Deferral of Blood Donors Potentially Exposed to the Agent of Variant Creutzfeldt-Jakob Disease (vCJD)
Spongiform Encephalopathies Advisory Committee (TSEAC)
June 28, 2001
Issue: FDA asks the TSEAC for advice to help decide if deferral of additional blood and plasma donor potentially exposed to the agent of bovine spongiform encephalopathy (BSE) can be safely implemented to reduce further the theoretical risk of transmitting vCJD by blood, blood components and plasma derivatives while maintaining adequate national and regional supplies.
other forms of CJD, in vCJD the abnormal protease-resistant prion protein
accumulates to substantial levels in lymphoid tissues.
This finding raised concern that the relatively reassuring
epidemiological evidence suggesting that blood was unlikely to be an important
vector for classic forms of CJD might not be predictive for vCJD--a disease with
which we still have only limited experience.
date, no epidemiological evidence suggests that vCJD has been transmitted by
blood, blood components or plasma derivatives.
However, animal models suggest that this may be possible (Taylor, 2000;
Houston et al., 2000), and studies of the infectivity of blood from
persons with vCJD, while negative so far, are limited (Brown P, personal
communication, 2001; Baron H,
presented at IBC Annual Biological Safety and Production conference, Vienna VA,
April 2, 2001). Although several
interesting new techniques have been proposed (Miele et al, 2001;
Saborio et al, 2001 among others), there is no validated test to screen
blood donors (Prusiner, 2001; Roos,
1999, concurrent with its issuance of guidance on donor deferral for risk of
vCJD, the FDA was charged by the Surgeon General of the United States to revisit
the issue of blood safety regarding possible transmission of CJD and vCJD as
frequently as needed, but at least every six months.
Uncertainty concerning the potential infectivity of human blood during
the long asymptomatic incubation period of vCJD prompted CBER’s current
policy, first announced in August and in final form in November 1999.
That policy recommended precautionary deferral of donors resident or
traveling in the United Kingdom (UK) for any cumulative period of six months or
more from the presumed start of the BSE epidemic in 1980 to the full
implementation (by the end of 1996) of a series of measures to prevent human
exposure to BSE-contaminated beef by protecting the food chain; those measures
included—in addition to a ban on feeding ruminant materials to other
ruminants, BSE surveillance and herd culling—an “age-based slaughter
scheme” requiring that all cattle used for meat products be slaughtered within
30 months after birth, careful removal of "specified risk materials"
from carcasses, and prohibition of mechanically recovered meat.
Taken together, those measures should have substantially reduced
potential contamination of products intended for human consumption.
FDA policy of November 1999 was intended to defer those donors with the greatest
possible exposure to the BSE agent. FDA
estimated that this deferral would remove almost 87% of the vCJD risk due to UK
exposure (risk expressed as the total number of days that donors were
potentially exposed to the BSE agent in the UK) and would result in a projected
loss of 2.2% of the US blood supply.
January 2001 the TSEAC reviewed information showing increasing numbers of BSE
cases and the recognition of vCJD in France (three cases) and Ireland (one case
in a former UK resident). TSEAC
advised that the FDA recommend deferring--in addition to donors who had been in
the UK for at least six months--anyone who had traveled or lived for ten years
or more in France, based on evidence that during some years of concern, a
substantial part of the French Beef supply had been imported from the UK.
(The number of vCJD cases in France through 2000 was approximately 5% of
those in a population of similar size in the UK, and a rough estimate suggested
that UK beef might have comprised about 5% of French consumption before import
restrictions were imposed.) The
TSEAC also advised deferring donors who had traveled or lived for ten years or
more in Portugal or the Republic of Ireland from 1980 to the present, because
those countries had many cases of BSE in native cattle and may have had
ineffective protection of human food against BSE risk.
The TSEAC further recommended deferrals for those US military personnel
and dependents who had been exposed to UK beef on European bases from 1980
through 1996 for an unspecified period of time longer than six months.
