Guidance for Industry
Supplemental Testing and the Notification of Consignees of
Donor Test Results for Antibody to Hepatitis C Virus (Anti-HCV)
[PDF version of this document]
Draft Guidance
This guidance document is being distributed for comment purposes only.
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technical/scientific questions, contact Robin Biswas, M.D.
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Written requests for single copies of this draft guidance document may be submitted to the Office of Communication, Training and Manufacturers Assistance
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U.S. Department of Health and Human Services
Food and Drug Administration
Center for Biologics Evaluation and Research (CBER)
March 1998
TABLE OF CONTENTS
- Introduction
- Background
- Recommendations
- Implementation
- References
Guidance for Industry1
Supplemental Testing and the Notification of Consignees
of Donor Test Results for Antibody to Hepatitis C Virus (Anti-HCV)
Draft - Not for Implementation
| This draft guidance document represent the agency's current thinking on consignee notification related to donor testing for
HCV. 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 requirements
of the applicable statute, regulations, or both. |
- INTRODUCTION
This document contains additional guidance supplementing the
Food and Drug Administration (FDA) memorandum of July 19, 1996,
"Recommendations for the 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)." FDA
recommends that consignees of certain blood and blood component
units collected since January 1, 1988, which were anti-HCV
negative or untested be notified when donors subsequently test
repeatedly reactive for anti-HCV in a licensed multiantigen screening
test and reactive in a licensed or investigational HCV supplemental
test. This would enable recipients to be informed that they had
been transfused with units potentially contaminated by the
hepatitis C virus in order to be further counseled.
Table of Contents
- BACKGROUND
Lookback (product retrieval and recipient notification) related
to HBV, HCV and HTLV-I testing has been discussed at open public
meetings, including meetings of FDA's Blood Products Advisory
Committee (BPAC), on multiple occasions since October, 1989. As
a response to these discussions, FDA provided detailed guidance
in the July 19, 1996, memorandum on the quarantine and disposition
of certain prior collections of blood and blood components from
donors who subsequently test repeatedly reactive for hepatitis B
surface antigen (HBsAg), antibody to hepatitis B core antigen
(anti-HBc), antibody to hepatitis C virus (anti-HCV), or antibody
to human T-lymphotropic virus, type I (anti-HTLV-I). The
memorandum recommended that blood establishments notify consignees
(such as the transfusion service, physician, fractionator, etc.)
for the purpose of quarantine and eventual disposition of products
made from prior collections. At that time, FDA did not recommend
notification of recipients of blood from donors who subsequently
test positive for anti-HCV, because no clear consensus on the
public health benefit of such action had emerged.
Improvements in the treatment and management of HCV infections have
occurred recently, and there is now significant evidence that an
individual who is reactive for anti-HCV in a supplemental assay is
likely infected with HCV. More specifically, in studies of blood
donors tested by the supplemental RIBA 2.0 assay (Chiron RIBA HCV
2.0 Strip Immunoblot Assay, Chiron Corporation, Emeryville, CA),
73 to 95% of test-positive and 14 to 21% of test-indeterminate
blood samples had detectable HCV RNA by PCR (1,2,3). Additionally,
it is recognized that prior negative or unscreened units from donors
later found reactive for anti-HCV may have been contaminated with
HCV. At public meetings on April 24 and 25, 1997, and August 11
and 12, 1997, the PHS Advisory Committee on Blood Safety and
Availability discussed recipient notification related to hepatitis
C. Consistent with recommendations of the PHS Advisory Committee,
FDA now is issuing the following guidance regarding such notification.
Table of Contents
- RECOMMENDATIONS
In addition to the actions recommended in the memorandum from FDA
to all registered blood and plasma establishments dated
July 19, 1996, the following recommendations are provided to
enable recipient tracing, notification, and medical counseling,
regarding transfusion with blood components potentially
contaminated with HCV.
