June 12, 2009 Transmissible Spongiform by hxe11278

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									            DEPARTMENT OF HEALTH AND HUMAN SERVICES
          UNITED STATES FOOD AND DRUG ADMINISTRATION
         CENTER FOR BIOLOGICS EVALUATION AND RESEARCH




 This transcript has not been edited or corrected, but appears as received
from the commercial transcribing service. Accordingly the Food and Drug
        Administration makes no representation as to its accuracy.




           TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHIES
                       ADVISORY COMMITTEE

                             21st Meeting




                       Friday, June 12, 2009

                               8:00 a.m.




                             Holiday Inn
                    2 Montgomery Village Avenue
                          Gaithersburg, MD
                                                              2
                      C O N T E N T S
                                                           Page
Opening Remarks and Introduction of Committee Members
          William Freas. Ph.D.
          Acting Executive Secretary                         6

Statement of Conflicts of Interest
          William Freas, Ph.D., Acting Executive
          Secretary                                          8

Opening Remarks, TSEAC Chairman, Nick Hogan, M.D., Ph.D.    13
                           TOPIC I
        FDA's Risk Assessment for Potential Exposure
     to vCJD in US-licensed Plasma-Derived Factor VIII

A. Introduction and Overview of BSE and vCJD
   Issues Worldwide
          David M. Asher, M.D., DETTD, OBRR,
          CBER, FDA                                         14

B. vCJD in the UK and the Transfusion Medicines
   Epidemiology Review
          Professor Robert G. Will, J.D., CJD
          Surveillance Unit and Western General
          Hospital, Edinburgh                               30

C. FDA Geographic Donor Deferral Policies
   to Reduce the Risk of Transmitting vCJD
   by Blood, Blood Components and Plasma
   Derivatives: Rational Policies and Effects
   on Risk and Supply
          Alan Williams, Ph.D., OBRR, CBER
          FDA                                               54

D. Introduction to TSE Clearance in the Manufacture
   of Plasma-Derived FVIII
          Dorothy Scott, M.D., D.H., OBRR, CBER,
          FDA                                               69

E. TSE Clearance Studies for FVIII Products
          Dr. Albert Gröner, PPTA, CSL,
          Behring GmbH                                      79




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                C O N T E N T S (Continued)

F. FDA Assessment of Possible Risks for
   Plasma-Derived Products in the UK
   and US
          Steven Anderson, Ph.D., OBE, CBER,
          FDA                                           89

Open Public Hearing                                    120

          Mark Skinner,
          World Federation of Hemophilia               122

          Dave Cavanaugh
          Committee of Ten Thousand                    126

          Theresa Matthews
          Consumer                                     139

          Val Bias
          National Hemophilia Foundation
          (read by Mark Skinner)                       145

          Robert G. Rohwer, Ph.D.
          V.A. Medical Center
          and University of Maryland                   149

Committee Discussion                                   154
                             TOPIC II

                Informational Presentations

A. BSE Surveillance and USDA-Regulated Food Controls
   in the US
          Janet Hughes, D.V.M., Ph.D., APHIS, USDA     205

B. BSE Surveillance and Food/Feed Controls
   in Europe
          Dr. Martial Plantady, European
          Commission                                   220

C. BSE Surveillance, Animal Feeds and Food
   Controls in Canada
          Dr. Noel Murray, Canadian Food Safety
          Inspection Agency                            239




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                 C O N T E N T S (Continued)


D. FDA Enhanced Animal "Feed Ban:" Current Status
          Burt Pritchett, D.V.M., CVM, FDA              260

E. FDA-Regulated Food Controls in the US
          Amber McCoig, D.V.M., CFSAN, FDA              278

F. FDA Proposed BSE "Medical Products" Rule:
   Current Status
          Theresa Finn, Ph.D., OBRR, FDA                283

G. Recent Progress in Developing a Relevant Animal
   Model for vCJD Agent in Blood
          Emmanuel Comoy, D.V.M., Ph.D., Commissariat
          a L'Energie Atomique, France                  292

H.   Recent Progress in Developing Antemortem
     Tests for TSEs: Prospects for Blood-
     Based and Urine-Based Tests
           Luisa Gregori, Ph.D., DETTD, OBRR
           CBER, FDA                                    309

I. Correlations Between Abnormal Forms of Prion
   Proteins and TSE Infectivity: Implications
   for Test Development
          Pedro Piccardo, M.D., DETTD, OBRR,
          CBER, FDA                                     325




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                           PARTICIPANTS

     R. Nick Hogan, M.D., Ph.D., Chair
     William Freas, Ph.D., Acting Designated
          Federal Official

MEMBERS:

           Leila M. Barraj, D.Sc.
           Michael D. Geschwind, M.D., Ph.D.
           Janice Hamilton
              (Consumer Advocate)
           Silvia Kreindel, D.V.M., MPH
           Laura K. Manuelidis, M.D.
           James A. Mastrianni, M.D., Ph.D.
           Stephan S. Monroe, Ph.D.
           Mark R. Powell, Ph.D.
           Christopher M. Templin
              (Consumer Representative)
           Douglas C. Lee, Ph.D.
              (Industry Representative, non-voting)

TEMPORARY VOTING MEMBERS

           Susan M. Leitman, M.D.
           James W. Lillard, Jr., Ph.D.
           Katherine A. McComas, Ph.D.
           Suzette A. Priola, Ph.D.
           Frederick P. Siegal, M.D.




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                      P R O C E E D I N G S

   Opening Remarks and Introduction of Committee Members

             DR. FREAS:    Mr. Chairman, members of the

Committee, members of the public, I would like to welcome

all of you to this, our 21st meeting of the Transmissible

Encephalopathy Spongiform Encephalopathies Advisory

Committee.    I am Bill Freas.     I will be the Acting Executive

Secretary for today.       Today's sessions are all open to the

public.

             At this time, I would like to go around and

introduce the members of the head table to the public.      I

will be starting on the right-hand side of the room--that is

the audience's right.

             Will the members of the public please raise their

hand when I call their name?       The first chair is occupied by

Dr. Susan Leitman.    She is Chief of the Blood Services

Section, Department of Transfusion Medicine, National

Institutes of Health.

             The next chair, which is empty right now, soon

will be filled by Dr. James Mastrianni, Associate Professor

of Neurology, University of Chicago.

             Next, we have Dr. Leila Barraj, biostatistician,


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Statistician Exponent, Incorporated.

          Next is our non-voting industry representative,

Dr. Douglas Lee, Senior Director, Pathogen Safety and

Research, Talecris Biotherapeutics.

          Next Dr. Sue Priola, Senior Investigator, Chief

TSE/Prion Molecular Biology Section, NIH, Rocky Mountain

Laboratories.

          The next empty chair will soon be occupied by Dr.

Michael Geschwind, Assistant Professor of Neurology,

Department of Neurology, University of California.

          Next, we have Dr. Silvia Kreindel, Animal Plant

Inspection Services, National Center of Import/Export

Regionalization and Evaluation Services, USDA.

          Around the corner of the table, we have Dr.

Frederick Siegal, Medical Director, Comprehensive HIV

Center, St. Vincent's Catholic Medical Centers.   Dr. Siegal

is also representing the Blood Products Advisory Committee.

 He is Chair of that committee.

          Next the Chairman for this committee and for

today, Dr. Nick Hogan, Associate Professor of Ophthalmology

and Pathology, University of Texas Southwestern Medical

School.


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           Around the table, we have Ms. Jan Hamilton,

Advocacy Consultant, Hemophilia Federation of American.

           Next is our Consumer Representative, Mr.

Christopher Templin, Health Care and Public Policy Advocate

for Hemophilia, Factor Health Services.

           Next we have Dr. Katherine McComas, Associate

Professor, Department of Communications, Cornell University.

           Next, Dr. Mark Powell, Risk Scientist, Office of

Risk Assessment and Cost Benefit Analysis, US Department of

Agriculture.

           Next we have Dr. Steve Monroe, Director, Division

of the Viral and Rickettsial Diseases, Centers for Disease

Control.

           The next empty chair will soon be filled by Dr.

Laura Manuelidis, Professor and Head of Neuropathology, Yale

University School of Medicine.

           At the end of the table, we have Dr. James

Lillard, Professor and Vice-Chair for Research, Microbiology

and Immunology, University of Louisville.

           I would like to welcome all the members who have

traveled here today.    Thank you very much.

                Conflict of Interest Statement


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           DR. FREAS:    I would now like to read into the

public record the Conflict of Interest Statement for this

meeting.

           The Food and Drug Administration is convening the

June 12, 2009 meeting of the Transmissible Spongiform

Encephalopathies Advisory Committee under the Federal

Advisory Committee Act, FACA, of 1972.     With the exception

of the industry representative, all participants on the

committee are special government employees or regular

federal employees from other agencies and are subject to

federal conflict-of-interest laws and regulations.

           The following information on the status of this

advisory committee's compliance with federal ethics and

conflict-of-interest laws including, but not limited to, 18

US Code Section 208 and 712 of the Federal Food, Drug and

Cosmetic Act, is being provided to participants at this

meeting and to the public.

           FDA has determined that all members of this

advisory committee are in compliance with federal ethics and

conflict-of-interest laws.     Under 18 US Code Section 208 of

the Food, Drug and Cosmetic Act, Congress has authorized FDA

to grant waivers to special government employees and regular


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government employees with potential conflicts, when

necessary, to afford the committee their essential

expertise.

             Related to the discussions of this meetings

members and consultants of this committee have been screened

for potential financial conflict of interest of their own,

as well as those imputed to them including those of their

spouses or minor children and, for purposes of 18 US Code

Section 208, their employers.    These interests may include

investments, consulting, expert witness testimony,

contracts, grants, CRADAs, research, teaching, speaking,

writing, patents and royalties, and primary employment.

             For Topic I today, the committee will discuss

FDA’s risk assessment for potential exposure to variant

Creutzfeldt-Jakob’s disease in US-licensed plasma-derived

Factor VIII.    This is a particular matter of general

applicability.    The committee will also hear informational

presentations on animal models of vCJD, diagnostic test

development for transmissible spongiform encephalopathies

and bovine spongiform encephalopathy surveillance and risk

management.

             These informational presentations are not for


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discussion by the committee and, therefore, the committee

members were not screened for their interests in these

informational presentations.

             Based on the agenda and all financial interests

reported by the members and consultants, no conflicts of

interest waivers were issued under 18 US Code Section

208(b)(3) and 712 of the Food, Drug and Cosmetic Act.

             With regards to FDA’s speaker guests, the agency

has determined that the information you provide is

essential.    The following information is being made public

to allow the audience to objectively evaluate any

presentation and/or comments.    Dr. Robert Will has

associations with the European plasma product manufacturers.

 Dr. Douglas Lee is serving as the industry representative,

acting on behalf of all regulated industry, and is employed

by Talecris Biotherapeutics.    He serves on PPTA’s Pathogen

Safety Steering Committee.    Industry representatives are not

special government employees and industry representatives do

not vote.

             In addition, there may be regulated industry and

outside organization speakers making presentations at

today’s meeting.    These speakers may have financial


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interests associated with their employers and other

regulated firms.    The FDA asks that, in the interest of

fairness, they address any current or previous financial

involvements with any firms whose products they may wish to

comment upon.    These individuals were not screened by the

FDA for conflicts of interest.

             This conflict of interest statement will be

available for review at the registration table.    We would

like to remind members, consultants and participants that if

the discussions involve any other products or firms not on

the agenda for which FDA participants have a personal or

imputed financial interest, the participants need to exclude

themselves from the discussions and their exclusions will be

noted for the record.

             FDA encourages all other participants to advise

the committee of any financial relationships they may have

with a sponsor, its products and, if known, its direct

competitors.

             That is the end of the conflict of interest

statement.    Before I turn the meeting over to the Chair, I

would like to ask everyone to please take a second to check

your cell phone and make sure it is either on silent or


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vibrate mode so it won’t interrupt the meeting.   Dr. Hogan,

I turn the meeting over to you.

                       Opening Remarks

          DR. HOGAN: Thank you, Dr. Freas.   I would like to

welcome everybody here today.    We have an information-packed

and very interesting program this morning, and I hope that

it is enjoyable for all of us.

          I would like to thank the staff, first of all, for

really working very hard over the past few months, and

especially last night, to make sure that all of us get here.

 And, I would like to thank the participants and the

speakers for being able to make it through the bad weather

we have here.   Some of you have traveled thousands of

milesB-I am sorry, Bob, thousands of kilometers to come to

this meeting and it is very much appreciated.

          So, I think my job as Chair is primarily to make

sure that everything runs on time and, so that we don’t have

to miss lunch, please excuse me if I get a little pushy

about time.   In any case, I would like to go ahead and call

the first speaker on the agenda.   We are going to have Dr.

David Asher give us an introduction and overview of BSE and

vCJD issues currently worldwide.


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            Dr. Asher?

   Topic I. FDA’s Risk Assessment for Potential Exposure

     to vCJD in US-Licensed Plasma-Derived Factor VIII

    A. Introduction and Overview of BSE and vCJD Issues

                              Worldwide

            DR. ASHER: Thanks, Nick. I would like to thank the

other speakers and the members of the committee for their

efforts to come today, and in particular Nick Hogan.        I know

how difficult it was for Nick to fit this into his busy

schedule.   I would particularly like to thank Nick for

setting today’s dress code.

            DR. HOGAN: Anybody without a bow tie, please

leave!

            [Slide]

            DR. ASHER: Thanks.    It has been a long time since

the TSE advisory committee meeting took place.

            [Slide]

            This meeting, as most of you know, was prompted by

the announcement on February 17 by the UK Health Protection

Agency that the abnormal prion protein, PrP-TSE, as we will

call it today, had been found in the spleen of a patient

with hemophilia at postmortem.      The patient was under


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surveillance because he was one of a number of people who

had received so-called vCJD-implicated plasma product, that

is, a plasma product prepared from a pool to which a known

vCJD patient, that is someone who had come down with vCJD

after the donation, had donated.   The treatment had taken

place 11 years earlier and it required the examination of 23

spleen sections before a positive section was examined.

          [Slide]

          A second publication from the HPA earlier this

week revealed that although the patient had also received

about 14 units of blood and had undergone an endoscopy,

neither of those appeared to be as likely a source of the

infection as a plasma derivative, either the implicated

plasma derivative or the risk associated in the UK, where

prevalence is high, of an unimplicated plasma derivative was

not trivial.

          At any rate, the report prompted the FDA which is

committed to reviewing our policies periodically.   It

prompted us to revisit our 2006 risk assessment, which is an

ongoing process that will be described to you later this

morning by Steve Anderson.

          [Slide]


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           We are going to ask the committee for help in

evaluating that revised risk assessment.    Here is the set of

questions that you will be asked by Steve later in the

morning.   Based on an updated risk assessment, FDA continues

to believe that the risk of variant Creutzfeldt-Jakob’s

disease to patients who received US-licensed plasma-derived

coagulation Factor VIII, because the coagulation factor

involved in the UK was US-licensed and not used here, the

risk is likely to be extremely small although we do not know

the risk with certainty.

[Slide]

           And, we are going to ask does the committee agree

with the updated and new inputs to the FDA risk assessment

model or US-licensed plasma-derived Factor VIII.   The

updated inputs will be estimated prevalence of vCJD

infections in the UK.   A sensitivity analysis reveals that

that is the main source of vCJD in the United States.    The

age of the susceptible population in the UK at the time of

infection; the time during the incubation period when

infectivity is present in blood.

           And then three new inputs: genotype at the PrNP,

the gene encoding, the prion codon 129; the genetic


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susceptibility to infection; and the proportions of the

genotype in the US population; distributions of vCJD

incubation periods for persons of different genotypes and

age distribution of persons with asymptomatic vCJD

infections.

          [Slide]

          The second question, despite the finding of

minimal additional risk in FDA’s modified risk assessment,

should the recent report from the UK Health Protection

Agency alter FDA’s interpretation of the risk for US-

licensed preparations of plasma-derived Factor VIII?

          Third question, based on the available

information, should FDA consider recommending additional

risk-reducing steps for manufacture of plasma derivatives,

for example, modifications to current donor deferral

policies, recommending revised warning labels, or

recommending modifications to FDA’s public communications?

          [Slide]

          I am going to try to set the scene by mentioning a

few background issues that will be addressed in greater

detail by subsequent speakers.

          First, bovine spongiform encephalopathy is


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important because it is the source of food-borne variant

Creutzfeldt-Jakob’s disease; recent trends and

uncertainties; then variant Creutzfeldt-Jakob’s disease

itself, briefly referring again to transfusion transmission

of vCJD by labile blood components and the presumptive

transmission by a plasma derivative, both of which will be

discussed in fuller detail by Bob Will who is going to be

the next speaker.   If time permits, I will review the agenda

for today’s meeting at the end.

          [Slide]

          BSE remains of great concern, again, because it is

the source of the original source of variant Creutzfeldt-

Jakob’s disease.    The outbreak began in the United Kingdom

more than 20 years ago and peaked there in 1992 and declined

markedly thereafter following implementation of a number of

preventive efforts by UK authorities.

          [Slide]

          The disease had spread from the UK to 24 other

countries mainly, we believe, through contaminated so-called

meat and bonemeal produced from the offal of cattle, some of

which was contaminated.   Canada has recognized 16 cases

since 2003 and the US two in native born cattle, and there


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will be more about that this afternoon.

           No new country, at least that I know of, has

reported BSE since 2000 to 2006 when Sweden found a single

case.   The UK reported only 37 cases last year, down from a

maximum of over 35,000 recognized cases in 1992.

           [Slide]

           Only six countries reported to the World

Organization for Animal Health, the OIE, an incidence last

year of more than one case per million adult cattle.     That

was led by Portugal which had over 20 cases per million

adult cattle but that is down 20-fold from Portugal’s peak

in 1999.   The UK reported an incidence of 7.5 cases per

million, which is down from its peak of over 6,500 cases per

million adult cattle in 1992.

           [Slide]

           Five other countries, including Canada, had

incidence reported last year of less than one case per

million.

           [Slide]

           Fourteen countries, shown here in black, that had

had BSE in the past reported no cases of BSE to the OIE last

year.


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             [Slide]

             So, overall the trend seems to be down, which is

very good news although we know that reporting is never

complete.    There does remain a concern regarding countries

to which the UK exported meat and bonemeal during the bad

BSE years, countries that have never reported a case.       These

data were taken from UK authorities and you can see that in

addition to the US and Canada which imported a small amount

according to UK records, a number of countries, including

the former Soviet Union and countries in South Asia and

Southeast Asia are on record as having imported the product

and have never recognized a case of BSE.      Of course, we

don’t know what they did with the product, whether they

trans-shipped it or whether any of it was used to feed

cattle.   But we do have to consider that BSE still

constitutes a potential global problem of uncertain

magnitude.

             [Slide]

             Cases of variant Creutzfeldt-Jakob’s disease

continue to decrease overall, 168 in the UK at my last count

and 43 in other countries, including one in Canada, and

three here, in the United States.    All four of the North


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American cases presumably were acquired abroad in people who

were citizens of other countries.    At least 36 cases,

however, seem to have been from infections acquired outside

the United Kingdom, especially in France which was a major

importer of UK beef.

          [Slide]

          While presumptive food-borne cases have declined

in the UK, deaths peaked there in 2001.       Since December of

2003, four transfusion transmitted cases, labile components,

all non-leukoreduced red blood cells by the way, were

reported, plus the plasma derivative-associated case that

prompted today’s meeting.

          One of the transfusion-transmitted cases was in a

person who was heterozygous for methionine valine on codon

129 of the prion protein encoding genotype that had

previously been spared of clinical disease, and that patient

did not have clinical illness.

          [Slide]

          I hope that Bob Will will comment on the somewhat

puzzling observation that the mean age of vCJD cases remains

less than 30 years, relatively young.    We would have

expected that that age would go up as the time since


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exposure got longer.

          In addition, there has been one report in the UK

popular press, not confirmed but not denied by UK

authorities, of a person with the methionine valine

heterozygous genotype with typical clinical evidence of

vCJD, but no tissue was available to confirm the diagnosis.

 But taken together with the one unapparent transfusion-

transmitted infection, some UK authorities have warned of a

second wave of variant Creutzfeldt-Jakob’s disease to come.

          [Slide]

          The incubation period of food-borne cases

estimated by three different indirect methods, which we

won’t discuss, all fall within about 10-12 years for the

minimum incubation period of people of the MM genotype.

Presumably, if there will be cases in other genotypes, they

will have much longer minimal incubation periods.

          The transfusion-transmitted cases had incubation

periods of 6.3 to 8.5 years.    If the case reported on

February 17 was acquired from the implicated plasma

derivative the incubation period would have been about 11

years.

          [Slide]


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             A number of questions remain to be answered.    How

long before onset of clinical variant Creutzfeldt-Jakob’s

disease is the blood of a donor infectious?      We can say that

at least during the past three and a half years of the

incubation period blood of some clinically healthy donors,

at least of the MM genotype who later developed vCJD, were

already infections.

             Open question, how much longer than three and a

half years might the blood be infectious, or how much

infectivity is present in the blood at different states of

infection?    Is the blood of infected donors with other

genotypes also infectious?    If so, how long?   How much

infectivity?    And, what is the prevalence of latent vCJD

infection in the UK and, secondarily, in other countries?

             [Slide]

             One of the ways in which the prevalence of vCJD

infections has been estimated in the UK is by tissue survey,

looking for the accumulations of PrP-TSE that are typical of

patients dying with vCJD but not of other forms of CJD.

             In 1999 Hill and colleagues in John Collinge’s

group reported finding PrP-TSE in tonsils as well as spleens

and lymph nodes of people dying with variant Creutzfeldt-


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Jakob’s disease.      The finding of this abnormal protein in

tonsils of living patients clinically ill with vCJD has been

useful for the antemortem diagnosis but we don’t know how

late in the incubation period this abnormal protein appears

in the tonsils.

            A recent study, reported last month by Clewley and

colleagues in the BMJ, provided some limited assurance. They

looked at over 63,000 frozen tonsils collected from people

of ages that should have been in cohorts at high risk for

vCJD.   They tested them by ELISA and none of them was

positive.   But the sensitivity of the ELISA compared to

immunohistochemistry is not clear and, again, we don’t know

when in the incubation period the tonsils would become

positive.

            [Slide]

            There is a little more information about

appendices that have been studied in a smaller survey.

Almost all vCJD cases at autopsy have the abnormal protein

detected in appendices.     For appendix two cases, eight

months and two years before onset of infection, were

available in archives and they were positive, while an

appendix collected ten years before onset was not positive.


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 So, one can be reasonably confident that for a couple of

years before onset the abnormal PrP can be detected in the

appendix.

             Based on that finding, a survey was done of

patients without overt Creutzfeldt-Jakob’s disease in the UK

and three out of more than 12,600 were positive.      James

Ironside’s group successfully sequenced the PrP gene from

two of the three positives and they were both homozygous for

valine at codon 129.    One doesn’t know what happened to

those subjects but we can say that nobody with a 129-VV

genotype has been reported by the CJD surveillance unit in

Edinburgh.

             [Slide]

             Some relatively good news, published several

months ago by Dorsey and colleagues from a joint CDC-

American Red Cross look-back study of recipients of blood

from people with conventional CJD sporadic, a few familial

and one iatrogenic cases in donors who donated labile

components, to date more than 144 patients survived for more

than five years after the transfusions.       None of them has

either died or has a death certificate suggestive of

Creutzfeldt-Jakob’s disease, although autopsy findings are


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not available.

          So, the risk of transfusion-transmitted

conventional Creutzfeldt-Jakob disease is much less than

that of variant Creutzfeldt-Jakob disease, and it remains

open to question whether the blood of any of those patients

is ever infectious.   Animal studies suggest to me that it is

unlikely that all patients never have infectivity in their

blood because it appears to be part of the typical life

cycle of the pathogen.

          [Slide]

          Some other good news, although it is unfortunate

that there have been transfusion- and plasma-transmitted

cases of variant Creutzfeldt-Jakob disease, that represents

the only new class of medical product implicated in an

iatrogenic transmission to date and that includes

contaminated surgical instruments.   A few cases were

documented before the early 1980s and none since, including

no reports of iatrogenic instrument-transmitted variant

Creutzfeldt-Jakob disease in the United Kingdom even though

the United Kingdom has taken that possibility very seriously

and asked people at increased risk to notify their surgeons

and dentists to take special precaution.


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           [Slide]

           I will just rush through these last few panels.

This is just to remind me that there are not so very good

news regarding blood screening tests based on the detection

of abnormal prion protein in blood.   You may recall that

back in 2005-2006 there was considerable activity in

developing such tests and none of them has been validated as

useful for the antemortem diagnosis of TSE in humans or

animals.

           [Slide]

           Another study that appears to me to be very

troubling and to constitute a warning is a nice review that

was done by Richard Knight and colleagues, published in

Neurology last year, reviewing attempts to treat spongiform

encephalopathies, a meta-analysis.    Only four of the drugs

had been used to treat more than three patients.   There was

only one randomized clinical trial reported.

           There was no convincing evidence for efficacy of

any treatment, although there were a few reports of

anecdotal improvements.   Two long-term survivors had been

treated with intrathecal pentosan polysulfate through a

ventricular catheter.   They showed no cognitive improvement


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and have progressive CNS atrophy.

           The importance of that for this group is that

prevention of exposure to the TSE agents remains the only

feasible way for controlling these diseases.   We don’t

anticipate a significant treatment any time soon.

           [Slide]

           I am running a little over time so perhaps I won’t

review the agenda, except to say that the morning is devoted

to the decisional issue that we have already outlined.     We

have two sessions that we hope will be useful for you,

informational sessions, in the afternoon.   The first is a

review of the worldwide situation regarding bovine

spongiform encephalopathy in both North America and Europe,

and we will end with three reports on research related to

blood safety.

           Before I surrender the microphone, I am going to

ask your indulgence to make one personal comment.    D.

Carleton Gajdusek died in Tromso, Norway exactly six months

ago.   He won the Nobel Prize.   For those of you who are too

young to remember, he won the Nobel Prize in 1976 for work

between 1957 and early 1970, work that showed that both kuru

and later Creutzfeldt-Jakob disease were transmissible


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infections.   That introduced to human medicine a new class

of slow infection, a concept that had never before been

known to neurology.

          Of course, others also played important roles in

those early years.    The names of Vincent Zigis, Igor Klatzo,

Joe Gibbs and Elizabeth Beck-Ball dead now--immediately come

to mind, as well as the important contribution of Bill

Hadlow who is, I believe, still alive.   But Carleton

Gajdusek was the initiator, the leader and the driving force

in the research program that led to those discoveries and

that should not be forgotten.

          I don’t believe that Carleton Gajdusek ever

participated in any FDA advisory committee but an unusual

number of alumni of his program have served on the

committee, have spoken before the committee, and one even

served as chairman of the committee but he ducked out the

side door before I had a chance to acknowledge that.    I

think that it is important that someone in the federal

government remember that Carleton Gajdusek served for more

than 50 years in one way capacity or another, that someone

from the United States Government remember his contributions

and recognize his passing.


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            With that, I will surrender the microphone to Bob

Will.   Thank you for your indulgence, Mr. Chairman.

            DR. HOGAN: I would like to second my gratitude to

Dr. Gajdusek.   I first got associated with prions in San

Francisco and then I came to NIH and Dr. Gajdusek was very

encouraging and I probably wouldn’t be here today without

him.    So, I thank you, Dr. Asher, for bringing his important

contribution to this field to light.

            Does anybody have a brief question for Dr. Asher?

 If not, Dr. Will, please.   He is going to talk to us about

vCJD in the UK and the transfusion medicine epidemiological

review.   He is from the Surveillance Unit, that we all know

very well, in Edinburgh.   Thank you.

             B. VCJD in the UK and the Transfusion

                 Medicines Epidemiology Review

            DR. WILL: Well, good morning.    Thank you very much

for the invitation to speak.   It is a privilege to have an

invitation to come to speak at one of these meetings again.

            [Slide]

            I feared I would have rather too much to say but

after Dr. Asher’s masterly presentation I think there are

some things I will be able to skip over.     I have been asked


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to talk about vCJD in the UK and the transfusion medicine

epidemiology review, but I will cover some other topics as

well.

          [Slide]

          These are the number of onsets of vCJD in the

United Kingdom to date and show this peak in 1991 and then a

clear decline, with only single onsets in 2007 and 2008.     Of

course, we might still get onsets in those years but it

seems clear from this slide that the outbreak of vCJD is in

decline in the UK.   There is, of course, concern about

future waves of cases, which I will talk about in a minute.

          At the bottom you will see, or maybe you won’t

see, that the mean age of death is 30 years and the median

is 28 years and that really hasn’t changed significantly

since vCJD was identified.

          As Dr. Asher raised this issue, we do not

understand why this age has been completely stable.    There

are a number of possible explanations, one of which is that

there is an age-related susceptibility.     The other is that

there may be an age-related exposure.   Of course, the

outbreak is not yet over and we could still see changes in

the age distribution.


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          [Slide]

          Codon 129 genotype, as you know, for the 148 to

168 tested cases in the UK are MM at codon 129.    For the 20

untested cases we did not have DNA to analyze because of

lack of consent primarily.   And, all the cases outside the

UK are also MM.   So, the question is where are the cases

with an MV or VV background?   I am talking about clinical

cases here.

          [Slide]

          There was publicity in the newspapers sometime ago

now in the UK about a possible case of vCJD in an individual

with an MV background.   This was a male aged 30 whose

clinical presentation was consistent with vCJD.    The patient

underwent a single MRI scan which was thought to be

equivocal on review, and it is a very important component of

the classification system for cases.   It is very important

if you want to classify cases probable that you either have

a positive MRI or a positive tonsil biopsy, and no tonsil

biopsy was carried out in this case.

          There was an MV genotype at codon 129.    The

patient died in 2009, with a total illness duration of 22

months, which is a little bit longer than the mean of about


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14 months in vCJD.   There was no postmortem and the final

classification in this case is possible vCJD.

          [Slide]

          So, there a number of questions this case raises.

 First of all, I think it is important that the clinical

phenotype in the MV case was similar to MM cases, of course,

excluding the MRI scan although this patient only had a

single MRI scan carried out fairly early in the clinical

course.

          We haven’t previously reported possible vCJD cases

relying on deaths and probables where we are very secure in

the diagnosis, but it is important to understand that there

have been three previous possible vCJD cases since 1996 in

the UK in 1991, 2001, 2002, all MM background, age 20, 21

and 41 at death.

          [Slide]

          This doesn’t really answer the question as to what

does a possible diagnosis of vCJD mean in terms of the

likelihood of this actually being vCJD.     So, we have done an

analysis, which is unpublished, and what we did was to look

at all the referred cases to the unit since the

identification of vCJD to identify all the cases that were


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classified as possible at some stage during the illness

evolution.    And, 94 out of 116 cases classified as possible

vCJD were finally classified as definite or probably vCJD,

suggesting in this analysis that there is about an 80

percent chance that a possible vCJD case actually is vCJD.

So, it may be that the MV case was actually suffering from

vCJD although we will never know.

             [Slide]

             This was covered, as I said already, in the media

on December 18: AHundreds could die as scientists identify

first case of second wave of vCJD.@    The reason I put this

up is because this article quoted Aanother 350 people could

die from the human form of mad cow disease, scientists have

warned, because of this case.@    The figure 350 I think is

derived from a previous mathematical analysis that was

carried out some years ago, and I can tell you that this

analysis is being repeated using up to date data.

             [Slide]

             Now, to turn to the second subject, which is the

transfusion medicine epidemiology review, this is a

collaborative study with the National Blood Service, the

Scottish National Blood Transfusion Service, the Welsh Blood


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Service, Northern Ireland Blood Transfusion Service, the

Surveillance Unit and, importantly, the Office of National

Statistics who supply death certificates on individuals who

die who were identified through this study.

             Essentially it is fairly simple, although it gets

much more complex when you look at the details, but

effectively every case of vCJD is notified to the blood

services.    They identify whether the individual had been a

blood donor, and the fate of those blood donations is

identified, including the recipients of labile blood

components.    The purpose of this study is to determine

whether any of those recipients themselves develop vCJD.

             There are 168 cases of vCJD to date in the UK, 158

who were eligible to donate.    That is, they were over 17

years old.    The number of cases from blood components

actually issued was 18, and we have 66 recipients identified

and we have four instances of vCJD infection via blood

components transfusion.    That is, there is good evidence

that vCJD is transmissible through blood transfusion.

             [Slide]

             This is donor 1 which donated red cells and the

recipient died of vCJD some years later.      Dr. Asher very


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clearly summarized this information.   Again, an individual

who received such blood later died of vCJD, but there were

two other recipients one of each donor who died of other

causes.

          [Slide]

          Then we have donor 3 who was implicated in two

further cases of transfusion transmission of vCJD, donation

1 and donation 2, and the development of vCJD in two

recipients.

          Of course, there were some other recipients

subsequently who also received blood from this donor, most

of whom died of other causes but there is one individual who

is still alive, having received such a blood transfusion.

          [Slide]

          This is rather a complex slide.   Many of you would

have seen it before, but this is a slide that was compiled

by Charlotte Llewellyn, from the study, which looks at the

survival period from transfusion to death in the 44 deceased

recipients according to the interval between the donation

and the onset of clinical symptoms in the donor.

          So, on this axis, here, we have the time from the

donation to the onset of clinical symptoms in the donor in


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years.   Importantly, you will see, as has been previously

pointed out, that the transfusion transmissions of infection

involved blood donations some years prior to the onset of

clinical symptoms.   Therefore, it is clear that patients

with vCJD have infection in the blood for a period of years

prior to the onset of clinical disease.

           This is the recipient survival after having

received such a blood transfusion and, as you can see, the

great majority of individuals die within a few years of the

blood transfusion as a reflection of the severity of the

illness for which they received the blood.

           But we do have a small number of individuals, and

I stress a small number of individuals, who survive for more

than five years after such a blood transfusion, and the

question is what was the outcome in these individuals.

           [Slide]

           This is a study which was recently completed.     It

is a review of diagnostic outcome in deceased recipients,

which is the slide I have just shown you.    Sixteen vCJD

donors, excluding two donors with single recipients, are

still alive.   The time from donation to symptom onset you

have already seen.   Symptom onset preceding donation in two


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individuals; 39 deceased recipients excluding the CJD

infections; and we have 33 cases with clinical information,

two postmortems which were not detailed postmortems.    They

were just identifying the cause of death.     They did not

include retention of brain material.    For 31 the cause of

death was established via medical records, two certified as

dying of dementia, with the same donor, but the clinical

features in these cases make it clear that this was not

vCJD.    We have seven individuals who had transient

neurological symptoms.

            Now, I don’t want to go on about this in detail

because of lack of time, but essentially the conclusion of

this study is that we have no evidence that any of these

deceased recipients had clinical evidence of vCJD.     But the

caveat to that, as I have already said, is that only a very

small number of these individuals survived for five years.

            [Slide]

            Here are the living recipients.   There are 22

individual living recipients.    Some received non-

leukodepleted red cells and a bunch of leukodepleted red

cells.    These individuals have, of course, been informed of

their risk status and they have been asked to partake, if


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they wish, in research.

          [Slide]

          Summarizing the TMER, this is all the cases.      This

is the survival after the transfusion.   All I wanted to

point out in this is that there are four vCJD infections--

three clinical cases, one subclinical case in those

individuals who survive more than five years.   This is a

relatively small cohort and this indicates that vCJD can be

transmitted relatively efficiently through blood

transfusion.

          [Slide]

          What about the plasma, which is one of the

important considerations at this meeting?   vCJD donors, CJD

donors, we have 11 donors from whom blood or plasma was sent

for fractionation, a total of 25 donations.   You can see the

timing of this from 1986 to 1998 when measures were

introduced in the UK to import plasma for plasma

fractionation, largely from the United States of America,

including four of those donations in 1996 when vCJD was

identified.

          [Slide]

          In February of this year there was an announcement


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in the newspapers that scientists had the first case of

human mad cow disease from blood plasma.   That is the

identification of vCJD infection, it is thought, in an

individual who was suffering from hemophilia.

          I know that everyone wants to know all about this

case and I would very much like to provide full information

but I very much regret that I am not in a position to do so.

 However, I will try and do my best to inform the committee

about the current situation.

          [Slide]

          This was the postmortem finding of asymptomatic

vCJD abnormal prion protein in a UK resident with

hemophilia.

          [Slide]

          The person with hemophilia was 70-plus years old,

died of unrelated cause with no signs or symptoms of CJD.

And, the reason this individual was looked at, at

postmortem, was because James Ironside and colleagues in the

hemophilia community have been carrying out a study of

postmortem tissues in individuals with hemophilia for some

years and this was part of this study.   There was evidence

of abnormal prion protein in the spleen.


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           [Slide]

           The individual, in the 1990s, received multiple

batches of UK source clotting factors.    The individual was

exposed to more than 9,000 units of Factor VIII made from

two plasma pools with a vCJD-implicated donor about 11 years

before death.

           [Slide]

           What was the source of vCJD infection in this

case?   The patient had been exposed to endoscopes having

undergone five endoscopic procedures with biopsy and a large

number of endoscopies without biopsy.    Of course, in the

United Kingdom there is a concern that surgical instruments

might play a role in secondary transmission of vCJD,

although I must stress that to date we have no evidence of

such a route of transmission.

           Exposure to red cells, the patient had received 14

transfusions of red blood cells, each from different donors.

 Of course, we know that transfusion transmission of vCJD is

a reality, exposure to implicated batches of plasma

products, perhaps exposure to non-implicated batches of

plasma products.     Or, perhaps a primary infection because

the individual had lived in the United Kingdom, it is


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inevitable that this individual was exposed to high titer

tissue in the human diet, which is the proposed hypothesis

for the cause of the primary cases of vCJD.

          [Slide]

          This report was published very recently from the

Department of Health, vCJD risk assessment calculation for a

patient with multiple routes of exposure, referring to this

specific case, by Peter Bennet and Jennie Ball from the

Health Protection analytical team of the Department of

Health.

          I am going to show you some sections of this and I

rarely do this but I am going to read sections precisely to

make sure that I give you the appropriate information.

          [Slide]

          If this finding is interpreted as an instance of

asymptomatic vCJD infection, this raises questions of the

operational meaning of the prevalence of infection, which is

such an important determinant of risk in the United Kingdom.

 The discovery of abnormal protein in a single spleen sample

was the only positive result after exhaustive investigation

of tissues taken at autopsy of an elderly hemophiliac

patient who died of other causes.   All other tissues from


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the patient tested for the presence of abnormal prion

protein fixed samples of brain, heart, liver, blood, vessel,

appendix, spleen and lymph nodes and frozen samples of

frontal lobe, occipital lobe, cerebellum, lymph node and 23

other frozen samples from the spleen were negative.

