Issue Summary

Transmissible Spongiform Encephalopathies Advisory Committee

16^th^ Meeting

Oct 14, 2004

Silver Spring, Maryland

> Topic #6. Consideration of Current FDA-Recommended Safeguards to
> Reduce the Possible Risk of Transmission of Creutzfeldt-Jakob Disease
> (CJD) and Variant Creutzfeldt-Jakob Disease (vCJD) by Blood and Blood
> Products

**Issue**

FDA seeks advice from the FDA Transmissible Spongiform Encephalopathies
(TSE) Advisory Committee (TSEAC) on whether recent data regarding vCJD
warrant consideration of the need for additional safeguards for blood
and blood products.

Background

Most attempts to detect infectivity in blood or serum of animals with
TSEs failed until 1978, when Elias Manuelidis and colleagues
demonstrated the transmissible agent in crude buffy coat preparations of
13 guinea pigs injected with brain material of other guinea pigs with
experimental Creutzfeldt-Jakob disease \[1\], detected throughout most
of the incubation period. Assay guinea pigs had long incubation periods
(some over a year), suggesting that amounts of infectivity in donor
guinea pig blood were probably very small. In 1983, NIH investigators
demonstrated that the blood buffy coats of mice infected with a TSE
agent derived from a patient with the Gerstmann-Sträussler-Scheinker
disease (GSS)---similar to familial CJD---also contained infectivity,
detectable from the middle of the incubation period through terminal
illness \[2\]. The finding of small amounts of TSE infectivity in blood
was later confirmed in a variety of other animals with TSEs \[3-5\],
including sheep with naturally-acquired scrapie \[6\] and experimental
bovine spongiform encephalopathy (BSE) \[7\] and chimpanzees injected
with brain material from a GSS patient \[8\]. Although much infectivity
was associated with nucleated cells \[5, 8-12\], plasma contained
substantial amounts as well \[13\].

During the past 20 years the FDA has made recommendations to the blood
industry intended to reduce the theoretical risk of transmitting the
infectious agents of Creutzfeldt-Jakob disease (CJD) and variant CJD
(vCJD) by blood and blood products. The history of FDA's policies in
this area is summarized in Appendix I. Because no validated screening
tests are available to identify infected units, safety must rely on
precautionary deferrals of donors thought to be at increased risk for
CJD and vCJD and withdrawal of products when post-donation information
reveals that a donor should have been deferred. The Agency, aware of the
uncertainties surrounding the magnitude of the risk, the effectiveness
of available risk-reducing measures, and the potential for contributing
to shortages of life-sustaining blood products, is committed to review
at frequent intervals its policies regarding CJD and vCJD. FDA has taken
a proactive approach in addressing potential risks from CJD and vCJD
consistent with the findings of the Institute of Medicine regarding
decision making that took place for HIV and the blood supply \[14\]. In
particular, FDA blood safety policies regarding CJD and vCJD have
generally been reviewed publicly with the TSE Advisory Committee,
especially when new information suggests that risks should be
reevaluated. Since the last meeting of the TSEAC in Feb 2004, the
following new information on vCJD has come forward.

**Presumptive transmission of vCJD from blood of a second clinically
healthy donor.** The UK Transfusion Medicine Epidemiology Review (TMER)
\[15\] has identified and enrolled 50 recipients of labile blood
components from 16 donors later found to have vCJD in an on-going
look-back" study. (In addition, TMER identified nine vCJD donors who
contributed plasma to 23 pools used for fractionation into derivatives
before 1999.) As of Aug 12, 2004, 13 of 18 surviving recipients of
labile blood components had been enrolled in TMER for at least five
years; thirty-two recipients had died, two with evidence of vCJD.

On 17 Dec 2003 the UK Department of health announced that one recipient
of non-leukoreduced red blood cells had died with vCJD. (The case has
been described in detail \[16\] and was presented at the 15^th^ meeting
of TSEAC \[17\].) In Mar 1996, a clinically healthy young blood donor
donated Whole Blood to the UK National Blood Service. Red blood cell
concentrate---not leukoreduced---was transfused into an older surgical
patient. Three years four months later the donor developed signs of
vCJD, confirmed at autopsy. Six and a half years after the transfusion
the recipient became progressively demented with other neurological
signs and died after 13 months; autopsy revealed vCJD. The recipient was
found to be homozygous for methionine at codon 129 of the
prion-protein-encoding (*PRNP*) gene, as had been all other persons with
vCJD tested. UK authorities estimated the recipient\'s age-adjusted
food-borne risk of vCJD to have been from 1:15,000 to 1:30,000.

