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From: TSS ()
Subject: TSE ADVISORY COMMITTEE MEETING OCT. 31, 2005 AGENDA AND SUMMARY
Date: October 27, 2005 at 7:34 am PST


Transmissible Spongiform Encephalopathies Advisory Committee
Center Date Time Location
CBER
October 31, 2005 8:00 a.m. - 5:30 p.m. Holiday Inn Select
8120 Wisconsin Ave.
Bethesda, MD

Agenda:
On October 31, 2005 the Committee will hear updates on the following topics: Current status of bovine spongiform encephalopathy (BSE) in the United States, incidence and prevalence worldwide of variant Creutzfeldt-Jakob Disease (vCJD), and a summary of the FDA Device Panel discussion on September 27, 2005 on criteria for considering label claims of effective decontamination for surgical instruments exposed to transmissible spongiform encephalopathy (TSE) agents. The Committee will then discuss progress in development of a risk assessment model for vCJD in U.S.-licensed human plasma-derived Antihemophilic Factor (Factor VIII). The latter discussion will focus on selection of input parameters for the model. In the afternoon, the Committee will discuss labeling claims for TSE clearance studies for blood component filters.

Background material and meeting information will become available no later than one business day before the meeting (Simply scroll down to the appropriate committee heading).

Procedure:
Interested persons may present data, information, or views, orally or in writing, on issues pending before the committee. Written submissions may be made to the contact person by October 21, 2005. Oral presentations from the public will be scheduled between approximately 12:30 p.m. and 1:00 p.m., and 4:15 p.m. and 4:45 p.m. on October 31, 2005. Time allotted for each presentation may be limited. Those desiring to make formal oral presentations should notify the contact person before October 25, 2005, and submit a brief statement of the general nature of the evidence or arguments they wish to present, the names and addresses of proposed participants, and an indication of the approximate time requested to make their presentation. Persons attending FDA's advisory committee meetings are advised that the agency is not responsible for providing access to electrical outlets.

FDA welcomes the attendance of the public at its advisory committee meetings and will make every effort to accommodate persons with physical disabilities or special needs. If you require special accommodations due to a disability, please contact William Freas or Sheila Langford at least 7 days in advance of the meeting.

Contact Person:
William Freas or Sheila D. Langford, Center for Biologics Evaluation and Research, HFM-71, Food and Drug Administration, 1401 Rockville Pike, Rockville, MD 20852, 301-827-0314.

Advisory Committee Telephone Information Line:
Please call the Information Line for up-to-date information on this meeting, 1-800-741-8138 (301-443-0572 in the Washington, DC area), code 3014512392.

http://www.fda.gov/oc/advisory/accalendar/2005/cber12392d103105.html

Food and Drug Administration
Transmissible Spongiform Encephalopathies
Advisory Committee

Monday, October 31, 2005
Holiday Inn Bethesda


--------------------------------------------------------------------------------

http://www.fda.gov/ohrms/dockets/ac/05/agenda/2005-4189A1_draft.htm



Food and Drug Administration

Transmissible Spongiform Encelphalopathies Advisory Committee
October 31, 2005

Briefing Information

Topic I. Issue Summary

ISSUE SUMMARY

TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHIES

ADVISORY COMMITTEE MEETING

October 31, 2005

Bethesda, MD

Topic # 1

Progress Report on FDA’s Risk Assessment for Potential Exposure to Variant

Creutzfeldt-Jakob Disease (vCJD) Agent in Human Plasma-Derived Antihemophilic

Factor (FVIII) Products

Issue: FDA is developing a risk assessment for vCJD exposure in U.S. licensed plasmaderived

FVIII products. We seek the Committee’s advice how best to refine the

input parameters that are used in the risk assessment model. Additionally, we

seek the Committee’s opinion on the value of the model as a basis for risk

communication in view of the large uncertainties.

Background:

Two cases of presumed transfusion transmission of vCJD were reported in the United

Kingdom (U.K.), in December 2003 and July 2004 (Llewelyn, Peden). Animal models of

endogenous infection have shown that TSE infectivity is associated with both plasma and

cellular blood elements (Brown). Although vCJD in recipients of plasma derivatives has not

been reported, TSE’s have long incubation periods, especially after low-dose exposures. If

there is vCJD exposure risk from plasma derivatives, it would be greatest in association with

products that (1) were made from plasma pools containing a donation from an individual

incubating vCJD; (2) have lower potential for TSE clearance by manufacturing; and (3) are

administered repeatedly for prolonged periods to treat chronic conditions.

At their February 2005 meeting, the TSEAC agreed with the general design of a risk

assessment model for vCJD in plasma derivatives proposed by FDA. FDA has been

developing the model and its inputs and is now undertaking to apply this model to FVIII

products. We intend subsequently to perform vCJD risk assessments for other plasmaderived

products. In this context, FDA seeks the Committee’s advice about its current

thinking, and suggestions on possible refinements with respect to important but uncertain

input parameters for the risk assessment. We also seek an overall opinion from the

Committee on the utility of the model as a basis for risk communication with patients and

their care providers in view of the present uncertainties both with regard to the input

parameters and the interpretation of the output of the risk assessment model.

