``Draft Guidance for Industry: Current Good Manufacturing Practice for Blood and Blood Components: (1) Quarantine and Disposition of Prior Collections from Donors with Repeatedly Reactive Screening Tests for Hepatitis C Virus (HCV); (2) Supplemental Testing, and the Notification of Consignees and Transfusion Recipients of Donor Test Results for Antibody to HCV (Anti-HCV);'' Availability

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. 99D-1878]

``Draft Guidance for Industry: Current Good Manufacturing

Practice for Blood and Blood Components: (1) Quarantine and Disposition

of Prior Collections from Donors with Repeatedly Reactive Screening

Tests for Hepatitis C Virus (HCV); (2) Supplemental Testing, and the

Notification of Consignees and Transfusion Recipients of Donor Test

Results for Antibody to HCV (Anti-HCV);'' Availability

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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

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

availability of a draft guidance (dated June 1999) entitled ``Draft

Guidance for Industry: Current Good Manufacturing Practice for Blood

and Blood Components: (1) Quarantine and Disposition of Prior

Collections from Donors with Repeatedly Reactive Screening Tests for

Hepatitis C Virus (HCV); (2) Supplemental Testing, and the Notification

of Consignees and Transfusion Recipients of Donor Test Results for

Antibody to HCV (Anti-HCV).'' The draft guidance is intended to provide

recommendations for donor screening and supplemental testing for

antibody to HCV, and notification of consignees and quarantine of prior

collections from a donor who later tests repeatedly reactive for

antibody to HCV (including single antigen and multiantigen screening

tests), notification of consignees and recipients of blood and blood

components at increased risk for transmitting HCV. The draft guidance,

when final, is intended to supersede the September 1998 guidance

entitled ``Guidance for Industry: Current Good Manufacturing Practice

for Blood and Blood Components: (1) Quarantine and Disposition of Units

from Prior Collections from Donors with Repeatedly Reactive Screening

Test for Antibody to Hepatitis C Virus (Anti-HCV); (2) Supplemental

Testing, and the Notification of Consignees and Blood Recipients of

Donor Test Results for Anti-HCV.''

DATES: Written comments on the draft guidance may be submitted at any

time, however, comments should be submitted by August 23, 1999, to

ensure their adequate consideration in preparation of the final

document. Submit written comments on the

[[Page 33310]]

information collection provisions by August 23, 1999.

ADDRESSES: Submit written requests for single copies of the draft

guidance entitled ``Draft Guidance for Industry: Current Good

Manufacturing Practice for Blood and Blood Components: (1) Quarantine

and Disposition of Prior Collections from Donors with Repeatedly

Reactive Screening Test for Hepatitis C Virus (HCV); (2) Supplemental

Testing, and the Notification of Consignees and Transfusion Recipients

of Donor Test Results for Antibody to HCV (Anti-HCV)'' to the Office of

Communication, Training, and Manufacturers Assistance (HFM-40), Center

for Biologics Evaluation and Research (CBER), Food and Drug

Administration, 1401 Rockville Pike, Rockville, MD 20852-1448. Send one

self-addressed adhesive label to assist the office in processing your

requests. The document 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. See the SUPPLEMENTARY INFORMATION section for electronic access

to the draft guidance. Submit written comments to the Dockets

Management Branch (HFA-305), Food and Drug Administration, 5630 Fishers

Lane, rm. 1061, Rockville, MD 20852. Requests and comments should be

identified with the docket number found in brackets in the heading of

this document.

FOR FURTHER INFORMATION CONTACT:

Sharon A. Carayiannis, Center for Biologics Evaluation and Research

(HFM-17), Food and Drug Administration, 1401 Rockville Pike, Rockville,

MD 20852-1448, 301-827-6210.

For technical/scientific questions, contact Robin M. Biswas, Center

for Biologics Evaluation and Research (HFM-325), Food and Drug

Administration, 1401 Rockville Pike, Rockville, MD 20852-1448, 301-827-

3011, or FAX 301-496-0338.

