufacture into non-injectable products from being used

for further manufacture into injectable products.

E. Comments on Sec. 610.46(b)

1. Two Week Limit for Completion of Licensed, More Specific Test

One comment supported proposed Sec. 610.46(b) which requires the 2-

week time limit for completion of the licensed, more specific test and

consignee notification, while twenty-three comments expressed

disagreement with the time limit. The 2-week time limit was cited as

too short due to shipping of samples, batching of laboratory work, the

additional number of tests run when the sample is not negative,

dependence upon reference laboratories for this work, and unforeseen

circumstances that are beyond the control of the blood establishment.

The suggestions for a more appropriate timeframe ranged from 3 weeks to

8 weeks to ``as soon as possible''.

After consideration of the additional information provided in the

comment letters, FDA believes that it is appropriate and reasonable to

change the time limit for completion of the licensed, more specific

test and consignee notification of the test results. FDA is amending

Sec. 610.46(b) by allowing a maximum of 30 calendar days for completion

of the licensed, more specific test for antibody to HIV and consignee

notification of the test results.

FDA's concern for the prompt notification of the transfusion

recipient, without undue burden to industry, dictates that the time

limit for completion of testing not exceed 30 days. FDA's extension of

the time limit for the completion of these steps is intended to give

blood establishments a reasonable time period to comply with the

regulation. FDA expects that blood establishments will initiate and

complete such testing expeditiously, but take no longer than 30

calendar days.

The written SOP's of the establishment required under

Sec. 606.100(b)(19) should be adequate to ensure that the required

testing and consignee notification is routinely completed within 30

days. In rare circumstances, such as when there are testing problems,

testing and notification may take longer than 30 days. In such cases

the establishment should document in its records the reason for the

failure to meet the requirement. If the establishment frequently fails

to meet the required time limits, the establishment should review its

procedures to determine how testing and consignee notification can be

expedited.

2. Positive Test for Antibody to HIV-2

Two comments on Sec. 610.46(b) requested clarification on further

testing and notification of consignee and recipients when donors

subsequently test positive for antibody to HIV-2.

In the Memorandum to All Registered Blood Establishments, Revised

Recommendations for the Prevention of HIV Transmission by Blood and

Blood Products, dated April 23, 1992, FDA provided guidance

recommending that all blood establishments collecting Whole Blood,

blood components, Source Plasma, or Source Leukocytes implement a

licensed test for detection of antibody to HIV-2 by June 1, 1992. FDA

modified existing recommendations for prevention of HIV transmission by

blood and blood products to include HIV-2 testing at that time. The

revised recommendations for donor testing, deferral, and reentry are

found in section II. and the recommendations on ``lookback'' are found

in section IV. of the April 23, 1992, memorandum.

This final rule is similar to the FDA guidance on supplemental

tests recommended in the April 23, 1992, Memorandum. FDA has amended

Sec. 610.46(b) of the final rule to clarify requirements for HIV-2

testing. Currently, there is no ``licensed, more specific'' test for

antibody to HIV-2. Thus, the final rule requires the following:

(1) When a donor's screening test for antibody to HIV is repeatedly

reactive, a licensed, more specific test for antibody to HIV shall be

performed.

(2) When the repeatedly reactive screening test is performed using

a single virus test for antibody to HIV-2 or combination test for

antibody to HIV-1/HIV-2, a second screening test for HIV-2, which is

different from the original HIV-2 test, must also be performed. This

second, different enzyme immuno-assay (EIA) test must be a licensed

test and can be either a single virus test or a combination test.

Whole Blood, blood components, Source Plasma and Source Leukocytes

from prior collections may be released from quarantine only if the

donor is tested for antibody to HIV-1 by a licensed, more specific test

and the result is negative; and if the screening test is repeated using

a different EIA test for antibody to HIV-2, either single virus or

combination test, and the result is negative, absent other informative

test

[[Page 47418]]

results. Release from quarantine is not permitted under any other test

results. Transfusion recipient notification is required when the

licensed, more specific test for HIV-1 is positive or when the second,

different EIA test for antibody to HIV-2 is repeatedly reactive.

Whole Blood, blood components, Source Plasma and Source Leukocytes

are exempt from quarantine if the collection occurred more than 12

months prior to the donor's most recent negative screening test(s). If

the most recent negative screening test for antibody to HIV was

performed prior to the implementation of HIV-2 testing in June of 1992,

then the negative screening test for HIV-1 is sufficient to establish

the 12-month time period.