          The individual was not tested positive on any of

the vCJD prevalence tests conducted so far.   I think that is

quite an important issue.   Just in passing, I will mention

something else that might be important.    Of course, the

tonsil study, which I need to discuss in a moment, is also

very important but there is a recent publication from France

in which tonsil biopsies were carried out in 23 clinical

cases of vCJD and one of them was negative.   This raises

issues about what the prevalence studies actually indicate.

          [Slide]

          This is the BMJ publication which Dr. Asher

referred to, and because of his clear comments I will only

say that these are the results.

          [Slide]

          This is the earlier study showing three positive

appendices out of 10,278 specimens and two of those were VV,

a totally negative study on this occasion.    My reading of


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the conclusions is that although the calculations of the

prevalence of infection that may be present in the United

Kingdom are a little lower in this study, they clearly

overlap with the previous study and do not really alter the

conclusion that there is likely to be a prevalent population

of individuals in the UK who are infected but cannot be

identified.

          [Slide]

          So, just to go back, what was the source of vCJD

infection in the person with hemophilia that was described?

 Was this primary infection through dietary exposure to BSE?

 Well, there are a number of calculations in the document.

I am just summarizing one in the main analysis.   The

relative probability of infection through plasma products

was 97-99 percent in comparison to less than 0.3 percent for

the primary infection.

          So, this analysis concludes that it is most

unlikely that this individual was exposed to BSE through

diet as the cause of the positivity of the findings in the

spleen.

          [Slide]

          The chance of the patient having been infected in


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an endoscopic procedure is very small.   This document is

available on the Internet.   If you want to look at the

details it is very easy to do so, and I am sure many of you

have already read it.

          [Slide]

          Comparing the blood-borne routes, the patient is

much more likely to have been infected through receipt of

plasma products rather than any of the 14 units of red cells

known to have been received.   The implied risk of each of

these 14 donors being infected appears to lie below the one

percent threshold that would trigger at-risk status.

          [Slide]

          Given the large pool sizes involved, 20,000

donations, the risk differential between implicated and non-

implicated batches of blood product is not marked.   This is

perhaps a surprising conclusion, that it may be more likely

that the individual was exposed to batches of product that

we do not yet know contained an implicated donation rather

than the specific donations that have been identified and

commented on previously.

          [Slide]

          Summary of findings, and this is just to summarize


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the fact that patients are more likely to have been infected

not by large quantities of non-implicated plasma but in

smaller quantities of implicated plasma.

          [Slide]

          But just to go back to the previous slide, I think

this is an important issue which I will come to at the end,

and I think I am doing all right for time at the moment.

Unless the prevalence of infection is very low, there is a

strong possibility of any given batch of blood products

prepared from a large pool source from UK donors in the

relevant period containing at least one infected donation.

This reinforces the logic of the CJD incident panel’s 2004

decision to consider all hemophilia and blood disorder

patients exposed to such UK source plasma products as an at-

risk group.

          [Slide]

          Finally, they did an analysis because the previous

risk assessment on which that policy was based was from Det

Norske Veritas and was thought by some to be overly

pessimistic.   So, what they have done, they have done

another analysis assuming that the greater proportion of the

infectivity would be removed during the manufacturing


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process.   But even if they do that the results that I

described still hold.

           [Slide]

           I will now just turn to that risk analysis, and I

am sorry if you can’t read this but I will read out the

relevant section.    This was published by Foster in 2000.   Of

course, you will recall that this individual patient with

hemophilia was exposed probably in the 1980s and 1990s.

           This is the risk analysis of Factor VIII in which

they assume a clearance factor in the production process of

1.5 and for another product from BPL of only 1.0.   So, in

simpler processes experiments show a clearance factor of 1.7

for the Scottish National Transfusion Service Factor VIII,

while for the BPL 8Y process a minimum of 1.0 log clearance

is indicated to represent cryoprecipitation.

           [Slide]

           This case has caused enormous concern among the

hemophiliac community and I do hope that full details of the

case will be published in the not too distant future.

           [Slide]

           However, this case raises another issue, and that

is whether any of the 165 primary cases of vCJD in the UK


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can themselves be attributed to plasma products.   We are

talking here, of course, about an individual who was not

clinically affected by vCJD but in which the positive

finding was found at postmortem specifically looking for

this.

          We have looked very carefully at vCJD cases, and

just to be clear, we obtain hospital records, GP records and

in the great majority of cases general practitioner records.

 So, we believe we have fairly full information on prior

treatments including potential exposure to plasma products.

 The number of casesB-I have already mentioned the 25 plasma

donations, and there were 178 batches of various products

that were derived from those implicated donations.

          [Slide]

          Nine cases of vCJD were known to have received

plasma products on 12 occasions between 1970 and 1998.     The

great majority of these were low risk products; five cases

anti-D; four cases IM immunoglobulin for travel; one

possibly low medium risk product.   The batch number was

known for four of the products.   None came from an

implicated batch.

          [Slide]


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          This is the summary of the plasma products which

these vCJD cases had received.    We have done an analysis of

the frequency of anti-D and we think that this is more or

less appropriate to this cohort of relatively young

individuals.   It is not excessive in terms of the number who

have received anti-D.    I am not in a position yet to provide

detailed information, but a significant number of these

products were not even sourced from the UK.

          [Slide]

          So, our conclusion is that it appears unlikely

that any of the UK vCJD cases to date were infected through

exposure to UK sourced plasma-derived products and I think

that is an important conclusion.    However, of course, this

possibility cannot be excluded in the future.

          [Slide]

          This is a headline from 2006 in which it indicated

that British blood products may pose risk for vCJD in 14

countries, and this is, of course, because some plasma

products that were produced in the UK were exported to other

countries and these countries were informed at that time and

have subsequently had further information about the relevant

plasma products.    This was done through the Health


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Protection Agency.

           I thought I would finish with this quote at the

bottom of this newspaper article: AThe risk of passing on

vCJD through blood products was considered only theoretical

until a transfusion patient was infected.A

           [Slide]

           I know you can’t read this but I am just going to

read out the precautions that have been introduced in

relation to blood in the UK over the years.   Since 1997 the

TMER study has been working to try and look for evidence of

transfusion transmission.

           In July, 1998 the Department of Health announced

that plasma for the manufacture of plasma products, such as

clotting factors, would be obtained from non-UK sources.

           Since September, 1999 white blood cells have been

removed from all blood used for transmission.

           In August, 2002 the DOH announced that FFP for

treating babies and young children born after January 1,

1996 would be obtained from the United States of America,

extended to all children under 16 years of age in the summer

of 2005.

           In December, 2002 the Department of Health


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completed its purchase of the largest remaining independent

plasma collector, Life Resources, Inc., to allow continuing

sourcing.

            All of these precautions were taken prior to the

identification of transfusion transmission of vCJD.    After

that blood donations have not been accepted from people who

have themselves received a blood transfusion in the UK since

1980.

            So, the point of this I think is that actions were

taken, and important actions, for many years prior to the

identification of an actual risk, and I think that is

exactly also what has happened in the United States.

            [Slide]

            Thank you very much.   These are my acknowledgments

or my colleagues at the Surveillance Unit, the HPA, etc.

Thank you very much.

            DR. HOGAN: Thank you very much, Bob.   As always,

this is packed with information and important insight that

few of us have entire arms around.

            I have one quick question.   You mentioned that

measures had been taken prior to the finding of transmission

by transfusion.   But all of the cases by blood transfusion


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that were transmitted were done without leukoreduced blood.

 Is that correct?

           DR. WILL: That is absolutely correct and you are

quite right to point that out.

           DR. HOGAN: Are there any other comments or

questions from any of the members?

           DR. MASTRIANNI: It looks like all the tissues--

there is an extensive number of samples taken from this

patient and they were found to be negative for any signs of

vCJD as far as measuring protein, looking at PK-resistant

PrP.   Do you know if there are any plans to do some

transmission studies to determine if there is any level of

infectivity?

           DR. WILL: Well, just to comment, that is not

actually what I said and I was very careful about what I

said, and I read out precisely what the statement was.    So,

I am sorry to disagree with you, and my understanding is

that there are plans to do transmission studies and it is a

very important issue.

           DR. MANUELIDIS: Yes, I also really appreciated

your talk on the real practical aspects of this but I agree

with James, and I mean not in the sense of the misquote, but


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I think that sometimes in looking at risk by looking only at

pathological PrP one ca be misled from what the real

prevalence or risk is because there are many examples,

including Jean Manson’s work, where you have high

infectivity with little abnormal PrP.   Cells in culture do

this.   I mean, there are many, many examples of this--the

old work of Dickinson where animals stay alive for their

entire life spans but actually carry the infection.

           So, I think to some degree there should be an open

question about how many people carry this peripherally but

don’t necessarily show the clinical disease.   And, that may

not correlated with spleen abnormal PrP.

           DR. HOGAN: Miss Hamilton?

           MS. HAMILTON: Yes, I had two quick questions, one

having to do with the reference to leukocyte reduction.     Is

it because that had not been used in those cases?

           DR. WILL: Yes, I think the problem is, as you are

implying, the period of followup.   So, of course, there is a

cohort of individuals who did receive leukodepleted red

cells who are still alive, but it is far too early to say

that they will not develop vCJD.

           MS. HAMILTON: My other question had to do with


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your comment on the young children and FFP.    Why not

recombinant?

            DR. WILL: I am not sure if I am in a position to

answer that question.    I don’t know the answer to that

question.

            DR. HOGAN: Thank you.   One last question, do we

know the 129 genotype for the hemophilic case?

            DR. WILL: Well, I would very much like to comment

on that but, unfortunately, and I very much regret this, I

am not in a position to do so.

            DR. HOGAN: So, the jury is still out.   Thank you

very much, Dr. Will.    I appreciate you coming to talk with

us.

            Moving right along, we wanted to have Dr. Alan

Williams now talk to us about geographic donor deferral

policies of the FDA and efforts to reduce the risk of

transmitting vCJD by blood, blood components and plasma

derivatives.    Dr. Williams?

  C. FDA Geographic Donor Deferral Policies to Reduce the

      Risk of Transmitting vCJD by Blood, Blood Components,

  and Plasma Derivatives: Rationale, Policies and Effects

                        on Risk and Supply


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            DR. WILLIAMS: Thank you and good morning.

            [Slide]

            It was felt important to conduct a quick overview

of the derivation and rationale for donor eligibility

criteria.   This has been one of the major regulatory

interventions to BSE and vCJD and has occupied a lot of the

energy of this committee over the past decade.   But also

because we have a lot of new members it was felt important

to provide this background.

            When the BSE and vCJD events were recognized in

the late >90s it was determined that the FDA needed to mount

an effective response to what appeared to be a rapid spread

of BSE and vCJD in the UK and Europe.   At that time the

transfusion risk was unknown and was considered theoretical.

            Of course, there were at that time and are now no

validated screening tests available to identify infected

blood units.   So, measures to maximize blood safety had to

rely on precautionary deferral of donors who may have had

dietary or transfusion exposure to BSE.

            [Slide]

            Critical considerations during these discussions

were the need to maintain an optimal balance between risk


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reduction for donors who may have had exposure to BSE, and

retaining the blood supply so that needs would be adequate

within the United States where the blood supply,

particularly in the summertime and over the holiday periods,

tends to be a little bit tenuous.

          In addition, because of concern about potential

contamination of the blood supply, there were several

different potential policies being proposed within the

private sector in addition to the government.   So, there was

a need to arrive at a coherent and uniform national policy

that would be in use throughout the United States.

          In addition, it was important to combine any donor

eligibility policy with ongoing monitoring related to the

further epidemiology of BSE and vCJD, the impact of the

actual donor deferral policy on the blood supply, and the

continued relevance of current policies given the evolution

of new scientific information.

          [Slide]

          So, as was mentioned in, I believe it was Dr.

Asher’s slides, typically when looking at a risk/benefit

determination for potential donor eligibility, one would

consider the likelihood of the infectious agent exposure,


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the length of the incubation period, the prevalence of an

asymptomatic carrier state if known, the presence of the

agent in blood during the incubation period, and the

susceptibility of the recipient population.    But, for the

most part, none of this data were available at the time that

these eligibility criteria were beginning to be put

together, and some are now just beginning to emerge.

          [Slide]

          So, what was left was the option of determining a

linear risk model for estimating donor exposure to the BSE

vCJD agent, and this linear model would be related to the

duration and likelihood of dietary exposure in countries

that had exhibited evidence of BSE and vCJD.

          The duration of dietary exposure can be estimated

in a fairly straightforward manner by travel or residence in

the endemic areas.   The likelihood of exposure for an

individual within these areas needed to be assumed, and that

assumption was that individuals who spent time in an endemic

area were likely to have had beef in their diet.   Although,

admittedly, some certainly did not, it wasn’t really

possible to make that distinction.

          [Slide]


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          So, one of the earliest discussions related to

derivation of a travel deferral policy was a discussion by

this committee as far as how to arrive at donor eligibility

criteria given the absence of data.   There was discussion in

January of 1999, given the epidemiology that was recognized

not only in the UK but in Portugal, the Republic of Ireland

and France that perhaps there needed to be an extension of

deferrals beyond the UK.

          But the ultimate conclusion was that a further

analysis of data was needed and this would include the need

for a survey of donor travel to be conducted, and it was

fortuitous that this need for data occurred at this time

because the National Heart, Lung and Blood Institute in the

US had at this time sponsored some very sophisticated

surveys for other factors within the blood donor population

so that we had sampling frames and blood centers that were

actually set up with staff and would quite easily adapt the

survey capability that was there to conduct a travel survey.

          So, in the winter of 1999 a probability sample of

accepted blood donors was conducted, a total of 19,000

travel surveys.   There was about a 50 percent response rate.

 The survey asked about travel not only to the UK but to


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Europe as a whole, and collected demographics about the

respondent population.

           [Slide]

           This, in summary, is the data that were collected

with respect to exposure in the UK from that initial

analysis of the survey.   These are simply two linear graphs

on the same X and Y axes, the bottom one reflecting the time

spent in the United Kingdom of the Republic of Ireland as a

function of the donors who had spent that particular period

of time.   So, as you see, at six months, 2.2 percent of the

population had a cumulative six-month exposure in the UK; 14

percent had a one-week exposure; and less than 1.5 had a

one-year exposure.

           Then, the top graph is a graph derived from the

total risk considered in the context of the proportion of

donors who had spent a certain period of time.   So, for

example, donors who had spent a year in the UK, deferring

all these donors would remove approximately 80 percent of

risk but add a cost ofB-I am sorry, I got myself a little

confused here.   At a six-month deferral period there would

be a loss of 2.2 percent of the donors and a residual risk

of 14 percent from this cohort of individuals who spent time


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in the UK.    That would equate to an 86 percent removal of

risk from this UK-exposed cohort.

             One could vary that and defer all donors who had

spent time in the UK or lesser proportions of donors but

this would, in fact, result in a higher loss of donors that

perhaps the blood supply would not be able to tolerate at

that time.

             [Slide]

             So, based on those discussions, a guidance was

issued by the FDA in November of 1999 that recommended

deferral for travel or residence in the UK for greater than

or equal to six months between 1980 and 1996.

             The recommendations also included deferral for

receipt of bovine insulin sourced in the United Kingdom

after 1980 and product retrieval was recommended if a donor

was later discovered to have vCJD.

             [Slide]

             These donor deferrals were undertaken concurrent

with a commitment to monitor the blood supply.    This was

based on the initial estimate that the blood supply loss

would be on the order of 2.2 percent with an 86 percent risk

reduction.


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          The deferral related to the UK is based on a 1980-

1996 period.    The 1996 cap is important because it reflects

within the UK an aggressive BSE and food chain control

program that was implemented in the country.   Also, the

guidance removed recommendations to withdraw plasma

derivatives containing plasma from donors with classic CJD

or CJD risk factors which had been in place on the basis of

a 1996 FDA memorandum.

          [Slide]

          The TSE advisory committee again discussed this

issue in June of 2001.   This was based on new epidemiologic

information, the first being that the US blood supply had

generally survived the 2.2 percent donor loss from the early

intervention.   There was recognized spread of BSE and vCJD

cases in Europe.    There was consideration of data that were

emerging about known UK beef importation, both at US

military bases in Europe and in France.

          There were epidemiologic observations supporting

differences in policies for dietary BSE exposure in the UK

versus other European countries.   So, there was actually a

weighting applied to risk that occurred in different

countries, with the UK considered as 1.0, Europe as a whole


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considered as 0.05, and UK bases having a little higher

ratio because of the proportion of UK beef that they

imported at 0.35 percent.

             There was also availability of early clearance

data for fractionated plasma derivatives which permitted

consideration of plasma donor exposures in light of the fact

that there was some clearance of the prion material.

             [Slide]

             So, in June of 2001 FDA issued the recommendations

that are still in place today.    These recommendations

included deferral for greater than or equal to three-month

residence or travel in the UK from 1980 to 1996; deferral

for greater than or equal to five years residence or travel

in Europe.    If you will notice, the risk weighting between

Europe and the UK was 0.05 and if you count the number of

months, it is three months compared to 60 months so that

actually reflects the 1:20 ratio in risk.

             Deferral also for greater than or equal to six

months on certain US military bases in Europe.    In fact, the

importation of beef to the bases was between 1980 and 1990

in the northern bases but up to 1996 in the southern

military bases.    So, in the interest of preserving donors in


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the donor pool a distinction was made in the recommendations

between the bases in the north and south of Europe.

Deferral was also instituted for transfusions in the UK from

1980 to the present and receipt of bovine insulin sourced in

the United Kingdom.

          [Slide]

          Based again on the initial survey and the re-

analysis, the estimated cumulative impact of the deferral

program was approximately 7.2 percent estimated donor loss,

with an overall risk reduction of about 91 percent.

          The actual impact on the blood supply was not

directly measurable.    At several of the meetings both the

blood community and some of the military blood programs

presented data which reflected disproportionate donor losses

not only in coastal cities, such as New York City and San

Francisco which appeared to have up to 10 percent donor loss

given the high degree of international travel, versus the

rural US where donor loss was in the 2-3 percent range.

          This FDA recommendation had an impact on the

importation of red cells, which was in place prior to this

FDA recommendation, from Europe.    A lot of group O red cells

were imported, particularly into New York City, and


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constituted a portion of the blood supply.   This blood

source from Europe was eliminated with this recommendation.

 And, there was an agreement at this meeting to conduct

periodic review of the FDA policy by this committee at

multiple subsequent meetings.

          At a couple of the meetings the committee did

review this policy, and the first I will mention is a

meeting in October of 2004.   The committee reviewed current

FDA recommendations regarding vCJD donor eligibility.     This

was based, as mentioned, on a presumption of transmission of

vCJD from blood of a second clinically healthy donor, the

observation of vCJD in an individual who was observed to be

heterozygous for methionine at codon 129 of the PrP gene.

          This was the observation that gave concern of a

potential second epidemic wave in endemic countries and the

fact that predictions of vCJD infection rates were beginning

to appear based on finding of abnormal prion protein

lymphoid tissues of preclinical cases.

          [Slide]

          At this meeting the committee did not recommend

further FDA deferral policy actions to protect the blood

supply but indicated a desire to see further data on the


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issues and, at the same time, did not recommend any

reductions in the current eligibility restrictions that FDA

had in place.

           Discussions at that meeting which were to be

followed up included the actual value of the donor questions

to exclude TSE risk and the predictive value, and the

feasibility of deferral for history of transfusion outside

of the United Kingdom.

           [Slide]

           The donor questionnaire is very important in

helping preserve a safe blood supply and it is used to help

defer donors who have been potentially exposed to a wide

variety of transfusion-transmitted infections.   However,

true validation of the donor screening process is very

difficult, in part because the incidence and prevalence in

the donor population of infectious disease is quite low, but

also just having the information to actually derive a

predictive value for a question is quite difficult.

           So, estimates currently are in the range of 85-99

percent.   The details of this were described at the meeting.

 But also developments in the donor history questionnaire

have helped to ensure that the questionnaire is standardized


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and it has now been validated for donor understanding with

the help of the AABB and investigators with CDC who helped

provide that validation.    So, we have really a quite high

quality questionnaire, as much as possible, currently.

             [Slide]

             At the February 8, 2005 meeting there were

additional developments.    There were two observed vCJD

transmissions associated with transfusion, and they were

recognized to be prior donations by two recent vCJD cases in

France and there had been implementation of deferral for

transfusion in several European countries.

             At that meeting data were presented showing that

the cost of deferring donors for transfusion in Europe would

be modest.    Transfusion in Europe was estimated to result in

deferral of two per 10,000 donors; France would be 1.4 per

10,000; any European transfusion three per 10,000, and

history of any transfusion anywhere was estimated to be five

percent based on an NHLBI survey data.

             [Slide]

             So, the TSE, in short, recommended deferral for

blood donors in France but not deferral for transfusion in

other areas at the February meeting.


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          [Slide]

          FDA issued a draft guidance in August, 2006

recommending deferral of donors who received a transfusion

of blood or blood components in France since 1980.   The

final recommendation has not been issued but, as mentioned,

the AABB Uniform Donor History Questionnaire is in place and

does include this question in a standardized form throughout

the country.

          [Slide]

          Just as stage setting for potential future

discussions, this is a list that David Asher showed earlier

of countries which have reported BSE.   Highlighted in yellow

are three countries where BSE is reported but for which

there are not currently donor deferrals.   This is in part

due to just continuing evolution of the epidemic, but also

the fact that there are no data to predict donor loss were a

donor deferral to be instituted for an area like Asia, which

could have a profound impact on the blood supply.

          [Slide]

          Although there has been BSE observed in Japan we

are not in a position at this point to recommend deferral

for travel to Japan or other areas of Asia, but this is an


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area for potential future discussion.

          [Slide]

          In addition, because control measures have been

instituted throughout countries in Europe, there is

potential to modify the deferrals currently in place

throughout Europe which include deferral for exposure from

1980 to the present, and potentially match the cap at 1996

that is in place in the UK.    However, some of the data

related to this are variable and whether or not to look at

this on a country by country basis is potentially a

consideration for the future.

          [Slide]

          There will be a presentation this afternoon by

Prof. Van Dyck which will look into some of the European

food chain controls that have been put in place and

potentially start to explore the feasibility of fine-tuning

the policy.   So, thank you very much.

          DR. HOGAN: Thank you, Dr. Williams.    Are there any

quick questions?    Yes, sir, Dr. Monroe?

          DR. MONROE: A quick question on the reliability of

donor deferral.    So, you answer the questions and then there

is this choice at the end where you can say despite what I


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said, don’t use my blood.      Is there any data on how often

people do that, presuming they don’t want to answer the

question about sexual risk factors but then really decide

that they shouldn’t have their blood be used?

            DR. WILLIAMS: That procedure is known as

confidential unit exclusion.      It largely is not in place

today.    FDA does not recommend it.    There are published data

showing the effectiveness of the confidential unit exclusion

process.    In fact, the reason that it isn’t recommended is

that its predictive value is very low and there is a lot of

blood lost inappropriately due to donors making that choice.

 And, there are studies that reflect that.

            DR. HOGAN: Thank you.    We will move ahead now and

Dorothy Scott will present some information to us on TSE

clearance in the manufacturing of plasma-derived Factor

VIII.    Thank you.

   D. Introduction to TSE Clearance in the Manufacture of

                      Plasma-Derived Factor VIII

            DR. SCOTT: Good morning.

            [Slide]

            I am going to briefly review aspects of TSE

clearance in the manufacture of plasma-derived Factor VIII.


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          [Slide]

          I am showing you this slide because it makes a

point about TSE clearance, at least with respect to the risk

assessment that you are going to be hearing about later.

This is a depiction of the impact of various factors that

are inputted into the risk assessment and their effect on

the level of risk.

          So, what you are seeing here is input variables,

log manufacturing reduction of the vCJD agent, the amount of

Factor VIII used by a patient per year, the prevalence of

vCJD in the UK, and so on.

          But the point here or what this graph is showing

you is that the magnitude of each of these individuals is

increased with all the other variables remaining the same.

It answers the question of whether the risk goes up or down

and, relatively speaking, how much.

          Without getting into the details, I really want to

make the point that the reduction of the TSE agent by

manufacturing process decreases the amount of risk by a far

greater magnitude than any of the other factors that either

increase or decrease the risk as a matter of fact.   So, for

example, the efficiency of the donor deferral policy does


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decrease risk but in comparison to manufacturing not as

much.

          [Slide]

          Most of you already know this but I am just going

to go over it very briefly, how is risk reduction by

manufacturing assessed?   It is assessed using a scaled-down

process that simulates the manufacturing process for step or

a series of steps in manufacturing.   A TSE infectious

material is spiked into a manufacturing intermediate.     It

undergoes the steps in the scaled-down process and the left

over infectivity in the product intermediate is measures, as

well as the infectivity in a byproduct fraction.

          Now, there are two types of preparations generally

that can be used for these studies.   One is the brain-

derived preparation, which we call exogenous, and that would

be spiked here, or endogenously infected plasma can be used.

 This committee discussed that at our last meeting.    Very

briefly and fairly superficially, I am going to mention the

major upsides and downsides of each method.

          [Slide]

          The exogenous spiking TSE clearance studies are

done using brain preparations and you can measure, because


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there is a high titer of infectivity in brain, very high

amounts of clearance in these studies because you are

starting with a lot of material that is infectious.

However, the similarity of the brain-derived spiking

preparations to natural infection isn’t fully understood and

that is because we don’t really understand everything about

the physicochemical form of the agent in plasma.

          Now, endogenous TSE clearance studies, which are

done using endogenously infected plasma so that is plasma

taken from an infected animal, are likely to be highly

relevant to the form of infectivity in human blood.    We can

only demonstrate very limited amounts of clearance because

the starting infectivity is so low.    So, you may have a

process where you can demonstrate to clear one or two logs

of endogenous infectivity but that is all there is.    In

fact, the process might clear much more but you can’t

measure it using that system.

          [Slide]

          We do evaluate voluntary TSE clearance studies,

that is, studies that are voluntarily submitted by industry

for labeling claims.    We discussed this with this committee

in 2003 and the committee agreed that we can consider


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granting a labeling claim for TSE clearance, just as we do

for viral clearance studies, if the sponsor submits a

detailed study report of the specific manufacturing process

and demonstrates the ability of that process to reduce TSE

infectivity.

          [Slide]

          This is what such a submission typically contains,

a rationale for the animal infectivity model selection; a

rationale for the spiking preparation that is being used; a

characterization and titration of the spiking agent.    The

study conditions have to replicate the manufacturing process

and there is a way to do this down-scaled validation.    There

needs to be experimental reproducibility and a well-

characterized bioassay needs to be used to measure TSE

infectivity of the starting and finishing material.

          [Slide]

          The estimated logs of clearance by processing

steps need to be calculated.   There should be a

demonstration of mass balance.   That is, the amount you put

in is the amount you get out in both fractions, the

byproduct fraction and the product fraction.

          There should be demonstration, if these are going


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to be claimed, that mechanistically similar steps are or are

not additive and this has, in fact, been done in a couple of

cases.   And, there needs to be an accounting for the

possible conditioning of TSE agent by prior manufacturing

steps that could affect the physical state and, therefore,

its clearance properties.   For example detergent-containing

steps would fall in this category.

           [Slide]

           So, what do you get if you submit all of these and

if we approve a labeling claim for TSE clearance?   In the

description section, which is also where viral clearance

studies are describedB-and I am quoting to you from a

typical package insert, additionally, the manufacturing

process was investigated for its capacity to decrease the

infectivity of an experimental agent of transmissible

spongiform encephalopathy considered as a model for the vCJD

and CJD agents.

           [Slide]

           Then, getting more specific, it can continue to

say several of the individual production steps in the

product manufacturing process have been shown to decrease

TSE infectivity of an experimental model agent.   The TSE


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reduction steps then can be named, the process, the amount

of log reduction, as many as were described.   These studies

provide reasonable assurance that low levels of CJD and vCJD

agent infectivity, if present in the starting material,

would be removed.

          [Slide]

          In addition to this, all products carry a warning

statement which has nothing to do with these studies.    This

actually is one of the things that we will be addressing in

question 3(b) to the committee concerning whether or not FDA

should consider a change in the warning statement.

          In the warning section for all plasma derivative

products and other products such as vaccines that contain

plasma derivatives like albumin, it states because this

product is made from human blood it carries a risk of

transmitting infectious agents, e.g. viruses and,

theoretically the CJD agent.   The statement was intended to

capture the uncertain but still possible risk.

          [Slide]

          One of the questions that we asked you at our last

meeting is how much clearance is enough.   So, the TSE

estimate in plasma, based on animal models, has been


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something on the order of 2-30 infectious doses/ml.    If you

multiply that by the volume of a typical plasma unit you get

3.2 to 4.4 logs of infectious doses in that plasma unit.

           Well, in the analogous case for viral clearance

studies usually we would like to see clearance at least for

the maximum amount of virus expected in an infected plasma

unit plus a margin of safety.

           [Slide]

           A typical margin of safety minimum would be at

least 2-3 additional logs of clearance and this is thought

to be prudent because manufacturing conditions aren’t

identical for every lot of material and you can’t study

every condition even in a scaled-down study with robustness.

           The viral titer in plasma could be greater in any

individual case than what is estimated based on published

reports, and virus models are not identical to field

viruses.   In a more extreme example, we also can’t always

actually use the virus in question because there are not

good culture methods so similar model viruses are used to

demonstrate clearance.

           [Slide]

           Well, at our last meeting we asked this committee,


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based on available scientific knowledge, would a minimum TSE

agent reduction factor, measured by bioassay, demonstrated

using an exogenous spiking model in scaled-down

manufacturing experiments, would this enhance vCJD safety of

the product?    For the most part, the committee agreed that

was the case.

          [Slide]

          But then we come to the more specific question, if

yes, what TSE agent reduction factor is the most

appropriate?    And, this committee did not identify a minimum

TSE reduction factor because of the uncertainties and gaps

in scientific understanding.

          Specifically, you were concerned about how much

infectivity really is in human plasma.   We don’t know.     And,

how well do spiking studies, or does a spiking model reflect

endogenous infectivity?   In other words, how similar is the

physicochemical property of infectivity in spiked brain

material to what really occurs in plasma?    I do want to

point out that we have not approved a labeling claim for

less than six logs of clearance for plasma derivatives.

          [Slide]

          These are the plasma derivatives for which claims


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are approved.   I am not going to mention them all but four

of these are immune globulins and this is thrombate III.

These are the steps that demonstrate clearance, and this is

the reduction factor for each of those steps.

          That is not to say that there haven’t been many,

many other studies done on TSE clearance for other products

that we are aware of, however, these are the ones so far

that have been submitted and approved.

          [Slide]

          Now, we are going to get to the details very soon.

 In 2006 the Plasma Protein Therapeutic Association made a

presentation and they summarized TSE clearance study results

for four US plasma-derived Factor VIII manufacturers.

          What they showed were clearance results from

precipitations, chromatographic procedures and filtrations,

and the clearance levels they reported for US products all

had at least one step or series of steps with an estimated

3.5 to 4 logs of clearance.   Three out of four of those

studies had binding assay readouts, not bioassay readouts.

And, there were varied study designs with respect to the TSE

agent preparation that was used for spiking, the number of

steps studied and the type of readout.


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             [Slide]

             So, now we get down to those details because PPTA

has agreed to update their TSE clearance studies for plasma-

derived Factor VIII products.    Dr. Gröner will be discussing

this in just a minute.

             DR. HOGAN: Thank you.   Are there any quick

questions?    If not, we will move ahead.     Thank you.   This is

Dr. Albrecht Gröner and he is going to talk to us a little

bit about the PPTA studies.

     E. TSE Clearance Studies for Factor VIII Products

             DR. GRÖNER: Good morning.   Thank you very much,

Dr. Scott, for the introduction of that topic.

             [Slide]

             I would like to present updated information from

the last presentation we did, and would like to state that

we are now covering all our manufacture of the member data

for licensed product in the US of Factor VIII.       When we are

discussing a risk assessment for the potential exposure of a

vCJD agent we have to consider, of course, the epidemiology

and the donor population, and we already have stated several

times today the donor deferral since 1999 already.         Then,

the other issue is the prion load and the incubation period


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and I will, of course, focus on the prion reduction capacity

of the manufacturing process of plasma-derived Factor VIII

concentrates.

            [Slide]

            As already mentioned, the issue is when we are

performing prion reduction studies that we have to a

validated down-scale when we are spiking, and you just saw

from Dr. Scott very nicely how it is done, and we can assure

that all our data are based on a validated down-scale.    That

means that our reduction factors we have demonstrated are

predictive for the manufacturing scale.

            Then, again as already mentioned, the choice of

the spiking agent, how that material will be prepared and

then, last but not least, what method we should use for

prion quantification, whether it would be a bioassay or an

immunochemical assay, and the conditioning of the spiking

material.

            [Slide]

            As we have more than ten years of experience with

prion reduction studies, I would now summarize some of these

data and come to that system.   When we are using exogenous

biomaterial, which is the normal way to use, we can


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demonstrate that brain-derived material from different

species is removed comparably.

            You see here three different human TSE, sheep and

hamster, and here two different human and hamster, and all

preparations were removed by a total of five different

manufacturing processes very comparably.

            [Slide]

            When we are now considering an endogenous

biomaterial, and here using for spiking, not using blood

which contains endogenous material but using it for spiking,

as already said, the material will be much too low in

infectivity to use it as a spiking agent.    And, when we are

preparing from endogenous material a spiking preparation we

may alter the physicochemical properties of the spiking

material.

            I would just like to show you very shortly what we

did, some experiments.   Low molecular weight material which

is derived from a high-speed supernatant, that means

200,000g supernatant was spiked in plasma intermediate and

then precipitated by means which are used in a normal

manufacturing process for Factor VIII products.   Here we are

using glycine.   Then that spiked material, precipitated with


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glycine, was centrifuged in a laboratory centrifuge and the

pellet was re-suspended in 10 mM TRIS and pelleted again

with low-speed centrifugation, laboratory centrifuge.

           As you can see, clearly we were able to recover

all the high-speed supernatant by a low-speed precipitation

step.   Therefore, we would alter significantly the

physicochemical properties of a prion material if we would

use endogenous material and prepare it so we have so we have

high titer material.    Therefore, there is no benefit, in our

opinion, to use that in contrast to brain-derived material.

           [Slide]

           The next issue, of course, is how we should deal

with quantification.    The FDA and also the European agency

are considering the bioassay as a gold standard.

Nevertheless, we did, of course, comparable studies and

could demonstrate, as you can see, for a range of different

manufacturing processes comparable reduction factors using a

bioassay or a biochemical/serological assay.

           The same is true for Factor VIII products that I

will discuss later on shortly.    Also very comparable

reduction factors.

           [Slide]


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             Last but not least, the conditioning of the

spiking material by the product intermediate when we are

spiking in the end or by the manufacturing process which is

performed.

             It is already known that ethanol will aggregate

prion material and, as I just explained, also low molecular

weight prion material will be aggregated by protein

precipitating agents.

             [Slide]

             I will now just show you some data we have

generated for a US-licensed product.    We have individual

steps which were spiked and tested up to four steps.       All

used the combined step approach when we spiked at the

beginning of step A and studied the result at step B, C or

D.   You can see here very nicely comparable reduction

factors whether we are using a single step approach or a

combined step approach, and come up with very comparable

reduction factors.

             [Slide]

             Now an update on the products you have already

seen at the last TSEAC meeting.    Here we have two steps

resulting in an overall reduction factor of 8.1.    Here, a


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bioassay again comparable to the biochemical assay, 9.1

versus 8.1.

            [Slide]

            Here are three steps resulting in an overall

reduction factor of 5.5.

            [Slide]

            Here, a little more complicated slide, there were

two different spike preparations, a microsome preparation

and PrPSc purified with two manufacturing steps, combined

manufacturing steps, microsome studied by the CDI as well as

the bioassay resulting in comparable data, coming up with an

overall reduction factor of 5.9 log for the bioassay and 7.9

log for the CDI using purified PrPSc.

            [Slide]

            Here is another product also using two different

spiking preparations, microsomes as well as glial brain

emulsion.   The assays are ongoing.   The Western blot data

are showing an overall reduction effect of 4 logs.

            [Slide]

            For product F, which is not licensed in the United

States, we have an overall reduction effect of 6.5 .

            [Slide]


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          We can now summarize it in one slide.   We see very

convincing more than 4 log reduction factor for the

bioassays for the studies and products which were performed

up to now, and from 4 log up to more than 9 log for the

immunochemical assay for different products.

          [Slide]

          When I now summarize the data, as I already said,

the reduction factors of plasma-derived Factor VIII products

licensed in the US are at least 4 log and, as already stated

several times and which is obvious, we are not using UK

plasma and appropriate donor deferral procedures are in

place.

          [Slide]

          Therefore, we conclude that the recent report from

the UK Health Protection Agency regarding the patients with

hemophilia has no bearing on the safety profile of products

manufactured by PPTA members.

          As already stated by Prof. Will, the implicated

product 8Y we saw from UK plasma and that UK product had a

very, very low prion reduction capacity, on the order of 1

log in contrast to at least 4 log of all our products which

are licensed in the United States.


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          Last but not least, I would like to emphasize that

the industry is committed to commit research in plasma

derivatives and TSE-related issues.   Thank you.

          DR. HOGAN: Thank you very much, Dr. Gröner.     Also,

thank you for coming in under time.   Are there any questions

regarding this?   Dr. Manuelidis?

          DR. MANUELIDIS: Maybe I missed it but could you

tell me what you are spiking with?    Are you spiking with

brain when you talk about endogenous, or are you talking

about some kind of blood that you are collecting from an

infected animal and, you know, what the problems are there?

 Again, the animal assay, I am not quite sure how you are

reading out the animal assay so I am missing a bunch of

things, you know, in terms of where you are and what you are

getting at each step.

          DR. GRÖNER: We are not using endogenous material

because, as Dr. Scott already explained, if we would use

infected blood we could not perform an appropriate down-

scaled validated experiment for human plasma-derived product

and, therefore, we are using brain-derived material,

differently prepared, either as a membrane-associated form

or as a non-membrane associated form and these type of


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things, brain homogenate is differently cleared.     These are

by different companies but all are using exogenous brain-

derived material for spiking.