SUPPLEMENTARY INFORMATION:

I. Background

FDA is announcing the availability of a draft guidance (dated June

1999) entitled ``Draft Guidance for Industry: Current Good

Manufacturing Practice for Blood and Blood Components: (1) Quarantine

and Disposition of Prior Collections from Donors with Repeatedly

Reactive Screening Test for Hepatitis C Virus (HCV); (2) Supplemental

Testing, and the Notification of Consignees and Transfusion Recipients

of Donor Test Results for Antibody to HCV (Anti-HCV).'' The draft

guidance is intended to provide recommendations for appropriate action

when a repeat donor subsequently tests repeatedly reactive for HCV

using either a single antigen or multiantigen screening test, commonly

referred to as HCV ``lookback.'' The draft guidance provides

recommendations for the following: (1) Quarantine (and disposition of

products) of prior collections from donors who later test repeatedly

reactive for anti-HCV using either a single antigen or multiantigen

screening test, (2) supplemental testing and notification of consignees

and transfusion recipients, (3) procedures and recordkeeping, (4)

review of records of donor testing for ``historical'' repeatedly

reactive donations, and (5) additional testing of donors with no record

of supplemental testing on the ``historical'' repeatedly reactive

screening test or with an indeterminate recombinant immunoblot assay

2.0 test result.

On March 20, 1998 (63 FR 13675), FDA announced the availability of

``Guidance for Industry: Supplemental Testing and the Notification of

Consignees of Test Results for Antibody to Hepatitis C Virus (Anti-

HCV),'' (the March 1998 guidance). The March 1998 guidance superseded

the recommendations related to HCV in FDA's July 19, 1996, guidance

entitled: ``Recommendations for Quarantine and Disposition of Units

from Prior Collections from Donors with Repeatedly Reactive Screening

Tests for Hepatitis B Virus (HBV), Hepatitis C Virus (HCV) and Human T-

Lymphotropic Virus Type I (HTLV-I)'' (the July 1996 guidance). The

March 1998 guidance did not, however, supersede the recommendations

related to HTLV and HBV in the July 1996 guidance. (Note: The scope of

the July 1996 guidance was limited to enzyme immunoassay (EIA) 2.0 and

3.0 screening performed since 1992.)

On June 18, 1998, at a public meeting of its Blood Products

Advisory Committee (BPAC), FDA announced plans to respond to public

comments submitted to the docket for the March 1998 guidance by

issuance of a comprehensive guidance. At the BPAC meeting, FDA

announced it was considering changes to the HCV ``lookback'' policy

based on considerations which had been raised by public comments. FDA

continued to receive extensive public comments to the docket which were

evaluated carefully by CBER. Under the agency's good guidance

practices, FDA issued a notice on September 8, 1998, to withdraw the

March 1998 guidance pending issuance of a second comprehensive

guidance.

In September 1998, FDA finalized a guidance entitled ``Guidance for

Industry: Current Good Manufacturing Practice for Blood and Blood

Components: (1) Quarantine and Disposition of Units from Prior

Collections from Donors with Repeatedly Reactive Screening Test for

Antibody to Hepatitis C Virus (Anti-HCV); (2) Supplemental Testing, and

the Notification of Consignees and Blood Recipients of Donor Test

Results for Anti-HCV'' (the September 1998 guidance). The September

1998 guidance superseded the March 1998 guidance. FDA announced the

availability of this document in the Federal Register of October 21,

1998 (63 FR 56198).

On January 28, 1999, the Public Health Service Advisory Committee

on Blood Safety and Availability (The PHS Advisory Committee) met to

consider whether to expand the targeted HCV ``lookback'' program to

include recipients of blood from donors subsequently identified as

repeatedly reactive by the single antigen EIA 1.0 screening test for

HCV infection that was licensed in 1990. Approximately 80 percent of

the EIA 1.0 repeatedly reactive donations occurred before the first

supplemental test became available. The PHS Advisory Committee

concluded that, for EIA 1.0 repeatedly reactive donations without

supplemental testing, it would be reasonable to limit the ``lookback''

based on the signal to cutoff value of the screening test in cases

where supplemental testing had not been done. The PHS Advisory

Committee concluded that it would be optimal to perform HCV

``lookback'' on a subset of the donors testing repeatedly reactive on

EIA 1.0 screening tests to capture the vast majority of the true

positives and minimize the unnecessary false recipient notifications.