Risk Assessment Framework

In the setting of uncertainties, risk assessments cannot predict risk precisely, but rather

supply a range of possible risks and elucidate the key factors that most affect the risk. These

ranges are refined over time, as more scientific information becomes known. The risk

assessment estimates the likelihood of potential exposure to an infectious dose (derived from

2

animal studies) of the vCJD agent for recipients of plasma-derived FVIII, but cannot, due to

limitations in currently available data, predict the risk that a recipient was actually infected

by the exposure or will develop clinical illness.

The risk assessment approaches used by the FDA generally follow the four-part framework

and guidelines of the National Academies of Science.1An assessment of vCJD exposure risk

in U.S. products is intended to provide:

• A framework for more precise risk assessments in the future as additional data

becomes available

• Analysis of product characteristics (such as manufacturing and plasma pool size)

that may have greater or lesser influence on margins of safety.

• Estimation of a range of likely, best-case, and maximum potential risks of

exposure to vCJD via products

• A model that can be used to help estimate the need for and potential effectiveness

of additional risk reduction measures

• Information that would be useful for policy considerations and for medical care

decisions by physicians and consumers.

• A basis for risk communication including to health care providers, patients, and

their families

Variant CJD risk assessments are limited because some of the needed information is not

available, is imprecise, or is based on extrapolations from indirect sources. In these cases,

the recommended approach is to use a range of estimates based upon current knowledge and

expert opinion. Because of the uncertainties associated with these components a

probabilistic model using statistical distributions to represent the information used for each

variable (called an "assumption"). The prevalence of vCJD infection is not known among

blood donors in the U.S. but is estimated to be very low. The amounts and period of

infectivity in blood of people incubating vCJD are also not known, but those can be

estimated based upon extrapolation from observations in animal models. The estimated TSE

clearance capacity of various manufacturing processes is based upon limited animal model

studies that have not been performed for all products and that used a variety of spiking

material that may not accurately reproduce the form of the TSE agent in plasma—currently

not known. The determinants of susceptibility to vCJD are largely unknown, although to

date clinical illness has only occurred in people homozygous for methionine at prion protein

(PrP) codon 129. However, vCJD infection without overt clinical illness was found in the

second presumptive transfusion-transmission case. The recipient, who died from unrelated

causes, was heterozygous (methionine/valine) at PrP codon 129. Our risk model has assumed

that all persons might be susceptible to infection with the agent of bovine spongiform

encephalopathy (BSE).

The exposure estimate is the product of all risk assessment parameters, and takes into

account a number of factors including:

1 Risk Assessment in the Federal Government: Managing the Process. 1983. Washington DC, National

Academy Press

3

• The likelihood that a donation from a vCJD infected individual is contained in a

plasma pool for fractionation

• The amount of infectivity that might be contained in a single dose of a specific

product made from a contaminated pool

• The amount of product given to a typical recipient per course of treatment or per

year

Risk Mitigation by Donor Deferral

Although no vCJD blood transmission had occurred at the time, as a prudent measure to

reduce risk, in 1999 the FDA recommended deferring plasma donors who might have been

exposed to the vCJD agent during travel or residence in the U.K. for any total period of six

months or more between 1980 and 1996. Based on FDA guidance that was issued in January

2002, these deferrals were expanded to include Source Plasma donors who resided in France

for five years or longer, donors who traveled or resided in the U.K. for any total period of 3

months or more (1980-1996), members of the military who may have consumed British beef

at military establishments in Europe during certain time periods (six or more months

exposure between 1980-1990 or 1980-1996 depending on where they were based), and

recipients of transfusions in the U.K. since 1980. The same deferrals applied to donors of

Whole Blood (including recovered plasma), with an additional deferral based on five years of

exposure in any part of Europe since 1980 (not including exposures in the U.K. after 1996).

These deferrals were intended to significantly reduce the likelihood for collection of plasma

from a donor infected with vCJD but could not totally eliminate that risk.

FDA proposes to estimate risk for at least two time periods: (1) current risk taking into

account donor deferral policies to reduce vCJD risk that have been in place since October

2002, and (2) the risk prior to 1999, prior to the implementation of donor deferrals to reduce

vCJD risk.

Discussion: Elements of vCJD Risk Assessment for Plasma-derived FVIII

Four main categories of information are needed to perform the vCJD risk assessment: the

likelihood of a contaminated donation, the potential amount of infectivity in the starting

material used for fractionation, the amount of infectivity cleared during manufacturing, and

the amount of product received by a recipient. Within these categories, FDA requests the

Committee’s advice on selection of appropriate input assumptions for the model:

• Prevalence estimates for vCJD in the U.K., needed to estimate possible prevalence

in U.S. donors taking into account the effectiveness of donor deferrals and foreign

travel/residence history for U.S. donors of Source Plasma and recovered plasma

• The time course (after initial infection and before the onset of overt illness) and

level of infectivity that may be present in plasma of a donor who is incubating

vCJD (in 50-percent infectious doses [ID50])

• The strategy for estimating TSE infectivity clearance achieved by various steps in

the manufacturing process (and the complete process), including whether the

4

infected material selected for spiking experiments adequately represented the

physical state of infectivity that might be present in human plasma

• Data needed to estimate a recipient exposure based on clinical use of product,

effects of plasma pool size on the risk of contaminating end products, and whether

it is feasible to incorporate the potential cumulative effect of repeated exposures

(especially multiple exposures to "sub-infectious" doses of infectivity)

Issue 1: Prevalence of vCJD in the U.K. and potential prevalence of vCJD in U.S. donors

exposed to British beef products. Estimates of vCJD prevalence in the U.K. must be used

to estimate the prevalence of vCJD in U.S. donors, based upon time spent in the U.K. or

opportunities to have eaten British beef while serving in the U.S. military in Europe.