             DR. MANUELIDIS: Again, is it 263K scrapie that you

are using?    Second, I would like to make the point that

there are animal models that can be used where there is

infectivity in blood.    Although it hasn’t been really looked

at exhaustively, there are now new vCJD models, for example

clearly, you know, where spleen is infected, etc., and there

are other assays of infectivity as well.

             So, I am not negating anything.   I am just saying

that perhaps it is possible to update some of these things

with a more specific model that is really more relevant for

the plasma study.

             DR. GRÖNER: We are using primarily the 263K but

also the ME7, but usually 263K.    As I just said, we are

committed to research and that means we are also looking at

other possibilities to use other material, also endogenous

material, but up till now we don’t have clear-cut,

scientific, solid information that we can use other spiking

material and/or use blood from an animal which will

fractionate differently and, therefore, our down-scale would


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not mimic the production process for human plasma-derived

product.

           DR. MANUELIDIS: Maybe I don’t understand.    Why

would human blood fractionate differently than an animal’s

blood in terms of these big generalities specifically?

           DR. GRÖNER: Different proteins are in different

concentrations in animal blood compared to humans.     They may

be small, considered to be small but they may have a huge

impact on the quality of the experiment because what we want

to demonstrate is that the down-scaled product is valid and

mimics the manufacturing process of a human plasma-derived

product.

           DR. HOGAN: Well, perhaps we can discuss this a

little bit more at the break.   I have one question.   You

said you are not using UK sourced plasma.    Are you using

plasma from any other European country or is this all US?

           DR. GRÖNER: For US licensed products it is only

US.

           DR. HOGAN: I just wanted to make that point.

Thank you very much for coming.

           I would like to move ahead now.   Dr. Anderson is

going to talk to us about the assessment of possible risk


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for plasma-derived products in the UK, and I believe some

insight into the model.

   F. FDA Assessment of Possible Risks for Plasma-Derived

                    Products in the UK and US

          [Slide]

          DR. ANDERSON: Today I am going to basically

provide a review of the risk assessment, which is basically

a risk assessment of potential vCJD risk for plasma-derived

Factor VIII products manufactured in the US.

          [Slide]

          So, just sort of getting right into the

presentation, just recall that FDA presented the Factor VIII

vCJD risk assessment at the December 15,2006 TSEAC.    Here is

the title of the document.    It was a draft quantitative risk

assessment, again, of vCJD risk potentially associated with

the use of human plasma-derived Factor VIII manufactured

under US license from plasma collected in the US.

          I wanted to remind the committee that there has

been a lot of input from this committee on this risk

assessment.   So, we came to the committee, I believe, in

February of 2005 with a concept model of this risk

assessment and asked for input on that concept model.


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            We came back again in October of 2005 and had

several inputs, I believe about half dozen inputs that we

requested comment and discussion from the committee on.      All

of that input and that discussion is integrated into this

2006 risk assessment.

            Finally, there was a peer review process for the

risk assessment.      We sent the model and the spreadsheets out

to three external experts.     They gave us back those

comments.   We integrated those comments into the risk

assessment.   That was done in the summer of 2006.    Finally,

just as part of this, when the risk assessment was released

that risk assessment was accompanied by a risk communication

effort by the FDA.

            [Slide]

            So moving into the current risk assessment, what

has changed since 2006?     You heard Dr. Will discuss the

emergence of vCJD in a person in their 70s who had

hemophilia, in the United Kingdom.

            There is actually probably a more important part

as far as the risk assessment goes.     There is now newer data

on vCJD susceptibility of populations.     At the time there

was some information coming forward in 2006 but now there is


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more confirmation, especially that vCJD infections have been

identified in persons who are methionine valine heterozygous

and valine homozygous at codon 129 of the PrPNP gene.

             I think Dr. Will also mentioned one possible death

from vCJD.    I believe that was an MV person that was

reported in the popular press.    So, again, we are coming up

with a higher susceptibility or broader susceptibility for

the population and what we are assuming now is that all

genotypes in the US and the UK are now susceptible to vCJD.

             What that does as far as the model goes is that it

changes our estimates of UK vCJD prevalence.    I will discuss

that a little bit more in depth as the presentation goes

along.

             [Slide]

             I wanted to start by saying that basically we

started with our 2006 model as a framework.    What we did

was, based on that model and that framework, we updated

three of the inputs in the 2006 model.    Those inputs we

updated, of course, with estimations of vCJD prevalence for

the United Kingdom.    I am referring to modules and you will

see these later in the overview diagram that I will present

later as part of the exposure assessment of the model.


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           So, in addition to UK vCJD prevalence, we also

integrated and updated the age of the susceptible population

and that is the time in which infection occurs in

individuals.   Then, we also updated the time during the

incubation period when infectivity is present in blood.

           So, those are three inputs that were already

present in the model so we also added three new inputs to

account for this sort of broader susceptibility of

populations.   So, what we added was inputs to account for

genotype susceptibility, and then specifically modeled the

genotype proportions in the population.     I will talk a

little bit more about that in a moment.

           We modeled the distribution of the incubation

periods.   We had an idea about the incubation periods for

the methionine homozygous populations but we now have gone

and added two distributions for the methionine valine

heterozygous population and also the valine homozygous

populations.   Finally, we generated and integrated an age

distribution for asymptomatic infection into the model.     I

will say more about this in a moment.

           [Slide]

           So, as we started the modeling process we came up


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with hypotheses before we began our process and hoped that

we were on the right track as far as what we were expecting

as far as outcomes.

          So, in this model we incorporated information on

increased vCJD susceptibility of populations and we thought

that that would likely result in little difference between

the risk predicted in 2006 and 2009.   I will qualify that by

saying we did assume and thought at the time that the risk

estimates generated using the lower vCJD case prevalence

estimates would likely resolve in about a five-fold increase

at the lower end of the spectrum of risk.    Finally, at the

higher end where we have the higher vCJD infection

prevalence we thought the results between 2006 and 2009

would be very similar.

          [Slide]

          Moving on, the scope of the risk assessment

remains the same as in 2006.   I will remind you this risk

assessment focuses on severe hemophilia A patients and

patients with severe von Willebrand’s disease, and I will

remind people that the potential risk estimates are really

pegged to one particular year, and that was the year 2002,

but generally we still believe that the model results are


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applicable to the current year, 2009.

           So, as far as our analytic approach, we have the

quantitative risk assessment.   Our input data have been

incorporated into the model as statistical distributions.

We use a probabilistic computer-based model and Monte Carlo

methods.   Your eyes are probably glazing over now as I talk

about that so get ready to glaze over more because I am

going to talk just on two slides about the Monte Carlo

methods.

           [Slide]

           So, what is the basis of Monte Carlo methods and

why is that important to this model?    Well, Monte Carlo

methods are basically a tool for combining input data as

distributions rather than using either deterministic or the

simpler forms of data.

           What the Monte Carlo method allows us to do is it

is an easier process for combining more than two

distributions which would be challenging under other

circumstances, or using other approaches.   So, what the

method actually does is it draws randomly from defined

distributions and performs the programmed mathematical

functions so it can be addition, subtraction, multiplication


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or whatever function and stores each number each time.        The

process is repeated thousands of times.       We call those

iterations.    Then the results are displayed as a new

aggregate distribution.

            [Slide]

            That whole process is illustrated here in this

diagram.    I took an example.   This is similar to what we

used in the model although not exactly the same, but this is

just purely an example of the methodology for Monte Carlo

analysis.

            In this simple example we are calculating the

ID50/ml of plasma.    So, we start out with the intracerebral

ID50/ml of blood.     We have a statistical distribution with a

minimum of 2 and a maximum of 30 and the most likely value

of 10, and that is called the triangular distribution.

            We have a single point estimate of 58 percent as

the percentage of ID50s in plasma, and then we have another

distribution that gets us to the ID50s which is the

adjustment from the intracerebral to intravenous ID50s,

another distribution, and this is called the uniform

distribution, from 0.1 to 1.0.

            What happens is one iteration picks one value from


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this distribution; multiplies it by this value; picks

another value from this distribution; does the

multiplication and that number goes somewhere on this graph.

 That is done 10,000 times and it generates a distribution

like this.    So, that is our aggregate distribution.

             So, why is that important?   What I wanted people

to keep in mind is this type of distribution.     You are going

to see a lot of tables and you have probably already seen

those in the issues summary.    So, all of those cells in the

table are really summarizing results from this distribution

so all of those cells in the table really are just

distributions and they are summary information in the cells

on the distribution.

             For instance, the mean in this particular instance

is 5.2.   There is a fifth percentile here I believe of 1.

It is buried under there.    And there is a 95th percentile of

about 12.3.    So, just keep that in mind as I go through the

results and that there is underlying distribution for all of

these results.

             [Slide]

             So, how do we do risk assessment at the FDA?   We

rely on a framework that was developed by the National


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Academy of Sciences in 1983.   I am not going to go through

all of the parts of this.   I will touch on various parts

though throughout the presentation.

          The major model portion of it is in portion 3,

which is going to be exposure assessment, and that is going

to make up the bulk of the presentation.   Finally, the risk

characterization part is really where the results are.    So,

when you see the tables, think that is the risk

characterization portion of the model.

          [Slide]

          I am going to start with hazard identification

though as far as the science goes, and this established

causality between the hazard, which is the vCJD agent, and

adverse effects, meaning illness or infection.

          [Slide]

          I am not going to go through all of the things

that are incorporated into the hazard identification but

just highlight a few of the major factors.

          So, factors really associated with the risk for

plasma-derived Factor VIII products are that plasma is

pooled from thousands of donors so there is an increased

chance of a plasma pool perhaps containing a vCJD donation


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if vCJD is present in the population.

            Also, another factor is that hemophilia A patients

and von Willebrand disease patients use large amounts of

these products over their lifetime so if vCJD is present in

the population and those persons donate to plasma pools,

then these patients have intense use of these products so

may have a higher likelihood of exposure to the agent if it

is present.

            But there are factors associated with decreases in

risk.   For instance, TSE clearance during manufacturing,

which Dr. Scott just mentioned, so I won’t go into that

particular aspect.

            [Slide]

            As far as the second part of risk assessment, it

is dose response for human vCJD.   What the risk assessment

does is it assumes a linear dose response based on animal

TSE data.   But I do have to sort of qualify this whole

process because I do remind people that human data are

absent for dose-response relationships so all of the dose-

response relationships, again, in the literature or any of

the data related to that are really based on animal model

studies.


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             So, there are a lot of uncertainties and

challenges for determining dose response, and those are

listed here.    And, one of the biggest questions is does use

of the animal data, does that really approximate human vCJD

infection well?

             [Slide]

             So, getting into the actual model, this is an

overview diagram of the model, a nice cartoon

representation.    I am mainly going to talk about the modular

components.    There are four modules in the model.     I am

going to orient you.    On the left, these are inputs of data

and on the right are outputs that are actual outputs from

the model.

             For instance, we have the epidemiological modeling

inputs for the lower vCJD estimates and the higher vCJD

estimates.    All of that information is here and finally we

get an estimate out that is a refined estimate of the higher

estimates and the lower estimates of prevalence, and so on

and so forth.

             For instance, as we get down to processing we are

interested in plasma pool size but also, as Dr. Scott

mentioned, reduction of vCJD agent during manufacturing,


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which is a major consideration in risk.

           So, we have our four components.    vCJD prevalence

in the UK is the basis of this model.   We, in turn, use that

prevalence to estimate the vCJD prevalence in US donors and

then what we are hoping to get, or what we do get out of

this portion of the model is we get the total number of vCJD

donations predicted for the US.

           Then, what we want to know is as those donations

go into plasma pools, this side of the diagram, what is the

effect of processing on reducing the quantity of agent that

might be present in a pool that contains a vCJD donation.

           Finally, what we get out of this module 3 is we

get the percentage of plasma pools and vials that may

contain vCJD agent and then we also get the quantity of

agent, again if it is present, in the vials.

           Finally, we are interested in how are those vials

used and how much product do patients actually use.    So, we

calculate that amount and then we integrate that with the

previous information to get the annual exposure of Factor

VIII recipients to vCJD agent and that is the dose that they

receive.

           [Slide]


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          So, that is a quick overview.     I am just doing

that very quickly because of the time limitation.    I wanted

to provide just some basic background on prevalence before I

jump too far into prevalence.

          I will remind people that UK has the highest BSE

prevalence in the world.   Then, as far as vCJD cases, these

have previously been presented.   There are 168 that are

associated with food-borne exposures in the UK, four

associated with transfusion transmission, and then one

possible case associated with plasma products.

          I will remind you again that UK has the highest

vCJD prevalence in the world and it is important to remember

that the prevalence of vCJD in the UK isn’t known and can’t

be estimated with certainty.

          [Slide]

          Going on to prevalence in the US, prevalence of

BSE is assumed to be negligible in the US.    Accordingly, our

prevalence of domestically acquired vCJD is likely very

small.

          There have been three reports of vCJD in the US.

All of those cases lived in the UK or probably acquired the

disease elsewhere.   So, at this time there are zero known


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food-borne cases of vCJD in the US and zero reported cases

of transfusion transmitted vCJD in the US.

          So, what does that say as far as our prevalence?

We can make a general conclusion that the vCJD prevalence

and risk for the US is likely several hundred-fold lower

than that of the UK.

          So, I will remind people that the FDA risk

assessment model really assumes that vCJD risk for donors is

associated with a history of travel or residence in the UK,

France or other countries in Europe since 1980.   So, we

found that the food-borne exposure route and the probability

of acquiring vCJD in this country through food-borne sources

is negligible for the purposes of the model.

          [Slide]

          So, as far as prevalence of vCJD in the United

Kingdom that is used in the model, our 2006 estimate was

based on work done by Clarke and Ghani in 2005.   That was

1.8 per million.    What we have done is we have extended that

estimate to include the entire population so, whereas this

estimate was valid for methionine homozygous, this estimate

is valid for all three genotypes, methionine homozygous,

methionine valine and valine-valine homozygous individuals.


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            As far as the tonsil/appendix study, again we used

the Hilton, et al. study.    That gets us a mean prevalence of

about 1 in 4,225 individuals.

            Now, the goal of estimating UK vCJD prevalence,

again, this prevalence estimate is used to estimate the

prevalence for France, other countries in Europe, as well as

military bases in Europe where US citizens may have spent

time or US military may have spent time.     Finally, it is

used to estimate the risk for plasma donors in the United

States.    So, that is how it is all linked.

            [Slide]

            Again, I just wanted to highlight the differences.

 So, looking at the December, 2006 model, the lower estimate

is 1.8.    We now have changed that to approximately 4.5 per

million.    As far as the higher estimate, there is a slight

adjustment but essentially it remains almost the same at 1

in 4,225.

            [Slide]

            Another component that I mentioned as far as one

of the updated model inputs is UK vCJD prevalence,

specifically the age of the susceptible population or the

age in which infection was acquired.    In 2006 we assumed


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essentially that infection was acquired, erroneously, at the

time that the case was observed.    So, what we have done this

time around is we have corrected that error and we are

adjusting prevalence based on age-specific rates of

susceptibility in the time of infection in the UK.

            [Slide]

            I have a diagram of that.   These are distribution

of clinical cases in the United Kingdom.      What we have done

is just applied the 12-year incubation period to this curve.

 So, this is the time of onset and this is now the time of

actual infection.     So, we have sort of shifted the curve

back 12 years to account for the time when individuals were

most likely infected.

            [Slide]

            So, that is a minor adjustment to the model.      As

far as uncertainties in estimating prevalence, again, there

are several uncertainties as far as epidemiological

modeling.   For instance, the Clark and Ghani approach

incorporates assumptions, for instance, about incubation

period, time of infection, effectiveness, and the

tonsil/appendix surveillance study also has limitations.

            For instance, the tissue surveillance lacks


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controls and patient outcomes.    We don’t know the outcomes

of the patients that were identified as positive in that

particular study.     Then there are, of course, several other

limitations as well.

            What I wanted to just sort of emphasize is that we

have these two prevalences in the model.      We have the lower

end prevalence that represents the vCJD case prevalence

estimate and then we have a higher estimate that represents

the vCJD infection prevalence based on the Hilton data.

What we are calling this, it is sort of a boundary approach

so what we think is that because there is so much

uncertainty we couldn’t choose one or the other estimate.

We either think it is one or the other or somewhere in

between.    So, I think that is an important concept to keep

in mind as we are going through this modeling work.

            [Slide]

            So, let’s move on to module 2, estimation of US

donor risk.    In this module, basically to sum it up, we

estimate the size of the US donor population that traveled

to UK, France or other countries in Europe since 1980.      We

modeled the travelers’ risk using survey data and blood

donors.    Then, we also adjusted the travel risk by the


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duration of the stay, the year that they stayed, and then we

estimated probability of infection in individual donors.

Finally, we also applied the effectiveness of the donor

deferral policy.

          So, our goal in this particular module is to

calculate, again, the total number of potential vCJD

infected donors as well as the number of donations in the

US.

          [Slide]

          So, just sort of going through two points that I

just made in that slide, we did a lot of adjusting for

duration of travel to the travelers and donors in the US.

We adjusted for specific years of travel, and that is really

to account for the BSE epidemic.

          So, obviously, the risk at the height of the

epidemic in 1992 to travelers was much greater than the risk

was in 1998, after the food control measures were put in

place and the feed ban was put in place in the UK, or

formally put in place.   I am sorry, I mis-spoke.   It is not

the feed ban but actually a lot of other food control

measures that were put in place in 1996 in the UK after the

identification of cases.   So, we applied age-specific rates


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to the disease as well as the donation rates, and then we

also considered type of donor.

          [Slide]

          Moving on, then we also considered again the

effectiveness of the US donor deferral policy as a risk

reduction measure.   Again, we assumed that the current

deferral policy has a mean of 92 percent effectiveness

essentially, and that ranges from a minimum of 85 percent

effectiveness to a maximum of 99 percent effectiveness.

That is based on the policy that Dr. Williams outlined in

his talk that I won’t go into.

          [Slide]

          As far as genotype susceptibility and genotype

proportion in the population, the model of 2006 considered

three aspects.   All genotypes were susceptible, equally

susceptible, but we thought that only MMs at the time

progressed to clinical symptoms.   The proportions in the

population are given here.   MMs were 40 percent, MVs 50

percent of the population and VVs were 10 percent.

          These two assumptions hold for our current model.

 What we now assume though is that all genotypes progress to

clinical symptoms.   That is the only change in this aspect


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in the 2009 model.

          [Slide]

          As far as the distribution of incubation periods,

basically if there was an incubation period that we

discussed in December of 2006, we assumed that the median

was 12 years for any incubation period.      I believe at the

time that was the assumed incubation period for the MM

population but since we had no information on the other two

populations we just assumed that distribution for all of the

populations.

          We have a little bit more information now but not

much more, so what we are assuming now is that the mean

incubation still is approximately 12 years for the MM

population, but we are changing that a bit to account for a

longer incubation period in the MV and VV genotypes.

          [Slide]

          That is sort of illustrated on this slide.     So,

this is the incubation period for the MM population.     This

is the incubation period that we have calculated for the VV

and MV populations.   That particular distribution in this

case has, I believe, a median of 32 years.

          [Slide]


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          Then, around that there are confidence intervals

at about 25 years, and at the higher end there is a 95th

percentile confidence of 55 years.   Again, these are just

assumptions and these assumptions can be changed if

additional information comes forward in the future.

          [Slide]

          The age distribution of asymptomatic infection,

what we have done is we have calculated the age distribution

in this model by combining the UK vCJD prevalence or the

time that persons were infected with the distribution of

incubation periods.   So, those two pieces of information are

combined to get ultimately the age distribution of

incubation periods for asymptomatic infections.

          [Slide]

          The time during incubation period when infectivity

is present is another model input.   That is one of the

updated model inputs.   In 2006 we assumed that infectivity

appeared in the last half of the incubation period.   With

additional data available now from animal studies, we are

assuming now that it appears in the last 75 percent of the

incubation period, and there is a range about that as well.

          [Slide]


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           Moving on, still about vCJD prevalence in US

plasma donors, there are considerable uncertainties in that

data.   Again, we don’t have travel data for source plasma

donors versus other donors.    As well, the percentage of

infections that become symptomatic disease remains unknown.

 So, there are a lot of uncertainties and these are just

some of those uncertainties but just keep those in mind as

we go through this exercise.

           [Slide]

           As far as Factor VIII processing in module 3, our

modeling approach was to estimate the probability that a

plasma pool contains a vCJD donation; estimate the quantity

of agent per milliliter of plasma and per pool if a donation

is present; estimate the efficiency of exposure through the

intravenous versus the intracerebral route; then also

incorporate the impact of log reduction on the quantity of

intravenous ID50s that eventually ends up in the product.

           So, again, our goal at the end of module 3 is to

estimate the percentage of vials with agent and then the

quantity of agent per vial.

           [Slide]

           Again, probably the most important step to discuss


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here is infectivity clearance in the products.    Each product

that is on the market, it is important to remember, has

different purification steps and clearance levels.    We don’t

have product specific data available for all products and

all process steps.

           Just cutting to what we actually did in the model

though is that FDA stratified the levels of clearance

according to two stratifications.   One was a 7-9 log level

of clearance and then a 4-6 log of clearance.    We will

present results for both levels of clearance.    But it is

important to note, finally, that we believe that most of the

plasma-derived products on the market at this time have at

least 4 logs of clearance.

           [Slide]

           As far as module 3 again, these are the

uncertainties of the data.   I won’t read through all of

these.   Suffice it to say there are several uncertainties

that need to be considered in considering the model results

that I will show you in a moment.

           [Slide]

           As far as module 4, our goal in estimating

utilization of Factor VIII, and what we want to get out of


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this particular module finally is to predict the annual

potential dose that vCJD patients may be exposed to, and

then the risk of infection based on animal dose-response

information.

           [Slide]

           Moving on, basically the input data for this

portion of the model as far as utilization was derived from

a CDC study that was conducted, a CDC-sponsored study of six

states as part of the hemophilia surveillance study and that

was conducted in 1993 through 1998.   That included a total

of approximately 18,000 records.

           [Slide]

           What I wanted to cover in this particular slide is

how do we get the results that you are going to see in a

moment.   So, what we do is we actually get the ID50 dose and

then we multiply that by the linear dose-response values

that we have and relationship.   For instance, if a patient,

heaven forbid, should get one ID50, their probability of

infection would be 50 percent.   If it is 0.1 ID50, that

would correspond in this model to a probability of infection

of 5 percent, and so on and so forth--lower levels, lower

probabilities of infection.


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          Finally what we do, and you will see these in the

tables, we estimate the risk which means the probability of

vCJD infection.

          [Slide]

          I wanted to mention the errata sheet that we have

circulated.   So, after the TSEAC issue summary had been

posted last week we had determined that we hadn’t basically

properly implemented an adjustment in the model for

susceptibility.   Especially, this would affect the lower

vCJD case prevalence scenarios.

          So, what we did was we correctly added this

adjustment, and what we did was the current estimate in the

model was at 40 percent and we just adjusted this up to

allow for 100 percent, and that is an approximate 2.5-fold

adjustment in the lower vCJD prevalence.    So, the tables

that you have in front of you, if they are errata tables,

reflect the errata and are the corrected values for the

lower vCJD case prevalence estimates.   I want to remind you

that the higher estimates for the higher vCJD prevalence

don’t change.

          [Slide]

          Moving on quickly, this is from Table 1.    I am not


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going to sort of walk you through everything but this is

basically Table 1.     Let me just point out that there is a

range of values.     Of course, these are the lower vCJD

prevalence values.     This is the value in ID50s.   We multiply

this ID50 value by 0.5 and then calculate and get the vCJD

risk per annum per person.

           You can see the range of results here ranging from

1 in 1.5 million for these lower estimates and up to the

higher prevalence estimates of a mean of annual risk in this

particular cell of the model that goes to a mean of 1 in

12,000.   There the confidence interval is at the 5th and the

95th percentiles, as I mentioned earlier.

           [Slide]

           I will just explain this.    So, basically we

multiply this number by 0.5 to get this particular number.

Since I am running out of time, or am out of time, I will

just sort of gloss over that particular one.

           [Slide]

           Table 3 presents a range of risk for hemophilia A.

 You will notice that we provide the 7-9 log reduction

numbers and the 4-6 log reduction numbers for lower vCJD

prevalence and then the higher vCJD prevalence.      The same in


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these two columns.

           Again, you can see the variability in the numbers.

 So, with higher levels of reduction you see lower levels of

risk.   For moderate levels of reduction you see more

moderate risk compared to this risk.

           [Slide]

           This is Table 3 again.    This is in your package as

well.   Table 3 compares the 2009 and 2006 results.

           [Slide]

           What I wanted to do is again just focus on the

2006 and 2009 results.   Again, you can see a lower level of

risk at the 7-9 and then a higher level.    I actually did the

calculations last night for cells.    So, if you just look at

the 4-6 again, and this is an excerpt from Table 3, at 4-6

is the lower prevalence.

           If you compare the 2006 results in this particular

cell for prophylaxis with no inhibitor to the 2009 results,

the 2009 results end up being 5-fold times higher.    So, for

prophylaxis with inhibitor the results for 2009 end up being

approximately 14-fold higher.   Then, for prophylaxis with

inhibitor with tolerance they end up being approximately 18-

fold higher.


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           [Slide]

           These are just the numbers for von Willebrand

disease at 4-6 logs of clearance.    Again, numbers are in a

similar range to what we were seeing, although slightly

different for the hemophilia A patients.

           [Slide]

           Again, I am just sort of going to summarize this

very quickly because Dr. Scott also mentioned this in the

next slide I am going to show you.   But we did a sensitivity

and importance analysis and what that showed was that

clearance of vCJD agent during manufacturing was the most

important factor that influenced the risk estimates in the

model but other factors did too.

           [Slide]

           That is shown here.   Again, you are have seen this

slide.   So, log manufacture Factor VIII use by a person,

prevalence, and then efficiency of i.c. versus i.v. route

are important.   Again, if this number is high for log

manufacturing that lowers the risk, and this positive means

if these numbers are higher, for whatever reason, the risk

would be higher.

           [Slide]


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            As far as conclusions, updates to the 2009 model

to account for susceptibility of the entire population were

not hypothesized initially to cause significant change

between the risk estimates between 2006 and 2009.

            The results from the model do indicate that at

least for the lower prevalence there was a 5- to 18-fold

difference in the risk estimates for the lower vCJD

prevalence.   So, that is one qualifier.     There is a

difference at the lower end.   However, the results at the

higher vCJD prevalence were pretty much similar between 2006

and 2009.

            So, in conclusion, you know, what we said is this

does not substantially change our interpretation of the risk

so it was based really on the estimate choosing the higher

vCJD prevalence estimates.

            Accordingly, as in 2006, we still assume that the

current vCJD risk for use of US-licensed plasma-derived

Factor VIII may not be zero but it is still most likely to

be extremely small.

            [Slide]

            Then, these are conclusions from 2006.    I am not

going to read through all of these but, again, it is


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important to mention that it is not possible to precisely

estimate the risk.   I have mentioned that the risk is small,

and so on and so forth.

           Manufacturing has an important role in reducing

risk, as do the donor deferral policies.    Finally, the risk

assessment overall highlights data gaps in the level of

clearance, product usage and several other factors.

           [Slide]

           Before I get to that, I want to acknowledge a

number of people that played a role in this risk assessment.

 This is sort of a team sport across the entire Center

almost.   So, several people had involvement in this,

especially Hong Yang, Rich Forshee and Mark Walderhaug, and

then all of the wonderful people who helped us to provide

the technical portions of the model.

           [Slide]

           So, I will go to the questions now.

           DR. HOGAN: Could we do the questions after the

break?

           DR. ANDERSON: Okay, sure.

           DR. HOGAN: We will reiterate the questions just

before it is time for us to consider them.   Are there any


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quick pending questions for Dr. Anderson that we need to ask

now?   No? We are about 15 minutes behind.   I’m sorry?   Press

the red button.

           DR. PRIOLA: I had a few questions on when you were

mentioning the percentile ranges, the 5th and 95th

percentiles.   Were these simply percentiles for

distributions or were these confidence intervals around the

estimates that you are presenting?

           DR. ANDERSON: They are confidence intervals about

the mean, the estimates.

           DR. PRIOLA: So, they are not taken off the curves.

 They are confidence intervals around the means.

           DR. ANDERSON: Oh, I am sorry, they are physical

distributions.

           DR. PRIOLA: And the ranges, all the ranges that

you put in for various parameters, were they representing

what you know to be true variabilities or uncertainties, or

a mixture of the two?

           DR. ANDERSON: No, we didn’t separate out

variabilities and uncertainties so uncertainty is really

probably the largest component.

           DR. PRIOLA: We can talk more I guess later.


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             DR. HOGAN: I am glad we have a statistician on

board here.

             DR. ANDERSON: We have a couple.

             DR. HOGAN: Okay.   So, we are 15 minutes behind

schedule but we will take a 15-minute break so everybody

should be here by 10:50 and we will start very promptly at

that time.

             [Brief recess]

                       Open Public Hearing

             DR. FREAS: At this time we are going to hold the

open public hearing.    This session is designed for those

people who are not on the agenda to bring their issues and

comments before the committee.

             We have received five requests to make comments in

this morning’s open public hearing session.     In addition, in

each member’s folder is this open public hearing clip that

contains two written comments.     The two written comments are

from Miss Jean Public and Mr. Terry Singletary.     They will

be made part of the official record of this meeting and will

be kept as such with the meeting.

             Dr. Hogan, at this time will you read the required

statement for the open public hearing?


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           DR. HOGAN: I am required to read this statement

verbatim: Both the Food and Drug Administration and the

public believe in a transparent process for information

gathering and decision-making.

           To ensure such transparency at the open public

hearing session of the advisory committee meeting, FDA

believes that it is important to understand the context of

an individual’s presentation.    For this reason FDA

encourages you, the open public hearing speaker, at the

beginning of your written or oral statement, to advise the

committee of any financial relationship that you may have

with any company or any group that is likely to be impacted

by the topic of this meeting.

           For example, the financial information may include

the company’s or group’s payment of your travel, lodging or

other expenses in connection with your attendance at this

meeting.   Likewise, FDA encourages you at the beginning of

you statement to advise the committee if you do not have any

such financial relationships.    If you choose not to address

this issue of financial relationship at the beginning of

your statement it will not preclude you from speaking.

           I believe we have five registered requests and we


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will begin with Mr. Mark Skinner who is the president of the

 World Federation of Hemophilia.   Mr. Skinner?

          MR. SKINNER: Good morning.   It is a pleasure to be

here today.   I had the privilege of serving with this

committee in 2006 and have appeared before you on a number

of occasions.

          I am a patient with severe hemophilia.    That is my

only conflict.   I have no financial interest or received no

financial support to be here today.

          I do have a PowerPoint presentation that goes with

this but I will talk while he is pulling it up.    The World

Federation of Hemophilia is an international organization.

We represent 113 nations with member organizations in each,

and we are the global organization recognized by the World

Health Organization, representing the bleeding disorders

community around the world.

          You have a copy I think of my slides in front of

you so I will just proceed in the interest of time.   The

reason that we are here today, quite simply, is because of

the significant importance of the US plasma supply to the

global treatment product supply.   Over 56 percent of the

world’s plasma that goes into the treatment products used


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today around the world comes from the United States, and it

is because of this that we have an acute interest in the

products manufactured in the US and the plasma supply in the

United States.

          The actual questions have changed since they were

first published so I am not going to answer question 1 as it

is listed in terms of the new inputs and the changed inputs,

but my testimony will parallel the questions the committee

will be asked to address momentarily.

          So, first to question number 1, should the recent

report change the FDA’s interpretation?    Our answer to that

question would be no.    Based on our understanding, we concur

with the previous assessment and believe that there is no

reason to change that.   The risk may not be zero but it is

certainly likely extremely small.

          The next slide.    The global community has

certainly watched over the years as vCJD has evolved.     It

was referenced just a few moments ago.    The UK Health

Department report, which was released on the 9th of this

month, now makes it clear that it is highly probable, with a

greater than 99 percent likelihood, that vCJD was

transmitted to the patient with hemophilia by the clotting


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factor concentrates.    And, I think this is probably the

strongest and most confirmatory statement of what we have

all assumed has been possible and we can now say is highly

probable.

            Next slide, please.   So, in terms of question 2,

although it was framed if I said yes, would you answer

question 2, I think they deserve answering irregardless.

So, first, should the FDA consider recommending additional

risk steps for the manufacture of plasma derivatives, I

think the question here-Bwhile we certainly recognize the

importance of donor deferral and we thank the industry for

the steps that they have done to improve the inactivation

and removal steps, there is the open question of what do we

do if and when there is testing, and as a global community

we remain very open to the implementation of a donor

screening test.

            In particular, if it is not implemented globally

we would suggest that perhaps it should first be initially

implemented in the United Kingdom and Ireland, and then in

those countries in which their plasma collection is destined

further for fractionation.    This does require some careful

consideration because, certainly, we don’t want to adversely


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impact the already fragile supply concentrates around the

world.

          Next slide.   Should the FDA consider recommending

revised warning labels for plasma derivatives?    This would

mirror my testimony back in 2006.   We do believe that the

FDA should list vCJD among the risk factors.    There is a

difference between CJD and vCJD and certainly recent

literature has indicated that vCJD has a greater likelihood

of transmissibility and CJD less, and we think that

clarification would be important.

          In terms of labeling claims for viral reduction,

we think the ultimate utility of such a labeling claim is

that it aids the patient and the clinician in understanding

and selecting their treatment products.    So optimally,

standardization of those labeling claims that physicians and

patients could compare would be most useful.

          Next slide, please.   Third, in terms of

communications globally, we do think that there has been

certainly a lack of transparency since the announcement.

You will note on the following slide, when I get to it, that

the WFH actually issued their statement prior to the

official release of the UK Health Protection authority’s


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announcement about the patient.    There were leaks early and

optimally we need to improve communication between patients

and the regulatory authorities.

            If we learnt anything from the Institute of

Medicine study back in the 1990s, it is that patients are

partners in the security of the health and blood systems in

the country and need to be brought in and communicated with

earlier.    I don’t understand this dribble of information

that is coming out of the UK and the failure to disclose all

the information that is known.

            Last slide.   This is just simply a copy of our

statement and some of the previous statements.    We do

believe that plasma-derived products are an important source

for patients globally, and remain so.

            Last slide.   This just simply is a summary of all

the statements of the World Federation dating back to 2001,

which are available for your reading and review

subsequently.   Thank you.

            DR. HOGAN: Thank you, Mr. Skinner.   Our second

speaker is Mr. Cavanaugh, from the Committee of Ten

Thousand.

            MR. CAVANAUGH: Thank you, Mr. Chairman and


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committee.     I am Dave Cavanaugh of the government and

relations staff for the Committee of Ten Thousand.     It is a

pleasure to be here today.

             On February 17th of this year it was reported in

the British press that an older man with hemophilia--a 70-

year old with hemophilia is something to celebrate as we

have not been living that long much in the last 20, 30

years-Bdied of unrelated causes and on autopsy presented

evidence of vCJD in his spleen.     He had received at least

one lot of United Kingdom-produced clotting factor which

contained the plasma from a donor who subsequently developed

vCJD.

             These revelations sent a shock wave through the

hemophilia community in the UK as well as in the United

States where CJD and vCJD transmissions through blood were

still considered a theoretical risk.

             By the end of February it appeared as if the

theoretical risk, blood-borne transfusion of vCJD through

human clotting factor, had become a known, actual risk.     The

Committee of Ten Thousand asked CBER for a teleconference on

the matter, during which we asked as well for a meeting with

this advisory committee, which had not met since December of


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2006.

            We want to remind the committee that this Sunday,

June 14th is World Health Organizations’s World Blood Donor

Day.    The global theme for >09 as articulated by WHO is

Aplacing a renewed emphasis on improving the safety and

efficacy of the world’s blood supply.@

            We concur with WHO’s efforts to raise safety and

efficacy.   Yet, we remain troubled by the British

revelations, as well as the propensity of the American blood

community, to have a short historical memory and at times a

perspective still needing to be informed by the events of

the last three decades.

            We remain, for example, deeply concerned about

source plasma collection by the US-Mexico border which

raises both safety and ethical questions and concerns.

Also, the inability of the American Red Cross to get its

house in order and move beyond the 16-year old, multi-

million dollar fine-laden consent decree it has been

operating under between the District Court, the FDA and the

ARC is shocking considering that this organization is

responsible for collection of over 40 percent of the whole

blood in the US annually.   Now we add to the mix the vCJD


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case being discussed today.

          We must seek to be more and more vigilant in

addressing both known and unknown threats despite the

progress made in the safety of the blood supply to date.

          While donor health is a high priority for the

blood system, recipient and end user health and trust must

also be a high priority.    Recent meetings of the FDA DPAC

and the DHHS Advisory Committee on Blood Safety and

Availability included discussions of donor health and safety

and transparency in the blood system.    Unfortunately, as

often before, end users were not a priority in terms of

either well being or trust.

          If the system is so safe, they why do we still

lack a more humane and rational policy approach to failure?

 A blood injury act or structure represents good public

policy, a more humane and compassionate approach to the

ultimate risk shouldered by the end users of the blood

supply, especially those chronic disease communities that

regularly depend on the blood supply to maintain their

health and wellness.

          Such a policy also makes good economic sense if we

consider the real costs of the AIDS blood and hepatitis


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blood-borne epidemics that have ravaged certain disease

communities.

             COTT has been calling for a blood injury act since

the early 1990s and will continue to do so, especially in a

climate where we are being consistently told how minimal the

risks are.

             While we understand risk and the ambiguity of

living with that risk when one depends on the blood supply,

we are still looking for the blood community and the federal

government to step up to the plate and substantively address

that risk by ensuring that those who are harmed by blood-

borne pathogens will be taken care of and not left to fend

for themselves as the hemophilia community was in the wake

of the AIDS blood and hepatitis C epidemics in this country.

For the hemophilia community this is at the core of our

perspective.    If the risk is as low as is stated, then why

have the blood community and the federal government

neglected to propose a structure to compensate those harmed?

             Consider the last decade of FDA regulation of CJD

issues.   After building up a substantial number of reasons

for deferral of potential blood donors with regard to

relationship with a person with CJD, including growth


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hormone, familial risk, etc., HHS in 1999 all at once

eliminated all deferrals related to CJD not specifically

related also to vCJD.

          The studies supporting this action must have

clearly shown that while vCJD is transmissible, any other

kind of CJD is not.   As new strains emerge and the sCJD

community expresses deeper doubt that the classical is not

transmissible, then action seems a bit precipitous and

definitely in the direction away from safety.