In Jul 2004, UK authorities announced that preclinical vCJD had been
diagnosed the previous year in a second person in the TMER cohort. (The
case has been partially described in the medical literature \[18\].) The
second recipient was transfused in 1999 with non-leukoreduced red blood
cells from a clinically healthy donor who developed signs of vCJD 18
months later, confirmed at death in 2001. Five years after transfusion,
the recipient died of a ruptured abdominal aortic aneurysm without signs
of neurological disease. Abnormal prion protein typical of vCJD was
detected at autopsy in several areas of the spleen and in a cervical
lymph node, suggesting that infection was present but had not yet spread
to the brain. It seems highly improbable that two cases of vCJD
resulting from coincidental food-borne transmission would occur by
chance in the small TMER cohort during a short period of time.

**Variant CJD in a person heterozygous for methionine at codon 129 of
the *PRNP* gene.** The second presumptive transfusion-transmitted case
of vCJD was in a person heterozygous for methionine at *PRNP* codon 129
\[18\]---the first time that genotype has been found in any patient with
vCJD to be tested. (As noted above, all other vCJD patients tested have
been homozygous for methionine at *PRNP* codon 129.) Although the case
was preclinical, it seems probable that infection would eventually have
progressed to involve the nervous system had the patient not died of an
unrelated disease. Homozygosity for methionine or valine at *PRNP* codon
129 is known to be over-represented in persons with iatrogenic and
sporadic forms of CJD \[19\], however heterozygotes have not been
completely spared from those diseases. The finding of a
transfusion-transmitted vCJD infection in a heterozygote implies that
such individuals are unlikely to be absolutely resistant to infection
with the BSE agent and that food-borne vCJD cases may be expected in all
*PRNP* genotypes, possibly in smaller numbers and with longer incubation
periods than for homozygous individuals. In any case, persons
heterozygous for methionine/valine at codon 129 of the *PRNP* gene
(comprising about half the population in the UK) appear to be
susceptible to blood-borne infection with human-adapted BSE agent.

New cases of vCJD per annum peaked in the UK in 1999 and deaths in 2000;
only one new case has been reported recently outside the UK \[17\]. The
current total stands at 157 definite or probable cases in UK, three
presumably UK-acquired cases dying outside UK (Canada, Ireland, US),
seven cases thought to have been acquired in France and one in Italy.
The times of residence in and departure from the UK of two cases in
North America suggest that the incubation periods of food-borne vCJD may
be as short as nine years (Will RG, unpublished observation).

Predictions of vCJD infection rates based on finding of abnormal prion
protein in lymphoid tissues of preclinical vCJD.

Shortly after the first descriptions \[20\], it was noted that lymphoid
tissues of a person dying with vCJD (spleen, lymph nodes) contained
detectable amounts of abnormal protease-resistant prion protein
(PrP^sc^) \[21, 22\]. The appendix removed from an otherwise healthy
person who developed signs of vCJD eight months later also contained
PrP^sc^ \[23\], as did another appendix removed two years before onset
(a third removed 10 years before onset was negative) \[24\]; those
fortuitous findings suggested that a survey of archived tonsils and
appendices might provide some estimate of the minimum number of persons
with preclinical vCJD in the UK population. Two such surveys have been
reported to date: the first found one positive appendix among 8318
adequate specimens saved from patients 10 to 50 years old between 1995
and 1999, yielding an estimated rate of 120/million (95% CI, 0.5 --
900/million) in that population \[24\]; the second yielded three
positives among 12,674 appendices for an estimated rate of 237/million
(95% CI, 49 -- 692/million) \[25\]. All tonsils were negative. It is
interesting to note that both tonsils and appendix of the second
presumptive transfusion-transmitted case were negative for PrP^sc^,
attributed to the non-food-borne route of infection \[18\].

# Charge to the TSE Advisory Committee

For many years the FDA and other regulatory authorities \[26\]) have
taken very seriously the theoretical possible transmission of all forms
of CJD by blood products and has advised blood and plasma establishments
to defer donors thought to be at increased risk for CJD.

There have been six general bases for CJD/vCJD-related deferrals \[27\]:

A.  [General CJD risk reduction]{.underline} (1) CJD in a donor, (2)
    history of treatment with pit-hGH or dura mater allograft, and (3)
    history of CJD in a relative unless confirmed to be other than
    familial CJD or the donor *PRNP* genotype is found to be normal

B.  [vCJD risk reduction]{.underline} (1) history of prolonged residence
    in most BSE countries (defined by USDA list of BSE-related import
    prohibitions) currently including UK, France or other European
    countries west of the Former Soviet Union (or residence/employment
    on a US military base in Europe during periods when beef was
    procured from UK), (2) history of transfusion in UK in or after
    1980, and (3) injection with bovine insulin of UK origin in or after
    1980

The FDA CJD/vCJD blood safety policies have been recommended to reduce
the risk that a donor might be incubating CJD of any kind while not
deferring so many donors as to compromise the supply of blood products.
The TSEAC is now asked to consider whether the CJD/vCJD deferral
policies currently recommended by FDA to protect the safety of the blood
supply remain justified and, if so and considering recent additional
information about BSE and vCJD, they are still adequate. If TSEAC
considers any current policy inadequate, FDA solicits its advice in
suggesting enhancements to existing policies or possible additional
policies that might reduce the risk further without jeopardizing an
adequate supply of life-sustaining and health-sustaining blood products.