However, there is uncertainty how recent U.K. tonsil and appendix surveillance data

and/or epidemiological models of the clinical outbreak can best be used to estimate the

prevalence of vCJD in the U.K.

Question: a) What estimate should be used to reflect prevalence of vCJD in the U.K.?

Background

Surgical surveillance data from a tonsil/appendix survey of tissues, mainly from

operations on people ages 20-29, demonstrated prevalence for disease-associated PrP

(PrPTSE) immunohistochemical staining of 1:4224 (three positive appendices detected

among samples from 12,674 individuals (Hilton) 95% confidence interval 49-692 cases

per million people in the U.K.). However, a recent epidemiological model predicted that

the current U.K. epidemic of vCJD may be much smaller than the figure suggested by the

surgical survey—final prevalence not to exceed 1:197,000-1:328,000people (Boelle).

The latter model, however, does not contain any adjustment for the possible emergence

of vCJD cases in individuals with either the MV or VV genotype at codon 129 of PrP.

Use of the surgical tissue surveillance data to estimate prevalence has been controversial,

because it yielded results so discrepant with epidemiological predictions of a much

smaller epidemic. The discrepancy could be explained by long incubation periods of

vCJD, or by the presence of subclinical vCJD (infections without illness). Clinical and

preclinical (asymptomatic) cases that may eventually progress to clinical illness are

addressed in many of the predictive models. However, the possibility of indefinitely

subclinical infections (a carrier state) is not reflected in most of the recent

epidemiological predictions.

Limitations of the surgical tissue surveillance data in estimating vCJD prevalence include:

• The tissues analyzed were mostly from people of ages 20-29, an age group that

may be more susceptible to vCJD (mean age at onset about 28 years). Older and

younger populations have had lower prevalences, based on epidemiological data.

The reason for the peculiar age distribution of vCJD remains unknown; it may

reflect either a more intensive exposure to the BSE agent (for example, due to a

greater consumption of some high-risk beef product) by young people or some

age-related increased susceptibility to vCJD (such as more frequent pharyngitis

5

in childhood which might have facilitated infection); both kinds of explanation

have been postulated by U.K. authorities.

• Identification of PrPTSE in lymphoid tissues by immunostaining does not

necessarily mean that blood from these subjects would be infectious (or that they

will develop disease).

• On the other hand, PrPTSE staining in a few appendices might not have detected all

subclinical vCJD infections. There is reason to suspect that PrPTSE staining

appears in the appendiceal lymphoid tissue rather late during the incubation

period of vCJD; for example, in the second presumed transfusion-transmitted

vCJD infection, tonsils and appendix of the subject were both negative for PrPTSE

staining while the spleen and a cervical lymph node were positive.

• The epidemiology and clinical course of patients with positive PrPTSE staining in

appendices is unknown, since the tissue samples in the study were anonymized.

Therefore other than age range, epidemiological information is unavailable from

the tissue survey.

Limitations for the prediction of vCJD prevalence based on epidemiological modeling of

the clinical outbreak of vCJD in the UK include:

• Data needed for the model are limited or not available. For example, information

is not available on the probability or quantity of exposure to the vCJD agent, time

of initial infection, minimum or maximum incubation period, or age-specific

susceptibility. Because these data are limited, predictive models rely on a number

of simplifying assumptions.

• Many of the current models may not adequately estimate the number of

asymptomatic vCJD cases in the population.

• Current models, to our knowledge, do not address the potential emergence of

vCJD cases in individuals heterozygous (MV) at PrP codon 129, or homozygous

for VV.

Proposal: We propose using the surgical tissue surveillance data as the assumed

prevalence of vCJD in the U.K. to provide a more conservative estimate for possible

exposure in the risk assessment than those from epidemiological models based observed

clinical cases of vCJD. However, we propose that the risk assessment also be done using

epidemiologic predictions based on diagnosed clinical vCJD cases as an alternative

assumption of prevalence (with adjustments for possible latent infections during the

incubation period of illness).

Issue 2: Prevalence of vCJD in US plasma donors with a history of extended travel or

residence in the U.K., France or elsewhere in Europe since 1980

Question: How effective are current donor deferrals for geographical risk of vCJD?

6

Background

The 2002 geographic deferral criteria for vCJD currently in place recommend deferring

donations from US blood and plasma donors with a history of three months total travel or

residence between 1980 and 1996 in the U.K., or five years of travel or residence in France

from 1980 until the present. Donors of Whole Blood (but not of Source Plasma) who have a

history of five years or more of travel or residence in Europe from 1980 until the present also

should be deferred. Donor deferrals are also recommended for members of the military (as

well as civilian employees and dependents) residing at certain European bases where British

beef comprised a large proportion of the commissary and other on-base beef supplies.

There are two main categories of donors of recovered plasma and Source Plasma who may

have vCJD risk, but remain in the donor pool: (1) donors with a deferrable history of travel or

residence who did not give an accurate or complete travel history (or who were not

adequately queried), and (2) donors with some geographical exposure risk whose exposure

does not meet current criteria for deferral as specified in FDA’s 2002 guidance.

