U.S. FOOD AND DRUG ADMINISTRATION

CENTER FOR BIOLOGICS EVALUATION AND RESEARCH

TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHIES ADVISORY COMMITTEE

17^th^ MEETING

TUESDAY,

FEBRUARY 8, 2005

The Committee met at 8:00 a.m. in the Maryland Room of the Hilton Hotel,
8727 Colesville Road, Silver Spring, Maryland, Dr. Suzette A. Priola,
Chairperson, presiding.

[PRESENT]{.underline}:

SUZETTE A. PRIOLA, Ph.D., Chairperson

JAMES R. ALLEN, M.D. Temporary Voting Member

ERMIAS D. BELAY, M.D. Temporary Voting Member

VAL D. BIAS Member

ARTHUR W. BRACEY, M.D. Member

LYNN H. CREEKMORE, D.V.M. Member

STEPHEN J. DeARMOND, M.D., Ph.D. Temporary Voting Member

DONNA M. DiMICHELE, M.D. Temporary Voting Member

PIERLUIGI GAMBETTI, M.D. Temporary Voting Member

DAVID W. GAYLOR, Ph.D. Temporary Voting Member

R. NICK HOGAN, M.D., Ph.D. Member

ALLEN L. JENNY, D.V.M. Member

RICHARD T. JOHNSON, M.D. Member

FLORENCE J. KRANITZ Consumer Rep

GEORGE J. NEMO, Ph.D. Temporary Voting Member

STEPHEN R. PETTEWAY, Jr., Ph.D. Acting Non-Voting Industry Rep

MO D. SALMAN, Ph.D. Member

LAWRENCE B. SCHONBERGER, M.D. Temporary Voting Member

GLENN C. TELLING, Ph.D. Member

WILLIAM FREAS, Ph.D. Executive Secretary

[FDA REPRESENTATIVES]{.underline}:

STEVEN ANDERSON, Ph.D., MPP

JAY S. EPSTEIN, M.D.

PEDRO PICCARDO, M.D.

DOROTHY SCOTT, M.D.

MARK WEINSTEIN, Ph.D.

ALAN E. WILLIAMS, Ph.D.

[INVITED SPEAKERS]{.underline}:

