GFI Creutzfeldt Jakob Disease

Revised Preventive Measures to
Reduce the Possible Risk of
Transmission of Creutzfeldt-Jakob
Disease and Variant Creutzfeldt-Jakob
Disease by Blood and Blood Products
Guidance for Industry

Additional copies of this guidance are available from the Office of Communication, Outreach
and Development (OCOD), 10903 New Hampshire Ave., Bldg. 71, Rm. 3128, Silver Spring,
MD 20993-0002, or by calling 1-800-835-4709 or 240-402-8010, or email [email protected], or
from the Internet at
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guida
nces/default.htm.
For questions on the content of this guidance, contact OCOD at the phone numbers or email
address listed above.

U.S. Department of Health and Human Services
Food and Drug Administration
Center for Biologics Evaluation and Research
May 2010
Updated January 2016

Contains Nonbinding Recommendations

Table of Contents
I.

INTRODUCTION..............................................................................................................1

II.

BACKGROUND ................................................................................................................3
A.
B.
C.
D.
E.

III.

EXPLANATION OF CURRENT VCJD RECOMMENDATIONS ...........................17
A.
B.
C.
D.
E.
F.
G.

IV.

Donor Deferral Criteria ..................................................................................... 24
Questions to Identify Donors at an Increased Risk for CJD .......................... 25
Donor Reentry after Donor Deferral for Risk of Familial CJD ..................... 26
Questions for Identifying Donors at Risk for Exposure to BSE ..................... 26

POST-DONATION INFORMATION: RECOMMENDATIONS FOR PRODUCT
RETRIEVAL AND QUARANTINE, CONSIGNEE NOTIFICATION, AND
BIOLOGICAL PRODUCT DEVIATION REPORTING ...........................................29
A.
B.

C.
D.

E.
F.
VI.

Exposure to British Beef in the U.K. ................................................................. 17
Exposure to British Beef Products Distributed Outside of the U.K. .............. 17
Indigenous BSE Exposure Outside the U.K. .................................................... 18
Potential Infection with vCJD Agent Acquired by Transfusion .................... 21
Exposure to Bovine Insulin ................................................................................ 21
Reports of Biological Product Deviations ......................................................... 21
Definitions ............................................................................................................ 22

RECOMMENDATIONS FOR DONOR DEFERRAL ................................................24
A.
B.
C.
D.

V.

CJD and vCJD....................................................................................................... 3
Evolution of the Global BSE epidemic ................................................................ 6
TSE Agents and Blood .......................................................................................... 7
FDA Regulatory History .................................................................................... 10
Rationale for Geographic Donor Deferrals ...................................................... 15

Whole Blood and Blood Components Intended for Transfusion, Cellular
Blood Components Intended for Further Manufacture into Injectable
Products, and Source Plasma From Donors with CJD or CJD Risk Factors 29
Whole Blood and Blood Components Intended for Transfusion, Source
Leukocytes and Other Cellular Blood Components Intended for Further
Manufacture into Injectable Products, from Donors with Geographic Risk
Deferrals and/or Exposure to Bovine Insulin Made in the U.K. since 1980 .. 30
Source Plasma and Recovered Plasma from Donors with Geographic Risk
Deferrals and/or Exposure to Bovine Insulin Made in the U.K. Since 1980 . 31
Whole Blood and Blood Components Intended for Transfusion, Recovered
Plasma, Source Leukocytes, Other Cellular Blood Components Intended for
Manufacturing into Injectable Products, and Source Plasma from Donors
with vCJD, suspected vCJD, or CJD and Age Less Than 55 Years............... 31
Plasma Derivatives .............................................................................................. 32
Disposal of Retrieved and Quarantined Products ........................................... 33

RECOMMENDATIONS FOR RECIPIENT TRACING AND NOTIFICATION ...34

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VII.

LABELING RECOMMENDATIONS...........................................................................34

VIII. IMPLEMENTATION OF RECOMMENDATIONS ...................................................36
IX.

THE IMPACT OF GEOGRAPHIC DONOR DEFERRALS THAT ARE MORE
STRINGENT THAN THOSE RECOMMENDED BY THIS GUIDANCE...............37

X.

SOURCES OF ADDITIONAL INFORMATION ........................................................38

XI.

REFERENCES.................................................................................................................39

APPENDIX TABLE 1: DONOR DEFERRAL, PRODUCT DISPOSITION, RECIPIENT
NOTIFICATION FOR WHOLE BLOOD, BLOOD COMPONENTS INTENDED
FOR TRANSFUSION, SOURCE LEUKOCYTES, AND OTHER CELLULAR
BLOOD COMPONENTS INTENDED FOR FURTHER MANUFACTURE...........45
APPENDIX TABLE 2: DONOR DEFERRAL, PRODUCT DISPOSTION, AND
RECIPIENT NOTIFICATION FOR SOURCE PLASMA (SP), RECOVER
PLASMA (RP) AND PLASMA DERIVATIVES (PD) ................................................47

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Contains Nonbinding Recommendations

Revised Preventive Measures to Reduce the Possible Risk of
Transmission of Creutzfeldt-Jakob Disease and Variant
Creutzfeldt-Jakob Disease by Blood and Blood Products
Guidance for Industry
This guidance represents the current thinking of the Food and Drug Administration (FDA or
Agency) on this topic. It does not establish any rights for any person and is not binding on FDA
or the public. You can use an alternative approach if it satisfies the requirements of the
applicable statutes and regulations. To discuss an alternative approach, contact the FDA staff
responsible for this guidance as listed on the title page.

I.

INTRODUCTION

This guidance is the latest in a series of guidances addressing the risk of Creutzfeldt-Jakob
Disease (CJD) and Variant Creutzfeldt-Jakob Disease (vCJD) 1 transmission by blood and blood
products.
•

•

•

In 1999, we, FDA, issued a document entitled “Guidance for Industry: Revised
Precautionary Measures to Reduce the Possible Risk of Transmission of CreutzfeldtJakob Disease (CJD) and New Variant Creutzfeldt-Jakob Disease (nvCJD) by Blood and
Blood Products” dated November 1999 (1999 guidance). 2
In 2002, we issued a document entitled “Guidance for Industry: Revised Preventive
Measures to Reduce the Possible Risk of Transmission of Creutzfeldt-Jakob Disease
(CJD) and Variant Creutzfeldt-Jakob Disease (vCJD) by Blood and Blood Products”
dated January 2002 (2002 guidance). 3
In 2006, we issued a draft document entitled “Draft Guidance for Industry: Amendment
(Donor Deferral for Transfusion in France Since 1980) to ‘Guidance for Industry:
Revised Preventive Measures to Reduce the Possible Risk of Transmission of
Creutzfeldt-Jakob Disease (CJD) and Variant Creutzfeldt-Jakob Disease (vCJD) by
Blood and Blood Products’” dated August 2006 (2006 draft guidance).

1
We have retained the same nomenclature used in previous guidance documents for the new variant of CJD
(originally abbreviated “nvCJD,” but later as “vCJD”). We refer to all other forms of CJD (sporadic, familial and
iatrogenic) as “CJD.”
2
The 1999 guidance addressed the theoretical possibility that a new variant of CJD that had been plausibly
attributed to human infection with the agent of bovine spongiform encephalopathy might be transmissible from
human to human through blood and blood products.
3
The 2002 guidance superseded the 1999 guidance and recommended new deferrals for certain donors at risk of
exposure to BSE.

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•

•

In 2010, we issued a document entitled “Guidance for Industry: Revised Preventive
Measures to Reduce the Possible Risk of Transmission of Creutzfeldt-Jakob Disease
(CJD) and Variant Creutzfeldt-Jakob Disease (vCJD) by Blood and Blood Products”
dated May 2010 (2010 guidance). 4
Finally, in 2012, we issued a draft guidance entitled “Draft Guidance for Industry:
Amendment to ‘Guidance for Industry: Revised Preventive Measures to Reduce the
Possible Risk of Transmission of Creutzfeldt-Jakob Disease and Variant CreutzfeldtJakob Disease by Blood and Blood Products,’” dated June 2012 (2012 draft guidance),
which recommended revised labeling of plasma-derived products to reflect current
understanding of vCJD transmission through blood and blood products.

This guidance amends the 2010 guidance and finalizes the 2012 draft guidance. This guidance
incorporates the recommendations from the 2012 draft guidance for revised labeling for plasmaderived products, including albumin and products containing plasma-derived albumin. This
guidance also provides manufacturers of plasma-derived products with recommendations on how
to report the labeling changes to FDA under 21 CFR 601.12. All other recommendations in the
2010 guidance are unchanged. 5
In addition, this guidance amends the 2010 guidance by: a) including information relevant to the
new labeling recommendations; b) providing updated information on the global vCJD and
Bovine Spongiform Encephalopathy (BSE) epidemics in Section II; c) clarifying the reentry
criteria for a donor with a family history of CJD in Section IV.C.; d) clarifying the requirements
related to biological product deviation reporting in Section V. and in Tables 1 and 2 of the
Appendix; and e) updating, adding, and removing certain footnotes and references.
Tests are being developed to detect CJD and vCJD infections in blood and plasma donors.
However, until suitable donor screening tests become available, FDA continues to recommend
interim preventive measures based on the available scientific data and the evolving state of
knowledge regarding these diseases.
We expect that additional epidemiological information will become available as the epidemics of
vCJD and BSE continue to evolve. We may update this guidance in the future, in light of
developments in testing technology, epidemiological information, and the impact of these
recommendations on the supply of blood and blood-derived products.
This guidance applies to Whole Blood and blood components intended for transfusion, and blood
components intended for use in further manufacturing into injectable and non-injectable products,
4

The 2010 guidance finalized the donor deferral recommendation from the 2006 draft guidance (for donors who
have received a transfusion of blood or blood components in France since 1980); provided updated scientific
information; and revised labeling recommendations for Whole Blood and blood components intended for
transfusion.
5
FDA discussed potential changes to the geographic exposure based deferrals for risk of vCJD with its
Transmissible Spongiform Encephalopathies Advisory Committee (TSEAC) in June 2015. Available at
http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/BloodVaccinesandOtherBiologics/Transmi
ssibleSpongiformEncephalopathiesAdvisoryCommittee/ucm444810.htm. FDA intends to address revised
recommendations for geographic donor deferrals in future guidance documents.

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including recovered plasma, Source Leukocytes and Source Plasma, and plasma derivatives. Within
this document, “donors” refers to donors of Whole Blood and blood components and “you” refers to
blood collecting establishments or manufacturers of plasma derivatives.

FDA’s guidance documents, including this guidance, do not establish legally enforceable
responsibilities. Instead, guidances describe the FDA’s current thinking on a topic and should be
viewed only as recommendations, unless specific regulatory or statutory requirements are cited.
The use of the word should in FDA’s guidances means that something is suggested or
recommended, but not required.
II.

BACKGROUND
A.

CJD and vCJD

CJD is a rare but invariably fatal degenerative disease of the central nervous system, one
of a group of transmissible diseases called transmissible spongiform encephalopathies
(TSEs) or prion diseases. TSEs are associated with a poorly understood transmissible
agent (Refs. 1-6), now designated TSE agents or prions (Ref. 7). Cases of sporadic
CJD—the most common human TSE—occur at low frequency by an unknown
mechanism. CJD may be acquired by an identified exogenous (usually iatrogenic)
exposure to infectious material; or it may be familial, associated with one of a number of
mutations in the prion-protein-encoding (PRNP) gene. Clinical latency for iatrogenic
CJD, following point exposures to contaminated materials, has sometimes exceeded 30
years (Ref. 8); incubation periods of kuru—another human TSE—appear to have
sometimes exceeded 50 years (Ref. 9).
In 1996, a previously unrecognized variant of CJD, now designated vCJD, was reported
in the United Kingdom (U.K.) (Ref. 10). vCJD is distinguished from CJD by differences
in clinical presentation, cerebral imaging and neuropathologic changes, summarized in
Table 1 (Refs. 10-14).

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Table 1. vCJD compared with CJD 6
vCJD
Differences in clinical
presentation

CJD

Age of onset

Earlier

Later

Median age at death

28 years

68 years

Psychiatric and sensory
symptoms

Frequent in early course
of illness

Appear later in course of
illness

EEG changes

No diagnostic EEG
changes

Diagnostic EEG changes
commonly seen

Median duration of illness
(Ref. 15)

13 months

4 months

MRI abnormalities
(Refs. 16-17)

Hyperintensity in
pulvinar; little atrophy in
cerebral cortical gray
matter

Hyperintensity in
putamen and caudate
nucleus; atrophy of
cerebral cortical gray
matter

Neuropathologic features

Florid prion protein
plaques, surrounded by
spongiform changes

Florid prion plaques
uncommon

Immunohistochemistry
(Ref. 18)

Abnormal accumulations
of prion protein
detectable in lymphoid
tissues

Abnormal accumulations
of prion protein not
detected in lymphoid
tissues

The unique accumulation of abnormal prion protein seen in vCJD lymphoid tissues led to
concerns that transmission of vCJD by blood might be a greater risk than for CJD (Ref.
19). Presumptive transmissions of vCJD by transfusions and possible transmission of
vCJD by plasma-derived Factor VIII were subsequently reported in the U.K. (see Section
II.C. below). Neuropathologic examination of brain tissue is required to confirm a
diagnosis of vCJD.
A confirmed (or definite) case of vCJD is currently defined by the following
neuropathologic findings:
1. Numerous widespread kuru-type amyloid plaques, surrounded by vacuoles, in
both the cerebellum and cerebrum (“florid” plaques);
2. Spongiform change most evident in the basal ganglia and thalamus, with sparse
distribution in the cerebral cortex; and
6

See Centers for Disease Control and Prevention (CDC) fact sheet at http://www.cdc.gov/prions/vcjd/index.html
for more information.