This final rule supersedes the existing recommendations for

``lookback'' procedures in section IV. of the April 23, 1992,

Memorandum, Exclusion/Retrieval of Potentially Contaminated Units From

Prior Collections and Notification of Consignees.

F. Comments on Sec. 610.46 (c) and (d)

1. Release From Quarantine and Western Blot Indeterminate Results

Two comments indicated confusion regarding the disposition of

components collected both greater than and less than the 12-month

period prior to the most recent nonreactive test result. Additionally,

two comments on the subject of Western blot indeterminate results asked

for clarification and for exemption from the ``lookback'' process due

to what the commentor believes is the unlikely occurrence that a unit

with an indeterminate Western blot test result would be infectious.

FDA is requiring prompt quarantine for Whole blood, blood

components, Source Plasma and Source Leukocytes collected from a donor

at increased risk for transmitting HIV infection. Quarantine is

required for units from such a donor collected within the 5years prior

to the repeatedly reactive test for antibody to HIV, if intended for

transfusion, or collected within 6 months prior to the repeatedly

reactive test result, if intended for further manufacture. Section

610.46(c) describes the situation in which Whole Blood, blood

components, Source Plasma and Source Leukocytes are exempt from

quarantine because there is serological evidence that the donation(s)

was not made during the ``window'' period.

In the preamble to the proposed rule, FDA stated that, based on

experience, current estimates predict with approximately 95 percent

confidence that in all cases of HIV infection, the person will test

positive for antibody to HIV by a licensed test within 6 months from

the date of infection. As stated in the preamble to the proposed rule,

to provide an additional margin of safety, FDA has extended the period

for quarantine to 12 months, to more closely approximate a 99 percent

confidence interval. Accordingly, FDA's requirement to quarantine all

Whole Blood, blood components, Source Plasma and Source Leukocytes

collected within 12 months prior to the most recent negative screening

test provides an added margin of safety during the months when an

infected donor may not yet test positive for antibody to HIV. All

donations made before this 12-month period would be outside the

``window'' period and would be exempt from quarantine.

The final rule is amended to clarify the requirements when other

informative test results are available. Section 610.46(d) of the final

rule states that a product may be released from quarantine if the

donor's blood is tested for antibody to HIV by a licensed, more

specific test and the test result is negative, absent other informative

test results. FDA believes that release from quarantine is possible

only if the more specific test is negative and there are no other

informative test results that show evidence of HIV infection. This

regulation does not allow the release from quarantine following and

indeterminate Western blot test result.

Blood establishments may voluntarily perform other FDA approved

informative tests for HIV and must consider those test results when

determining the status of the donor and the suitability of prior

collections. For example, FDA has recently recommended donor screening

for HIV-1 antigen(s) using approved tests. Testing for HIV-1 antigen(s)

using seroconversion samples has shown that donors with recent HIV

infection test repeatedly reactive for antibody to HIV, yet test as

negative or indeterminate by a more specific antibody test but positive

for HIV-1 antigen(s). Prior collections from such a donor would not be

exempt from quarantine unless collected more than 12 months prior to

the donor's most recent negative screening test for HIV antibody.

Disposition of prior collections at increased risk for transmitting

HIV infection should follow the establishment's SOP for appropriate

disposal of blood products that are unsuitable for transfusion, in

accordance with Sec. 606.40. The Memorandum to All Registered Blood

Establishments from the Director, Center for Biologics Evaluation and

Research, Control of Unsuitable Blood and Blood Components, dated April

6, 1988, provides additional guidance for quarantine and disposition of

products unsuitable for transfusion.

In situations where an establishment fails to comply within the 30-

day limit for completion of further testing, and subsequently the test

result is negative, the Whole Blood, blood components, Source Plasma

and Source Leukocytes may be released from quarantine and consignees

must be notified promptly upon availability of the test results.

Destruction of quarantined units is not required merely because further

testing was completed after the 30-day deadline. No release of

quarantined Whole Blood, blood components, Source Plasma and Source

Leukocytes is permitted before the results of the further testing are

available.

2. Use of Test Results From Other Laboratories

Two comments asked that blood establishments be allowed to use the

laboratory test results from other laboratories as evidence of the most

recent negative screening test for antibody to HIV, thus allowing the

quarantine and notification to be limited to units collected within 12

months prior to that negative result. One comment stated that evidence

of such negative screening results could be provided by independent

clinical laboratories, State health departments, military laboratories,

other blood banks, etc.