# Questions for the Committee

1.  Are the measures currently recommended by FDA to reduce the risk of
    transmitting CJD and vCJD by blood and blood products still
    justified?

2.  Do the recent scientific data on vCJD warrant consideration by FDA
    of any additional potentially risk-reducing measures for blood and
    blood products?

3.  If so, please comment on the additional potentially risk-reducing
    measures that FDA should consider at this time.

# Appendix I

## History of FDA Policy Making

**Regarding Risk of Transmitting CJD and vCJD by Transfusion**

In Aug 1983, FDA learned that a US blood donor had been diagnosed with
CJD; in-date components and plasma derivatives were voluntarily
withdrawn. Over the next 12 years there were nine other CJD-related
voluntary withdrawals of US blood products. In Nov 1987, FDA, aware that
TSE infectivity had been found in animal blood and concerned about a
growing number of iatrogenic cases of CJD among people treated with
injections of human cadaveric pituitary growth hormone (pit-hGH), issued
a memorandum recommending precautionary deferral of blood donors
previously treated with pit-hGH---acknowledging a concern about
potential transmission of CJD by products from blood of clinically
normal at-risk donors \[28\]. In subsequent years, FDA recommended
deferral of other donors thought to be at increased risk for CJD:
recipients of dura mater grafts and people with a family history of CJD.
In Aug 1995 \[29\], FDA also recommended---in addition to donor
deferrals---precautionary withdrawal of blood, blood components, and
plasma derivatives \[30\] from donors recognized post-donation to have
CJD or to be at increased risk for iatrogenic or familial CJD.

After a public announcement in Sept 1998 (and in guidance published in
Aug 1999 for immediate implementation with a request for comment and in
revised form in Nov 1999 \[31\]), FDA no longer recommended withdrawal
of plasma derivatives from donors at increased risk for most forms of
CJD, for several reasons: (1) epidemiological studies failed to find
that transfusion with human blood or components or treatment with plasma
derivatives was a risk factor for sporadic CJD (summarized most recently
at the 15^th^ meeting of the FDA TSE Advisory Committee \[32\](2) the
very large pools of plasma used to prepare derivatives have a high
probability of containing a contribution from a donor incubating CJD
33\], because CJD has a lifetime risk of one in nine thousand persons
with long silent incubation periods, sometimes exceeding 38 years
\[34\], and it is not possible to identify those donors; (3) in
experimental spiking studies, the processes used to fractionate plasma
have demonstrated a substantial capacity to reduce if not eliminate the
infectivity of TSE agents from most final products \[35\] (though only
modestly effective for factor VIII ), and (4) withdrawals, while
possibly reducing a theoretical risk of transmitting CJD, were thought
to contribute to shortages of some plasma derivatives. However, FDA has
continued to recommend deferring donors at increased risk for all forms
of CJD and to retrieve in-date components when post-donation information
revealed that donors either developed CJD or should have been deferred
because they had an increased risk for CJD \[27\].

While no longer recommending withdrawal of plasma derivatives from
CJD-at-risk donors, FDA has continued to recommend withdrawals of all
plasma derivatives prepared from pools to which any donor later
diagnosed with vCJD contributed; fortunately, that has never been
necessary in the US, although donors who later became ill with vCJD have
contributed to pools used in the manufacture of plasma derivatives in
other countries \[36\]---thus far without evidence of transmission.
(Some recipients of plasma derivatives in the UK \[15\] were recently
notified of the results of an assessment exercise to estimate the
potential risk \[37\].)

FDA was more concerned about the theoretical possibility of transmitting
vCJD than other forms of CJD via plasma derivatives because vCJD has an
age distribution, clinical presentation and course of illness,
histopathology and pathogenesis substantially different from those of
other forms of CJD \[20\], and experience with vCJD is much more
limited. Hence, the reassuring epidemiological studies that failed to
implicate blood products as a risk factor for other forms of CJD might
not be predictive for vCJD. For those reasons, FDA concluded that
additional precautionary steps were justified to reduce the risk of
transmitting vCJD by transfusion of blood components or injection of
plasma derivatives. In Aug and Nov 1999 \[31\] following discussions in
TSEAC on Dec 18, 1998 \[38\]\] and using information from a travel
survey of blood donors \[39, 40\], FDA recommended that blood
establishments defer blood donors who had spent six months or more in
the UK from the start of 1980 (estimated to be a probable earliest date
when a significant number of cattle were infected with the BSE agent in
the UK) and the end of 1996 (when UK fully implemented a variety of
measures to control BSE and prevent human exposure to the BSE agent
\[41\]. That geographically based policy was estimated to reduce
exposure to the BSE agent (as total days spent by blood donors in UK) by
about 87%, while predicted to defer about 2.2% of US blood donors
\[40\]).

