Draft Risk Assessment:

Potential Exposure to the vCJD agent in United States recipients of
Factor XI coagulation product manufactured in the United Kingdom

**Center for Biologics Evaluation and Research**

**U.S. Food and Drug Administration**

**January 31, 2005**

**EXECUTIVE SUMMARY**

In December 2003 the U.K. government announced that vCJD had likely been
transmitted via blood transfusion to a 69 year-old patient that had
died. This was followed by the announcement in July 2004 of a second
presumptive case of transfusion-transmitted vCJD that had occurred in a
patient that had displayed no symptoms of the disease and had died of
other causes. Cases of variant Creutzfeldt-Jakob disease (vCJD) were
first reported in humans in the U.K. in 1996 -- and as of January 2005
over 170 cases have been reported worldwide. Variant CJD is a fatal
neurodegenerative disease attributed to human infection with the agent
of Bovine Spongiform Encephalopathy (BSE), most often transmitted by the
consumption of beef products from infected cattle.

The probable transmission of vCJD via whole blood or blood components
raised a similar possibility that plasma derivatives might also pose a
risk of vCJD transmission. Accordingly, U.K. authorities recently
notified some recipients of plasma derivatives that they might be at
increased risk of vCJD. These products included coagulation factors
VIII, IX, and XI, as well as antithrombin III, and intravenous
immunoglobulins. The derivatives of concern were manufactured from
plasma of U.K. donors between 1980 and late in 1999, when\--consistent
with a decision announced in 1998---U.K. manufacturers stopped using
U.K. plasma. The last expiry date for any of the U.K. products was in
2001.

**Problem:** Some Factor XI made from U.K. plasma was used between 1989
and 1997 to treat relatively small number of patients participating in
several Investigational New Drug (IND) studies in the U.S. No Factor XI
product used in the U.S. was manufactured from a pool containing plasma
from a donor diagnosed with variant CJD (that is,\
there were no known \"implicated\" lots). However, U.K. plasma donors
are at a significantly higher risk for vCJD.

**Question addressed by risk assessment:** *Given the probable* *recent
transmission of vCJD via transfusion of whole blood and component
products, what is the risk to US recipients that received human plasma
derived Factor XI product manufactured in the* *U.K.?*

###### 

###### Results from the Model

The prevalence of vCJD in the U.K. population is estimated as 1 in 4,225
based on a surveillance study by Hilton, *et al* (2004). Therefore, the
model assumes that there is nearly 100% likelihood that a plasma pool
containing 20,000 donations will contain at least one donation from a
vCJD-infected individual. Results from the model are presented in Table
I. The intravenous (i.v.) ID~50~ per single unit and per vial of Factor
XI was estimated by the model. A single ID~50~ is defined as exposure to
an amount of infective material that causes infection in 50% of the
population. Three scenarios were modeled to depict various plausible
levels of utilization of FXI. [Scenario 1]{.underline} involves the
treatment of a 60 kg individual prior to surgery with 50 units/kg, or a
total of 3,000 units given to restore FXI levels to normal. FXI doses in
the literature typically range from 20 -- 50 u/kg, but doses as high as
15,000 u/patient have been administered in the postoperative setting,
over a period of days [Scenario 2]{.underline} and [Scenario
3]{.underline} assume a treatment regimen consisting of 9,000 units, and
15,000 units of FXI, respectively. Clinical treatment under the three
scenarios suggests patients may be exposed to vCJD i.v. ID~50~ during
the course of treatment that may pose a risk of causing infection. It is
not possible to estimate the precise magnitude of risk faced by patients
that received U.K.-manufactured FXI product.

**Table I -- Potential** **exposure to vCJD agent i.v. ID~50~ via Factor
XI.** Results are expressed as per unit or vial of FXI. Hypothetical
scenarios provide an estimate of the magnitude of exposure to vCJD agent
i.v. ID~50~ that might occur [per surgery]{.underline} incident. A
surgical incident includes prophylactic treatment prior to surgery and
possibly several post-operative treatments with FXI.

+---+-------------------+----------+----------------+-------+---------+
|   | **Scenario**      | **Qu     | **Mean         | **    | *       |
|   |                   | antity\* | vCJD^(1)^**    | 5^th^ | *95^th^ |
|   |                   | Factor   |                | ^(    | ^(1)^** |
|   |                   | XI**     | **i.v.         | 1)^** |         |
|   |                   |          | ID~50~**       |       | **perce |
|   |                   | **Ut     |                | **pe  | ntile** |
|   |                   | ilized** |                | rcent |         |
|   |                   |          |                | ile** |         |
+---+-------------------+----------+----------------+-------+---------+
|   |                   |          |                |       |         |
+---+-------------------+----------+----------------+-------+---------+
|   | **A single unit   | 1 u      | 2 x 10^-5^     | 6.8 x | 7.0 x   |
|   | FXI**             |          |                | 1     | 10^-5^  |
|   |                   |          |                | 0^-7^ |         |
+---+-------------------+----------+----------------+-------+---------+
|   | **One vial FXI**  | 1,000 u  | 2 x 10^-2^     | 6.8 x | 7.0 x   |
|   |                   |          |                | 1     | 10^-2^  |
|   |                   |          |                | 0^-4^ |         |
+---+-------------------+----------+----------------+-------+---------+
|   | **Scenario 1**:   | 3,000 u  | 6 x 10^-2^     | 2.1 x | 0.21    |
|   |                   |          |                | 1     |         |
|   | Treatment 3,000 u |          |                | 0^-3^ |         |
+---+-------------------+----------+----------------+-------+---------+
|   | **Scenario 2:**   | 9,000 u  | 0.17           | 6.2 x | 0.6     |
|   |                   |          |                | 1     |         |
|   | Treatment 9,000 u |          |                | 0^-3^ |         |
+---+-------------------+----------+----------------+-------+---------+
|   | **Scenario 3:**   | 15,000 u | 0.28           | 1.0 x | 1.0     |
|   |                   |          |                | 1     |         |
|   | Treatment 15,000  |          |                | 0^-2^ |         |
|   | u                 |          |                |       |         |
+---+-------------------+----------+----------------+-------+---------+

###### \*u - represents international units of Factor XI

\(1\) Estimates may have been rounded

###### Conclusions

No U.K.-manufactured FXI product distributed in the US from 1989 to 1997
is known to have been manufactured from "implicated" plasma pools that
were known to have contained plasma from a donor later diagnosed with
vCJD. If the prevalence of vCJD in the U.K. is assumed to be 1/4,225, it
is likely that most plasma pools used to manufacture FXI until 1998
could have contained a plasma donation from a person infected with vCJD.
Although results of the model suggest that exposure may have occurred,
it is not possible to provide a *precise* estimate of the vCJD risk to
patients that may have used Factor XI manufactured in the U.K. in the
1990s.

## Background

###### Factor XI 

Factor XI is a clotting factor present in blood plasma that plays a role
in the very early stages of the blood coagulation pathway. It is a
precursor to plasma thromboplastin, which is one of the proteins that
alters the shape of blood platelets and facilitates clotting. Factor XI
is normally present at concentrations of 50-70 u/dl in human plasma.

Factor XI (FXI) deficiency is a rare bleeding disorder that was first
described in the 1950s. Unlike other hemophilias, it is an autosomal
bleeding disorder that affects both genders equally. Generally, bleeding
with FXI deficiency is less severe than with hemophilias A and B and
does not usually involve joints or muscles or spontaneous bleeding in
those areas. (<http://www.hemophilia.org/bdi/bdi_types9.htm> ). Factor
XI deficiency is usually categorized as (1) severe or (2) partial. Those
with severe deficiency have FXI levels below 15 u/dl and are at high
risk of excessive bleeding if injured, or after surgery or dental
extractions. Medical intervention that brings FXI levels to the 50 u/dl
to 70 u/dl range is recommended prior to surgical procedures on severely
deficient patients. Therapy can include infusion with fresh plasma,
antifibrinolytic agents, or FXI preparations.

Factor XI manufactured in the U.K. between 1989 and 1997 was used by a
small group of patients in several IND studies in the U.S. and this risk
assessment estimates the potential exposure to vCJD agent via that
product. Currently, there is no Factor XI product commercially licensed
in the United States.

[I. Hazard Identification]{.underline}

The hazard identification portion of the risk assessment provides an
in-depth overview and analysis of information from laboratory studies,
epidemiological studies, the scientific literature, government reports
and other credible or peer-reviewed sources of data that establish a
causal relationship between the hazard and adverse effects on humans. To
date, no epidemiological evidence suggests that vCJD has been
transmitted by plasma derivative products.

A new human variant Creutzfeldt-Jakob disease (vCJD) was first described
in the U.K. in 1996. As of January 2005, 171 cases have been reported
including 157 in the U.K., 9 (not U.K.-acquired) in France, and single
non-U.K. acquired cases in Ireland and Italy. In addition, single cases
of vCJD in former long-time residents of the U.K. have occurred in
Ireland, Canada, and the U.S.