          Also, after reviewing a raft of industry studies

that show something like a five-log reduction of prions in

fractionation, prior to having any clinical indication as to

what constitutes a safe level of prions, the agency exempted

numerous countries from the vCJD-driven blood donor

deferrals based on travel and intervals of residence, saying

to all go ahead and collect plasma; we know that whatever

infection there is will be negated in the processing.

          Taking comfort from these same studies, industry

studies, none of which have completely replicated the

fractionation process but instead using a spike amount of a

surrogate TSE, the agency has developed a risk management

model that allegedly demonstrates that America’s blood is


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safe from TSEs.

          Does the FDA computer-driven model factor in,

compensate for, the USDA’s poor levels of surveillance for

BSE in the United States?   Does it factor in the numerous

strains of CJD other than vCJD and sporadic CJD?   Some may

be more infectious than others.   Evidence given at the last

meeting of this committee suggests it has not.

Nevertheless, the results were in.    The answer was clear.

The matter was closed.

          I do know this is in the materials for this

meeting, a phrase that was used before, the risk is very

small but not zero.   The Anot zero@ has been left out and it

is very noticeable to our community.

          We still do not know the relationship between

prion reduction and risk reduction.    A simple point, that is

fundamental to risk analysis.   The agency’s actions, taken

in the face of very little field data, is an example of how

not to do public policy.    The precautionary principle in

such cases dictates that the only change allowable absent

better data is a change to increase safety.

          Consider now the families of persons with

hemophilia in the United Kingdom.    For years they have been


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seeking knowledge on what batches or lots of plasma-derived

factor that they consumed years previously included blood or

plasma from a donor who subsequently turned out to contract

vCJD.   There has been little peace in this community while

this search has been going on.   Some of the information was

withheld from them for years.

           It is a roiled community, 4,000 households, that

in 2004 received a standard letter from the government: You

are at high risk.   You must tell your doctors, dentists,

etc. this fact.   You must take precautions against further

spread of the disease.

           Not one word about how the public health

leadership in the country has provided for this community’s

care, starting with the date of the letter.    It is like the

early days of AIDSB-since there is no treatment and it is

universally fatal, you should tidy up your affairs and wait.

           Now comes word of one case of prions discovered in

a person with hemophilia, not at a symptomatic level but

also not in the normal digestive tract as would be the

typical case with beef-related disease.     Based on these

facts alone the conclusion announced was that it was likely

due to infusion of plasma-derived factor over ten years


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previously from a lot, a donor who subsequently contracted

the disease.

          This was in February.   Today is June 12th.    No

expanded explanation, clarification or other augmented

report of any kind has been issued since, and the hemophilia

community worldwide has been on the edge of its seat to

learn what implications this case might have for them.

          I have been told in the break that the publication

was out two days ago, three days ago.   I don’t have a

computer to get on it and see what they have to say in time

of this talk but I sure wish there was a stack of them on

the handouts table at eight o’clock this morning.   We

understand a description of the case is in press.

          Why is not the UK Health Protection Agency issuing

at least monthly updates on the circumstances of this find,

if not planning a large and far more widely distributed case

report of its own?   Why, in fact, has this not already been

done?

          We urge the FDA to learn from the UK way of

handling the hemophilia population there and, instead, be a

ready source for those at higher risk and for the general

public of ample information including on the strains of the


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disease, on the changing size and other characteristics of

the population with CJD in the US, of a primer on how the

USDA conducted its surveillance, and how a more developed

methodology would have produced more credible results.

          Our other specific requests are as follows:

Recommend that Commissioner Hamburg request of Secretary

Sibelius that the NIH research agenda on human TSEs and

their relationship to animal TSEs be reactivated.    This

should include study of the several strains of CJD now

recognized, their evolution and any contagion risk.     It

should also specifically study the rapidity, both intra- and

interspecies, of transmission in all known TSEs.    A

particular focus of this work should be transmissibility of

different TSEs in humans, particularly through blood.

          The committee should also petition the

Commissioner to request that CDC augment its surveillance

system for hemophilia treatment centers, HTCs, around the

country to include a comprehensive in-service training

program for all HTC staff with patient contact, particularly

physicians on human TSEs, particularly on the differences

between CJD and vCJD.

          Included in the training should be strong


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encouragement that families request autopsy in any HTC

patient death involving dementia, other neurological

symptoms, or otherwise possibly associated with TSE for

purposes of positive diagnosis as at present postmortem

determination offers the only evidence for positive

diagnosis of CJDs.

          CBER should prepare a report for the Commissioner

on the adequacy of the USDA BSE surveillance program,

including each of its phases, during the last eight years.

We realize that this is a touchy issue.

          If the finding is that the methodology and

execution of the field phases of the process may have failed

to find and include all cases of BSE in the United States,

the Commissioner should request of the Secretary an inter-

departmental memo to Secretary Vilsack of Agriculture

specifically identifying the points made, and asking that

the surveillance program be reactivated at a higher level of

investment than previously to aid in properly identifying a

contagion risk that jeopardizes human health as well as

animal health.

          In terms of surveillance of human TSEs, we

strongly recommend that the committee petition the


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Commissioner to request that CDC hereafter require reporting

of any human TSE, vCJD, CJD or any other strain and, should

it develop, TSEs from deer or other vectors.

          We understand that states voluntarily submit

reports to CDC for its tabulations, but we feel it is

derelict for there not to have been a national collection

and reporting requirement on these diseases to date and that

this must be rectified.    Twenty states have made CJD

reportable to date on their own.

          We have long followed these diseases and

appreciate the FDA’s forthright attempts to track, research

and develop preventive strategies around them.    We trust

that will continue.   Further, as can be seen from the nature

of some of our recommendations, there is a lack of inter-

departmental coordination, if not White House task force

status, on the diseases.

          The fact that the core of those who are ill are

cases that come to people from the food chain complicates

the regulatory public health issues, some would say almost

to a standstill.   This committee alone is in a position to

call out to the key players involved to put in place inter-

organizational oversight structure to break this logjam.


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Thank you very much.

          DR. HOGAN: Mr. Cavanaugh, thank you very much for

your comments.   They have been entered into the minutes and

certainly will be taken into consideration, and I thank you

for being here today.

          MR. CAVANAUGH: My pleasure.    Thank you.

          DR. HOGAN: Continuing on, next speaker is Ms.

Theresa Matthews.   Before you start, Miss Matthews, Dr.

Epstein would like to make a comment.

          DR. EPSTEIN: Thank you very much.    Yes, just one

technical point that FDA, in its 1999 guidance document, did

not remove risk-based deferrals of donors for risk of

sporadic CJD or familial CJD.

          What we changed was the recommendation to withdraw

product lots if an affected donor was found to have

previously donated to a plasma pool.    The reason for that is

that the experience since the 1996 memo was that between 25-

100 percent of all available products of certain types

became subject to withdrawal and it was simply an

intolerable policy for product supply.

          Fortunately, at the same time we started to have

results of the look-back studies, organized by the CDC in


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cooperation with the Red Cross, which showed an apparent low

risk for blood transmissibility of the classic CJD agent.

          So, I just want to clarify that whereas there was

a change in policy about product withdrawals, there was not

a change in policy about risk-based deferral of donors for

classic CJD.

          DR. HOGAN: Thank you, Dr. Epstein, for that

clarification.   Miss Matthews?

          MS. MATTHEWS: Good morning.   Before I begin, I

would like to thank Dr. Freas, the committee and the FDA for

the opportunity to speak today.   I have no financial

conflict of interest.

          My name is Theresa Matthews and I am addressing

TSEAC as an informed consumer, an expert witness to the

flailing CJD surveillance system in this country and, above

all, a CJD victim that was forced to travel the path of most

resistance through the public health system of our nation.

          Minutes from the last TSEAC meeting in December,

2006 briefly addressed two committee members’ questions

about serious issues impeding CJD surveillance and how these

issues impact FDA risk assessment.   I wish to summarize my

personal journey to highlight the excellent point being made


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by those practitioners.

            My father, Don Ringenberg, succumbed to SCJD on

October 31, 2005.   A glimpse of my family’s story was

captured in a Peoria Journal Star article published on April

30, 2006, entitled, AFamily Waits for Answers on Rare

Disease.@

            Though my father initially presented to a teaching

hospital completely fulfilling the Master’s criteria, UCSF

criteria and WHO criteria for diagnosis of CJD, he wasted

nine of the best last days of his life receiving defensive

medicine and a misdiagnosis of Lewy Body dementia, an

atypical presentation.    They proposed on day 2 a brain

biopsy could be done.    Luckily and wisely I declined that

offer.

            Mayo Clinic spent less than two hours total time

reviewing the outside chart and assessing my father when

they delivered their suspect diagnosis.      I reflexively asked

what was the risk factor.    His answer, without pause,

neurosurgery.   I asked which one, he had two?    He proceeded

to give a detailed explanation of why he thought it was the

second.   Mayo had two whole days to rethink their position.

            This is what was said directly to my father in the


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followup: We think that your lumbar laminectomy was the

cause.    I am sorry.    We see it.   It happens.

             My father’s reply: Goddamn doctors, I knew they’d

get me.    Sorry, doc.    And so he did.   CJD was his only real

fear in life.    He regularly discussed his theories and

concerns with his family over the course of the BSE years.

             We asked if Mayo would perform the autopsy.        They

refused.    Their answer: We do not like to autopsy or biopsy

these patients because of risk.

             Though they agreed to accept autopsy results, they

would not report to Illinois.      CJD was not a reportable

communicable disease in Illinois in 2005.       I learned this

firsthand when I returned from Mayo and tried to report my

father’s suspect case.      This began a long, drawn-out and

unnecessary battle with public health officials.       During the

course of this uphill battle a second Peoria victim was

diagnosed.

             This was the first CJD case to be investigated by

IDPH.    This was the most significant case in decades.

Eventually the CDC was called in.       Many mistakes were made

along the way.    It was painful to watch.      I submitted a

letter to the director of the NPDPSC to have this case


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worked up as an iatrogenic presentation.   I received their

reply in March, 2006.    We were never interviewed by him.    I

have included his response for your thoughtful review.

          To my understanding, the tests to differentiate

between sporadic and iatrogenic CJD have not even been

developed yet or perfected yet.   In 2007, I spoke directly

with the NPDPSC researcher developing this test and he told

me that he cannot definitively evaluate my father’s case

because he never received the butcher’s tissue.   So, there

you have it, a scientific dead-end.   Wasted money, wasted

time, wasted science.    The sentinel case was a butcher by

trade.

          Accurate disease reporting is a basic and

fundamental step of epidemiology.   The issue as to whether a

cluster was ever or is currently in evolution would take

years of aggressively looking forward and backward, and not

just on the surgical unit in question.   This cannot possibly

be done if you are not even counting the cases.   The current

state of CJD epidemiology in this country is a joke and it

is no laughing matter.    In 2009 seven states still do not

even mandate reporting.

          Since the last TSEAC meeting we have all witnessed


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a 143 million pound beef recall; the discovery of multiple

unsafe healthcare practices at a Las Vegas surgical center;

and convictions in two major body parts scandals.

          How can the FDA possibly even begin to evaluate

the risk of pooled bone bank bone, let alone the risks posed

by tissues being provided for brain recoveries in these

macabre scenarios?   You can’t, especially if we are not even

getting an accurate CJD count, with reporting criteria

varying widely from state to state.

          The recent disclosure of improper sterilization

techniques in the endoscopy departments of two VA hospitals

is very disconcerting.   Military personnel pose some of our

greatest ongoing risks for vCJD exposure.   These are all US

current events that present profound risks to the health and

well being of the citizens in our country, not to mention

those abroad, as we engage in the sale of blood and tissues.

          My father was a two-time neurosurgical candidate,

with a 20-year gap between surgeries and a generous, 30-plus

year history of blood and later pheresis donations who was

deferred from the look-back study.    According to two lead

authors for this ongoing study, the hospital and blood

center refused to release recipient records.   Apparently


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this was a problem they were encountering on a more frequent

basis.   Mayo Clinic could not completely discount the

possibility of a tainted dura mater graft from the 1977 OR.

 The dense scar tissue found at this site makes that a

plausible concern.

           This is the picture of a very desirable blood and

tissue organ donor in June.   This is the true measure of the

quality of those tissue donations just three months later.

Deferring blood and tissue from areas at high risk for CJD

cluster potential can and should be done.   It can be done

because the investigation of this case stemmed from a

previous cluster of four cases not looked at.   So, it can be

done.

           When I open my newspaper and see an article that

discusses the reprocessing of medical devices meant for

single use or promises to expand the age of corneal donation

to 75, I am troubled by the decisions being made in 2009 by

a few.   The injection of more than 8,000 children with human

growth hormone should be a strong reminder that utilizing

cadaveric tissues poses great risks with lingering

consequences.

           I urge the FDA and the CDC to resolve the


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disconnect that exists between these agencies with respect

to CJD epidemiology in this country.    Thank you for your

time and attention.

          DR. HOGAN: Thank you, Miss Matthews.    You brought

up some important points and we appreciate your comments and

your personal conviction in this regard.

          Our next speaker was to have been Val Bias, who is

CEO of the National Hemophilia Foundation, but he is, as we

speak, speaking with the Commissioner of the FDA who called

him to speak to him.    Instead, Mr. Mark Skinner is going to

read what Mr. Bias was going to present to us.

          MR. SKINNER: Thank you.    Val Bias extends his

regards and his apologies for not being here but the reason

has already been presented.

          So, for the record, I believe you have a copy of

his testimony and I would like to read it so that it is

properly entered into the record.

          As was said, Mr. Bias is the CEO of the National

Hemophilia Foundation.    He has severe hemophilia Factor IX.

 He was exposed to all of the complications related to

plasma-derived products and continues to rely on those

products to control his bleeding disorder.    Although the


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updated risk assessment does not address his individual

product, he shares the concerns many in the community have

about this new and important information.

             First, he would like to thank the committee for

holding this meeting, the first in a few years.    As a former

member of TSEAC, he appreciates the importance of the

committee and its work to evaluate the risks of exposure to

vCJD faced by the bleeding disorders community and all

Americans.    He also wishes to thank you for this opportunity

to share his views and those of the National Hemophilia

Foundation on this important subject.

             The recent event in the UK reminds all of us that

vCJD remains an important issue for the bleeding disorders

community.    However, the National Hemophilia Foundation does

not believe there should be cause for panic.    As the news of

the UK incident started emerging, representatives from

National Hemophilia’s blood safety working group and medical

and scientific advisory council met to discuss the issue and

what NHF’s response should be on behalf of the US bleeding

disorders community.    NHF released medical advisory number

409: Signs of vCJD found in a UK patient with hemophilia; no

added risk seen for US patients, which states in part:


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          Currently, UK-sourced plasma is not used in any

product worldwide, and it has never been used in products

licensed for use in the United States.   In the US, plasma

donors who have spent time in the UK are deferred from

donating blood or plasma.   Therefore, there should be no

change in the safety profile of US-licensed products or in

any treatment recommendations.

          The recently updated risk assessment does not

change this view.   Thank you to FDA for revising the 2006

risk assessment on the potential exposure of vCJD to US-

licensed plasma-derived factor VIII.

          It is imperative that the FDA keep abreast of

emerging data on vCJD and adjust its risk assessments

accordingly.   While there are significant limitations in the

data modeling, simply because there are many unknown

variables, we are reassured that the risk of exposure to

vCJD remains extremely low.   At the same time, we

acknowledge that the risk is not zero, and it is our

responsibility to ensure that this fact is communicated as

well.

          In the 1980s the bleeding disorders community

learned the hard way that, though information about risks to


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product safety may be incomplete, it is vitally important to

communicate it in a timely, accurate and open manner.   We

also learned that we must not create barriers to

communication between government, the medical and scientific

community, industry and patients.    Rather, where we find

those barriers, we must tear them down.

          Therefore, NHF remains committed to working with

TSEAC, the FDA and others to ensure that all consumers have

appropriate and timely information about risks of exposure

to vCJD and other potential health risks.   For NHF’s part,

we will continue to employ all means at our disposal to

communicate with consumers, including our communications

tools, our strong network of chapter organizations and our

HANDI information service.

          However, since communication is only as valuable

as the information we have to share, we strongly encourage

the FDA and other agencies to keep us engaged and informed

going forward.   This recently updated risk assessment and

this meeting is an important step.

          Finally, we must acknowledge that vCJD is only one

component of our overall efforts to protect the community

from blood-borne pathogens.   Many individuals with bleeding


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disorders and other health conditions depend on a reliable

supply of safe blood and plasma-derived products.

Government, industry, and the medical and scientific

community and patient organizations must all work together

to identify and respond to potential risks to the blood and

plasma supply.    The lives and health of people in our

community depend on it.    Thank you.

           DR. HOGAN: Thank you, and thank you for speaking

for Mr. Bias.    We have one more remaining registered

speaker.   Dr. Robert Rohwer would like to speak with us, a

person well known to this committee.

           DR. ROHWER: Thank you, Nick.

           My name is Robert Rohwer.    I am director of the

Molecular Neurovirology Laboratory at the VA Medical Center

in Baltimore, and I am an associate professor of neurology

at the University of Maryland Medical School in Baltimore.

I have been investigating TSE diseases for over 30 years.       I

have been a former member and a frequent advisor to this

panel on the biology, risks and management of TSE

infectivity in blood.

           But I am here today for these few moments wearing

the hat of one of the founders of a company called PRDT, and


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I will be describing to you the affinity ligands that we

developed for removal of TSE infectivity.    And, I have an

interest in this company.

            In the mid 1990s my laboratory developed a

quantitative method for measuring the concentration of TSE

infectivity in rodent blood, and began systematic

investigations of the concentration, distribution and

transmissibility of blood infectivity that are ongoing to

this day.

            Our very first measurements revealed that a

diagnostic based on blood-borne infectivity would be

problematic.   The concentration of TSE infectivity in blood,

even in the late states of infection, was very low and was

even lower during the long asymptomatic period of the

infection where a screening assay is most needed.

            Moreover, an assay would have to differentiate the

infective form of the prion protein from a 100,000-fold

greater concentration of the normal prion protein that is

naturally present in plasma.

            As an alternative to testing, in 2001 Dr. Hammond

and Dr. Carbonell, both experts in combinatorial chemistry,

and myself, founded Pathogen Reduction and Diagnostics


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Technologies, PRDT from henceforth, to find combinatorial

ligands that could be used to remove TSE infectivity by

absorption.    PRDT screened millions of compounds and other

materials to obtain a small group of ligands that bind both

normal and infection-associated prion protein with high

efficiency and selectivity in the presence of human blood

and plasma.

             The first product to incorporate a PRDT affinity

resin is the P-Capt filter, manufactured and licensed by

MacoPharma, a major European supplier of blood collection

sets.   The P-Capt filter is a single-use sterile device that

removes TSE infectivity from red blood cell concentrates

prior to transfusion.    The filter received a CE mark in 2006

and has been available commercially from MacoPharma since

that time.

             Independent evaluation by the UK Blood Services

has been ongoing since product of the first batches in 2006

and, to date, the filter has met all performance and safety

requirements set by that regulatory group.    The P-Capt

filter was selected by Scientific American as one of the top

50 scientific innovations of 2007.    It is the only product

that has so far been shown to be effective in the removal of


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endogenous blood-borne prion infectivity.

          PRDT affinity resins are also being deployed to

improve the safety of plasma and plasma derivatives.

Octapharma AG, a major manufacturer of plasma products, has

adopted PRDT’s resin technology to enhance the safety of

solvent-detergent treated plasma.   The resin has been

incorporated into the manufacture of Octaplas where it

provides an estimated 20,000 to 200,000-fold increase in the

margin of safety.

          Prion-reduced Octaplas is currently undergoing

regulatory review and approval in Europe.   It is highly

likely that PRDT resins could significantly reduce residual

risks from vCJD or other TSEs contaminating anti-hemophilic

agents or other plasma derivatives as well.

          Removal offers many advantages for the mitigation

of prion disease risks.   Importantly, removal works even at

very low concentrations of infectivity.    The PRDT affinity

resins continue to remove infectivity even at concentrations

that are undetectable by tests.

          Filters do not have to discriminate between

infectious and uninfectious forms of the prion protein when

removing infectivity.   By design PRDT’s affinity resins bind


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both forms.

           The PRDT affinity resins remove other strains of

human prion disease besides vCJD.   The resin in the P-Capt

finds all filter strains so far tested and several animal

strains as well.   New prion diseases would likely also bind.

           A major concern with implementing screening tests

for low incidence diseases like vCJD is that the false-

positive rate must also be extremely low.    Obtaining a low

false-positive rate is especially difficult when true

positives are at the limit of detection.    The risk of

omission will be greatest for persons incubating the

disease.   This is not a problem for a removal strategy.

           Implementation of PRDT affinity ligand mitigations

are likely to be less costly than screening when one

considers the follow-on costs for every positive detected,

whether false or not.

           Blood-related transfusions of vCJD now implicate a

plasma derivative and by extension plasma.    Whatever

measures are taken to reduce the risks to the blood supply,

the sooner they are implemented the more effective they will

be in stemming future transfusions.

           PRDT resins have been incorporated into a CE


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marked device to absorb prion infectivity from red blood

cells, and a batch removal process for SD plasma.    Moreover,

these technologies are approved and available now.

          It has been estimated that had the feed ban that

ultimately arrested the BSE epidemic been delayed by even a

few months, the epidemic would have affected millions of

additional cattle and exposed millions more people.    If

there is ever to be mitigation, the earlier it is deployed

the more effective it will be in reducing the magnitude of a

future incident.   Deployment of P-Capt filters and PRDT bulk

resin solutions for vCJD risk mitigation could begin

immediately.

          DR. HOGAN: Thank you, Bob, for this very

interesting bit of information, and I thank you for

presenting today to this committee.

          DR. ROHWER: Thank you.

                     Committee Discussion

          DR. HOGAN: That concludes the registered speakers

for the open public hearing.   Are there any speakers in the

audience who have not registered who wish to address the

committee at this time?   I see none.   There will be another

opportunity at the afternoon session.


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             So, I would like now to continue with the

committee discussion of the meeting, and we can perhaps

start with presentation of the questions for the committee.

             DR. ANDERSON: I think the plan is to read through

all of the questions first and then read through the

questions singly for the discussion.

             So, the questions for the committee are based on

an updated risk analysis.    FDA continues to believe that the

risk of variant Creutzfeldt-Jakob disease to patients who

receive US-licensed plasma-derived coagulation factor VIII,

or plasma-derived Factor VIII, products is likely to be

extremely small, although we do not know the risk we

certainty.

             So, question 1 is does the committee agree with

the updated and new inputs to the FDA risk assessment model

for US-licensed plasma-derived Factor VIII?

             Then specifically looking at the inputs, the

updated inputs are the first set.    Do you agree with the

estimated prevalence of UK vCJD infection as it is now in

the risk assessment?    The age of susceptible population at

time of infection?    And, (c), the time during incubation

period when infectivity is present in blood?


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          Then going on to the new inputs, the genotype at

the PRNP codon 129, specifically the genetic susceptibility

to vCJD infection and genotype proportions in the US

population?

          Part (e), the distributions of vCJD incubation

periods for persons of different PRNP-129 genotypes?    Then,

finally, the age distribution of persons with asymptomatic

vCJD infections?

          So, that is question 1.   Question 2 is despite the

finding of minimal additional risk in FDA’s modified risk

assessment, should the recent report from the UK Health

Protection Agency, attributing a case of vCJD infection to

treatment 11 years earlier with a vCJD implicated plasma-

derived Factor VIII, alter FDA’s interpretation of the risk

for US-licensed preparations of plasma-derived Factor VIII?

          Then, moving on to question 3, based on the

available information, should FDA consider (a), recommending

additional risk-reducing steps for manufacture of plasma

derivatives, such as modifications to current donor deferral

policies, etc.?

          Part (b), and/or recommending revised warning

labels for plasma derivatives?


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            Part (c), recommending modifications to FDA’s

public communications, to Web posting and other postings,

regarding the risk of vCJD associated with the use of FDA-

licensed plasma derivatives?

            DR. HOGAN: Thank you, Steve.   We will take these

in order.   What the FDA is interested in is a discussion of

these components and in a couple of occasions a vote.     So,

we will first discuss if we agree or if we do not concerning

the updating inputs and the new inputs presented into the

model for the risk of plasma-derived Factor VIII.      We can

take them individually, if you would like, or as a group.

Does anybody have any comment about the prevalence

estimation of the vCJD infection?    Dr. Powell?

            DR. POWELL: I had a preliminary question.    Does

this question to the committee preclude discussion of inputs

that are not new or updated?

            DR. ANDERSON: I don’t believe so.   I think we

would be interested in all, anything you have to say.

            DR. HOGAN: Dr. Monroe?

            DR. MONROE: Yes, I just have a question.    I guess

I am uncertain in sort of the relationship between I guess

1(c) andB-anyway, the relationship between the period of


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infectibility, if you will, and the difference in the

genotype at codon 129.   So, to me, there is no real data

there so there is uncertainty there.   I am not sure that the

time of infectivity for people who have other than MM is

fully known and, as I understand it, in the model it is

assumed to be the same as for the people with MM.

           The question as it is posed, do we agree with the

inputsB-I mean, I agree it is important to consider but I

think there is a fair bit of uncertainty around the

relationship between those two inputs.

           DR. HOGAN: Does anybody want to speak to that?    I

will if you don’t.   Concerning the time during incubation

period when infectivity is present in blood, I believe it is

derived from animal data that suggest that there may be some

infectious prion protein present in the blood of animals in

the first, second and third proportions of infectivity.

           It was based on a presentation that Dr. Brown, who

unfortunately is not here at the moment, presented in a 2007

article.   I don’t know if staff can enlighten us more on

that, but it is purely based on animal data and it is a very

conservative estimation of when prion proteins might be

hanging around.


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          DR. MONROE: My point is I think there is clear

data now that people who are non-MM are infectible.   The

question is are they infectious.

          DR. HOGAN: That is a very good question and I

think the stuff we have heard today brings that point out.

Dr. Asher has something to say.

          DR. ASHER: Yes, well we do have a little

information about humans, and that is that blood is

infectious at least for three and a half years of a presumed

12-year incubation period and we thought it was

precautionary to consider that it might be considerably more

than half the incubation period, at least in MM donors.

And, I agree, we have no idea about the other phenotypes how

long they would be infectious.

          DR. HOGAN: I would like to bring up a couple of

other uncertainties.    I agree that you should consider the

MV and VV based on what has been presented in the

literature, but I would like to also bring out that a

prevalence rate that is linked to the tissue sampling--the

appendices that were looked at by Dr. Hilton et al., there

were three cases that were found to be positive.    Only one

of those things showed IHC patterning which was similar to


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that that had been seen in known vCJD appendices.

             The other two positives had fine granular

deposits.    In fact, in the article it was mentioned that

these might even be, quote, false positives.    So, whether

this is really one true positive or three true positives is

unclear but you have to accept that it is three.

             The other issue is that when Dr. Ironside went

back and looked at the 129 genotyping for those three

samples he did not have enough DNA from the sample which was

most likely to be vCJD appendix, only for the other two

which were thought to be perhaps false positives, which were

both VV.

             So, we still don’t really know a lot of the

answers to some of our questions here but I do agree we need

to consider them.    But there are some further uncertainties

that are thrown in if you look closely at the data.

             Any other comments regarding any of this?   Dr.

Geschwind?

             DR. GESCHWIND: Maybe a point of clarification for

Dr. Asher.    So, my understanding is that now they are saying

that 75 percent of the total disease duration is the new

part of the model and that is an increase from before.


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             DR. ANDERSON: Right.   So, previously, in 2006, the

assumption was that the 50 percent point and beyond of the

incubation period was assumed to have infectivity.     Now we

have expanded to the three genotypes and now we are starting

at the 25 percent point and for the remaining 75 percent of

the incubation period there is infectivity for all three

genotypes.    So, that is what we did in the model.

             DR. GESCHWIND: And other than the fact that we can

say three and a half years over a 12-year incubation period

blood is infected, this is just being more cautious but it

is not derived from any specific data pointing toward 75

percent being more accurate.    Or, am I wrong on that?

             DR. HOGAN: I guess Dr. Asher is going to address

this but my understanding is it is the animal data.

             DR. ASHER: Paul who was here and Bob Rohwer I

think is still here--and the animal data, as I recall, was

60 percent.    The first infectivity was detected about 40

percent of the way through the incubation periods of some

hamsters with 263K scrapie.    So, extending to 75 percent

under the circumstances, now that we have to concede that we

have moved from theoretical risk to demonstrated risk,

seemed to be prudent and precautionary.


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            DR. HOGAN: Do you have anything you want to say,

Bob?    Please come to the microphone.

            DR. ROHWER: We first detected infectivity at that

point, but that was part of several measurements over the

incubation period and you could extrapolate that curve and

it extrapolated to zero back around 30 percent of the

incubation time.

            DR. HOGAN: Dr. Manuelidis?

            DR. MANUELIDIS: Yes, I think there are a couple of

things that concern me.    One is that using one model of

animals may not always be the most effective one.   In 1978

we wrote an article in Science showing that infectivity was

present basically from about half way in the disease and

went through the end and at the end it became highly

infectious, much more infectious in the guinea pig for

instance than in Bob’s models.

            I would also like to point out that, for instance,

vCJD is BSE and basically in a cow blood is not infectious

and in primates it is.    So, one must be very careful about

this.

            The third thing which is a concern of mine is that

in the report here it says we are talking about vCJD and my


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concern is that we are limiting things to vCJD.   It says

because BSE has been detected in so few US cattleB-now,

anybody who works with the USDA knows that the USDA has been

impossible about letting anybody work with BSE and we

actually had no surveillance.   So, we have no idea about how

many US cattle are really infected as compared to places

like Japan that look at every single cow.

          The fourth thing is that there are recent reports

that have been going back for several years and have now

become more important of variants of BSE which are not vCJD,

some of which people believe have more of a linkage to

sporadic CJD.   We also do not look for these things.

          So, I think that in looking at what we say about

what should be done, although this has no practical

application right now to what the FDA is going to do about

saying we can’t use this blood or that blood, I think it is

a much broader problem.

          I also agree with people in the audience who came

and said that CJD is not a reportable disease in many

places, and I think this is very frustrating in terms of

knowing what is really going on in our population.    So, I

would like to add that.


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           DR. HOGAN: I think those are most important points

that a lot of us agree with, and I know that the staff is

looking at some of those in the future.     What we are

specifically charged with today is a little bit less

encompassing issue but, nonetheless, exactly what you say

should be considered.   Anyone else want to say anything

here?   Yes?

           DR. BARRAJ: Based on what I just heard, at least

your first comment, that if infectivity seems to increase

towards the end of the period, you know, can your model

allow for something like that for this increased

infectivity?

           DR. ANDERSON: Certainly.   We can adjust the model.

 I mean, what we are assuming right now is that, you know,

infectivity is equivalent, infectiousness is equivalent

throughout the period but, you know, that can be adjusted if

we had the data to do that.   So, we could assume, say, lower

earlier on and then increases later on.     Again, we would

just like to see data to support that.

           DR. HOGAN: Dr. Leitman?

           DR. LEITMAN: I have a question along the same

lines of how one estimated the mean incubation period to be


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32 years with codon VV or MV.      Is that since there is no

case documented one would assume that it has to be longer

than any incubation period that has currently occurred?

            DR. ANDERSON: Right.    I mean, that is a pure

hypothesis.   So, if you do have suggestions or discussion on

that we would appreciate that.     Essentially our range is 25

years to 55 years.   Fifty-five years is the reported max in

the literature at this point, and 32 was sort of a bias

downward because that is sort of how the infection curves

look.    But, again, we are open to adjusting that, again with

the support of information and data.

            DR. HOGAN: For which there are no data, as I

understand it.   So, that is a guess but it is a reasonable

guess.

            DR. ANDERSON: But I would qualify that by saying,

you know, this model is sort of an evolutionary process and

as that information becomes available we would love to put

that into the model.

            MR. TEMPLIN: I just want to make two comments.     I

am sort of troubled that we don’t know how much is actually

infectious.   A comment too about what Dr. Manuelidis said

about cattle.    If a farmer has cattle that he thinks may e


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infectious he is going to throw it out in the back 40 and

cover it up or throw it on the compost pile and never report

it to the government because he is going to lose everything

he or she owns.

          DR. HOGAN: I think we are going to have some

speakers this afternoon that are going to address the

current USDA situation.    So, we will have questions for them

at that point.    Miss Hamilton?

          MS. HAMILTON: I have a comment about what Dr.

Manuelidis said to a question.     It troubles me because a few

years ago there was a lot of hype about the downed cattle

that were getting through and being used in food for animals

and what-not, and now we don’t hear anything else about it,

and she was saying that there is no surveillance in that

area at all.   My big question is why.

          DR. HOGAN: Well, we will ask the USDA this

afternoon, but I am not sure that zero is correct.    I think

it has been lowered significantly from its initial stages

but it is not zero.    Dr. Kreindel?

          DR. KREINDEL: We are going to have a presentation

on the USDA surveillance, but we do have surveillance and

our surveillance is according to international standards.


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You know, it is not surveillance that really protects the US

population.   You know, we do have surveillance and there was

a lot of surveillance going on.     We called that surveillance

enhanced surveillance.   We are going to have information

about that.   We still have surveillance going on, you know,

at the level requested by international standards but we do

cover a lot of mitigations about sequential interlocking

that really prevent, you know, if any BSE is present to be

recycled.

            DR. HOGAN: Thank you.   Perhaps we will defer the

discussion of surveillance till this afternoon.    Do any of

the statistics experts on the panel have anything to say

relative to the mathematical accuracy of this model, since

all those equations make me dizzy?

            DR. BARRAJ: Well, I don’t think I can say much

about the model itself because all I have seen is the

report.   But I wanted to actually answer maybe the question

here about whether 35 or 32 years was the right number or

not.

            Given the assessment that Dr. Anderson has

conducted to try and see, you know, the importance of the

various variables that could affect risk, and the duration


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of the incubation period is not one of the variables that

seems to be affecting this risk, then maybe resources could

be spent towards something else that seems to be affecting

the risk estimates rather than this variable.

          DR. POWELL: I have a question regarding that.

Have you replicated or conducted a new importance analysis

based on the new inputs?

          DR. ANDERSON: You know, we have and it is very

similar to what we have now.   But I think we have to do

further examination of that as well.   So, we have conducted

it and it is very similar to what was presented.   So, the

results basically stand from 2006.

          DR. POWELL: So, the incubation period remains one

of the lesser input variables.

          DR. ANDERSON: Correct, and you can see that in the

model because, you know, basically we had an exercise on

that earlier on.   We implemented all of these changes and

there was minimal effect.   The one largest change actually

was adding the additional population that was at risk.     So.

          DR. HOGAN: Dr. Geschwind?

          DR. GESCHWIND: I guess one concern I had with the

model is when you show those bar graphs showing the


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different processes that the processing removes the vast

majority of risk, and the fact that, maybe relating to Dr.

Manuelidis’ comment, the models being tested are pretty

limited.    The scrapie 263 I think was the main one.   And, it

has been shown that human prions are as much as 100,000

times harder to remove or simply to decrease infectivity.

             So, I think those should also be taken into

account.    At least one paper I am referring to is the Peretz

paper in 2007, the SDS.

             DR. ANDERSON: I would say if you could forward us

those references that would be great.

             DR. HOGAN: Dr. Powell?

             DR. POWELL: Yes, this gets back to the discussion

that we had at the last meeting, in 2006.     The model assumes

a three, four, five, or whatever, log reduction that is

different than demonstrating that a given technology

achieves that.    So, the importance analysis is based on the

assumption that, in fact, it does achieve that log

reduction.    If that is the case, then it is a driving

variable.    But we had the discussion last time about whether

or not that is actually demonstrable.    Is that an accurate

characterization of the 2006 meeting?


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          DR. HOGAN: As I understand it, I think so, yes.

          DR. POWELL: Another variable that came out as

important in the analysis, particularly as you go towards

the lower prevalence estimate, is the amount of usage in the

treated population, the manufactured usage.    I noticed that

the appendix CB-I wasn’t able to find that on the Web, but

that demonstrates the overlay of the input assumptions, the

add-on factors versus the empirical data that you had from

the survey from CDC.    Do you have those by any chance?

Appendix C of the 2006 report is not available.

          DR. ANDERSON: That is posted on the Web.     That is

part of supplemental information.    If not, maybe it dropped

off with the update of the website and we can check on that.

          DR. POWELL: Well, I have an old version of it.        I

was just wondering if you might be able to pull it up.     In

any event, you can see from the summary tables that you have

that the 95th percentiles, the input distributions that you

have assumed based on your best fitB-they used a software

package to fit to the empirical data to come up with

generalized beta distributions to characterize the quantity

of Factor VIII that was used by the different subpopulations

within the treated community.    But consistently the input


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distributions don’t really represent very well, particularly

in the tail of the distribution.    The 95th percentiles of

the input distributions are far below the 95th percentiles

of the empirical distributions.

          So, one recommendation that I would encourage you

to consider is to simply use the empirical distributions so

that you capture those tails.   In many cases you can see

that the use distribution is not a smooth, continuous

distribution.   It is lumpy, multi-modal, especially with

spikes out on the tails.   So, you may be underestimating the

risk considerably in those subpopulations.

          DR. ANDERSON: Right, for some of those there was

enough to actually use the data and for some of those we had

to, obviously, fit distributions.

          DR. POWELL: Well, at least according to the

documentation that I have seen you used generalized beta

distributions in all cases, and the generalized beta

distribution does not avoid the problem that you have with

the empirical distribution which is that you have to specify

a min and a max.   If you are going to use an empirical

distribution or you are going to use a generalized beta

distribution you still have that problem.


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           So, you are really not, you know, working yourself

out of that problem by using a smooth generalized beta.    So,

I would encourage you to reconsider that and use empirical

distributions that will better characterize the multi-modal

nature of that data.

           DR. ANDERSON: You know, we probably went to using

one specific type of distribution just for consistency

overall as a fitting because it probably fit in most cases.

 There were some patient groups where we had actually fairly

small amounts of data on utilization.    So.

           DR. HOGAN: But I think your comment is noted and

perhaps the staff could take it into consideration.

           DR. ANDERSON: We will do that, of course.

           DR. HOGAN: I am going to go through these item by

item and see if there are any big objections.

           The question is do we agree with the updated

inputs.   Oh, Dr. Priola, I guess you can talk.

           DR. PRIOLA: I just had a question about why

exactly you decided to assume that the risk was equivalent

for all three genotypes.    And, if you didn’t make that

assumption, would it change your model?

           DR. ANDERSON: You mean the susceptibility?