As diagnosed cases of vCJD continued to increase in the UK and former UK
residents in other countries and several cases were reported in
residents of France (currently seven) and Italy (one), affecting persons
who had not visited the UK, FDA, on advice of TSEAC, issued a second
Guidance for Industry reducing the recommended time that suitable donors
might have spent in the UK to three months and broadening the range of
countries considered to pose a risk of exposure to the BSE agent
sufficient to justify deferring donors who had spent substantial time
there \[27\]. The acceptable maximum times that otherwise suitable
donors might have spent in those other countries were adjusted to
reflect risks relative to that in the UK, where the both BSE and vCJD
epidemics were the largest: (1) US military bases in Europe were
estimated to have about one-third the risk of UK during periods when up
to a third of the beef used there was procured from UK. (The recommended
acceptable time spent on affected military bases was six months, to
provide an additional margin of safety.) (2) France was estimated to
have about 5% of the UK risk, because at least 5% of beef products
consumed in France until the early 1990s were thought to have been
imported from UK, and, at that time, the number of cases of vCJD in
France was about 5% of those in UK, while both countries had roughly
similar populations. (3) Other European countries were assigned a
nominal BSE risk based on BSE surveillance data from Switzerland,
estimated to be about 1.5% of UK risk; although it seemed likely that a
number of countries might have actual risks lower than that of
Switzerland, the quality of their BSE surveillance was uncertain.

In addition, FDA, concerned about UK blood donors who might be
incubating vCJD and a theoretical possibility of further adaptation of
the BSE agent to replicate in humans after a transmission by blood, also
recommended deferring anyone who had received a blood transfusion in the
UK after 1979. No deferrals of donors transfused in France other BSE
countries were recommended, however, because the risk of BSE infections
of humans was so much lower there. FDA also recommended deferring donors
who had been treated with bovine insulin from the UK in or after 1980.
(Those and other CJD/vCJD-related policies recommended for donors of
Whole Blood are summarized in Table 1 of the Jan 2002 Guidance Document
\[27\].)

The policies recommended for donors of Source Plasma (apheresis plasma)
were somewhat different from those for blood (Table 2 \[27\]). FDA did
not recommend deferring donors of Source Plasma for any period of
residence in BSE countries other than in the UK and France. (FDA
recommended that recovered plasma be treated like all other components
so as to discourage the intentional collection of Whole Blood from
deferred donors.)

The modified donor deferral policy was estimated to reduce the overall
BSE-related risk by 91% (72% of the risk remaining after implementation
of the 1999 policies), with a final overall donor loss of 4.6-5.3%;
however, considerable geographic variation was expected, including
potentially higher donor losses in coastal states and near military
bases. (If blood establishments were to be more aggressive in their
deferral policies, then both overall donor loss and risk reduction might
be higher.) Implementation was recommended in two stages, to be
completed by Oct 21, 2002. Because of normal variability in blood
donations, probable self deferrals by some donors, encouragement of
increased donations by repeat donors, and active recruitment of new
donors by blood programs, it has not been possible to evaluate the
actual effects of the new policies on the blood supply, except to
conclude that obvious shortages have not resulted.

In a joint meeting of the TSEAC and Blood Products Advisory Committee
(BPAC) on Jan 17, 2002 \[42\], FDA solicited advice on whether food
chain controls to prevent human exposure to BSE implemented in the UK
since 1996 were sufficient to obviate a need to defer blood and plasma
donors based on their subsequent travel or residence there. The reason
for review was that a major US blood program had begun to defer blood
donors based on time they spent in UK not only after 1980 through 1996
but also after 1996 to the present. The measures thought to be effective
in protecting humans from food-borne exposures to BSE agent in the UK
were BSE control in ruminants[^1] and a number of steps to reduce the
likelihood that infectivity present in cattle with unrecognized BSE
would enter the food chain[^2].

In subsequent meetings of the TSEAC, FDA has acknowledged that three
other countries had BSE in native-born cattle: Canada (two cows, one
resident in USA at time of diagnosis), Israel (one cow), and Japan (12
cows). The FDA was unable to estimate either the potential risk
reduction or the effect on the blood supply of deferring residents in
those countries, and the TSEAC did not suggest deferring donors for any
period of residence in those countries; therefore the FDA did not
recommend deferring donors who lived in or spent time in those
countries.