Both vCJD and BSE belong to a class of diseases known as transmissible
spongiform encephalopathies (TSEs). The leading theory is that the
transmissible infectious agent is a proteinaceous infectious agent, or
"prion," that originates in the misfolding of a ubiquitous prior protein
(Prp) normally expressed in many cells. The altered PrP, known as
PrP^res^, is highly stable and resistant to degradation by high heat and
many chemical treatments commonly used to denature proteins. The
incubation period for TSEs is long. For example, the mean incubation
period for BSE in cattle (interval between first exposure to
contaminated feed and onset of illness) has been estimated at about 5
years, and that for blood-borne vCJD to exceed 10 years. Individuals
become symptomatic with most forms of CJD only in the last few months of
life, making early detection very difficult. Diagnostic tools can
usually detect BSE in the later stages, usually in cattle more than 24
months old. Confirmation of vCJD requires postmortem examination of
brain tissue to confirm diagnosis, but abnormal prion protein has been
detected in antemortem tonsil biopsies early in clinical illness and
archived appendices of two asymptomatic individuals one and two years
prior to the onset of symptoms. There are currently no rapid tests
available to detect the vCJD in its early stages or to detect the
presence of TSE agents in blood.

# I.A. Transmission of TSEs through transfusion of blood products in animal models

Transmission of TSEs through the transfusion of blood or blood products
has been demonstrated in animal models on multiple occasions. At least
four studies reported transmission vial blood transfusion in the same
animal species: sheep experimentally infected with BSE(Houston *et al*
2000) and naturally infected with scrapie (Hunter *et al* 2002), and
experimentally infected rodents (hamsters with scrapie and mice with a
human TSE ( (Rohwer *et al* 2004, Brown *et al* 1999).

Brown, Rohwer, Taylor and others have attempted to estimate the amounts
of infectivity present in blood, which generally fell between two and 20
icLD50/ml. A recent study of scrapie-infected hamsters concluded that
more than 40% of the infectivity present in whole blood was associated
with plasma (approximately 58% \[Gregori L, *et al*. 2004\].) The model
uses the more conservative of the two outcomes and assumes that 58% of
infectivity is associated with plasma.

**I. B. Transfusion transmission of vCJD in the U.K.**

In December 2003 the U.K. government announced that vCJD had likely been
transmitted via blood transfusion to a 69 year-old patient. The patient
had received a transfusion of non-leucoreduced red blood cells in 1996
from a donor that died three years later of vCJD. This first case was
followed by the announcement in July 2004 of yet another probable case
of transfusion-transmitted vCJD that died of ruptured aortic aneurysm
without signs of vCJD, but postmortem testing detected PrP^sc^ in spleen
tissue and cervical lymph node.

It is possible that dietary exposure may have been responsible for the
cases, however the probabilities for either or both of these two events
are small. As Llewelyn *et al* (2004) pointed out in their publication
discussing the first presumed transfusion-transmitted case "the age of
the patient was well beyond that of most vCJD cases, and the chance of
observing a case of vCJD in a recipient in the absence of transfusion
transmitted infection is about 1 in 15,000 to 1 in 30,000." The combined
probability that two elderly patients in a small cohort of transfusion
recipients---in an age group underrepresented among vCJD cases---both
acquired infection from food, is remote.

The presumptive transmission of vCJD via by labile blood components
raises the possibility that plasma derivatives may pose a risk. The U.K.
authorities recently notified some recipients of plasma derivatives that
they might be at increased risk of vCJD. These products included
coagulation factors, as well as antithrombin III, and intravenous
immunoglobulins. The derivatives of concern were manufactured from
plasma of U.K. donors between 1980 and late in 1999, when\--consistent
with a decision announced in 1998---U.K. manufacturers stopped using
U.K. plasma. The last expiry date for any of the U.K. products was in
2001. To date, no cases of vCJD have been detected in patients that have
received human plasma-derived coagulation products from implicated lots
made in the U.K.

The focus of this risk assessment is on the risk of vCJD for patients in
the U.S. that received Factor XI manufactured in the U.K. in the 1990s.

[II. Hazard Characterization]{.underline}

The hazard characterization component (also known as dose-response)
relates the information in the exposure assessment, which determines the
dose, to the adverse consequence(s) such as infection, illness, etc., at
the individual, subpopulation, or population level. Determining
dose-response relationships are extremely complex and often difficult to
accomplish because data are limited, especially exposure and outcome
data for humans. Other factors such as characteristics of the hazard
(e.g. strain, chemical make-up, etc.), route of introduction, genetics
of exposed individuals, influence the dose-response relationship but are
often difficult to characterize. Often in lieu of human data, animal
data are used and appropriately extrapolated to estimate the
dose-response relationship for humans. Another challenge is estimating
the probability of infection when the exposure to TSEs is small and/or
occurs repeatedly over a period of time. It is unknown whether there is
a minimal amount of the agent, or threshold, that is needed to initiate
infection in an individual. Furthermore, it is not known whether the
effects of small multiple exposures over a period of time are cumulative
and may result in infection and disease. Some risk assessments have made
assumptions concerning the exposure and dose for TSE agent that leads to
infection. For instance, the Det Norske Veritas (Feb 2004) blood
products risk assessment assumes that exposure to infectivity,
quantified in ID~50~ units, is cumulative over the period of one year.
The ID~50~ is the common metric used to quantify the infectivity of
transmissible spongiform encephalopathies (TSEs). One ID~50~ is defined
as the amount of infectious material or tissue that is necessary to
initiate infection in 50% of the population. The route of exposure to
TSE infectious material influences the efficiency of transmission of the
disease and it has been shown that the intracerebral (i.c.) route
(injection directly into the brain) is the most efficient mode, the
intravenous (i.v.) route is approximately 5 to 10 times less efficient
than the i.c. route.

In estimating the dose-response relationship for TSEs one could use a
strict interpretation of the ID~50~ and assume a linear relationship
between exposure and infection. In such a case exposure to 1 ID~50~
would suggest a 50% probability of infection, exposure to 0.1 ID~50~
would suggest a 5% probability of infection, and so on. However, given
the lack of information and high degree of uncertainty on the
dose-response relationship for TSE agents it is plausible that low level
exposures, even on a chronic basis, may not attain the threshold
necessary to initiate infection in humans. The conservative assumption
is that low-level exposure to a TSE agent could potentially lead to
infection.

## III. Exposure Assessment 

Exposure assessment evaluates the routes of exposure to a hazard, the
probability that exposure occurs and the amount of a hazardous agent to
which a person or population may be exposed. This exposure assessment
specifically addresses exposure to the vCJD agent that may have been
present in Factor XI manufactured in the U.K. and administered to U.S.
patients during a clinical study under an IND application. The
administration of Factor XI, and thus the route of exposure, is
intravenous and used in the clinical treatment of individuals
prophylactically prior to surgery and after surgery to control bleeding.

Pools consisting of 20,000 or more plasma donations collected from U.K.
plasma donors were used as the starting material from which FXI was
purified. Because of the relatively large number of donations per plasma
pool and the prevalence of vCJD in the U.K. population it is possible
that at least one or more plasma donations per pool may have been
collected from asymptomatic individuals unknowingly infected with vCJD.
The worst-case assumption is also that TSE infectivity is present in the
blood of an incubating donor at any stage of incubation.

[Assumption used in the model:]{.underline} The probability of at least
one donation from a vCJD-infected individual being present in a plasma
pool used to manufacture Factor XI in the U.K. in the 1990s is nearly
100%.

# 

# Overview of Model

[Module A]{.underline} (vCJD ID~50~ per plasma pool) uses estimates of
vCJD i prevalence in the U.K. population of 1 in 4,225 (Hilton *et al*
2004) to estimate the number of vCJD donations that could be present in
a plasma pool of 20,000 donations. The output of this module is an
estimate of the vCJD ivID~50~ per plasma pool. [Module B]{.underline}
approximates the reduction of vCJD agent during manufacturing. The model
estimates a reduction of between 0 and 4 log~10~ reduction (10,000 fold)
in the amount of agent with a most likely level of reduction of 2
log~10~ reduction (100 fold). The output of this module is an estimate
of the ID~50~ per vial of Factor XI. [Module C]{.underline} (Dose for
Pre- / Post- surgical treatment) estimates utilization of FXI by
patients. The outcomes are expressed in i.v. ID~50~ per single unit FXI,
per vial (1,000 units) and for three possible clinical treatment
scenarios.