FDA agrees that test results from the Clinical Laboratories

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

or licensed blood establishments may be accepted as evidence of the

most recent negative screening test for antibody to HIV, provided that

the blood establishment has assurance that the laboratory is certified

and is using a licensed test kit. The blood establishment should

receive and retain testing records documenting the test results.

G. Comments on Sec. 610.47(a)

1. Notification of Transfusion Recipient Prior to Completion of

Licensed, More Specific Test

Two comments disagreed with the proposed requirement to notify

recipients of potentially infectious units based upon screening results

if the licensed, more specific test results are not available within 2

weeks. One comment stated that upon notification, the transfusion

recipient would experience unnecessary worry since

[[Page 47419]]

more than 90 percent of repeatedly reactive screening results are not

confirmed by Western Blot testing.

As previously discussed in this final rule, the time limit for the

completion of the licensed, more specific test for HIV and the

consignee notification of those test results has been extended from 2

weeks to a maximum of 30-calendar days. This change makes it highly

unlikely that complete results will not be available prior to the

deadline for notification. If a situation of noncompliance occurs,

however, FDA has amended Sec. 610.47(a) so that recipient notification

prior to completion of the licensed, more specific test for HIV is not

required. This change is consistent with FDA's proposal to notify

recipients only if there are positive test results but not when the

test results are indeterminate.

FDA agrees that notification of transfusion recipients that the

transfused blood or blood component was at increased risk for

transmitting HIV is very likely to cause the recipient, and possibly

others, extreme anxiety and concern. Based on the rate of repeatedly

reactive screening tests that are not confirmed by further testing, a

significant percentage of recipients would be subjected to a tentative

notification which would prove to be alarming, confusing, and

unnecessary. Such recipients would be notified when the increased risk

for transmitting HIV has been confirmed by further testing.

2. Establishments Subject to ``Lookback'' Regulations

One comment asked for clarification on Sec. 610.47(a) which

addresses those establishments subject to FDA's rule and those

hospitals subject to HCFA's rule. Two comments asked if these

regulations apply to all regulated blood establishments, including

small, hospital-based transfusion services that also draw blood donors.

Section 610.47(a) specifically states that transfusion services that

are not subject to HCFA's regulations on the conditions of Medicare

participation for hospitals (42 CFR part 482) are subject to this rule.

FDA inspects establishments where activities include more than the

performance of compatibility testing, e.g., blood collection, washing

or freezing of red blood cells, and irradiating of blood components.

Therefore, small, hospital-based transfusion services that also draw

blood donors would be subject to this rule and inspection by FDA.

Certain establishments that do not participate in Medicare, such as

Indian Health Services and Veteran's Administration hospitals, are also

subject to FDA regulations.

HCFA's regulations apply to hospital transfusion services where

activities do not include more than the performance of compatibility

testing and that participate in Medicare. Section III. of this document

describes the division of responsibilities between FDA and HCFA for

inspections of blood establishments. HCFA's final rule is published

elsewhere in this issue of the Federal Register. This division of

responsibilities between FDA and HCFA, consistent with the MOU,

eliminates duplication of effort and reduces the burden on blood

establishments and hospitals.

H. Comments on Sec. 610.47(b)

1. Clarification of Responsibility for Transfusion Recipient

Notification

Two comments asked for clarification as to which entity is

responsible for notification of the transfusion recipient or his or her

physician in situations where the transfusion services are provided to

hospitals by community blood centers. One comment suggested more

consistent requirements between FDA and HCFA because it appeared that

the HCFA proposal makes the hospital responsible for the notification

of the recipient's physician rather than the transfusion service, as is

the case in the FDA proposed rule.

It is not the intention of FDA to designate the individual or the

department that will contact the recipient but rather to designate that

the transfusion service that issues the Whole blood or blood component

for transfusion will be ultimately responsible for ensuring that the

notification takes place. In a similar manner, HCFA holds the hospital

responsible for ensuring the notification is completed.

2. Process and Documentation for Transfusion Recipient Notification

Twenty-five comments expressed concern over the process and

timeframe for notification of the transfusion recipient. There were

some questions as to where the ultimate responsibility falls for

transfusion recipient notification and as to the documentation that is

required. Three comments asked that attending physicians be required to

comply with these regulations and asked for guidance in situations

where the recipient's physician declines to notify the recipient due to

conditions such as terminal illness, celibacy, or when the harmful

effects may exceed the benefits of notification. Additionally, two

comments expressed concern over respect for the doctor-patient

relationship and the authority to interfere with that relationship.