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3. High-density accumulations of abnormal prion protein, particularly in the
cerebrum and cerebellum as shown by immunohistochemistry and other
techniques (Ref. 20).
However, a clinical diagnosis of “suspected” vCJD can be made based upon certain
clinical features, if adequate neuropathological specimens are unavailable. Although
recommended diagnostic evaluations and criteria for vCJD are evolving, the Centers for
Disease Control and Prevention (CDC) classifies cases in the United States (U.S.) with
all of the following features as suspected vCJD:
1. Current age (if alive) or age at death less than 55 years;
2. Persistent painful sensory symptoms and/or psychiatric symptoms at clinical
presentation;
3. Dementia, and delayed development (>four 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 electroencephalogram (EEG) but not the diagnostic EEG
changes often seen in classic CJD;
5. Duration of illness of at least six months;
6. Routine investigations do not suggest an alternative non-CJD diagnosis;
7. A history of possible exposure to BSE (e.g., residence or travel in a BSE-affected
country from 1980 to the present);
8. No history of iatrogenic exposure to CJD, such as receipt of a dura mater allograft
or injection of human cadaveric pituitary-derived hormones; and
9. Absence of a mutation in the PRNP gene, or, if this has not been determined, no
history of CJD in a first-degree relative.
As of May 2015, 228 patients, including 177 in the U.K., 27 in France and 25 in ten other
countries (including four in the U.S. and two in Canada), have been diagnosed with
clinical vCJD (definite and probable cases). 7 The size of the vCJD epidemic has not yet
been determined with certainty. (Refs. 21-24). Deaths from vCJD in the U.K. appeared
to have peaked in 2000 and have subsequently decreased. 8 However, additional “waves”
of cases in the U.K. and elsewhere have been predicted by some experts and the
possibility of an increased incidence of cases in the future cannot be dismissed (Refs. 2225). 9 Of the four cases of vCJD identified in the U.S., two were in former residents of the
U.K., one in a former resident of Saudi Arabia and one in a former resident of Kuwait

7

The European and Allied Countries Collaborative Study Group of CJD (EUROCJD) plus the Extended European
Collaborative Study Group of CJD (NEUROCJD) at http://www.eurocjd.ed.ac.uk/surveillance%20data%201.html.
NCJDSU at http://www.cjd.ed.ac.uk.
9
See also, McKie, R. “Warning over second wave of CJD cases. Scientists say that threat of brain illness returning
will persist for decades,” Observer, Aug. 3, 2008 at 11; Collinge, J. et al. (2006) “Kuru in the 21st century—an
acquired human prion disease with very long incubation periods.” Lancet 376: 2068-74.
8

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and the former Soviet Union. 10 Cases of vCJD have also been reported from the Republic
of Ireland (4), Japan (1), Italy (2), the Netherlands (3), Portugal (2), Saudi Arabia (1),
Taiwan (1) and Spain (5). Most of these cases occurred in persons who had never resided
in the U.K. Laboratory and epidemiologic studies have linked vCJD to human infection
with the agent of BSE, probably acquired from contaminated beef products (Refs. 25-26).
B.

Evolution of the Global BSE Epidemic

The vCJD and BSE epidemics have continued to evolve. BSE cases have been reported
in over 20 countries of Europe, including Austria, Belgium, the Czech Republic,
Denmark, Finland, France, Germany, Greece, the Republic of Ireland, Italy,
Liechtenstein, Luxembourg, the Netherlands, Poland, Portugal, Slovakia, Slovenia,
Spain, Sweden, Switzerland, and the U.K. BSE has also been identified in Japan (36
cases) and Israel (1 case). 11
1.

BSE in Europe

In the U.K., BSE infections probably first occurred in cattle in about 1980,
although the disease was not recognized there until 1985. Cases of BSE in the
U.K. peaked in 1992. That year, over 37,000 confirmed cases were reported to
the World Organization for Animal Health (OIE), with reports falling to low
levels by 1996 as a result of control measures. U.K. authorities reported 114
confirmed cases to the OIE in 2006. 12 While the current prevalence of BSE is
much lower a few cases continue to be reported yearly in Europe. 13
2.

BSE in Asia and the Middle East

Following the first recognized case of BSE in Japan in 2001, a total of 36 cattle
with the disease have been reported to OIE. 14 Israel reported a single case of BSE
in 2002 but no additional cases have been reported. 15
3.

BSE in North America

BSE was first confirmed in Canada in 1993 in a cow imported from the U.K. The
first reported case of BSE in a native-born Canadian cow occurred ten years later.
As of February 2015, 21 cases of BSE in Canada have been detected, 20 of which

10

See CDC fact sheet at http://www.cdc.gov/prions/vcjd/vcjd-reported.html and
http://www.cdc.gov/prions/vcjd/news.html; also see Maheshwari A, et.al. Recent US case of variant CreutzfeldtJakob disease—global implications. Emerging Infectious Diseases 2015;21:750-9.
11
World Organization for Animal Health (OIE) at http://www.oie.int/en/anial-health-in-the-world/bse-specific-data/.
12
OIE at http://www.oie.int/en/animal-health-in-the-world/bse-specific-data/.
13
OIE at http://www.oie.int/en/animal-health-in-the-world/bse-specific-data/.
14
OIE at http://www.oie.int/en/animal-health-in-the-world/bse-specific-data/.
15
OIE at http://www.oie.int/en/animal-health-in-the-world/bse-specific-data/.

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are in native-born Canadian cattle. 16 The first case of BSE in the U.S. was
confirmed in 2003 in a Canadian-born cow. Three cases were later detected in
U.S.-born cows. 17 The overall prevalence of BSE in U.S. cattle was estimated by
the United States Department of Agriculture (USDA), based on the results of a
temporarily enhanced active surveillance program, to be very low—less than one
case per million cattle at the 95 percent confidence level, based on an adult cattle
population of 42 million animals. 18
C.

TSE Agents and Blood
1.

Potential Risk of Transmitting CJD by Transfusion

In 1978, blood of guinea pigs experimentally infected with the CJD agent was
found to transmit infection to normal guinea pigs (Ref. 27). Subsequently, blood
of mice with experimentally induced TSE was also found to contain the
transmissible agent (Ref. 28). Transmission of BSE has been repeatedly achieved
by blood transfusions from experimentally infected sheep to normal sheep (Refs.
29-30), and infection has also been transmitted by transfusions of blood from
scrapie-infected sheep (Refs. 30-31). In blood of hamsters infected with
scrapie—the most thoroughly studied model of TSE—infectivity, although
detectable in all components, appeared to be mainly associated with both
nucleated cells and plasma (Ref. 32).
Based on repeated demonstrations that the blood of animals infected with a
variety of TSE agents sometimes contained infectivity (Ref. 33) and the
recognition that iatrogenic CJD had been transmitted by human cadaveric
pituitary growth hormones (Ref. 34), FDA recommended in 1987 19 that persons
identified by history to be at increased risk for CJD because they had received
human cadaveric pituitary growth hormone injections be deferred from donating
blood. These recommendations were later broadened in August 1995 and slightly
revised in December 1996 20 to include deferral of donors who had been treated
with human dura mater allografts, also implicated in iatrogenic transmission of
CJD (Ref. 35), and donors who had a family history of CJD, because of its
association with a transmissible agent similar to those found in sporadic and
16

OIE at http://www.oie.int/en/animal-health-in-the-world/bse-specific-data and the Canadian Food Inspection
Agency at http://www.inspection.gc.ca/animals/terrestrial-animals/diseases/reportable/bse/factsheet/eng/1363892691907/1363893176627.
17
OIE at http://www.oie.int/eng/info/en_esbmonde.htm and USDA at
http://www.ars.usda.gov/research/publications/publications.htm?seq_no_115=197033.
18
USDA at
http://www.usda.gov/wps/portal/usda/usdahome?contentid=BSE_Ongoing_Surveillance_Information_Center.html&
contentidonly=true.
19
See FDA memo at
http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/OtherRecom
mendationsforManufacturers/MemorandumtoBloodEstablishments/UCM063012.pdf.
20
June 2, 1999 TSEAC meeting transcript: http://www.fda.gov/ohrms/dockets/ac/99/transcpt/3518t1.rtf.

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iatrogenic CJD (Refs. 2 and 36). Subsequently, a number of published
epidemiological studies failed to suggest that CJD (sporadic, familial, and
iatrogenic forms) had been transmitted by blood and blood products. This
evidence included five case-control studies of over 600 CJD cases, two lookback
studies tracing recipients of components from blood of donors later found to have
CJD, and two autopsy studies of patients with hemophilia (Refs. 37-43). None of
these studies linked CJD to receipt of blood or blood products. Nonetheless, FDA
continues to recommend (1) deferrals for donors at increased risk for CJD; and (2)
market withdrawal and retrieval of labile blood components from donors when
post-donation information reveals an increased risk of CJD.
In 1998, FDA recommended that—with the exceptions discussed below—plasma
derivatives no longer be withdrawn when post-donation information reveals that a
plasma donor had been diagnosed with CJD or was at increased risk for CJD. 21
That change in policy was based mainly on the following information: (1) the
CDC reviewed 3,642 reported CJD deaths over a period of 16 years (later
increased to 4,468 reports) and concluded that no reported CJD case had any other
diagnosis of a condition associated with frequent receipt of blood or blood
products (hemophilia, thalassemia, or sickle cell disease (Ref. 44)); and (2)
experimental studies with animal models suggested that procedures used in
manufacture consistently and substantially lowered the amounts of infectious
material present in most plasma derivatives (Ref. 45).
Also in 1998, the U.S. Surgeon General 22, in collaboration with NIH, CDC and
FDA, concluded that previous withdrawals of plasma derivatives from donors
who were later determined to have CJD or have been at increased risk for CJD did
not improve the safety of plasma derivatives. In addition, the U.S. Surgeon
General concluded that the withdrawal of plasma derivatives from such donors
contributed to serious shortages of immunoglobulin products. Further
withdrawals of “CJD-implicated” plasma derivatives would be indicated only if a
plasma donor was later found to have vCJD (or CJD with onset before age 55
where vCJD could not be excluded on a case-by-case basis). Since then,
accumulating evidence has repeatedly confirmed that several manufacturing
processes commonly used to manufacture plasma derivatives are effective in
removing from plasma both abnormal forms of the prion protein and infectivity
spiked into blood (Refs. 46-52). 23 However, as detailed below in Section II.C.2,
there has been one case of transmission of vCJD in the U.K. that may be due to

21

December 18, 1998 TSEAC meeting transcript: http://www.fda.gov/ohrms/dockets/ac/98/transcpt/3484t1.rtf.
FDA website at http://www.fda.gov/NewsEvents/Testimony/ucm115104.htm.
23
February 20, 2003 TSEAC meeting transcript: http://www.fda.gov/ohrms/dockets/ac/03/transcripts/3923t1.htm.
22

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treatment of a patient with a plasma derivative product. 24 Recipients of plasma
derivatives are the subject of a continuing lookback study in the U.K. as part of
the Transfusion Medicine Epidemiology Review. 25
2.

Evidence that vCJD Has Been Transmitted by Blood Products

Soon after the first description in the U.K. of vCJD affecting 10 young patients in
1996 (Ref. 10), vCJD was recognized to be an emerging infectious disease with
several unique clinical and pathological characteristics differing from those of
previously known forms of CJD. It was uncertain whether human blood might
transmit the vCJD agent. FDA therefore recommended in the 1999 guidance a
donor deferral policy more stringent for donors at increased risk of vCJD than for
those at increased risk of the “classical” forms of the disease (see Section IV
below), including a recommendation to withdraw plasma derivatives should a
plasma donor later be diagnosed with vCJD (a situation never recognized in the
U.S. to date) and a case-by-case review when a plasma donor is suspected of
having vCJD (including all donors with onset of CJD before the age of 55 years)
instead of a more common form of CJD.
In December 2003, U.K. authorities reported a case of vCJD in a recipient of nonleukoreduced red blood cell concentrate obtained from a clinically healthy donor
who later developed typical vCJD (Ref. 53). In July 2004, a second recipient of
non-leukoreduced red blood cell concentrate from another such donor in the U.K.
was reported to have died of other causes without clinical or neuropathological
evidence of vCJD, but at autopsy the recipient had abnormal accumulations of
prion protein in lymphoid tissues (Ref. 54). This finding is typical of vCJD,
although the recipient had a PRNP genotype (heterozygous for the sequences
encoding methionine and valine at PRNP codon 129 [129 MV]) not previously
found in cases of vCJD (all of which have been 129 MM homozygous). Two
additional recipients of non-leukoreduced red blood cell concentrates from a
donor incubating vCJD were subsequently reported by U.K. authorities in
February 2006 (Refs. 55-56) and January 2007 26 to have died with confirmed
vCJD. These four cases provided convincing epidemiological evidence that vCJD
infections have been transmitted by non-leukoreduced red blood cell concentrates.
Although no other blood components have been associated with transfusiontransmitted vCJD, experience is still too limited to allow a conclusion that other
blood components cannot transmit the infection.

24

U.K. Health Protection Agency (HPA), “vCJD abnormal prion protein found in a patient with haemophilia at post
mortem,” dated February 17, 2009, and “Variant CJD and plasma products,” dated July 27, 2009 at
http://www.hpa.org.uk.
25
Transfusion Medicine Epidemiology Review: http://www.cjd.ed.ac.uk/TMER/TMER.htm.
26
Transfusion Medicine Epidemiology Review: http://www.cjd.ed.ac.uk/TMER/TMER.htm.

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In February 2009, the United Kingdom Health Protection Agency announced
evidence of vCJD infection in a patient with type-A hemophilia at postmortem. 27
The patient had been treated with human plasma-derived Factor VIII clotting
factor manufactured using plasma from U.K. donors, including one batch that was
manufactured using plasma from a donor who later developed typical vCJD. This
is the first report that vCJD abnormal protein has been found in a patient with
hemophilia or any patient treated with plasma products. The patient, who was
over 70 years old, died of other causes and may have been exposed to other risk
factors for vCJD. A risk assessment performed by U.K. health authorities
concluded that, assuming that the abnormal prion protein finding was a marker for
asymptomatic vCJD infection, the most likely source of such an infection was
plasma-derived Factor VIII, rather than dietary exposure, endoscopy procedures,
or red blood cell transfusions.
At this time, plasma derivatives have not been implicated in vCJD transmission in
any country other than the U.K. To date, no U.S.-licensed plasma-derived
products have been manufactured from a donor known to have developed vCJD
and no cases of vCJD have been reported from use of a U.S.-licensed plasma
derivative. In addition, published studies and information submitted to FDA
show that certain plasma derivative manufacturing steps can remove TSE
infectivity, although such experiments have inherent limitations (Refs. 51, 57).
Based on animal studies as well as on FDA risk assessments, the possibility of
vCJD transmission by a U.S.-licensed plasma derivative is extremely small.
D.

FDA Regulatory History

On December 11, 1996, we 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.” We recommended as
a preventive measure that manufacturers should 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. We also recommended permanent deferral of donors with CJD or CJD risks,
unless, in cases of a family member with CJD, the donor underwent genetic testing that
demonstrated absence of a familial-CJD-associated abnormality (mutation) of the prion
protein gene—generally requiring complete nucleotide sequencing of both PRNP genes.
We made no specific recommendations regarding vCJD in that document. Changes to

27
U.K. Health Protection Agency (HPA), “vCJD abnormal prion protein found in a patient with haemophilia at
postmortem,” dated February 17, 2009, and “Variant CJD and plasma products,” dated July 27, 2009, at
http://www.hpa.org.uk.