**[Model of Exposure Assessment]{.underline}**

#  

# III. A. Total intravenous vCJD infectivity ( i.v. ID~50~ ) per plasma pool 

III\. A.1. **P~vCJD~** - *Probability of vCJD-infected individual in
U.K. population*

In the scientific literature estimates of the rate of incubating vCJD
cases in the U.K. have been derived from two potential sources -- (1)
mathematical modeling and (2) surveillance testing of tissues such as
tonsil and appendix. For this risk assessment we used the estimates
derived from the tonsil and appendix studies since they are surveillance
studies and would be expected to provide a more representative estimate
of the potential rate of vCJD in the population. In vCJD patients the
distribution of infectivity in tissues throughout the body is different
than for other forms of CJD. Infectivity has been observed in the tonsil
and spleen (Bruce *et al* 2001) as well as in the lymph nodes (Wadsworth
*et al* 2001) of vCJD patients at the time of death. PrP^sc^ has also
been observed in appendices of two asymptomatic vCJD individuals one and
two years (but not 10 years) prior to the onset of symptoms (Hilton *et
al* 1998).

The most recent surveillance results for the U.K. by Hilton *et al*
(2004) indicated three appendectomy samples from different patients
showed accumulation of prion protein in tonsil and/or appendix samples
examined from a total of 12,674 individuals. For the risk assessment
model we converted this 3 in 12,674 individuals sampled to an average
rate of vCJD in the U.K. population of 1 in 4,225 ( 1 / 20,300 to 1 /
1,450 at 95% CI ). The data from tissue studies were then used to
generate variables and parameters representing the potential number of
vCJD donations that may be present in a batch of 20,000 recovered plasma
donations used to manufacture Factor XI product in the U.K. in the
1990s. Assuming an average prevalence of 1 in 4,225 ( 1 / 20,300 to 1 /
1,450 at 95% CI ) there would be an estimated 4.7 (95% CI 0.98 - 13.8)
potential vCJD donations per plasma pool of 20,000 donations (20,000
donations x 1/ 4,225 = 4.7).

Although the potential rate of vCJD is derived from surveillance studies
there may be some limitations on the data because the number of samples
tested is still relatively small (about 12,000) and even in the U.K.
population, vCJD is a rare illness. Therefore, many caveats are given
with these estimates. For instance, the survey may underestimate the
number of cases in the population if PrP^sc^ is not detected in the
tissues of vCJD-infected individuals until later in the disease process.
It is also possible that the estimates derived from the tissue testing
surveillance programs may in some way overestimate the risk. For
example, the population surveyed for the tonsil and appendix studies may
not be identical, e.g. in terms of age, to the plasma donor population.
However, this estimate is selected as the most conservative estimate.

[Assumption used in the model:]{.underline} An average prevalence of
vCJD in the U.K. population was assumed to be 1 in 4,225 ( 1 / 20,300 to
1 / 1,450 - 95% CI ).

Table II. Summary of surveillance testing of tissues including tonsil
and appendix in the UK.

+------------+--------+---------+-------+--------+--------+----------+
| Reference  | Ages   | Type    | Years | Number | Total  | Rate per |
|            | of     | tissue  | t     | of     | s      | million  |
|            | popu   | e       | issue | pos    | amples |          |
|            | lation | xamined | taken | itives | ex     | (95% CI) |
|            | ex     |         |       |        | amined |          |
|            | amined |         |       |        |        |          |
+------------+--------+---------+-------+--------+--------+----------+
| Ironside   | 10--50 | Tonsils | 1995  | 0      | \      | 0        |
| JW, et al. | yr     | and     | -1999 |        | >3,000 |          |
| 2000       |        | app     | (?    |        |        |          |
|            |        | endices | 2000) |        |        |          |
+------------+--------+---------+-------+--------+--------+----------+
| Hilton DA, | 10--50 | Tonsils | 1995  | 1      | 8,318  |          |
| et al.     | yr     | and     | -1999 | ap     |        |          |
| 2002       |        | app     |       | pendix |        |          |
|            |        | endices |       |        |        |          |
+------------+--------+---------+-------+--------+--------+----------+
| Hilton DA, | 20 --  | Tonsils | 1995  | 3      | 12,674 | 237      |
| et al.     | 29 yrs | and     | -     | appe   | appe   | /million |
| 2004       |        | app     |       | ndices | ndices |          |
|            |        | endices | 1999  |        |        | (49--692 |
|            |        |         |       |        |        | per      |
|            |        |         |       |        |        | million) |
+------------+--------+---------+-------+--------+--------+----------+

**III.** **A.2.** **D~Tpool~ -** *Total number of donations per pool*

[Assumption used in the model:]{.underline} Factor XI was manufactured
from a pool of approximately 20,000 recovered plasma donations.

**III.** **A.3.** **D~vCJD~ -** *Total number of vCJD donations per
pool*

The estimate in the model of the total number of donations from
individuals incubating vCJD that may be present in a pool of 20,000
plasma donations used to manufacture Factor XI was estimated from
surveillance studies that tested lymphoreticular tissue from patients in
the U.K. for the presence of vCJD agent. Surveillance studies testing
for the presence of prion protein in tonsil and appendectomy samples
from U.K. health clinics identified a total of 3 prion protein positive
appendix samples from a total of 12,674 individuals tested (Hilton *et
al* 2004). These testing results for appendices and tonsils suggest a
potential prevalence of 1 positive vCJD case per 4,225 individuals in
the U.K. Hilton *et al* (2004) suggest that an average of 237 vCJD
infections per million individuals with a 95% CI of 49 to 692 vCJD cases
per million.

Given the potential vCJD prevalence of 1 case per 4,225 individuals in
the U.K. from Hilton *et al*. (2004) it is likely that there is nearly a
100% probability that one or more donations from vCJD infected
individuals will be present in each pool. The model represents the
uncertainty of the estimated number of vCJD donations per plasma pool
using a statistical distribution.

Assuming an average prevalence of 1 in 4,225 ( 1 / 20,300 to 1 / 1,450
at 95% CI ) there would be an estimated 4.7 (95% CI 0.98 - 13.9)
potential vCJD donations per plasma pool of 20,000 donations (20,000
donations x 1/ 4,225 = 4.7). The model assumed all donations were
comparable in volume and there were no partial donations; all partial
donations were rounded to the nearest whole number.

[Assumption used in the model:]{.underline} The number of vCJD donations
per pool is represented by a triangular distribution that assumes a
minimum of 0 donations from vCJD individual will be present, it is most
likely that as many as 2 donations (or an average of approximately 5
donations) from vCJD cases could be present, and a there is a small
probability that a maximum of 14 donations from vCJD individuals may be
present in a plasma pool consisting of 20,000 donations.

**III.** A.4. **I~D~** - *Estimated Total Infectivity (or i.c.ID~50~)
per vCJD donation*

The model estimates the total infectivity or i.c. ID~50~ per vCJD
donation as a function of the volume of plasma per donation multiplied
by the infectivity associated with plasma. The i.c. ID~50~ in plasma are
calculated from the percentage of infectivity that is estimated to be
present in plasma. The model expresses intracerebral (i.c.) vCJD
infectivity in terms of the i.c. ID~50~ as the amount of tissue
material, in this case blood or plasma, that when injected into the
brain causes infection in 50% of the population. More details on the
variables and parameters for this portion of the model are described
below.

**III. A.4.a.** **D~V~** - *Amount of recovered plasma per donation*

> **D~V~** *- The amount of plasma recovered from a unit of whole blood
> is represented in the model by a single value point estimate of 200
> milliliters*
>
> A unit of whole blood has a volume of approximately 450 milliliters.
> Recovered plasma is the plasma portion separated from the cellular
> portion of a unit of whole blood within hours of its collection.
>
> [Assumption used in the model:]{.underline} The model assumes that
> approximately 200 milliliters (mls) of plasma can be separated away
> from the blood cells.
>
> **III. A.4.b.** **I~bl~** - *Infectivity of vCJD (or i.c.ID~50~)
> present in infected blood per ml*
>
> **I~bl\ ~** *- The potential amount of vCJD agent present in whole
> blood collected from a vCJD infected individual is represented in the
> model by a triangular statistical distribution of (*0.1, 10,1000*)*
> i.c. ID~50~/ml *(minimum, most likely, and maximum).*
>
> Conclusions from two research groups arrive at somewhat similar
> estimates for the quantity of infectivity that might be present in the
> whole blood of mice and hamsters. Using a murine model and human CJD
> Brown *et al* (1999) found that infectivity in the blood of mice rose
> to as high as 100 infectious units (iu) per ml of buffy coat.
> Furthermore, Brown *et al* (1998, 1999) conducted experiments to
> determine the infectivity of buffy coat material and plasma but not
> red blood cells. Assuming that red blood cells retain approximately
> 25% of the infectivity of whole blood, then the infectivity present in
> whole blood could be estimated to be in the range of approximately 10
> i.c. ID~50~ and 20 i.c. ID~50~ per ml. Cervenakova *et al* (2003)
> found levels of 20 -- 30 infectious doses per ml ( 10-15 i.c. ID50 per
> ml) associated with buffy coat and plasma during incubating and
> symptomatic stages of the disease. Red blood cells were not found to
> be infectious. Transfusion of blood products using the hamster scrapie
> model by Rohwer suggests that addition of infectivity levels derived
> for individual blood components would generate a titer for whole blood
> of approximately 2 to 20 i.c. ID~50~/ml.
>
> [Assumption used in the model:]{.underline} Whole blood collected from
> a vCJD-infected individual potentially carries a minimum of 0.1 i.c.
> ID~50~ per ml, a most likely of amount of 10 i.c. ID~50~ per ml, and a
> maximum of 1,000 i.c. ID~50~ per ml. Attempts to identify vCJD
> infectivity titers in human blood have not been successful, but the
> assay sensitivity for vCJD in vitro and in animal models is limited
> (Bruce *et al* 2001 and Wadsworth *et al* 2001). Wadsworth *et al*
> estimated a limit of sensitivity of about 1,000 ID~50~/ml by their
> assay (Wadsworth, 2001).