SHEILA M. BIRD, MA, Ph.D. Cambridge University

LISA A. FERGUSON, D.V.M. USDA

ANNA M. MOLESWORTH, BAHons, Msc U.K. Health Protection Agency

LYNNE SEHULSTER, Ph.D., M(ASCP)Centers for Disease Control and Prev

KATE SOLDAN, Ph.D. U.K. Health Protection Agency

A-G-E-N-D-A

Welcome and Introductions,  **WILLIAM FREAS, Ph.D.** 5

Executive Secretary

Informational Presentation

Update on BSC Surveillance in the U.S., 13

**LISA A. FERGUSON, D.V.M.**, USDA

**Topic 1 - Possible vCJD Risk from Investigational**

**Coagulation Factor XI Manufactured before 1998**

**from Plasma of Donors Residing in the United**

**Kingdom**

A. Introduction (10\') - **MARK WEINSTEIN,** 29 **Ph.D.**  OBRR, FDA

B. U.K. Risk Assessment Methods and 33

Assumptions ,**KATE SOLDAN, Ph.D.**, and

**ANNA MOLESWORTH, BAHons, Msc**, U.K.

Health Protection Agency

C. Risk Assessment for Factor XI, 86

**STEVEN ANDERSON, Ph.D.,** OBE, FDA

D. Recommendations on Surgical \] 135

Instruments Used on TSE Patients,

**LYNNE SEHULSTER, Ph.D.,** CDC

Open Public Hearing 151

Committee Discussion and Vote 162

**Topic 2 - Risk Assessment Models for Potential**

**Risk of Exposure to variant Creutzfeldt-Jakob**

**Disease (vCJD) Agent in Plasma Products**

A. Introduction - Rationale for risk 182 assessments; question to
Committee

(10\') **ELIZABETH SCOTT, M.D.,** OBRR,

FDA

B. Preliminary Risk Assessment - U.S. 185

1\. Potential TSE clearance steps

In U.S. Products, FVIII, FIX,

IGIV (10\') **ELIZABETH SCOTT, M.D.**

OBRR, FDA

2\. Risk Assessment Model for U.S. 192

Plasma derivatives (40\') **STEVEN ANDERSON, Ph.D., MPP**

Questions for Speakers

[AGENDA - (Continued):]{.underline}

Open Public Hearing 213

Committee Discussion and Vote 217

**Topic 3 - Potential Deferral of Blood and Plasma**

**Donors for History of Transfusion in European**

**Countries**

A. Introduction (10\'), **ALAN WILLIAMS,** 234

**Ph.D.**, OBRR, FDA

B. Epidemiology of vCJD in France 236

and risk assessments for blood and

plasma derivatives (25\'),

**PEDRO PICCARDO, M.D.**, FDA

**STEVEN ANDERSON, Ph.D., MPP** 241

Epidemiosurveillance Network

C. Estimates of blood-borne vCJD risk 261

in the U.K. and other European

populations (20\'), **SHEILA M. BIRD,**

**M.A., Ph.D.**, Health, Cambridge

University, U.K.

D. Risks and benefits of deferring 287

donors transfused in France and other

European countries: potential impact

on blood and plasma supplies, and

presentation of questions for the

committee (20\'), **ALAN WILLIAMS, Ph.D.**

Open Public Hearing 308

Committee Discussion and Vote 324

P-R-O-C-E-E-D-I-N-G-S

8:06 a.m.

EXECUTIVE SECRETARY FREAS: Mr. Chairperson, Members of the Committee,
invited guests, and members of the public, I would like to welcome all
of you to this, our 17^th^ Meeting of the Transmissible Spongiform
Encephalopathies Advisory Committee. I am Bill Freas, the Executive
Secretary for today\'s meeting.

The entire meeting today will be open to the public.

At this time, I would like to go around the table and introduce the
public to the members seated at the table. We will start on the
right-hand side of the room. Would the members please raise their hand
as their name is called, so people can see who is who?

In the first chair is Doctor Larry Schonberger, Assistant Director for
Medical Science, Division of Viral and Rickettsial Diseases, Centers for
Disease Control and Prevention.

Next, Doctor Nick Hogan, Assistant Professor of Ophthalmology,
University of Texas Southwestern Medical School.

Next, Doctor Arthur Bracey, Associate Chief, Pathology, of St. Luke\'s
Hospital, Houston, Texas.

Next is Doctor Allen Jenny, Pathologist, National Veterinary Services
Laboratory, U.S. Department of Agriculture.

Next, Doctor David Gaylor, President, Gaylor Associates, Eureka Spring,
Arkansas.

Next, Doctor George Nemo, Chief, Blood Resources Section, Division of
Blood Diseases and Resources, National Heart, Lung and Blood Institute.

Next, Doctor Richard Johnson, Professor of Neurology, Johns Hopkins
University.

Next, Mrs. Florence Kranitz, President of the CJD Foundation, Akron,
Ohio.

Around the corner of the table is Doctor James Allen. Doctor Allen is
Chair of FDA\'s Blood Products Advisory Committee, and he\'s also
President and CEO of the American Social Health Association.

Next is the Chairperson of this Committee, Doctor Suzette Priola. Doctor
Priola\'s term was extended for one year so she could continue to serve
as a leader of this committee, and we thank you very much for that
willingness to do so. Doctor Priola is also an Investigator, Laboratory
of Persistent and Viral Diseases, Rocky Mountain Laboratories.

Next is Doctor Glenn Telling, Associate Professor, Department of
Microbiology, Immunology, and Molecular Genetics, University of
Kentucky.