As stated previously, FDA intends that each establishment have the

flexibility to develop SOP's that describe the steps in this process

and all appropriate documentation. The SOP should address documentation

of person(s) contacted, by whom, when and whether the physician agreed

to notify the recipient, and any additional, pertinent information.

Some institutions may choose to designate a specific department or

person within the hospital to conduct the notification and counseling

for the recipient.

The SOP should be consistent with applicable local and State laws

and shall specify both a well designed system for accomplishing

notification and the required documentation of the outcome of these

efforts.

FDA believes that because the attending physician has developed as

relationship with the patient and is most familiar with that patient's

history, the patient's interests are best served when the attending

physician takes the responsibility for contact and counseling. In those

instances when this does not prove to be appropriate or possible, the

transfusion service is ultimately responsible for ensuring that the

notification takes place. If the patient is competent, but the

physician believes the information should not be given to the patient

and State law permits a legal representative or relative to receive

information on the patient's behalf, then the transfusion service or

physician should notify the patient's legal representative or relative.

Further, FDA believes that transfusion services should, upon learning

of the death of the transfusion recipient, continue the notification

process to inform the patient's family. Public health concerns would

warrant the notification process continue and include the deceased

patient's legal representative or relative. It would not be appropriate

for a physician or transfusion service to determine that the patient or

someone acting on his or her behalf need not be informed. The final

rule has been amended to clarify the notification requirements in

Secs. 610.46(c) and 610.47(b).

FDA has no regulatory authority over physicians in their role as

attending physicians, and for that reason, the agency is not able to

require their participation. Upon accepting responsibility for

recipient notification and counseling, it is reasonable to expect that

the physician would, in good faith, determine the appropriate

[[Page 47420]]

content and completeness of information provided to the recipient.

FDA is relying on HCFA's expertise in the area of hospital practice

in setting time limits for transfusion recipient notification.

Consistent with HCFA's final rule, published elsewhere in this issue of

the Federal Register, FDA believes that the hospital's notification

effort should consist of, at the minimum, three attempts by telephone

or in writing to reach the recipient, the recipient's legal

representative or relative. The final rule has been amended to clarify

that the transfusion service's notification effort should begin

immediately after receiving results of further testing for HIV and

should be completed 8 weeks later. The rule has also been amended to

clarify that the transfusion service should notify the patient, the

patient's legal representative or relative, as appropriate.

VI. Analysis of Impacts

FDA has examined the impacts of the final rule under Executive

Order 12866 and the Regulatory Flexibility Act (Pub. L. 96-354).

Executive Order 12866 directs agencies to assess all costs and benefits

of available regulatory alternatives and, when regulation in 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 agency believes that

this final rule is consistent with the regulatory philosophy and

principles identified in the Executive Order, and has determined that

this is not a significant regulatory action.

The purpose of the ``lockback'' requirement is to reduce the risk

of transfusion transmitted HIV infection through the quarantine of

blood and blood components that might have been collected during the

``window'' period, when the antibody to HIV is not yet detectable by a

screening test. Notification of consignees to quarantine the affected

products, until a more specific test for antibody to HIV is completed,

will prevent any further transmission of the virus. Upon completion of

more specific testing, all recipients of prior collections from a donor

that subsequently tests positive for antibody to HIV will be notified

by their attending physician, when possible, or by the transfusion

service. Such transfusion recipients shall receive notification for the

purpose of testing for evidence of HIV infection, early treatment, if

indicated, and counseling to take appropriate precautions to prevent

the further spread of the virus such as to sexual partners.

Most blood establishments already participate in a ``lookback''

program. Ninety-five percent of blood establishments, collecting 98

percent of the nation's blood supply, already participate in a

``lookback'' notification of their customers to quarantine previously

shipped blood later determined to be at increased risk for transmitting

HIV. Thus, requirements for written procedures, records of consignee

notification, and records that relate the prior collections to the

donor, later found to be repeatedly reactive for antibody to HIV, would

affect at most about 5 percent of blood establishments; the remaining

establishments may need to make minor changes to their existing

procedures. Therefore, FDA believes this final rule should have a

minimal impact. FDA expects the total annualized cost of the final rule

to blood establishments to be $3,248,354. FDA anticipates only a small

number of cases per year that will involve transfusion recipient

notification. In conclusion, FDA has determined that the final rule is

not a significant regulatory action as defined in Executive Order

12866.