10

Contains Nonbinding Recommendations
those recommendations were announced on September 8, 1998, and were incorporated
into an August 1999 guidance that was revised and updated in November 1999. Those
changes were as follows:
•
•
•

that you no longer withdraw plasma derivatives containing plasma from
donors with CJD or CJD risk factors;
that you withdraw all material collected from donors diagnosed with vCJD or
suspected vCJD; and
that you defer donors based on their potential exposure to BSE in the U.K., or
injection of insulin made from bovine sources in the U.K.

Because the potential for transmission was unknown, in August 1999, we recommended
that, as a preventive measure, you withdraw blood components and derivatives collected
from donors diagnosed with vCJD. As a further preventive measure, we also
recommended that you defer donors who have resided in the U.K. for a total of six
months or more, between the beginning of 1980 and the end of 1996. We estimated that
this policy would result in deferral of donors accounting for approximately 87% of total
days of potential dietary exposure to the BSE agent in the U.K. (“donor exposure days”).
The period from 1980 through 1996 reflects the peak years of the U.K. BSE epidemic. In
1998, FDA, advised by the Transmissible Spongiform Encephalopathies Advisory
Committee (TSEAC), concluded that measures implemented in the U.K. since 1996 have
been adequate to keep the BSE agent out of the human food chain there. 28 As other
countries institute similar food chain protections against BSE and the prevalence of BSE
in their national cattle herds declines, we expect to reconsider this and other geographic
donor deferral policies for other countries.
At its meeting, on June 1, 2000, the TSEAC discussed the possible deferral of donors
from other countries known or suspected to be affected by BSE. 29 The TSEAC voted not
to recommend new donor deferrals for potential exposures in European countries outside
the U.K. at that time. This decision was based on conclusions that: (1) the extent of the
BSE epidemic in Europe was undetermined; and (2) U.S. donor deferrals for U.K.
residence had only recently been fully implemented so that the potential for adverse
impact on the availability of blood and blood products had not yet been fully appreciated.
The TSEAC also recommended against changing the U.K. donor deferral period to one
shorter than six months.
At its meeting on January 18, 2001, 30 the TSEAC reviewed more recent epidemiological
information on exposure to BSE in European countries, and again discussed possible
changes to donor deferrals for vCJD risk. The TSEAC again voted that epidemiological
and other currently available scientific information did not support changing the current
deferral for donors who had resided or traveled in the U.K. The TSEAC did recommend
28

December 18, 1998 TSEAC meeting transcript: http://www.fda.gov/ohrms/dockets/ac/98/transcpt/3484t1.rtf.
June 1, 2000 TSEAC meeting transcript: http://www.fda.gov/ohrms/dockets/ac/00/transcripts/3617t1.rtf.
30
January 18, 2001 TSEAC meeting transcript: http://www.fda.gov/ohrms/dockets/ac/01/transcripts/3681t1.rtf.
29

11

Contains Nonbinding Recommendations
that deferrals be considered for donors potentially exposed to beef products exported
from the U.K. to U.S. military bases in Europe, and for donors potentially exposed to
BSE since 1980 in France, Portugal, and the Republic of Ireland. In response to advice
from the TSEAC that FDA should consider recommending deferral of donors for
residence or travel in Portugal and the Republic of Ireland (i.e., countries where BSE
exposure was not related to human consumption of British beef per se), we decided to reexamine the issue publicly with the TSEAC on June 28-29, 2001. 31 At this meeting, the
TSEAC considered the estimated potential human exposures to the BSE agent in the U.K.
and other parts of Europe, as well as estimates of risk reduction and donor loss expected
to result from tightened geographic donor deferrals. Specifically, the TSEAC considered
three deferral options (including the option proposed by the TSEAC at its January 2001
meeting) and voted (10 for and 7 against) to endorse instead a revised set of
recommendations proposed by FDA.
The main features of the recommendation were: (1) deferral of donors for any
cumulative travel or residence for a period of five years or more in any European country
except the U.K. from 1980 through the present; (2) deferral of donors who spent three
months or more in the U.K. from 1980 through the end of 1996; (3) deferral of donors
who spent more than six months in Europe on a base of the U.S. Department of Defense
(DoD) from 1980 through the end of 1996 (or 1980 through 1990 if all exposure after
1990 was on bases in Northern Europe); and (4) deferral of any recipient of a blood
transfusion in the U.K. from 1980 to the present. Deferrals were to be recommended for
implementation in two stages within six months of publication by FDA of a final
guidance. FDA estimated that the new policy might lead to a loss of 4.6% to 5.3% of
blood donors with a 72% reduction in existing vCJD risk, for a total reduction of 90%
relative to the risk that had existed prior to implementation of the 1999 recommendations.
The TSEAC also evaluated information suggesting that measures taken in the U.K. to
prevent human exposure to food-borne BSE agents were adequate to reduce the risk there
markedly after the end of 1996. The proposed deferral policy was endorsed by a majority
of TSEAC members and used by FDA as the basis for the 2002 guidance.
At its meeting, held jointly with the Blood Products Advisory Committee on January 17,
2002, the TSEAC reviewed the FDA guidance of January 2002 and agreed again - by
unanimous vote - that the combination of measures implemented in the U.K. by the end
of 1996 to protect the human food chain from BSE contamination were sufficient to
obviate the need for donor deferrals based on subsequent travel or residence in the U.K. 32
However, TSEAC members stressed that U.K. authorities must assure vigorous,
sustained, and consistent application of aggressive food-protective measures with active
BSE surveillance and monitoring of BSE-safety-related efforts.
In December 2003, as noted in Section II.C.2 above, the first case of presumptive
transfusion-transmitted vCJD was reported from the U.K. and the first U.S. case of BSE
31

June 28-29, 2001 TSEAC meeting transcript: http://www.fda.gov/ohrms/dockets/ac/01/transcripts/3762t1.rtf and
http://www.fda.gov/ohrms/dockets/ac/01/transcripts/3762t2.rtf.
32
January 17, 2002 TSEAC meeting transcript: http://www.fda.gov/ohrms/dockets/ac/02/transcripts/3834t2.rtf.

12

Contains Nonbinding Recommendations
was diagnosed postmortem in a Canadian-born cow slaughtered in Washington State
(seven months after the first native-born cow was diagnosed with BSE in the Canadian
Province of Alberta). At its meeting on February 12-13, 2004, the TSEAC discussed
those two events and their possible implications for U.S. blood safety. 33 The TSEAC
expressed confidence that the deferral policies already in place were likely to be effective
and were concerned that additional restrictions on blood donor eligibility, while probably
adding little to safety, might seriously reduce supply. The TSEAC discussed the possible
benefit of leukoreduction, which had been introduced in several BSE countries in the
hope of reducing the risk of transfusion-transmitted vCJD (Ref. 58). 34 Experimental
studies using blood of rodents infected with scrapie agent as a model for human TSE
(Ref. 59) subsequently confirmed previous findings, suggesting that a substantial portion
of blood-borne infectivity was in plasma and not removed by leukoreduction filtration
(Ref. 32). The TSEAC concluded that, whatever its other benefits, leukoreduction
remains of unproven value in reducing the risk of transfusion-transmitted vCJD and
should not be relied upon to replace a donor deferral policy. At its meeting, on October
14, 2004, the TSEAC discussed: (1) whether the policies recommended by FDA in the
guidance of January 2002 were still justified; and (2) whether additional preventive
measures were indicated to enhance blood safety. 35 The TSEAC voted unanimously that
the measures FDA had recommended in the 2002 guidance were still justified. The
TSEAC voted (13 for and 1 against) that FDA should continue to recommend those
deferral policies without enhancements and also should follow the situation closely and
consider adding risk-reducing measures if indicated. One TSEAC member expressed the
opinion that FDA should seriously consider recommending deferral of donors transfused
in some BSE countries besides the U.K.
At its meeting, on February 8, 2005, the TSEAC discussed available information and
recommendations for deferral of U.S. donors transfused in France and in other European
countries since 1980. 36 The TSEAC voted (12 in favor, 3 against, with one abstention) to
recommend deferral of blood donors with a history of transfusion in France since 1980.
However, the TSEAC voted unanimously against advising deferral of both blood donors
and Source Plasma donors transfused in other European countries besides France and the
U.K., reasoning that many more cases of vCJD had occurred in France than in any other
country except the U.K. In a closely divided vote, the TSEAC advised FDA not to
recommend deferral of Source Plasma donors with a history of transfusion in France (five
members favored deferral of Source Plasma donors while seven members opposed it and
one abstained), based on information presented at the October 14, 2004 TSEAC meeting
showing that the processes used to manufacture plasma derivatives had the capacity to

33

February 12-13, 2004 TSEAC meeting transcript:
http://www.fda.gov/ohrms/dockets/ac/04/transcripts/4019t1.htm and
http://www.fda.gov/ohrms/dockets/ac/04/transcripts/4019t2.htm.
34
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1621089/pdf/pmed.0030342.htm.
35
October 14, 2004 TSEAC meeting transcript: http://www.fda.gov/ohrms/dockets/ac/04/transcripts/20044075T1.htm.
36
February 8, 2005 TSEAC meeting transcript: http://www.fda.gov/ohrms/dockets/ac/05/transcripts/20054088t1_01.pdf.

13

Contains Nonbinding Recommendations
remove substantial amounts of TSE infectivity (Refs. 47-49 and 51-52). 37 Subsequent
presentations on the capacity of processes used to manufacture plasma derivatives to
remove TSE infectivity were made to the TSEAC on September 18, 2006, 38 and
December 15, 2006. 39
In the 2006 draft guidance, FDA summarized interim events, including advice from the
TSEAC, and proposed to amend the 2002 guidance to include a recommendation that
blood establishments indefinitely defer blood donors who have received transfusions of
blood or blood components in France since 1980. In the 2006 draft guidance, FDA,
while again relying on laboratory studies showing that steps used in certain processes
used to manufacture fractionated plasma products reduce TSE infectivity, cautioned that
“ … not all products have been thoroughly studied [and] … it remains uncertain whether
the models accurately reflect the form of infectivity in blood.” Therefore, we also
recommended in the 2006 draft guidance that Source Plasma donors who have received a
transfusion of blood or blood components in France since 1980 be indefinitely deferred,
and stated that we will continue to monitor the BSE epidemic and re-evaluate the
necessity of deferring donors transfused in other European countries.
After the 2006 draft guidance was issued for comment, FDA received additional
information concerning the risk of transmitting vCJD by plasma derivatives (uncertain
but small in most although not all scenarios analyzed by probabilistic computer models 40)
and remains concerned about the increasing number of vCJD cases reported from France.
The 2010 guidance recognized new information and incorporated advice we received
from the TSEAC since the 2002 guidance was issued, and included revisions made in
response to comments received on the 2006 draft guidance.
In October 2010, we sought the advice of the TSEAC on our proposed labeling
recommendations to reflect potential risk of vCJD in plasma-derived products. We
proposed recommendations for labeling for plasma-derivatives that included mention of
vCJD for the first time, and the potential risk for its transmission.
Similarly, we proposed revisions to the labeling for plasma-derived albumin and products
containing plasma-derived albumin. In addition to its indications for direct infusion into
patients, albumin may be used in the manufacture of other biological products. For
example, it is used in the culture media of certain licensed vaccines or as a stabilizer in
certain recombinant clotting factor products. Licensed albumin and albumin contained in
other licensed products have never been known to transmit viruses, CJD or vCJD, and
laboratory experimental evidence suggests albumin is less likely to contain CJD-like
agents when compared with other fractionated products (Refs. 45, 60-61). There is no
37

Presentation slides at: http://www.fda.gov/ohrms/dockets/ac/04/slides/2004-4075S1_05_files/frame.htm.
Presentation slides at: http://www.fda.gov/ohrms/dockets/ac/06/slides/2006-4240S1-index.htm.
Presentation slides at: http://www.fda.gov/ohrms/dockets/ac/06/slides/2006-4271S1_00-index.htm.
40
September 18, 2006 TSEAC meeting transcript:
http://www.fda.gov/ohrms/dockets/ac/06/slides/2006-4240S1-index.htm and December 15, 2006 TSEAC meeting
transcript: http://www.fda.gov/ohrms/dockets/ac/06/slides/2006-4271S1_00-index.htm.
38
39

14

Contains Nonbinding Recommendations
epidemiological evidence for transmission of CJD or vCJD in the U.S., U.K., or
elsewhere by products containing plasma-derived albumin. Therefore, our
recommendations for revised warning statements for vCJD risk for plasma-derived
albumin and products containing plasma-derived albumin contained additional language
to reflect the extremely low likelihood of vCJD and CJD transmission through these
products.
TSEAC agreed unanimously that labeling for the potential risk of vCJD is warranted for
plasma derivatives, including albumin and products containing albumin. 41 The revised
recommendations for labeling plasma-derived products, including albumin and products
containing plasma-derived albumin in this guidance are based upon current knowledge
and the advice from TSEAC.
We are not recommending changes to the elements of the warning label for CJD. The
transmission of CJD is currently described as a theoretical risk, given that there is no
evidence that CJD is transmitted by blood (Refs. 56, 62-64).
E.

Rationale for Geographic Donor Deferrals

This guidance document contains recommendations for donor deferral, product retrieval,
and quarantine and disposition based upon consideration of risk in the donor and product,
and the effect that withdrawals and deferrals might have on the supply of life- and healthsustaining blood, blood components, and plasma derivatives. In particular, we
distinguish donors with vCJD from those with CJD or with CJD risk factors because of
differences in the demonstrated risk of transfusion transmission. While no case of
classical CJD has been attributed to transfusion, vCJD has several times been transmitted
by blood transfusion (Ref. 65). 42
These recommendations reflect a continuing effort to minimize the possible risk of
transmitting vCJD by blood and blood products while maintaining their availability. We
have previously estimated that vCJD-related donor deferrals might result in a 90%
reduction in total person-days of risk-weighted (relative to U.K. risk 1980-1996) donor
exposure to the agent of vCJD. We calculated risk as the sum of relative risk-weighted
person-days exposure in the U.K. (weight =1.0), France (weight = 0.05), other European
countries (weight = 0.015), and members of the U.S. military and their dependents
(weight = 0.35). 43 We later estimated that deferring donors transfused in France after
1980 might result in the loss of fewer than 2 in 10,000 otherwise suitable blood donors. 44
Donor loss, under the policy recommendations in the 2002 guidance, was projected to be
41
October 28, 2010 TSEAC meeting transcript:
http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/
BloodVaccinesandOtherBiologics/TransmissibleSpongiformEncephalopathiesAdvisoryCommittee/ucm244061.htm.
42
October 14, 2004 TSEAC meeting transcript:
http://www.fda.gov/ohrms/dockets/ac/04/transcripts/2004-4075t1_01.pdf.
43
January 18, 2001 TSEAC meeting transcript: http://www.fda.gov/ohrms/dockets/ac/01/slides/3681s1.htm.
44
October 14, 2004 TSEAC meeting transcript: http://www.fda.gov/ohrms/dockets/ac/04/transcripts/20044075T1.htm.