**III. A.4.c.** **I~Pl-perc~** - *Percentage infectivity associated with
plasma (i.c.ID~50~/ml)*

**I~Pl-perc~** - The percentage of vCJD agent associated with the plasma
portion of whole blood is represented in the model by a single value
point estimate of 58%.

Studies have shown that greater than 50% of transmissible spongiform
encephalopathy agent present in whole blood is associated with plasma.
Two sets of experiments

> (Gregori *et al*. 2004) using a hamster -- sheep scrapie model showed
> that approximately 58% of infectivity in whole blood is associated
> with plasma.
>
> [Assumption used in the model:]{.underline} The model uses the more
> conservative of the two outcomes and assumes that 58% of infectivity
> is associated with plasma.

**III. A.4.d.** **I~D~** - *Total infectivity (or i.c.ID~50~) per vCJD
recovered plasma donation*

Total i.c.ID~50~ per vCJD donation is represented by the equation:

> **I~D~** = **D~V\ ~** x **I~bl~** x **I~Pl-perc~**
>
> In this case **I~D~** or total infectivity or i.c. ID~50~ per vCJD
> donation equal to the volume of plasma per donation (**D~V~)**
> multiplied by the infectivity associated with plasma which is derived
> from the ID~50~s present in blood (**I~bl~**) times the percentage of
> infectivity present in plasma (**I~Pl-perc~**). Total vCJD infectivity
> is expressed in terms of the ID~50~ or the infectious dose needed to
> cause infection in 50% of the population.
>
> [Assumption used in the model:]{.underline} One ID~50~ is the amount
> of material containing infectious agent that has a 50% probability of
> causing infection in an individual or population.

**III. A.4.e.** **A~ic-iv~** - *Adjustment for intravenous route of
infection*

> **A~ic-iv~** *- is represented in the model by a uniform distribution
> between 5 and 10. This variable provides an adjustment for the
> difference in efficiency between the intravenous and intracerebral
> routes of introduction in initiating infection.*

Studies with mouse-adapted scrapie agent suggest that the i.v. route of
administration is approximately 10 times less efficient in causing
infection than the intracerebral route (Kimberlin *et al* 1996). Brown
*et al* (1999) used a mouse-adapted human TSE agent to show that i.v.
injection of plasma was about seven times less efficient and i.v.
injection of buffy coat approximately 5 times less efficient than were
i.c. inoculations of the same materials in transmitting infection.

> [Assumption used in the model:]{.underline} Exposure to infectivity by
> the i.v. route is between 5 and 10 times less efficient at causing
> infection than introduction via the intracerebral route.

**III. A.5. I~iv-pool~ -** *Total intravenous infectivity or i.v.ID~50~
per plasma pool of 20,000 donors*

The output of this component of the model, total i.v. ID~50~ per plasma
pool, is represented by the equation:

**I~iv-pool~** = **D~vCJD~** x **I~D~**

> **A~ic-iv~**

Total intravenous vCJD infectivity per plasma pool (**I~iv-pool~**) was
calculated in the model by multiplying the total vCJD donations per
pool, **D~vCJD~**, by the total quantity of infectivity, **I~D~**,
(ID50) per donation and dividing the product by the adjustment for
intravenous route of introduction, **A~ic-iv~**.

# III.B. Total i.v. ID~50~ per vial after processing / production of Factor XI

This component of the model estimates the total i.v. ID~50~ of vCJD
infectivity that may be present in a vial of Factor XI that was
manufactured in the U.K. and used in the U.S. under IND. Production of
Factor XI in the U.K. involved the pooling of recovered plasma from a
pool of approximately 20,000 donations. Some steps during production may
be expected to remove vCJD infectivity, thereby reducing the amount in
the finished product. There were two steps that reduced the amount of
infectivity. First, the original starting plasma material was
approximately 5,000 kg of plasma from which approximately 800 kg was
removed and used to produce the Factor XI product. This means that only
approximately 16% (800/5,000) of infectivity from the large pool of
20,000 donations remained. Finally, because of the processing steps used
in the manufacture of Factor XI we assumed a most likely reduction in
infectivity of 2 log~10~ (or 99%). These two steps would result in a
significant reduction in the amount of vCJD present in the Factor XI
product from the U.K. However, the model assumes that infectivity would
only be reduced and not eliminated. Therefore, some vCJD infectivity is
predicted by the risk assessment model to have been present in vials of
Factor XI produced in the U.K. and may have posed a risk of transmitting
vCJD to patients that received the product.

**III.B.1. R~W%~ -** *Percentage of pool used to manufacture Factor XI*

The initial starting amount of material from 20,000 recovered plasma
donations in the U.K. was estimated to weigh 5,000 kg of which 800 kg
(or 16%) of the material was removed and used to produce Factor XI. As
stated earlier this step represents an 84% reduction in infectivity from
the pool of 20,000 plasma donations.

[Assumption used in the model:]{.underline} Approximately 16% of
starting plasma material from 20,000 donations was used in the
manufacture of FXI.

**III.B.1.a. W~st~** - *Weight of starting product*

> [Assumption used in the model:]{.underline} Weight of starting product
> is represented in the model by a single value point estimate of 5,000
> kg.

**III.B.1.b. W~m~** - *800kg portion removed and used to extract Factor
XI*

> **W~m~** *- Portion of total product used in manufacturing is
> represented in the model by a single value point estimate of 800 kg.*
>
> [Assumption used in the model:]{.underline} 800 kg of material was
> removed and used to produce Factor XI.
>
> Portion used is represented by the equation and calculations:
>
> **R~W~ = W~m\ ~**~/~ **W~st~**
>
> **R~W~ = 800 / 5,000**
>
> **R~W%~ = 0.16**
>
> The removal of 800 kg or 16% of the pooled product from the original
> starting material of 5,000 kg represents an 84% reduction in the
> amount of i.v. ID~50~s present in the original pool of 20,000
> donations.

III.B.2. **R~Log~ -** *Log reduction in ID~50~ during processing*

> *Represented in the model by a triangular statistical distribution
> representing a reduction in ID~50~ during processing of (0, 2,4)*
> *Log~10~ i.v.* ID~50~/ml *(minimum, most likely, and maximum).*

TSE agents are highly resistant to conventional inactivation methods
such as alcohol, other solvents, and heat denaturation. At least one
step during the production of Factor XI has potential to reduce the
amount of agent present by physical separation (partitioning). CBER has
estimated by internal expert opinion that the level of removal of agent
during processing corresponds to a reduction of a minimum of 0, a most
likely reduction of 2 Log~10~ ID~50~, and a maximum possible reduction
of 4 Log~10~ ID~50~ per ml. Empirical verification of these estimated
levels of reduction has not been done to our knowledge.

[Assumption used in the model:]{.underline} Processing reduction is
represented by a triangular statistical distribution representing a
reduction in ID~50~ during processing of (0, 2, 4 ) Log~10~ i.v.
ID~50~/ml (minimum, most likely, and maximum).

[Assumption used in the model:]{.underline} The model assumes that
infectivity is reduced but not entirely eliminated from plasma and the
product during processing. Therefore, although the amount of
*ID~50\ ~*vCJD agent may be reduced the percentage of pools and vials
containing the agent still remains the same.

**III.B.3. I~pp~ -** *Total i.v. ID~50~ present per pool of Factor XI
post-processing*

**I~pp~ = I~iv-pool~ x R~W~ x 1/R~Log~**

> The total i.v. infectivity (i.v. ID~50~s) present in processed product
> (**I~pp~**) is a function of the total infectivity present in the pool
> (**I~iv-pool~**) prior to processing steps that might reduce the
> amount of infectivity present in the final Factor XI product. The
> infectivity in the pool (**I~iv-pool~**) is multiplied by **R~W~**
> because only 800kg out of the original 5,000 kg (or 16%) of starting
> plasma pool is used and multiplied by processing reduction steps
> (**R~Log~**), which are expected to reduce the infectivity in the
> final Factor XI product by a most likely of Log~10~ 2 (or 99%), or by
> a maximum level of Log~10~ 4 (or 99.99%).