Around the corner of the table is Mr. Val Bias, Co-Chairman of the Blood
Safety Working Group, National Hemophilia Foundation, Oakland,
California.

Next is Doctor Lynn Creekmore, Staff Veterinarian, APHIS Veterinary
Services, U.S. Department of Agriculture.

Next is Doctor Stephen DeArmond, Professor, Department of Pathology,
University of California, San Francisco.

Next is Doctor Ermias Belay, Medical Epidemiologist, Division of Viral
and Rickettsial Diseases, Centers for Disease Control.

Next is Doctor Mo Salman, Professor and Director, Animal Population
Health Institute, College of Veterinary Medicine and Biomedical
Sciences, Colorado State University.

In the empty chair we will soon ? it will soon be occupied by Doctor
Donna DiMichele, Associate Professor of Clinical Pediatrics, the Weill
Medical College and Graduate School of Cornell University.

Next is Doctor Pierluigi Gambetti, Professor and Director, Division of
Neuropathology, Case Western Reserve University.

At the end of the table is our Acting, Non-Voting Industry
Representative, Doctor Stephen Petteway, Director of Pathogen Safety and
Research, Bayer Corporation.

Doctor DiMichele, you are just in time.

On a solemn note, I do have an announcement to make about a dear friend
of this Committee. She wasn\'t just one of our friends, she was a former
TSEAC member and a prominent researcher. Doctor Beth Williams, who
served on this committee from January, 1999 to January, 2003, along with
her husband, Tom Thorne, died in a tragic automobile accident on
Wednesday, December 29, 2004.

At this time, I would like to ask that we take a moment of silence to
honor the contributions that Doctor Elizabeth Williams made to us here
at FDA, to the contributions she made to the lives of her students at
the University of Wyoming, the contributions she made as a wildlife
veterinarian through research in the field of chronic wasting disease,
and most important, the contributions that she made to everyone she met,
whom she treated as her friend. Please join me in a moment of silence.

Next, I would like to read into the public record the Conflict of
Interest Statement for this meeting.

The following announcement is made part of the public record to preclude
even the appearance of a conflict of interest at this meeting.

Pursuant to the authority granted under the Committee Charter, the
Director of Center for Biologics Evaluation and Research has appointed
the following participants as temporary voting members: Doctor James
Allen, Doctor Ermias Belay, Doctor Stephen DeArmond, Doctor Donna
DiMichele, Doctor Pierluigi Gambetti, Doctor David Gaylor, Doctor George
Nemo and Doctor Larry Schonberger.

Based on the agenda, it has been determined that the committee will not
be providing advice on specific firms or products at this meeting. The
topics being discussed by the committee are considered general matters
issues.

To determine if any conflicts of interest exist, the Agency reviewed the
agenda and all relevant financial interests reported by the meeting
participants. The Food and Drug Administration prepared general matters
waivers for participants who required a waiver under 18 U.S. Code 208.
Because general topics impact on so many entities, it is not prudent to
recite all potential conflicts of interest as they apply to each member.
FDA acknowledges that there may be conflicts of interest, but because of
the general nature of the discussions before the committee these
potential conflicts are mitigated.

We would like to note for the record that Doctor Stephen Petteway is
acting as the Non-Voting Industry Representative for this committee, on
behalf of regulated industry. Doctor Petteway\'s appointment is not
subject to 18 U.S. Code 208, he is employed with Bayer Healthcare
Biological Products, and thus has a financial interest in his employer
and other similar firms. In addition, in the interest of fairness, FDA
is disclosing that Doctor Petteway is a Scientific Advisor for
Hemocellular Incorporated.