This draft guidance represents the agency's current thinking on the

management of prior collections from donors testing repeatedly reactive

at a later date using a single antigen or multiantigen screening test

for antibody to HCV, including product quarantine, further testing of

the donor, and notification of consignees and transfusion recipients.

It does not create or confer any rights for or on any person and does

not operate to bind FDA or the public. An alternative approach may be

used if such approach satisfies the requirement of the applicable

statute, regulations, or both. As with other guidance documents, FDA

does not

[[Page 33311]]

intend this document to be all-inclusive and cautions that not all

information may be applicable to all situations. The document is

intended to provide information and does not set forth requirements.

II. Comments

The draft guidance is being distributed for comment purposes only

and is not intended for implementation at this time. Interested persons

may submit to the Dockets Management Branch (address above) written

comments regarding this draft guidance document. Two copies of any

comments are to be submitted, except individuals may submit one copy.

Comments should be identified with the docket number found in brackets

in the heading of this document. A copy of the document and received

comments are available for public examination in the Dockets Management

Branch between 9 a.m. and 4 p.m., Monday through Friday.

III. The Paperwork Reduction Act of 1995

Under the Paperwork Reduction Act (the PRA) (44 U.S.C. 3501-3520),

Federal agencies must obtain approval from the Office of Management and

Budget (OMB) for each collection of information they conduct or

sponsor. ``Collection of information'' is defined in 44 U.S.C. 3502(3)

and 5 CFR 1320.3(c) and includes agency requests or requirements that

members of the public submit reports, keep records, or provide

information to a third party. Section 3506(c)(2)(A) of the PRA (44

U.S.C. 3506(c)(2)(A)) requires Federal agencies to provide a 60-day

notice in the Federal Register concerning each proposed collection of

information before submitting the collection to OMB for approval. To

comply with this requirement, FDA is publishing notice of the proposed

collection of information set forth in this document.

With respect to the following collection of information, FDA

invites comments on: (1) Whether the proposed collection of information

is necessary for the proper performance of FDA's functions, including

whether the information will have practical utility; (2) the accuracy

of FDA's estimate of the burden of the proposed collection of

information, including the validity of the methodology and assumptions

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

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

collection of information on respondents, including through the use of

automated collection techniques, when appropriate, and other forms of

information technology.

Guidance for Industry: Current Good Manufacturing Practice for

Blood and Blood Components: (1) Quarantine and Disposition of Units

from Prior Collections from Donors with Repeatedly Reactive

Screening Tests for Hepatitis C Virus (HCV); (2) Supplemental

Testing, and the Notification of Consignees and Transfusion

Recipients of Donor Test Results for Antibody to HCV (Anti-HCV).

This draft guidance recommends that blood establishments prepare

and follow written procedures when blood establishments have collected

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

later determined to be at risk for transmitting HCV infections. This

draft guidance provides recommendations, similar to the requirements

now in effect for HIV ``lookback'' (21 CFR 610.46 and 610.47 reported

and approved under OMB Control No. 0910-0336), to clarify the status of

the donor who later tests repeatedly reactive for HCV, to quarantine

prior collections from such donors, and to notify consignees and

transfusion recipients, as appropriate, based on further testing of the

donor. The draft guidance recommends that when a donor who previously

donated blood is tested in accordance with this draft guidance on a

later donation, and tests repeatedly reactive for antibody to HCV, the

blood establishment should perform an additional test using a licensed

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

Source Plasma, and Source Leukocytes from prior collections so that

appropriate action is taken. The draft guidance document recommends

that blood establishments and consignees quarantine previously

collected Whole Blood, blood components, Source Plasma and Source

Leukocytes from such donors, and if appropriate, consignees should

notify transfusion recipients. In addition to these ``lookback''

recommendations, which are similar to the ``lookback'' requirements for

HIV, this draft guidance recommends a retrospective review of testing

records dating back indefinitely to the extent that electronic or other

readily retrievable records are available, to indentify collections

from donors who had tested repeatedly reactive in the past, prior to

the existence of guidance recommending ``lookback'' activities.