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          DR. PRIOLA: Yes, the susceptibility.

          DR. ANDERSON: Well, we think there is data coming

forth that suggests they are not equally susceptible but I

don’t know if the body of data is there yet.   So, it is sort

of assigned susceptibility ranges for each of those

particular genotypes.

          DR. PRIOLA: I am sure this is a completely naive

question, you can’t base it just on the relative percentage

of genotypes in the population versus how many have been

diagnosed with subclinical or clinical vCJD?

          DR. ANDERSON: For the asymptomatic, you know,

those would be under-represented and we would also want to

capture those as well.

          DR. PRIOLA: So for the second part of my question,

if you change that assumption that each genotype is not

equally susceptible, do you think it would impact the model

in any significant say?

          DR. ANDERSON: You know, I think it would be just a

mild effect and it wouldn’t be a major effect.   But again,

you know, we did think about actually doing that so when

more information becomes available we will incorporate that.

          DR. HOGAN: Dr. Mastrianni?


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          DR. MASTRIANNI: Yes, I was just going to add to

that and say that it is probably a more conservative

approach to assume that all are at equal risk and that way

the model is stronger.

          DR. HOGAN: And that is my sense of why it was done

this way because there certainly isn’t enough data to

stratify those susceptibility data I think at this point.

          So, in terms of prevalence estimates for the vCJD

infections, it essentially is changing from just considering

MM genotype to considering all of them.     Is there any big

disagreement with that updating and input?    No?

          How about the age of the susceptible population at

the time of infection, which is essentially taking into

account the incubation period or the MM, VV, MV which is

believed to be at least a 12-year shift to the left?    So, it

takes into account incubation period, as I read it.    Any

problem with that?   No?

          Time during incubation periodB-Dr. Geschwind?

          DR. GESCHWIND: I thought it was 32 years.

          DR. HOGAN: Thirty-two years is for the MV and VV

but 12 years for the MM.

          DR. GESCHWIND: But all are being incorporated into


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the model now.   Right?

           DR. HOGAN: Right, but I think that only the 12

years is included here in terms of incubation period.

Correct?

           DR. ANDERSON: Yes.   Let me just go back to this

slide.

           [Slide]

           This is the slide we are talking about.   It is the

susceptibility so it is item number 2.   So, it is not

incubation period per se; it is just time of infection.     So,

this is just an age distribution for the time people were

infected, and this is based, again, on the clinical cases,

the clinical onset.   So, most of that affects persons, let’s

say, at a median of 30 years of age.

           The data suggests that they were probably infected

at age 18, let’s say, if you are a 30-year old person.    So,

that is what we are accounting for here.     Originally in the

model we just assumed, and we incorrectly assumed, that the

time of onset was equal to the time of infection.    So, this

is just a correction of that.

           DR. HOGAN: I think my problem with this was not

understanding clearly what the term susceptibility meant,


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but I think he has explained it.

             DR. ANDERSON: Yes, it is time of infection.   I

apologize for the mis-wording of that but it is time of

infection.    This curve represents the age of persons at the

time of infection.

             DR. HOGAN: Dr. Leitman?

             DR. LEITMAN: I am still unclear on something.     It

sounds like you are skewing something for which there is no

basis for the skew.    If you take the MV and VV and in your

new model they have a 32-year period of incubation in the

last 75 percent of that they are potentially infectious, and

that is 60 percent of the population, that group now is

contributing in your model a huge proportion of the

potential risk as opposed to the well-documented folks.

             DR. ANDERSON: Can I clarify sort of relating to

this?   What we are assuming is that all patient groups, all

phenotypes, MM, MV and VV, have the same sort of

susceptibility so they are all sort of infected at a very

young age.    So, the difference comes in the incubation

period.   So, we haveB-I forget which one it is, the

distribution of incubation periods comes later.    So, on top

of that we want to know when they are infected so this is


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telling us when they are infected and at what age.

            So, we are assuming that everybody basically of

the three groups who are infected are infected all about the

same age.   The difference is on top of that what we added.

So, that starts the clock and then the clock basically for

MMs is an average of 12 years.      The clock for the VVs and

the Mvs is, you know, a much longer incubation period with

this median of 32.   Does that clarify?

            DR. HOGAN: So, they are just shifting the time

they have to worry about the infection, I guess.     It is a

modeling question.

            DR. ANDERSON: So, on top of that, you know, we

also include the period of time where infectivity is present

in the blood.   So, that is incorporated on top of that as

well.

            DR. HOGAN: But I don’t think there is any data

about infectivity for MV or VV individuals.

            DR. ANDERSON: You are correct.    So, we are making

the assumption across all groups.

            DR. HOGAN: All right.    Any more comments on that

particular part?

            Then time of incubation period when infectivity is


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present in blood.    We have been told that is based on animal

data, and Dr. Rohwer explained some of that.       So, they are

being very conservative, taking 75 percent instead of 60

percent or some other number.    Again, a conservative model

estimate, which could be refined once more information about

human infectivity is known.    Dr. Powell?

             DR. POWELL: One question I have about how the

model was performed for the low prevalence estimate in

particular is that you said there were 10,000 iterations in

the model.

             DR. ANDERSON: Well, we did probably 20 runs of

those 10,000 iterations so 20 runs of separate 10,000

iterations just to compare stability of the model, yes.

             DR. POWELL: So, what you then report is an average

over multiple simulations, each consisting of 10,000

iterations per simulation?

             DR. ANDERSON: You know, I would have to check and

see exactly what was done.    We actually just updated the

numbers again, but I think it is representative around the

mean.   It is probably representative at run actually of the

20 runs.

             DR. POWELL: Then my concern stands.    At those very


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lowB-at the lower end of the prevalence estimate you are

estimating that, you know, something like 0.2 percent of the

plasma pools actually contain an infected donor, which means

that your entire non-zero portion of the distribution is

being estimated based on, like, two or three out of those

10,000 iterations.   So, your mean, which is in excess of

your 95th percentile, is very unstable.

           So, there are a couple of ways of getting around

this.   One is do more iterations until you get to stability.

 Just kind of a brute force approach and let it run over a

week, or what have-you.

           The alternative would be to simply estimate the

proportion that are clean plasma pools with no infected

donors contributing to them, and then simply simulate on

ones that you know have one or more donors and focus on that

and do important sampling, re-weighting those back to the 2

percentile of the curve.

           But the point estimates that you are reporting out

there beyond the 95th percentile are going to be very

unstable based on that number of iterations.

           DR. ANDERSON: Sure.   We would agree with that.

So, you know, we will take that into consideration.     You


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know, there is still more work to cross-check the stability

of the model.

          DR. HOGAN: Important comments.     So, we will take

the infectivity data as stands.    Now, new inputs, the

genotype 129, now looking at the proportions in the US

population, MM 40 percent, MV 50, VV 10 percent.     I think

that is pretty standard data.    I think there are a few

points off on each one.    Any problems with that?

          Okay, distribution of vCJD incubation periods from

persons of different genotypes.    We have addressed that

somewhat, shifting the infectivity period 12 years earlier

but developing a possible median incubation time of age 32.

 Any problems with that?    Miss Hamilton?

          MS. HAMILTON: I had a question going back to the

age at time of infection.    I kept looking for it and

listening today but I don’t remember seeing anything.      How

did you arrive-BI mean, what are the reasons for that early

age of onset of infection?

          DR. ANDERSON: The reason is that we have the

reported cases of clinical onset of disease, and they

calculated that the incubation period is approximatelyB-the

median I guess is 12 years, and that has been done through


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several studies and Ezra Ghani, whom we quoted, also

developed studies on the incubation period.   So, all we are

doing is we are moving that back by the 12-year median.

          MS. HAMILTON: I understand that but is there any

data to suggest why?    I mean, I know you are moving it back.

 Why that age?

          DR. ANDERSON: Basically, that is based on the

literature and the incubation period studies in the

literature but there is no hard data on incubation periods.

 That is a mathematical synthesis.    So.

          MS. PRIOLA: I think Dr. Will mentioned that they

don’t really understand why there is this specific age

relatedness in vCJD; that it could be due to susceptibility

issues or exposure issues.

          So, I was wondering in a way the same thing.    In

your model when you shift that back 12 years you are

assuming exposure, that the median age of 28, or whatever,

is related to exposure and not an age-related susceptibility

to infection?

          DR. ANDERSON: No, this is susceptibility.    I mean,

we are assuming the entire population was probably exposed

at similar rates but I don’t know.    So, on exposure I can’t


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really say.    In the model we account for exposure through

just intensity of the BSE outbreak because we don’t have

dietary information for these populations incorporated into

the model.    So, I don’t know beef consumption or any of that

so I can’t really, you know, say much more.      So, we make the

same assumption about exposure for every age group.

             MS. PRIOLA: Well, I must be really dense.    I don’t

understand the graph then because the graph says

susceptibility to vCJD infection.

             DR. ANDERSON: It should be age the infection is

acquired, is what that should say.    So, that is confusing.

So, just sort of set aside the susceptibility issue.

             DR. HOGAN: Change the word susceptibility.

             MS. PRIOLA: It is really difficult to understand.

             DR. ANDERSON: Sorry about that.   So, just focus on

the age infection was acquired because you are right,

susceptibilityB-you know, there is a broad range for

susceptibility.

             MS. PRIOLA: Well, there might be.   I guess that is

one of the issues, if I understood Dr. Will correctly, that

they are not sure.    It could be that people are most

susceptible when they are, you know, 10 or 15 which would be


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really unusual, obviously, in prion infection.

            DR. HOGAN: This is one advantage of getting older

I think.    Dr. Will, do you have anything to say towards

this?   Would you like to say anything towards this point?

            DR. WILL: Well, I think Dr. Priola is quite right.

 It is very difficult to be definitive about this in any way

at all.    We do know that there was a model done by Dr.

Valeron, from Paris, in which he tried to fit incubation

periods to the age distribution and the only way he could

get them to fit was if there was an age-related

susceptibility to infection which probably peaked in the

teenage years and then declined.

            That is combined with some dietary data that was

done by Prof. Bird in which he tried to estimate the age-

related dietary exposure of the UK population, which also

suggested that there was an age-related exposure issue.

That is, younger people were probably more exposed to higher

titer tissues than older people.

            Therefore, the best hypothesis is that the reason

for the age distribution is a combination of susceptibility

and exposure.    But it is hypothetical and, of course, it

begs the question as to what is the biological mechanism of


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age-related susceptibility.

          DR. HOGAN: So, I think we have got some

information from the staff about this and I can attest that

teenagers--my 16-year old son eats a good deal more

hamburger than I do.

          So, we are going to move on to number 2 now if

there is no objection.    Number 2 states that despite the

finding of minimal additional risk in FDA’s modified risk

assessment, should the recent report from the UK Health

Protection Agency, attributing a case of vCJD infection to

treatment 11 years earlier with a, AvCJD implicated@ pdFVIII

pool, alter FDA’s interpretation of the risk for US-licensed

preparation of plasma-derived Factor VIII?    We are going to

take a vote on this, yes/no, in terms of how you feel about

it.

          But I think what we have discussed so far is it

has been suggested there is very little change in terms of

modeling information and, from the epidemiological data that

has been presented to us from several different sources,

that there is very little reason to change it.   That is my

personal feeling.   Are there any comments relative to this?

 Dr. Monroe?


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           DR. MONROE: I would comment just based on the

wording here of attributing exposure to the implicated dose

11 years prior.    I thought we heard data earlier that

suggested that, in fact, it is equally likely that one of

the non-implicated doses may actually be as high or higher

risk than implicated batches.    So, I would suggest tweaking

the wording.

           DR. HOGAN: So noted, tweaking the wording if that

is okay with staff.    How about the information and knowledge

of this case?   Is that all right with the staff?   Dr.

Epstein?

           DR. EPSTEIN: Yes, I think we need to strike the

phrase Atreated 11 years earlier with implicated product@

because, as we learned from the recently published risk

estimate, the likelihood of infection from non-implicated

product in the UK in that period was probably greater than

from implicated.    So, yes, I think that is an appropriate

correction.

           But the question still stands, and what we are

really asking is, okay, you have seen the risk analysis that

suggested no change in the risk estimate, does the fact of a

probable case now change the landscape in any more


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fundamental way.

          DR. HOGAN: So, that is the issue, does it change

it in a more fundamental way?    Does anybody want to comment

before we vote?    Dr. Barraj?

          DR. BARRAJ: I am going back to something Dr.

Powell said about the number of iterations that were run,

and now we are seeing that the differenceB-it is related to

this question that is why I have to go back to it.   The

numbers have not changed drastically from the 2006 risk

assessment and the question is had more iterations been run

or had we taken care of the upper tail of the distribution

would the numbers have changed?

          DR. HOGAN: My sense is no, it would be minimal,

but maybe the experts could answer that.

          DR. POWELL: It is very certain to be an unstable

mean estimate given that very low prevalence of vCJD-

contaminated plasma pools.    I don’t know how unstable but it

is virtually certain to be an unstable estimate.

          DR. HOGAN: But is it a significant concern?      That

is the issue.   What does unstable mean?

          DR. POWELL: The point estimate that you get is

going to vary considerably from simulation to simulation


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because it is only based on two or three positive numbers.

You have a string of, you know, 99,998 zeroes and two

positive numbers and you are averaging those two.

             DR. HOGAN: Dr. Epstein?

             DR. EPSTEIN: Yes, just for the sake of an accurate

record I just want to be specific about the revised wording

of question 2.    I am suggesting that the words A11 years

earlier@ be struck and that the words Aa vCJD-implicated@ be

struck and then at that location we add AUK.@

             So, the question would read as follows: Despite

the finding of minimal additional risk in FDA’s modified

risk assessment, should the recent report from the UK Health

Protection Agency, attributing a case of vCJD infection to

treatment with UK pdFVIII, alter FDA’s interpretation of the

risk for US-licensed preparations of pdFVIII?

             DR. HOGAN: Thank you for clarifying that.    Dr.

Geschwind?

             DR. GESCHWIND: I guess I would just like to boil

things down simply to make sure I understand this.       Really

what we are saying in this question is the fact that we now

have likely a pdFVIII case in the UK, given the risk in the

United States it is still very low.    Is that really what it


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boils down to?    We already know that Factor VIII is a risk.

 We now know that Factor VIII is a risk factor, but in the

United States, given the risk of vCJD and BSE, and what-not,

it is still very low.   It is, therefore, not going to change

significantly the total risk estimate.   Is that a way of

summarizing it?   Is that sort of the question?

           DR. HOGAN: I think that is good.    One of the

factors is they are talking about vCJD-implicated based on

the UK population.   It would be very different for the

United States, which should lower that concern somewhat,

unless somebody criticizes that.   Dr. Mastrianni?

           DR. MASTRIANNI: No, I was going to say the same

thing.   That is the major distinction, that that was a UK

source and the risk is quite different here.    So, I think

that is it, that it really hasn’t changed our assessment of

the risk for that product in the US.

           DR. HOGAN: Any other comments before voting?     Dr.

McComas?

           DR. McCOMAS: I have a question in relation to this

and it may come in with question 3, but in the TSE warning,

in warnings section for plasma derivative products, it talks

about because this product is made from human blood it poses


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a risk for transmitting infectious diseases, e.g., viruses

and theoretically Creutzfeldt-Jakob disease agent.

          Now, am I to understand that this is no longer a

theoretical risk because, indeed, it has been shown that it

probably happened in the UK?    So, I am wondering to what

extent does striking the idea of theoretically from this

alter the FDA’s interpretation of the risk, i.e., it is no

longer a theoretical risk.

          DR. HOGAN: We are going to address the labeling

issue question in just a second.

          DR. McCOMAS: I get that.    I am just wondering does

that alter the interpretation of the risk.

          DR. HOGAN: I think the risk in the US population

is still low.   Does anyone have any disagreements?   I mean,

one case in the UK, we know sourced in the UK.   I still

think it remains theoretical.   Yes, sir?

          DR. EPSTEIN: I just want to perhaps clarify the

actual interpretation statement that is being discussed here

for the voting.   The interpretation is that the risk isB-

quote/unquoteB-likely to be extremely small, although we do

not know the risk with certainty.    As was pointed out by

David Cavanaugh, the actual summary also states not zero,


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although that is implicit in saying small.

            So, that is the risk interpretation that we are

talking about.   The assessment is the number and that

statement is the interpretation.   So, what the committee is

being asked essentially is, with all its blemishes and

uncertainties, we have a risk assessment that has shown

essentially no change under worst case assumptions.    If you

look at the outer limit estimates, the worst case

assumptions in 2006 and 2009, with all the other changes in

the model, you get the same numbers within, you know, range

of error.   Okay?

            And, what we are asking is, given that there is

now a probable case, should we change the interpretation

that risk, again for the US-licensed plasma-derived

coagulation Factor VIII products, is likely to be extremely

small although we do not know the risk with certainty?    We

are asking whether that statement should change.

            DR. HOGAN: It is no longer theoretical, I over-

spoke, but it is certainly very small but not zero.

            So, we are going to take a vote.   Dr. Freas is

going to tell us how to do that with this new equipment.

            DR. FREAS: We have never had this new equipment


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before.   If you look on your microphone, above the red

button there is a plus sign.    If you choose to vote yes you

will push the plus sign.    If you choose to abstain you will

push the zero.    And, if you choose to vote no on this

question you will push the minus sign.    We are going to go

ahead and vote simultaneously.

           DR. MANUELIDIS: Question.   So, plus means we don’t

want any changes; it is fine the way it is?

           DR. EPSTEIN: Plus means yes, you want changes.       No

means no, you don’t want changes.

           DR. MANUELIDIS: So, that is minus.

           DR. HOGAN: Maybe you can clarify this, Dr.

Epstein, for us.

           DR. EPSTEIN: Yes means you want changes and then,

of course, you will tell us what changes.     The question is

despite the finding of minimal additional risk in the risk

assessment, should the report alter the interpretation.     So,

if you say yes, you are saying we should change the

interpretation.    If you say no, you are saying you continue

to believe that the risk is likely to be extremely small.

           DR. HOGAN: Any questions?   So, we all vote

simultaneously then.    Thank you.


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             DR. FREAS: The industry rep is not voting at this

time.   There are 15 voting members at the table.

             DR. HOGAN: We are voting on the revised question

2, which is should the FDA change its approach based on this

new information.    Yes, they should or no, they shouldn’t.

Is everybody locked in?

             [Electronic voting]

             DR. FREAS: It was a unanimous vote.    Nobody

abstained.    Fifteen people voted no.

             DR. HOGAN: Moving on, we are now at number 3,

which includes all of the above information: Based on the

available information, should the FDA consider, number one,

recommending additional risk-reducing steps for manufacture

of plasma derivatives, which might include modifications to

current donor deferral policies?    Any comments on that?

Manufacturing donor deferral modifications?    Sir?

             MR. TEMPLIN: I think we need to look at other

locations that have BSE and think about potentially

deferring those folks from donating plasma in the US if

those folks have ever received blood transfusions in those

locations.    Maybe on vacation they get hurt and need a blood

transfusion.    That blood could be contaminated.    Therefore,


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they come back to the US and donate plasma and they may be

putting contaminated plasma into the pool.

           DR. HOGAN: Some of those concerns have been

addressed and it is currently UK and France and military

bases, as I understand it.    Other European countries with

BSE were not included currently.    But that is an important

thing to look at and consider, and I think the FDA is

hearing our conversation on this.    It is not something we

need to vote on specifically.    Any other comments about

that?

           Hearing none, how about should they consider

recommending revised warning labels for plasma derivatives,

which brings up Dr. McComas’ comment?

           DR. McCOMAS: Just to underscore, I think that

striking the word Atheoretical@ would be prudent.

           DR. HOGAN: I see a number of hands going up and

down.   So, is this something we want to vote on?   Does the

committee want to vote on it?

           DR. LEITMAN: I think once a case has happened it

is no longer theoretical.    I think theoretical was

appropriate until now and it is no longer appropriate.

           DR. HOGAN: Dr. Priola?


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           DR. PRIOLA: So, would there be any suggestion for

adding something like Dr. Epstein said, extremely small or

just strike theoretical?

           DR. LEITMAN: This is a label on the warning so it

says viruses.   Viruses are also extremely small but not

zero.   So, I wouldn’t call attention to the TSE agent as

compared to viruses.

           DR. HOGAN: Does the staff require a vote on this

or can you just hear that we are suggesting that theoretical

be altered to indicate that the risk is no longer

theoretical but very small?

           DR. EPSTEIN: I think we hear the point.     We don’t

really require a vote.    I don’t see any arguments against it

here.

           DR. HOGAN: I don’t think so.   Thank you.   Lastly,

based on the available information, should FDA recommend

modifications to their public communications, that is, to

the Web postings, regarding the risk of vCJD associated with

the use of FDA-licensed US plasma derivatives?   Any comments

on that?   Miss Hamilton?

           MS. HAMILTON: This is something that we have been

very concerned about.    One concern that we have is that the


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biggest fear in the community is fear of the unknown, and

that when information comes out--for instance, this came out

about UK in February and here we are, June, and there have

been probably 50 different disseminations of information

regarding it, no two probably being alike.

             So, I would like to see some kind of way that

everything could be coordinated and not let out in bits and

dribbles but have a coordinated effort to communicate to the

community.    Because when it comes out in 20, 30, 40

different ways everybody just gets confused and the fear

goes up.

             DR. HOGAN: I agree with you and I think some of

the other people from the patient representative populations

mentioned that today.    I would agree.   When I look at the

handouts that were given to us on the questions and answers

regarding Factor VIII and vCJD, the last update was on March

23rd and it doesn’t mention this case at all.    I have been

hearing from the hemophilia community here today that they

have all heard about it, and they are all worried, and they

don’t know what to do about it, and we are not disseminating

that we even are looking at it.

             So, perhaps having another question in there,


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something like we have heard this is going on and

investigation is ongoing, it will be looked at, stay tuned,

might be reasonable.

           MS. HAMILTON: Perhaps maybe when that does come

out that it get immediately disseminated to the major

organizations that have the most communication with the

community so that everybody is kind of on the same page.

           DR. HOGAN: Dr. Priola?

           DR. PRIOLA: Yes, so in our handout we had a couple

ofB-I think you just referred to themB-questions and answers

about vCJD and risk and it most definitely has to be

updated.   And, I think what Janice said is exactly right.

If they updated this to accurately reflect what is known and

then made the community aware that this was now out on the

Web and provide the website, that is something along the

lines of what you are saying because then all the

information is in one spot and it is updated routinely.

           But as it is now, I mean, one of the questions is,

is it known that Factor VIII can transmit vCJD and it says

no.   Now we have just struck Atheoretically@ from the label

so things like that have to be updated.

           MS. HAMILTON: Exactly.   And, I think one of the


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other things that maybe should be included, and I don’t have

that list in front of me, is to maybe point out we keep

saying it is safer in the US, and those who have been

intimately involved in it know what those changes are and

what has happened with the manufacturing process, but it

wouldn’t hurt to have a small synopsis of what has been done

to make it less in the United States.

          DR. HOGAN: I am sure that can be made available.

I think there are some legal issues about what you put on

warning labels that the FDA has to consider, but that is a

good point.

          MS. HAMILTON: I am not talking about warning

labels though.   I am talking about general information.

          DR. HOGAN: Dr. Priola?

          DR. PRIOLA: So, you are talking about a bit of an

explanation why US plasma is so much safer than UK plasma,

and that all has to do with what we have been discussing.

          DR. HOGAN: Mr. Templin?

          MR. TEMPLIN: Yes, I think it can only help for

more information to be disseminated by the FDA and even by

the manufacturers on the safety of the products, especially

when certain treatment centers around the country are making


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their patients sign waivers that they understand that there

are risks involved, and all the risks involved.      If I don’t

have the information to waive those risks I can’t

effectively make a decision that I understand what the risks

are.

             DR. HOGAN: Miss Hamilton?

             MS. HAMILTON: One more question.    It was stated in

the materials that 25 percent of the US patients are still

using plasma-derived and I am just curious as to what it is

that drives that.    Do we know if it is insurance?    Do we

know if it is certain states or certain areas in the country

where it is more prevalent?    I mean, I know it is a lot

safer but is it inhibitors?

             DR. HOGAN: I think that is a very important

question that you and I talked about before.      We can have

somebody address the issue of why they can’t all use

recombinant.    Could you mention who you are?

             DR. WEINSTEIN: Oh, this is Mark Weinstein, OBRR,

CBER, FDA.    There are a number of reasons.    One of them, of

course, has to do with the von Willebrand community where

all of the presently licensed products for treatment of von

Willebrand disease are plasma-derived materials.      That is


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one population.

          There is some cost consideration I think for

products that people have to take into account.

Particularly for older folks who have been exposed to

plasma-derived products for a long period of time, they

perhaps do not regard significantly reduction in their

vulnerability to take recombinant products at this time.    Of

course, the fact of the matter is that plasma-derived

products for a very long time have not been shown to be

infectious, particularly regarding viral infections.

          I should also mention that the figure of 25

percent is an estimate and some other folks have said 20

percent, and so forth.   So.

          DR. HOGAN: It sounds like there is a move towards

the manufactured product.

          DR. WEINSTEIN: Well, there are considerations.

People have also felt, for treatment for example of

inhibitors, that there might be an actual benefit of taking

recombinant to help in immune tolerance, that plasma-derived

materials potentially might be effective.

          DR. HOGAN: Thank you for that enlightenment.     Are

there any other comments?


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           DR, McCOMAS: I think I agree with what everybody

said today in regards to updating the information.    I would

just like to push another couple of areas.   One is that I

think that it has been evident that there is still a lot of

confusion or uncertainty about the links between vCJD and

CJD.   We were hearing that from some of the speakers today.

So, perhapsB-I was just going to say beef--upBaugment what

is currently on the site in relation to some of the

similarities and differences.

           I would also like to suggest that perhaps the FDA

could look to more innovative technology, social networking

sites, to get the information out in a more timely and quick

fashion.   The CDC has been using that this past year in

relation to some of the recalls and other disease

information.

           So, given that there are questions about

coordination being raised today, perhaps there is a model or

template out there that can move the FDA communication into

the 21st century, which would allow more back and forth

between FDA and the stakeholder groups.

           That brings me to the last point, which is that I

believe that there has been some consultation with the


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stakeholder groups in terms of what messages they want to

see.   I would just encourage that as these risk

communication messages or key points are updated that there

is input from the key groups, the key target audiences that

inform what is there and, hopefully then we will build more

trusting relationships.

           DR. HOGAN: I think those are important points,

especially coming from someone who is in the Department of

Communication at Cornell.

           Are there any other comments or any input from any

of the speakers or panel members before we adjourn for the

morning?   Any of the staff?

           DR. LILLARD: This may be going back a little too

far.   It seemed like we talked about this in 2006 at our

last meeting.   I wanted to hear some views by the panel

regarding kind of standardizing the manufacturing processes

in regards to reducing the risk.

           So, there is a simple question I have.    You know,

we saw earlier today that, you know, with the spiking

materials they are able to reduce some 4-log clearance

versus 7-log.   How should we view that?    Could steps be

taken to, you know, kind of raise the standard for


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clearance?

             DR. HOGAN: The question isn’t clear to me.   Are

you asking if steps could potentially be taken-BI couldn’t

hear you very wellB-can steps be taken to alter the

manufacturing process?

             DR. LILLARD: Not necessarily alter but I just

wanted some clarity on the process, not process improvements

but the clearance rates that manufacturers use that were

described earlier today.    Some disclosed things as low as 4-

log clearance versus 7-log.    Why aren’t those more standard?

Why aren’t they all 7?

             DR. LEE: The clearance numbers Dr. Gröner

presented earlier today, they are all based on by per

process.   So, different companies have different processes.

 Therefore, clearance would be different for every process

as you go along.    Once a process is locked in you perform

clinical trials and demonstrate that the product is out

there changing the process becomes, obviously from a

regulatory as well as a technical standpoint, quite a

challenge.

             So, as modifications are made you review the

pathogen and safety profile, not just of CJD but certainly


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that as well as other viruses, and manufacturers look to

improve those as improvements can be made.

             DR. LILLARD: So the manufacturer that uses a

process that has a 7-log clearance, is it a safer product

than something that is 4 log?

             DR. LEE: I think from a scientific standpoint you

would say the risk assessment of the profile would be

different and would appear to be improved relative to the

other one.

             DR. HOGAN: One final comment, Dr. Manuelidis?

             DR. MANUELIDIS: It is really a question for the

FDA.   You know, we haven’t had a meeting for a very long

time here on TSEs and a lot has happened in terms of

research, in terms of assays, in terms of models and I think

that you might want to consider really having more

scientific input or panel discussion again about some of

these things to help industry also beef up their thing, and

even have more information that is more relevant.     I think,

you know, some of these things have changed.

             DR. HOGAN: That is a good point.   We have some

this afternoon but your point is well taken on other culture

methods, etc.


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           DR. LEE: And I would like to add that industry is

always looking at new methodologies that are applicable and

practical to make these sort of measurements in our process.

           DR. HOGAN: Thank you.   We are going to adjourn.

There is a table in the restaurant for the committee

members.   We will reconvene for the afternoon session at

1:30.   Thank you.

[Whereupon, the committee was recessed for lunch at 12:30,

           to reconvene at 1:30 p.m.]




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            A F T E R N O O N   P R O C E E D I N G S

            DR. HOGAN: Welcome to this afternoon’s session.

This afternoon, for Topic II there are going to be

informational presentations.    There will be committee

discussions, any questions, etc., that you have but there

will be no issues for us to specifically vote on.

            We are going to start with some surveillance

issues, including some animal feed control questions, and

then talk about some medical products rules.    So, we will

start with Dr. Janet Hughs, who has graciously agreed to

talk about BSE surveillance and USDA-regulated food controls

in the United States.    Dr. Hughes?

              Topic II: Informational Presentations

    A. BSE Surveillance and USDA-Regulated Food Controls

                            in the US

            [Slide]

            DR. HUGHES: I am Dr. Hughes, from USDA Veterinary

Services.    I am the BSE program manager and ruminant health

programs, and I am going to talk to you about the BSE

surveillance here, in the United States.

            [Slide]

            We have had active surveillance since 1990.    We


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target populations where the disease is most likely to be

diagnosed or high risk animals.   This is based on data from

the European Union.   BSE cases are 20 to 30 times more

likely to be seen in animals that have clinical signs of

central nervous system signs; non-ambulatory cows, these are

also known as downer cattle; cattle with other signs that

are associated with BSE; or cattle that are just found dead

on farms.

            [Slide]

            The selection of animals to target in a BSE

surveillance program is largely dependent on the limitations

of the diagnostic test.   Currently, the test that is used is

a postmortem test.    There are no valid antemortem tests yet.

 We rely on detecting a cumulative PrPd or abnormally folded

prion protein in brain tissue.    The current test can only

detect PrPd in animals that are a few months prior to

showing clinical signs or clinical cases.

            [Slide]

            If BSE is present there are three groups of

animals in a population, non-infected animals, animals that

are infected but not able to be detected yet, and also the

preclinical and clinical group that are detectable by


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current tests.

            [Slide]

            Testing does not protect human or animal health.

The specified risk material removal and feed bans do this if

infectivity is present.    The testing is for surveillance

purposes.   Some countries have used BSE tests to restore

consumer confidence but it is not really the science-based

application of BSE testing.

            Extensive evidence suggests testing all animals is

inefficient for actually finding cases.      It is not supported

by epidemiological data.   It is very expensive.    It is

impractical in a test and hold situation.     What I mean by

that is that after animals are tested the carcasses must be

held until they get a negative test.   The carcasses must be

held either at the slaughter plants or a rendering facility.

            [Slide]

            The United States has a lot of BSE mitigation

measures and these do protect human health.     The major one

of those is removal of the specified risk materials, and

those are mainly the brain and spinal cords and tissues that

are known to contain the PrPd agent.

            We also have a ban on non-ambulatory or downer


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cattle.   We have a number of other methods, the prohibition

of air-injection stunning and other meat recovery system

bans.   Basically, that is to prevent any of the specified

risk materials from being mixed in with any of the other

tissues of the cattle.

             [Slide]

             The major protection for animal health are the

feed bans.    I know there is going to be another talk later

from the FDA on their feed bans, going to more description,

but basically in 1997 the FDA had feed ban prohibiting

mammalian protein in ruminant feed.    Their more recent 2008

feed ban enhanced this by prohibiting any high-risk cattle

material from all animal feed.    That was effected in April

of this year.    The compliance date will be in October of

this year.

             [Slide]

             BSE enhanced surveillance was conducted from June,

2004 to August, 2006 after the identification of an infected

dairy cow in December, 2003.    This was in a cow that was

imported from Canada.

             More than 830,000 samples were tested.   Two

animals tested positive.    Both were born before the


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implementation of that 1997 feed ban.

          [Slide]

          The enhanced surveillance was a one-time intensive

attempt to detect BSE if at a very low level and provide

information about prevalence of BSE.    The premise was to

sample as many as possible from the high-risk categories.

Again, these were animals that exhibit central nervous

system signs, downer cattle and any other signs that are

associated with BSE.

          [Slide]

          The estimate of BSE prevalence in the United

States used the data from seven years of BSE surveillance,

including the data from the enhanced surveillance, and found

that the BSE prevalence in the United States is very low,

less than one infected animal per one million based on a

population of 42 million adult cattle.

          [Slide]

          In May, 2005 changes were adopted to the BSE

chapter of the World Organization for Animal Health

surveillance appendix.    This allowed aggregation of data

over seven years.   Surveillance standards were based on

points that reflect the likelihood of finding BSE.    Samples


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were allocated to four different surveillance streams.    And,

the clinical suspect stream sample was worth hundreds to

even thousands of times more than the healthy surveillance

stream.

          [Slide]

          The standards for Type A BSE surveillance, and

this is what the United States strives for since we are a

controlled risk country, is designed to detect one case in

100,000 adult cattle with 95 percent confidence.   Countries

with large cattle populations, like the United States, are

directed to accumulate over 300,000 OIE points over a seven-

year period, which is approximately 43,000 OIE points per

year.

          [Slide]

          This is a chart showing the surveillance streams

and age categories for OIE and the points assigned.   For the

clinical suspects you can see the much increased point

values for animals that are collected in that category.

          [Slide]

          The four different surveillance streams are

routine slaughter.   These are healthy cattle at slaughter.

They have the lowest number of points.   Fallen stock, found


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dead on farm; casualty slaughter and the clinical suspects,

again, these are where the highest number of points are.

            [Slide]

            This is data from the United States or submission

to the OIE for controlled risk status.   I think in the

handout you can better see the number of points we

accumulated over a period of seven years.    Again, remember,

the goal is to at least accumulate 300,000 OIE points over a

seven-year period or about 43,000 points per year, and the

United States has exceeded that goal.

            [Slide]

            The ongoing BSE surveillance plan was launched in

August of 2006.   It kind of picked up where the enhanced

surveillance left off, with continued sampling at a

maintenance level.    We actually use a BSurvE model in the

United States which is a more sensitive design than the OIE

standard.   It actually is capable of detecting one case per

million adult cattle.

            [Slide]

            The ongoing BSE surveillance continues to exceed

established international standards, with focus on the

highest value samples, which are clinical suspects.   The


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targeted populations for ongoing surveillance include cattle

of any age with CNS signs, and these include rabies negative

cases and animals highly suspicious for BSE.

          Cattle over 30 months of age, any that are

condemned on antemortem inspection are excluded from

slaughter due to poor health status; cattle without specific

central nervous system signs that have other clinical signs

that might be associated with BSE; and also cattle from

rendering or 3D/4D facilities, and those are the ones that

handle the dead, disabled and downed cattle.

          [Slide]

          This is the data from the 2007 surveillance

showing our OIE points that we accumulated.    Again, the

target was to at least get 43,000 points per year or 300,000

over a seven-year period.

          [Slide]

          These are the data from fiscal year 2008 showing

the OIE points accumulated during that time.   Again, the

United States has exceeded the goals of accumulating 43,000

points.

          [Slide]

          The primary purposes of the ongoing surveillance


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are to continue to assess and monitor change in the BSE

status of United States cattle; provide mechanisms for

detection of BSE if the prevalence were to increase above

one infected animal per million adults; and also to meet or

exceed internationally accepted surveillance practices

recommended by the International World Health Organization.

             [Slide]

             The BSE comprehensive rule will follow the import

rules.    Right now the proposed rule will more closely align

our import regulations with guidelines in the OIE code.       It

will be based on BSE risk status as far as negligible,

controlled or undetermined.    Thank you.

             DR. HOGAN: Thank you, Dr. Hughes.   I have a couple

of points.    By points, do you mean cattle tested?

             DR. HUGHES: No.

             DR. HOGAN: It isn’t clear to me what a point is.

             DR. HUGHES: Points are awarded based on the

category of cattle.    So, if you had a clinical suspect in

the category of two to four years, they would be awarded 260

points.

             DR. HOGAN: If you tested them.

             DR. HUGHES: That same age cattle, if they were


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just fallen stock with no clinical signs, that is only

awarded zero points, two points.    So, the points are awarded

based on their epidemiological value.    So, clinical suspects

are awarded, you know, vastly more points than just random

dead animals.

          DR. HOGAN: I have got it now.       Thank you.   The

other question I have is you said on your next to the last

slide the proposed rule will more closely align, what is

that proposed rule?

          DR. HUGHES: This is an import rule to follow our

current import rule.    This is a comprehensive rule that is

still in the proposal stages.

          DR. HOGAN: Are there any other questions?        Yes?

          DR. KREINDEL: Currently we have a lot of

restrictions in the Federal Register regarding importation

of animals from countries that experience BSE.      So, after we

propose this rule and if this rule is finalized we will lift

the restrictions and we will be aligning our restrictions

with international standards for BSE.

          DR. HOGAN: Does Japan still refuse to import US

cattle?

          DR. KREINDEL: We have restrictions in place now


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from Japan, except for Kobe beef.   That was a final rule I

guess a few years ago.   We allowed importation of boneless

beef from Japan.   But after we finalizeB-you know, if the

comprehensive rule is finalized I think Japan is considered

controlled risk, has been considered controlled risk for BSE

so there will be different standards.

           DR. HOGAN: I appreciate that.     I was really asking

the reverse.    Does Japan import US cattle, or is there a

restriction?

           DR. KREINDEL: Oh, okay, what they import from us.

 I really don’t know the current status but they do have

some imports.   You know, there are always some negotiations

but they imported boneless meat from animals younger than 24

months.   I don’t know if now it is 30 months of age.

           DR. HOGAN: Are there any other questions about

this?   Dr. Powell?