With regards to FDA\'s invited guests, the Agency has determined that
the service of these speakers are essential. The following interests are
being made to allow meeting participants to objectively evaluate any
presentation and/or comments made by these invited speakers. Doctor
Sheila Bird is employed by the Medical Research Council in Edinburgh,
United Kingdom. Doctor Lisa Ferguson is employed by the USDA Veterinary
Services in Hyattsville, Maryland. Ms. Anna Molesworth is employed by
the Health Protection Agency, Centre for Infections and Communicable
Disease Surveillance Centre, London, United Kingdom. Doctor Lynne
Sehulster is employed by the Centers for Disease Control and Prevention,
Atlanta, Georgia. Doctor Kate Soldan is employed by the Health
Protection Agency, Communicable Disease Surveillance Centre, London,
United Kingdom.

Members and consultants are aware of the need to exclude themselves from
discussions involving specific products or firms for which they have not
been screened for conflict of interest. Their exclusion will be noted
for the public record.

With respect to all other meeting participants, we ask in the interest
of fairness that you address any current or previous financial
involvement with any firm whose product you wish to comment upon.
Waivers are available by written request under the Freedom of
Information Act.

So ends the Conflict of Interest Statement for the public record.

Before I turn the microphone over to the Chair, I would like to request
if you have a cell phone on, could you please put it on silence, or turn
it off. Your neighbors would appreciate it.

Next, I would also like to say that we always have a timing light to
time the speakers to make sure that everything stays on schedule, but,
unfortunately, the timing light is in a car, and the car is impounded in
a parking lot at this time. If we get the timing light back with the car
attached, we will be using it later on in the meeting. However, in the
meantime, when your presentation has about two minutes left, I\'m going
to turn my little red speaker light on, and that will be your warning to
think about concluding your presentation in the next couple of minutes.

Doctor Priola, I turn the meeting over to you.

CHAIRPERSON PRIOLA: Thank you, Bill.

First of all, welcome back, everybody, from the last committee and the
new members as well. I think if you\'ve gone over the topics we all
realize that the first two topics, the questions that are asked are not
necessarily voting questions; they are more essay questions, which is
going to ? could make things very difficult a we go through and discuss
matters, but, fortunately, the first two topics, I think, will overlap
significantly in many ways.

So the things you want to keep in mind as you hear the presentations is
that we\'ve been asked to, essentially, assess the risk models that the
FDA is using for risk of exposure to variant CJD from plasma products,
and so we\'ve been asked to comment, essentially, to give these a
critical review and to comment on the validity of the models, the
sensitivity, are the parameters sufficient, are they varied enough,
should we use U.K. survey data as input? Just as examples, these are
things that you should keep in mind as you listen to the presentations
as we get ready for our discussion.

So, because we have a very full schedule, and because we don\'t have a
timing light, which makes things a little bit tougher, I\'d like to get
started with our first speaker, who I believe is Doctor Lisa Ferguson,
who is going to update us in an informational presentation on BSC
surveillance in the U.S.

DOCTOR FERGUSON: Thank you. Good morning, everybody.

My presentation, actually, will probably be pretty quick, because I
think most of you all have heard me do this several different times, and
just with updates on numbers.

So, I\'m primarily going to talk about what we\'re doing in surveillance
in the U.S., but just as a reminder for everybody as to what\'s
happening worldwide, and to try to make a point, cumulative total,
actually, at this point in time, identified cases worldwide are greater
than 189,000. The vast majority of those, greater than 96 percent, are
still in the U.K. Actually, perhaps, more interestingly, more than 89
percent of those have actually occurred in 1996 and before, so if you
look at the curve in the U.K. I think everybody is real familiar with
that, where you had a peak in \`92-\`93, and then a significant drop
off, but even if you look at the curves in Europe it also appears to be
dropping off again. So, we do appear to know what we are doing, at least
in the animal health community and are getting things under control
worldwide.

Actually, if you are interested in the numbers, the OIE, the World
Organization for Animal Health, does post fully-updated numbers on their
website, which is oie.int, and go over on the left under animal health
status and they\'ve got a few pages specifically for BSE, with reported
cases worldwide.