The FDA acknowledges
TSEAC concerns expressed in January 2001, agreeing that risk of transmission of
vCJD is theoretical and that the potential loss of blood donors from increased
deferrals is substantial. The FDA
also understands the reluctance of the TSEAC to lump together in one deferral
policy all 30 countries that, in addition to UK, are on the current USDA BSE
list (USDA, 1998). However, the FDA
has not been convinced that existing information is adequate to justify
recommending a stratified risk-based policy for deferral of donors potentially
exposed to the BSE agent in France, Ireland and Portugal while accepting the
risk of exposure in other continental European countries.
vast majority of BSE cases--more than 180,000--have been diagnosed in the UK;
Britain reported 1352 cases for the year 2000 and 177 through the end of
April of this year (UK MAFF, 2001). Although
Ireland and Portugal indeed had the next highest numbers--613 and 568 cases to
date according to recent OIE figures (June 2001)--BSE cases in Switzerland were
also substantial (382), exceeding the number reported from France (296).
Numbers of BSE cases in cattle born in Germany and Spain to date seem
more modest--75 and 46--but it is troubling that all those cases were found
within the past year. Furthermore, the recent finding of BSE in the Czech Republic
casts some doubt on the ability of available risk assessments to provide
reliable estimates of potential human exposure to BSE agent in various
countries; the Czech Republic is a country to which the EC Scientific Steering
Committee (July 2000) had previously assigned a low probability of BSE.
(The USDA , on which FDA has relied to determine countries with a
significant risk of BSE, placed the Czech Republic—with the rest of Europe
west of the Former Soviet Union—on its BSE list at the end of 1997.)
On this basis, it is difficult for the FDA to be confident that a bright
line can be drawn distinguishing the risk of human exposure to the BSE agent in
France, Ireland and Portugal from risk elsewhere in Europe.
American Red Cross (ARC), which collects approximately half the US blood supply,
has most recently proposed
a precautionary deferral policy considerably more aggressive than that offered
by TSEAC. The policy of the ARC is
to defer donors who lived or traveled for any aggregate period of three months
or more in the UK from 1980 to the present or for six months or more in any
other European country from 1980 to the present.
ARC has announced that it intends to implement the new deferrals
throughout its system in mid-September 2001.
Concluding that the probable donor loss that might result was not
justified in light of current BSE-related risk, TSEAC rejected a similar ARC
proposal (deferring donors who spent ³12
months in Europe from 1980 to present) at its January 2001 meeting.
In light of the fact that ARC collects nearly half the US blood supply,
non-ARC collectors may face legal and public relations pressures to institute
deferral policies similar to that of the ARC.
However, other major blood programs have publicly expressed doubts that
they will be able to meet projected needs for blood if they attempt to follow
the proposed ARC policy.
FDA continues to believe that, until the results of research permit development
of policies based on reliable scientific data, it is prudent to reduce the use
of donors potentially exposed to the BSE agent as much as feasible.
However, the USA must also maintain an adequate supply of safe blood and
blood products, the lack of which would cause immediate harm to the population.
Estimation of Absolute
factors influence the likelihood of transfusion transmission of vCJD by blood
and its components. Those include
Likelihood that donors have been infected by dietary or other exposures
Overall prevalence of the asymptomatic carrier state in the exposed
The length of the pre-clinical incubation period (mean value and range)
Presence of the vCJD agent in blood of infected blood donors (during
various stages of incubation) at levels sufficient to
transmit disease by allogeneic transfusion
Susceptibility of the recipient population to infection
studies of TSE infection in sheep and rodent models support the concept that the
vCJD agent may be transmissible by allogeneic transfusion. However, no data exist regarding the natural history of the
infection in the human host. For
that reason, it is currently impossible to estimate with any confidence the
number of vCJD infections potentially transmitted by transfusion or to model how
intervention strategies would affect the risk.
of Risk Reduction and Donor Loss Based on Cumulative Travel and Residence in BSE
April 1999, a collaborative survey of donor travel was conducted among 12 blood
centers. This survey was primarily
targeted to collection of blood donor travel and residence data for the UK.
Limited information about overall travel to other European BSE countries
was also collected, but country-specific intervals could only be extrapolated
using numerous assumptions. With those assumptions stated, the existing data
have been applied to models that assign various risk ratios relative to the UK
for BSE exposures in different European countries and for exposures on US
military bases in Europe. These
models have been useful to estimate the
additive and cumulative reductions in vCJD risk as well as the donor losses
expected to result from various deferral policies. In the absence of
additional data, estimates derived from this model are dependent upon an
assumption of linearity—that exposures to the BSE agent are stochastic and so
are directly related to time spent in a country where beef products are
contaminated with the BSE agent.