Estimating the current number of new donors presenting for blood donation that should be

but are not deferred for potential vCJD travel/residence risk is especially difficult. It was

reported recently that, since the vCJD policies were implemented, 0.37% of Whole Blood

donors have been deferred annually for vCJD risk history. The prevalence of deferrable risk

for Source Plasma donors has not been estimated through travel surveys. Absent this

information, the prevalence has been estimated from travel survey data on Whole Blood

donors, with an adjustment for age.

In previously published anonymous donor surveys that described an overall prevalence of

deferrable risk among Whole Blood donors, unreported risk was found in 1.9% (Williams)

and 3.1% (Sanchez) of donors. These estimates are also supported by post-donation

identification of risk factors in individuals who later test positive for HIV and other

transfusion transmitted infections. No survey to validate the efficiency of the more recent

2002 geographic deferral criteria for vCJD has been conducted. Many former repeat donors

and some potential new donors, aware of the current deferral criteria for vCJD risk, are

thought to have self-deferred from donation. Because they no longer present to collection

centers, it is difficult to estimate the size of this population; that uncertainty confounds the

estimation of the true total number of donors deferred for vCJD risk and also the number of

deferrable donors who have continued to donate while at increased risk for vCJD.

Source Plasma and recovered plasma are collected largely from repeat donors who have

undergone multiple rounds of donor screening. The American Red Cross estimated that

approximately 83 percent of all units collected from 1991 through 1993 were from repeat

donors (Lackritz). Consistent with policies of the plasma industry since 1991, all donations

of Source Plasma are obtained from "Qualified Donors" who have donated on more than one

occasion in the last six months. Overall, less than 20 percent of plasma is collected from

first-time donors who may be at higher vCJD risk than repeat donors since they have been

screened less often.

7

Proposal: FDA is seeking additional information on the efficiency of donor deferrals for

Source Plasma. Based on the currently available previous surveys of unreported risk for other

conditions (and allowing for a margin of error), we propose to estimate that the FDArecommended

deferral policy has 90% to 95% efficiency for deferring donors with the

specified increased vCJD risk.

Risk amongst persons with exposure not meeting the deferral criteria is estimated in

proportion to time spent, adjusted for the time period of exposure in relation to the BSE

outbreak. Age adjusted travel survey data on Whole Blood donors will be taken also to

represent Source Plasma donors.

Issue 3: Level of vCJD infectivity in human plasma

Question (a) what intravenous (IV) infectivity range (in ID50) should be selected for plasma,

based on animal studies

Background

a. Quantitation of infectivity in FVIII model

i. A FXI risk assessment model (presented to TSEAC on Feb 8, 2005) incorporated

the variability and uncertainty of the available scientific information about TSE

infectivity in blood using a triangular statistical distribution with a minimum

value of 0.1 intracerebral (ic) ID50, a most likely value of 10 ic ID50, and a

maximum value of 1,000 ic ID50 (mean of ~ 343 ic ID50). The latter value of

1,000 was based on a report of a study that failed to demonstrate vCJD infectivity

in human blood, using an assay that had a limit of detection at about 1,000

ID50/ml (Wadsworth et al).

ii. Participants at a meeting on TSE risks convened by Health Canada (in Feb 2005)

suggested that a maximum infectivity of 1,000 ICID50 in human blood was likely

to have been an overestimation. This level is greater than any reported to date for

an animal model.

iii. Re-evaluation of scientific literature revealed that levels of infectivity measured in

animal models were most often in the range of 10 to 20 IC ID50 per ml of blood.

In one animal experiment a maximum level of 310 ic ID50 was observed

(Casaccia). So far as we know, no published report has ever claimed to detect

any greater concentration of TSE infectivity in blood.

iv. Recent experiments in primates by Lasmezas and coworkers showed that the

incubation periods were the same after inoculations of primate-adapted BSE agent

by the IC and IV routes, suggesting that the efficiency of infection was equivalent

by both routes (Herzog). However, experimental TSE infections in rodent models

have generally demonstrated that the IC route is 5 to 10 fold more efficient than

IV. (Brown)

8

Proposal: FDA proposes that the FVIII model will use a statistical distribution for

infectivity, with a minimum value of 0.1 IC ID50, a most likely value of 10 IC ID50 and a

maximum value of 310 IC ID50. Since the BSE agent in primates may more closely

approximate the human situation than rodent models, we propose to model the IC/IV ratio for

infectivity over a range of 1 and 5.

Question (b) Is there sufficient evidence available to estimate when during the incubation

period of vCJD human plasma is infectious?

Background

Animal studies monitoring the appearance of infectivity after exposure have shown that

blood infection can first be detected about halfway through the incubation period). The

incubation period for human vCJD is not known, which makes animal estimates difficult to

extrapolate. The year of travel-related exposure among donors is also not known. The two

transfusion transmitted cases of vCJD in the U.K. demonstrate that blood of one donor was

infectious at least 3 years prior to the onset of symptoms and the second at least 18 months.

Proposal: Because of uncertainties about the incubation periods of food-borne vCJD and the

time during the incubation period at which infectivity appears, FDA proposes to adopt a

conservative approach, and assumes plasma to be potentially infectious throughout the

incubation period.