**Appendix II.**

**TABLE 1 (From Reference \[27\]): 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**  | **De     | **Disposition of  | *      | **Recipient     |
|           | ferral** | Product**         | *BPDR\ | Tracing         |
|           |          |                   | (21    | /Notification** |
|           |          |                   | CFR    |                 |
|           |          |                   | 606    |                 |
|           |          |                   | .171)\ |                 |
|           |          |                   | if     |                 |
|           |          |                   | prev   |                 |
|           |          |                   | iously |                 |
|           |          |                   | distr  |                 |
|           |          |                   | ibuted |                 |
|           |          |                   | pro    |                 |
|           |          |                   | duct** |                 |
+-----------+----------+-------------------+--------+-----------------+
| Diagnosed | P        | Immediately       | Yes    | Consignee       |
| with      | ermanent | retrieve,         |        | notified,       |
| vCJD, or  |          | quarantine/notify |        | consignee       |
| suspected |          | consignees for    |        | informs         |
| vCJD,     |          | all in-date       |        | responsible     |
| CJD, or   |          | products and all  |        | caretaker for   |
| CJD and   |          | out-of-date       |        | discretionary   |
| age \<55  |          | cellular blood    |        | recipient       |
| years     |          | components        |        | notification,   |
|           |          | intended for      |        | counseling      |
|           |          | manufacturing     |        |                 |
|           |          | into injectable   |        |                 |
|           |          | products.         |        |                 |
+-----------+----------+-------------------+--------+-----------------+
| Risk      | P        | Immediately       | Yes    | Consignee       |
| factors   | ermanent | retrieve,         |        | notified,       |
| for CJD:  |          | quarantine/notify |        | consignee       |
| Receipt   |          | consignees for    |        | informs         |
| of        |          | all in-date       |        | responsible     |
| pituitar  | Ind      | products and all  |        | caretaker for   |
| y-derived | efinite; | out-of-date       |        | discretionary   |
| growth    | reentry  | cellular blood    |        | recipient       |
| hormone,  | if       | components        |        | notification,   |
| or dura   | genetic  | intended for      |        | counseling      |
| mater     | testing  | manufacturing     |        |                 |
| t         | does not | into injectable   |        |                 |
| ransplant | reveal   | products.         |        |                 |
|           | CJD-as   |                   |        |                 |
| Family    | sociated |                   |        |                 |
| history   | prion    |                   |        |                 |
| of CJD in | protein  |                   |        |                 |
| \>1       | allele   |                   |        |                 |
| family    |          |                   |        |                 |
| member    |          |                   |        |                 |
+-----------+----------+-------------------+--------+-----------------+
| CJD in    | Ind      | Immediately       | Yes    | No              |
| only 1    | efinite; | retrieve,         |        |                 |
| family    | reentry  | quarantine/notify |        |                 |
| member    | if       | consignees for    |        |                 |
|           | genetic  | all in-date       |        |                 |
|           | testing  | products and all  |        |                 |
|           | does not | out-of-date       |        |                 |
|           | reveal   | cellular blood    |        |                 |
|           | CJD-as   | components        |        |                 |
|           | sociated | intended for      |        |                 |
|           | prion    | manufacturing     |        |                 |
|           | protein  | into injectable   |        |                 |
|           | allele   | products.         |        |                 |
+-----------+----------+-------------------+--------+-----------------+

**TABLE 1 (From Reference \[27\]): Continued**

  ------------------------ -------------- --------------------- ---------------- ------------------------
  **Risk**                 **Deferral**   **Disposition of      **BPDR\          **Recipient
                                          Product**             (21 CFR          Tracing/Notification**
                                                                606.171)\        
                                                                if previously    
                                                                distributed      
                                                                product**        

  **Phase I** Geographic   Indefinite     Immediately retrieve, No - if prior to No
  donor deferrals                         quarantine/notify     deferral         
  (U.K.[\>]{.underline}3                  consignees for all    implementation   
  months 1980-1996; France                in-date products and                   
  [\>]{.underline}5 years                 all out-of-date                        
  1980-present; military                  cellular blood                         
  in Europe as specified,                 components intended                    
  transfusion in U.K.                     for manufacturing                      
  since 1980)                             into injectable                        
                                          products.                              