III.B.4. **Y~fT~ -** *Total yield of Factor XI from plasma pool*

Factor XI is present in trace amounts in human plasma.

[Assumption used in the model:]{.underline} The estimated the yield of
FXI per kg plasma was approximately 150 to 180 units, subsequently the
model estimates the total yield of Factor XI as 120,000 to 144,000 units
per batch of 800 kg starting material. FXI was distributed in vials
containing 1,000 units each. The term unit (u) is equivalent to the term
international unit (i.u.).

The yield of Factor XI from the starting material was represented in the
model by the equation:

**Y~fT~ = W~M~ x Y~f-kg~**

**III.B.4.a.** **Y~f-kg\ -\ ~***Yield of Factor XI per kg of plasma*

Yield in the model was estimated to be between 150 to 180 units of FXI
per kg plasma This variable was represented in the model using a uniform
distribution with a minimum yield of 150 units and a maximum yield of
180 units per kg of starting plasma material.

III.B.5. **V~iu~ -** *Vial size or number of units per vial*

It was assumed that each vial contained 1,000 units of factor XI.

III.B.6. **V~T~ -** *Total number vials produced*

The Factor XI product was aliquoted into vials with approximately 1,000
units each, and the total number of vials produced was estimated in the
model by the simple equation:

**V~T~ = Y~fT~ / V~iu~**

III.B.7. **I~vial~ -** *Total i.v. ID~50~ per vial*

The total i.v. ID~50~ present in each vial of Factor XI was estimated by
dividing the total estimated i.v. ID~50~ per pool (**I~pp~**) of
starting material by the total number of vials produced. Calculations
used in the model are represented by the equation:

**I~vial~ = I~pp~ / V~T~**

or including all component variables by the equation:

**D~vCJD~** x **D~V\ ~**x **I~bl~** x **I~pl-perc~**

**I~vial~ = x R~W%~ x 1/R~Log~ (W~m~ x Y~f-kg~ / V~iu~)**

**A~ic-iv~**

Summary of variable names used above are:

**D~vCJD~ -** *Total number of vCJD donations per pool*

**D~V~** - *Amount of recovered plasma per donation*

**I~bl~** - *Infectivity of vCJD (or i.c.ID~50~) present in infected
blood per ml*

**I~Pl-perc~** - *Percentage infectivity associated with plasma
(i.c.ID~50~/ml)*

**A~ic-iv~** - *Adjustment for intravenous route of infection*

**R~W%~ -** *Percentage of pool used to manufacture Factor XI*

**R~Log~ -** *Log reduction in ID~50~s during processing*

**W~m~** *- Portion of total product used in manufacturing(800 kg).*

**Y~f-kg\ -\ ~***Yield of Factor XI per kg of plasma*

**V~iu\ -\ ~***number FXI units per vial*

# III.C. Utilization by patients with Factor XI deficiency undergoing Surgery

Factor XI normally circulates in the human bloodstream at a
concentration of approximately 50 u/dl and has been observed by some
researchers to be present at concentrations as high as 70 u/dl. Those
with very severe Factor XI deficiency have \< 15 unit per deciliter
(u/dl) of blood. The commonly used treatment dose is 50 units per kg
body weight. Individuals at risk for excessive bleed prior to surgery
can receive prophylactic treatment at the recommended dose in
anticipation of surgery. Because the half-life of FXI is approximately
52 hrs (Mannucci *et al* 1994), patients may need additional
post-surgical maintenance treatments every 2 to 3 days to maintain
therapeutic levels.

**III.C.1. Total Dose for Pre- and Post-surgical treatment with Factor
XI**

Published data are available on the per surgical event utilization of
Factor XI (Mannucci *et al* 1994, Aledort *et al* 1997) manufactured in
the U.K. so that potential exposure to the vCJD agent can be estimated
more accurately. It is difficult to determine the exact dose given to
each patient without the patient medical record because only the dose
per body weight of 50 u/kg is provided. The scenarios described below
approximate the amount of factor XI given per patient to provide insight
into the possible magnitude of risk. In this portion of the model we lay
out three possible scenarios:

**Scenario 1** -- Treatment of a 60kg individual with Factor XI (50
u/kg) once during or after surgery for a total patient dose of
approximately 3,000 units.

**Scenario 2** - Treatment of a 60kg individual both pre- and
post-surgery with a total of approximately 9,000 units of Factor XI.

**Scenario 3** - Treatment of a 60kg individual both pre- and
post-surgery with a total of approximately 15,000 units of Factor XI. .

**III.C.1.a. D~Pre~ -** *Prior to major Surgery - doses of 50 u/kg
given*

[Assumption used in the model:]{.underline} The dosage prior to surgery
is approximately 50 u/kg body weight. This dosage scheme is represented
in the model with a point estimate.

**D~Pre\ ~**= **Dose** (*50 iu/kg)* x **Patient weight (kg) x Number
treatments**

**III.C.1.b. D~Post~ -** *Post-surgical maintenance of 50 u/kg every 2 -
3 days*

[Assumption used in the model:]{.underline} The post-surgery maintenance
dosage is assumed to be 50 u/kg given every two to three days. This
dosing scheme is represented in the model with a point estimate.

> **D~Post\ ~**= **Dose** (*50 u /kg)* x **Patient weight (kg) x Number
> treatments**

**III.C.1.c. D~T~ - Total Factor XI doses given per patient per surgical
procedure**

The output is a sum of all doses of Factor XI given pre- and
post-surgery to prevent or minimize bleeding by Factor XI deficient
patients. The sum of doses is represented by the equation:

**D~Tu~** = **D~Pre~** + **D~Post~**

III.C.2. **Scenario 1: Treatment 60 Kg individual**

A 60 Kg person receives one dose factor XI to minimize potential
bleeding episodes at a concentration of 50u/kg would receive a total of
approximately 3,000 units. Output is the estimated total units Factor XI
received and estimated vCJD ID~50~ received. This dosing regimen for one
IND using U.K. manufactured factor XI in the United States is described
in Aledort *et al* (1997). It should be noted that 12 of the patients in
the study received 50 u /kg but one patient in the study received only
20 u / kg.

III.C.3. **Scenario 2**: **Treatment with 9,000 units Factor XI**

[Assumption used in the model:]{.underline} During preparation and
recovery from surgery the model assumes that a patient receives a total
dose of 9,000 units Factor XI to minimize potential bleeding episodes.
Output is the estimated total units Factor XI received and estimated
vCJD ID~50~ received.

Scenario 2 is similar to amounts of Factor XI given in three dosing
regimens given at 50 units per kg body weight -one treatment given prior
to surgery and two treatments given during post-operative recovery
(Mannucci *et al* 1994).

III.C.4. **Scenario 3: Treatment with 15,000 units Factor XI**

[Assumption used in the model:]{.underline} During preparation and
recovery from surgery the model assumes that a patient receives a total
dose of 15,000 units Factor XI to minimize potential bleeding episodes.
This scenario may involve a 60 kg individual that receives approximately
five treatments both prior to and following surgery at a dose of 50
u/kg.

Output Scenario 3: Estimated Total units Factor XI received and
estimated vCJD ID~50~ received.

**[IV. Risk Characterization]{.underline}**

The risk characterization section of the risk assessment integrates the
hazard identification, hazard characterization and the exposure
assessment components to arrive at estimates of the risks posed by a
hazard.

In this risk assessment data for hazard characterization are lacking, so
we could not develop a human vCJD dose-response. The dose-response
relationship provides information needed to use the exposure (dose)
assessment results to estimate the probability of adverse responses
including infection, illness or mortality -- based on assessment of
exposure (dose) to the hazard. Many TSE models and risk assessments,
including our model, use the ID~50~, or amount of material that leads to
infection in 50% of the population, as a semi-quantitative estimate of
the amount of TSE agent. It is possible to interpret the ID~50~ as
representing a linear dose-response relationship or linear relationship
between exposure and the probability of infection. In such a case
exposure to 1 ID~50~ would suggest a 50% probability of infection,
exposure to 0.1 ID~50~ would suggest a 5% probability of infection, and
so on. Given the limited data available, any extrapolation or
interpretation has limited utility in actually estimating clinical
outcomes such as infection and illness. Therefore, any estimate of the
risk based on estimates of exposure to the vCJD agent through use of
Factor XI will be imprecise and extremely uncertain.