Issue 4: Selection of appropriate values for clearance of TSE infectivity from plasmaderived

FVIII

This parameter is used to estimate the clearance of vCJD by manufacturing processes and is

one of the most important determinants of risk.

Questions: Does the Committee agree with FDA’s proposed approach for estimating

clearance of vCJD infectivity from FVIII products by manufacturing processes? What

experiments might enable refinement of these estimates and allow comparison of clearance

offered by various steps in the methods used to manufacture plasma-derived FVIII?

Background:

The potential removal of TSE infectivity clearance from products is estimated based upon

evaluation of steps in manufacturing that have been shown by pilot studies with animal

models to clear spiked or endogenous infectivity (Table). Each FVIII product is unique in its

details of manufacturing, and available generalizable data are limited, so that identical levels

of clearance cannot automatically be assumed for different products, even those using similar

manufacturing steps (Foster).

The estimates of TSE clearance for specific products are incomplete, because published,

peer-reviewed detailed studies for specific steps in the manufacture of FVIII are not available

for all products, nor is a comprehensive set of data available to FDA. In addition, there

9

remain uncertainties about the general relevance of studies in which various materials

prepared from TSE-infected brain tissues are spiked into a pilot process for manufacturing

plasma derivatives. Clearance of TSE agents extracted from infected brain tissues may not

precisely reflect partition of endogenous TSE agents, since the physical form of blood-borne

form of infectivity is still unknown. High-titer preparations from TSE-infected brain

(homogenates, microsomal fractions, scrapie fibrils, or other) have been used, none of which

is likely to completely reflect the properties of TSE agents in blood. Clearance has been

measured either as reduction in infectivity measured by bioassay in animals or as reduction in

PrPTSE measured by various assays, which makes direct comparison across studies and across

products difficult.

Until clearance data from laboratory studies of individual steps as well as the entire

manufacturing process for each marketed product becomes available, we believe it might still

be informative to estimate the range of clearance based on the presence of specific

manufacturing steps that have been studied for FVIII. Many of these studies have not been

peer-reviewed or submitted to FDA. A review of the literature, and of unpublished

information available to FDA permits rough estimates of infectivity clearance values offered

by specific steps in the manufacture of Factor VIII (Table).

Several methods are commonly used to manufacture FVIII. These include cryoprecipitation,

PEG precipitation, ion exchange chromatography, and affinity chromatography using heparin

or monoclonal antibodies to VWF (followed by elution of FVIII). The table summarizes

experimental data for various process steps that are common among many FVIII products.

Based on the available data, cryoprecipitation does not appear to be a robust clearance step

(one log10 or less prion removal). Other single steps such as PEG precipitation have

consistently demonstrated 2-3 log10 of clearance for spiked TSE infectivity, and 3-4 log10

clearance for ion-exchange chromatography and monoclonal affinity steps, respectively.

Data currently available to FDA suggest, as an estimate, that FVIII products lacking affinity

purification are likely to have less clearance, whereas plasma products manufactured using

an affinity purification step are likely to have more TSE infectivity clearance.

Proposal: FDA proposes to model three clearance values for the risk assessment model: 2, 5,

and 8 logs, to represent likely minimal, likely mid-range and likely maximal clearance of the

vCJD agent from products manufactured using a variety of methods.

Issue 5: Recipient use of FVIII

Several scenarios for use of FVIII by typical recipients over a given time period, in

combination with assumptions, will be incorporated in the FDA model to estimate potential

exposures to the vCJD agent.

Question (a) What data should be used to estimate how much FVIII is used by typical

patients?

The CDC has provided summary data on patient utilization of plasma-derived FVIII

products. CDC Hemophilia Treatment Center (HTC) data were collected for approximately

10

3000 hemophilia patients from 1993 through 1998. Incorporation of the CDC data into the

model should enhance the precision of the risk estimates.

Proposal: We propose using CDC HTC data to estimate use of plasma-derived FVIII by

subgroups of hemophilia patients with more severe disease and frequent prophylactic

treatments, less severely affected patients treated intermittently, and people with severe von

Willebrand’s disease.

Question (b) What is the effect of plasma pool size (i.e. number of donors per final product)

for FVIII recipients treated repeatedly?

Use of larger plasma pools increases the risk that a lot of product will be infected with any

infectious agent potentially present in the donor population if the agent is not cleared from

the product during manufacturing. Lynch et al. estimated such risks for a range of plasma

pool sizes (Lynch). They concluded that, while risk of exposure increases with pool size,

repeated treatments attenuate this effect because exposure risk is also increased by repeated

treatments. In the case of treatment for hemophilia using plasma-derived FVIII, most

patients received many doses over time, and thus the effect of plasma pool size on potential

vCJD exposure should be minimal.

Proposal: FDA proposes to estimate plasma pool size as a range, between 20,000 and 60,

000 donations, with a bimodal distribution to reflect expected Source Plasma and recovered

plasma pool donor numbers. FDA will seek additional data from plasma fractionators to

clarify the distribution of pool sizes based on actual practices.

Question (c) Can a possible cumulative effect from repeated exposures to low doses of vCJD

agent be incorporated into the risk model?

Background

Two hamster scrapie studies suggested that the risk of infection after repeated exposures to

low doses of infectivity might be cumulative (Diringer, Jaquemot). In the latter study,

repeated intraperitoneal injections of low doses of infectivity were given once, twice, or 5

times weekly for 200 days. The repeated low-dose injections resulted in higher disease

frequency than when an equivalent dose or even a larger dose was given only once.

