|
U.S. Department of
Health and Human Services
Food and Drug Administration
Center for Biologics Evaluation and Research (CBER)
November 1999
________________________________________________________________
TABLE OF CONTENTS
I. INTRODUCTION
II. BACKGROUND
III. RECOMMENDATIONS FOR DONOR DEFERRAL
IV. RECOMMENDATIONS FOR PRODUCT RETRIEVAL AND QUARANTINE
V. RECOMMENDATIONS FOR RECIPIENT TRACING AND NOTIFICATION
VI. LABELING RECOMMENDATIONS
VII. IMPLEMENTATION OF RECOMMENDATIONS
VIII. REFERENCES
________________________________________________________________
This guidance document
represents the agency's current thinking on
precautionary measures to reduce the possible risk of transmission
of Creutzfeldt-Jakob Disease (CJD) and new variant CJD (nvCJD) by
blood and blood products and to assure that blood and blood products
are not adulterated or misbranded, within the meaning of the Federal
Food Drug and Cosmetic Act, and are safe, pure and potent within the
meaning of the Public Health Service Act. 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.
________________________________________________________________
GUIDANCE FOR INDUSTRY
Revised Precautionary
Measures To Reduce The Possible Risk of
Transmission of Creutzfeldt-Jakob Disease (CJD) and New Variant
Creutzfeldt-Jakob Disease (nvCJD) by Blood and Blood Products
I. INTRODUCTION
On August 17, 1999,
the Food and Drug Administration (FDA) issued
a guidance document entitled, "Revised Precautionary Measures to
Reduce the Possible Risk of Transmission of Creutzfeldt-Jakob Disease
(CJD) and New Variant Creutzfeldt-Jakob Disease (nvCJD) by Blood and
Blood Products." FDA issued the guidance for immediate implementation,
and requested that comments on the guidance document be submitted
within 60 days of publication in the Federal Register of the notice
announcing the availability of the guidance.
After reviewing the
comments received, FDA has revised the August 1999
guidance by issuing this document. This guidance provides
comprehensive current recommendations, including new recommendations
concerning nvCJD. This guidance is released for immediate
implementation. FDA interprets immediate implementation to mean as
soon as feasible, but not later than April 17, 2000.
FDA recognizes that
the scientific technology for determining
individuals at risk for CJD and nvCJD, and detecting the infectious
agents in tissues and in products, is continuing to advance, and that
there may be a need for future updating of the relevant guidance.
II. BACKGROUND
CJD is a rare but
invariably fatal degenerative disease associated
with a poorly understood transmissible agent (1, 2). CJD cases occur
at low frequency by an unknown mechanism (sporadic CJD). It may also
be acquired by exogenous (usually iatrogenic) exposure to infectious
material; or may be familial, caused by a genetic mutation of the
prion protein gene. Clinical latency for iatrogenic CJD may exceed
30 years.
In 1996, a previously
unrecognized variant of CJD was described
almost exclusively in the United Kingdom (3), and is referred to as
new variant CJD (nvCJD). Although to date only 48 patients have died
of nvCJD, the extent of a nvCJD epidemic in the United Kingdom cannot
yet be determined. No cases of nvCJD have been identified in the
United States. Laboratory and epidemiologic studies have linked nvCJD
to an outbreak of bovine spongiform encephalopathy (BSE) in the United
Kingdom (4, 5). BSE infection in cattle appeared in 1980, peaked in
1992, and fell to low levels by 1996.
On December 11, 1996,
FDA issued a Memorandum to all registered blood
and plasma establishments and all establishments engaged in
manufacturing plasma derivatives entitled "Revised Precautionary
Measures to Reduce the Possible Risk of Transmission of Creutzfeldt-
Jakob Disease (CJD) by Blood and Blood Products." The memorandum
recommended as a precaution, to quarantine and destroy in-date Source
Plasma and plasma derivatives, and in-date transfusion products
prepared from donors who were at increased risk for developing CJD or
who were subsequently diagnosed with CJD. The memorandum recommended
permanent deferral of donors with CJD or CJD risks, unless, for cases
of genetic risk, the donor underwent genetic testing which did not
reveal a familial-CJD associated abnormality of the prion protein
gene. This document did not make recommendations specific to nvCJD.