- Current Testing
Donors currently testing repeatedly reactive for anti-HCV in a
licensed screening test should be further tested for anti-HCV
using a licensed multiantigen supplemental test, or an
investigational multiantigen supplemental test obtained for
study under an appropriate IND exemption. If the supplemental
test result is positive, or, in the case of RIBA 2.0, if the
supplemental test is either positive or indeterminate (except if
an indeterminate RIBA 2.0 is followed by a negative or
indeterminate RIBA 3.0 as described in 3, below) the blood
establishment should identify previously distributed (screened
or unscreened) units collected from the same donor dating back
10 years prior to the anti-HCV repeatedly reactive donation,
whenever such records exist, or to the date 12 months prior to
the donor's most recent negative licensed multiantigen screening
test for anti-HCV, whichever is the lesser period. Within 30
calendar days of the donor's repeatedly reactive screening test,
consignees of such identified units (such as hospitals, transfusion
services, physicians, etc.) should be notified of the donor's
current test results (including supplemental testing) and the
fact that the previously distributed units potentially were
contaminated with HCV, based on the subsequent test results
obtained on the donor. Blood establishments are reminded of
their requirements under 21 CFR 606.160(d) to maintain records
for five years after blood processing has been completed, or 6
months after the latest product expiration date, whichever is a
later date. When there is no expiration date, records must be
retained indefinitely. Records required under 21 CFR 606.160
and 21 CFR 606.165 permit identification of donations with
reactive screening test results, and tracing of the distribution
and disposition (including, for transfusion services, a record of
transfusion) of prior collections from the same donor. To improve
the effectiveness of these activities, blood establishments should,
beginning on the date this guidance is implemented, maintain
adequate records of the source and disposition of all units of
blood and blood products for at least 10 years from the date of
disposition, and maintain these records in a manner which permits
their rapid retrieval (e.g., within 5 working days). Blood
establishments should also ensure that these records are
transferred to another appropriate entity if the former
establishment ceases operations for any reason.
- Previous Testing
For donations tested before the date of implementation of
recommendation 1 of this guidance (above), blood establishments
should review records of donor testing, dating from the facility's
implementation of a licensed multiantigen screening test for
antibodies to HCV, to identify repeatedly reactive donations from
donors with a record of prior donation. If, in addition, there
is a record of a multiantigen supplemental test result on the
repeatedly reactive donation which was positive on an
investigational RIBA 3.0 assay, or was either positive or
indeterminate on a licensed or investigational RIBA 2.0 assay
(except if an indeterminate RIBA 2.0 result is followed by a
negative or indeterminate RIBA 3.0 result as described in 3, below),
then, as records permit, the blood establishment should identify
previously distributed (screened or unscreened) units collected
from the same donor dating back to January 1, 1988, or the date
12 months prior to the donor's most recent negative licensed
multiantigen screening test for anti-HCV. Consignees of such
identified units released for transfusion (such as hospitals,
transfusion services, physicians, etc.) should be notified
of the donor's test results (including supplemental testing)
and the fact that the previously distributed units potentially
were contaminated with HCV, based on the subsequent test results
obtained on the donor. Notification of consignees should
commence and be completed as soon as feasible. Blood
establishments should begin notification of consignees within
six months of the date of publication of this guidance. The FDA
expects that this notification should be completed within one
year of implementation of this activity.
- If the supplemental test result of record is an indeterminate
test result obtained using Chiron's RIBA 2.0 assay, a fresh
sample from the donor or the original stored sample may be
tested again (under an appropriate IND exemption), using Chiron's
investigational RIBA HCV 3.0 assay. If the additional test by
RIBA 3.0 is positive, then lookback as described in recommendations
1 & 2 should be performed, whereas lookback need not be performed
if the test result is negative or indeterminate. [NOTE: This
alternative is based on current research which indicates absence
of PCR reactivity for HCV RNA in RIBA 2.0 indeterminate/RIBA 3.0
negative samples (4), and infrequent (0.5% to 4%) PCR reactivity
in RIBA 2.0 indeterminate/RIBA 3.0 indeterminate samples (4,5).]
- In the case of donations that tested as repeatedly reactive
in a multiantigen anti-HCV screening assay which was performed
prior to the date of implementation of this guidance, where there
is no record of a supplemental assay result, but units were
distributed for transfusion from any prior donation dating back
to January 1, 1988, blood establishments should perform supplemental
testing on a stored or newly acquired donor sample. Such
additional testing should be performed within six months of the
date of publication of this guidance, according to the following
options:
- The blood establishment should retrieve a previously frozen
serum or plasma sample from the repeatedly reactive donation
and perform a currently licensed, or, if available under an IND
exemption, an investigational multiantigen supplemental test
for antibodies to HCV. Notification of consignees, as
appropriate, should then be conducted within 30 days of
obtaining the additional test result, consistent with
recommendations 2 and 3, above.
- Alternatively, where feasible, a fresh blood sample from the
donor may be tested for antibodies to HCV by a currently
licensed multiantigen screening test. If the result is
negative, then no further action is needed regarding
notification of consignees of the donor's prior collections.