15

Contains Nonbinding Recommendations
approximately 5%, based upon analysis of data from a 1999 multi-center blood donor
travel survey, 45 which was conducted using methodology described for Retrovirus
Epidemiology Donor Studies (Ref. 66). We recognized that these deferrals might
adversely affect the available supply of blood and plasma derivatives and warned that
supplies needed to be monitored closely. The impact was expected to vary locally and
regionally depending upon the dynamics of supply and demand and other characteristics
such as demographics of the donor populations. More specifically, we were concerned
that donors with a history of travel to the U.K. and other parts of Europe might be as
much as 50% higher in urban coastal cities than in central and rural areas of the U.S. 46
As noted above BSE has been found in 36 Japanese cattle, one cow in Israel, 19 cattle in
Canada and three in the U.S. 47 Residence in those countries, and residence in the U.K.
after the end of 1996, has not been considered by FDA as cause to recommend donor
deferral. The news media reported that other countries also received U.K. meat-and-bone
meal, 48 implying that those countries might also have introduced the BSE infection into
their cattle herds but have no recognized cases. We considered additional deferrals based
upon possible donor exposure to BSE in Asian and other countries after the
recommended deferrals were fully implemented in the fall of 2002, their impact assessed,
and additional information about the potential level of BSE exposure and food chain
controls in various countries sought. Following the recognition of BSE in North
American cattle in 2003, the entire worldwide situation was considered by FDA and
implications discussed publicly at meetings of TSEAC. We reasoned that additional
deferrals would probably yield only a negligible benefit in reducing risk while
compromising, to some uncertain but potentially significant degree, the continued supply
of Whole Blood and blood components. The question whether additional geographically
based donor deferrals should be considered for exposure in the Kingdom of Saudi Arabia
was discussed with TSEAC in April 2011. Geographic deferrals were more broadly
discussed with TSEAC in June 2015 in consideration of the results of a new FDAdeveloped quantitative assessment model for vCJD global geographic risk and the
estimated risk reduction achieved by voluntary implementation of leukocyte reduction for
red blood cells. We will reconsider our recommendations as appropriate based on the
impact of expanded or reduced donor deferrals on the safety and availability of blood
products.

45

June 28, 2001 TSEAC meeting transcript: http://www.fda.gov/ohrms/dockets/ac/01/transcripts/3762t1.rtf.
January 18-19, 2001 TSEAC meeting transcript: http://www.fda.gov/ohrms/dockets/ac/01/transcripts/3681t1.rtf
and http://www.fda.gov/ohrms/dockets/ac/01/transcripts/3681t2.rtf.
47
OIE at http://www.oie.int/eng/info/en_esb.htm.
48
“Japan’s Beef Scandal.” Nature 413 (6854): 333.
46

16

Contains Nonbinding Recommendations
III.

EXPLANATION OF CURRENT vCJD RECOMMENDATIONS
A.

Exposure to British Beef in the U.K.

The vCJD epidemic in the U.K., while markedly reduced since deaths peaked in 2000 49
(Ref. 21), continues. Furthermore, it has not been excluded that additional “waves” of
cases may occur and that some uncertain but potentially substantial number of persons in
the U.K. may have pre-clinical or sub-clinical infections (Refs. 67-70). 50
To increase protection of the U.S. blood supply, we continue to recommend that you
defer blood and plasma donors who have traveled or resided in the U.K. for a cumulative
period of three or more months from the beginning of 1980 through the end of 1996.
B.

Exposure to British Beef Products Distributed Outside of the U.K.

In January 2001, the TSEAC recognized two types of risk outside the U.K.: (1) exposure
to BSE from infected cows in the country of residence (“indigenous” BSE exposure); and
(2) exposure to BSE from bovine products exported from the U.K. during the BSE
epidemic prior to full implementation of food control measures in 1996 (“imported” BSE
exposure).
Available data suggest that France imported a substantial amount of beef from the U.K.
during the peak years of the BSE epidemic; 51 at least 5% of beef consumed in France is
estimated to have come from the U.K. during the late 1980s. The number of French
vCJD cases (23) is currently about 13% of those in the U.K. 52 It has been speculated that
many French vCJD cases might have been infected by consumption of British beef in
France, since only one of the 23 individuals had lived in the U.K. for six or more months,
and the indigenous French BSE epidemic has been much smaller and more recent than
that in the U.K. Substantial amounts of British beef also were exported to the
Netherlands, but it appears that much of this meat was apparently then exported from the
Netherlands to a variety of other countries. 53
On January 18, 2001, the TSEAC voted to defer potential donors who resided in France
for 10 years or more, from 1980 until the present. 54 The suggested 10-year (120-month)
deferral period for France reflected an estimated 5% risk of exposure to BSE, compared
49

CJD Statistics from the British Department of Health at www.doh.gov.uk.
See also, McKie, R. “Warning over second wave of CJD cases. Scientists say that threat of brain illness returning
will persist for decades,” Observer, Aug. 3, 2008 at 11; Collinge, J. et al. (2006) “Kuru in the 21st century—an
acquired human prion disease with very long incubation periods.” Lancet 376: 2068-74.
51
June 1-2, 2000 TSEAC meeting transcript: http://www.fda.gov/ohrms/dockets/ac/00/transcripts/3617t1.rtf and
http://www.fda.gov/ohrms/dockets/ac/00/transcripts/3617t2.rtf.
52
Chart at: www.invs.sante.fr/publications/mcj/donnees_mcj.html.
53
June 1-2, 2000 TSEAC meeting transcript: http://www.fda.gov/ohrms/dockets/ac/00/transcripts/3617t1.rtf and
http://www.fda.gov/ohrms/dockets/ac/00/transcripts/3617t2.rtf.
54
January 18-19, 2001 TSEAC meeting transcript: http://www.fda.gov/ohrms/dockets/ac/01/transcripts/3681t1.rtf
and http://www.fda.gov/ohrms/dockets/ac/01/transcripts/3681t2.rtf.
50

17

Contains Nonbinding Recommendations
to exposure of donors who resided in the U.K. for at least six months. However, in our
2002 guidance, FDA recommended a more stringent deferral for exposure of five or more
years in Europe (see Section III.C. below) consistent with a revised recommendation of
deferral for three months exposure in the U.K. Although more recent data suggest that
the relative risk of BSE exposure in France compared with the U.K. may have exceeded
5%, we continue to recommend deferral of blood and plasma donors with a history of
five or more years of cumulative residence or travel in France since 1980.
Some U.S. military personnel, civilian military personnel, and their dependents in Europe
were also potentially exposed to British beef procured for consumption or sale on U.S.
military bases between 1980 and 1996. British beef was distributed to U.S. military
bases in Northern Europe (Germany, U.K., Belgium, and the Netherlands) between 1980
and 1990, and to U.S. military bases elsewhere in Europe (Greece, Turkey, Spain,
Portugal, and Italy), between 1980 and 1996. While exposure varied widely, it is
estimated that in some areas, up to 35% of beef consumed on U.S. military bases in
Europe came from the U.K. 55 In January 2001, the TSEAC recommended deferring such
donors but advised that more information was needed to assess the impact of deferral for
various time periods in Europe on the supply of blood products.
Due to a history of potential consumption of U.K. beef by persons on U.S. military bases
in Europe, we continue to recommend that current and former U.S. military personnel,
civilian military personnel, and their dependents stationed at European bases for six
months or more during the timeframes outlined in the preceding paragraph be deferred
indefinitely. Based upon information provided by the DoD, we estimated that
approximately 1.8% of U.S. blood donors might be deferred by this recommendation.
Since as of 1996, DoD no longer procures U.K. beef for any U.S. military bases, such
deferred donors now constitute a smaller percentage of otherwise suitable donors.
C.

Indigenous BSE Exposure Outside the U.K.

BSE in Europe is likely to have originated from infected cattle and cattle feed that were
exported from the U.K. to other parts of Europe. The risk of human exposure to the BSE
agent in any country is based upon several factors, including the prevalence of BSE and
the implementation of control measures to prevent the BSE agent from entering the
human food chain. Control measures have included some of the following:
•

prohibition of air injection stunning methods for cattle;

•

active surveillance through testing of slaughtered cattle more than 30 months old
for BSE;

•

prohibitions on the use of carcasses from disabled cattle (so-called “downer”
cattle not inspected and passed for human consumption);

55

January 18-19, 2001 TSEAC meeting transcript: http://www.fda.gov/ohrms/dockets/ac/01/transcripts/3681t1.rtf
and http://www.fda.gov/ohrms/dockets/ac/01/transcripts/3681t2.rtf.

18

Contains Nonbinding Recommendations
•

holding of all carcasses from cattle tested for cause until non-positive results have
been received;

•

exclusion of high-risk material (e.g., brain, other neural tissues, lymphoid tissues,
and many parts of the intestines) from human food;

•

a ban on human consumption of slaughtered cattle more than 30 months old;

•

prohibition of mechanically recovered meat;

•

a ban on mammalian-derived feed for ruminants;

•

use of certain rendering processes; and

•

additional herd control and surveillance. 56

BSE has been detected in many European countries. 57 Food chain control measures (and
their enforcement) have varied in Europe and cannot be assured for all time periods in
question. Because of these uncertainties and the evolving BSE epidemic, donor deferrals
on a country-by-country basis have not been practical. Therefore, FDA developed a
uniform recommendation for donor deferral based on exposure in Europe outside of the
U.K. The highest prevalence of BSE that has been observed in a European country with
a strong surveillance program (Switzerland) is approximately 1.5% of the BSE
prevalence that was observed for the U.K. between 1980 and 1996. Also, as noted in
Section III.B above, residents in France may have consumed at least 5% of their total
beef as imported British beef during the epidemic period, while other Europeans almost
certainly consumed less. Therefore, the estimated maximum risk of BSE exposure in
Europe was taken to be approximately 1.5-5% of that in the U.K. Assuming a “worstcase” relative risk of 5% per day of exposure, a European donor deferral of five years (60
months) was equivalent to a three-month deferral for cumulative travel or residence in the
U.K. This remains the basis for our current recommendation to defer donors of Whole
Blood and blood components intended for transfusion and Source Leukocytes who have a
history of five or more years of residence or travel in Europe outside of the U.K.
As discussed in Section II.C.2., there has been one case of transmission of vCJD in the
U.K. that may be due to the use of human plasma. In 2006, the TSEAC discussed risk
assessments for potential exposure to vCJD risk from certain plasma-derived products. 58
The risk of transmitting vCJD by plasma derivatives was estimated based upon the
probable infectivity of plasma from pre-symptomatic or asymptomatic donors with vCJD
infections, the prevalence of vCJD in the donor population (mainly dependent on the
56
European Commission Scientific Steering Committee opinions on the Geographical Risk of BSE:
http://ec.europa.eu/food/fs/bse/scientific_advice01_en.html.
57
January 18-19, 2001 TSEAC meeting transcript: http://www.fda.gov/ohrms/dockets/ac/01/transcripts/3681t1.rtf
and http://www.fda.gov/ohrms/dockets/ac/01/transcripts/3681t2.rtf, and June 1-2, 2000 TSEAC Meeting Transcript:
http://www.fda.gov/ohrms/dockets/ac/00/transcripts/3617t1.rtf and
http://www.fda.gov/ohrms/dockets/ac/00/transcripts/3617t2.rtf.
58
Risk assessments for plasma-derived factors VIII and XI presented to the TSEAC on December 15, 2006:
http://www.fda.gov/ohrms/dockets/ac/cber06.html#TransmissibleSpongiform and draft risk assessments presented
to the TSEAC on October 15, 2006: http://www.fda.gov/ohrms/dockets/ac/06/briefing/2006-4271b1-index.htm.

19

Contains Nonbinding Recommendations
number infected in the U.K., not all of whom are deferred by recommended policies), the
size of the plasma pool used for fractionation, and the removal of vCJD infectivity during
the manufacturing process. In experimental studies, model TSE agents were removed
from plasma products by a number of manufacturing steps, including precipitation, depth
filtration, and column chromatography (Refs. 48-49, 57-60). Other unpublished data
provided to FDA also suggested that the vCJD agent was similarly removed from most
plasma derivatives by the same manufacturing steps.
The relative risks and benefits of excluding plasma donors who have lived or traveled in
Europe for five years or more have not been established. In particular, the effect of such
a donor deferral upon the supply of life and health-sustaining plasma derivatives has not
been determined, but could be significant. 59 However, the implementation in October
2002, of the previous enhanced vCJD deferral policies for donors of Source Plasma was
not followed by reported shortages of plasma-derived products in the U.S. Furthermore,
in contrast to blood, plasma derivatives are highly processed materials. Considering the
estimated low prevalence of vCJD infections in most countries of Europe compared to
the U.K. and France, the likelihood that plasma fractionation processes reduce TSE
infectivity, and the uncertain effect of additional deferrals upon the supply of plasma
derivatives, we have not recommended that you defer Source Plasma donors who lived or
traveled in other countries of Europe, although we are recommending that donors who
lived in France for five or more years from 1980 to the present should be deferred from
donating Source Plasma. Moreover, we are recommending, in consideration of the
relatively greater risk of vCJD in persons with exposure to beef products from the U.K.
that you should not collect Source Plasma from donors with a history of travel or
residence in the U.K., U.S. military bases in Europe, and in France, as described in
Sections III.A. and B. of this document.
Blood donors who are deferred for history of European travel or residence (except as
stated for the U.K., France, and U.S. military bases in Europe) remain eligible to donate
Source Plasma in a Center for Biologics Evaluation and Research (CBER) approved
program. We will continue to evaluate this recommendation in light of evolving
experimental and epidemiological information.
Given these considerations, we recommend that you defer donors of Whole Blood and
blood components intended for transfusion, Source Leukocytes, and recovered plasma,
but not donors of Source Plasma, who have resided in the countries of Europe listed in
the Appendix to this document for a cumulative period of five years or more, between the
beginning of 1980 and the present. We recommend that donors of Source Plasma who
resided in the U.K., France, and U.S. military bases in Europe, be deferred as noted in the
previous sections of this guidance. 60

59

June 28, 2001 TSEAC meeting transcript: http://www.fda.gov/ohrms/dockets/ac/01/transcripts/3762t1.rtf.
We continue to refer to donor deferrals both for risk of exposure to BSE due to residence in BSE countries,
consumption of British beef products, injection of U.K. bovine insulin, and history of transfusion in the U.K. or in
France after 1980 as “geographic risk deferrals.”