New FDA recommendations announced on September 8, 1998, specified:
1) reversal of the recommendation to withdraw plasma derivatives from
donors with classic CJD or CJD risk factors; and 2) recommendation to
withdraw all material from nvCJD donors. These recommendations were
incorporated into a guidance published on August 17, 1999 entitled
"Revised Precautionary Measures to Reduce the Possible Risk of
Transmission of Creutzfeldt-Jakob Disease (CJD) and New Variant
Creutzfeldt-Jakob Disease (nvCJD) by Blood and Blood Products," which
is replaced by this guidance. This document contains changes and
clarifications undertaken as a result of comments to the August 1999
publication.
A. CJD: Rationale for
Not Withdrawing Plasma Derivatives from
Donors with CJD or CJD Risk
Accumulating
epidemiologic information and laboratory studies
have indicated that transmission of the CJD infectious agent by
blood products is highly unlikely. Five published case-control
studies analyzed over 600 CJD cases. None of these studies
showed that blood transfusion increased the risk for CJD (6-8).
Investigations of recipients of blood components from known CJD
donors have not revealed transmission of the CJD agent (9, 10),
although these cohort studies are limited by the small numbers
of such recipients, especially with long-term follow-up, and
thus would only be likely to reveal a high transmission rate.
National mortality surveillance performed by the Centers for
Disease Control and Prevention (CDC) indicates that patient
populations with increased exposure to blood or blood products
are not at increased risk for CJD (11). During a 18-year period
(1979-96), 4,468 cases of CJD were reported to CDC. When death
records were searched, none of these cases were reported to have
had hemophilia, thalassemia, or sickle cell disease. More
directed evaluation of persons with hemophilia have not shown a
link to CJD. In one study, brain tissue from 24 hemophiliacs
who died with neurologic disease was examined; none had evidence
of CJD (12). In a second study, brain tissue from 33
hemophiliacs in the United Kingdom, who died of various causes
was examined, and none had evidence for CJD (13). Additional
surveillance of cryoprecipitate recipients is underway in
Seattle, WA. Through 1997, no CJD cases have been reported
among 101 patients who, together, received over 238,000 units
of cryoprecipitate between 1979-85; 76 of these subjects are
alive from 12.5 to 18.5 years later (14). Three of these
recipients were known to have received at least one unit of
cryoprecipitate from donors known to have developed CJD.
While epidemiological
studies have not revealed transmission of
CJD in humans by blood and blood products, and laboratory
experiments have demonstrated that manufacturing significantly
lowers the amount of the CJD infectious agent in plasma
derivatives, some laboratory experiments have shown that blood
and plasma fractions from experimentally infected animals
transmit CJD to recipient animals when directly injected into
the brain (15-17). In two cases, transfusion of blood directly
from an infected hamster transmitted disease to the recipient
(Transmissible Spongiform Encephalopathy (TSE) Advisory
Committee transcript, December 1998; Paul Brown, personal
communication) (26).
In contrast, other
laboratory studies have not supported the
transmission of CJD through transfusion of blood. Transfusion
of blood units from 3 CJD patients failed to transmit CJD to
chimpanzees (15), and the validity of reported positive
transmissions to animals using blood from patients with CJD
has been questioned (17).
Plasma derivatives are
unlikely to transmit disease in humans
because: 1) a CJD-implicated plasma unit would be diluted into
a large plasma pool, leading to a low number of infectious units
in a dose of the final product, 2) intravenous and intramuscular
inoculation alone is less efficient than cerebral inoculation
for CJD transmission, and 3) further processing of plasma pools
by Cohn fractionation and manufacturing processes such as column
chromatography, precipitation, and filtration, have been shown
to diminish titers of CJD-like agents, in spiking experiments
using scaled-down manufacturing procedures (16, 25) (FDA TSE
Workshop, September 13-14, 1999).