                                                                Yes - if after   
                                                                deferral         
                                                                implementation   

  **Phase II** Geographic  Indefinite     Collected prior to    No - if prior to No
  donor deferrals (Europe                 deferral              deferral         
  [\>]{.underline}5 years                 implementation - No   implementation   
  1980-present)                           retrieval,                             
                                          quarantine, consignee                  
                                          notification                           

                                          Collected after       Yes - if after   
                                          deferral              deferral         
                                          implemented -         implementation   
                                          Immediately retrieve,                  
                                          quarantine/notify                      
                                          consignees for all                     
                                          in-date products and                   
                                          all out-of-date                        
                                          cellular blood                         
                                          components intended                    
                                          for manufacturing                      
                                          into injectable                        
                                          products.                              

  Bovine insulin injection Indefinite,    Immediately retrieve, Yes              No
                           donor reentry  quarantine/notify                      
                           if proof of    consignees for all                     
                           non-U.K.       in-date products and                   
                           insulin source all out-of-date                        
                                          cellular blood                         
                                          components intended                    
                                          for manufacturing                      
                                          into injectable                        
                                          products.                              
  ------------------------ -------------- --------------------- ---------------- ------------------------

**TABLE 2 (Modified from Reference \[27\]): Donor Deferral, Product
Disposition, and Recipient Notification for Plasma and Plasma
Derivatives**

+---------------+-----+---------------------+-----------+-------------+
| **Risk**      | **D | **Disposition of    | **BPDR\   | **Recipient |
|               | efe | Product**           | (21 CFR   | Tracing/Not |
|               | rra |                     | 606.171)\ | ification** |
|               | l** |                     | if        |             |
|               |     |                     | p         |             |
|               |     |                     | reviously |             |
|               |     |                     | di        |             |
|               |     |                     | stributed |             |
|               |     |                     | product** |             |
+---------------+-----+---------------------+-----------+-------------+
| **Phase I**   | I   | SP and RP:          | No - if   | No          |
| Geographic    | nde | Collected prior to  | prior to  |             |
| donor         | fin | deferral            | deferral  |             |
| deferrals     | ite | implementation- No  | imple     |             |
| (U.K.         |     | retrieval,          | mentation |             |
| [\>]          |     | quarantine,         |           |             |
| {.underline}3 |     | consignee           |           |             |
| months        |     | notification        |           |             |
| 1980-1996;    |     |                     |           |             |
| France        |     |                     |           |             |
| [\>]          |     |                     |           |             |
| {.underline}5 |     |                     |           |             |
| years         |     |                     |           |             |
| 1980-present; |     |                     |           |             |
| military in   |     |                     |           |             |
| Europe as     |     |                     |           |             |
| specified,    |     |                     |           |             |
| transfusion   |     |                     |           |             |
| in U.K. since |     |                     |           |             |
| 1980)         |     |                     |           |             |
+---------------+-----+---------------------+-----------+-------------+
|               |     | SP and RP:          | Yes- if   |             |
|               |     | Collected after     | after     |             |
|               |     | deferral            | deferral  |             |
|               |     | implementation -    | imple     |             |
|               |     | Immediately         | mentation |             |
|               |     | retrieve,           |           |             |
|               |     | quarantine, notify  |           |             |
|               |     | consignees of       |           |             |
|               |     | in-date SP and all  |           |             |
|               |     | RP unless known to  |           |             |
|               |     | be previously       |           |             |
|               |     | pooled              |           |             |
+---------------+-----+---------------------+-----------+-------------+
|               |     | PD: No retrieval,   | No        |             |
|               |     | quarantine,         |           |             |
|               |     | consignee           |           |             |
|               |     | notification        |           |             |
+---------------+-----+---------------------+-----------+-------------+
| **Phase II**  | No  | SP: *All phase I    | Not       | No          |
| Geographic    | de  | deferrals remain in | A         |             |
| donor         | fer | place,* e.g., U.K.  | pplicable |             |
| deferrals     | ral | [\>]{.underline} 3  |           |             |
| (Europe       |     | months 1980-1996;   |           |             |
| [\>]          |     | France              |           |             |
| {.underline}5 |     | [\>]{.underline} 5  |           |             |
| years         |     | years 1980-present; |           |             |
| 1980-present) |     | military in Europe  |           |             |
|               |     | as specified;       |           |             |
|               |     | transfusion in the  |           |             |
|               |     | U.K. since 1980.    |           |             |
| SP            |     | There is no Phase   |           |             |
|               |     | II deferral for SP. |           |             |
+---------------+-----+---------------------+-----------+-------------+
| **Phase II**  | I   | RP: Collected prior | No- if    |             |
| Geographic    | nde | to deferral         | collected |             |
| donor         | fin | implementation- No  | prior to  |             |
| deferrals     | ite | retrieval,          | deferral  |             |
| (Europe       |     | quarantine,         | imple     |             |
| [\>]          |     | consignee           | mentation |             |
| {.underline}5 |     | notification        |           |             |
| years         |     |                     |           |             |
| 1980-present) |     |                     |           |             |
|               |     |                     | Yes - if  |             |
|               |     |                     | collected |             |
|               |     |                     | after     |             |
| RP            |     |                     | deferral  |             |
|               |     |                     | imple     |             |
|               |     |                     | mentation |             |
+---------------+-----+---------------------+-----------+-------------+
|               |     | RP: Collected after |           |             |
|               |     | deferral            |           |             |
|               |     | implementation:     |           |             |
|               |     | Immediately         |           |             |
|               |     | retrieve,           |           |             |
|               |     | quarantine, notify  |           |             |
|               |     | consignees for all  |           |             |
|               |     | RP unless known to  |           |             |
|               |     | be previously       |           |             |
|               |     | pooled              |           |             |
+---------------+-----+---------------------+-----------+-------------+
|               |     | PD: No retrieval,   | No        |             |
|               |     | quarantine,         |           |             |
|               |     | consignee           |           |             |
|               |     | notification        |           |             |
+---------------+-----+---------------------+-----------+-------------+