A subset of people with Hemophilia A may receive, or may have in the past received

prophylaxis with plasma-derived FVIII twice or three times a week. Other patients may

receive only intermittent treatments as needed. Both kinds of patients might have repeated,

low-dose exposures to the vCJD agent. It is not feasible to model all possible scenarios since

individual patient treatment regimens vary so much in their frequency and duration.

FDA proposes that, to allow for the theoretical possibility of cumulative effects, the model

provide a cumulative risk for a 1-year period.

11

Issue 6: Risk communication based on risk assessment estimates of potential exposure to

vCJD in US recipients of FVIII.

In the United Kingdom, where all plasma-derived FVIII was manufactured from U.K.

donations until 1999, the risk to recipients was deemed sufficient to trigger risk

communication and risk management measures. These included direct communication

between health care providers and their patients to explain risk, detailed website information

for patients and healthcare providers, and precautionary recommendations to patients to

inform their dentists and surgeons of their increased vCJD risk. While the UK exposure and

risk are likely higher, and the uncertainties in any risk estimate will be extremely large, FDA

believes that the US FVIII risk assessment may be useful in providing risk estimates to

consumers and health care providers, and in formulating policy.

Question to the Committee: Given the present scientific uncertainties in the underlying

assumptions of the FVIII risk assessment, does the Committee believe that the risk

assessment model could provide a useful basis for risk communication to patients, their

families, and healthcare providers?

References

1. Brown, P., et al. Further studies of blood infectivity in an experimental model of

transmissible spongiform encephalopathy, with an explanation of why blood

components do not transmit Creutzfeldt-Jakob disease in humans. Transfusion

39:1169-78, 1999.

2. Boelle, P.-y. et al. Modeling the epidemic of variant Creutzfeldt-Jakob disease in the

UK based on age characteristics: updated, detailed analysis. Stat. Meth. Med. Res.

12:221-3, 2003.

3. Casacchia, P. et al. Levels of infectivity in the blood throughout the incubation

period of hamsters peripherally injected with scrapie. Arch. Virol. 108:145-9, 1989.

4. Cervenakova, L., et al. Factor VIII and transmissible spongiform encephalopathy: the

case for safety. Haemophilia 8:63-75, 2002.

5. Diringer, H. et al. Effect of repeated oral infection of hamsters with scrapie. J. Gen.

Virol. 79:609-612, 1998.

6. Foster, PR et al. Studies on the removal of abnormal prion protein by processes used

in the manufacture of human plasma products. Vox Sang 78:86-95, 2000.

7. Hilton, D.A. et al. Prevalence of lymphoreticular prion protein accumulation in UK

tissue samples. J. Pathol. 203:733-9, 2004.

8. Jaquemot, C. et al. High incidence of scrapie induced by repeated injections of

subinfectious prion doses. J. Virol. 79:8904-8, 2005.

9. Lackritz, E.M. et al. Estimated risk of transmission of the human immunodeficiency

virus by screened blood in the United States. NEJM 333:1721-5, 1995.

10. Herzog, C. et al. Tissue distribution of bovine spongiform encephalopathy agent in

primates after intravenous or oral infection. Lancet 363:422-28, 2004.

12

11. Llewelyn, C.A. et al. Possible transmission of variant Creutzfeldt-Jakob disease by

blood transfusion. Lancet 363:417-21, 2004.

12. Lynch, T., et al. Considerations of pool size in the manufacture of plasma

derivatives. Transfusion 36:768-9, 1996.

13. Peden, A.H. et al. Preclinical vCJD after blood transfusion in a PRNP codon 129

heterozygous patient. Lancet 364:527-9, 2004.

14. Sanchez, A.M. et al. Prevalence, donation practices, and risk assessment of blood

donors with hemochromatosis. JAMA 286:1475-81, 2001.

15. Williams, A.E. et al. Estimates of infectious disease risk factors in US blood donors.

JAMA 277:967-72, 1997.

13

Prion Removal Factors for FVIII

Removal Steps Ref./

Cryoprecipitation

PEG-

precipitation

Ion

Exchange

Chromatograph

y

Monoclonal

Antibody

Affinity

Purification

1 1.0 3.1 4.1

2 <1.0

3 1 2.2, 3.0

4 1.0 3.5 4.1

5 1.7 – 3.3

6 1.0

Estimated

Reduction

for each step

<1.0

(uncertain)

2.0 3.0 4.0

Contribution

of each step

Not Effective Contributes

to Removal

Contributes

to Removal

Significant

Removal

Total

contribution

of the p

steps

rocess

Manufacturing processes demonstrate a significant capacity to

remove TSE infectivity or TSE-associated prions

References:

1) Foster et al., Vox Sang. (2000) 78: 86

2) Lee et al. J. Virol Method (2000) 84:77

3) Lee et al. Transfusion (2001) 41: 449

4) Rohwer / Baxter & ARC (PPTA presentation)

5) Vey et al., Biologicals (2002) 30: 187

6) Brown et al., Transfusion (1999) 39: 1169

http://www.fda.gov/ohrms/dockets/ac/05/briefing/2005-4189B1_01.pdf

Topic II. Issue Summary

ISSUE SUMMARY

TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHIES

ADVISORY COMMITTEE MEETING

October 31, 2005

Bethesda, Maryland

Topic 2: Labeling Claims for Filters Intended to Remove TSE Infectivity from

Blood Components

Issue: FDA seeks the advice of the Committee on the minimal scientific criteria

for validation of a claim for reducing TSE infectivity in blood products by

filtration.