B. NvCJD: Current Case
Definitions, and Rationale for Withdrawing
Plasma Derivatives From Donors with NvCJD
NvCJD is distinguished
from CJD by differences in clinical
presentation and neuropathologic changes (3, 18-20). Clinically,
nvCJD patients have an earlier age of onset, with mean age at
death of 29 years, compared to CJD patients, whose mean age at
death is 67 years. NvCJD presents with predominantly psychiatric
and sensory symptoms, and absence of diagnostic EEG changes
frequently seen in CJD. NvCJD patients have a more prolonged
duration of illness (median survival 14 months) than patients
with CJD (median survival 4 months) (21). Neuropathologic
features of nvCJD include florid prion protein plaques
surrounded by spongiform changes, which are rarely found in CJD.
In addition, prion protein can be detected immunohistochemically
in the lymphoid tissues of nvCJD, but not CJD patients (22).
This observation led to concerns that transmission of nvCJD by
blood might be possible.
Neuropathologic
examination of brain tissue is required to
confirm a diagnosis of nvCJD. A confirmed or definite case of
nvCJD is currently defined by the following neuropathologic
findings: 1) numerous widespread kuru-type amyloid plaques,
surrounded by vacuoles, in both cerebellum and cerebrum
("florid plaques"); 2) spongiform change most evident in the
basal ganglia and thalamus, with sparse distribution in the
cerebral cortex; and 3) high density accumulation of prion
protein, particularly in the cerebrum and cerebellum as shown
by immunohistochemistry.
In cases where
adequate neuropathology specimens are not
available, a clinical diagnosis of "suspected" nvCJD could be
made based upon certain atypical clinical features. Although
recommended diagnostic evaluations and criteria for nvCJD are
evolving, at present the CDC would classify cases in the United
States with all of the following features as "suspected" nvCJD:
1. Current age (if
alive) or age at death <55.
2. Persistent painful sensory symptoms and/or psychiatric
symptoms at clinical presentation.
3. Dementia, and delayed development (>4 months after illness
onset) of ataxia, plus at least one of the following
three neurologic signs: myoclonus, chorea, or dystonia.
4. A normal or abnormal EEG, but not the diagnostic EEG
changes often seen in classic CJD.
5. Duration of illness greater than 6 months.
6. Routine investigations do not suggest an alternative,
non-CJD diagnosis.
7. A history of possible exposure to bovine spongiform
encephalopathy (BSE), e.g., having been a resident or
traveler to a BSE-affected country from 1980 through 1996.
8. No history of iatrogenic exposure to CJD, such as receipt
of a dura mater graft, or human pituitary-derived hormones.
9. The patient does not have a prion protein gene mutation,
or, if this has not been determined, there is no history
of CJD in a first degree relative.
The transmissibility
of nvCJD by blood or blood products is
unknown, although laboratory and epidemiologic studies are
underway to evaluate this risk. NvCJD appears to be distinct
from classic variants of CJD both clinically and biologically
and therefore transmissibility cannot confidently be predicted
from studies of CJD. Until more is known about the possibility
of nvCJD transmission by blood components or plasma derivatives,
a precautionary policy of withdrawal for all of these products
is recommended for material from donors with nvCJD.
C. Current CJD and
NvCJD Recommendations
On January 29, 1998,
the Public Health Service (PHS) Advisory
Committee on Blood Safety and Availability reviewed laboratory
and epidemiologic information concerning CJD transmissibility
by blood, as well as the impact of CJD-related withdrawals upon
the supply of medically necessary plasma derivatives. Based
upon this review, the committee recommended that FDA consider
revising its December 11, 1996 guidance to the extent necessary
to relieve shortages of medically necessary plasma derivatives.
Subsequently, epidemiological and laboratory studies were
evaluated by the Department of Health and Human Services Blood
Safety Committee, which determined at its July 23, 1998 meeting,
that the current CJD guidance on quarantine and withdrawal of
blood products should be revised. A policy position to modify
the withdrawal recommendations for plasma derivatives was
announced by Surgeon General David Satcher, M.D. on August 27,
1998, at a public meeting of the PHS Advisory Committee on
Blood Safety and Availability. It was recommended that plasma
derivatives be withdrawn and intermediates quarantined only if
a blood donor develops nvCJD and that previously recommended
withdrawals and quarantines be discontinued for classical CJD
and CJD risk factors. A consistent recommendation was made
available on the Internet by the FDA on September 8, 1998.