So, let\'s talk about what we are doing in the U.S. I think as everybody
knows, beginning in June of 2004 we started an enhanced BSE surveillance
project, and our goal is to get as many samples as we can from the
targeted high-risk population in a 12 to 18-month period.

We\'re targeting population where the disease is most likely to be
diagnosed, so if it\'s present, this targeted population, which are
adult animals with some type of clinical abnormality that could even
remotely be considered consistent with BSE, and this is the most
efficient way to help us identify is the disease here, and if so, to
help us put some parameters around the possible prevalence level.

We\'ve had lots of questions raised about how we\'ve set up our program
and why we are doing it this way, but our assumption was, if we can\'t
find disease in this targeted population, or the most likely place to
find it if it\'s here, then it\'s even more unlikely to be found in the
non-targeted population or the clinically-normal animals.

We can use the data that we collect from the targeted population to
extrapolate information to the broader cattle population.

We estimate that our targeted population is about 446,000 animals. It
was a bit of a challenge to try to come up with these estimates, but
we\'ve used different surveys that we\'ve done to try to estimate
animals that die on the farm. We have worked with our colleagues in Food
Safety Inspection Service to get estimates of animals that they condemn
on ante mortem inspection, for reasons that would be consistent with our
target. This is out of an adult-cut cattle population of 45 million.

So, these are the types of animals that we are looking for, clearly
non-ambulatory animals, those animals that are down for some reason,
can\'t get back up, dead stock animals that die for unexplained reasons,
field cases of central nervous system signs, on-farm suspects. We are
working with veterinary diagnostic labs, if they get these neuro cases,
or dead stock, or downers, also working with public health labs as they
get rabies suspects that would also fit our target, and last but not
least, we are continuing to work with our colleagues in the FSIS that
are in slaughter plants, and any animals that are condemned on ante
mortem inspection for slaughter are sampled.

Now, just to step back for a minute and look at where we\'ve been in the
past, these are total numbers of samples that we\'ve examined previously
on a fiscal year basis. You can see our sampling really stepped up in
2002, 2003, with approximately 20,000 samples each year. That last bar
of \`04, actually is just the first part, these are fiscal years, which
start in October, so this is our fiscal year that started in October,
\`03 through the end of May, \`04. When we started the enhanced program,
we stopped collecting, we essentially, made a break in our data and are
reporting that out separately.

Just to show you proportions of where that\'s been in the past. The
yellow bar are total samples collected per year. The purple bar are
those animals that are non-ambulatory or down, and the blue bar are dead
stock, so the vast majority of our samples collected in the past are
dead stock and downers. The other remaining ones in there would be CNS
cases, other clinical signs that would be consistent with BSE.

So this is where we\'ve gotten to since we started our enhanced program
the first part of June. We are up over 221,000 samples so far.
Primarily, we are using rapid screening tests, one of the ELISA tests
for the initial sampling, many inconclusives then are sent to our
National Veterinary Services Lab, where we are using
immunohistochemistry as our primary confirmatory test. We are doing some
screening, though, still with IHC, about 4,200 of those. So we feel like
we are actually on track for where we need to be about halfway into this
project, and we\'re continuing to analyze the data. We haven\'t released
a lot of the detail publicly, that\'s still going through some
clearances. Hopefully, we\'ll be able to distribute some of that
shortly, because I know people are keenly interested in how we are doing
and some breakdowns of that, rather than just raw numbers.

But, we are looking at this routinely, making sure that we\'re getting
appropriate geographic distribution, and that we are getting the
populations that we expected. So, geographically, actually, we feel like
we are doing very well. The vast majority of our samples are still from
non-ambulatory dead stock, clearly as we expected, and we are also
getting good representation from all the different collection sites that
we are working with.

Just to re-emphasize, for folks that aren\'t familiar with the
industries, primarily, we are working with animal disposal facilities,
renderers, 3D/4D salvage slaughter facilities, dead stock haulers, these
types of places. So, as expected, that\'s really where we are getting
the vast majority of our samples.