60

20

Contains Nonbinding Recommendations
D.

Potential Infection with vCJD Agent Acquired by Transfusion

As discussed in Section II.C., there have been four reports of presumptive transmissions
of vCJD to humans by blood transfusions, three resulting in clinical cases of vCJD and
one in an infection with typical abnormal accumulations of prion protein in lymphoid
tissues. FDA has little doubt that vCJD has been efficiently transmitted by nonleukoreduced Red Blood Cells from clinically healthy donors who later became ill with
vCJD. Other components, while not implicated in transfusion transmissions of vCJD to
date, cannot be considered safe. In addition, there has been one reported case of vCJD
transmission in the U.K. that may be due to use of plasma-derived Factor VIII.
Therefore, as a preventive measure, donors who have received transfusions of blood or
blood components in the U.K. and in France since 1980 should be indefinitely deferred.
E.

Exposure to Bovine Insulin

No cases of transmission of vCJD have been reported in recipients of bovine insulin or
other injectable products manufactured in BSE-affected countries. However, as a
safeguard, most material from cattle in BSE countries should not be used in the
manufacture of FDA-regulated products. 61 We are aware that some diabetic patients have
imported bovine insulin for personal use. 62 Additionally, some insulin products legally
distributed in the U.S. since 1980 were manufactured from cattle in the U.K. Therefore,
as a preventive measure, you should indefinitely defer blood donors who have injected
bovine insulin since the beginning of 1980, unless you can confirm that the product was
not manufactured after 1980 from cattle in the U.K. We are not aware that bovine insulin
has been imported into the U.S. from France or any other European BSE country.
F.

Reports of Biological Product Deviations

The biological product deviation regulation 63 requires blood establishments to submit a
biological product deviation report (BPDR) when the event meets the standard set out in
21 CFR 606.171. The regulation requires an establishment to report to FDA events that:

• occurred while the product was in the establishment’s control; and
• EITHER represents a deviation from current good manufacturing practice,
•

applicable regulations, applicable standards, or established specifications; OR
represents an unexpected or unforeseeable event; and
may affect the safety, purity or potency of a distributed product.

Some establishments have asked questions about submitting a BPDR in the context of
these donor deferral recommendations.
61

59 FR 44591, Aug. 29, 1994.
For examples, see: http://www.fda.gov/OHRMS/DOCKETS/dailys/02/Dec02/122302/80042e34.txt and
http://www.gopetition.co.uk/petitions/restore-beef-insulins-to-the-united-states.html.
63
65 FR 6635, Nov. 7, 2000, as amended at 70 FR 14984, March 24, 2005.
62

21

Contains Nonbinding Recommendations
Example #1: On the first day after implementing new donor criteria, a repeat donor
provided information of living for seven years in France between 1981 and 1988. The
donor was deferred at this donation. Must the establishment submit a BPDR with respect
to units previously collected from that donor, if those units were distributed?
The regulation does not require the establishment to submit a BPDR. At the time of prior
donations, collection from that donor did not represent a deviation from current good
manufacturing practice, applicable regulations, applicable standards, or established
specifications, and the donor would not have been deferred. Nor was the collection an
unexpected or unforeseeable event.
Example #2: One year after implementing new donor criteria, the establishment
discovers that one of its repeat donors provided information of living in France between
1981 and 1988. The donor donated Source Plasma eight weeks earlier and Whole Blood
five months earlier. Despite the donor's unsuitability under the new donor criteria, the
establishment accepted those donations. Must the establishment submit a BPDR with
respect to those units, if those units were distributed?
The establishment must submit a BPDR (21 CFR 606.171). At the time of the donations,
collection from that donor represented a deviation from current good manufacturing
practice, applicable regulations, applicable standards, or established specifications.
Example #3: The establishment discovers that one of its repeat donors has developed
CJD or vCJD. The donor donated Whole Blood three months earlier, and has a long
history of donating. Must the establishment submit a BPDR with respect to units
previously collected from that donor, if those units were distributed?
The establishment must submit a BPDR (21 CFR 606.171). Collection from that donor
represented an unexpected or unforeseeable event that may affect the safety, purity, or
potency of the product. Neither the blood establishment nor the agency expected or
foresaw that the establishment would collect donations from individuals with CJD or
vCJD.
Example #4: Six months after implementing new donor criteria, a repeat donor provided
information of receiving a blood transfusion to treat a bleeding ulcer during a vacation in
France 20 years ago. The donor donated Whole Blood three months earlier, at which
time the donor provided the same information. Must the establishment submit a BPDR
with respect to units previously collected from that donor, if those units were distributed?
The establishment must submit a BPDR (21 CFR 606.171). At the time of the donation,
collection from that donor represented a deviation from current good manufacturing
practice, applicable regulations, applicable standards, or established specifications.
G.

Definitions

Audio CASI: computer assisted interactive donor questioning program that is
accompanied by an audio component. The donor reads the questions on a computer
display screen and hears the questions through a speaker or headphones.
22

Contains Nonbinding Recommendations
Blood components intended for transfusion: Red Blood Cells, Platelets, Plasma,
Cryoprecipitate, or Granulocytes derived from human blood collected by either manual
Whole Blood collection or automated apheresis techniques and intended to be transfused
to human recipients.
Military employee or dependent: An individual who is or was a member of one of the
U.S. military services (Army, Air Force, Navy, Marines, Coast Guard), a civilian
employee of one of the U.S. military services or a dependent (e.g., a spouse, child, parent,
other) of a member of one of the U.S. military services or a civilian employee of one of
the U.S. military services.
Recovered Plasma: the fluid portion of human blood obtained from Whole Blood or as
a byproduct of apheresis procedures (e.g., plateletperesis) in conjunction with the
preparation of blood components for transfusion and Source Leukocytes. Recovered
plasma, an unlicensed product, is intended for further manufacturing into injectable and
non-injectable products.
Source Leukocytes: a blood component derived from human blood collected by either
manual or automated apheresis techniques and intended for further manufacturing into
injectable products, like interferon. Source Leukocyte donors may donate once every
eight weeks or more frequently and must meet Whole Blood or Source Plasma donor
suitability criteria depending on the type and frequency of donation. 64
Source Plasma: the fluid portion of human blood collected by plasmapheresis and
intended for use as a source material for further manufacturing. Source Plasma may be
manufactured into products intended for either injectable or non-injectable uses
(21 CFR 640.60).
Source Plasma Donors:
•

Frequent Source Plasma Donor: a donor who donates more frequently than
once every four weeks. These donors are subject to the requirements in
21 CFR 630.15 and 21 CFR 640.65(b)(1)).65

•

Infrequent Source Plasma Donor: a donor who has 1) not donated plasma by
plasmapheresis or a co-collection of plasma with another blood component in the
preceding 4 weeks and 2) not donated more than 12.0 liters of plasma (14.4 liters
of plasma for donors weighing more than 175 pounds) in the past year.
(See 21 CFR 630.3(e) and 21 CFR 630.25). 65

64

See 21 CFR 630.10 and 630.15. See Requirements for Blood and Blood Components Intended for Transfusion or
for Further Manufacturing Use; Final Rule (80 FR 29842, May 22, 2015). The rule is effective May 23, 2016.
Current requirements are in 21 CFR 640.3 and 640.63.
65
See Requirements for Blood and Blood Components Intended for Transfusion or for Further Manufacturing Use;
Final Rule (80 FR 29842, May 22, 2015). The rule is effective May 23, 2016.

23

Contains Nonbinding Recommendations
IV.

RECOMMENDATIONS FOR DONOR DEFERRAL
A.

Donor Deferral Criteria

Donor deferral criteria 1-7 apply to all donors. Donor deferral criterion 8 (residence in
Europe for 5 years or more between 1980 and the present) applies to all donors with the
exception of donors of Source Plasma.
1.

You should permanently defer donors who have been diagnosed with vCJD
or any other form of CJD. 66

2.

You should permanently defer donors at increased risk for CJD (as identified
by questions 2 and 3 in Section IV.B. Donors are considered to have an
increased risk for CJD if they have received a dura mater transplant or an
injection of human cadaveric pituitary-derived growth hormone. Donors
with one or more blood relatives diagnosed with CJD (as identified in
Section IV.B., Question 1 below) are also considered to be at increased risk
of CJD, and should be indefinitely deferred (see Section IV.C. for donor
reentry recommendations).

3.

You should indefinitely defer donors who have spent three months or more
cumulatively in the U.K. from the beginning of 1980 through the end of
1996.

4.

You should indefinitely defer donors who have spent five years or more
cumulatively in France from the beginning of 1980 to the present.

5.

You should indefinitely defer former or current U.S. military personnel,
civilian military personnel, and their dependents as follows:

6.

a.

Individuals who resided at U.S. military bases in Northern Europe
(Germany, United Kingdom, Belgium, and the Netherlands) for six
months or more from 1980 through 1990, or

b.

Individuals who resided at U.S. military bases elsewhere in Europe
(Greece, Turkey, Spain, Portugal, and Italy) for six months or more from
1980 through 1996.

You should indefinitely defer donors who have received a transfusion of
blood or blood components in the U.K. or in France between the beginning
of 1980 and the present.

66

For the purposes of this document, FDA considers the less common TSEs, Gerstmann-Sträussler-Scheinker
syndrome and fatal insomnia syndromes, to be equivalent in risk to familial and sporadic CJD. The blood
establishment need not name these rare syndromes in the questionnaire but might consider them as equivalent in risk
to CJD if, in response to a question about CJD, the donor offers information that a family member has been
diagnosed with one of them.

24

Contains Nonbinding Recommendations

7.

You should indefinitely defer donors who have injected bovine insulin since
1980, unless you can confirm that the product was not manufactured after
1980 from U.K. cattle.

8.

You should indefinitely defer donors of Whole Blood, blood components for
transfusion, and Source Leukocytes, who have lived cumulatively for five
years or more in Europe from the beginning of 1980 until the present. (Note
this criterion includes time spent in the U.K. from 1980 through 1996 and
time spent in France from 1980 to the present.) Unless otherwise unsuitable
(for example, because they lived in the U.K. or France or on U.S. military
bases for the periods of time noted previously), these donors remain eligible
for Source Plasma donation.

NOTE: Donors who are otherwise deferred based upon the above criteria 2-8 may
continue to donate if they are participating in a CBER-approved program that allows
collection of Source Plasma solely for use in manufacturing of non-injectable products.
We recommend special labeling for products obtained from such donors (see Section
VII.A).
B.

Questions to Identify Donors at an Increased Risk for CJD

You should question frequent Source Plasma donors at the first donation following
implementation of the recommendations in this guidance, and annually thereafter. You
should question donors of Whole Blood and blood components, infrequent Source
Plasma donors and Source Leukocyte donors at each donation. If the donor is not
familiar with the term “Creutzfeldt-Jakob Disease,” you may take that as a negative
response. These questions are similar to those in the 1999 and 2002 guidances. We
consider donors who answer “Yes” to any of the questions below to have an increased
risk for developing CJD.
Question 1:

Have any of your blood relatives ever had Creutzfeldt-Jakob
Disease? 67

Question 2:

Have you ever received growth hormone made from human
pituitary glands?

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?” This
question needs to be asked only once, since human cadaveric pituitary growth
hormone is no longer available.

67

See footnote 66.

25

Contains Nonbinding Recommendations
Question 3:

Have you ever received a dura mater (brain covering) graft?

NOTE: This question may be preceded by the more general question “Have you
ever had brain surgery?” Ask the specific question only if the donor responds
“yes” to the general question.
C.

Donor Reentry after Donor Deferral for Risk of Familial CJD
If you defer a donor because of family history of CJD, you may reenter that donor
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 a mutation associated with familial CJD. Note that gene
sequencing of the donor is not necessary to demonstrate that the donor
is not at risk for familial CJD. Sequencing of the family member with
CJD or the appropriate parent of the donor, if the CJD-affected family
member was a second-degree relative, may be sufficient to
demonstrate that the donor does not have a mutation associated with
familial CJD.

D.

Questions for Identifying Donors at Risk for Exposure to BSE
1.

Method of Donor Questioning

Due to the added complexity of screening donors for cumulative periods of
potential exposure to BSE, a trained staff member should administer the revised
geographic donor deferral criteria by face-to-face interview to each new donor (as
defined in your blood establishment’s standard operating procedures (SOP)).
Instead of face-to-face interviews, you may use a computerized interactive donor
interview program that includes an audio component (audio-CASI) as described
in the FDA guidance entitled “Guidance for Industry: Streamlining the Donor
Interview Process: Recommendations for Self-Administered Questionnaires,”
dated July 2003. 68 You should submit changes to your donor interview procedure
according to 21 CFR 601.12. For repeat donors, you may use alternative methods
for introducing and emphasizing the new questions. Your alternative method
should provide the repeat donor with a detailed description of the changes to the
donor questionnaire, to highlight any new questions and modifications.

68
Available at
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Blood/ucm07
5086.htm.

26

Contains Nonbinding Recommendations
2.

Donor Questions

You should indefinitely defer donors who answer “Yes” to the following
questions:
To identify donors with geographic risk of BSE exposure.
Since the beginning of 1980, have you ever lived in or traveled to Europe?
a. If the donor answers “No,” you need not take any further action.
b. If the donor answers “Yes,” then ask the following questions:
1)

Between 1980 through 1996 did you spend time that adds up to three
months or more in the U.K. (England, Northern Ireland, Scotland,
Wales, the Isle of Man, the Channel Islands, Gibraltar, or the
Falkland Islands)?
2) Since 1980 have you received a transfusion of blood, platelets,
plasma, cryoprecipitate, or granulocytes in the U.K. (England,
Northern Ireland, Scotland, Wales, the Isle of Man, the Channel
Islands, Gibraltar, or the Falkland Islands) or in France? 69
3) Between 1980 through 1996, were you a member of the U.S. military,
a civilian military employee, or a dependent of a member of the U.S.
military?
If the donor answers “No,” you need not take any further action.
If the donor answers “Yes,” ask the following question:
Did you spend a total time of six months or more associated with a
military base in any of the following countries:
•
•

From 1980 through 1990 in Belgium, the Netherlands, or
Germany, or
From 1980 through 1996 in Spain, Portugal, Turkey, Italy, or
Greece?

NOTE: For Questions 1 and 3, you need to question donors only once, because
these questions encompass a discrete time frame. You should administer
Question 2 to frequent Source Plasma donors at intervals of no greater than four
months, and to all other donors, at each donation.