United Kingdom
residents have an increased risk of developing
nvCJD. The number of people incubating nvCJD in the United
Kingdom cannot yet be predicted. The FDA received additional
advice from the TSE Advisory Committee (25) on December 18, 1998,
concerning deferral of donors who have traveled to or resided
in the United Kingdom for a certain period of time, and
therefore could have been exposed to the nvCJD agent. The TSE
Advisory Committee recommended deferring such donors, but
requested additional information concerning the impact of
deferrals on the blood supply in order to provide more specific
advice about time of residence in the United Kingdom. On
June 2, 1999, the TSE Advisory Committee reaffirmed its
recommendation to defer donors who have traveled to or resided
in the United Kingdom, until more is known about the potential
risk of nvCJD incubation in such donors and about the ability
of blood to transmit nvCJD (26).
Comprehensive revised
recommendations based upon the above
discussions and PHS and FDA internal deliberations are contained
in this guidance document. Recommendations for donor deferral,
product retrieval, quarantine, and disposition, and recipient
tracing and notification have been developed based upon
consideration of risk in the donor, risk in the product, and
the effect of withdrawals on the supply of life- and health-
sustaining blood components and plasma derivatives. In
particular, nvCJD is distinguished from CJD and CJD risk
factors, based on lack of sufficient historical and
epidemiological experience, and lack of available scientific
studies relevant to the likelihood of transmission of nvCJD
via blood components or derivatives.
III. RECOMMENDATIONS
FOR DONOR DEFERRAL
A. Recommended Donor
Deferral Criteria
1. FDA recommends that
donors who have been diagnosed with nvCJD
or CJD be permanently deferred.
2. FDA recommends that
donors at increased risk for CJD (as
identified by questions in section III.B.) be indefinitely
deferred and appropriately counseled. Donors are considered
to have an increased risk for CJD if they have received a
dura mater transplant, human pituitary-derived growth hormone,
or have one or more blood relatives with CJD.
3. FDA believes that
donors who have resided in the United
Kingdom (as identified by questions in section III.D.) may
be at risk for acquiring nvCJD. As a precaution, FDA
recommends that donors who have spent six months or more
cumulatively in the United Kingdom from 1980 through 1996
(i.e., from January 1, 1980 through December 31, 1996) be
indefinitely deferred.
4. FDA recommends that
donors who injected bovine insulin since
1980 be indefinitely deferred unless it has been established
that the product was not manufactured since 1980 from cattle
in the United Kingdom. FDA has previously recommended that
material from cattle in BSE countries not be used in the
manufacture of FDA regulated products (59 FR 44591, August
29, 1994). At this time, FDA recommends that donors known
to have injected insulin be further questioned to exclude
the possibility that they received bovine insulin since 1980.
B. Recommended
Questions for Identifying Donors at an Increased
Risk for CJD
FDA recommends that
Source Plasma donors be questioned at the
first donation and at each annual physical examination
thereafter, and that Whole Blood donors be questioned at the
time of each donation. If the donor is not familiar with the
term "Creutzfeldt-Jakob Disease," it may be taken as a negative
response. These questions are similar to those in the December
11, 1996 guidance.
Question 1) "Have
you or any of your blood relatives had
Creutzfeldt-Jakob Disease or have you ever
been told that your family is at an increased
risk for Creutzfeldt-Jakob Disease?"
NOTE: This may be asked as one or two
questions in order to elicit complete
information regarding a family history of
CJD.
Question 2) "Have
you ever received human pituitary-derived
growth hormone?"
NOTE: If the donor is uncertain about his or
her treatment, the following question
describing human pituitary-derived growth
hormone injections may be asked: "Was the
hormone treatment given repeatedly by
injection?"
Question 3) "Have
you received a dura mater (or brain
covering) graft?"
This question may be preceded by the more
general, "Have you ever had brain surgery?"
The specific question needs to be asked
only if the donor responds in the affirmative
to the general question.
FDA considers that
donors who answer "Yes" to any of the above
questions are at an increased risk for developing CJD.