At the time of the proposed rule, the agency certified that the

proposed requirements would not have a significant impact on a

substantial number of small entities. However, in response to industry

comments and in light of amended requirements for analyzing impact on

small entities (as enacted by Pub. L. 104-121), it was determined that

a final regulatory flexibility analysis would be useful. Accordingly,

the agency has assessed this final rule in accordance with the

Regulatory Flexibility Act, with the following results:

Need for, and objective of, the rule. As described elsewhere in

this preamble, FDA is taking this action to help ensure the continued

safety of the blood supply, and to help ensure that information is

provided to consignees of Whole Blood, blood components, Source Plasma

and Source Leukocytes and to recipients of Whole Blood and blood

components from a donor whose subsequent donation test positive for

antibody to HIV.

Types and number of small entities affected. This rule will affect

all of the 3,015 registered U.S. blood establishments. Of these

registered establishments, approximately 400 are part of the American

Red Cross, which supplies approximately 45 percent of blood products

nationally. An additional 286 are Federal or State facilities. Many, or

most, of the remaining 2,204 establishments may be small entities as

defined by the Regulatory Flexibility Act.

The affect of this rule is greatest for those blood establishments

that have not already voluntarily implemented ``lookback'' procedures

similar to those required here. As stated in the proposed rule (58 FR

34962), FDA estimated that at least 95 percent of establishments,

supplying 98 percent of the nation's blood, have such voluntary

procedures and would need to make only minor changes to ensure that

they are in compliance with this rule. The remaining up to 150

establishments would require more substantial changes in their

procedures. FDA considers 150 to be an upper bound, since it is likely

that liability concerns and advances in automated data technology have

prompted most establishments that did not previously have ``lookback''

procedures to have them in place by now.

Projected reporting, recordkeeping, and other compliance

requirements. To comply with this rule, all blood establishments

subject to this rule, including small entities, must: (1) Review and,

if necessary, modify their SOP's; (2) maintain the necessary records to

carry out these procedures; and (3) notify consignees within 72 hours

of repeatedly reactive test results. Blood establishments that provide

transfusion services and that are not subject to HCFA regulations must

also notify physicians of prior donation recipients, or the recipients

themselves, of the need for HIV testing and counseling. The estimated

time needed for establishments to comply with the reporting,

disclosure, and recordkeeping requirements of this rule are described

in detail in the reporting and recordkeeping tables in section VII. of

this document.

FDA estimates that two types of skills will be necessary to meet

these reporting and recordkeeping requirements. The skills of a medical

technologist, or a person with equivalent training and experience, will

be necessary to record donor, quarantine, testing, and disposition

information, and to notify consignees of test results. Updating SOP's

and notifying physicians and recipients of test results will require a

person knowledgeable and experienced in medical laboratory practice.

Based on the reporting, disclosure, and recordkeeping burden

described in section VII. of this document, FDA estimates that

establishments that currently have ``lookback'' procedures will require

approximately 27 hours per year to bring their procedures into

compliance with this rule, while establishments without such procedures

will require approximately 40 hours

[[Page 47421]]

annually to complete the required tasks. Establishments whose

transfusion services are also covered by this rule will require an

additional 8 hours per year to comply. Based on an estimated average

hourly cost of $37.98 to perform the required tasks, FDA predicts that

the average annual cost of these requirements for establishments that

currently lack ``lookback'' procedures is $1,520 per facility for most

establishments and $1,820 for facilities that transfuse as well as

collect blood. Average annual costs for the great majority of

establishments that already have ``lookback'' procedures are expected

to be approximately $1,030 for most establishments and $1,340 for

covered establishments that also provide transfusions.

In addition to these reporting and recordkeeping costs, all

facilities will bear the additional cost of disposing of any affected

units; conducting licensed, more specific tests for HIV; and replacing

discarded units.

With the exception of the initial development of SOP's, all costs

related to implementing the requirements of this rule are related to

the number of units of blood collected from repeat donors who test

positive for HIV, which in turn is related to total blood collections.

The average number of units of blood drawn per establishment covered by

this rule is approximately 8,000 units per year. Smaller establishments

will have lower costs of compliance than the averages described above,

while larger blood facilities will have higher costs, in proportion to

the number of units of blood drawn per year.