           DR. POWELL: I would just add as a point of

clarification that in the most recent meeting of the World

Animal Health Organization they modified the code.     Correct

me if I am wrong, animals from controlled risk countries,

boneless beef will be permitted from animals of any age.

           DR. KREINDEL: Actually, boneless beef will be


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unrestricted.   Any country will be able to export regardless

of the BSE status.

          DR. MANUELIDIS: I am just curious if you can

explain to me the difference between the testing that is

going on now in Europe with all the other variants or other

strains of BSE, the test that is used, and whether the USDA

still refuses to sort of use tests that other countries use,

and what might our tests have that may be different and are

they still restricted, or what is the rationale for that?

          DR. HUGHES: Well, the USDA uses tests that have

been validated.

          DR. MANUELIDIS: I believe that the tests have been

validated for the European and the Japanese stuff, they all

use a standard test.    So, I am curious about why the USDAB-

there was the import I think you were referring to where the

Japanese stopped importing food because, as I understood it

and this is, of course, from places like The New York Times

that may be totally wrong but as I understood it, the USDAB-

this must have been about three or four years ago, said that

they refused to use the test even though the plant was

willing to use it.   They said they had their own tests and

they said they would only use their own tests.


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           Maybe you can clarify that for me and tell me what

the difference is between the tests, and whether you think

that you can pick up the variants of BSE, not just the UK

version of BSE.   If there is really a difference in the

sensitivity of the tests, if any independent side-by-side

comparison has been done.

           DR. KREINDEL: I am not sure I can answer your

question but I think you are referring to the fact that they

wanted to test all animals, rather than following the USDA

requirements for testing.

           DR. HUGHES: The question was why don’t we test all

animals.

           DR. MANUELIDIS: There is a test that is used in

Europe and in Japan.    It is used all over I think.   It is a

bioride[?] test and what the plant was willing to do, I

understood from The New York Times, was to test their

animals according to that protocol.    The USDA said no, even

though everybody else uses it, we want to use our own test.

 Then they never really did those tests.

           So, what I am really getting at is are our tests

in the USDA as sensitive and as comprehensive even if we

don’t test every animal--


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            DR. HUGHES: Yes.

            DR. MANUELIDIS: -Bfor all the variants of BSE and

on what basis?   Have you ever picked up any cases of BSE-H

or BSE-L?   Would you have an independent control that shows

you that you can pick up these things with the tests as

currently employed?   Have there been any blind controls

where an animal has a little bit of this or that just to see

if you can pick it up out of a group?

            DR. HUGHES: I think what you might be referring to

is the Creekstone case.

            DR. MANUELIDIS: Yes.

            DR. HUGHES: Okay.   Of course, I can’t comment on

current litigation but, basically, the USDA is unwilling to,

you know, have a test be validated as a food safety test.

Again, this gets back to what I spoke about earlier, that

the BSE test really isn’t a food safety test.    It is

possible to test an animal for BSE and have it be negative

and still have the animal be positive for BSE.

            So, using that to put on a package label is just

very confusing and kind of disingenuous to the public

because it gives them a false sense of security about it.

Our main focus for protecting human health is on other


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mitigation measures, such as the feed ban the FDA has in

place; removal of specified risk materials.   So, the tissues

that we know are likely to contain agent never make it into

the food chain in the first place.   So, that is the basis of

the refusal to allow that private company to do their own

testing.

           DR. MANUELIDIS: I don’t want to be difficult

because BSE is not my specialty, minus the vCJD version of

it, but as I understand, some of the BSE cases, like the

typical UK BSE case, have been found in muscle where muscle

has been found to be infectious.   So, the food ban wouldn’t

really deal with those.

           That is why I was asking what is the test.   If you

did a side-by-side comparison with blind controls would you

be able to pick up what Europeans and Japanese pick up?

That is really what I am asking.

           DR. HUGHES: And I am afraid I can’t answer that,

and I am not sureB-you know, the experts on that would be

the folks at NVSL that are responsible for validating the

test and choosing which test we use.   But evidently they are

not convinced that the other tests are better than what we

use currently.   But, again, I am sorry, I am not the expert


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in that particular category.

             DR. HOGAN: Mr. Templin?

             MR. TEMPLIN: Have there been any studies to see if

infectivity can be transmitted through the semen or the eggs

because artificial insemination is quite popular these days

and they are sold all over the world?

             DR. HUGHES: Right, and the tests to date show that

there is no infectivity in semen and eggs.       So, animals

that, you know, are used for breeding purposes, bull studs

and all, even if they are under quarantine for BSE can still

be used for those purposes because they have shown no

infectivity.

             DR. HOGAN: Thank you, Dr. Hughes.    We appreciate

you.    We will now move on to the second speaker, Dr. Van

Dyke, who is going to speak on BSE surveillance and food and

feed controls in Europe.

             I apologize, apparently there was an agenda change

that I was unaware of.    So, this is taking things a little

out of order.    I apologize.   I guess Martial Plantady is

going to be speaking in his place.

       B. BSE Surveillance and Food/Feed Controls in Europe

             DR. PLANTADY: Thank you.   Good afternoon to


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everyone.

            [Slide]

            First of all, I would like to thank FDA and this

committee for giving me the opportunity to present these

slides.

            So, my name is Martial Plantady.   I work for the

European Commission, DG SANCO which is the directorate

general for health and consumers in Brussels.    I am

legislative officer, which means basically that I am in

charge of drafting some legislation in some area of

protecting.

            [Slide]

            So, I have been asked today to present you

measures which are existing in Europe to prevent, control

and eradicate BSE.

            [Slide]

            Before going further with the legal background, we

have in this field two important regulations.    The first one

is regulation EC, number 178/2002, which is the general food

law.   We have another regulation which is very important,

which is regulation 999/2001, which deals with specific

rules for CJD.


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          [Slide]

          The regulation 178/2002 provides for high level of

health protection and development of food law, applied in a

non-discriminatory manner whether food or feed is traded on

the internal market or internationally.

          This regulation was adopted first in 2002 and is

based on the general principle and general disposition of

food safety legislation, and it sets up also the European

food safety authority which is an independent body, which is

located in Parma, in Italy, in charge of providing

scientific advice to the European Union and in particular to

the European Commission.

          [Slide]

          The general principles of the regulation 178 are

the following:   We have a Afarm to fork@ approach.   The

regulation states that the risk analysis is a key principle,

precautionary principle as well; protection of consumer

interests and transparency.

          [Slide]

          This regulation provides as well general

regulation of security, responsibility and traceability for

producers, and provides for responsibility of member states


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for controls.    This is very clear in the regulation.

             [Slide]

             Let’s go now to the specific legislation on TSE,

which is regulation 999 of 2001, which provides measures to

prevent, control and eradicate BSE.    In this regulation you

have public health measures, animal health measures, feed

ban and surveillance and eradication measures.

             [Slide]

             Let’s go further to specific specified risk

materials.    SRMs are specific specified risk material and we

can define them as animal tissue which are the most at risk

for harboring BSE agent, the pathogenic prion of BSE.

             [Slide]

             In EU the removal of specified risk material is

compulsory and SRMs have to be removed from the food and

food chain to avoid the risk of transmission and recycling

of the BSE agent, and this is a key element, the key measure

to protect public health from the risks posed by this

disease, by BSE.

             [Slide]

             SRM is identified based on scientific advice from

the European Food Safety Authority and formerly from the


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scientific steering committee of the European Union before

2004.   The identification is based on pathogenicity studies

as well and on transmissibility studies.

            [Slide]

            There is a list of the infectivity of tissues and

you see very clearly that the brain is the most infected

tissue.    After that you have the spinal cord and certain

ganglia, ileum and eyes.

            [Slide]

            What is the current list of SRM for bovine

animals?   For bovine animals, age over 12 months you have

this curve, which is SRM, excluding the mandible, the brain,

the eyes and the spinal cord.   For animals age above 30

months, vertebral column, and the dorsal root ganglia are

SRM.    For animals of all ages tonsils, intestines from the

duodenum to the rectum and the mesentery are considered as

SRM in EU, which goes beyond the international standards.

            [Slide]

            SRMs have to be disposed of.   All SRMs shall be

stained or marked immediately on removal at the

slaughterhouse level and have to be disposed of in

accordance with another regulation, which is what we call


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the ABP regulation, animal byproduct regulation, and SRMs

have to be disposed of by the means of incineration mainly.

             [Slide]

             There are some trade rules for SRM, the regulation

999/2001.    Indeed, all products of animal origin containing

material from bovine or caprine animals imported to EU must

not contain or must not be derived from SRM, except if this

product comes from a country with negligible risk status

according to the OIE.

             [Slide]

             Let’s go now to the feed ban, the rule regarding

feed ban.    First of all, what is the purpose of the feed

ban, the BSE feed ban?    The danger here is to let bovine

which is potentially infected with BSE enter into the feed

chain by the means of meat and bone meal through processing

plants, and after go to the feed mill and be fed to

ruminants.    So, the first barrier to prevent this is to

monitor first, and to remove the SRM, and the third barrier

is to have in place a feed ban.

             [Slide]

             Here you have a history of the feed ban.   The

first measure was taken in 1994, which was a ban to use a


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protein derived from mammals for feeding ruminants.   A

second measure was adopted in 1997, which was a pressure

cooking system for processing mammalian waste into meat and

bonemeal.   At the end of 2000 there had been a general

prohibition of use of SRM in the EU.

            [Slide]

            On January 1, 2001 the European Union decided to

have what we call an extended BSE ban or total feed ban.

This feed ban has been extended to the feeding of all farm

animals kept, fattened or bred for the production of food,

and has been extended as well to protein of all animals.

            The purpose of this extended feed ban was and is

to prevent cross-contamination, which may still occur, and

this feed ban has been proposed and adopted by the member

states because it was very difficult to identify the species

of origin in meat and bonemeal because of the drastic heat

treatment of mammalian proteins, pressure cooking.

            [Slide]

            You have here a graph which represents the number

of BSE cases detected in EU between 2001 and 2007 according

to the year of these cases, except UK.   You see that the

ruminant feed ban has been put in place in 1994 and, as you


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see, the result was not very satisfactory because the number

of cases has continued to increase.   In 1997 the pressure

cooking system has been put in place and in 2001 the total

feed ban entered into force.

           [Slide]

           Some derogations exist for certain proteins, in

particular for fish meal.   Indeed, fish meal, dicalcium and

tricalcium phosphate, both products derived from non-

ruminants, are authorized for feeding non-ruminants, but are

forbidden for feeding ruminants.   Blood meal and blood

products are authorized for feeding fish.

           But these derogations are possible under very

strict channeling conditions, with or without delivery, feed

production and transport of feed in order to avoid any

contamination of feed in which protein is prohibited.     The

processing is very strict and the importation conditions are

similar.   There is as well clear labeling of these feeding

stuffs.

           [Slide]

           Export outside of EU of processed animal protein

derived from ruminants is prohibited, and product containing

such protein is prohibited, the export is prohibited as


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well.   There is an exception for pet food.

             Concerning other processed animal protein, except

fish meal, exportation is authorized only if the member

state or the country of destination does not use the feed

for usage which is prohibited by EC.    There is an obligation

to have a written agreement with the country which imports

these proteins.

             [Slide]

             Controls of the feed ban, so for controlling the

feed ban we use feed microscopy which is the method of

reference for controlling the feed ban.       There is the zero

tolerance rule, which means that if you find one particle of

bone, for example, in feed the batch is considered as non-

compliant.    More than 50,000 samples are carried out each

year, and the controls are based on risk so they are

targeted controls.

             [Slide]

             Let’s see now surveillance and eradication

measures.

             [Slide]

             What are the objectives of BSE surveillance?    The

first objective is to collect epidemiological information in


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order to be able to assess the BSE prevalence in the

European Union and, at the same time, in order to be able to

evaluate the effect of the risk-reducing measures which have

been decided.

          Another objective is to have additional measures

to protect public health by removing infected animals from

the food chain and feed chain as well when they are

detected, and to eradicate the herd of origin.

          There is a further objective, which is more a

political one, which is to restore consumer confidence.

          [Slide]

          There are two types of BSE surveillance in EU.

The first one is passive surveillance, which consists of

examination of all animals suspected of being infected by

BSE, examination of all clinical suspects actually.    And, we

have active surveillance, which is systematic monitoring,

systematic testing in certain categories of animal which do

not show any BSE health signs.

          [Slide]

          Active surveillance is in place in the European

Union since July 1, 2001.   It concerns two subgroups of

bovine animals.   The first one is the group of risk animals,


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at risk animals.

          The rule is the following: All bovine animals age

over 24 months of age have to be tested if they are

subjected to special emergency slaughtering; if they show

symptoms of disease or disorder of their general condition

when they arrive to the slaughterhouse; or if they are

fallen stock or dead on farm animals which have died or were

killed and found.   So, 100 percent of these animals have to

be tested if they are over 24 months of age.

          [Slide]

          The second subpopulation which has to be tested is

the subpopulation of healthy cattle.   In this case all

bovine animals age over 30 months of age have to be tested

if they are subjected to normal slaughter for human

consumption; or of they are slaughtered in the context of

disease eradication campaign, for example, if we have a foot

and mouth disease epidemic.

          [Slide]

          What do we do when we discover positive cases?

Member states do a kind of inquiry which consists of feed

history, birth history, progeny history and cohort history,

and eradication measures are carried out in the herd of


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origin of the positive case.

           So, according to the regulation 999/2001 two

options are possible.    You can cull the entire herd of

origin, or you can perform what we call selective cull or

cohort cull, which consists in killing all the bovine

animals which may have consumed the same feed as the

positive one consumed.    There is a possibility to extend

this culling to related holdings if, for example, the animal

has moved during its life and all animals which are culled,

which are killed, are subjected to BSE testing.

           [Slide]

           What do we do if a positive animal is found at the

slaughterhouse?   The entire carcass of the positive case is

destroyed, of course, and there is a specific rule which has

to be applied, which is destruction of the carcass before

and two carcasses after the positive one in the

slaughterhouse chain in order to avoid possible cross-

contamination.    Of course, the same rule as before applies

to herd and to cohort.

           [Slide]

           So, is it working?   Is this scheme of surveillance

working?   The purpose of the BSE surveillance, the first


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point, is to exclude infected animals from the food chain

and to establish good prevalence data, to monitor BSE and

effectiveness of measures.

          It is very important to remember that surveillance

cannot be viewed separately from other measures, other BSE

measures and in particular separately from the feed ban and

SRM removal.   To monitor the effectiveness of the measures,

in particular the feed ban and SRM removal, we can have a

look at the effectiveness, what we call the effectiveness

parameters which are the overall incidence and the mean age

of the positive animals detected.

          [Slide]

          In 2008, in the EU27, we performed more than 10

million tests and the vast majority of these tests have been

carried out on healthy slaughtered animals.   On risk animals

we have performed more than 1.5 million tests.

          [Slide]

          This test represents for risk animals

approximately three percent of the total adult cattle

population in the EU27 and the healthy slaughter animals

tested represents approximately 17 percent of the total

adult cattle population in EUB-I don’t have the figures with


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me, which is more than 40 million cattle.

          [Slide]

          Here you have the distribution of positive basic

cases according to active or passive surveillance.   You see

that the vast majority of positive cases have been detected

with active surveillance.   In new member states, member

states which have joined the European Union after May 1,

2004, all the positive animals detected have been detected

by active surveillance, by testing.

          [Slide]

          On this slide you can see a graph which is quite

interesting.    I don’t know if you can read it but here, in

2001, we introduced the active surveillance and you see that

after this date, as shown before, the vast majority of

positive cases detected have been detected by active

surveillance.   The red is active surveillance.   It is not

very easy to see here but in yellow you have the

contribution, if I may say, of the new member states, which

is very modest.

          [Slide]

          Here you have the evolution of the number of tests

carried out in the European Union from 2001 to 2008, and you


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see that the level of surveillance has remained more or less

constant since 2001, and in 2008 we performed more than 10

million tests.

           But, on the other hand, you have here the

evolution of the incidence, the annual incidence of BSE in

the European Union and it is very clear that with the same

level of surveillance maintained we have a clear decrease in

the trend of the epidemic.

           [Slide]

           This parameter is quite interesting.   This is the

average age, the mean age of the positive cases detected

from 2001 to 2007.   You see that the mean age of the cases

has continuously increased since 2001, which means that the

exposure to the TSE agent has been stopped or almost

stopped.

           [Slide]

           If you want more details or if you want to have

access to the full results of the monitoring system you can

have a look at the website of the European Commission, the

DG SANCO website, at the following address and you will have

all the monitoring results, all the annual reports of the

Commission on BSE monitoring, also on the scrapie monitoring


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and on the CWD monitoring.

          [Slide]

          In conclusion, you can say that we have to return

to the principle of the double barrier to protect from BSE

with SRM and the monitoring system, plus the feed ban; the

very strict condition in place within the feed ban itself

with the total feed ban in order to avoid cross-

contamination; the extensive and very strict controls; and

the favorable results observed in the monitoring programs

since 2001 until today.

          That is it.     Thank you for your attention.

          DR. HOGAN: Thank you very much.     It is very

interesting and informative, a lot of information there.

Are there any comments from the committee?    Dr. Powell?

          DR. POWELL: I had a question.     In previous annual

reports of the TSE surveillance in the EU the directorate

has said that there are not yet sufficient data to evaluate

whether the strengthened feed ban had any impact on the

slope of the epidemic curve.    Have you acquired sufficient

data now so that you can evaluate whether the curve

deflected after implementation of the strengthened feed ban?

          DR. PLANTADY: In fact, we intend to submit this


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kind of question to our European Food Safety Agency in Parma

in order to have scientific advice, but according to these

figures we guess that the total feed ban, the extended feed

ban, has had quite a great effect.

             DR. POWELL: I am asking whether the slope of the

epidemic curve before and after the strengthened feed ban is

different.    The EC has said in the past that there were not

yet sufficient data to test the hypothesis.    Is this the

question that you are going to put to your advisory

committee?

             DR. PLANTADY: I don’t have any details on that

because before the extended feed ban the problem was that

not all the member states performed tests.    So, to be in a

position to judge the decrease of the epidemic, it is quite

difficult.

             DR. HOGAN: Any other comments or questions?

             DR. GESCHWIND: My understanding is that in Japan

they have been inspecting all cattle so they have active

surveillance.    They have found a few cases of BSE in cattle

under 24 months of age.    That being the case, why isn’t

there stricter testing in Europe?    Why don’t they actively

survey younger cattle?    And, the same question would apply


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in the United Sates, of course.

           DR. PLANTADY: In fact, we have decided to test at

24 months based on scientific advice.   That is the first

thing.   And, recently we have received advice from the

European Safety Authority saying that it was no more

justified to test cattle above 30 months-Bit was mainly for

slaughter cattle, above 30 months for cattle coming from the

old member states, the 15 member states.    Is that the sense

of your question?

           DR. GESCHWIND: Yes, I understand.   The 24 months

was all animals greater than 24 months if they are subject

to special emergency slaughter, show signs of disease or

they have fallen.   Then, all healthy animals over 30 in age

that are subject, and then your two qualifying comments on

those.   So, are you inspecting every cattle over 30 or only

certain cattle over 30 months?

           Then, the second one, you answered by question.

You said the scientific advisors have said you don’t need to

test cattle less than 24 months.   I realize that the

incidence is very low, but we know that BSE exists in cattle

less than 24 months based on the Japanese data.   So, what

level of risk is being taken by doing that?    So, there are


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two questions there.

            DR. PLANTADY: Concerning your first question, the

answer is yes, we test 100 percent of animals over 30 months

of age which arrive to the slaughterhouse.    It is systematic

testing.

            As regards the age for testing, in Europe we have

never observed a positive case under 24 months of age.   I

know that in Japan this is the case but in Europe we have

never observed that.    And, each time we pose the question,

we ask EFSA, European Food Safety Authority, they reply that

there is no obvious reason or scientific reason to decrease

the age for testing.

            DR. GESCHWIND: Just as a comment, I guess in Japan

technically they didn’t observe BSE in cases under 24

months.    They only found it by doing active surveillance of

every cattle.   So, the cattle they found were not

symptomatic, is my understanding.

            I guess my point is that that being the case you

wouldn’t have necessarily expected to see it.   Just because

you haven’t seen it in Europe doesn’t mean that it is not

there and the animals just haven’t become symptomatic.

            DR. PLANTADY: Theoretically it is possible to have


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an infected animal less than 24 months old, but this

situation is more a situation of the past I think, in Europe

at least.    So, for the moment we do not have any intention

to decrease this limit or to change this limit.

            DR. HOGAN: One more quick question before we move

on?   No?   Thank you very much.   I appreciate you standing

in.

            Our next speaker will be Dr. Noel Murray who is

going to speak on BSE surveillance, animal feed and food

control in Canada.    Thank you for coming, Dr. Murray.

      C. BSE Surveillance, Animal Feeds and Food Controls

                            in Canada

            DR. MURRAY: Thank you.

            [Slide]

            My name is Noel Murray.     As explained, I am with

the Canadian Food Inspection Agency.      I am a veterinary

epidemiologist and I have done a lot of work with BSE over

the last number of years.

            I would just like to clarify the question about

the Japanese BSE cases.    I think it is really important to

understand a couple of issues here.      These have never been

confirmed as actually being BSE.      The Japanese at the time,


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I think it is very important to remember, had ramped up

their surveillance.   They instituted blanket testing of

animals of all ages in response to a huge domestic crisis, a

complete collapse in consumer confidence.

          The test they were using at the time was a

modified version of the Western blot.   Unfortunately,

samples from those animals were never shared with the

International Reference Laboratory in the UK so we could

never confirm whether they were BSE cases or not.

          The Japanese did undertake some infectivity trials

using mice, as far as I understand.   There was a paper, I

think published a couple of years ago, detailing the results

of that, but basically, from my understanding, the mice died

from old age.   In other words, they couldn’t demonstrate

infectivity.

          It is kind of curious that with the massive

amounts of testing that they have done these are the only

two animals they ever found with possible BSE.   One would

expect, indeed, if this was an ongoing sort of problem that

they would have found a few more.

          I think one could be forgiven for suggesting that

perhaps these were political cases of BSE and not actual


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BSE.    So, just a point of clarification.   I think we don’t

want to assume that these animals actually had BSE because I

don’t think the evidence is there for that.

            [Slide]

            Anyway, just to turn attention now to my

presentation, I just want to give a quick overview of the

risk factors for BSE in Canada; the animal feed controls

that we have in place; some results from our BSE

surveillance program; and then some comments about

protecting the human food supply.

            [Slide]

            So, just quickly looking at some of the risk

factors, just to sort of set the scene really, I think it is

important to appreciate that the situation in Canada is

quite different to that which existed in the UK and a lot of

the European countries.

            The most likely source of BSE for Canada would

have been one or two cattle imported from UK in the 1980s.

In other words, imports of meat and bonemeal, or feed

containing meat and bonemeal essentially posed a negligible

risk.    This is basically because meat and bonemeal for feed

for livestock hadn’t been imported from the UK or Europe


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since 1978.   That was mainly because of ongoing concerns in

relation to foot and mouth disease.   So, that was actually

quite fortuitous.

          So, the most likely source was one or two animals

imported from the UK.   That obviously resulted in an

extremely small challenge.   Certainly the rendering for

feeding practices at that time would have allowed the agent

to begin to cycle through cattle and to initiate a small-

scale epidemic.

          [Slide]

          It is also important to appreciate that the

initial spread would have been extremely slow.   We just have

to think about the epidemiology of BSE itself.   Basically,

animals that became infected after the initial insult

wouldn’t actually reintroduce the BSE agent back into the

feed chain for a number of years.   We all know that BSE has

a fairly lengthy incubation period.

          Another important fact to consider there is that

the actual levels of the agent in an infected animal are

very low for all but the last couple of months prior to the

end of the incubation period.   The majority of any animals,

the limited number of animals that might have been infected,


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would have been either slaughtered or died from other

reasons before reaching this critical phase in the potential

incubation period.

            One more factor there to consider is that

supplementary feeding with bonemeal was not as extensively

practiced as it was perhaps in the UK.    Canada has always

had a very suppliable alternative compared with protein

supplements, for example soy bean meal and fish meal.

            [Slide]

            In 1997 we introduced the feed ban which at that

stage was preemptive in nature.   We hadn’t actually had BSE

in Canadian-born animals at that point.      It was basically

introduced to guard against the potential spread of BSE if,

in fact, it had been introduced at some point in the past.

The introduction of the feed ban at this time really stands

in stark contrast to UK, certainly, and a number of other

European countries where feed bans were only introduced

after BSE cases were actually detected.      Of course, by this

stage there was already significant buildup of the BSE agent

within the cattle population and quite some level of cycling

going on.

            [Slide]


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           So, the nature of the feed ban as it is today, in

August of >97 we introduced the original feed ban, which was

characterized as a mammalian to ruminant feed ban with

exceptions.   Basically, it is a ruminant to ruminant feed

ban with a ban on feeding proteins of ruminant origin back

to ruminants.   These are defined as prohibited materials. We

include salvage pet food, plate waste and poultry litter

within the scope of those materials on the assumption that

they may contain ruminant proteins.

           A couple of exceptions to the ban, milk, blood

from any species, gelatin and tallow from any species are

exempt.   There has been a lot of effort on focusing on

preventing cross-contamination at all points along the feed

production and distribution chain, and that ranges from the

rendering facilities themselves through to feed mills, and

livestock producers.    A lot of inspection effort goes into

looking at these different establishments, particularly the

high end of the chain, the renderers and the feed mills.

           Then, in July, 2007 we saw the introduction of the

so-called SRM ban.   The SRMs had actually been excluded from

the human food chain since 2003.    Then that ban was extended

to the animal feed chain, the terrestrial and aquatic animal


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feed chain, as well as fertilizer from July, 2007.    There

was an exemption lifted for tallow.   Previously tallow of

any grade was able to be fed, but from this date tallow

itself could contain no more than 0.15 percent in soluble

impurities if it was going to be fed to ruminants.

            [Slide]

            So just quickly, specified risk material is pretty

much consistent with what other countries define as

specified risk material.   I won’t spend too much time on

that.    These materials have been banned, as I said before,

from the human food chain since 2003.   That is certainly the

key public health measure for BSE.

            These tissues are removed during the slaughter and

cutting or boning operations to prevent cross-contamination

of edible meat with these tissues.    Stunning processes that

involve pithing or injection of compressed air or gas are

also banned, and vertebral columns from animals over 30

months of age are also banned as raw material for the

production of mechanically separated or finely textured

meats.

            These tissues, the SRMs from 2003 were redirected

to the edible prohibited material waste stream where they


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were still banned from being fed to ruminants but not other

species.   From July, 2007 they have now been banned from all

the terrestrial and aquatic animal species as well.

           [Slide]

           So, the SRMs themselves are segregated at source

and redirected for disposal or destruction.     That ensures

that the consequence of any potential cross-contamination

that might arise--and we have to acknowledge that we have

really a complex network of rendering, feed production,

transport, storage and that exists in any country.     So there

are ongoing challenges with potential cross-contamination.

But by taking the SRMs out, the tissues with the vast

majority of BSE infectivity, we eliminate the consequences

of any cross-contamination events that arise and that should

significantly accelerate our progress to eradicating BSE.

           [Slide]

           We control the flow of SRM by segregating and

staining at source, much as is done in the EU.     Then we

restrict subsequent transport of processing with destruction

or disposal of those SRMs to operate all facilities that

hold a valid permit issued by the CFRA.     These permit

holders or operators are subject to an on-site inspection


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prior to receiving a permit, with follow-up inspections

throughout the year.

            [Slide]

            Just a bit of an oversight here.   I am not sure

how well this comes up, but just looking at the complexity

of the SRM flowchart, if you like, here we have the farm

level.    We can see a live animal may be sent to slaughter.

It may die during transport.    Perhaps it is condemned at the

slaughterhouse.   Well, SRMs are generated from that animal

and that then flows through these different pathways.

            These lines are basically meant to indicate that a

transport permit is required to move that material that is

generated at the slaughterhouse.    If the animal dies during

transport or is condemned it may end up at a salvage or a

dead stock operator.

            If the animal dies on the farm it may end up being

buried on the farm and we don’t control that.    But if it is

picked up and is moved off farm, it has to be done under a

permit.   If it goes to a veterinary clinic for autopsy the

veterinary clinic would have to have a permit to receive the

SRM in that case, and on it goes.

            We can see here we have a couple of intermediate


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processing steps.    One is rendering and the other is

composting those materials.    The material from rendering

could be disposed of on site or it could go back out into

landfill and perhaps even incineration, thermal hydrolysis

or alkaline.   These three here are the three methods that we

have approved for destruction.    Something like burial would

be containment.

           [Slide]

           So, just looking at surveillance, just like is

happening in the US, we have had a long history of

surveillance, going back as far as 1992, where we have been

testing animals displaying clinical symptoms consistent with

BSE.   At that stage, the goal is to determine whether BSE

was present in the country at the rate of one in a million.

           Prior to 2003, detecting our first homegrown case,

we tested about 10,500 animals.    Back in 1993 we did

actually find a BSE case.    However, this was in an animal

originally imported from the UK.    At that time, well, in

1990 further imports from the United Kingdom were banned due

to growing concerns about the BSE situation there.

           Those animals, any imported animals were then

placed under a monitoring program and that is how we


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discovered this case in 1993.   One of those animals being

closely monitored came out with BSE.   At that stage any UK

imports that were still alive were either re-exported back

to the United Kingdom or destroyed.    Then we ran it for ten

years or so, probably roughly two incubation cycles and we

had our own homegrown case.

           [Slide]

           Of course, at that stage the objectives of the

testing program did change.   We wanted to gain a more

accurate idea about the level of BSE in Canada, as well as

to determine the effectiveness of the original >97 feed ban.

           Just like happens in the US, cattle 30 months of

age from certain groups are targeted for our surveillance

program.   I won’t go through that because that has already

been covered.

           [Slide]

           So, we are certainly testing many more animals for

BSE these days.   So, from 2004 to May, 2009 we tested over

260,000 cattle from these targeted populations.   Now, 12 of

the 16 cases that we have identified in Canada have actually

been detected on farm.   These animals that we target come

from a variety of sources, so on farm, either rendering or


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dead stock operators and limited numbers through federal or

provincial abattoirs.    It would be condemned animals.    Most

of those would go to a dead stock operator for sampling.

            [Slide]

            This is just a slide showing the cases of BSE so

far.    However, we haven’t really had an awful lot, 17 to

date that would be attributable to Canada, that is 16 that

we detected in Canada.    Thanks very much to the US, you

discovered one for us, this blue one, here, back in 2003.

Then we have had two atypicals as well, one H type and one L

type.   So, we have the full spectrum of BSE.

            [Slide]

            Just in terms of trying to get an idea about what

is actually happening in Canada with BSE, one really useful

way of looking at it is through a cycle of birth cohort

analysis.   You have already heard mention a little bit about

BsurvE.   That is an analytical tool.   Basically it was

developed by some BSE experts from Europe, Australia and New

Zealand for the European Commission.    It is a model that is

based on an understanding of BSE and the extensive testing

results that have occurred in the UK and Europe since 2001.

            As has already been mentioned, it calculates the


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number of points as a guide to the adequacy of the country’s

testing program and it requires, of course, certain inputs.

 For example, the age, distribution of the cattle population

in the country, and the test results stratified by age and

subpopulation.

          [Slide]

          Now, the surveillance pointsB-there is a rational

basis for surveillance points.    Essentially it is the ratio

of probabilities, the first one being what is the

probability that an infected animal would leave by a

particular stream at a particular age and test positive

compared to an animal that would leave by the same stream at

the same age that is uninfected.    So, there is a rational

basis for that.

          [Slide]

          This is the table from BSurvE itself, and it just

is emphasizing once again that the animals you are more

likely to find, BSE cases, would be in the so-called

clinical suspect class.    That peaks out around about four

years of age.    That is obviously consistent with the

incubation period of BSE.

          [Slide]


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             As we have also seen, the OIE prescribes a certain

number of points to be achieved.    For Canada, we have a

population of six million annual cattle approximately and

our surveillance target is the same as the US basically.

Once you get above a million animals the points target does

stabilize.    So, we have exceeded that by a significant

amount.   We have accumulated over a million points to date,

or at least up to August, 2008 when the analysis was done

for OIE update last year.

             [Slide]

             Let’s look now at the results from the birth

cohort analysis that we can do.    This gives you an idea of

the level of exposure within any one particular birth year.

 Important assumptions, of course, with a birth cohort

analysis are that the animals are probably more susceptible

to BSE in their first year of life and they are more likely

to perhaps be exposed during that time.

             But what it does enable you to do is to monitor

the trend of BSE in your particular country at a time.      We

can see here we have a rising trend up until >97.    We have

the expected value of distribution here and the upper 95

percent confidence interval here.


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          Then, following the introduction of the feed ban

the level of exposure drops off.   There was a bit of a blip

round about 2000, but we can see that the level of BSE in

these cohorts is very, very low indeed.

          [Slide]

          Here are the results from BSurvE basically.     We

have the number of cases and the points attributable to each

birth cohort.   Of course, you can accumulate points with

each succeeding surveillance year, and the more information

you the more confident you can be.   So, you can see back

here the confidence intervals are obviously quite wide.     We

hadn’t accumulated a lot of information on these birth

cohorts and we are not going to because simply the animals

are too old and have more than likely left the system.

          But we can see in the more recent birth cohorts,

even though we have had some cases, the confidence intervals

are quite tight and it gives us a good measure of confidence

that BSE is certainly not amplifying.   With ongoing

opportunities for recycling there is no evidence whatsoever

for amplification.

          [Slide]

          But since this analysis was done here, from


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August, 2008, we have had two more cases of BSE detected in

Canada, one born in 2001 and another born in 2002.    So, you

can ask, well, what is the likely impact of these additional

cases on these birth cohort estimates.

           We collated our data across Canada for the period

of August 1 to July 31 each year.    This fits in with the OIE

reporting cycle.     Of course, at this stage that data is not

quite yet available.    But perhaps we could take a worst case

assumption and say we have gained no additional information

for the 2001-2002 birth cohorts from amongst over 30,000

cattle tested since August, 2008, apart from finding a

couple of BSE cases.    In other words, all those negative

animals we are not taking into account in the analysis.

           [Slide]

           Then, we can see the impact here, or lack of much

of an impact.   The purple line is the latest estimate.   Of

course, there are no changes to these birth cohorts here.

The impact is in 2001 or 2002 where we found cases.    I am

not sure if you can see, but really the line has not shifted

much.   It has gone up a little bit but it is essentially

confirming that the level of BSE in these birth cohorts

remains extremely low.


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            [Slide]

            So, these results, to our mind, effectively

demonstrate that BSE is being effectively controlled in

Canada.   The >97 feed ban itself had a dramatic effect on

the evolution of a small-scale epidemic, and we could say

that our feed ban is epidemiologically effective.    The

prevalence with any particular birth cohort is extremely

low.   We could certainly expect if the feed ban itself

hadn’t so effectively arrested amplification and reduced

recycling that we would see more cases of BSE, for sure.

            [Slide]

            So, what did these additional bases of BSE that we

seem to keep on finding really mean?   Despite what a lot of

people claim, to my mind, and the results of our

surveillance really support this, detection of a few

additional cases does not indicate that prevalence of BSE is

increasing.   What has actually increased is the sensitivity

of our surveillance program since 2004 through testing many

more targeted animals in our surveillance program.

            In other words, for the same prevalence level of

BSE, if you like, we are perhaps more likely to find those

cases.    I think it is reassuring that we have found 16 among


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over 260,000 animals.    That is really not a lot of cases.

          [Slide]

          So, people talk about animals born after the feed

ban, so-called BABs.    This would be any animals born in the

more recent birth cohorts.    We can see from our birth cohort

analysis that the occurrence of these animals does not

indicate the feed ban is failing.    What they provide

evidence of is ongoing limited opportunities for recycling,

absolutely not amplification.

          I think it is important to acknowledge that, you

know, while it doesn’t take a lot of contaminated feed to

result in transmission, amplification itself requires

significant recycling.    Certainly, the experiences in UK and

Europe would support that, that these so-called BABs, or

animals born after the feed ban, are actually

epidemiologically unimportant.

          [Slide]

          So, it is not going to lead to a resurgence of the

epidemic because, remember, we do have the ongoing

application of the feed ban, particularly the enhancements

from July, 2007 when the SRMs have been excluded from the

entire aquatic and terrestrial animal feed chain.


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          [Slide]

          So, in conclusion for the feed ban, we have an

epidemiologically effective feed ban that has dramatically

limited exposure to BSE.    We can conclude that the

prevalence of BSE in Canada is extremely low and is being

effectively controlled.    In fact, it has been recognized a

couple of years ago by the OIE in its designation of Canada

as a controlled BSE country.

          [Slide]

          So, just some final comments, just one slide on

protecting the human food supply, adding a little bit to

what I said before, just some thoughts about, you know,

really protecting the human food supply does involve

continuing measures and it is important to recognize these.

          Firstly, the prevalence of BSE in Canada is

extremely low.   Most animals infected with BSE are not

likely to actually survive long enough to post a public

health risk as such.

          Remember that the levels of infectivity really

don’t start building up until the latter stages of the

incubation period.   But even if it did survive long enough

to develop into a case, the majority of BSE cases, if you


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like, are unlikely to be passed as fit for human

consumption.   Most of the cases are actually found among

dead animals or animals displaying certain symptoms,

including downers and animals with nervous symptoms.   These

would certainly be screened out at any inspection.

          The next measure, of course the most important

one, is that the SRMs themselves are excluded from the human

food supply.

          Finally, all the evidence to date seems to

indicate that the transmission of BSE to humans through food

is actually quite difficult and that perhaps a significant

species barrier does exist.

          So, all those factors combine to lead us to the

conclusion that we can be confident about the sanitary

safety of the food supply.    Thank you

          DR. HOGAN: Thank you very much.    We have a few

comments or questions?   Dr. Geschwind?

          DR. GESCHWIND: Maybe just some clarification about

this recycling issue and how that is causing these cases of

BSE that occurred after the bans.    Maybe you could clarify

exactly what is the recycling and how does it differ from

the things that have led to an epidemic.


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            DR. MURRAY: Well, I think it is a numbers game.

You know, we would say for recycling the most likely

explanation would be that it has arisen as a result of some

cross-contamination during the feed production and

distribution process.   It depends how much recycling is

going on.   With limited opportunities for recycling, you

know, you are still going to get some BSE cases popping up

but you are not going to get an epidemic emerging until you

get quite a lot of recycling occurring.

            DR. GESCHWIND: So, where is the recycling

occurring if you have the SRM ban in place?