Background

Concerns about the potential transmission of variant Creutzfeldt-Jakob disease (vCJD) by

blood and blood products emerged soon after the first report of the disease in 1996 (Will,

RG. Lancet 1996; 347:921-25). Precautionary measures were subsequently introduced

by many nations to protect against transfusion transmission of vCJD. Many countries,

including the USA, adopted precautionary blood donor deferral policies for individuals

who had lived in or traveled to regions endemic for BSE for substantial periods of time.

Additionally, based on theoretical considerations, leukoreduction was instituted as a

possible added safeguard in the UK and in some other countries where bovine

spongiform enecephalopathy (BSE) was prevalent.

Leukoreduction of blood components can be achieved by collection of the products with

an apheresis instrument capable of preparing a blood product with low leukocyte content

or by filtration with specific filters that reduce leukocyte content of blood products.

Transfusion of leukoreduced blood has been shown to reduce the incidence of transfusion

associated febrile nonhemolytic reactions, alloimmunization of platelet recipients and

transmission of cytomegalovirus (CMV). In the US a blood product labeled as

leukoreduced has to have less than 5 x10 6 leukocytes while in Europe this cutoff is at 1 x

106 leukocytes. Although leukoreduction of blood products is associated with several

beneficial outcomes, so far no filter manufacturer has made claims that use of their filter

will lead to such benefits.

In 2003, a patient in the UK was diagnosed with vCJD that appeared to have been

transmitted by a transfusion of non-leukodepleted red cells six years earlier from a donor

who developed vCJD three years after the donation (Llewelyn CA. Lancet 2004;

363:417-21). In August 2004, a case of preclinical vCJD was reported in a patient who

had received non-leukodepleted red blood cells from a donor who developed vCJD 18

months after donation (Peden AH. Lancet 2004; 364:527-529). The recipient died from a

non-neurological disease five years after receiving the blood transfusion. Proteaseresistant

prion protein (PrPsc) was detected in the spleen and in a cervical lymph node but

not in the brain. The patient was heterozygous for methionine and valine at codon 129 of

the prion-protein-encoding gene (PRNP), suggesting that susceptibility to vCJD infection

is not confined to methionine homozygous PRNP genotype, as had been previously

suggested. These findings may increase the estimated number of future vCJD cases to be

expected in the UK (Peden, AH. Lancet 2004; 364:527-529) and other countries.

In 1999, UK authorities implemented universal leukoreduction as a precaution against

transmission of vCJD by transfusion of blood. This measure was based on an

assumption—taken from a limited amount of research with animals experimentally

infected with the agents of transmissible spongiform encephalopathies (TSEs)—that most

of the infectivity in human blood would be associated with white blood cells (Williamson

ML. Br J Haematol 2000; 110: 256-272). Even then, findings in blood of TSE-infected

mice and hamsters suggested that at least 40% of the infectivity might be plasmaassociated

(Rohwer et al. unpublished). In agreement with this observation, other

investigators found no loss of infectivity when TSE-infected plasma was passed through

some leukocyte reduction filters (Brown P. Transfusion 1998; 38:810-816). Similarly, no

significant removal of abnormal scrapie-type prion protein (PrPsc) was detected when

units of human whole blood, spiked with microsomal fractions from a TSE-infected

brain, were passed through leukoreduction filters from commercial sources (Prowse, CV.

Vox Sang 2000; 79: 248).

Gregori et al. recently reported studies attempting to assess how effectively

leukoreduction had reduced TSE infectivity in components of blood from hamsters that

had been experimentally infected with the scrapie agent. Their data indicated that

leukoreduction removed only 42% of the TSE infectivity present in whole blood. The

authors concluded that leukoreduction using the filter studied had been insufficient to

remove most of the infectivity from an infected blood unit and that substantial amounts of

the transmissible agent remained in plasma (Gregori, L. Lancet 2004; 364:529-531).

Discussion

Current considerations:

FDA’s TSEAC concluded, on June 2, 2000, that the then current scientific data were

insufficient to support reliance on leukocyte reduction to reduce the infectivity of CJD

and vCJD agents potentially present in blood components—at that time still only a

theoretical possibility. TSEAC did not recommend leukoreduction in addition to or as a

substitute for FDA’s precautionary blood donor deferral policy.

Since the last review of leukoreduction by the TSEAC, the recognition of two

presumptive transfusion-transmitted cases of vCJD in the UK has established with high

likelihood that transmission of vCJD by blood transfusion can occur (Wilson, K. Lancet

2004; 477-479). Additionally, during the past year, the Council of Europe has granted

their "mark" to a leukoreduction filter, acknowledging that a manufacturer had presented

data in support of a claim that the filter had reduced the risk of transmitting vCJD by

blood (www.pall.com/pdf/TSE_timeline.pdf). Pall Corporation is the first manufacturer

to obtain a CE Mark in Europe for reduction of prions in blood products (Leukotrap

Affinity Prion Reduction filter), which, the company has stated, "may reduce the risk of

vCJD through blood transfusion" (www.pall.com/pdf/TSE_timeline.pdf). There are at

present no devices that have been licensed in the US for the purpose of removing TSE

infectivity from blood or a blood component.