However, the recommendations provide for the review of records to be

limited to a lesser period of time, that is, 12 months prior to the

last negative licensed multiantigen screening test, whenever there is a

record of such a prior test. The draft guidance recommends that blood

establishments notify consignees of the risk of HCV transmission that

exists for prior collections based on the retrospective review of

records and the results of the additional testing performed before or

as a result of the retrospective review of records. In addition, the

draft guidance recommends that blood establishments notify consignees

of the risk of HCV transmission that exists for prior collections from

a donor who tested repeatedly reactive on a screening test for HCV and

for whom the blood establishment has no record of further testing and

the repeatedly reactive results cannot be clarified because further

testing is impractical or infeasible. This draft guidance recommends

that blood establishments maintain records of the source and

disposition of all units of blood and blood products for at least 10

years from the date of disposition or 6 months after the latest product

expiration date, whichever is the later date. Under 21 CFR 606.160

(reported and approved under OMB Control No. 0910-0116), such records

are required to be retained for 5 years. FDA is recommending an

extended records retention period because advances in medical diagnosis

and therapy have created opportunities for disease prevention or

treatment many years after recipient exposure to a donor later

determined to be at increased risk for transfusion-transmitted disease.

Additionally, methods of recordkeeping have advanced, improving the

ability of blood establishments to more easily maintain and retrieve

records. Also, this draft guidance recommends that any consignee of a

blood establishment notify the transfusion recipients or their

physicians of blood and blood components at increased risk for

transmitting HCV. The agency is issuing this draft guidance to promote

the continued safety of the blood supply, to help provide users with

critical information about blood and blood components, and to promote

notification to transfusion recipients who have received blood and

blood components at risk for transmitting HCV so that recipients may

receive medical counseling.

Respondents to this information collection are blood establishments

(business and not-for-profit) and consignees of blood establishments,

including hospitals, transfusion services, and physicians. The total

[[Page 33312]]

reporting and recordkeeping burden is estimated to be 723,508 hours.

However, of this total, approximately 715,986 hours would be expended

on a one-time basis for establishing the written procedures and doing

the one-time retrospective review of records. Therefore, 8,242 hours is

estimated as the ongoing annual burden related to this draft guidance.

The total ongoing prospective annual burden for blood establishments is

estimated to be 2,880 hours. The prospective annual burden for

consignees of blood establishments is estimated to be 5,362 hours.

Based on the June 1998 registration records, there are

approximately 2,800 FDA registered blood collection facilities in the

United States that collect approximately 27 million units of whole

blood and source plasma annually of which, based on the Centers for

Disease Control and Prevention (CDC) estimates, there are approximately

9,750,000 donations from repeat donors per year. Based on the

prevalence of HCV among donors from 1996 to 1998, CDC estimates that

7,200 of those repeat donors per year would test repeatedly reactive

for HCV. For each of these donors, the recommendations in this draft

guidance call for blood establishments to notify the consignee

(transfusion service) two times, once for quarantine purposes and again

with additional test results for a total of 14,400 notifications as an

annual ongoing burden. Based on estimates from CDC, FDA expects that

for the one-time review of records, as many as 1,117,000 blood products

would be at increased risk for transmitting HCV. For each of these

products, blood establishments would notify consignees to quarantine

these products, report additional test results to consignees, and

consignees would notify recipients or recipients' attending physicians.

In March 1999, CDC estimated that there could be approximately 566,000

recipients that should be notified after a retrospective review of

donor records between May 1990 and June 1998. FDA estimates that a

total of 2,234,000 notifications, 1,117,000 affected blood products

times 2 notifications, would result from the retrospective review. The

total annual responses for blood establishments is estimated to be the

combined number of notifications, prospective and retrospective, or

2,248,400. FDA estimates the amount of time for each notification of a

consignee by a blood establishment will be approximately 6 minutes (0.1

hours). Consequently, the total estimated reporting burden hours for

blood establishments is 224,840 hours. However, the ongoing annual

burden not associated with the retrospective review would be 1,440

hours, 14,400 prospective notifications times 0.1 hour per

notification.