C. Recommendations
Regarding Donor Reentry After Donor Deferral
for Risk of Familial CJD
If a donor is deferred
because of family history (one or more
family members with CJD), that donor may be reentered if:
1) The diagnosis of
CJD in the family member(s) is
confidently excluded, or CJD in the family member(s) is
iatrogenic, or the family member(s) is(are) not a blood
relative(s); or
2) Laboratory testing
(gene sequencing) shows that the donor
does not have mutations associated with familial CJD.
D. Recommended
Questions for Identifying Donors at Risk for
Exposure to BSE
Note that the United
Kingdom is defined as England, Scotland,
Wales, Northern Ireland, Isle of Man, and Channel Islands.
Residence in the Republic of Ireland is not counted as
contributing to risk of nvCJD exposure. FDA recommends that,
within an Establishment, current donors need only be questioned
once and new donors questioned at the first donation only.
1. Donors who have
resided or traveled to the United Kingdom
Question 1) Have you
visited or lived in the United
Kingdom (England, Northern Ireland, Scotland,
Wales, the Isle of Man, or the Channel
Islands) from 1980 through 1996?
Question 2) If so,
have you spent a total time of 6 months
or more in the United Kingdom from 1980
through 1996?
FDA recommends that
donors who answer "Yes" to both of the above
questions be indefinitely deferred. These questions may be
combined into a single question which contains all of the above
information.
2. Donors who have
been injected with bovine insulin since 1980
No cases of
transmission of nvCJD have been reported in
recipients of bovine insulin or other injectable products
manufactured in BSE-affected countries. However, as a
precaution, FDA has recommended that material from cattle
in BSE countries not be used in the manufacture of FDA
regulated products (59 FR 44591, August 29, 1994). FDA
is aware that some diabetic patients are importing bovine
insulin for personal use. Additionally, some insulin
products legally distributed in the United States since
1980 were manufactured from cattle in the United Kingdom.
As a precaution, FDA recommends that blood donors who have
injected bovine insulin since 1980, be indefinitely deferred
unless it has been established that the product was not
manufactured since 1980 from cattle in the United Kingdom.
The following question
or a similar question is recommended to
be asked of applicable potential donors:
Question: Have you at
any time since 1980 injected
bovine (beef) insulin?
Since the above
question is only applicable to a subset of
potential donors, FDA recommends that the question be asked as
a secondary question when a donor responds to a general
medication question that the donor is taking insulin. Blood
establishments should review their policies regarding acceptance
of insulin dependent diabetic patients as donors and their donor
history questions to determine if or at which point in the
interview process the above question should be asked. If the
donor answers "yes" or "don't know" to the question, FDA
recommends that the donor be indefinitely deferred, unless it
has been established that the product was not manufactured since
1980 from cattle in the United Kingdom.
IV. RECOMMENDATIONS
FOR PRODUCT RETRIEVAL AND QUARANTINE
A. Blood Components
The recommended
disposition of blood components is the same for
all of the following: donors with CJD, donors with CJD risk
factors, donors with nvCJD, and donors with potential exposure
to nvCJD (travel or residence in the United Kingdom for 6 months
or more, cumulatively from 1980 through 1996, or recipients of
bovine-derived insulin since 1980 unless it has been established
that the product was not manufactured since 1980 from cattle in
the United Kingdom).
1. FDA recommends that
all in-date blood components under
the control of the Establishment (Whole Blood, blood
components, Source Leukocytes, Pooled Platelets, unpooled
Source Plasma) that were collected from the donor and
intended for use in transfusion or for further
manufacturing into injectable products be immediately
retrieved and quarantined for subsequent destruction.
An exception can be made for Source Plasma and recovered
plasma based on knowledge that product distributed to a
given consignee prior to a certain time will no longer
exist in the form of unpooled units. FDA is not
recommending the withdrawal and quarantine of classical
CJD materials intended for further manufacturing into
non-injectable products; however FDA recommends that
such products be labeled appropriately (see section VI.A.
for labeling recommendations). FDA recommends that
material from nvCJD donors be immediately retrieved and
quarantined, but may be saved for use in research on
nvCJD by laboratories qualified to use this material
(see section VI.A. for labeling recommendations).