69

For purposes of this guidance, the United Kingdom should be taken to include all of the following: England,
Northern Ireland, Scotland, Wales, the Isle of Man, the Channel Islands, Gibraltar, and the Falkland Islands; France
should be taken to include its overseas departments (e.g., Martinique and others).

27

Contains Nonbinding Recommendations
To identify donors of Source Plasma who have additional geographic risk of BSE
exposure, you should ask the following questions:
4) Since 1980, have you spent time that adds up to five years or more in
France?
For donors of Whole Blood, components intended for transfusion, and Source
Leukocytes, you should substitute the following for question 4):
Question 4 (alternative): Since 1980, have you spent time that adds up to five
years or more in Europe (including time spent in the U.K. from 1980 through
1996)?
Donors deferred from donating Whole Blood based on this question remain
eligible to donate Source Plasma in a CBER-approved program, unless they are
otherwise unsuitable.
For Donors of Source Plasma, however, you should continue to ask the original
version of Question 4, as described above, rather than the alternative.
European countries with BSE risk that FDA has identified as a basis for donor
deferral are listed in the Appendix to this document. We will periodically issue
new guidance to update the list of countries with BSE risk, to be used as a basis
for donor deferral. FDA does not currently consider those European and nonEuropean countries that are not listed in the Appendix to this document to pose a
BSE-exposure risk warranting deferral of donors who have spent any period of
time there, even if these countries have reported cases of BSE to the OIE. 70
To identify donors who have been injected with bovine insulin since 1980, you
should ask donors with diabetes the following question:
5)

Since 1980, have you ever injected bovine (beef) insulin?

Since the above question applies to a subset of potential donors, you may ask it as
a secondary question to a general medication question if a donor responds that
they have taken insulin. If the donor answers “Yes” or “I don’t know” in
response to the question, you should indefinitely defer that donor, unless it can be
documented that the product was not manufactured from cattle in the U.K. after
1980.
NOTE: Donors of Source Plasma who otherwise should be indefinitely deferred
based on their responses to the questions specified in Sections IV.D.2.(b)(3) and
IV.D.2.(b)(4), may continue to donate if they are participating in a CBER-

70

OIE at http://www.oie.int/en/animal-health-in-the-world/bse-specific-data.

28

Contains Nonbinding Recommendations
approved program that allows collection of Source Plasma solely for use in
manufacturing of non-injectable products. We recommend special labeling for
products obtained from such donors. (See Section VII.A.)
V.

POST-DONATION INFORMATION: RECOMMENDATIONS FOR PRODUCT
RETRIEVAL AND QUARANTINE, CONSIGNEE NOTIFICATION, AND
BIOLOGICAL PRODUCT DEVIATION REPORTING
A.

Whole Blood and Blood Components Intended for Transfusion, Cellular
Blood Components Intended for Further Manufacture into Injectable
Products, and Source Plasma from Donors with CJD or CJD Risk Factors
1.

Product Disposition

If you receive post-donation information about a donor with CJD or CJD risk
factors, you should immediately retrieve and quarantine for subsequent
destruction all in-date blood components (including Whole Blood, blood
components intended for transfusion, Source Leukocytes, and Source Plasma), all
in-date cellular blood components intended for manufacturing into injectable
products, and all recovered plasma that are under your control. We also
recommend that you follow your SOPs or update your SOPs regarding notifying
consignees to immediately retrieve, quarantine, and subsequently destroy (or
arrange for the destruction of) the implicated components. Such notification
should occur within one week of receiving the post-donation information.
NOTE: If you have sent Source Plasma or recovered plasma to a consignee and
receive post-donation information about a donor with CJD or CJD risk factors, at
a time when you know the plasma units have been pooled, you should not conduct
product retrieval or consignee notification for those units.
2.

Biological Product Deviation Reports

If you received post-donation information about a donor with CJD, you must
submit a BPDR (21 CFR 606.171) for any distributed components. The
regulation requires you to submit a BPDR as soon as possible but not to exceed
45 calendar days after you discover the event (21 CFR 606.171(c)). If you
received post-donation information about a donor with CJD risk factors, you must
submit a BPDR (21 CFR 606.171) for any distributed components collected after
the implementation of donor deferral. A BPDR is not required if components
were collected prior to the implementation of donor deferral.

29

Contains Nonbinding Recommendations
B.

Whole Blood and Blood Components Intended for Transfusion, Source
Leukocytes and Other Cellular Blood Components Intended for Further
Manufacture into Injectable Products, from Donors with Geographic Risk
Deferrals and/or Exposure to Bovine Insulin Made in the U.K. since 1980
Donors with Geographic Risk Deferrals
1.

Product Disposition

If you receive post-donation information about a donor with geographic risk
factors, you should immediately retrieve and quarantine for subsequent
destruction all in-date blood components (including Whole Blood, blood
components intended for transfusion, and Source Leukocytes), and all in-date
cellular blood components intended for manufacturing into injectable products,
that are under your control. We also recommend that you follow your SOPs or
update your SOPs regarding notifying consignees to immediately retrieve,
quarantine, and subsequently destroy (or arrange for the destruction of) the
implicated components. Such notification should occur within one week of
receiving the post-donation information.
2.

Biological Product Deviation Reports

If you received post-donation information about a donor with geographic risk
factors, you must submit a BPDR (21 CFR 606.171) for any distributed
components collected after the implementation of donor deferral. A BPDR is not
required if components were collected prior to the implementation of donor
deferral.
Donors with Exposure to Bovine Insulin Made in the U.K. since 1980
1.

Product Disposition

If you receive post-donation information about a donor exposure to bovine insulin
made in the U.K. since 1980, you should immediately retrieve and quarantine for
subsequent destruction all in-date blood components (including Whole Blood,
blood components intended for transfusion, and Source Leukocytes), and all indate cellular blood components intended for manufacturing into injectable
products, that are under your control. We also recommend that you follow your
SOPs or update your SOPs regarding notifying consignees to immediately
retrieve, quarantine, and subsequently destroy (or arrange for the destruction of)
the implicated components. Such notification should occur within one week of
receiving the post-donation information.

30

Contains Nonbinding Recommendations
2.

Biological Product Deviation Reports

If you received post-donation information about a donor exposure to bovine
insulin made in the U.K. since 1980, you must submit a BPDR (21 CFR 606.171)
for any distributed components collected after the implementation of donor
deferral. A BPDR is not required if components were collected prior to the
implementation of donor deferral.
C.

Source Plasma and Recovered Plasma from Donors with Geographic Risk
Deferrals and/or Exposure to Bovine Insulin Made in the U.K. Since 1980
1.

Product Disposition

If you receive post-donation information about a donor with geographic risk
factors, or exposure to bovine insulin made in the U.K. since 1980, you should
immediately retrieve and quarantine for subsequent destruction all in-date Source
Plasma and all recovered plasma under your control. We also recommend that
you follow your SOPs or update your SOPs regarding notifying consignees to
immediately retrieve, quarantine, and subsequently destroy (or arrange for the
destruction of) the Source Plasma and recovered plasma. Such notification should
occur within one week of receiving the post-donation information.
NOTE: If you have sent Source Plasma or recovered plasma to a consignee and
receive post-donation information about a donor with geographic risk factors, or
exposure to bovine insulin from the U.K. at a time when you know the plasma
units have been pooled, you should not conduct product retrieval or consignee
notification for those units.
2.

Biological Product Deviation Reports

If you received post-donation information about a donor with geographic risk
factors or exposure to bovine insulin made in the U.K. since 1980, you must
submit a BPDR (21 CFR 606.171) for any distributed components collected after
the implementation of donor deferral. A BPDR is not required if components
were collected prior to the implementation of donor deferral.
D.

Whole Blood and Blood Components Intended for Transfusion, Recovered
Plasma, Source Leukocytes, Other Cellular Blood Components Intended for
Manufacturing into Injectable Products, and Source Plasma from Donors
with vCJD, suspected vCJD, or CJD and Age Less Than 55 Years
1.

Product Disposition

We recommend you contact the Office of Blood Research and Review (OBRR),
CBER at 240-402-8360 as soon as possible upon receiving post-donation
information about a donor with vCJD, suspected vCJD, or CJD and age less than
55 years. You should immediately retrieve and quarantine for subsequent

31

Contains Nonbinding Recommendations
destruction all in-date blood components (including Whole Blood, blood
components intended for transfusion, Source Leukocytes, and Source Plasma), all
recovered plasma, and all in-date cellular blood components intended for
manufacturing into injectable products that are under your control. We also
recommend that you follow your SOPs or update your SOPs regarding notifying
consignees to immediately retrieve, quarantine, and subsequently destroy (or
arrange for the destruction of) the implicated components. Such notification
should occur within one week of receiving the post-donation information.
You may save the collected material for use in research on vCJD by qualified
laboratories (see Section VII.A for labeling recommendations).
2.

Biological Product Deviation Reports

If you received post-donation information about a donor with vCJD, suspected
vCJD, or CJD and age less than 55 years, you must submit a BPDR (21 CFR
606.171) for any distributed components. The regulations require you to submit a
BPDR as soon as possible but not to exceed 45 calendar days after you discover
the event (21 CFR 606.171(c)).
E.

Plasma Derivatives
1.

Plasma derivatives manufactured using plasma from donors with CJD or CJD
risk factors, or geographic risk deferrals, as defined in Section IV.D. We are
not recommending that you withdraw pooled plasma, intermediates, and
plasma derivatives manufactured from these donors.

2.

Plasma derivatives manufactured using plasma from donors diagnosed with
vCJD or suspected vCJD
a.

Product Disposition

We recommend you contact OBRR, CBER at 240-402-8360 as soon as
possible upon receiving post-donation information about a donor with
vCJD or suspected vCJD. You should immediately retrieve and
quarantine for subsequent destruction any pooled plasma, intermediates,
derivatives, and any other material containing plasma from such a donor.
Alternatively, you may save the material for use in research on vCJD by
qualified laboratories (see Section VII.A. for labeling recommendations).
You should not use such material for non-injectable products.
We also recommend that you follow your SOPs or update your SOPs
regarding notifying consignees to immediately retrieve, quarantine, and
subsequently destroy (or arrange for the destruction of) the pooled plasma,

32

Contains Nonbinding Recommendations
intermediates, and derivatives, and any other materials containing plasma
from the vCJD donor. Such notification should occur within one week of
receiving the post-donation information.
b.

Biological Product Deviation Reports

You must submit a BPDR (21 CFR 600.14) if a plasma derivative product
is manufactured using plasma collected from a donor who was diagnosed
with vCJD or suspected vCJD and the product was distributed. The
regulations require you to submit a BPDR as soon as possible but not to
exceed 45 calendar days after you discover the event (21 CFR
606.171(c)).
3.

Plasma derivatives manufactured using plasma from donors with a
physician’s clinical or pathological diagnosis of CJD and age less than 55
years.
a.

Product Disposition

We recommend you contact OBRR, CBER at 240-402-8360 as soon as
possible upon receiving information about a donor’s diagnosis of CJD
when less than 55 years old. We will make recommendations to
quarantine and withdraw plasma derivatives from such donors on a caseby-case basis, depending upon results of the investigation. We may
recommend quarantine and withdrawal of products if available
information is ambiguous and does not clearly eliminate the possibility of
vCJD. You should treat quarantined and withdrawn material from such
donors in the same manner as for vCJD (see Section V.D.).
b.

Biological Product Deviation Reports

You must submit a BPDR (21 CFR 600.14) if a plasma derivative product
is manufactured using plasma collected from a donor with a physician’s
clinical or pathological diagnosis of CJD and age less than 55 years, and
the product was distributed.
The regulations require you to submit a BPDR as soon as possible but not
to exceed 45 calendar days after you discover the event
(21 CFR 600.14(c)).
F.

Disposal of Retrieved and Quarantined Products

TSE agents are quite resistant to most disinfecting regimens. There is no current
consensus on specific details of decontamination requirements for blood products.
However, methods of destruction of TSE-implicated material include steam autoclaving
at 132°C for 1-4 hours, incineration, or treatment with 1 N or 2 N NaOH or concentrated

33

Contains Nonbinding Recommendations
sodium hypochlorite for at least 1 hour. These treatments are known to diminish (but
may not completely eliminate) infectivity (Refs. 71-72). 71 You may save blood
components and plasma derivatives from donors with vCJD, or which have been
withdrawn because the donor might have vCJD, to use in research on vCJD by qualified
laboratories (see Section VII.A. for labeling recommendations).
VI.

RECOMMENDATIONS FOR RECIPIENT TRACING AND NOTIFICATION

It may be appropriate to identify blood components for transfusion prepared from prior
collections from any donor found to have CJD, vCJD, suspected vCJD, risk factors for CJD, or if
withdrawal is recommended in cases under investigation for vCJD (CJD diagnosis and age less
than 55). In those situations, consignee notification could enable the consignee to inform the
physician, or other qualified personnel responsible for the care of the recipients, so that recipient
tracing and medically appropriate notification and counseling may be performed at the discretion
of health care providers.
For transfusible components from a donor with one family member diagnosed with CJD, or with
risk factors for vCJD (due to geographic risk deferral, transfusion in the U.K. or in France
between 1980 and the present, or due to injection of bovine insulin), we believe it is not
appropriate to conduct tracing and notification of recipients of prior donations.
It may be appropriate to identify plasma derivatives prepared from prior collections from any
donor found to have vCJD, suspected vCJD, or if withdrawal is recommended in cases under
investigation for vCJD (CJD diagnosis and age less than 55 years). In those situations,
consignee notification could enable the consignee to inform the physician, or other qualified
personnel responsible for the care of the recipients, so that recipient tracing and medically
appropriate notification and counseling may be performed at the discretion of health care
providers.
VII.

LABELING RECOMMENDATIONS
A.

Labeling of Blood and Blood Components from Deferred Donors for
Research, or Intended for Further Manufacture into Non-Injectable
Products

You should label blood and blood components from donors with CJD, who are at
increased risk for CJD, or who have potential exposure to the agent of vCJD with the
following statements, as appropriate:
•

“Biohazard”;

71

World Health Organization (WHO) Infection Control Guidelines for Transmissible Spongiform Encephalopathies
at http://www.who.int/csr/resources/publications/bse/WHO_CDS_CSR_APH_2000_3/en/.

34

Contains Nonbinding Recommendations
•
•

“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 variant CJD”; and
“Caution: For laboratory research use only”; or “Caution: For use in
manufacturing non-injectable products only.” 72

You should not use blood or blood components from donors diagnosed with vCJD for
further manufacture into non-injectable products. However blood components and
plasma derivatives from donors with vCJD, suspected vCJD, or which have been
withdrawn on a case-by-case basis for suspicion of vCJD, may be used in laboratory
research on vCJD by qualified laboratories. You should label these products with the
following statements:
•
•
•
B.