So, we are very encouraged by our results, and by the success that
we\'ve had in getting the samples. We do plan on continuing this, at
least for a 12-month period, and we\'ll see where we are here in a few
months.

As we analyze the data, then we\'ll decide where to go from here. We are
already looking at different options for surveillance when we get this
project done. No decisions have yet been made. Clearly, a lot of that
depends on what we find in the rest of our surveillance effort, what our
neighbors to the north find, and how that might impact us.

We do have a lot of information on our website, and here\'s the website
address, click under Hot Issues in BSE, and we update our testing
numbers weekly, and also a lot of other detail about how we are going
about things can be found on that same website.

So, questions?

CHAIRPERSON PRIOLA: Yes, Doctor Belay?

DOCTOR BELAY: Yes, in one of your slides you had the targeted population
of about 400,000. It looks like the captive population was about
200,000. Is that just based upon the fact that the estimate was sort of
on the high side, or is there some issue with compliance in the testing?

DOCTOR FERGUSON: Our estimate of the targeted population is, that\'s how
many animals would show up in that population in a year, so at the end
of a year we hope to be fairly closer to that. We are about halfway into
this, with more than 221,000, so we think we are ? both our estimate was
on track, and our numbers are on track.

CHAIRPERSON PRIOLA: Doctor DeArmond?

DOCTOR DeARMOND: Could you explain what the compliance rules are? Is
this still voluntary? How are you getting these? How are you encouraging
people to give you these samples, and what do they actually send you?

DOCTOR FERGUSON: Okay.

We have a field force throughout the U.S., where we have APHIS employees
in every state, and they are working with the various facilities and
with on-farm producers to obtain these samples.

The whole question of voluntary versus mandatory does get a bit
complicated. At this point in time, these industries are cooperating
with us. We\'ve built up a lot of good will with them over the past
several years. We recognize that we each need the other, so they\'ve
always been very cooperative, and we\'re building on that.

We do, however, have the authority, in March of last year we published
what we call the Blood and Tissue Collection Docket, where the
Department does have the authority in slaughter and rendering facilities
to go in and mandate that we take samples for surveillance, not just for
BSE, but for any other animal disease.

We have chosen to try to work cooperatively with the industry, first of
all, and not go in with a big hammer and make people do things. And, we
feel like we\'re getting very good cooperation.

We did get a significant amount of emergency funding to help us run this
program, and we\'re using that to do cost recovery. Essentially, these
guys are incurring additional costs, so we are covering those costs for
them. Also, with producers, if they are calling us directly to help
encourage that, then we will pick up the cost of disposal of the carcass
for them, so it makes it a cost-neutral option for the producer. And,
essentially, for the rendering facilities through a D40, if they are
doing additional things, specifically for this program, then we are
covering those costs for them.

DOCTOR DeARMOND: And, the tissues that you get?

DOCTOR FERGUSON: Oh, sorry, sorry, yeah, they are collecting,
essentially, brain stem, sending those in, fresh tissues. It\'s either
an APHIS person doing the collecting, either a permanent employee,
we\'ve hired a bunch of temporary employees also, in some instances we
have hired a contractor to do that collection for us, but it is fresh
tissue that they are sending in to one of the designated labs. If you
are in a given state you send stuff to a designated lab.

DOCTOR DeARMOND: Do they scoop it out from the foramen magnum?

DOCTOR FERGUSON: Yes, yes, the standard scoon \-- spoon scoop technique,
yes. Sorry. It\'s too early for me.

CHAIRPERSON PRIOLA: Doctor Gambetti?

DOCTOR GAMBETTI: Can you tell us what are the criteria to declare an
animal positive, or a result positive? I see that you run two tests, the
ELISA and the immunohistochemistry. What are the criteria to run the two
tests, or do you run two tests, the two tests together, or
alternatively, and what are the criteria for declare an animal positive?
Is it just positive with one criteria or both, or can you tell us about
this?