Furthermore, FDA recommends that Establishments
immediately notify the CJD Surveillance Unit of the
Division of Viral and Rickettsial Diseases of the Centers
for Disease Control and Prevention (CDC) at (404) 639-3091,
and the FDA, Director, Division of Hematology at
(301) 496-4396, if they receive a report of a donor with
nvCJD.
FDA also recommends
immediate notification of CDC and
FDA in case of a post donation report of a donor with a
physician's clinical or pathological diagnosis of CJD
and age less than 55 years. Donors under 55 years of
age who are diagnosed with CJD will be investigated and
reviewed by FDA in collaboration with CDC. The purpose
of such investigations will be to assess the likelihood
of nvCJD, in order to identify any case which occurs in
the United States.
2. FDA recommends that
all consignees should be notified
within one week after receipt of post donation
information, to immediately retrieve and quarantine any
implicated in-date blood components intended for use in
transfusion or for further manufacturing into injectable
products, for subsequent destruction. NvCJD-implicated
material may be saved for use in research on nvCJD by
qualified laboratories (see section VI.A. for labeling
recommendations).
B. Plasma Derivatives
1. Plasma derivatives
from donors with CJD or CJD risk
factors, or potential exposure to nvCJD (as defined in
section III.A.)
a. FDA recommends that
pooled plasma, intermediates, and
derivatives should not be withdrawn.
b. FDA recommends
consignee notification for all plasma
intended for further manufacture into derivatives. An
exception can be made for Source Plasma and recovered
plasma based on knowledge that product distributed to
a given consignee prior to a certain time will no
longer exist in the form of unpooled units. Consignee
notification is recommended in order to effect
withdrawal of plasma that has not already been pooled
for manufacture. FDA recommends that single, unpooled
units of plasma be retrieved and quarantined for
subsequent destruction. FDA does not recommend
retrieval and quarantine of plasma that has been
pooled prior to consignee notification.
2. Plasma derivatives
from donors diagnosed with nvCJD
FDA recommends that
Establishments immediately notify the
CJD Surveillance Unit of the Division of Viral and
Rickettsial Diseases of the Centers for Disease Control
and Prevention (CDC) at (404) 639-3091, and the FDA,
Director, Division of Hematology at (301) 496-4396, if
they receive a report of a donor with nvCJD.
a. FDA recommends that
if an Establishment receives a
post donation report of nvCJD diagnosis, the
Establishment immediately retrieve and quarantine
for subsequent destruction pooled plasma,
intermediates, and derivatives, and any other
materials containing plasma from the nvCJD donor.
Alternatively, material from nvCJD donors may be
saved for use in research on nvCJD by qualified
laboratories (see section VI.A. for labeling
recommendations). FDA recommends against the use
of such material for non-injectable products.
b. FDA recommends
that, within one week of receiving a
post donation report of nvCJD diagnosis, the
Establishment notify all consignees to immediately
retrieve and quarantine for subsequent destruction
pooled plasma, intermediates, and derivatives, and
any other materials containing plasma from the
nvCJD donor. Alternatively, this material may be
saved for use in research on nvCJD (see section
VI.A. for labeling recommendations).
3. Plasma derivatives
from donors with a physician's
clinical or pathological diagnosis of CJD and age
less than 55 years
FDA recommends that
Blood or Plasma Establishments
immediately notify the CJD Surveillance Unit of the
Division of Viral and Rickettsial Diseases of the Centers
for Disease Control and Prevention (CDC) at (404) 639-3091,
and the FDA, Director, Division of Hematology at
(301) 496-4396, if they receive a report of a donor with
a physician's clinical or pathological diagnosis of CJD
and age less than 55 years.
Donors under 55 years
of age who are diagnosed with CJD
will be investigated and reviewed by FDA in collaboration
with CDC. The purpose of such investigations will be to
assess the likelihood of nvCJD, in order to consider
precautionary withdrawal of plasma derivatives.
a. Recommendations to
quarantine and withdraw plasma
derivatives from such donors will be made by FDA on
a case-by-case basis, depending upon results of the
investigation. Precautionary quarantine and
withdrawal may be advised if available information
is ambiguous, and does not clearly eliminate the
possibility of nvCJD.
b. FDA recommends that
quarantined and withdrawn
material from such donors should be treated in the
same manner as for nvCJD (see section IV.B.2.).