Impact of Additional Blood Donor Deferrals on Blood Supply:
Maintaining adequate blood supplies across the US (the benefit) is a
prime consideration for any proposed deferral option taken to reduce the
theoretical risk of transmitting vCJD. While
the estimated 2.2% donor loss from the initial ³6-month
UK donor deferral, implemented in early 2000, was generally well tolerated
across the country, the US blood supply has never experienced a one-time donor
loss of more than 3.0%. (Such a
loss occurred over a period of two years after donor screening for antibodies to
hepatitis B virus core was introduced in 1986.
The ARC estimated that it may have lost 6% of its donors—or 3% of all
US donors nationwide—after it replaced ear lobe hematocrit testing with
fingerstick testing last year.) Objective
measures to assess adequacy of the US blood supply are currently very limited,
however blood collection and utilization data gathered by the National Blood
Data Resource Center indicate that whole blood collections increased 10.1%
between 1997 and 1999 (at a time of extensive donor recruitment in the news
media). Blood use has also
increased by approximately 4.5% each year.
Such data do not provide information about local availability, which is
affected unevenly by differences in demand, donor demographics and other
York area blood supply.
"Euroblood" comprises approximately 25% of supply in the
greater metropolitan area of New York City, which imports about 145,000 units
from Europe each year. None of this
blood would be available after any pan-European deferral.
In addition, the New York Blood Center anticipates an approximate 10%
loss of donors in the NYC area who are frequent travelers, bringing the
predicted total loss there to 35% or 190,000 units each year.
To date, no assured alternate sources of supply for the New York area
adequate to replace those losses have been identified.
and former US Department of Defense (DoD) personnel and dependents stationed on
European bases since 1980.
Up to 4.5 million DoD service
personnel and dependents were exposed to UK beef supplied to US bases in Europe
between 1980 and 1990 (all bases) and from 1990 through 1996 (on bases South of
the Alps). Based upon DoD
estimates, the maximum exposure of DoD staff and dependents to UK beef during
this time might have been equivalent to 35% of the exposure of UK residents.
Based upon National Center for Health Statistics data about blood donations
among the US population, such individuals are likely to provide approximately
3.0% of the current US blood supply. Deferral of donors who spent six months or
more cumulative on a European DoD base from 1980 through the end of 1996
would cost an estimated 2.2% of US donors.
If screening questions can be designed to eliminate from deferral those
donors who were on bases North of the Alps after 1990, then the overall loss
would be reduced to 1.8% of US donors.
internal blood supply.
DoD currently uses for transfusion 105,000 fully qualified collections
per year. Under a six-month deferral policy, the predicted loss of acceptable
donors is approximately 21 to 24% (from 21,725 to 25,515 donors).
Using major media (newspaper) recruitment campaigns, DoD has already
taken steps to increase donations by the active duty troops about 3% overall. DoD has stated that it is desirable to have a unified BSE
policy and that DoD is prepared to adopt a policy compatible with the ARC
proposal if necessary.
Note that proportions of current active duty troops with potential exposure to
BSE agent in Europe are less than the historical figures used to estimate impact
on the civilian supply due to major reductions in size of the European DoD bases
over the past ten years.
Policy Recommendations and Additional Deferral Options:
CBER concurs with the TSEAC that an extension of the current policy to
defer donors potentially exposed to the BSE agent in the UK is needed.
This policy must address the additional theoretical risk of exposures to
BSE in continental European countries as well as prior exposure of US military
personnel and their dependents to UK beef at European bases.
FDA also shares TSEAC’s concern about the adverse effects that might
result from anticipated losses to the US blood supply and is equally committed
to maintaining adequate supplies of safe blood and blood products.