            DR. MURRAY: Well, remember, what we are looking at

here is results that point to what was happening

historically.   This goes back a number of years.   The most

recent birth cohort that has been effected to date is 2003.

 We introduced the SRM ban from the animal feed chain, if

you like, in 2007 and we haven’t got enough information to

make any conclusions about that.

            There were some comments before about the

situation in the EU, whether they have accumulated enough

evidence to date to look back at their 2000 enhancements.

You know, realistically, it is going to take four to five


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years as a minimum to accumulate information, and probably

at that stage begin to be in a position to look back and say

what was happening in that particular birth cohort.    So, we

would anticipate that we are not going to start getting a

lot of information about the impact of the SRM ban in 2007

probably until at least 2012, 2013 with our current

surveillance and testing program.

          DR. HOGAN: Well, that provides a great segue to

our next speaker.   Thank you very much, sir.   Dr. Burt

Pritchett is going to talk about the FDA enhanced animal

feed ban, its current status.

     D. FDA Enhanced Animal AFeed Ban@: Current Status

          DR. PRITCHETT: Good afternoon.

          [Slide]

          I am Burt Pritchett.    I am a veterinary medical

officer in the Division of Animal Feeds at FDA’s Center for

Veterinary Medicine.

          To first summarize for the committee and then

explain in more detail, CVM has finalized new regulations to

strengthen BSE feed controls in the United States.

          [Slide]

          The 2008 BSE feed rule, as we refer to it to


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distinguish it from the 1997 feed ban, was published in the

Federal Register on April 15, 2008.   There was a 12-month

implementation period built into the rule so it was

scheduled to take effect on April 27, 2009.

          We recently affirmed the April 27 effective date

but, to allow more time to deal with disposal problems

caused by the rule, we established an October 26 compliance,

date, meaning the rule is currently in effect but we will

not begin enforcing it until October 26.

          The rule adds a new section 21 CFR 589.2000 that

applies to feed and feed ingredients for all animal species

and amends the >97 rule at 589.2000 to add new requirements

for tallow.

          The 2008 rule prohibits use in feed for all animal

species the following material, referred to as cattle

material prohibited in animal feed, or CMPAF:

          [Slide]

          The brains and spinal cords from cattle 30 months

of age and older; the entire carcass of cattle not inspected

and passed for human consumption, and these would be dead

stock cattle, unless they are shown to be less than 30

months of age or the brain and spinal cord are removed.


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            We closed a regulatory loophole by prohibiting for

use in animal feed the entire carcass of BSE positive

cattle, including tallow; tallow made from CMPAF that

contains more than 0.15 percent insoluble impurities; and

mechanically separated beef made from CMPAF, meaning that

the brain and spinal cord from over 30-month cattle must be

removed before material is subjected to the mechanical

separation process.

            [Slide]

            Looking at the chronology, it is apparent that

this has been a very lengthy process and that we looked at a

number of options.      We also had a couple of changes in plans

so we caused some confusion about which measures were

actually adopted.

            In response to the Washington State case, we

announced in January, 2004 our intention to strengthen the

>97 feed ban by banning the use of blood products, poultry

litter and plate waste, and this was one of the changes in

the plan.

            *** ALICE

We did not follow through with this set of measures.     After

considering the recommendations of the international review


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team we, instead, published an advance notice of proposed

rule-making in July, 2004 jointly with USDA.

          In that proposal we tentatively proposed to ban

SRMs from all animal feed.    What we actually proposed in

October, 2005 was a partial SRM ban, limited to brain and

spinal cord tissues.

          It took us until April 25, 2008 to finalize the

proposal because we significantly underestimated the costs

associated with the measures.    Also, commensurate with

USDA’s surveillance results and prevalence estimates, and

the high level of compliance with our >97 rule, we modified

the rule to apply only to brains and spinal cords from

cattle 30 months of age and older, rather than cattle of all

ages.

          Due to complaints about not being able to dispose

of CMPAF, especially complaints from state departments of

agriculture, we proposed, on April 6, to delay the

effectiveness by 60 days and opened a seven-day comment

period.

          We specifically said we would only consider

comments pertaining to the delay but, nevertheless, received

a large number of comments saying the rule is unnecessary


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due to the low BSE prevalence in the United States, and

asking that the rule be reopened or rescinded.

          To send a clear signal that FDA intended to go

forward with the rule, the agency decided to confirm the

April 17th effective date, but allow the extra six months

before enforcing it.

          [Slide]

          The bottom line of the new tallow requirements is

that the rule creates a two-tier approach to tallow so it is

that tallow for use in ruminant feed must meet the 0.15

percent insoluble impurities standard, while tallow for

other species need not meet the standard.

          [Slide]

          The rule also contains a marking provision,

requiring that CMPAF for disposal be marked with an agent

visible to the naked eye to indicate that it is not for use

in animal feed and this requirement does not apply to dead

stock disposed of on farm.

          [Slide]

          Consistent with regulations by USDA and FDA that

pertain to human food, there is a provision in the rule

allowing for countries to request exemption from the


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requirements in the feed regulation.   We have already

designated Australia as exempt, and just this week received

a request from New Zealand asking to be designated as

exempt.

          [Slide]

          The rule places no requirements on renderers.

Renderers that handle any cattle material must maintain

records sufficient to demonstrate that rendered material for

use in animal feed does not contain CMPAF.   Renderers that

intend to render dead cattle for animal feed use must ensure

that deads are under 30 months of age or ensure that brain

and spinal cord are effectively removed; use separate

equipment for rendering CMPAF once it is removed; label

materials containing CMPAF Ado not feed to animals;’ mark

CMPAF with an agent that is readily detected visually;

maintain records sufficient to track CMPAF *tp ensure it

does not enter animal feed; and comply with the new

restrictions on tallow.

          The practical effect of the new requirements is

that renderers will likely either increase collection fees

to cover the costs of meeting the new requirements or

discontinue processing deads.   Decisions are being made on a


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company by company and region by region basis.    Customers of

the renderers, namely packing plants and cattle producers,

in turn, react to decisions made by the renderers.

            Some of these customers were not aware until late

in the implementation period that they were losing rendering

service or facing increased costs.    Some also planned to

utilize landfill, only to find that the landfill would not

accept the material.    These kinds of problems, reported

across the country, were what led to the decision to delay

enforcement.

            [Slide]

            Impact on slaughter facilities, slaughter

establishments will need procedures for segregating the

brains and spinal cords from cattle 30 months of age and

older from the rest of their offal.    They will need to

provide certification to renderers that offal to be rendered

for animal feed us is free of CMPAF.    And, if the

establishment slaughters cattle 30 months of age and older,

they will need to identify other non-feed means of disposing

of CMPAF.

            [Slide]

            Impact on cattle producers, cattle producers will


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be asked by renderers who collect their dead stock to verify

their animal is less than 30 months of age or be charged for

removing the brain and spinal cord.   Some renderers have

said they will only accept deads that are under 30 months of

age.   Therefore, producers may need to identify alternative

means of disposing of dead stock.   If renderers discontinue

some collection routes, this could impact disposal of

horses, hogs, sheep and goats.

           [Slide]

           To help with the implementation process, we

published as set of Q&As last July, essentially responding

to questions from the impacted industry on what is in the

rule and what they need to do to comply.    The Q&As have been

updated several times.

           [Slide]

           We also published more formal draft guidance last

November, small entities compliance guide number 195, which

is similar to guidance documents for the 1997 feed ban.

This document provides further clarification and

interpretation of the regulation and contains non-binding

recommendations for complying with the rule.

           [Slide]


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          During the implementation period we have been

making preparations to enforce the rule.     We have provided

some initial training through *webenars to our federal and

state inspection force, and we will be holding classroom

style training.   We have added a module to our BSE

inspection checklist, which is also a data entry form that

applies to the 2008 requirements.

          We estimate that out of the approximately 260

rendering plants in the US, about 130 of them process bovine

material and will be subject to the new rule.    Enforcement

is not expected to be significantly different from how we

enforce the >97 rule.

          We have made comparisons of how we expect to

evaluate aging procedures and brain and spinal cord removal

procedures to how we have evaluated clean-out procedures

under the >97 rule.   That is, we will review the written

procedures.   We will observe the procedures being carried

out, and then we will review the records they have

demonstrating that the procedures have been followed.

          [Slide]

          The rule does create a disposal challenge.    We

estimate that 15,000 tons of CMPAF from slaughter


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establishments will be diverted from rendering to other

forms of disposal, most going to landfill.       Of the 4.2

million head of beef and cattle mortalities in the US each

year, 45 percent are currently being rendered for animal

feed use.    The new rule is expected to decrease that by 26-

42 percent.    This means alternative disposal will be needed

for 300 to 350 thousand tons of dead stock cattle each year.

             As a country, we want to preserve rendering

services as much as possible unless we have something to

replace it with.       Even the national rendering service

doesn’t know their members plans well enough to know the

full extent of how much of the rendering service will be

preserved and what is going to replace it.       From what we can

tell, composting will take up much of the slack from lost

rendering.

             [Slide]

             The 1997 feed ban remains in effect.    It prohibits

feeding mammalian protein to ruminant animals, except those

proteins which are specifically exempted by the rule.         Those

are milk products, blood products, gelatin, pure porcine or

pure equine protein and plate waste.

             It requires that firms that handle prohibited


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material and also make ruminant feed have adequate measures

in place for preventing cross-contamination.   Firms that

handle prohibited material must maintain receipt, processing

and distribution records for one year, and label products

containing prohibited material with a caution statement Ado

not feed to cattle or other ruminants.@

           [Slide]

           We are still devoting considerable resources to

enforcement of the >97 rule, conducting approximately 8,000

inspections per year.   Most inspections are conducted by the

states.   Regardless of whether they are conducted by FDA or

the states, the inspection results are submitted to the BSE

coordinator in FDA’s district office, with the final outcome

posted on the CVM website.

           We are also continuing our feed testing program

with a target of 400 samples of imported product and 800

samples of domestic product.   We are having trouble

identifying enough import shipments that qualify for

sampling to meet the import target but we are meeting the

domestic target.

           The first week of June we had a group of analysts

from FDA labs in for training on our new real-time PCR


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method, and this week and next week we have two groups from

state labs that will be coming in for training on the new

method.

          Both our inspection results and our feed testing

results continue to indicate a very high level of compliance

with the >97 rule.

          [Slide]

          So, the current status of our enhanced feed

controls is that we have effectively extended the 12-month

implementation period to 18 months.    The impacted industry

continues to prepare to comply with the rule, and we

continue to prepare to enforce the rule.

          DR. HOGAN: Thank you very much, sir.      I had a

couple of questions.    You were commenting about ruminant to

ruminant feed ban.   Does this include poultry litter being

restricted from re-feed recycling?

          DR. PRITCHETT: Poultry litterB-the >97 ruminant to

ruminant feed ban is silent on poultry litter.     Regulation

of poultry litter is left to the states by virtue of, I

believe, a 1980 Federal Register notice.      It is left to the

states because it commonly does not cross state lines.

Because of the bulk of shipping poultry litter, it is


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typically used by poultry producers that also raise cattle,

or it is shipped a short distance away.     Therefore, it is

regulated by the states.

          DR. HOGAN: I have one more question.     You talked

about all of the enforcement rule, the 2008 rule.    Are you

going to be reviewing records?   Is there going to be any

reinspection or are you just going to review the written

records of their compliance?

          DR. PRITCHETT: I am sorry, did you say ingredient?

          DR. HOGAN: No, no, reinspection.     In other words,

you are going to review the written processes for

compliance.   Then you are going to observe their compliance.

 Then you are going to review records that suggest they are

really compliant.   Will there be any reinspection, rather

than just looking at written records, after that?

          DR. PRITCHETT: No, the first thing I mentioned was

that they have to have written procedures in place that

describe how, for example, they will remove the brain and

spinal cord from cattle 30 months of age and over, or how

they will be aging cattle.   We will watch them do those

procedures.

          They also, you know, between inspections have to


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document that they have performed the measures in their

written procedures.   So, we will be reviewing those records.

            DR. HOGAN: You mentioned training.    I heard you

mention real-time PCR.   What is your target?    What is the

applicability of that assay?

            DR. PRITCHETT: I think it may be only bovine or it

may be bovine and ovine mitochondrial DNA.    So, currently

our screening method is feed microscopy so we check for the

presence of bone, hair, blood, etc.    If those feed

microscopy results are positive, then we have to verify the

species that that material came from.    It may be porcine

origin bone rather than bovine origin bone.      So, with the

new real-time PCR and the faster throughput of this method

we plan for our feed testing assignment that goes out this

fall to sort of reverse that order, to use the real-time PCR

method for screening to detect the presence of bovine

material.   If we find that, then we will go to the feed

microscopy and see if it is bone or hair rather than a

material that is accepted for use in ruminant feed, like

mild or blood.

            DR. HOGAN: Mr. Templin?

            MR. TEMPLIN: Thank you.   Has there been any


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thought into the possible ecological damage that composting

and disposing of the animals on the farm will do in the

future to the aquifer because where I live a lot of the

communities are rural and everybody has their own wells?

So, if all the farmers decide not to send their dead animals

to the rendering plant because of cost, they are just going

to dig a hole or compost it and eventually that will leach

down into the ground and the neighbors will start drinking

it from their wells.

          DR. PRITCHETT: Yes, the environmental impact has

been a major concern.    We did publish an environmental

assessment that accompanied the rule.    Basically, it talks

about those issues that are potential to contaminate ground

and surface water.   It talks about pathogens present, odors,

and so forth.

          Basically, it concludes that the environmental

impact is not significant because of the 12-month

implementation period allowing time to, you know, identify

appropriate alternative means of disposing of the material.

 You know, back when the rule was published there was some

indication that there were a lot of very good disposal

procedures that could have taken the place of the current


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rendering system, like disposal rendering where you just

reduce the volume of the material, obtain the tallow to

recover some of the cost, and then dispose of just the meat

and bone meal rather than all of the raw material.

           FDA has no authority, has no expertise in other

disposal methods.   The impacted industry doesn’t like to

hear us say that.   The FDA Commissioner has told us that we

need to do more to deal with the disposal problem rather

than just saying that, you know, we have no authority to do

it.

           So, we have started that effort.   We held a 50-

state conference call a couple of weeks ago to try to

involve the environmental people in each state rather than

the feed control officials that we normally work with.    We

have been in discussions with the Environmental Protection

Agency.   They came out with a statement that they posted on

their website, saying that CMPAF does not meet the hazardous

waste standard and, therefore, it should be considered solid

waste.

           This doesn’t really require that landfill

operators, which in many cases are private or municipally

ownedB-it doesn’t obligate them to accept this material but


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it may, you know, help them decide to accept the material.

             We have begun involving the Natural Resources

Conservation Service, which is part of USDA, and they have

considerable expertise.    A lot of it is related to

composting, but they do work directly with cattle producers

to develop a daily animal mortality disposal plan and an

emergency mortality disposal plan.    We are putting together

a disposal page on our website to just list some of the

resources that we have identified, and a lot of states have

already gone through this process and there is some very

good material out there already talking about how to dispose

of it.

             Basically, you know, we have no data to show what

happens to BSE infectivity in composted animals, but we

would certainly believe that by composting it, relative to

leaving it in the animal feed supply, you certainly reduce

the risks.    So.

             DR. HOGAN: One last question.

             DR. POWELL: This presentation actually reminded me

of a question I had back in 2006 and I don’t recall whether

I got an answer at that point.    What is the fate of the

infectivity that is fractioned out during the processing of


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plasma-based products?

            DR. HOGAN: Who are you asking this question of?

            DR. POWELL: The experts.

            DR. LEE: The fate of that is any waste downstream

is processed through your typical biohazard waste disposal

methodologies that are recognized for plasma-derived

proteins.   But, considering the risk is quite low in terms

of relative infectivity, it is really quite negligible.

            DR. POWELL: It wouldn’t be that a fraction ends up

in a different product?

            DR. LEE: That is not feasible really because you

would have to create a specialB-for anything that you

thought would remove prions, everything at that point would

have to be treated in some way to remove prions.   It is kind

of the same work we are doing here.

            MR. POWELL: My understanding was that processes

haven’t been designed to remove prions, that they are as a

result of the processing that has been licensed and

approved, that it is a byproduct essentially of the way that

the procedure is already done.   So, would those fractions be

treated as biomed hazardous waste?

            DR. LEE: Yes, all waste out of the plasma


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processing stream is treated that way.

             DR. HOGAN: I assume that is incinerated.

             DR. LEE: Yes.

             DR. HOGAN: Any other questions here?   Thank you

very much, sir.    Informative.   We have two more to go and we

are getting a little behind here.     We are now going to have

Dr. Amber McCoig-BI hope I pronounced that correctlyB-talk

to us about FDA-regulated food controls in the United

States.

             E. FDA-Regulated Food Controls in the US

             DR. McCOIG: You pronounced it correctly.     One of

the benefits of going a little bit later in the day is that

many of the things I am going to talk about have already

been covered so I should be able to make this pretty short

and sweet.

             [Slide]

             I am Amber McCoig.   I am with the Office of Food

Safety, Center for Food Safety.     I am a veterinarian in the

Division of Plant and Dairy Food Safety.      I will be

discussing today FDA-regulated TSE food controls in the US.

             [Slide]

             As is apparent from the previous speakers, there


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is a lot of interagency collaboration involved in the

prevention of BSE in the United States.      The USDA and the

FDA have to work together to identify possible sources of

BSE and to prevent it from entering the US food supply.

            FDA’s rules and regulations include implementation

of animal feed bans, such as what Dr. Pritchett spoke of

just before me, and also policies and regulations in regards

to ingredients that could cause BSE risk in human food,

cosmetics, biologics and medical devices.

            [Slide]

            The Federal Food, Drug and Cosmetic Act provides

FDA authority to prevent any food that is impure or unsafe

or fraudulently labeled from entering the interstate

commerce.   This also covers any food that is not covered by

the Federal Meat Inspection Act, the Poultry Products

Inspection Act and the Egg Products Inspection Act.     FDA

also has authority under the Public Health Services Act, the

Fair Packaging and Labeling Act, the Bioterrorism Act and

the Code of Federal Regulations.

            [Slide]

            In the Center for Food Safety our responsibilities

include regulating dietary supplements, anything that goes


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into dietary supplements; infant foods; canned and frozen

foods; bakery goods; snack foods; candy including chewing

gum; food ingredients, and many food ingredients are also

called GRAS substances which means they are generally

recognized as safe; food additives and this also includes a

category of substances that come into contact with food;

cosmetics and cosmetic ingredients.

            [Slide]

            FDA has three main regulations that have come out

in order to prevent BSE entering the food chain.

            [Slide]

            The first of these was an interim final rule that

came about in July of 2004 and was published in the Federal

Register.   This regulation encompasses cattle materials with

potential risk of BSE in the human food supply and, as I

said before I know this has been covered several time,

prohibited cattle materials include specified risk

materials, materials from non-ambulatory, disabled cattle,

materials from cattle not inspected or passed for human

consumption and mechanically separated beef.

            [Slide]

            The specified risk materials covered in this rule


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were for cattle of any age tonsils and small intestines and

for cattle greater than 30 months of age the brain, skull,

eyes, trigeminal and dorsal root ganglion, spinal cord and

parts of the vertebral column.

             [Slide]

             In September of 2005 the interim final rule was

amended, and this permitted the use of the small intestine

if the distal ileum was removed.    This was based on

infectivity studies.    This also clarified that milk and mild

products, hide and hide derivatives, and tallow derivatives

 were not prohibited or considered to be specified risk

materials.

             [Slide]

             In April of 2008 there was another amendment to

the interim final rule published in the Federal Register.

This allowed countries to apply for exemption from some of

the BSE-related restrictions.    This was in order to address

countries with BSE-free status or negligible status and

countries that had comprehensive prevention and control

programs.    This is congruent with OIE standards and also

complies with the world trade organization SPS agreement

that requires member states to recognize regionalization of


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diseases in order to not restrict trade any more than

necessary.

             [Slide]

             In order to apply for exemption status a country

must submit a written request to the director of the FDA

CFSAN.   This request must include comprehensive BSE case

history, risk factors and all measures of prevention for

introduction of BSE into the food supply.

             These countries are evaluated on their import

controls, including the geographic origin of the cattle, as

well as the ruminant feed; their mandatory notification of

neurologically challenged animals; their policies,

regulations and protocols, and surveillance and

investigation.

             [Slide]

             To date, there have been two countries that have

applied for status and both have been granted it.    Those

would be Australia and New Zealand.

             [Slide]

             As I said, this is kind of short and sweet because

a lot of it was already covered by other people, but we, at

the FDA, are working with the USDA in order to prevent BSE


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from entering in our food supply.    We want to keep

stakeholders informed of what we are doing, and we want to

stay on top of what is happening scientifically.    We want to

know if there are any changes, if we need to make changes in

our policies and regulations.   If anyone has any questions,

here is my contact information also.

           DR. HOGAN: Well, thank you.   You certainly gave us

some time back.   I appreciate it.   We were about 20 minutes

behind.   We are not anymore.   Does anyone have any questions

for Dr. McCoig or related to the issues she covered?    Thank

you very much.

           Our final speaker before the break will be Dr.

Theresa Finn.    She is going to talk about the proposed BSE

medical products rule, its current status.

F. FDA Proposed BSE AMedical Products@ Rule: Current Status

           DR. FINN: Good afternoon.

           [Slide]

           I am with the Office of Vaccines at the Center for

Biologics at FDA, and I have been asked to provide a brief

update on the FDA proposed rule, which has the rather

unwieldy title that you see on this slide, Athe use of

materials derived from cattle in medical products intended


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for use in humans and drugs intended for use in ruminants.@

             The medical products that the rule refers to are

drugs, biologics, medical devices used in or on patients,

and human cell tissues and cellular- and tissue-based

products.

             The lead office for this rule is the Office of

Policy within the Office of the Commissioner, and there are

representatives from each of the medical product centers and

the Center for Veterinary Medicine.

             [Slide]

             The proposed rule was published for comment in the

Federal Register in January of 2007.    The rule is a risk

reduction measure which harmonizes the requirements for

bovine material used in human medical products with the

requirements of USDA-regulated meat and FDA-regulated foods

and animal feeds, and we just heard about the foods in the

last talk.    The rule applies to materials derived from

cattle slaughtered after the date the rule is finalized, and

there is a provision for exemptions based on risk and

benefit.

             [Slide]

             You should by now know what the prohibited


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materials might be.   They are the usual specified risk

materials, mechanically separated beef, material from non-

ambulatory disabled cattle, and material from cattle not

inspected and passed for human consumption.

          [Slide]

          If the agency feels that additional protections

are needed for specific products, for example for products

containing cattle materials that are not prohibited

materials but which have direct routes of exposure to the

bloodstream or neural tissue, the rule permits FDA to

provide these additional protections through the application

review process.

          [Slide]

          The prohibited materials do not include the

materials shown on this slide, hide and hide-derived

products; milk and milk products; tallow derivatives; tallow

containing no more than 0.15 percent insoluble impurities;

and fetal calf materials.

          Fetal calf materials actually are not a food so we

had to specifically address these.   For example, fetal calf

material that are often used in medical products is fetal

calf serum, or fetal bovine serum, and this is generally


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collected from the fetuses of dairy cows culled for their

mild production.       These culled animals are often older than

30 months.

             In this proposed rule fetal calf derived materials

are not prohibited as long as they were obtained from fetal

calves from cows that were inspected and passed, and

obtained by procedures adequate to prevent contamination

with the specified risk materials.

             [Slide]

             Now, as I mentioned in an earlier slide, the rule

contains a procedure under which FDA can permit an exemption

or an alternative to the restrictions on the use of

prohibited cattle material.      If a manufacturer wants an

exemption they would have to submit a written request

articulating why the prohibited cattle material has to be

used.   And, in the case of medical products intended for use

in humans the written request would need to include a

risk/benefit evaluation.

             [Slide]

             The proposed rule contains a requirement that

applicants and manufacturers establish and maintain records

that demonstrate that any bovine-derived material used is


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consistent with the proposed rule.    These records should be

retained for the same time as other records for the product

type.   In the case of drugs for humans, this is one year

beyond the date of expiry of the drug.

           [Slide]

           When the rule was published we extended the

comment period and we received 45 comments.    In general, the

comments covered the spectrum from the rule is just too

burdensome to the rule is not adequately protective.     So,

some comment areas are noted in the next two slides.

           [Slide]

           There were a lot of comments about the record-

keeping requirement.    For example, requests that

manufacturers not be required to keep records for each lot

of materials, and questions about the requirements for

exempt materials.

           There were comments that the proposed rule was too

burdensome; that it was unnecessary to get slaughterhouse

affirmations and to keep records from the slaughterhouse and

the supplies of all intermediates.

           One company noted that the company that collects

the fetal bovine serum, not the slaughterhouse, should apply


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the affirmation that the serum was collected in an

appropriate manner.

          There were comments asking how long to retain

records and how and where the records should be maintained.

 There were comments asking whether adult bovine serum was

now a prohibited material.    Another comment asked FDA to

require purification procedures for bovine blood products.

          Some comments noted that live cattle-derived

products appear to be prohibited because these animals are

not inspected for slaughter, and requested that we exempt

materials sourced from such live, healthy animals.

          There was a request that the rule be modified to

note that hides used as raw materials should be from animals

that have been inspected and passed.    A request was made

that gelatin be listed as an exempt material.   There was one

comment that the rule should cover materials derived from

other animal species in addition to cattle.

          Responding to the requirement that exempt tallow

contain less than 0.15 percent insoluble impurities, one

comment asked that FDA require written sampling procedures

to ensure that the tested sample of tallow is representative

of the entire batch.


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             [Slide]

             To continue with some of the comments, there were

requests that FDA harmonize with the European Union and

accept the Union’s certificates of suitability.    There was a

request that FDA harmonize with the US Department of

Agriculture’s Animal and Plant Health Inspection Service,

APHIS, with regard to geographic requirements for bovine

sourcing, and a request for harmonization with FDA’s Center

for Food Safety and Applied Nutrition, CFSAN, with regard to

the record-keeping requirements.

             Several comments requested that FDA have different

requirements for bovine-derived materials depending on the

country of origin, and that bovine materials from certain

countries be exempt.

             There were several comments about importations,

for example, a request that FDA extend beyond five days the

time required to provide records that a particular product

is not containing prohibited materials.

             There were requests for clarification of terms,

importer, importer of record, and a request for a definition

of affirm.    There were requests that FDA withdraw or revise

various guidances to be consistent with this rule.    And, one


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comment asked all products manufactured using bovine-derived

materials be labeled to that effect, and one comment

recommended that banned animal parts and materials be

disposed of in a specific manner that was described in the

comment.

           [Slide]

           So, what is the current status of this rule?

Well, the comment period has closed.    The comments have been

reviewed and the responses are being drafted.    As with all

proposed rules, even though the comment period is closed,

there is always an opportunity to comment.    The rule has not

been finalized and the Office of Policy within the FDA has

the lead finalizing this rule.

           DR. HOGAN: Thank you.    So, stay tuned for the

final.   Any questions here?

           DR. PRIOLA: Could you elaborate a bit more on the

exception for fetal bovine serum?    I seem to recall that

there is some record-keeping, significant record-keeping

involved with that because it is a material that is often

used in vaccine development and propagation.    So, even

though it is excluded here if cows were inspected and

passed, there is still a certain level of record-keeping


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that companies have to do, right, to ensure that that

material was sourced from non-BSE?

            DR. FINN: The reason that fetal calf serum is

actually specifically mentioned in the rule is actually sort

of interesting.    The USDA considers fetal calf material to

be prohibited materials.     So, we had to specifically pull

that out.   It turns out that with regard to the record-

keeping on that, there are some comments that specifically

address that, and there are concerns about the record-

keeping for that.

            DR. PRIOLA: But there is some requirement?    Right?

For companies that produce vaccines?

            DR. FINN: There are requirements, yes, and there

are specific tests that have to be done as well on that.

            DR. HOGAN: Any other comments or questions?    Good.

 We are now only ten minutes behind.    That means you are

going to have a ten-minute break because people have to get

out of here to go to the airports.    So, we will reconvene at

3:50 promptly.    Thank you.

            [Brief recess]

            DR. HOGAN: We are going to now start the second

part of the afternoon, again, more informational


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presentations with discussion, but no decision-making or

voting will be involved.    These largely involve issues

around animal models of vCJD and testing paradigms for

antemortem usage.     We begin with Dr. Emmanuel Comoy--I hope

I pronounced that rightB-here, from France, talking about

recent progress in development of a relevant animal model

for vCJD in blood.    Dr. Comoy.

            I will mention briefly that there have been

several individuals that asked what the final wording was

for a question that we had this morning that we changed the

wording on, and it is presented up here on the slide and can

be given to you directly once the meeting is over.    Thank

you.

       G. Recent Progress in Developing a Relevant Animal

                 Model for vCJD Agent in Blood

            DR. COMOY: Thank you very much.

            [Slide]

            First I would like to thank the FDA for welcoming

me and for making this presentation on our experimental

model of primate infection with BSE and vCJD agents.

            [Slide]

            Here you recognize the different data that we


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spoke this morning about that correspond to the different

cases of secondary transmission of vCJD in humans,

presumably from blood transfusion.   In fact, we clearly saw

that there are many shadows that are still present on this

topic, including, in fact, what is the duration of the

incubation period during which the blood can be infectious.

 Secondly, what is the duration of incubation for

recipients, and also we saw that there is a big concern

about the distribution of infectivity between the different

components of blood, including plasma.

          For giving an answer to the different questions we

have all the epidemiological approach but also we need to

have an experimental approach, with the big question of what

is the relevant model for human contamination.

          [Slide]

          In our hands, we have been working with

cynamologous macaque for more than 15 years, and the first

illustration that we had in vCJD was the publication that

was made by Karin Lasmezas in Nature, in 1996, when she

infected primates by the intracerebral route with brain

issued from a BSE-infected cattle at the terminal stage.

          With this primate we saw clinical signs that were


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corresponding to neurological intracerebral signs,

corresponding to TSE disease and, notably, we observed

specific lesions in the brain of the macaque that we

compared to what was observed in first vCJD patients.    We

saw very similar lesions, including the florid plaques and

also the multicentric amyloid plaques that are depositions

of PrP.

          [Slide]

          So, we used this model for going further and

giving some risk assessment about primary and secondary

passages of BSE-related brain prion strains in the primate,

in the cynamologous macaque.

          The first point about the primary macaque passage

was published also by Karin, in 2005 in Lancet, showing

that, in fact, with 5 g of BSE-infected brain, cattle brain,

it is sufficient to contaminate a primate by the oral route.

 With a secondary passage we also showed in 2004 that it is

possible to contaminate primate by the intravenous route by

using primate brain.

          [Slide]

          Now what I will show you is yet unpublished data

that should be published soon.    Here you observe the first


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study that we had about intravenous just to have feasibility

studies.   We took two different amounts of brain materials

issued from a primate infected with BSE and several

dilutions were injected by the intravenous route to

recipient primate.

           We observed dose-response curves with the

different dilutions, and this was published in Lancet.    But

after this publication a fourth animal died, injected with

14 micrograms of brain by the intravenous route after 51

months of incubation.

           When you compare this incubation period to what we

can observe by the intracerebral route, it is to show that,

in fact, the intravenous route seems very efficient compared

to the intracerebral route in this model

           In parallel, since here it is just brain material

that is injected by the intracerebral route, we also made a

real transfusion experiment.   In fact, we had the chance to

get some brain issued from a patient, this is from vCJD, and

we inoculated primate with brain of this patient by the

intracerebral route, but also we injected some brain at the

level of the tonsils, in fact, having the expression of the

infectivity in the peripheral organs.


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          So, these recipient animals developed disease,

classical vCJD in primates, after 37 months.   He died after

37 months of incubation and at the terminal stage of the

disease, at the moment of autopsy of this animal, we sampled

40 mL of blood of these animals and made a transfusion to a

recipient primate, and 40 mL of blood, regarding the weight

of this animal, would correspond to the equivalent of one

500 mL pouch of blood for human.

          So, the recipient animals developed the disease 60

months by inoculation and after six months of illness were

autopsied and you will see what we observed.   With this

primate we made sequential sampling of inguinal lymph node

to have control of the infection.   In fact, for this primate

45 months post inoculation we were able to observe the

position in the inguinal lymph node of this animal a long

time before the expression of the disease.

          So, when you compare first the incubation period

of this animal with the incubation period of the other

animals you observe that we should have a level of

infectivity in blood that would correspond to 2-minus-6 or

2-minus-7 less than in brain, which is consistent with what

is observed in other experimental models, including rodent


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models and sheep models.   The second part is that for this

recipient primate it is possible to detect, in fact,

infectivity at least during the last 25 percent of the

incubation period.

          [Slide]

          We made different ELISAs in this primate,

including immunohistochemistry and biochemical analysis with

ELISA or Western blot, and we observed different types of

staining by immunohistochemistry using different types of

antibodies.    We have particularly staining of follicular

dendritic cells at the level of the follicles in the

lymphoid organs, and this classical position of replication

is detectable both with 3FR antibody or with other

antibodies in place of SAF-32 that is recognizing the N-

terminal part of the protein.

          But we have also other proteins that can be

stained either at the level of the follicle but also as

lipid cells that correspond, in fact, to either *tingible

body macrophages or macrophages that are, in fact, very

weakly stained but recognized with this very peripheral

antibody but, for example, with SAF-32 we are not able to

detect them.   In fact, such different staining has also been


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observed in sheep, for example, and has been published by

Martin G. Free two years ago.

          [Slide]

          So, when we look to this immunohistochemistry we

compare, in fact, primary and secondary animals, so one

animal infected by the oral route and two secondary infected

animals, one that was been injected with brain and the other

with blood.

          The three animals that developed clinical signs

that were indiscernible, they all were positive at the liver

and the brain, and when you looked at the organs that are

classically used for analysis, including either tonsils or

at the level of the appendix, you see that the tonsils were

positive for the three animals but, in fact, the appendix,

the germinal center at the level of the ileum was only

positive after oral contamination.   We were not able to

detect in the intravenous recipient.   Conversely, we would

have positivity at the level of the enteric plexus.

          Also, all the other lymphoid organs were positive

at the level of the spleen.    All the germinal centers of the

three animals were positive.    But at the level of the lymph

nodes, it seems that we have a higher number of lymph nodes


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that were positive for intravenously inoculated animals

compared to the oral route contamination.

          In the same way, there were more germinal centers

positive by the intravenous route than by the oral route,

and also we observed a high number of isolated cells

positive after the intravenous route, meaning that after an

intravenous inoculation it seems like you have more diffuse

spread of the infectivity compared to the oral route, where

you have just one point of entry and then sort of a specific

track that is followed.

          [Slide]

          So, after this proof of concept, we tried to mimic

more precisely what can happen in the human situation,

meaning that the primary contamination occurs through the

oral route.

          So, with this first primate that I told you

previously that was infected with five rounds of BSE, he

developed the disease after 63 months of incubation and here

you still found what I showed you in the previous slide.

          With this animal that died at 63 months post

inoculation, we sampled 20 mL of its blood at the mid period

of incubation.   That means at 30 months post inoculation.


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We transfused these 20 mL of blood to a recipient primate.

This recipient primate is for the moment still alive 100

months post inoculation.   It means that we are close to nine

years post inoculation, meaning clearly that if we compare

it to the different curve, if it has been infected, the

level of initial infectivity to which it has been submitted

is very low compared to the previous primate.

          Conversely, what is important is that the

screening of the inguinal lymph node showed, at 60 months

post inoculation, 3FR staining in two different samples that

have been made on two different dates, while at 51 months

post inoculation it was negative, meaning clearly that at

the mid period of incubation a primary infected donor has

infectivity in his blood, infectivity that can be

transmitted and this 20 mL of blood is enough to transmit.

          [Slide]

          In fact, when we made contamination by the oral

route, we inoculated two primates on this date, one who

developed disease at 63 months post inoculation but the

second one, in fact, did not develop at all the disease

until 117 months.   In fact, at this date, that means close

to the double of inoculation, ten years post inoculation


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this primate began to show some strange signs of mutilation,

of self-mutilation, and we were obliged for ethical reasons

to stop the study.

          For this animal, when we tested the brain we did

not find any accumulation of PrPs in brain with any

technique we used, and we did not observe positivity in the

ileum but we observed positivity in some lymph nodes and,

notably, here in the mesenteric lymph node you can observe

some isolated cells that are stained by 3FR while the

follicle are not stained at all.

          For all the lymph nodes and spleen of these

animals, no follicle was stained, while we always observed

the isolated cells that show this staining for this animal.

 In fact, when you look to the different biopsies that were

made on this animal, they were negative 83 and 99 months

post inoculation but positive 103 months post inoculation,

meaning clearly that after the same route of contamination

it seems that we can have sort of a silent carrier that

develops an unusual distribution of pathological PrP that is

not proliferating in the lymph nodes.

          [Slide]

          In fact, it was on these two primates that we


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based a publication in Lancet, 2005, showing that with 5 g

half of the animals developed the disease, and we compared

it to what happens with cattle.

          From this study we showed that, in fact, the

species barrier between primates and cattle was something

between 10 and 20 and we show here with cattle that, in

fact, the DL50 is between 100 mg and 1 g with animals that

are still developing disease once they are exposed to 1-10

mg by the oral route, meaning clearly that in cattle, after

oral exposure, in fact, the curve is very, very flat

compared to what we used with the experimental model.

          [Slide]

          We participated in the European Project that

finished last year.   In this project, with different other

groups, we made a titration of a pool of 11 BSE-infected

cattle brains, a sample at the terminal stage.   I am sorry,

it is not very visible with the colors, but, in fact, you

see the different serial doses of this brain were given by

the oral route to different primates.

          In fact, with this dose of 5 g that I showed

previously, in fact, three animals among six developed the

disease, while two animals died from unrelated reasons.    But


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among these two animals one showed positivity in lymphoid

organs while the other did not.

             With a lower dose you can see that at 50 mg one

animal developed the disease, while at 500 mg there was one

animal that died of unrelated reasons that also showed

positivity, and one animal that is still alive that has an

inguinal lymph node that is positive.

             [Slide]

             So, from this table I will just have as

conclusions that there is very important inter-individual

variability in the primate because we are clearly seeing

this variability can also be observed in human and also we

can see that, in fact, with the infectious dose for a

primate is lower than 5 g, meaning clearly that cattle to

primate species barrier is, in fact, very, very weak.