# IV.A. The Model

This risk assessment and model link the available scientific and
epidemiological data together to mathematically approximate the
processes (predicted presence of vCJD in U.K. population, manufacturing,
reduction of vCJD agent, and patient utilization) leading to exposure of
US patients to vCJD agent present in U.K.-manufactured Factor XI. A
summary of the variables, parameters and equations used in the model
were described in Section III. Exposure Assessment and a summary of the
variables and equations are provided in Appendix A. Where data were not
available, simplifying assumptions were used in the model and are
detailed in the preceding documentation. Assumptions used in the model
are presented in tabular form in Appendix B.

The model was run using \@Risk software package (Palisades Corp, NY) to
conduct the Monte Carlo analysis. Simulations of 10,000 iterations were
run.

The model provided predictions of estimated exposure to the vCJD agent
in the form of intravenous (i.v.) ID~50~ in patients treated with
U.K.-manufactured Factor XI. Because an accurate dose-response
relationship (or hazard characterization) for vCJD exposure and the
probability of human illness has not been developed it is not possible
to predict with any accuracy the probability of vCJD infection and
illness in an individual exposed to the agent.

###### 

###### IV. B. Results from the Model

Results from the model are presented below in Table 4.1. The intravenous
(i.v.) ID~50~ per single unit and per vial (of 1,000 units) of Factor XI
was estimated by the model. Additionally, results that predict exposure
for 3 scenarios depicting various levels of utilization that approximate
clinical treatment with FXI are presented.

**Table I -- Potential exposure to vCJD agent i.v. ID~50~ via Factor
XI.** Results are expressed as per unit or vial of FXI. Hypothetical
scenarios provide an estimate of the magnitude of exposure to vCJD agent
i.v. ID~50~ that might occur [per surgery]{.underline} incident. A
surgical incident includes prophylactic treatment prior to surgery and
possibly several post-operative treatments with FXI.

+---+-------------------+----------+----------------+-------+---------+
|   | **Scenario**      | **Qu     | **Mean         | **    | *       |
|   |                   | antity\* | vCJD^(1)^**    | 5^th^ | *95^th^ |
|   |                   | Factor   |                | ^(    | ^(1)^** |
|   |                   | XI**     | **i.v.         | 1)^** |         |
|   |                   |          | ID~50~**       |       | **perce |
|   |                   | **Ut     |                | **pe  | ntile** |
|   |                   | ilized** |                | rcent |         |
|   |                   |          |                | ile** |         |
+---+-------------------+----------+----------------+-------+---------+
|   |                   |          |                |       |         |
+---+-------------------+----------+----------------+-------+---------+
|   | **A single unit   | 1 u      | 2 x 10^-5^     | 6.8 x | 7.0 x   |
|   | FXI**             |          |                | 1     | 10^-5^  |
|   |                   |          |                | 0^-7^ |         |
+---+-------------------+----------+----------------+-------+---------+
|   | **One vial FXI**  | 1,000 u  | 2 x 10^-2^     | 6.8 x | 7.0 x   |
|   |                   |          |                | 1     | 10^-2^  |
|   |                   |          |                | 0^-4^ |         |
+---+-------------------+----------+----------------+-------+---------+
|   | **Scenario 1**:   | 3,000 u  | 6 x 10^-2^     | 2.1 x | 0.21    |
|   |                   |          |                | 1     |         |
|   | Treatment 3,000 u |          |                | 0^-3^ |         |
+---+-------------------+----------+----------------+-------+---------+
|   | **Scenario 2:**   | 9,000 u  | 0.17           | 6.2 x | 0.6     |
|   |                   |          |                | 1     |         |
|   | Treatment 9,000 u |          |                | 0^-3^ |         |
+---+-------------------+----------+----------------+-------+---------+
|   | **Scenario 3:**   | 15,000 u | 0.28           | 1.0 x | 1.0     |
|   |                   |          |                | 1     |         |
|   | Treatment 15,000  |          |                | 0^-2^ |         |
|   | u                 |          |                |       |         |
+---+-------------------+----------+----------------+-------+---------+

###### \*u - represents international units of Factor XI

######  (1) Estimates may have been rounded 

# IV. C. Sensitivity Analysis

Sensitivity (or importance) analysis is a process of varying the value
of variables in the model to identify those with the greatest influence
on the estimated risk outcome(s). A simple sensitivity analysis of the
Factor XI model suggests that the estimated number of vCJD donations per
plasma pool (**D~vCJD\ ~**) had the greatest influence on the final risk
estimate. In the model **D~vCJD~** was bounded by a minimum value of 0
vCJD donation per pool, a most likely estimate of 2 (average of
approximately 5) vCJD donations per pool and a maximum value of 14 vCJD
donations per pool. The second most influential factor in the model was
the log reduction of vCJD agent (**R~Log~**) during processing and
manufacture of Factor XI product. For **R~Log~** it was assumed that the
minimum level of reduction was 0, the most likely level of reduction was
2 log~10~ and the maximum level of reduction in agent that could occur
was 4 log~10~.

# IV. D. Uncertainty and Data Gaps

Uncertainty arises from the absence of information or availability of
limited information. In our probabilistic model statistical
distributions are used to represent the uncertainty of the information
used in the model. We express the uncertainty of the final risk
estimates generated from the model using a mathematical mean (average)
of exposure in ID~50~ units and the 5% and 95% confidence intervals for
each estimate. The uncertainty for the risk estimates generated from by
this FXI risk assessment model is significant and decision makers should
use the results with caution. In the future, additional research and
information may be substituted for assumptions or used to improve
estimates for the individual parameters and ultimately improve the
precision of the final risk estimates generated by the model.

Even considering the associated uncertainty of estimated risks, risk
assessment provides a best estimate of risk based on the current and
known information. It is still a useful tool that informs the
science-based decision making process. It can identify data gaps and
research priorities where additional research and information would have
the greatest impact on enhancing the final risk estimates. Results from
the sensitivity analysis in Section IV.C. indicated that the risk
assessment results are highly dependent upon

-   Estimation of the prevalence of vCJD in the U.K., and in turn, the
    parameter for vCJD donations per plasma pool (**D~vCJD\ ~**), and

-   Log reduction of vCJD agent (**R~Log~**) during the manufacturing
    process

Improved data and surveillance studies on the estimated vCJD prevalence
in the U.K. would enhance the precision of the estimated number of
incubating donors that would contribute to a plasma pool. Data from
laboratory studies could improve the estimate of the reduction of vCJD
during manufacturing. The modeled estimates were based upon levels of
reduction seen for a manufacturing step that was similar in some but not
all respects to that used for FXI.

No data are available on the level of infectious units or ID~50~ units
present in the bloodstream of vCJD infected individuals at the time of
blood donation. The model extrapolates an estimate of the level of vCJD
agent that might be present in human blood based on data from several
animal models. However, the presence and level of agent present in an
infected individual at the time of blood donation could differ from our
assumption and this adds to the uncertainty of the risk assessment
outcomes.

The model estimates exposure to the vCJD agent in the form of
intravenous ID~50~ units. Data are not available to estimate the
probability of various clinical outcomes, such as infection or illness
that might be predicted to arise from exposure to a particular level of
agent. Therefore, we did not estimate a probability of infection or
illness in our model. However, a meaningful dose-response model will
need to be generated for vCJD exposure in humans to estimate the
probability of adverse clinical outcomes for humans. Until then,
estimates of the probability of vCJD infection or illness arising from
exposure to the agent are extremely uncertain and should be viewed with
caution.

###### IV. E. Conclusions

Potential exposure to vCJD agent present in Factor XI manufactured in
the U.K. and used during investigational studies in the U.S. from 1989
to 1997 was estimated in this probabilistic risk assessment.

Although no U.K.-manufactured FXI product distributed in the U.S. during
the 1990s is known to have been manufactured from "implicated" batches
that contained donations from an individual(s) later diagnosed with
vCJD, it is possible that FXI product manufactured from U.K. plasma in
the 1990s may have been manufactured from plasma pools that contained a
plasma donation(s) from an individual that was incubating vCJD. To date,
no recipients of plasma derivatives in the U.K. or elsewhere have been
diagnosed with vCJD. However, given the potentially prolonged incubation
times for human TSEs, it is still theoretically possible that such
transmissions occurred are yet to be identified.