DOCTOR FERGUSON: Yes. I can tell you in somewhat general terms. If you
want to get into specifics about literally how we are doing each of the
tests at NVSL I\'ll call on one of my colleagues on the committee.

But, in general terms, the first screening test is done at one of our
network laboratories. We have seven state/federal labs that are working
with us, and they are using one of the commercially-available rapid
screening tests. They are running that according to manufacturer\'s
instructions, and if they get a reactive ? or, above a certain OD
reading, in accordance with the manufacturer\'s instructions, that\'s
deemed to be an inconclusive. They then forward that tissue to NVSL,
fresh tissue at this point in time.

NVSL reruns the rapid screening test, concurrently then they are putting
that tissue in formalin to fix for IHC, and then they are running IHC
according to their standard SOP to do an IHC test.

If for some reason they got that tissue and it was not of adequate
quality to do an IHC, then we would use a Western Blot in that instance.
Also, if we got an IHC positive, we\'d then also do a Western Blot to
help us characterize what we might have.

DOCTOR GAMBETTI: And, both have to be positive, or only one can be
positive?

DOCTOR FERGUSON: Okay.

Essentially, we are calling things positive based on the IHC. So, if we
got reactions on the rapid screening test, you know, a strong reaction
at the network lab, a strong reaction at NVSL, that would still be
inconclusive. We are not going to call that positive until we get an IHC
positive, and then at that point that would be deemed positive, based on
the IHC results.

DOCTOR GAMBETTI: Let\'s assume the Western Blot is positive, and the IHC
is negative, then it will be called negative?

DOCTOR FERGUSON: Well, we are using Western Blot only if we have tissue
that is not of sufficient quality to do IHC at this point in time, or if
we already have an IHC positive.

CHAIRPERSON PRIOLA: Doctor Hogan?

DOCTOR HOGAN: Yes

My understanding is you are testing animals that are submitted to some
facility or rendering plant or something like that. Is there any ?
what\'s the percentage, if you can guess, of dead or downers never make
it to a facility that aren\'t even submitted for testing?

DOCTOR FERGUSON: I don\'t know that you\'d ever be able to come up with
a percentage. I mean, you know, it\'s a wild guess to try to say how
many animals die on a farm in a given year. We\'ve done different
surveys to try to come up with, or used information from general animal
health surveys that we\'ve done to try to come up with estimates of
that. Whether that\'s accurate or not, we have no clue.

That 446,000 number that I showed as an estimated high-risk population,
probably about 220,000 to 250,000 of those were from that estimated die
on the farm. Now, that just means they die on the farm, that doesn\'t
mean they stay there, because we recognize that a lot of producers, they
don\'t want a carcass on their farm, and many of them have environmental
issues, they can\'t bury animals, et cetera, so we recognize that a lot
of those are going to the rendering facility, the dead stock guy, the
3D/4D plant, just to get them off a producer\'s place.

We are, however, looking at the information that we have. We are trying
to track, you know, collection sites, whether it\'s on the farm, whether
it\'s a rendering facility, a 3D/4D, in those states where, based on
their local knowledge, our folks say, you know, there\'s not a rendering
facility, and they are really focusing on getting on-farm collections,
they are doing very well.

So, those numbers are looking pretty good. We are getting a good
proportion of those.

CHAIRPERSON PRIOLA: Doctor Schonberger.

DOCTOR SCHONBERGER: Lisa, could you remind us, assuming that the
targeted surveillance continues and everything is negative, what is the
conclusion about the prevalence of BSE in the United States? The sample
was selected so you could come to a specific conclusion, is that not
true?

DOCTOR FERGUSON: Well, sort of true. And we\'ve had lots of questions,
and lots of entertaining discussions with various entities about our
statistical calculations and conclusions.