“Biohazard”;
“Collected from a donor with variant CJD”; and
“Caution: Only for laboratory research on variant CJD.”
Labeling of Non-Implicated Products

As a prudent notice, we recommend that all blood, blood components, and plasmaderived products include labeling to address the possible risk of transmission of vCJD
and CJD. 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, the package insert for albumin, and products containing albumin,
may contain a more specific statement:
1.

For Whole Blood and blood components intended for transfusion, the
instruction circular should include the following warning statement:
“Because Whole Blood and blood components are made from human
blood, they may carry a risk of transmitting infectious agents (e.g.,
viruses, bacteria, parasites, the variant Creutzfeldt-Jakob disease
(vCJD) agent, and, theoretically, the Creutzfeldt-Jakob disease (CJD)
agent.” 73

72

Donors who are otherwise deferred based upon donor deferral criteria 2 through 8 of this guidance, may continue
to donate if they are participating in a CBER approved program that allows collection of Source Plasma solely for
use in manufacturing of non-injectable products (see Section IV.A.).
73
This language is included in the AABB “Circular of Information for the Use of Human Blood and Blood
Components,” dated November 2013, which FDA has recognized as an acceptable mechanism that is consistent with
FDA requirements and recommendations for the labeling of Whole Blood and blood components intended for
transfusion. If you do not utilize the AABB Circular of Information, you may attach the recommended labeling
statement to your current circular until it is revised.

35

Contains Nonbinding Recommendations
2.

For plasma-derived products other than albumin, you should revise the
statement in the Warnings and Precautions section of your labeling 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, the variant CreutzfeldtJakob disease (vCJD) agent and, theoretically, the Creutzfeldt-Jakob
disease (CJD) agent.”

3.

For plasma-derived albumin, you should revise the statement in the Warning
and Precautions section of your labeling 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 and variant
Creutzfeldt-Jakob disease (vCJD). There is a theoretical risk for
transmission of Creutzfeldt-Jakob disease (CJD), but if that risk
actually exists, the risk of transmission would also be considered
extremely remote. No cases of transmission of viral diseases, CJD or
vCJD have ever been identified for licensed albumin.”

4.

For products containing plasma-derived albumin, you should revise the
statement in the Warnings and Precautions section of your labeling 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 and
variant Creutzfeldt-Jakob disease (vCJD). There is a theoretical risk
for transmission of Creutzfeldt-Jakob disease (CJD), but if that risk
actually exists, the risk of transmission would also be considered
extremely remote. No cases of transmission of viral diseases, CJD or
vCJD have ever been identified for licensed albumin or albumin
contained in other licensed products.”

VIII. IMPLEMENTATION OF RECOMMENDATIONS
We recommend that you implement the new recommendations contained in this guidance, (i.e.,
those recommendations related to labeling of plasma-derived products, including albumin and
products containing plasma-derived albumin), within six months of publication of this
guidance. 74 Manufacturers must submit the labeling change to FDA in accordance with
21 CFR 601.12(f)(2).
74

As stated in the 2010 guidance, all recommendations contained therein should have been implemented no later
than November 2010.

36

Contains Nonbinding Recommendations

IX.

THE IMPACT OF GEOGRAPHIC DONOR DEFERRALS THAT ARE MORE
STRINGENT THAN THOSE RECOMMENDED BY THIS GUIDANCE

A more stringent geographic donor deferral policy (deferral for a cumulative period of six
months or more in Europe since 1980 or a cumulative period of three months or more in the U.K.
since 1980) was proposed as an initiative in early 2001 by a member of the blood industry.
Based upon the BSE geographic relative risk model proposed by the FDA and CDC and
reviewed by the TSEAC in 2001, both the industry-proposed and FDA-proposed deferrals
resulted in an estimated one-log reduction of theoretical risk. Importantly, the donor loss for the
industry proposal, if implemented on a national basis, was estimated by FDA to be at least 8-9%
(3-4% higher than the FDA-recommended policy announced in January 2002). Some countries
have recommended deferring donors who received transfusions in countries other than the U.K.
and France (Ref. 58). Some authorities have noted that potential exposure of some U.S. military
personnel residing in certain bases in Europe to the BSE agent between 1980-1996 might have
exceeded that in France and suggested that persons transfused with their blood also be deferred
as blood donors.
FDA’s recommendations for donor deferral related to risk of CJD and vCJD are based on our
current consideration of the relative benefits of risk reduction compared with the potential
adverse effects of a decrease in availability of the blood supply, and may be updated in the future
as better scientific information becomes available. Nevertheless, we recognize that some blood
establishments may wish to implement geographic donor deferrals that are more stringent than
the FDA-recommended policy. We are concerned that blood availability may be more severely
affected by periods of deferral more stringent than those outlined by this guidance. If you wish
to implement donor deferrals other than those recommended in this guidance, consider strategies
for offsetting projected donor losses and maintaining an adequate blood supply to meet hospital
demands for blood products.

37

Contains Nonbinding Recommendations
X.

SOURCES OF ADDITIONAL INFORMATION
Subject

Contact

FDA policies on CJD, Division of Emerging and Transfusion-Transmitted Diseases, OBRR, CBER at
vCJD and BSE exposure
240-402-8360
This guidance and FDA
policies for
implementing acceptable
DHQ documents

Division of Blood Components and Devices, OBRR, CBER at 301-402-8360

Receipt of post-donation
information about a
donor with vCJD,
suspected vCJD or CJD
and under age 55.

Division of Blood Components and Devices, OBRR, CBER at 240-402-8360

The vDHQ-1.3 or other
AABB DHQ documents

AABB at 301-907-6977, attention of the AABB Donor History Task Force

DHQ documents that
FDA has recognized as
acceptable

http://www.fda.gov/BiologicsBloodVaccines/BloodBloodProducts/Approved
Products/LicensedProductsBLAs/BloodDonorScreening/ucm164185.htm.

Biological product
deviation reporting

Division of Inspections and Surveillance, OCBQ, CBER,
at 240-402-9160
or by email at
http://www.accessdata.fda.gov/scripts/email/cber/bpdrcontact.cfm.

38

Contains Nonbinding Recommendations
XI.

REFERENCES

1.

DeArmond, S. J. and S. B. Prusiner (1995). “Etiology and pathogenesis of prion
diseases.” Am J Pathol 146(4): 785-811.

2.

Masters, C. L., J. O. Harris, et al. (1979). “Creutzfeldt-Jakob disease: patterns of
worldwide occurrence and the significance of familial and sporadic clustering.” Ann
Neurol 5(2): 177-88.

3.

Chesebro, B. (1998). “BSE and Prions: Uncertainties About the Agent.” Science
279(5347): 42-3.

4.

Erdtmann, R. and L. Sivitz, Eds. (2001). Advancing Prion Science. Guidance for the
National Prion Research Program (Institute of Medicine, U.S. Committee on
Transmissible Spongiform Encephalopathies. Assessment of Relevant Science).
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5.

Chesebro, B. (2003). “Introduction to the transmissible spongiform encephalopathies or
prion diseases.” Br Med Bull 66: 1-20.

6.

Manuelidis, L., Z. X. Yu, et al. (2007). “Cells infected with scrapie and Creutzfeldt-Jakob
disease agents produce intracellular 25-nm virus-like particles.” Proc Natl Acad Sci U S
A 104(6): 1965-70.

7.

Prusiner, S. B. (1982). “Novel proteinaceous infectious particles cause scrapie.” Science
216: 136-144.

8.

Croes, E. A., G. Roks, et al. (2002). “Creutzfeldt-Jakob disease 38 years after diagnostic
use of human growth hormone.” J Neurol Neurosurg Psychiatry 72(6): 792-3.

9.

Collinge, J., J. Whitfield, et al. (2006). “Kuru in the 21st century--an acquired human
prion disease with very long incubation periods.” Lancet 367(9528): 2068-74.

10.

Will, R. G., J. W. Ironside, et al. (1996). “A new variant of Creutzfeldt-Jakob disease in
the UK.” Lancet 347(9006): 921-5.

11.

Cousens, S. N., E. Vynnycky, et al. (1997). “Predicting the CJD epidemic in humans.”
Nature 385(6613): 197-8.

12.

Zeidler, M., E. C. Johnstone, et al. (1997). “New variant Creutzfeldt-Jakob disease:
psychiatric features.” Lancet (London) 350(9082): 908-10.

13.

Zeidler, M., G. E. Stewart, et al. (1997). “New variant Creutzfeldt-Jakob disease:
neurological features and diagnostic tests.” Lancet 350(9082): 903-7.

14.

Ironside, J. W. (1998). “Neuropathological findings in new variant CJD and experimental
transmission of BSE.” FEMS Immunol Med Microbiol 21(2): 91-5.

15.

Cousens, S. N., M. Zeidler, et al. (1997). “Sporadic Creutzfeldt-Jakob disease in the
United Kingdom: analysis of epidemiological surveillance data for 1970-96.” BMJ
315(7105): 389-95.

16.

Zeidler, M., R. J. Sellar, et al. (2000). “The pulvinar sign on magnetic resonance imaging
in variant Creutzfeldt-Jakob disease.” Lancet 355(9213): 1412-8.

39

Contains Nonbinding Recommendations
17.

Collie, D. A., R. J. Sellar, et al. (2001). “MRI of Creutzfeldt-Jakob Disease: imaging
features and recommended MRI protocol.” Clin Radiol 56(9): 726-39.

18.

Hill, A. F., R. J. Butterworth, et al. (1999). “Investigation of variant Creutzfeldt-Jakob
disease and other human prion diseases with tonsil biopsy samples.” Lancet 353(9148):
183-9.

19.

Will, R. G. and R. H. Kimberlin (1998). “Creutzfeldt-Jakob disease and the risk from
blood or blood products.” Vox Sanguinis (Basel) 75(3): 178-80.

20.

Zeidler, M., C. Gibbs, Jr, et al., Eds. (1998). WHO Manual for Strengthening Diagnosis
and Surveillance of Creutzfeldt-Jakob Disease. Geneva, World Health Organization.

21.

Andrews, N. J., C. P. Farrington, et al. (2000). “Incidence of variant Creutzfeldt-Jakob
disease in the UK.” Lancet 356(9228): 481-2.

22.

Ghani, A. C., N. M. Ferguson, et al. (2000). “Predicted vCJD mortality in Great Britain.”
Nature 406(6796): 583-4.

23.

Collinge, J. (1999). “Variant Creutzfeldt-Jakob disease.” Lancet 354(9175): 317-23.

24.

Mead, S., S. Joiner, et al. (2007). “Creutzfeldt-Jakob disease, prion protein gene codon
129VV, and a novel PrPSc type in a young British woman.” Arch Neurol 64(12): 1780-4.

25.

Collinge, J., K. C. Sidle, et al. (1996). “Molecular analysis of prion strain variation and
the aetiology of 'new variant' CJD.” Nature 383(6602): 685-90.

26.

Bruce, M. E., R. G. Will, et al. (1997). “Transmissions to mice indicate that 'new variant'
CJD is caused by the BSE agent.” Nature 389(6650): 498-501.

27.

Manuelidis, E. E., E. J. Gorgacs, et al. (1978). “Viremia in experimental CreutzfeldtJakob disease.” Science 200(4345): 1069-71.

28.

Kuroda, Y., C. J. Gibbs, Jr., Amyx, H. L., et al. (1983). “Creutzfeldt-Jakob disease in
mice: persistent viremia and preferential replication of virus in low-density
lymphocytes.” Infection and Immunity 41: 154-161.

29.

Houston, F., J. D. Foster, et al. (2000). “Transmission of BSE by blood transfusion in
sheep.” Lancet 356(9234): 999-1000.

30.

Hunter, N., J. Foster, et al. (2002). “Transmission of prion diseases by blood transfusion.”
J Gen Virol 83(Pt 11): 2897-905.

31.

Hunter, N. and F. Houston (2002). “Can prion diseases be transmitted between
individuals via blood transfusion: evidence from sheep experiments.” Dev Biol (Basel)
108: 93-8.

32.

Gregori, L., N. McCombie, et al. (2004). “Effectiveness of leucoreduction for removal of
infectivity of transmissible spongiform encephalopathies from blood.” Lancet 364(9433):
529-31.

33.

Brown, P. (2007). “Creutzfeldt-Jakob disease: reflections on the risk from blood product
therapy.” Haemophilia 13 Suppl 5: 33-40.

40

Contains Nonbinding Recommendations
34.

Gibbs, C. J., Jr., A. Joy, et al. (1985). “Clinical and pathological features and laboratory
confirmation of Creutzfeldt-Jakob disease in a recipient of pituitary-derived human
growth hormone.” N Engl J Med 313(12): 734-8.

35.

Thadani, V., P. L. Penar, et al. (1988). “Creutzfeldt-Jakob disease probably acquired from
a cadaveric dura mater graft. Case report.” J. Neurosurg. (Baltimore MD) 69: 766-69.

36.

Asher, D. M., C. L. Masters, et al. (1983). ‘’Familial Spongiform Encephalopathies.’’
Res Publ Assoc Res Nerv Ment Dis 60: 273-91.

37.

Esmonde, T. F., R. G. Will, et al. (1993). “Creutzfeldt-Jakob disease and blood
transfusion.” Lancet 341(8839): 205-7.

38.

Heye, N., S. Hensen, et al. (1994). “Creutzfeldt-Jakob disease and blood transfusion.”
Lancet 343(8892): 298-9.

39.

Wientjens, D. P., Z. Davanipour, et al. (1996). “Risk factors for Creutzfeldt-Jakob
disease: a reanalysis of case-control studies.” American Academy of Neurology 46(5):
1287-1291.

40.

Sullivan, M., L. Schonberger, et al. (1997). “Creutzfeldt-Jakob disease (CJD)
Investigational lookback study.” Transfusion 37 suppl: 2s.

41.

Evatt, B., H. Austin, et al. (1998). “Surveillance for Creutzfeldt-Jakob disease among
persons with hemophilia.” Transfusion 38(9): 817-20.

42.

Lee, C., J. Ironside, et al. (1998). “Retrospective neuropathological review of prion
disease in UK haemophilic patients.” Thromb Haemost 80: 909-11.

43.

van Duijn, C. M., N. Delasnerie-Laupretre, et al. (1998). “Case-control study of risk
factors of Creutzfeldt-Jakob disease in Europe during 1993-95. European Union (EU)
Collaborative Study.” Lancet (London) 351: 1081-85.

44.

Holman, R. C., A. S. Khan, et al. (1996). “Creutzfeldt-Jakob Disease in the United States,
1979-1994: Using national mortality data to assess the possible occurrence of variant
cases.” Emerg Infect Dis 2(4): 333-7.