In this regard, the FDA is already cooperating with the Centers for
Disease Control and Prevention and other agencies in the Department of Health
and Human Services to develop strategies for more effective monitoring of the US
blood supply and for improved recruitment and retention of blood and plasma
donors. (In the past, use of
intensive campaigns to increase donor recruitment and retention as well as
economic incentives attracting blood to regions with insufficient local
supplies, while at least temporarily successful, have entailed substantially
increased costs.) The FDA has also
long encouraged adoption of clinical guidelines for appropriate use of
transfusions both to reduce the occurrence of preventable transfusion-associated
adverse events and to conserve blood. The
potential of such strategies to increase and conserve supplies of blood over
prolonged periods of time is not known.
The FDA asks the TSEAC to consider, taking account of new information
about BSE and vCJD, three options for extending the current policy intended to
reduce the risk of transmitting vCJD by blood and blood products.
FDA has conducted an extensive assessment of the theoretical BSE risk
reduction and estimated donor losses associated with three donor deferral
scenarios described here; they are
summarized and compared with current policy using a “risk-weighted exposure”
model in the attached appendix including a table comparing the three options.
The FDA would also entertain proposals for other donor deferral options
consistent with its overall efforts to reduce the theoretical risk of
blood-borne transmission of vCJD while maintaining adequate national and
regional supplies of human blood and blood products.
We anticipate that, based in part on TSEAC’s advice, the FDA will issue
for comment a proposed revision of its Guidance for Industry and that
implementation will be requested within six months after issuance of a final
revised Guidance. In addition, FDA
will encourage well-designed and well-monitored pilot programs to explore the
feasibility of various deferral options that exceed FDA policy.
#1 (policy consistent with advice offered by TSEAC in January 2001)
donors traveling or resident for any cumulative period of ten years or more in
France, Portugal, or the Republic of Ireland from 1980
to the present.
traveling or resident for any cumulative period of six months or more in UK
(This would be unchanged from current FDA policy.)
resident for any cumulative period of six months or more on
a European DoD base
from 1980-1996 (or 1980-1990 if all exposure after 1990
was on DoD bases North of the Alps).
Impact: 2.2% donor loss; 44% reduction of current risk; 82% reduction of
If ARC implements its announced policy and some other blood programs follow,
then both donor loss and reductions in risk would be greater than these
Limits donor loss
overall: Euroblood and DoD blood
supply would be only marginally affected.
Deferral is based
upon actual observations and is directly linked to observed BSE exposures in
France, Portugal, and the Republic of Ireland.
questions would allow distinction between exposures on Northern and Southern
European DoD bases.
Policy was previously
recommended by TSEAC.
Limitation of UK
deferral to the years 1980-96 establishes precedent recognizing the protective
value of effective food controls.
Policy is based on
observations that may be biased against deferring for exposure in European
countries with BSE where surveillance has been inadequate.
continued importing of Euroblood, which (assuming a 1.5% risk compared to UK)
carries a substantial level of theoretical risk of exposure.
(Most Euroblood donors have lived in Europe since the beginning of the
Targeting of deferral
policy at specific countries creates a “moving target” probably requiring
rapid introduction of new deferrals as the epidemic involves new countries. The
ability to define risk for individual countries will depend upon BSE and vCJD
data of variable reliability reported by the country involved.
The policy is based
on surveillance and ignores the
fact that BSE is probably under-reported and may already be present elsewhere in
The option would
result in non-uniform national blood donor suitability policies if ARC proceeds
to implement its proposed policy as planned.
questions would be moderately more complex than at present.
There is no
protection against the possibility that the BSE agent has further adapted to
humans who were infected by prior transfusions from donors exposed in UK
Reduction of European
risk is minimal, and most risk reduction gained by the proposed policy would
result from DoD-related deferrals.
#2 (policy proposed by the American Red Cross)
donors for cumulative travel or residence in Europe for any period of six months
or more from 1980 through the present or in
the UK for three months or more from 1980 to the present.
donors who received a transfusion in the UK at any time from 1980 through the
plans to implement the new deferral policy throughout their system in September
Impact: 7.8 to
9.1% donor loss; 76% reduction of current risk;
92% reduction of total risk.
Donor questions would
be straightforward; DoD theoretical risk would be captured without the need for
any separate questions.
There would be a
single national donor suitability policy, presuming that ARC proceeds with its
The policy provides
the most aggressive deferral of non-DoD donors who were in continental Europe
and consequently the most proactive should non-UK Europe prove to be a major
contributor to overall risk of human exposure to BSE.