# 

**Appendix A**

######### Summary of Model Components

+-----+---------------------------+----------------+------------------+
| *   |                           | **Input**      | **Numerical      |
| *Va |                           |                | input / output** |
| ria |                           |                |                  |
| ble |                           |                |                  |
| nam |                           |                |                  |
| e** |                           |                |                  |
+-----+---------------------------+----------------+------------------+
| *   |                           |                |                  |
| *A. |                           |                |                  |
| To  |                           |                |                  |
| tal |                           |                |                  |
| in  |                           |                |                  |
| tra |                           |                |                  |
| ven |                           |                |                  |
| ous |                           |                |                  |
| v   |                           |                |                  |
| CJD |                           |                |                  |
| in  |                           |                |                  |
| fec |                           |                |                  |
| tiv |                           |                |                  |
| ity |                           |                |                  |
| (   |                           |                |                  |
| i   |                           |                |                  |
| .v. |                           |                |                  |
| ID~ |                           |                |                  |
| 50~ |                           |                |                  |
| )   |                           |                |                  |
| per |                           |                |                  |
| pla |                           |                |                  |
| sma |                           |                |                  |
| poo |                           |                |                  |
| l** |                           |                |                  |
+-----+---------------------------+----------------+------------------+
| #   |                           |                |                  |
| ### |                           |                |                  |
| ##  |                           |                |                  |
|     |                           |                |                  |
| #   |                           |                |                  |
| ### |                           |                |                  |
| ##  |                           |                |                  |
| Inp |                           |                |                  |
| uts |                           |                |                  |
+-----+---------------------------+----------------+------------------+
| A   | *Probability individual   | **P~vCJD~**    | 1 / 4,225        |
| .1. | has vCJD in U.K.          |                |                  |
|     | population*               |                | (5% CI = 1 /     |
|     |                           |                | 1,452)           |
|     |                           |                |                  |
|     |                           |                | (95% CI = 1 /    |
|     |                           |                | 20,280)          |
+-----+---------------------------+----------------+------------------+
| A   | *Total number of          | **D~T\ ~**     | 20,000 donations |
| .2. | donations per pool*       |                |                  |
+-----+---------------------------+----------------+------------------+
| A   | *Total number of vCJD     | **D~vCJD\ ~**  | ####### Triangu  |
| .3. | donations per pool*       |                | lar distribution |
|     |                           |                |                  |
|     |                           |                | Minimum = 0      |
|     |                           |                | donations        |
|     |                           |                |                  |
|     |                           |                | Most likely = 2  |
|     |                           |                | donations (Mean  |
|     |                           |                | \~5)             |
|     |                           |                |                  |
|     |                           |                | ####### Maximu   |
|     |                           |                | m = 14 donations |
+-----+---------------------------+----------------+------------------+
| A.4 | *Amount of recovered      | **D~V~**       | 200 mls          |
| .a. | plasma per donation*      |                |                  |
+-----+---------------------------+----------------+------------------+
| A.4 | *Infectivity of vCJD in   | **I~bl~**      | ####### Triangu  |
| .b. | infected blood per ml*    |                | lar distribution |
|     |                           |                |                  |
|     |                           |                | Minimum = 0.1    |
|     |                           |                | ID~50~           |
|     |                           |                |                  |
|     |                           |                | Most likely = 10 |
|     |                           |                | ID~50~           |
|     |                           |                |                  |
|     |                           |                | Maximum = 1,000  |
|     |                           |                | ID~50~           |
+-----+---------------------------+----------------+------------------+
| A.4 | *Percentage infectivity   | **I~pl-perc~** | 58%              |
| .c. | in plasma (ID~50~/ml)*    |                |                  |
+-----+---------------------------+----------------+------------------+
| A.4 | *Adjustment for           | **A~ic-iv~**   | ####### Unif     |
| .e. | intravenous route of      |                | orm distribution |
|     | infection*                |                |                  |
|     |                           |                | Minimum = 5      |
|     |                           |                |                  |
|     |                           |                | Maximum = 10     |
+-----+---------------------------+----------------+------------------+
| # O |                           |                |                  |
| utp |                           |                |                  |
| uts |                           |                |                  |
+-----+---------------------------+----------------+------------------+
| A.4 | *Total infectivity (or    | **I~D~** =     |                  |
| .d. | i.c.ID~50~) per vCJD      | **D~V\ ~**x    |                  |
|     | donation*                 | **I~bl~** x    |                  |
|     |                           | **I~pl-perc~** |                  |
+-----+---------------------------+----------------+------------------+
| A   | *Total i.v. ID~50~ per    | **T            |                  |
| .5. | plasma pool of 20,000     | ~iv-pool\ ~**= |                  |
|     | donors*                   | **D~vCJD~** x  |                  |
|     |                           | **I~D~**       |                  |
|     |                           |                |                  |
|     |                           | **A~ic-iv~**   |                  |
+-----+---------------------------+----------------+------------------+
| S   |                           |                |                  |
| umm |                           |                |                  |
| ary |                           |                |                  |
| of  |                           |                |                  |
| out |                           |                |                  |
| put |                           |                |                  |
| at  |                           |                |                  |
| t   |                           |                |                  |
| his |                           |                |                  |
| po  |                           |                |                  |
| int |                           |                |                  |
| in  |                           |                |                  |
| the |                           |                |                  |
| mod |                           |                |                  |
| el: |                           |                |                  |
|     |                           |                |                  |
| **  |                           |                |                  |
| T~i |                           |                |                  |
| v-p |                           |                |                  |
| ool |                           |                |                  |
| \ ~ |                           |                |                  |
| **= |                           |                |                  |
| **  |                           |                |                  |
| D~v |                           |                |                  |
| CJD |                           |                |                  |
| ~** |                           |                |                  |
| x   |                           |                |                  |
| **  |                           |                |                  |
| D~V |                           |                |                  |
| \ ~ |                           |                |                  |
| **x |                           |                |                  |
| **I |                           |                |                  |
| ~bl |                           |                |                  |
| ~** |                           |                |                  |
| x   |                           |                |                  |
| **  |                           |                |                  |
| I~p |                           |                |                  |
| l-p |                           |                |                  |
| erc |                           |                |                  |
| ~** |                           |                |                  |
|     |                           |                |                  |
| **A |                           |                |                  |
| ~ic |                           |                |                  |
| -iv |                           |                |                  |
| ~** |                           |                |                  |
+-----+---------------------------+----------------+------------------+
|     |                           |                |                  |
+-----+---------------------------+----------------+------------------+
| #   |                           |                |                  |
|     |                           |                |                  |
| # B |                           |                |                  |
| . T |                           |                |                  |
| ota |                           |                |                  |
| l i |                           |                |                  |
| .v. |                           |                |                  |
|  ID |                           |                |                  |
| ~50 |                           |                |                  |
| ~ p |                           |                |                  |
| er  |                           |                |                  |
| via |                           |                |                  |
| l a |                           |                |                  |
| fte |                           |                |                  |
| r p |                           |                |                  |
| roc |                           |                |                  |
| ess |                           |                |                  |
| ing |                           |                |                  |
|  /  |                           |                |                  |
| pro |                           |                |                  |
| duc |                           |                |                  |
| tio |                           |                |                  |
| n o |                           |                |                  |
| f F |                           |                |                  |
| act |                           |                |                  |
| or  |                           |                |                  |
| XI  |                           |                |                  |
+-----+---------------------------+----------------+------------------+
| #   |                           |                |                  |
| ### |                           |                |                  |
| ##  |                           |                |                  |
| Inp |                           |                |                  |
| uts |                           |                |                  |
+-----+---------------------------+----------------+------------------+
| B.1 | *Weight of starting       | **W~st~**      | *5,000 kg*       |
| .a. | product*                  |                |                  |
+-----+---------------------------+----------------+------------------+
| B.1 | *Portion removed and used | **W~m~**       | *800kg*          |
| .b. | to extract Factor XI*     |                |                  |
+-----+---------------------------+----------------+------------------+
| B   | *Percentage of pool in    | **R~W%~ =      | 0.16             |
| .1. | manufacture Factor XI*    | W~m\ ~**~/~    |                  |
|     |                           | **W~st~**      |                  |
+-----+---------------------------+----------------+------------------+
| B   | *Log reduction in ID~50~s | **R~Log~**     | ####### Triangu  |
| .2. | during processing*        |                | lar distribution |
|     |                           |                |                  |
|     |                           |                | Minimum = 0      |
|     |                           |                | log~10~          |
|     |                           |                |                  |
|     |                           |                | Most likely = 2  |
|     |                           |                | log~10~          |
|     |                           |                |                  |
|     |                           |                | Maximum = 4      |
|     |                           |                | log~10~          |
+-----+---------------------------+----------------+------------------+
| B.4 | ######## Yield of F       | **Y~f-kg\ ~**  | ####### Unif     |
| .a. | actor XI per kg of plasma |                | orm distribution |
|     |                           |                |                  |
|     |                           |                | Minimum = 150    |
|     |                           |                | iu/kg            |
|     |                           |                |                  |
|     |                           |                | Maximum = 180    |
|     |                           |                | iu/kg            |
+-----+---------------------------+----------------+------------------+
| B   | *Vial size or \# iu per   | **V~iu~**      | 1,000 iu         |
| .5. | vial*                     |                |                  |
+-----+---------------------------+----------------+------------------+
| ##  |                           |                |                  |
| ### |                           |                |                  |
| # O |                           |                |                  |
| utp |                           |                |                  |
| uts |                           |                |                  |
+-----+---------------------------+----------------+------------------+
| B   | *Total ID~50~ in Factor   | **I~pp~=       |                  |
| .3. | XI post-processing*       | I~iv-pool~ x   |                  |
|     |                           | R~W~ x         |                  |
|     |                           | 1/R~Log~**     |                  |
+-----+---------------------------+----------------+------------------+
| B   | *Total yield of Factor XI | **Y~fT~ = W~m~ |                  |
| .4. | from plasma pool*         | x Y~f-kg~**    |                  |
+-----+---------------------------+----------------+------------------+
| B   | *Total number vials and   | **V~T~ = Y~fT~ |                  |
| .6. | vial size produced*       | / V~iu~**      |                  |
+-----+---------------------------+----------------+------------------+
| B   | *Total ID~50~ per vial*   | **I~vial~ =    |                  |
| .7. |                           | I~pp~ / V~T~** |                  |
+-----+---------------------------+----------------+------------------+
| S   |                           |                |                  |
| umm |                           |                |                  |
| ary |                           |                |                  |
| of  |                           |                |                  |
| out |                           |                |                  |
| put |                           |                |                  |
| at  |                           |                |                  |
| t   |                           |                |                  |
| his |                           |                |                  |
| po  |                           |                |                  |
| int |                           |                |                  |
| in  |                           |                |                  |
| the |                           |                |                  |
| mod |                           |                |                  |
| el: |                           |                |                  |
|     |                           |                |                  |
| **  |                           |                |                  |
| D~v |                           |                |                  |
| CJD |                           |                |                  |
| ~** |                           |                |                  |
| x   |                           |                |                  |
| **  |                           |                |                  |
| D~V |                           |                |                  |
| \ ~ |                           |                |                  |
| **x |                           |                |                  |
| **I |                           |                |                  |
| ~bl |                           |                |                  |
| ~** |                           |                |                  |
| x   |                           |                |                  |
| **  |                           |                |                  |
| I~p |                           |                |                  |
| l-p |                           |                |                  |
| erc |                           |                |                  |
| ~** |                           |                |                  |
|     |                           |                |                  |
| **I |                           |                |                  |
| ~vi |                           |                |                  |
| al~ |                           |                |                  |
| = x |                           |                |                  |
| R   |                           |                |                  |
| ~W~ |                           |                |                  |
| x   |                           |                |                  |
| 1/  |                           |                |                  |
| R~L |                           |                |                  |
| og~ |                           |                |                  |
| (W  |                           |                |                  |
| ~m~ |                           |                |                  |
| x   |                           |                |                  |
| Y   |                           |                |                  |
| ~f- |                           |                |                  |
| kg~ |                           |                |                  |
| /   |                           |                |                  |
| V~  |                           |                |                  |
| iu~ |                           |                |                  |
| )** |                           |                |                  |
|     |                           |                |                  |
| **A |                           |                |                  |
| ~ic |                           |                |                  |
| -iv |                           |                |                  |
| ~** |                           |                |                  |
+-----+---------------------------+----------------+------------------+
|     |                           |                |                  |
+-----+---------------------------+----------------+------------------+
| #   |                           |                |                  |
| ### |                           |                |                  |
| ##  |                           |                |                  |
| Tot |                           |                |                  |
| al  |                           |                |                  |
| Uti |                           |                |                  |
| liz |                           |                |                  |
| ati |                           |                |                  |
| on  |                           |                |                  |
| of  |                           |                |                  |
| Fac |                           |                |                  |
| tor |                           |                |                  |
|  XI |                           |                |                  |
+-----+---------------------------+----------------+------------------+
| ### |                           |                |                  |
| ### |                           |                |                  |
| # * |                           |                |                  |
| *In |                           |                |                  |
| put |                           |                |                  |
| s** |                           |                |                  |
+-----+---------------------------+----------------+------------------+
| C.1 | *Prior to major Surgery - | **D~Pre~**     | 50 u/kg          |
| .a. | dose 50 iu/kg given*      |                |                  |
+-----+---------------------------+----------------+------------------+
| C.1 | *Post-surgical            | **D~Post~**    | 50 u/kg          |
| .b. | maintenance of dose 50    |                |                  |
|     | iu/kg given every 2 - 3   |                |                  |
|     | days*                     |                |                  |
+-----+---------------------------+----------------+------------------+
| #   |                           |                |                  |
| Out |                           |                |                  |
| put |                           |                |                  |
+-----+---------------------------+----------------+------------------+
| C.1 | ##### Total               | **D~Tu~ =**    |                  |
| .c. |  Utilization of Factor XI | **D~Pre~** +   |                  |
|     |                           | **D~Post~**    |                  |
+-----+---------------------------+----------------+------------------+