Steps to minimize the economic impact on small entities. The

significant issues raised by public comments on the costs of putting in

place the required procedures, and the burdens imposed by the

timeframes in the proposed rule, are described elsewhere in this

preamble, FDA agrees with the numerous comments suggesting that 2 weeks

is too short a time period to allow for completion of the licensed,

more specific test and subsequent notification of consignees, and that

4 weeks is a more reasonable period. Accordingly, FDA has amended the

rule to allow 30 calendar days for the completion of these tasks. This

change should reduce the impact of the rule on small entities and

reduce the chance that blood transfusion recipients will fail to

receive notification that they had received blood or blood components

that are at increased risk of transmitting HIV infection and or fail to

receive appropriate counseling. In response to another comment, FDA

amended the proposed rule to specify that certain pooled blood products

intended for further manufacture into noninjectable products are exempt

from quarantine. This change should also reduce the burden of the rule

on some small entities. FDA rejected the option of excluding all small

entities from the rule, because to do so would exempt a substantial

proportion of establishments and defeat the objective of ensuring that

all establishments have appropriate procedures in place to ensure the

continued safety of the blood supply.

FDA's selection of the regulatory option described in this rule is

based on its legal authority under sections 351 and 361 of the Public

Health Service Act and section 501 of the Federal Food, Drug, and

Cosmetic Act (21 U.S.C. 351). The need for regulatory action results

from the fact that a small but significant number of new HIV infections

each year continue to be transmitted through blood transfusions; the

fact that a small minority of blood establishments still lack

appropriate procedures for identification of blood products at

increased risk for transmitting HIV infection and notification of

recipients of such products; and the need to ensure that those

establishments with voluntary ``lookback'' procedures in place have

procedures that are adequate and vigorously followed. The primary

policy consideration in the formulation of this rule is to protect the

public health.

VII. Paperwork Reduction Act of 1995

This final rule contains information collections which are subject

to review by the Office of Management and Budget (OMB) under the

Paperwork Reduction Act of 1995. The title, description, and respondent

description of the information collection are shown below with an

estimate of the annual reporting and recordkeeping burden. Included in

the estimate is the time for reviewing procedures, searching existing

data sources, gathering and maintaining the data needed, and completing

and reviewing the collection of information.

Title: Current Good Manufacturing Practices for Blood and Blood

Components; Notification of Consignees Receiving Blood and Blood

Components at Increased Risk for Transmitting HIV Infection.

Description: The final rule requires that blood establishments

prepare and follow written procedures when the blood establishments

have collected Whole Blood, blood components, Source Plasma and Source

Leukocytes later determined to be at risk for transmitting HIV

infections. This final rule requires that when a donor who previously

donated blood is tested in accordance with Sec. 610.45 on a later

donation, and tests repeatedly reactive for antibody to HIV, the blood

establishment shall perform more specific testing using a licensed

test, and notify consignees who received Whole Blood, blood components,

Source Plasma or Source Leukocytes from prior collections so that

appropriate action is taken. Blood establishments and consignees are

required to quarantine previously collected Whole Blood, blood

components, Source Plasma and Source Leukocytes from such donors, and

if appropriate, notify transfusion recipients. The agency is issuing

this final rule to help ensure the continued safety of the blood

supply, to help ensure that information is provided to users of blood

and blood components, and to help ensure that transfusion recipients of

blood and blood components at risk for transmitting HIV will be

notified as appropriate.

Description of Respondents: Blood establishments (Business and Not-

for-Profit).

Individuals and organizations had an opportunity to comment on the

information collection requirements in the proposed rule. FDA has

revised these estimates based on current data. These estimates are an

approximation of the average time expected to be necessary for the

collection of information. They are based on such information as is

available to FDA. There are no capital costs, or operating and

maintenance costs associated with this information collection.

As required by the Paperwork Reduction Act of 1995, FDA will submit

a copy of this rule to OMB for review and approval of these information

requirements. Individuals and organizations may submit comments on the

information collection requirements by November 8, 1996. FDA

particularly invites comments on: (1) Whether the proposed collection

of information is necessary for the proper performance of FDA's

functions, including whether the information will have practical

utility; (2) the accuracy of FDA's estimate of the burden of the

collection of information, including the validity of the methodology

and assumption used; (3) ways to enhance the quality, utility, and

clarity of the information to be collected; and (4) ways to minimize

the burden of the collection of information on respondents, including

through the use of automated collection techniques, when appropriate,

and other forms of information technology. Comments

[[Page 47422]]

should be directed to the Dockets Management Branch (address above).

At the close of the 60-day comment period, FDA will review the

comments received, make revisions as necessary to the information

collection requirements, and submit the requirements to OMB for review

and approval. Additional time will be allotted for public comment to

OMB on the requirements and OMB review. Prior to the effective date of

this final rule, FDA will publish a notice in the Federal Register of

OMB's decision to approve, modify, or disapprove the information

collection requirements. 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 control number.