The policy provides
limited protection against human passage of vCJD from blood of persons who
received a prior transfusion.
The policy is
comparatively inefficient if the risk of human exposure to the BSE agent in
continental Europe is ~1.5% of the risk in the UK as current observations
The impact of the
predicted unprecedented 8 to 9% donor loss is unknown and probably severe,
especially in the New York City metropolitan area and in other urban areas on
both East and West Coasts where donors travel disproportionately more.
The policy appears to
recognize no protective effect on the human food chain by those measures that
have been recommended for implementation by all countries having BSE in cattle.
#3 (FDA proposal)
donors for cumulative travel or residence of five years or more in any European
country except UK from 1980 to the present
donors who spent any cumulative period of three months or more in UK from 1980
through the end of 1996.
donors who spent more than six months on
a European DoD base from 1980 through the end of 1996 (or
1980 through 1990 if all exposure after 1990 was on DoD bases North of the Alps)
any recipient of a blood transfusion in UK from 1980 to the present.
deferrals within six months of final FDA Guidance.
Impact: 4.6 to
5.3% donor loss; 72% reduction of
current risk; 91% reduction of
ARC implements its announced policy and some other blood programs follow, then
donor loss would be greater and reductions in risk would be slightly greater
than these estimates.)
Deferral is based on
current observational BSE data.
The option allows
blood establishments to institute stricter policies cautiously and with the
possibility of relaxing suitability criteria if needed to maintain blood
supplies adequate to meet local needs.
Impact on blood
availability is unknown but estimated to be controllable by instituting both a
national recruitment campaign and a system to monitor adequate blood supply.
The policy attempts
to be proactive by assigning the current ratio of risk for BSE exposure
throughout continental Europe countries as 5% of that in the UK, which is
thought to represent a worst case. (Deferral
is recommended for cumulative five-year residence in continental Europe, a
period that is 20 times the period of three months recommended for deferral of
donors resident in UK.)
will less prone to frequent revisions than if criteria are recommended for
individual countries based on current estimates of BSE.
The policy offers
limited protection against the possibility of increased adaptation of the BSE
agent to humans by previous human-to-human passage via prior transfusion.
The option will
result in a non-uniform national policy if ARC proceeds with current plans.
questions will become more complex than they are now.
The short-term and
long-term effects of the predicted substantial donor losses (from 4% to 6%) on
national and regional supplies are unknown.
P. Bovine spongiform encephalopathy
and variant Creutzfeldt-Jakob disease. Brit
Med J 2001;322:841-844
P, Will RG, Bradley R, Asher DM, Detwiler L.
Bovine spongiform encephalopathy and variant Creutzfeldt-Jakob disease:
background, evolution and current concerns.
Emerging Infectious Diseases 2001;7:6-16
CA. Likely size of the French BSE
epidemic. Nature 2000;408:787-788
Commission. Final opinion of the
Scientific Steering Committee on the geographical risk of bovine spongiform
encephalopathy (GBR). July 6, 2000; available
Houston F, Foster JD, Chong A, Hunter N, Bostock CJ. Transmission of BSE by blood transfusion in sheep. Lancet 2000;356:999-1000
Miele G, Manson J, Clinton M. A novel erythroid-specific marker of transmissible spongiform encephalopathies. Nature Medicine 2001;7:361-364
Office International des Epizooties. Number of reported cases of BSE worldwide (excluding the United Kingdom). OIE Webpage 2001; available at <www.oie.int/eng/info/en_esbmonde.htm>
SB. Shattuck Lecture. Neurodegenerative diseases and prions. New Engl J Med 2001;344:1516-1526
RP. Controlling new prion diseases.
New Engl J Med 2001;344:1548-1551
GP, Permanne B, Soto C. Sensitive
detection of pathological prion protein by cyclic amplification of protein
misfolding. Nature 2001;411:810-813
DM, Fernie K, Reichl HE, Somerville RA. Infectivity
in the blood of mice with a BSE-derived agent.
J Hosp Infect 2000;46:78-79
UK Ministry of Agriculture, Fisheries and Food. BSE status report. MAFF BSE Enforcement Bulletin 2001;58:2
Department of Agriculture, Animal and Plant Health Inspection Service.