             From this point, we can wonder about the situation

in the UK.    How can you say that we have 200,000 diagnosed

cases of BSE cattle that have been diagnosed, and it is

supposed that we should have perhaps two million total cases

that would not have been diagnosed in terms of the human

food chain and there are only 166 diagnosed cases if, in

fact, the species barrier is so low, is so weak?


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          Perhaps this has to be answered and perhaps one

element of information can be brought by this old document

issued by the European Committee where, in fact, they plot

the exposure risk depending on the industrial process and

the size of the different industrial batches, meaning

clearly, in fact, that here you have the infectious dose

exposed to people and here are the number of people that are

exposed, and you see clearly, in fact, that either you have

a very low number of people that are exposed to very high

risk or, contrarily, a high number of people that are

exposed, in fact, to very, very low risk with the two doses

*pf 500 mg and 5 g.

          [Slide]

          So, coming back to our intravenous experiments,

with these particular animals, so with this unusual

distribution, we also did blood sampling of these animals

also at 30 months post inoculation, like for this one, but

here it is not half of incubation but it is the first

quarter of the incubation, and here we did not make a

classical transfusion.   We separated plasma and buffy coat

and we inoculated by the intracerebral route this plasma and

buffy coat.


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          In fact, we injected either 500 microliters of

plasma or we injected buffy coat that corresponds to 20 mL

of total blood.    So, the recipient animals are for the

moment still alive 100 months post inoculation.    They don’t

show any clinical signs, but for these animals we made

sterile pyritic biopsies of the inguinal lymph node.

          For the animals that were injected with buffy coat

by the intracerebral route, the three biopsies did not show

any staining with 3FR antibodies, but the animals inoculated

with plasma, while 50 months post inoculation biopsies were

negative, it was found positive two-fold at 18 months post

inoculation, so 66 and 84 months post inoculation.

          So, we also did similar studies with this donor,

but here the blood was sampled at 4.5 years after

inoculation.   It means, in fact, it corresponds to six

months before the onset of clinical signs in the donor.

When we made the same thing as here, it means separating

plasma and buffy coat and inoculated by the intracerebral

route, the two recipients are still alive 33 months post

inoculation.   They were both found negative at the level of

the biopsies 54 months post inoculation, but it is very,

very fresh data.


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          Two months ago, when we biopsied this animal the

buffy coat was still negative, while the biopsy with the

plasma-inoculated animal showed 3FR staining.    So, this is

very preliminary data that needs to be confirmed, but it

goes in the same way, in the same sense as what we have

here.

          [Slide]

          So, as conclusion I would say that the infectivity

in the blood of the non-human primate is not yet at the

clinical phase but can already be present at least in the

mid period of incubation.   In fact, we can have infectivity

during incubation that is lower at the terminal stage but 20

mL could be enough to contaminate.

          These secondarily transmitted animals would

present wider distribution of pathological PrP in the lymph

nodes compared to the primarily infected animals, and mostly

what I would keep from this study is that we observed

asymptomatic carriers with a long incubation period that

present a very unusual distribution of pathological PrP in

lymphoid organs located at the level of individual cells.

          [Slide]

          So, we are now developing models.     We inoculate


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with very high amounts of brain by the intravenous route and

we are able to observe staining of the lymph nodes earlier

than six months post inoculation, and by regularly sampling

these animals we now have blood collection from the

different primates that are available for study, for

example, of different antemortem diagnostic tests that would

be available, and we would like to test the efficiency on

such samples.

            [Slide]

            Last, I would like to thank the different persons

that participated in this study that was partly supported by

the European Commission and, notably, all the primates that

gave samples.    Thank you very much.

            DR. HOGAN: Well, thank you.   That is clearly an

awful lot of data and an awful lot of work but it covers

some very important points.    Any comment?   Questions from

anyone?    We will allow you to ask a question from the

audience.    Please identify yourself.

            DR. CERVENAKOVA.   I am Larisa Cervenakova, from

the American Red Cross, and I would like to ask the

following question which is pertinent to the human situation

I think.


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            When you show the differences in susceptibility of

monkeys to oral inoculation with BSE, did you sequence all

of them to see if there are some polymer [?] in their PrP

gene to show that there is some genetic factor determines

your results?

            DR. COMOY: So, we did not completely sequence all

the primates.   What we know is that they are all methionine-

methionine for the 129 codon, but they were not all

sequenced and we have to have some more information on those

data.

            DR. HOGAN: Good question.   Anyone else?   Any

comments?   Questions?    Well, thank you, sir, especially

coming all this way.     Our next speaker will be Luisa

Gregori.    Dr. Gregori is going to talk about recent progress

in developing antemortem tests for TSEs, prospects for

blood-based and urine-based tests.

            While she is getting her slides up, there have

been

            *** ALICE

of SRMs that were obtained in Mr. Pritchett’s talk, I

believe, and there have been several studies now that have

shown that infectivity is retained in composted or soil


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contained experiments for years later.     So, I think it is

important for the FDA, in terms of their surveillance and

enforcement, to look at what happens to those landfills over

an extended period of time, that the composting doesn’t get

made into fertilizer and put in people’s yards, etc.     We can

provide some of that data if it is necessary.     I am sorry

for putting that in but I was asked to and I believe it is

necessary.    Dr. Gregori, thank you.

H. Recent Progress in Developing Antemortem Tests for TSEs:

      Prospects for Blood-Based and Urine-Based Tests

             DR. GREGORI: Thank you.

             [Slide]

             Good afternoon.   In this presentation I will give

a very quick update on the antemortem tests for TSE.     This

update is since the last TSE advisory meeting in 2006.

             [Slide]

             Actually, I will skip pretty much the introduction

since everybody has already heard what I was going to say.

I will speak about prevalence and transmissibility; the

assay challenges and requirements.      I will have an update on

the developments and I will touch on urine as potential

substrate for the test, and finally I will wrap up with


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conclusions.

           [Slide]

           We already heard many times that we know that

there have been four transfusion transmitted vCJD or from

not leukoreduced red blood cells, and one probable

transmission from plasma derivative.

           In terms of risk management, the FDA has

recommended over several years already deferral of high risk

donors.   However, we think that an alternative approach to

further protect the public from potential risk of

transfusion could be desirable.   Those methods could be

infectivity removal, this is a new approach, or assay

screening, which is what I am going to talk about.

           [Slide]

           We also heard a lot about prevalence.    The Hilton

study suggests a prevalence that is much higher than the

cases that are already known, the clinical cases.     There are

possible explanations for this apparent inconsistency.

           It is possible these individuals that have

positive appendices are preclinical infections and in due

time they will develop vCJD.   That means there will be more

vCJD cases in the future.   It is also possible that


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individuals are subclinical carriers.   They have positive

lymphoid tissue but they will not develop vCJD, and the

question would be whether these individuals have infectivity

in blood.   Of course, at this point we have to consider the

possibility that those were false positive appendix tests.

            The Health Protection Agency in the UK has started

a study, the National Animal Tonsil Archive study, in which

they will test 100,000 tonsil donations.     At this point they

have tested 63,000.   They just reported the results of this

study.   They found no reactive.

            However, the NATA study has been questioned, the

design of the study has been questioned from the start.

Mostly, the issue was about tissue chosen; the assay that

was selected; and also the age of the donors.

            The Health Protection Agency is also scheduled to

start a new study, a large-scale survey of appendices this

year.

            [Slide]

            Bob Will has described the TMER program.   It is

clear from this program that the transmissibility of vCJD

blood is very high.   The question remains whether the

sporadic vCJD is also transmissible by blood.


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          Epidemiological evidence and other survey studies

have indicated that this risk, if it is there, is very, very

low, and the American Red Cross has just published results

from their study, a look-back study in which they were able

to identify 436 recipients of blood of donors who developed

CJD, sporadic CJD.   They found 144 of these recipients

survived five years post transfusion.   They found no

clinical cases or sporadic CJD, but also the individuals

were tested for PrP-TSE deposits in the brain.

          So, from this data we can say that sporadic CJD

has a lower transmissibility rate than vCJD.   That is clear.

 But I think low rates of sporadic CJD cannot be excluded at

this time, mostly because the number of patients is very

small, and also because the patient must be followed for a

longer period of time.   So, I think we have to wait for this

study to be continued, and also we have to come perhaps to

the point that we will never know if sporadic CJD is

transmissible if the rate is too low to be detected.

          [Slide]

          There are many challenges to the assay.

          [Slide]

          The first challenge is the target protein, the


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abnormal protein PrP-TSE.    What you see here is a schematic

cartoon of the normal PrP and the PrP-TSE, the abnormal form

which is associated with the disease.    The two proteins are

identical.    The only difference that we know at this point

is that the confirmation of the two proteins is different so

the assay has to be able to detect this form, the form

associated with the disease, not the normal PrP.

             So, PrP-TSE is not really the ideal target protein

but, unfortunately, we don’t have another one.    This is the

only marker for TSE infection and actually you will hear

from Pedro Piccardo after me that there are cases in which

this correlation of PrP-TSE and infection does not occur.

We don’t really know what is happening in blood, if blood is

one of those cases.

             [Slide]

             The other challenge to the assay is the choice of

the test material.     All tests so far under development use

plasma but plasma is a very complex protein mixture and

plasma protein concentrations span over 10 logs of

magnitude, from the high abundant protein to the very least

abundant.    And, if we place normal PrP in plasma-Bhere it is

10 ng/mL, some authors have a higher concentration, around


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100 ng/mL.    In the hamster model the concentration that we

measured is about 3 ng/mL.

             The concentration of PrP-TSE in plasmaB-I have to

say first that PrP-TSE has never been detected in plasma so

we don’t really know what the concentration is.    I have here

the concentration of 30 fg/mL.    This derives from studies

that were done in our laboratory when I was in Baltimore at

the VA Medical Center.    What we used in that case is the

hamster model infected with the 263K strain of scrapie.      So,

this number, this 30 fg/mL, is based on the titer of the

hamster plasma, hamster infectivity in blood which is about

10 infection dose per mL, and the specific infectivity of

PrP-TSE in brain.

             So, at least in the hamster model there are 5 logs

of difference in the concentration of these 2 proteins.      So,

in addition to a very high analytical sensitivity of the

assay, because the assay detected an extremely low

concentration of the analyte of PrP-TSE, the assay has to be

also extremely specific because it has to be able to

distinguish between these two proteins and the protein PrP-

TSE is present in huge excess.

             [Slide]


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             The other basic requirements for the assay are

that it has to be able to detect individual donations.       It

has to be suitable for rapid mass screening tests; and, as I

mentioned, the sensitivity has to be very high so that it

has a low false negative; and the specificity also has to be

very high.    That means that it is capable of discriminating

genuine PrP-TSE from PrP-C, which will lead to low false

positives.

             [Slide]

             Just to illustrate the issues about sensitivity

and specificity, I have here an example that I modified from

a recent publication by Bennett and Dobra.    In the United

States there are 50 million donations a year.    If we assume

a prevalence of about 1-10,000 and assay sensitivity of 70

percent, we will have 450 blood donations that are false

negative.    Those are not picked up by the assay.

             If the assay is 99.5 percent specific there would

be 75,000 false positives, and that is definitely not

something that we can accept.    That is not an assay that can

be used.

             [Slide]

             Even if the assay specificity goes up to 99.9


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percent, there are still 15,000 false positives.    This could

be acceptable if we had an alternative test, a secondary

test, a confirmatory test, but without that, this makes the

assay highly difficult.    Decreasing the prevalence to 1-

100,000 makes no difference in the number of false

positives.

             [Slide]

             So, for a disease like vCJD for which there is no

treatment and it is a fatal disease, to have such a high

false positive generates a problem, a logistical problem and

a practical problem and also an ethical problem.

             [Slide]

             In the TSEAC meeting in September, 2006 several

companies presented their tests that were under development.

 The FDA has also outlined a path for the companies for

assay development and validation.    Of course, the assay will

first go through analytical studies, and then spike studies

using tissues suspensions.    This was left to the companies

at the time to decide how they want to do it.    But then the

panel has suggested that the assay will be challenged with

blind panels of human plasma spiked with diluted vCJD brain

and spleen suspensions.    Those panels are prepared now and


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available to be tested.

            Eventually, the assay will have to detect

endogenously infected blood.   At that time, the idea was to

use different animal models, like sheep or rodents, and also

different type of strains of TSE.

            At the time also the FDA had recognized the

possibility that some tests that are developed for human use

cannot be applied to animal models.   So, at the time we

suggested or we encouraged to have a panel of blood from

non-human primates.   As far as I know, this has not been

done yet.

            Also, validation was going to be done with well-

characterized blood reference material.      The blood was

supposed to have been tested by the bioassay to confirm that

it was positive, that it was infected.    Finally, the company

will be allowed to use human blood.

            [Slide]

            At that time seven companies presented.    Actually,

there are three more companies that joined the group later

on but they did not present at the advisory meeting at that

time.   I have divided the type of assays in three big

groups, those that use the epitope protection, that is to


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use the epitope differently exposed in PrP-C and PrP-TSE to

distinguish and discriminate between the two molecules.

Those are the companies that use this type of approach.

          [Slide]

          I am not going to go over each company because it

would take too long.

          [Slide]

          For the other type of assay the companies had

specific ligands.    Some of these ligands were specific for

PrP-TSE and others required the digestion or somehow the

elimination of PrP-C from the assay.

          [Slide]

          The third type of assay was with signal

amplification.   The signal was PrP-TSE amplified either

directly with sonication or indirectly via conformationally

sensitive peptide.   Those are the two companies that had

this type of test.

          [Slide]

          In 2009 more than half of those companies have

stopped their work on TSE assay development.   The companies

that are still interested in developing this test are

represented here in this table.    The information that I am


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giving you now is all available on the company’s website or

from publications or meetings so they are all in the public

domain.   All four companies are still doing tests, their

research-based tests.

           Amorfix has recently tested 10,000 donations from

French donors.   They have six repeat reactive.    So, with the

assumption that those six individuals were false positives,

the specificity of the test would be 99.94 percent.      Of

course, we don’t really know if they are false positives so

what we can say is that, at worst, the Amorfix test has a

specificity of 99.94.   It could be higher than that.

           Prionics is still using their antibody specific

for PrP-TSE-15B3, and this is what is mentioned in their

company website.

           Alicon, Allprion, is using the ligand to

concentrate PrP-TSE from biological matrices.     They

indicated they are able to detect the PrP-TSE from plasma,

urine and milk, although I have not seen the data.       The data

are not on the website.

           Microsens indicated that they are studying in

collaboration with Ames Laboratory in Iowa to incorporate

capillary electrophoresis into their technology.


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          So, FDA still encourages companies to develop a

test but, as you can see, the number of companies has been

reduced a lot since three years ago.

          [Slide]

          As I mentioned earlier, urine could be perhaps an

alternative test material.    Infectivity was demonstrated in

urine of rodents with scrapie and deer infected with Chronic

Wasting Disease.    There has been no demonstration of

infectivity in human urine, although the studies are ongoing

in other laboratories.

          We have shown that infectivity is present in urine

with titers as close to that in plasma, at least using the

hamster model infected with scrapie.    That means that

perhaps the concentration of PrP-TSE in urine is closer than

in plasma but, of course, there is more than 1,000-fold less

protein concentration in urine compared to plasma so that

makes urine perhaps a better or more suitable test material.

          For logistical reasons, maybe in the beginning

maybe this test could be developed as a diagnostic rather

than a screening test, and that would provide some

information about the suitability of urine.

          [Slide]


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            Finally, the conclusion is all tests so far under

development are based on plasma as the test material and

PrP-TSE as the target.    So far there has been no proof of

concept that PrP-TSE is present in plasma, and also none of

the tests so far have detected human infected blood.

            There are still many unresolved issues that I

talked about.    Most important are the lack of reference

materials and lack of a confirmatory assay which is really

necessary because of the high level of false positives that

are inevitable for a disease like vCJD which has a very,

very low prevalence.

            [Slide]

            I would like to acknowledge all the people that

worked with me to prepare this presentation, and in

particular I would like to acknowledge Bob Rohwer, where the

work with hamster plasma, infectivity in plasma and in urine

was done.    Thank you.

            DR. HOGAN: Thank you, Dr. Gregori for a very nice

summary.    Does anyone have any comments or questions?   Miss

Hamilton?

            MS. HAMILTON: What is the likelihood, or when

could this be generally available?    Say, if a physician or a


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patient might exhibit some of the symptoms, would he be able

to have that patient tested at this time, or when do you see

it in the future?

          DR. GREGORI: There is really no test for pre-

mortem at this time.    There are some tests that will rule

out perhaps other diseases and there are tests, like the 14-

3-3 protein, but there is really no test for pre-mortem for

humans or animals.   I don’t know.   I mean, obviously, in

2006 we were more optimistic about the tests but now we see

that there are serious challenges to developing the test.

          DR. HOGAN: Dr. Geschwind, you had a comment?

          DR. GESCHWIND: Yes, I just had a comment about the

percent sensitivity of the tests and what is really

reasonable.   I think you had a cutoff of 99.-something

percent and you still had 15,000 false positives out of a

very large sampling of blood.    I know when the CDI was

trying to be approved through the NIH, they had a cutoff of

97 percent.   I don’t even know of a test that is out there

in medicine where you have the levels that you are asking

for, 99.9-something.    So, I think we have to have some

degree of reasonability, you know, what is reasonable.

          DR. GREGORI: Yes, I agree, 99.9 percent is very,


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very high for a test.   I don’t really have a solution to it.

 I think what we need is to have a confirmatory test.    I

don’t see how we can go around that, some other way to

assess whether blood is, in fact, positive or not.

          DR. GESCHWIND: It is sort of a circular argument.

 You are asking for a confirmatory test.   You know, even if

you do have a test that is 99.9, let’s say you have two

tests that are 99.9, is that a confirmatory test?    If you

have two tests?

          DR. GREGORI: Yes, I think so.

          DR. GESCHWIND: What numbers do you need?    What is

reasonable?

          DR. GREGORI: That would be fine.

          DR. HOGAN: I think Dr. Epstein has a comment

relative to this.

          DR. EPSTEIN: We deal with this problem routinely

with laboratory-based donor screening.    We need tests with

very high specificity for the system to work.   That has been

achieved for the viral markers.   We routinely have tests

99.9 percent specific, some even better.   And, even at that

level we have an obligate need for additional, we call it

supplemental testing to separate the true positives from the


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true negatives.

             That can be a daunting challenge.   The secondary

test, as it were, always has to have as good a sensitivity

as the primary screen, otherwise you can’t use it.        Its

specificity can actually be a little bit lower because you

are testing a culled out population, and the positive

predictive value is higher because the prevalence in the

selected screened positive cohort is much, much higher than

in the untested population.

             But the technology challenge here requires some

different format because otherwise it is redundant

information, and essentially what you are looking for is two

tests that have non-overlapping sources of false positivity

and then you are able to have a useful discrimination.

             So, I quite agree with you that this is a daunting

challenge.    It has been achieved for the majority of viruses

for which we screen, and I think it is an unsolved problem

for prion testing.

             DR. HOGAN: Thanks for the clarification.     Anyone

else?   Thank you very much, Dr. Gregori.     Last, but

certainly not least, is Dr. Pedro Piccardo, from the FDA,

who is going to talk to us about correlations between


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abnormal forms of prion proteins and TSE infectivity,

implications for test development.

   Correlations Between Abnormal Forms of Prion Proteins

   and TSE Infectivity: Implications for Test Development

           [Slide]

           DR. PICCARDO: It has been postulated that

unprecedented infectious pathogens cause TSEs, and that

these pathogens are composed of the prion protein.     So, the

purpose of this talk is to review the correlation between

the abnormal prion protein PrP-TSE and infectivity in

selected animal models, and also what would be the

implication of the development of these tests.

           [Slide]

           The prion hypothesis, as has been said earlier and

we all know, predicts that abnormal PrP is the infectious

agent.   Therefore, the presence of this abnormal protein

implies the presence of infectivity.    And, the development

of a diagnostic test is based on assays to detect this

abnormal protein.    So, in short, the diagnosis of TSEs

relies on the detection of PrP-TSE.

           [Slide]

           For example, we have the 263K scrapie model which


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has been talked about already.    In this model there is a

very strong correlation between the accumulation of the

abnormal protein and infectivity.    That has also been

demonstrated in other models.

          However, abnormal PrP derived from atypical

scrapie cases display lower resistance to proteinase K which

is one of the key physicochemical properties to define

abnormal PrP, although not the only one.

          In these atypical cases the resistance to

proteinase K is less than the resistance to proteinase K in

typical cases.    And, these scrapie cases display an

inconsistent reaction pattern that currently use rapid

tests.

          Laura Manuelidis, who is a member of this

committee, described 25 nm virus-like particles that claim

to be the likely cause of TSEs.    In addition, disease has

been transmitted from infected animals lacking detectable

abnormal PrP.    In these animal tissues contain little or no

PrP-TSE can be infectious and harbor high titers of

infectivity.    There have been several of those reports

throughout the years.

          [Slide]


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           In short, the association between the abnormal

protein and the transmission of disease is not yet fully

understood.

           [Slide]

           This is a schematic representation of abnormal

protein.   In short, what you have are two parts.   This part,

which is highly flexible, which is the N-terminal region of

the protein and has an octarepeat repeat region and a

globular, a C-terminal half, and in this area there are

sugars attached to the prion protein, actually two sites,

two consensus sites for sugar attachments.

           A number of familial TSEs have been associated

with the presence of point-point mutations in the globular

region of the molecule, and also familial TSEs have been

associated with insertional mutations in the octarepeat

region of a molecule.

           [Slide]

           Years ago, in collaboration with David Harris and

Roberto Chiesa in Washington University, St. Louis, we

characterized what we thought would be a transgenic model

for familial TSEs with insertional mutation.   Therefore,

what happened is that this transgenic model expressed PrP


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with extra repeats.   We called it PG14 because that is the

number of extra repeats for a total of 14.

          What we observed is that these animals developed

clinical signs of disease, as you can see here.   Therefore,

they had a neurological disease characterized by ataxia.

When we did the neuropathologic analysis of these transgenic

mice-Bthese are the controls and this is the cerebellumB-we

observed that in these animals that expressed PG14 with

extra repeats there was significant atrophy of the

cerebellum and there was significant accumulation of PrP by

immunohistochemistry in this area.   Also, we saw that

abnormal PrP was present in other areas of the brain, for

example, the hippocampus.

          Biochemical analysis showed that these animals not

only accumulate abnormal PrP as revealed in pathology, but

also are weakly resistant to proteinase K digestion.

Therefore, in short, what we were able to find was that this

model produced a phenotype that mimics TSE.

          Therefore, the question was if there was

infectivity associated with this neurological disease and we

tried to transmit the disease to well typed mice, or to

transgenic mice that express normal PrP, or to transgenic


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mice that express abnormal PrP with extra repeats, we saw

that after almost 600 days none of the animals that were

inoculated with brain tissue from these animals developed

the disease.

             In short, this is an informative phenotype.   There

is neurological disease and accumulation of abnormal PrP.

However, we did not see spongiform degeneration in these

animals and we did not see the transmission of the disease

and clinical disease.

             Therefore, we concluded that there appears to be a

discrepancy between the infectious particles and the

neurotoxic properties of abnormal PrP because what we

observed was that the atrophy of the cerebellum in these

animals was due to apoptosis.

             [Slide]

             Now, this leads into another set of studies, and

what we observed was that in human TSEs the phenotypes could

be very heterogeneous.    This is an example of that.   This

represents two cases, human cases.    We call it patient 1 and

patient 2.    Both patients have a familial form of TSE-GSS

associated with mutation 102.

             In patient 1, as you can see here with hematoxylin


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and eosin, there was significant spongiform degeneration,

and there was a significant amount of abnormal PrP in the

brain of this patient.   By Western blotting we observed that

he had proteinase K resistant PrP with a non-glycosylated

isoform of 21-KV.   Therefore, the phenotype in this patient

was very much like the one we see in Creutzfeldt-Jakob

disease.

           In patient 2 this was dramatically different

because this patient, although he had the same mutation, had

no spongiform degeneration in the brain, as shown with

hematoxylin and eosin, frontal cortex, but we observed a lot

of abnormal PrP by immunohistochemistry, and we observed,

using thioflavin-S, that a lot of that accumulation

corresponded to amyloid.

           Interestingly enough, when we did biochemical

analysis of prion protein in the brain of this patient we

observed that prion following proteinase K digestion we

observe a low molecular weight fragment of approximately 8

daltons.

           So, the question that we posed was, okay, here we

have two patients, two very different phenotypes.   Both

patients, again, have the same mutation, the same genotype,


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and both accumulate a significant amount of abnormal PrP.

Is there infectivity associated with both?

          [Slide]

          So, what we did was, in collaboration with Jean

Manson and that group in the UK, in Scotland, we performed

transmission studies in a transgenic model that expressed

the same mutation of the patients under study.

          This summarizes what I showed you already, the

biochemistry of patient 1, 21-KV proteinase-K resistant PrP

and significant accumulation in the frontal cortex.    When we

inoculated these transgenic mice, after 290 days

approximately all the animals came down with spongiform.

Interestingly enough, in some these cases there was a lot of

spongiosis, however very little amount of accumulation of

abnormal PrP in the brain of some of these animals.    In

others we could see more.

          Then we performed a second passage from mouse to

mouse and we observed once again that in these animals, now

with a shorter incubation period, as expected, there was a

lot of spongiform degeneration and significant amount of

accumulation of abnormal PrP by immunohistochemistry.

          Therefore, in conclusion, what we observed


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following the transmission studies of patient 1 was that

there was a very efficient transmission of spongiform

encephalopathy into these transgenic mice.

            [Slide]

            Now, what happened when we tried to transmit the

disease from patient 2?   This is a summary of what we

observed in patient 2.    No spongiform degeneration and this

proteinase-K resistant low molecular weight fragment in this

patient.

            So, we again inoculated purified PrP from this

patient into transgenic mice that express, once again, the

same mutation, the knock-in model developed in the UK, in

Scotland.   What we observed is that these animals did not

come down with clinical disease.   This experiment took over

800 days, and what we observe is that when we analyzed the

brain of these mice, using hematoxylin and eosin, we did not

observe spongiform degeneration.   However, when we did

immunohistochemistry we observed a significant amount of

amyloid plaques in the area of the corpus callosum in over

50 percent of these animals, and this was very evident.

            In addition, then we said, well, what are the

physicochemical properties of this abnormal PrP that we see


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here in a significant number of mice inoculated with

material from this patient?   This is Western blotting again.

 Using proteinase-K, we observed a small amount but a clear

amount of proteinase-K resistant PrP in the brain of some of

these animals.

          Then, following completion of this experiment, we

performed sub-passage.   The reason for this is that the very

interesting work done by Bruce Ghetti and collaborators

showed that sometimes on the first passage the animals do

not develop disease but following subsequent passaging the

agent gets adapted to the animal model and then they start

having disease.

          So, following that train of thought, we performed

sub-passage once again into transgenic mice.   We let these

animals go all their life span, 740 days, and none of these

animals developed clinical disease.

          Once again we looked, using hematoxylin and eosin,

for spongiform degeneration and we did not see spongiform

degeneration in the brain of any of these animals.   Once

again we observed a significant amount of PLP amyloid in the

brain of 70 percent of these animals.   Once again, the

amyloid plaques were in the area of the corpus callosum.


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This is the hippocampus.   This is the area where the corpus

callosum is and here is where the cortex is.

          So, we thought that this was very interesting.

Therefore, we performed a third passage, once again hoping

that in subsequent passaging the animals will develop

spongiform encephalopathy.   Although this work is still in

progress, I just came down two weeks ago from the UK and I

started analyzing passage three, and what we observed, first

of all, we know for sure that none of these animals

developed clinical disease, and we let them go through all

their life span, and already in the animals that I analyzed

it was possible to see once again the presence of PrP

accumulation in the corpus callosum of these animals.

          [Slide]

          So, summarizing what I just showed you, these

animals accumulate significant amounts of amyloid plaques

with abnormal PrP.   This happens to be amyloid that is shown

with thioflavin.    Therefore, what we conclude from these

experiments was the observation of the presence of PrP

amyloid in the absence of clinical disease or spongiform

degeneration.

          [Slide]


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          So, the conclusion of the studies following

passaging of material from patient 2, the patient with no

spongiform degeneration, is that there could be several

interpretations and I will try to go slowly through these.

          One interpretation could be that the low molecular

weight band is present in patient 2, that there are low

levels of infectivity in this material.    However, the

transgenic mouse model that we use is highly susceptible to

a number of TSE agents.   Therefore, we think that that

probably is unlikely.

          The second possibility is that the mice inoculated

with PrP are asymptomatic carriers.   As I showed you, we are

on passage three and still the animals do not develop

disease or spongiform degeneration.   So, we tend to think

that that seems to be unlikely.

          Another interpretation would be that the agent

associated with PrP-8 is an amyloidogenic strain.    However,

the amyloid plaques that I showed you in the animals do not

mimic the phenotype of the patient because patient 2 with

GSS had accumulation of normal PrP and amyloid plaques in

all areas of the brain, including the cerebellum, while the

amyloid plaques present in the transgenic model are only


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associated with the corpus callosum.

          Another possibility is that the PrP-8 present in

this patient is unstable, therefore is cleared and therefore

does not allow enough time to develop disease.   We tend to

think that that seems to be unlikely because it is stable

enough to elicit the production of significant amounts of

accumulation of PrP in the form of plaques.

          Another interpretation is that in the end the

amyloid plaques produced in these animals represent a

protective mechanism.   And, the other interpretation is that

PrP amyloid is not infectious.

          So, what we conclude from these experiments is

that so far we could see a good correlation between

spongiform degeneration and clinical disease and

infectivity.    However, in this model we did not see so far a

correlation between transmission of disease and accumulation

of abnormal PrP.

          [Slide]

          Now we will move to a third model that we are

working with.   This is, again, work in collaboration with

Gene Manson, in Scotland.   What this model represents is

that we are studying the effect of host PrP glycosylation in


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the pathogenesis of this disease.

             The model is a transgenic model, once again knock-

in, in which these animals produce PrP without sugars.     So,

what happened is that when we inoculated these mice that

produce PrP without sugars, that we call G3, with AMY

serine, which is a mouse-adapted scrapie strain, very well-

characterized, we let these animals go all their life span,

over 700 days, these animals do not develop clinical

disease, do not develop spongiform encephalopathy.    However,

once again, they accumulate the amyloid plaques in different

parts of the brain.

             The plaques are localized in restricted areas of

the brain.    Once again, this happens to be the corpus

callosum area, like this, and this happens to be the

subventricular area, this would be the septum.

             One question was that, well, maybe these animals

are just not susceptible to disease.    That is not true

because when we inoculated the same line of mice with 79A,

which is another mouse adapted scrapie agent, we saw that

the animals came down with disease and accumulated diffuse

abnormal PrP in several parts of the brain.

             Therefore, these animals are susceptible to


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disease, however, in this particular model they accumulate

these large amyloid plaques in the absence of clinical

disease and spongiform degeneration.

          [Slide]

          To conclude, the detection of Pro-TSE, at least in

the mouse that I showed you, may not be a reliable marker of

infectivity.

          [Slide]

          I want to acknowledge long-standing collaboration

with Dr. Ghetti at Indiana University where all the work

using human tissue was done, and the long-standing

collaboration with David Harris and Roberto Chiesa at

Washington University, in St. Louis, and Gene Manson, Rhona

Barron and Enrica Cancellotti and the group at the

University of Edinburgh in the UK.

          [Slide]

          These are the references, and thank you.

          DR. HOGAN: Thank you very much, Pedro.     That is

fascinating work.   I have two questions.   First of all, how

old were the transgenic mice when they were inoculated?    I

am sure they are all the same but how old were they?

          DR. PICCARDO: Yes, after weaning they were


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inoculated.

           DR. HOGAN: Relatively young.

           DR. PICCARDO: Yes, young.

           DR. HOGAN: Secondly, the cerebellar atrophy that

you saw in some of these mice, are you sure it was an

atrophy, or was it a dystrophy?   That is, did they just

never develop or did they actually develop and they atrophy?

           DR. PICCARDO: We know it is atrophy.    I mean, one

of the questions was whey there was atrophy.    So, we went

out of the way to look for the cause of atrophy.    The first

observation was a very simple analysis using hematoxylin and

eosin, just that, in which we saw pyknotic nuclei in the

granular cell of a layer of the cerebellum.    So, immediately

it came to our mind that that was apoptosis.

           As you know, apoptosis is a physiological event in

mammals.   I mean, we produce many more neurons than we need

but we get rid of most of them at the very beginning of our

lives.   In mice the physiological apoptosis occurs probably

during the first 20 or 30 days of life.     These animals have

apoptosis throughout and we could see a significant amount

of apoptosis at day 120, 200, 300, etc.

           Then we also looked for caspases, activation of


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caspases, which is the cascade that leads to apoptosis, DNA

laddering.    We did extensive work which I didn’t show at all

here.   So, definitely these animals have cerebellar atrophy.

             DR. HOGAN: You have convinced me.

             DR. PICCARDO: Let me clarify one thing, only in

the animals with PG14, the ones that produce extra long PrP,

not in the more developed gene in Edinburgh.

             DR. HOGAN: I understand.    Thank you.   Other

comments, questions?    Dr. Geschwind:

             DR. GESCHWIND: Agnani and others have shown,

particularly with the recombinant PrP, that the smaller

particles are the ones that are much more infective.          There

is a shorter incubation period.    That may be related to work

that came out of Byron Kowie [?] and maybe your lab too

about the size of particles.    I mean, that might explain the

last comments that you had in your slide that when they are

too long it is a protective effect and you are not getting

the small particles.

             DR. PICCARDO: That might explain, and we are just

initiating another series of experiments to address that

particular issue.

             DR. GESCHWIND: It would be very related to Steven


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Finkbeiner’s work in Huntington’s Disease where he followed

every Huntington cell and showed that the cells actually

kept the Huntington-Bthe nuclear inclusion, were the ones

that actually survived, suggesting again a protective effect

of taking the protein and clumping it together.

          DR. PICCARDO: Thank you for that comment.   I think

the bottom line of these experiments are two-Bwell, I hope

there are several but at least two.   One is, and I want to

be very clear in this, that in these experimental models the

detection of abnormal PrP is not associated with spongiform

encephalopathy or clinical disease.   This was the first

observation that we thought was very interesting because TSE

is considered the agent and the marker, the surrogate marker

for diagnosis of disease.   I wanted to tell you something

else.

          DR. GESCHWIND: While you are thinking of that, it

made me think of a second point, and that is part of Pierre

Luigi’s and separately Yuri Saffo’s [?] work.   Pierre Luigi

presented a nice published paper of about 10 or 11 cases,

similar cases, where all the PrP-TSE was PK sensitive.     So,

we know that exists now.    Then, Yuri, also with the CDI has

shown that there is a component of the PrP-TSE that is


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sensitive to PK.    Whether it is infectious or not I think is

still unknown.

             DR. PICCARDO: I can make a comment on that.   I

showed you a Western blot showing PK-resistant PrP in the

model we are developing with Gene in Edinburgh.    However, it

took us a while to observe PK-resistant PrP by Western

blotting.    So, because we are very obsessive, we went again

and again and again.

             In the meantime, we said, well, maybe these

animals accumulate a significant amount of PK sensitive

abnormal PrP.    And we did a lot of cold PK digestion and we

did not observe the 22KV band which is characteristically

seen in PK-sensitive PrP.    So, we know that these animals do

not accumulate PK-sensitive PrP.    We went out of our way to

try to look for that and we did not see it.

             The other thing I wanted to tell you is that when

we talk about the accumulation of normal PrP, usually we use

the word enhancing autocatalytic, like an event that, once

it starts cannot be stopped.    It goes forever and destroys

the brain.

             One thing that I think is fascinating in these

modelsB-and I didn’t show you that because there was not


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enough timeB-is that those plaques are not the original

inoculum.   Remember that the inoculum came from humans.   So,

we used antibody species and specific antibodies to human

and to mouse and we observed that those plaques are not

composed of human PrP.   They are composed of mouse PrP.

            That generated a lot of trains of thought be we

said, well, then what we inoculate is good enough to induce

the endogenous PrP from the mouse to mis-fold and

precipitate, which is exactly what is the information for

the prion hypothesis.

            However, something happens and it is self-limited

because these plaques do not develop all over the brain.

They develop only in the corpus callosum.    There is

something very specific about the intercision in that part

of the brain, and this is something that was a long

discussion with Sue Priola, what happens in intercision in

that region of the brain that makes the thing happen but at

the same time stop.

            DR. GESCHWIND: Well, the sooner you can find out,

the sooner I can start treating my patients.

            DR. PICCARDO: I will let you know.

            DR. HOGAN: Dr. Priola?


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            DR. PRIOLA: Just a few really quick questions.     I

just want to be really clear that in the experiment where

you have now passaged three times the plaques are always

associated with the corpus callosum.   You see nothing

anywhere else?

            DR. PICCARDO: That is correct, more anterior or

more posterior but always associated with the corpus

callosum.

            DR. PRIOLA: In the G3 mice, in the ME7

transmission, are those plaques thioflavin-S positive or

negative?

            DR. PICCARDO: Positive.

            DR. PRIOLA: And, have you done a secondary

transmission there yet?

            DR. PICCARDO: We are working on that because we

cannot follow all these experiments at the same time.    The

first set of experiments took us seven years and we did not

finish.   So, it will happen.   We are very interested in

this.   It will happen and I will let you know.

            DR. HOGAN: These experiments take a long time.

That is why you should never look at somebody’s CV who works

in the prion field and say, oh my gosh, they haven’t


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published much.   Any other comments?

          Well, these have been some fascinating papers.      We

have had no registered speakers for the open public hearing

but I must ask if there is anyone from the audience who

wishes to make any public remarks to the committee?    If they

could, please, make themselves known at this point?

Everybody is tired so, not seeing any public speakers, I

would ask Dr. Epstein to give us some closing remarks,

please.

          DR. EPSTEIN: Well, I principally just want to

thank the many participants of the meeting for their

contribution, specifically the committee members, including

the new committee members and their very able new

chairperson.   I want to thank the presenters, many of whom

have traveled long distances, and also to specially thank

our colleagues from other FDA centers, and also to thank the

meeting attendees.

          I think we have had a very fruitful meeting.     FDA

appreciates the advice of the committee.    You can expect us

to come back to the committee with refinements to the risk

assessment model and other follow-ups in pursuit of these

very scientific advancements that we have been learning


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about today.    So, I very much appreciate everybody’s

assistance here today.

          DR. HOGAN: Thank you, all, very much and have a

good weekend.

[Whereupon, at 5:10 p.m., the proceedings were adjourned]




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