Estimated Annual Reporting/Disclosure Burden

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

Annual

Number of frequency Total Hours per

21 CFR section respondents per annual response Total hours

response responses

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

610.46(a)..................................... 3,015 60 180,900 .17 30,753

610.46(b)..................................... 3,015 60 180,900 .17 30,753

610.47(b)..................................... 200 16 3,200 .5 1,600

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

Total................................... ........... ........... ........... ............ 63,106

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

Estimated Annual Recordkeeping Burden

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

Annual Total

21 CFR section Number of frequency of annual Hours per Total hours

recordkeepers recordkeeping records recordkeeper

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

606.100(b)(19)............................ 3,015 1 3,015 2 6,300

606.160(b)(1)(vii)........................ 150 160 24,000 12.8 1,920

606.160(b)(1)(viii)....................... 3,015 60 180,900 4.8 14,472

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

Total............................... ............. ............. ........... ............ 22,422

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

VIII. Environmental Impact

The agency has determined under 21 CFR 25.24(c)(10) 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.

List of Subjects

21 CFR Part 606

Blood, Labeling, Laboratories, Reporting and recordkeeping

requirements.

21 CFR Part 610

Biologics, Labeling, Reporting and recordkeeping requirements.

Therefore, under the Federal Food, Drug, and Cosmetic Act, the

Public Health Service Act, and under authority delegated to the

Commissioner of Food and Drugs, 21 CFR parts 606 and 610 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: Secs. 201, 301, 501, 502, 505, 510, 520, 701, 704 of

the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321, 331, 351,

352, 355, 360 360j, 371, 374); secs. 215, 351, 353, 361 of the

Public Health Service Act (42 U.S.C. 216, 262, 263a, 264).

2. Section 606.100 is amended by adding new paragraph (b)(19) to

read as follows:

Sec. 606.100 Standard operating procedures.

* * * * *

(b) * * *

(19) Procedures in accordance with Sec. 610.46 of this chapter to

look at prior donations of Whole Blood, blood components, Source Plasma

and Source Leukocytes from a donor who has donated blood and

subsequently tests repeatedly reactive for antibody to human

immunodeficiency virus (HIV) or otherwise is determined to be

unsuitable when tested in accordance with Sec. 610.45 of this chapter.

Procedures to quarantine in-house Whole Blood, blood components, Source

Plasma and Source Leukocytes intended for further manufacture into

injectable products that were obtained from such donors; procedures to

notify consignees regarding the need to quarantine such products;

procedures to determine the suitability for release of such products

from quarantine; procedures to notify consignees of Whole Blood, blood

components, Source Plasma and Source Leukocytes from such donors of the

results of the antibody testing of such donors; and procedures in

accordance with Sec. 610.47 of this chapter to notify attending

physicians so that transfusion recipients are informed that they may

have received Whole Blood and, blood components at increased risk for

transmitting human immunodeficiency virus.

* * * * *

3. Section 606.160 is amended by adding paragraphs (b)(1)(vii) and

(b)(1)(viii) to read as follows:

Sec. 606.160 Records.

* * * * *

(b) * * *

(1) * * *

(vii) Records to relate the donor with the unit number of each

previous donation from that donor.

(viii) Records of quarantine, notification, testing, and

disposition performed pursuant to Secs. 610.46 and 610.47 of this

chapter.

* * * * *

PART 610--GENERAL BIOLOGICAL PRODUCTS STANDARDS

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

follows:

Authority: Secs. 201, 501, 502, 503, 505, 510, 701 of the

Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321, 351, 352, 353,

355, 360, 371); secs. 215, 351, 352, 353, 361 of the Public Health

Service Act (42 U.S.C. 216, 262, 263, 263a, 264).

[[Page 47423]]

5. Section 610.45 is amended by adding a new paragraph (d) to read

as follows:

Sec. 610.45 Human immunodeficiency virus (HIV) requirements.

* * * * *

(d) For a donor whose test results for antibody to HIV are

repeatedly reactive or otherwise determined to be unsuitable when

tested in accordance with paragraph (a) of this section, the blood

establishment shall comply, as applicable, with Secs. 610.46 and

610.47.

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

follows:

Sec. 610.46 ``Lookback'' requirements.