45.

Brown, P., R. G. Rohwer, et al. (1998). “The distribution of infectivity in blood
components and plasma derivatives in experimental models of transmissible spongiform
encephalopathy.” Transfusion 38(9): 810-16.

46.

Foster, P. R. (1999). “Assessment of the potential of plasma fractionation processes to
remove causative agents of transmissible spongiform encephalopathy.” Transfus Med
9(1): 3-14.

47.

Foster, P. R. (2000). “Prions and blood products.” Ann Med 32(7): 501-13.

48.

Foster, P. R., C. McLean, et al. (2000). “Removal of abnormal prion protein by plasma
fractionation.” Transfus Sci 22(1-2): 53-6.

49.

Foster, P. R., A. G. Welch, et al. (2000). “Studies on the removal of abnormal prion
protein by processes used in the manufacture of human plasma products.” Vox Sang
78(2): 86-95.

41

Contains Nonbinding Recommendations
50.

Reichl, H. E., P. R. Foster, et al. (2002). “Studies on the removal of a bovine spongiform
encephalopathy-derived agent by processes used in the manufacture of human
immunoglobulin.” Vox Sang 83(2): 137-45.

51.

Foster, P. R. (2004). “Removal of TSE agents from blood products.” Vox Sang 87 Suppl
2: 7-10.

52.

Foster, P. R., B. D. Griffin, et al. (2004). “Distribution of a bovine spongiform
encephalopathy-derived agent over ion-exchange chromatography used in the preparation
of concentrates of fibrinogen and factor VIII.” Vox Sang 86(2): 92-9.

53.

Llewelyn, C. A., P. E. Hewitt, et al. (2004). “Possible transmission of variant CreutzfeldtJakob disease by blood transfusion.” Lancet 363(9407): 417-21.

54.

Peden, A. H., M. W. Head, et al. (2004). “Preclinical vCJD after blood transfusion in a
PRNP codon 129 heterozygous patient.” Lancet 364(9433): 527-9.

55.

U.K. Health Protection Agency (2006). “New case of transfusion-associated vCJD.”
Commun Dis Resp CDR Wkly 16: serial online.

56.

Hewitt, P. E., C. A. Llewelyn, et al. (2006). “Creutzfeldt-Jakob disease and blood
transfusion: results of the UK Transfusion Medicine Epidemiological Review study.”
Vox Sang 91(3): 221-30.

57.

Lee, D.C., Streland, J.C., et al. (2001). “A direct relationship between the partitioning of
the pathogenic prion protein and transmissible spongiform encephalopathy infectivity
during the purification of plasma proteins.” Transfusion. 41: 449-55.

58.

Seitz, R., F. von Auer, et al. (2007). “Impact of vCJD on blood supply.” Biologicals
35(2): 79-97.

59.

Gregori, L. and R. G. Rohwer (2007). “Characterization of scrapie-infected and normal
hamster blood as an experimental model for TSE-infected human blood.” Dev Biol
(Basel) 127: 123-33.

60.

Brown, P., L. Cervenakova, et al. (1999). “Further studies of blood infectivity in an
experimental model of transmissible spongiform encephalopathy, with an explanation of
why blood components do not transmit Creutzfeldt-Jakob disease in humans.”
Transfusion 39(11-12): 1169-78.

61.

Brown, P. Rowher, RG, et al. (1998). ”The distribution of infectivity in blood
components and plasma derivatives in experimental models of transmissible spongiform
encephalopathy.” Transfusion. 38(9):810-16.

62.

Dorsey, K., Zou, S., et al. (2009). ”Lack of evidence of transfusion transmission of
Creutzfeldt-Jakob disease in a US surveillance study.” Transfusion. 49: 977-84.

63.

Puopolo, M., Ladogana, A., et al. (2011). ”Transmission of sporadic Creutzfeldt-Jakob
disease by blood transfusion: risk factor or possible biases.” Transfusion. 51: 1556-66.
3004.

64.

Molesworth, A., Mackenzle, J., et al. (2011). “Sporadic Creutzfeldt-Jakob disease and
risk of blood transfusion in the United Kingdom.” Transfusion. 51: 1872-73.

42

Contains Nonbinding Recommendations
65.

Zou, S., C. T. Fang, et al. (2008). “Transfusion Transmission of Human Prion Diseases.”
Transfus Med Rev 22(1): 58-69.

66.

Williams, A. E., R. A. Thomson, et al. (1997). “Estimates of Infectious Disease Risk
Factors in US Blood Donors. Retrovirus Epidemiology Donor Study.” JAMA 277(12):
967-72.

67.

Hill, A. F. and J. Collinge (2003). “Subclinical prion infection.” Trends Microbiol
11(12): 578-84.

68.

Hill, A. F. and J. Collinge (2003). “Subclinical prion infection in humans and animals.”
Br Med Bull 66: 161-70.

69.

Hilton, D. A., A. C. Ghani, et al. (2004). “Prevalence of lymphoreticular prion protein
accumulation in UK tissue samples.” J Pathol 203(3): 733-9.

70.

Ironside, J. W., M. T. Bishop, et al. (2006). “Variant Creutzfeldt-Jakob disease: prion
protein genotype analysis of positive appendix tissue samples from a retrospective
prevalence study.” BMJ 332(7551): 1186-8.

71.

Taylor, D. M., H. Fraser, et al. (1994). “Decontamination studies with the agents of
bovine spongiform encephalopathy and scrapie.” Arch Virol 139(3-4): 313-26.

72.

World Health Organization (1999). “WHO Infection Control Guidelines for
Transmissible Spongiform Encephalopathies.” Report of a WHO consultation, Geneva,
Switzerland, 23-26 March 1999 at
http://whqlibdoc.who.int/hq/2000/WHO_CDS_CSR_APH_2000.3.pdf.

43

Contains Nonbinding Recommendations
APPENDIX: List of European Countries with BSE or at Risk of BSE Applicable to
Donor Deferral
European Countries List to be Used for Deferral of Donors Based on Geographic Risk of BSE 75
Albania, Austria, Belgium, Bosnia-Herzegovina, Bulgaria, Croatia, Czech Republic, Denmark,
Finland, France, Germany, Greece, Hungary, Republic of Ireland, Italy, Liechtenstein,
Luxembourg, Macedonia, Netherlands, Norway, Poland, Portugal, Romania, Slovak Republic,
Slovenia, Spain, Sweden, Switzerland, United Kingdom, and Federal Republic of Yugoslavia.

75

For purposes of this guidance, the United Kingdom should be taken to include all of the following: England,
Northern Ireland, Scotland, Wales, the Isle of Man, the Channel Islands, Gibraltar, and the Falkland Islands; France
should be taken to include its overseas departments (e.g., Martinique and others); Spain should be taken to include
the Canary Islands and Spanish North African territories; Portugal should be taken to include the Azores.

44

Contains Nonbinding Recommendations
APPENDIX TABLE 1: DONOR DEFERRAL, PRODUCT DISPOSITION, RECIPIENT NOTIFICATION FOR WHOLE BLOOD,
BLOOD COMPONENTS INTENDED FOR TRANSFUSION, SOURCE LEUKOCYTES, AND OTHER CELLULAR BLOOD
COMPONENTS INTENDED FOR FURTHER MANUFACTURE

Risk

Deferral

Diagnosed with vCJD or CJD, or
suspected vCJD

Permanent

Risk factors for CJD: Receipt of
pituitary-derived growth hormone,
or dura mater transplant

Permanent

Family history of CJD in >1
family member

CJD in only 1 family member

Indefinite;
reentry if genetic
testing does not
reveal CJDassociated prion
protein allele**
Indefinite;
reentry if genetic
testing does not
reveal CJDassociated prion
protein allele

Recipient Tracing/
Notification

Disposition of Product

BPDR

And Consignee Notification

(21 CFR 606.171)
for previously
distributed product

Immediately retrieve, quarantine, and follow /update
SOPs regarding notifying consignees for all in-date
products and cellular blood components intended for
manufacturing into injectable products.

Yes

Consignee notified,
consignee informs
responsible caretaker
for discretionary
recipient notification,
counseling

Immediately retrieve, quarantine, and follow/update
SOPs regarding notifying consignees for all in-date
products and cellular blood components intended for
manufacturing into injectable products.

Yes*

Consignee notified,
consignee informs
responsible caretaker
for discretionary
recipient notification,
counseling

Immediately retrieve, quarantine, and follow/update
SOPs regarding notifying consignees for all in-date
products and cellular blood components intended for
manufacturing into injectable products.

Yes*

No

* As stated in Section V. of this guidance, a BPDR is not required if components were collected prior to the implementation of donor deferral.
** Note that gene sequencing of the donor is not necessary to demonstrate that the donor is not at risk for familial CJD. Sequencing of the
family member with CJD or the appropriate parent of the donor, if the CJD-affected family member was a second-degree relative, may be
sufficient to demonstrate that the donor does not have a mutation associated with familial CJD.

45

Contains Nonbinding Recommendations

Risk

Deferral

Disposition of Product

BPDR

And Consignee Notification

(21 CFR 606.171)
for previously
distributed product

Recipient Tracing/
Notification

Geographic donor deferrals (U.K.
>3 months 1980-1996; France >5
years 1980-present; military in
Europe as specified)

Indefinite

Immediately retrieve, quarantine, and follow/update
SOPs regarding notifying consignees for all in-date
products and cellular blood components intended for
manufacturing into injectable products.

Yes*

No

Geographic donor deferrals
(Europe other than U.K. >5 years
1980-present)

Indefinite

Immediately retrieve, quarantine, and follow/update
SOPs regarding notifying consignees for all in-date
products and cellular blood components intended for
manufacturing into injectable products.

Yes*

No

Bovine insulin injection

Indefinite, donor
may be reentered after
proof of nonU.K. insulin
source

Immediately retrieve, quarantine, and follow/update
SOPs regarding notifying consignees for all in-date
products and cellular blood components intended for
manufacturing into injectable products.

Yes*

No

Transfusion in U.K. or in France
from Jan 1, 1980 to the present

Indefinite

Immediately retrieve, quarantine, and follow/update
SOPs regarding notifying consignees for all in-date
products and cellular blood components intended for
manufacturing into injectable products.

Yes*

No

46

Contains Nonbinding Recommendations
APPENDIX TABLE 2: DONOR DEFERRAL, PRODUCT DISPOSTION, AND RECIPIENT NOTIFICATION FOR SOURCE
PLASMA (SP), RECOVER PLASMA (RP) AND PLASMA DERIVATIVES (PD)
BPDR
Risk

Deferral

Disposition of Product
And Consignee Notification

Diagnosed with vCJD, suspected
vCJD

Permanent

SP and RP: Immediately retrieve, quarantine, and
follow/update SOPs regarding notifying consignees for
in-date SP and all RP
PD: Immediately retrieve, quarantine, and
follow/update SOPs regarding notifying consignees

Diagnosed with CJD (and age
<55)

Permanent

SP and RP: Immediately retrieve, quarantine, and
follow/update SOPs regarding notifying consignees for
in-date SP and all RP
PD: Disposition decided case-by-case depending upon
investigation results

Diagnosed CJD (and age >55)

Permanent

SP and RP: Immediately retrieve, quarantine, and
follow/update SOPs regarding notifying consignees for
in-date SP and all RP unless plasma known to be
previously pooled
PD: No retrieval, quarantine, consignee notification

47

(21 CFR 606.171
or 600.14) for
previously
distributed
product
SP and RP: Yes
PD: Yes
SP and RP: Yes

Recipient Tracing/
Notification

Consignee notified,
consignee informs
responsible caretaker for
discretionary recipient
notification, counseling
Case-by-case
recommendation,
depending upon
investigation results

PD: Decided upon
case-by-case
SP and RP: Yes

SP and RP: N/A

PD:

PD:

No

No

Contains Nonbinding Recommendations
BPDR
Risk

Deferral

Disposition of Product
And Consignee Notification

Risk factors for CJD: Receipt of
pituitary-derived growth
hormone, or dura mater transplant
Family history of CJD in >1
family member

CJD in only 1 family member

Geographic donor deferrals (U.K.
>3 months 1980-1996; France >5
years 1980-present; military in
Europe as specified, transfusion
in U.K. or France since 1980)

Permanent

SP and RP: Immediately retrieve, quarantine, and
follow/update SOPs regarding notifying consignees for
in-date SP and all RP unless plasma known to be
previously pooled

(21 CFR 606.171,
600.14) for
previously
distributed
product

Recipient Tracing/
Notification

SP and RP:

SP and RP:

Yes*

N/A

PD:

PD:

PD: No retrieval, quarantine, consignee notification

No

No

Indefinite;
reentry if genetic
testing does not
reveal CJDassociated prion
protein allele**

SP and RP: Immediately retrieve, quarantine, and
follow/update SOPs regarding notifying consignees for
in-date SP and all RP unless plasma known to be
previously pooled

SP and RP: Yes*

SP and RP: N/A

Indefinite

SP and RP: Immediately retrieve, quarantine, and
follow/update SOPs regarding notifying consignees for
in-date SP and all RP unless plasma known to be
previously pooled

Indefinite

PD: No
PD: No

PD: No retrieval, quarantine, consignee notification

PD: No retrieval, quarantine, consignee notification

48

SP and RP: Yes*

SP and RP: N/A

PD: No

PD: No

Contains Nonbinding Recommendations
Risk

Deferral

Disposition of Product

BPDR
(21 CFR 606.171,
600.14) for
previously
distributed
product

Geographic donor deferrals
(Europe other than U.K.. >5 years
1980-present)

RP: Indefinite
SP: No deferral

RP: Immediately retrieve, quarantine, and
update/follow SOPs regarding notifying consignees
unless plasma known to be previously pooled
SP: N/A

Consignee
Notification

RP: Yes*

RP: N/A

SP: N/A

SP: N/A

PD: No

PD: No

SP and RP: Yes*

SP and RP:N/A

PD: No

PD: No

PD: No retrieval, quarantine, notification of consignee
Bovine insulin injection

Indefinite

SP and RP: Immediately retrieve, quarantine, and
update/follow SOPs regarding notifying consignees for
all RP and for in-date SP unless plasma known to be
previously pooled
PD: No retrieval, quarantine, notification of consignee

* As stated in Section V. of this guidance, a BPDR is not required if components were collected prior to the implementation of donor deferral.
** Note that gene sequencing of the donor is not necessary to demonstrate that the donor is not at risk for familial CJD. Sequencing of the
family member with CJD or the appropriate parent of the donor, if the CJD-affected family member was a second-degree relative, may be
sufficient to demonstrate that the donor does not have a mutation associated with familial CJD.

49