Restrictions on the importation of ruminants, meat and meat products for
ruminants, and certain other ruminant products.
Interim rule and request for comments (6
Jan 1998). Federal Register
Department of Health and Human Services, Food and Drug Administration, Center
for Biologics Evaluation and Research. Guidance
for Industry. Revised precautionary
measures to reduce the possible risk of transmission of Creutzfeldt-Jakob
disease (CJD) and new variant Creutzfeldt-Jakob disease (nvCJD) by blood and
blood products. (November) 1999.
CBER Guidance Documents available at <www.fda.gov/cber/guidelines.htm>
Questions for the TSEAC
Do TSEAC members concur with the FDA proposal (Option #3) to defer
additional blood and plasma donors based on potential exposure to the agent of
If not, do TSEAC members advise the FDA to recommend the blood and plasma
donor deferral policy recently proposed by the American Red Cross (Option #2)?
If not, do TSEAC members advise the FDA to recommend the blood and plasma
donor deferral policy proposed by the TSEAC on 18 January 2001 (Option #1)?
If not, do TSEAC members advise FDA to recommend some other revised
policy to reduce further the risk of blood-borne transmission of vCJD while
maintaining adequate regional and national supplies of blood and blood products?
Please comment on steps that should be taken to monitor and ensure
adequate national and regional supplies of blood, blood components and plasma
derivatives if additional donors are deferred based on possible exposures to BSE
Issue 1 Summary: Appendix
June 28, 2001
of Blood Donors Potentially Exposed to the Agent of vCJD:
risk reduction and donor loss estimates
based upon a FDA/CDC-proposed
Risk-weighted exposure day model**
7.8 - 9.1%
9.7 - 8.4
4.6 - 5.3%
15.7 - 13.6
Total risk is defined as total estimated BSE risk burden to the US blood supply
prior to any intervention. (See model explanation below.)
Current risk is defined as total estimated BSE risk minus the component of UK
risk removed by the November 1999 deferral for ³6
loss is the additive loss for a modified deferral policy (i.e. not including the
previous 2.2% donor loss). Projected
loss includes Euroblood loss (1.2%) for all proposed pan-European deferrals
is defined as % current risk reduction / % donor loss
January 2001 TSEAC-recommended
deferral for >10 yr
France or Portugal or Republic of Ireland 1980-present; >6 mo time
spent on DoD European base 1980-1996
plans to implement deferral for all donors who have spent >3
mo in UK 1980-present and/or 6 mo in Europe 1980-present
proposes deferral for >6 mo
time spent on DoD European base 1980-1996; >3 mo.
travel/residence in the UK 1980-1996; >5
yr travel/residence in Europe 1980-present, and deferral for any transfusion in
the UK 1980-present
Notes: FDA/CDC proposed risk model:
= 1.0; France = 0.05; Other Europe = 0.015; DoD
The UK has experienced the greatest impact from both BSE and vCJD and is the
reference value for other geographic exposures. There were an estimated 998,064 person-years (P-Y) exposure
to the current US blood supply, based on travel/residence patterns measured by
the 1999 blood donor travel survey. A total of
868,316 P-Y (87%) were removed by the 1999 >6
mo UK travel/residence deferral.
A 5% risk of BSE is estimated for France (compared to UK) based upon reports of
extensive shipments of UK beef to France during the years 1980-1996 and the
recognition of two known (and one probable) vCJD cases. (35,580 P-Y)
UK beef shipments to other parts of Europe are less well documented, and BSE
exposures for other European countries are estimated primarily by observed BSE
in indigenous herds. Switzerland
has experienced high rates of BSE, and surveillance in Switzerland has been
intensive. The herd size-adjusted
BSE rate in Switzerland is 1.5% that of the UK.
As a worst-case scenario, all European countries other than France have
been assigned a 1.5% risk level. (19,155 P-Y European travel/residence estimated
from 1999 donor travel survey + 45,150 P-Y estimated for annual
imports of Euroblood).
Department of Defense European-base risk (35%) is estimated from DoD-supplied
data regarding UK beef shipped to European bases (North of Alps1980-1990; South
of Alps 1980-1996 yielding Total: 172,625 P-Y)