C. Disposal of
Retrieved and Quarantined Products
The transmissible
agent of CJD is quite resistant to most
disinfecting regimens. There is no current consensus of
specific details of decontamination requirements for blood
products. However, the preferred methods of destruction of
CJD-implicated material are steam autoclaving at 132 degrees C
for 1-4 hours, incineration, or treatment with 1 N NaOH or
concentrated sodium hypochlorite for at least 1 hour at room
temperature (23, 24, 27). These treatments are known to
diminish, but may not completely eliminate, infectivity.
FDA believes that
blood components and plasma derivatives from
donors with nvCJD, or which have been withdrawn because the
donor might have nvCJD, may be saved for use in research on
nvCJD by qualified laboratories (see section VI.A. for labeling
recommendations).
V. RECOMMENDATIONS FOR
RECIPIENT TRACING AND NOTIFICATION
If a donor is found to
have CJD, nvCJD, risk factors for CJD (see
NOTE, below) or if withdrawal is recommended in cases under
investigation for nvCJD, FDA recommends that Establishments identify
blood components prepared from prior collections from that donor.
FDA recommends that the search of records to identify prior
collections from that donor extend back no less than five years,
and indefinitely to the extent that computerized electronic records
are available. Following identification of prior collections,
Establishments should inform all consignees (i.e., transfusion
services) of previously distributed blood components from that
particular donor. Consignee notification will enable the consignee
to inform the physician or other qualified personnel responsible for
the care of the recipient so that recipient tracing and medically
appropriate notification and counseling may be performed at the
discretion of care providers.
In cases of donors
diagnosed with nvCJD or donors under investigation
for nvCJD, FDA recommends that Establishments inform consignees of
affected plasma derivatives as well as blood components.
NOTE: If a donor has a
history of CJD in only one family member, or
if a donor is found to have risk factors for nvCJD (due to six months
domicile in the United Kingdom from 1980 through 1996, or due to
injection of bovine insulin), FDA recommends consignee notification
for the purpose of quarantine and disposition of in-date blood
components (see section IV.A.). However, FDA does not recommend
consignee notification for the purpose of tracing and notifying prior
recipients.
VI. LABELING
RECOMMENDATIONS
A. Labeling of
Implicated Products for Research or Intended for
Further Manufacture into Non-Injectable Products
FDA recommends that
blood components from donors with CJD or who
are at increased risk for CJD or exposure to nvCJD, intended to
be used in research or manufacture into non-injectable products,
be appropriately labeled with the following statements:
1.
"Biohazard";
2. "Collected
from a donor determined to be at risk
for CJD"; or "Collected from a donor diagnosed
with CJD"; or "Collected from a donor with
potential risk of exposure to new variant CJD";
and
3. "For
laboratory research use only"; or "Caution:
for use in manufacturing non-injectable products
only."
FDA believes that
blood components from donors with nvCJD should
not be used for further manufacture into non-injectable products.
However blood components and plasma derivatives from donors with
nvCJD or which have been withdrawn on a case-by-case basis for
suspicion of nvCJD, may be used in laboratory research on nvCJD
by qualified laboratories. FDA recommends that these products
be labeled with the following statements:
1.
"Biohazard";
2. "Collected
from a donor with new variant CJD"; and
3. "Only for
laboratory research on new variant CJD".
B. Labeling of
Non-Implicated Products
No transmission of CJD
or nvCJD by human blood components or
plasma derivatives has been documented to date. However, as a
precaution, FDA recommends that all blood components and
plasma-derived products include labeling to address the
theoretical risk. Because albumin has never been known to
transmit viral diseases, and because laboratory experiments
suggest that albumin is less likely to contain CJD-like agents
than other plasma fractions, FDA believes that a more specific
statement may be provided in the package insert for albumin and
products containing albumin.