**Appendix B**

###### Summary of Model Assumptions

  ---------------- ------------------------- ----------------------------------
  **Section**      **Variable and            **Assumptions used in the model**
                   description**             

  **III.**         Not applicable            The probability of at least one
                                             donation from a vCJD-infected
                                             individual being present in a
                                             plasma pool used to manufacture
                                             Factor XI in the U.K. is nearly
                                             100%.

  **III. A.1.**    **P~vCJD~** -             An average prevalence of vCJD in
                   *Probability individual   the U.K. population was assumed to
                   has vCJD in U.K.          be 1 in 4,225.
                   population*               

  **III. A.2.**    **D~Tpool~ -** *Total     Production of Factor XI included
                   number of vCJD donations  the pooling of plasma donations
                   per pool*                 recovered from whole blood from
                                             approximately 20,000 donations

  **III. A.3.a.**  **D~V~** - *Amount of     The model assumes that
                   recovered plasma per      approximately 200 milliliters
                   donation*                 (mls) of plasma can be separated
                                             away from the blood cells.

  **III. A.3.b.**  **I~bl~** - *Infectivity  Whole blood collected from a
                   of vCJD (or i.c.ID~50~s)  vCJD-infected individual
                   present in infected blood potentially carries a minimum of
                   per ml*                   0.1 i.c. ID~50~ per ml, a most
                                             likely of amount of 10 i.c. ID~50~
                                             per ml, and a maximum of 1,000
                                             i.c. ID~50~ per ml.

  **III. A.3.c.**  **I~Pl-perc~** -          The model uses the more
                   *Percentage infectivity   conservative of the two outcomes
                   associated with plasma    and assumes that 58% of
                   (i.c.ID~50~/ml)*          infectivity is associated with
                                             plasma.

  **III. A.3.d.**  **I~D~** - *Total         One ID~50~ is the amount of
                   infectivity (or           material containing infectious
                   i.c.ID~50~) per vCJD      agent that has a 50% probability
                   recovered plasma          of causing infection in an
                   donation*                 individual or population.

  **III. A.3.e.**  **A~ic-iv~** -            Exposure to infectivity by the
                   *Adjustment for           i.v. route is between 5 and 10
                   intravenous route of      times less efficient at causing
                   infection*                infection than introduction via
                                             the intracerebral route.

  **III.B.1.**     **R~W%~ -** *Percentage   Approximately 16% of starting
                   of pool used to           plasma material from 20,000
                   manufacture Factor XI*    donations was used in the
                                             manufacture of FXI.

  **III.B.1.a.**   **W~st~** - *Weight of    Weight of starting product is
                   starting product*         represented in the model by a
                                             single value point estimate of
                                             5,000 kg.

  **III.B.1.b.**   **W~m~** - *800kg portion 800 kg of material was removed and
                   removed and used to       used to produce Factor XI.
                   extract Factor XI*        

  **III.B.2.**     **R~Log~ -** *Log         Processing reduction is
                   reduction in ID~50~s      represented by a triangular
                   during processing*        statistical distribution
                                             representing a reduction in
                                             ID~50~s during processing of (0,
                                             2,4) Log~10~ i.v. ID~50~/ml
                                             (minimum, most likely, and
                                             maximum).

                                             The model assumes that infectivity
                                             is reduced but not entirely
                                             eliminated from plasma and the
                                             product during processing.
                                             Therefore, although the amount of
                                             *ID~50\ ~*vCJD agent may be
                                             reduced the percentage of pools
                                             and vials containing the agent
                                             still remains the same.

  **III.B.4.**     **Y~fT~ -** *Total yield  The yield of FXI per kg plasma was
                   of Factor XI from plasma  approximately 150 to 180 units,
                   pool*                     subsequently the model estimates
                                             the total yield of Factor XI as
                                             120,000 to 144,000 units per batch
                                             of 800 kg starting material. FXI
                                             was distributed in vials of 1,000
                                             units each.
  ---------------- ------------------------- ----------------------------------

# 

# 

# 

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