FDA remains very concerned about the risk from blood products derived from donors

with asymptomatic vCJD, and possibly other forms of CJD. FDA wishes to assess

whether, when used in combination with donor deferral policies already in place (or

under consideration), clearance of TSE agents from blood by newer filters, including

leukocyte reduction filters, is likely to contribute substantially to the safety of blood,

blood components or plasma derivatives. Consequently, FDA seeks to clarify the

scientific criteria that would be appropriate for approval of filters (or other methods)

labeled with a claim to reduce prions in blood or blood components.

Evaluation of the potential efficacy of filtration devices or other techniques to remove

pathogens from contaminated blood is not unique to TSE agents. FDA has reviewed a

number of methods purported to reduce the risk of transmitting bacteria and viruses

present in donor blood. Criteria FDA used for evaluating such methods may be of some

value in similar review of methods to remove TSE agents from blood; those criteria have

been summarized in by the FDA at www.fda.gov/ora/inspect_ref/igs/viralcl.html - 07-09-

2004 and in an ICH consensus document (Fed Reg 1998;

www.fda.gov/cber/gdlns/virsafe.txt). However, any attempt to apply the criteria used to

review previous methods for reduction of other infectious agents is limited by the present

scientific uncertainties regarding the interpretation of TSE clearance studies, which

include the following:

• Imperfect knowledge about the physical-chemical characteristics of the TSEagent

in blood and plasma

• Very low titers of TSE infectivity in endogenously infected whole blood and

plasma, below the sensitivity for detection by current immunological methods

(i.e. without bioassay)

• Relevance of various animal models with endogenous TSE infectivity in blood—

their similarities to human blood containing TSE infectivity

• Relevance for human blood of experiments using various preparations derived

from infected tissues—usually brain tissue—containing large amounts of TSE

infectivity

FDA Proposal

Based on these considerations, FDA proposes that the following minimal scientific

criteria should be applied in validation of candidate submissions to FDA for claims of

reducing TSE infectivity in blood and blood components by leukoreduction filters:

• Demonstration of a reduction of endogenous TSE infectivity by bioassay in two

animal models (rodent and sheep)

i) The study should use a full-scale blood unit and leukoreduction filter.

ii) The infectivity should be from BSE or vCJD strains of TSE disease.

iii) Reduction of PrPres content by filtration will be considered is as supportive

data but not sufficient to obtain a claim.

• Each study should be done at two separate sites to minimize issues of cross

contamination and differences in laboratory practice.

• Study size should be sufficient to support a statistically valid conclusion on the

ability of the filter to decrease endogenous infectivity in a blood product.

Based on the results of the animal studies, FDA currently would consider clearing filters

with the following labeling:

This filter has been shown to reduce transmission of TSE infectivity by transfusion in an

animal model. Due to lack of feasibility, studies have not been performed to validate this

claim in a human population.

Questions for the Committee

FDA asks the TSEAC to consider whether, in addition to blood donor and plasma donor

suitability policies that currently are recommended, the safety of blood products might be

enhanced by use of leukoreduction filters validated to remove TSE agents from blood or

blood components. More specifically, we ask the committee to address the following

questions:

1) Are the FDA’s proposed minimal criteria for validation of TSE infectivity reduction

by filtration adequate and appropriate?

In particular, please comment on the following elements of the FDA’s proposed criteria:

• Rationale for the use of specific animal models to study the properties of bloodborne

TSE infectivity (Are experiments in rodents sufficient, or should

experiments also be done in sheep?)

• Is it necessary that each experiment should be done at two separate laboratory

sites (i.e. to ensure reproducibility, and accuracy of clearance)?

• General description of informative scaled-down processes for reducing TSE

infectivity in blood

• Levels of clearance acceptable for claims of reduced TSE infectivity in blood

components as used in clinical settings

• Estimated logs of clearance of TSE infectivity required to conclude that blood

filters have effectively removed infectivity from blood components

• Methodology appropriate to use in evaluating TSE agent clearance (bioassays for

infectivity, Western blot or other assay for prion proteins, other methods)

2) Please comment on FDA’s proposed labeling for a filter that meets appropriate

criteria for a claim to reduce TSE infectivity in blood or blood components.

http://www.fda.gov/ohrms/dockets/ac/05/briefing/2005-4189B1_02.pdf

Bibliography

Other References Sent to Committee Members

For TSEAC Meeting on Oct. 31, 2005

Department of Health, DNV Consulting, Risk Assessment of vCJD Infectivity in Blood,

Appendix II, Infectivity of Blood, February 2004:

www.dnv.com/binaries/AppII_tcm4-74416.pdf

Hunter, N. et al. Transmission of prion diseases by blood transfusion. Journal of General

Virology, 83: 2897-2905, 2002

Chadeau-Hyam, M and A. Alperovitch. Risk of variant Creutzfeldt-Jakob disease in

France. IJE vol. 34 no. 1: 46-52, 2005.

Foster, P.R., Removal of TSE agents from blood products. Vox Sang. 87 (suppl.2): S7-

S10, 2004

http://www.fda.gov/ohrms/dockets/ac/05/briefing/2005-4189b1_03_bibliography.pdf

TSS




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