1. For Whole Blood and
blood components, FDA recommends
the Circular of Information be revised to include
under "Side Effects and Hazards," the following
statement:
"Because this product is made from human blood,
it may carry a risk of transmitting infectious
agents, e.g., viruses, and theoretically, the
Creutzfeldt-Jakob disease (CJD) agent."
Until the circular is
revised, this statement may be
inserted or attached to the current circular.
2. For plasma-derived
products other than albumin, FDA
recommends the package insert warning section be
revised to include the following statement:
"Because this product is made from human blood,
it may carry a risk of transmitting infectious
agents, e.g., viruses, and theoretically, the
Creutzfeldt-Jakob disease (CJD) agent."
3. For plasma-derived
albumin, FDA recommends the
package insert warning section be revised to include
the following statement:
"Albumin is a derivative of human blood. Based
on effective donor screening and product
manufacturing processes, it carries an extremely
remote risk for transmission of viral diseases.
A theoretical risk for transmission of
Creutzfeldt-Jakob disease (CJD) also is
considered extremely remote. No cases of
transmission of viral diseases or CJD have ever
been identified for albumin."
4. For products
containing plasma-derived albumin, FDA
recommends the package insert warning section be
revised to include the following statement:
"This product contains albumin, a derivative of
human blood. Based on effective donor screening
and product manufacturing processes, it carries
an extremely remote risk for transmission of
viral diseases. A theoretical risk for
transmission of Creutzfeldt-Jakob disease (CJD)
also is considered extremely remote. No cases
of transmission of viral diseases or CJD have
ever been identified for albumin."
VII. IMPLEMENTATION OF
RECOMMENDATIONS
The recommendations
contained in this guidance may be implemented
without prior approval from the agency. FDA recommends that
Establishments implement this guidance as soon as feasible, but not
later than April 17, 2000. Licensed Establishments implementing
these recommendations should submit in their annual reports
(21 CFR 601.12(d)) a statement indicating the date that revised
standard operating procedures (SOPs) consistent with the recommendations
have been established and implemented. If Establishments elect to
use an insert to incorporate the language recommended in this guidance
(until the Circular of Information is revised), the annual report may
also reference the date of use of the insert. In the event that a
Blood Establishment elects to use other wording, FDA requests the
Establishment to submit the labeling in accordance with 21 CFR
601.12(f)(2). FDA further requests manufacturers of plasma-derived
products to submit labeling changes in accordance with 21 CFR
601.12(f)(2).
If a manufacturer of
blood components or plasma-derived products
believes that an alternative approach to the recommendations contained
in this guidance document would provide equivalent protection, the
manufacturer is invited to discuss the approach with FDA.
VIII. REFERENCES
1. Am. J. Pathol. 1995
146:785-811.
2. Ann Neurol. 1979 5:177-88.
3. Lancet 1996 347:91-5.
4. Nature 1996 383: 685-690
5. Nature 1997 389: 498-501
6. Neurol. 1996 46:1287-91.
7. Lancet 1993 341:205-7.
8. Lancet 1998 351:1081-5.
9. Lancet 1994 343:298-9.
10. Transfusion 1997 37(suppl.):2S.
11. Emerging Inf. Diseases 1997 2(4):333-36.
12. Transfusion 1998 38:817-20.
13. Thromb. Haemost. 1998 80:909-11.
14. A. Thompson, unpublished.
15. Ann Neurol. 1994 35: 513-29.
16. Transfusion 1998 38:810-16.
17. Brown, P. Curr. Op. Hematol. 1995 2:472-77
18. Lancet 1997 350: 903-7.
19. Lancet 1997 350: 908-10.
20. FEMS Immunol. Med. Microbiol 1998 21:91-5.
21. Br. Med. J. 1996 315:389-95.
22. Lancet 1999 353:183-9.
23. Biologics 1992 20: 155-58.
24. Arch. Virol. 1994 139:313-26.
25. TSE Advisory Committee Transcripts, December 18, 1998:
http://www.fda.gov/ohrms/dockets/ac/cber98t.htm
26. TSE Advisory Committee Transcripts, June 2-3, 1999:
http://www.fda.gov/ohrms/dockets/ac/99mtbc.htm
27. http://www.ehs.ucsf.edu/manuals/BSM/appendix%20L.html
|