Abbreviations: SP, Source Plasma; RP, recovered plasma; PD, plasma
derivatives; BPDR, Biological Products Deviation Report

Table 2 (Modified from Reference \[27\]) Continued

+-------------+-----------+---------------+--------+------------------+
| **Risk**    | **D       | **Disposition | *      | **Recipient      |
|             | eferral** | of Product**  | *BPDR\ | Tracin           |
|             |           |               | (21    | g/Notification** |
|             |           |               | CFR    |                  |
|             |           |               | 606    |                  |
|             |           |               | .171)\ |                  |
|             |           |               | if     |                  |
|             |           |               | prev   |                  |
|             |           |               | iously |                  |
|             |           |               | distr  |                  |
|             |           |               | ibuted |                  |
|             |           |               | pro    |                  |
|             |           |               | duct** |                  |
+-------------+-----------+---------------+--------+------------------+
| Bovine      | In        | SP and RP:    | Yes    | No               |
| insulin     | definite, | Immediately   |        |                  |
| injection   | donor     | retrieve,     |        |                  |
|             | reentry   | quar          |        |                  |
|             | if proof  | antine/notify | No     | No               |
|             | of        | consignees    |        |                  |
|             | non-U.K.  | for in-date   |        |                  |
|             | insulin   | SP and all RP |        |                  |
|             | source    | unless plasma |        |                  |
|             |           | known to be   |        |                  |
|             |           | previously    |        |                  |
|             |           | pooled        |        |                  |
|             |           |               |        |                  |
|             |           |  PD: No       |        |                  |
|             |           | retrieval,    |        |                  |
|             |           | quarantine,   |        |                  |
|             |           | consignee     |        |                  |
|             |           | notification  |        |                  |
+-------------+-----------+---------------+--------+------------------+
| Diagnosed   | Permanent | SP and RP:    | Yes    | Consignee        |
| with vCJD,  |           | Immediately   |        | notified,        |
| suspected   |           | retrieve,     |        | consignee        |
| vCJD        |           | quar          |        | informs          |
|             |           | antine/notify | Yes    | responsible      |
|             |           | consignees    |        | caretaker for    |
|             |           | for in-date   |        | discretionary    |
|             |           | SP and all RP |        | recipient        |
|             |           |               |        | notification,    |
|             |           |  \            |        | counseling       |
|             |           | PD:           |        |                  |
|             |           | Immediately   |        |                  |
|             |           | retrieve,     |        |                  |
|             |           | quarantine,   |        |                  |
|             |           | notify        |        |                  |
|             |           | consignees    |        |                  |
+-------------+-----------+---------------+--------+------------------+

Abbreviations: SP, Source Plasma; RP, recovered plasma; PD, plasma
derivatives; BPDR, Biological Products Deviation Report