If the result is repeatedly reactive, then a licensed, or, if
available under IND exemption, an investigational multiantigen
supplemental test for antibodies to HCV should be performed,
and notification of consignees, as appropriate, should be
conducted within 30 days of obtaining the additional test
result, consistent with recommendations 2 and 3, above.
- If the blood establishment does not retest a previously stored
sample from the repeatedly reactive collection, and
additionally does not test a fresh sample from the donor, then
consignees of previously collected units released for
transfusion should be notified of the donor's test results,
including lack of availability of results from supplemental
testing, and the fact of prior receipt of a unit potentially
contaminated with HCV. The FDA expects that this notification
should be completed within one year of implementation of this
activity.
- It is recommended that any hospital or transfusion
service or any other appropriate entity that is notified of the
prior transfusion of a unit potentially contaminated with HCV
should take the following actions:
- Promptly make at least three attempts to notify the patient's
physician of record or the physician who ordered the blood or
blood product that potentially contained HCV.
- Ask the physician to immediately notify the patient, or other
individuals as described under paragraph h of this section, of
the need for HCV testing and counseling.
- If the physician is unavailable, declines to make the
notification, or later informs the hospital that he or she was
unable to notify the patient, promptly make at least three
attempts to notify the patient, or other individual as
permitted under paragraph h.
- Document in the patient's medical record the notification or
attempts to give the required notification.
- The notification effort should begin when the blood bank
notifies the hospital that it received potentially HCV
infectious blood and blood products and should continue for 8
weeks unless-
- The patient is located and notified; or
- The hospital is unable to locate the patient and documents
in the patient's medical record the extenuating
circumstances beyond the hospital's control that caused the
notification effort to be discontinued prior to 8 weeks or
unduly delayed.
- Recipient notification should include the following
information:
- A basic explanation of the need for HCV testing and
counseling.
- Sufficient oral or written information so that the
transfusion recipient can make an informed decision about
whether to obtain HCV testing and counseling.
- A list of programs or places where the patient can obtain
HCV testing and counseling, including any requirements or
restrictions the program may impose.
- The hospital should establish policies and procedures for
notification and documentation that conform to federal, state,
and local laws, including any requirements for confidentiality
of medical records.
- If the patient has been judged incompetent by a state court,
the physician or hospital should notify a legal representative
designated in accordance with state law. If the patient is
competent, but state law permits a legal representative or
relative to receive the information on the patient's behalf,
the physician or hospital should notify the patient or his or
her legal representative or relative.
To achieve this result, hospitals or other entities should,
beginning on the date this guidance is implemented, maintain
adequate records of the source and disposition of all units of
blood and blood products for at least 10 years from the date of
disposition, and maintain these records in a manner which permits
their rapid retrieval (e.g., within 5 working days). Hospitals
or other entities should also ensure that these records are
transferred to another appropriate entity if the former
establishment ceases operations for any reason.
Table of Contents
- IMPLEMENTATION
The recommendations contained in this guidance document may be
implemented immediately without prior approval by FDA. Licensed
establishments implementing these recommendations should submit
in their annual reports a statement indicating the date that
revised SOP's consistent with the recommendations have been
established and implemented.
Table of Contents
- References
- Sayers, M.H., and Gretch, D.R. Recombinant immunoblot and
polymerase chain reaction testing in volunteer whole blood
donors screened by a multiantigen assay for hepatitis C virus
antibodies. Transfusion 33:809-813 (1993).
- Kleinman, S. et al. Increased detection of hepatitis C virus
(HCV)- infected blood donors by a multiple-antigen HCV enzyme
immunoassay. Transfusion 32:805-813 (1993).
- Yun, Z. et al. Detection of hepatitis C virus (HCV) RNA by PCR
related to HCV antibodies in serum and liver histology in Swedish
blood donors. Journal of Medical Virology 39:57-61 (1993).
- Alter, H. et al. (Unpublished data). Department of Transfusion
Medicine, National Institutes of Health, Bethesda, MD
- Dow, B.C. et al. Relevance of RIBA-3 supplementary test to
HCV PCR positivity and genotypes for HCV confirmation of blood donors.
Journal of Medical Virology 49:132-136 (1996).
Table of Contents
1 The procedures
cited in this guidance document are recommendations. If an
establishment believes that an alternative approach would provide
equivalent protection, the establishment is invited to discuss
the approach with FDA for evaluation. FDA recognizes that the
scientific technology for controlling the risk of transmission of
HCV may continue to advance and that this document may become
outdated as those advances occur.
Table of Contents
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