(a) Quarantine and notification. (1) All blood and plasma

establishments are required to take appropriate action when a donor of

Whole Blood, blood components, Source Plasma and Source Leukocytes

tests repeatedly reactive for antibody to human immunodeficiency virus

(HIV), or otherwise is determined to be unsuitable when tested in

accordance with Sec. 610.45. For Whole Blood, blood components, Source

Plasma and Source Leukocytes collected from that donor within the 5

years prior to the repeatedly reactive test, if intended for

transfusion, or collected within the 6 months prior to the repeatedly

reactive test, if intended for further manufacture into injectable

products, except those products exempt from quarantine in accordance

with Sec. 610.46(c), the blood establishment shall promptly, within 72

hours:

(i) Quarantine all such Whole Blood, blood components, Source

Plasma and Source Leukocytes from previous collections held at that

establishment; and

(ii) Notify consignees of the repeatedly reactive HIV screening

test results so that all Whole Blood, blood components, Source Plasma

and Source Leukocytes from previous collections they hold are

quarantined.

(2) Consignees notified in accordance with paragraph (a)(1)(ii) of

this section shall quarantine Whole Blood, blood components, Source

Plasma and Source Leukocytes held at that establishment except as

provided in paragraph (c) of this section.

(b) Further testing and notification of consignees of results.

Blood establishments that have collected Whole Blood, blood components,

Source Plasma or Source Leukocytes from a donor as described in

paragraph (a) of this section shall perform a licensed, more specific

test for HIV on the donor's blood, and in the case of distributed

products, further shall notify the consignee(s) of the results of this

test, within 30 calendar days after the donor's repeatedly reactive

test. Pending the availability of a licensed, more specific test for

HIV-2, a second, different screening test for antibody to HIV-2 shall

be used along with a licensed, more specific test for HIV-1.

(c) Exemption from quarantine. Products intended for transfusion

need not be held in quarantine if a determination has been made that

the Whole Blood, blood components, Source Plasma or Source Leukocytes

was collected more than 12 months prior to the donor's most recent

negative antibody screening test when tested in accordance with

Sec. 610.45. Pooled Source Plasma and Source Leukocytes are exempt from

quarantine.

(d) Release from quarantine. Whole Blood, blood components, Source

Plasma and Source Leukocytes intended for transfusion or further

manufacture which have been quarantined under paragraph (a) of this

section may be released if the donor is subsequently tested for

antibody to HIV as provided in paragraph (b) of this section and the

test result is negative, absent other informative test results.

(e) Actions under this section do not constitute a product recall

as defined in Sec. 7.3(g) of this chapter.

Sec. 610.47 ``Lookback'' notification requirements for transfusion

services.

(a) Transfusion services that are not subject to the Health Care

Financing Administration's regulations on conditions of Medicare

participation for hospitals (42 CFR part 482) are required to take

appropriate action in accordance with paragraphs (b) and (c) of this

section when a recipient has received Whole Blood or blood components

from a donor determined to be unsuitable when tested for human

immunodeficiency virus (HIV) infection in accordance with Sec. 610.45

and the results of the additional tests as provided for in

Sec. 610.46(b) are positive.

(b) Notification of recipients of prior transfusion. If the

transfusion service has administered Whole Blood or blood components as

described in paragraph (a) of this section, the transfusion service

shall notify the recipient's attending physician (physician of record)

and ask him or her to inform the recipient of the need for HIV testing

and counseling. If the physician is unavailable or declines to notify

the recipient, the transfusion service shall notify the recipient and

inform the recipient of the need for HIV testing and counseling. The

notification process shall include a minimum of three attempts to

notify the recipient and be completed within a maximum 8 weeks of

receipt of the result of the licensed, more specific test for HIV. The

transfusion service is responsible for notification, including basic

explanations to the recipient and referral for counseling, and shall

document the notification or attempts to notify the attending physician

or the recipient, pursuant to Sec. 606.160 of this chapter.

(c) Notification to legal representative or relative. If the

transfusion recipient has been adjudged incompetent by a State court,

the transfusion service or physician must notify a legal representative

designated in accordance with State law. If the transfusion recipient

is competent, but State law permits a legal representative or relative

to receive the information on the recipient's behalf, the transfusion

service or physician must notify the recipient or his or her legal

representative or relative. If the transfusion recipient is deceased,

the transfusion service or physician must continue the notification

process and inform the deceased recipient's legal representative or

relative. Reasons for notifying the recipient's relative or legal

representative on his or her behalf shall be documented pursuant to

Sec. 606.160 of this chapter.

Dated: July 11, 1996.

David A. Kessler,

Commissioner of Food and Drugs.

Donna E. Shalala,

Secretary of Health and Human Services.

[FR Doc. 96-22709 Filed 9-6-96; 8:45 am]

BILLING CODE 4160-01-M