**Table 2 (Modified from Reference \[27\]) Continued**

+------------+------------+---------------+---------+-----------------+
| **Risk**   | **         | **Disposition | **BPDR\ | **Recipient     |
|            | Deferral** | of Product**  | (21 CFR | Tracing         |
|            |            |               | 60      | /Notification** |
|            |            |               | 6.171)\ |                 |
|            |            |               | if      |                 |
|            |            |               | pre     |                 |
|            |            |               | viously |                 |
|            |            |               | dist    |                 |
|            |            |               | ributed |                 |
|            |            |               | pr      |                 |
|            |            |               | oduct** |                 |
+------------+------------+---------------+---------+-----------------+
| Diagnosed  | Permanent  | SP and RP:    | Yes     | Case-by-case    |
| with CJD   |            | Disposition   |         | recommendation, |
|            |            | decided       |         | depending upon  |
| and age    |            | case-by-case  |         | investigation   |
| \<55 years |            | depending     | Decided | results         |
|            |            | upon          | upon    |                 |
|            |            | investigation | case-   |                 |
|            |            | results       | by-case |                 |
|            |            |               |         |                 |
|            |            |  \            |         |                 |
|            |            | PD:           |         |                 |
|            |            | Disposition   |         |                 |
|            |            | decided       |         |                 |
|            |            | case-by-case  |         |                 |
|            |            | depending     |         |                 |
|            |            | upon          |         |                 |
|            |            | investigation |         |                 |
|            |            | results       |         |                 |
+------------+------------+---------------+---------+-----------------+
| Diagnosed  | Permanent  | SP and RP:    | Yes     | No              |
| with CJD   |            | Immediately   |         |                 |
|            |            | retrieve,     |         |                 |
| (and age   |            | quar          |         |                 |
| [\>]{.un   |            | antine/notify | No      | No              |
| derline}55 |            | consignees    |         |                 |
| years)     |            | for in-date   |         |                 |
|            |            | SP and all RP |         |                 |
|            |            | unless known  |         |                 |
|            |            | to be         |         |                 |
|            |            | previously    |         |                 |
|            |            | pooled        |         |                 |
|            |            |               |         |                 |
|            |            |  \            |         |                 |
|            |            | PD: No        |         |                 |
|            |            | retrieval,    |         |                 |
|            |            | quarantine,   |         |                 |
|            |            | consignee     |         |                 |
|            |            | notification  |         |                 |
+------------+------------+---------------+---------+-----------------+
| Risk       | Permanent  | SP and RP:    | Yes     | No              |
| factors    |            | Immediately   |         |                 |
| for CJD:   |            | retrieve,     |         |                 |
| Receipt of |            | quar          |         |                 |
| pituita    | Indefinite | antine/notify | No      | No              |
| ry-derived |            | consignees    |         |                 |
| growth     |            | for in-date   |         |                 |
| hormone,   |            | SP and all RP |         |                 |
| or dura    |            | unless known  |         |                 |
| mater      |            | to be         |         |                 |
| transplant |            | previously    |         |                 |
|            |            | pooled        |         |                 |
|  \         |            |               |         |                 |
| Family     |            |  \            |         |                 |
| history of |            | PD: No        |         |                 |
| CJD in \>1 |            | retrieval,    |         |                 |
| family     |            | quarantine,   |         |                 |
| member     |            | consignee     |         |                 |
|            |            | notification  |         |                 |
+------------+------------+---------------+---------+-----------------+
| CJD in     | I          | SP and RP:    | Yes     | No              |
| only 1     | ndefinite; | Immediately   |         |                 |
| family     | reentry if | retrieve,     |         |                 |
| member     | genetic    | quar          |         |                 |
|            | testing    | antine/notify | No      | No              |
|            | fails to   | consignees    |         |                 |
|            | reveal     | in-date SP    |         |                 |
|            | CJD-       | and all RP    |         |                 |
|            | associated | unless known  |         |                 |
|            | PrP allele | to be         |         |                 |
|            |            | previously    |         |                 |
|            |            | pooled        |         |                 |
|            |            |               |         |                 |
|            |            |  \            |         |                 |
|            |            | PD: No        |         |                 |
|            |            | retrieval,    |         |                 |
|            |            | quarantine,   |         |                 |
|            |            | consignee     |         |                 |
|            |            | notification  |         |                 |
+------------+------------+---------------+---------+-----------------+

Abbreviations: SP, Source Plasma; RP, recovered plasma; PD, plasma
derivatives; BPDR, Biological Products Deviation Report; PrP, prion
protein

# References

(Transcripts of the FDA TSE Advisory Committee Meetings cited may be
found through the FDA Web Page at
<http://www.fda.gov/ohrms/dockets/ac/acmenu.htm> by date and page
number.)

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[^1]: ^a^ Ruminant feed ban (prohibition of the feeding of
    ruminant-derived meat-and-bone meal---and most other mammalian
    proteins---to cattle, sheep and goats), a national BSE surveillance
    program (including prion protein testing of appropriately selected
    brain tissues from cattle at increased risk of BSE) compliant with
    the requirements of the Office International des Epizooties (OIE) to
    which the USA is signatory, prompt condemnation and destruction of
    animals with signs of BSE, preventive culling of animals at
    increased risk, and adequate compensation to owners of condemned
    cattle in order to encourage compliance

[^2]: ^b^ Age-based slaughter schemes (meat from cattle more than 30
    months old no longer considered edible in UK), separation of
    high-risk bovine tissues (specified-risk materials \[SRM\]) from
    edible meat and prohibition of slaughter methods that embolize brain
    tissue into meat, e.g., intracranial air injection and "pithing",
    application of the same controls to imported and domestic meat
    products