CDC expects that approximately 2,232 repeat donors who have

repeatedly reactive HCV screening test results will confirm positive

for HCV each year. Based on CDC's research and information, a donor who

confirms positive for HCV will have donated on the average only two

previous times and on the average two components will have been made

from each donation. Based on this information, there could be 8,936

transfusion recipients that should be notified per year. The total

notifications by consignees is estimated to be 574,936 annually,

566,000 recipients notified due to the retrospective review plus 8,936

recipients due to the prospective review. The time estimated for

consignees to make a notification is 30 minutes or 0.5 hours on

average. This time allows for the possibility of a consignee having to

make up to 3 attempts to complete the notification process and creates

a total reporting burden of 287,468 hours. According to the Health Care

Financing Administration, there are approximately 6,200 consignees that

should be responsible for notification.

In Table 2 of this document, the 40 hours per blood establishment

recordkeeper represents the time to develop written procedures for the

HCV ``lookback'' recommendations and to update an estimated 4 HCV

repeat reactive records as an ongoing annual burden. FDA estimates that

it takes approximately 5 minutes to update each record. Therefore, the

total recordkeeping by blood establishments is estimated to be 112,000

hours 2,800 registered blood establishments times 40 hours per

establishment. FDA estimates that each consignee recordkeeper would

need 16 hours to develop written procedures for the HCV ``lookback''

notification process and to update approximately 1 to 2 transfusion

recipient records. FDA estimates that it takes approximately 5 minutes

to update each record. Therefore, the total recordkeeping burden for

consignees is estimated to be 99,200 hours. The combined total

recordkeeping burden for both blood establishments and consignees is

estimated to be 211,200 hours. However, based on the prospective number

of repeat donors per year and the number that confirm positive for HCV,

the ongoing annual recordkeeping burden may only be 2,334 hours. Over

time, we expect the ongoing annual recordkeeping burden to decline as

the prevalence of HCV among donors has declined due to the

implementation of screening tests for anti-HCV, which helps to reduce

the number of persons infected with HCV from the donor pool.

FDA estimates the burden for this collection of information as

follows:

Table 1.--Estimated Annual Reporting Burden1

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

Collection Annual Frequency Total Annual

Activity No. of Respondents per Response Responses Hours per Response Total Hours

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

Blood 2,800 803 2,248,400 0.1 224,840

Establishme

nts

Consignees 6,200 93 574,936 0.5 287,468

Total 512,308

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

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

information.

[[Page 33313]]

Table 2.--Estimated Annual Recordkeeping Burden1

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

Collection No. of Annual Frequency Total Annual Hours per

Activity Recordkeepers per Recordkeeper Records Recordkeeper Total Hours

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

Blood 2,800 5 10,000 40 112,000

Establishme

nts

Consignees 6,200 2.5 15,136 16 99,200

Total 211,200

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

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

information.

Maintenance costs were not estimated for the additional maintenance

of records beyond the current 5 years to the recommended 10 years

because modern storage technology has markedly reduced the space needed

to store records.

In compliance with section 3507(d) of the PRA (44 U.S.C. 3507(d)),

the agency has submitted the information collection provisions of this

draft guidance to OMB for review. Interested persons may submit

comments regarding this information collection by August 23, 1999, to

the Office of Information and Regulatory Affairs, OMB, New Executive

Office Bldg., 725 17th St. NW., rm. 10235, Washington, DC 20503, Attn:

Wendy Taylor, Desk Officer for FDA.

IV. Electronic Access

Persons with access to the Internet may obtain the document using

the World Wide Web (WWW). For WWW access, connect to CBER at ``http://

www.fda.gov/cber/guidelines.htm''.

Dated: June 16, 1999.

Margaret M. Dotzel,

Acting Associate Commissioner for Policy Coordination.

[FR Doc. 99-15754 Filed 6-21-99; 8:45 am]

BILLING CODE 4160-01-F