If you look just in the targeted population, and based on, you know,
what we could collect in the targeted population, if we get 268,000
samples, just based on a straight statistical calculation, if there are
five cases in that targeted population, then we should be able to find
those sampling at that level.

There is lots of different ways to extrapolate that data to the broader
cattle population. We\'ve looked at probably at least three of those and
played with different ways to do that. There you can do sort of a ratio
comparison, based on what they\'ve done in Europe, where you are 29
times as likely to find disease in the targeted population as in the
clinically-normal, and you sort of work that ratio and you can
extrapolate information out.

John Wilesmith and Roger Morris have developed a computer model to look
at surveillance data. We are also playing with that and plugging numbers
into that. Our folks at Harvard, that have worked with this in the
risk-assessment model, have suggested a couple of different ways to
extrapolate data. All of those really get you back towards a
one-in-a-million type level in the total population.

CHAIRPERSON PRIOLA: One final question from Doctor DeArmond.

DOCTOR DeARMOND: Whenever we try to do this work, we are criticized on
exactly having the correct area in the obex region.

DOCTOR FERGUSON: Uh-huh.

DOCTOR DeARMOND: Do you rule out ? when you make an IHC declaration of
positivity or negativity, do you always have to include the nucleus of
solitary track, the dorsal nucleus, the vagus and the trigeminal ?
descending trigeminal nucleus, because that\'s where we are always
criticized, because that\'s the hottest area, and down into the
reticular formation is often a later stage of disease.

So, do you ? when you make your declaration, is it when you have seen
those three structures, or at least one or two of those structures, in
your IHC?

DOCTOR FERGUSON: My understanding is, we are not necessarily having to
look at all of those structures, I mean, if we see something that\'s
lighting up and it is an appropriate location, we are going to call that
positive.

I guess ?

DOCTOR DeARMOND: Those structures should be included in your sample.

DOCTOR FERGUSON: Yeah, absolutely, and that\'s one of the big advantages
that we feel with using IHC, is you can look at that and, hopefully, you
know, if your tissue is not a total mess, you know, you can still see
some of that tissue architecture and know that, yes, you are in the
right place.

Al, do you want to weigh in there, yeah or nay?

DOCTOR JENNY: Yes. The samples are surprisingly good, for the most part,
the ones that are collected fresh and put on ice packs, are very good,
and we see the level that we want to see of the obex.

CHAIRPERSON PRIOLA: Okay, all right, thank you very much, Lisa.

Okay, so we\'ll get on now to topic one, and to present that topic is
Doctor Weinstein from the FDA.

DOCTOR WEINSTEIN: Okay.

I think we\'ll go to the next slide, please.

In this section of the meeting, we will discuss the possible risk of
variant CJD, the patients in the United States who were treated with a
Factor XI concentrate in investigational new drug studies, performed
between 1989 and 1997.

The coagulation Factor XI concentrate was manufactured from the plasma
donors living in the United Kingdom. We are looking for the Committee\'s
advice on a risk assessment model that describes potential exposure of
these patients to variant CJD.

I\'ll give a very brief overview of this issue. We will then hear more
in-depth presentations from speakers from the U.K., the FDA, and the
CDC, followed by questions to the Committee.

Now, in September of 2004, officials of the United Kingdom notified
patients with bleeding disorders and congenital anti-thrombin III
deficiency that they might be at increased risk of variant CJD. The
products used by these patients were manufactured between 1980 and 1998,
with a final out date of 2001. In 1999, U.K. plasma was no longer used
to manufacture these products.

The reason for the increased concern in the United Kingdom about the
transmission of variant CJD through plasma derivatives was the
observation that the disease was probably transmitted in two cases,
through transfusion of non-leukocyte-reduced red blood cells. The two
donors of these cells developed variant CJD subsequent to their
donations. U.K. donors of blood in plasma in general are at increased
risk of variant CJD infection from eating BSE-infected meat.

Now, patients in the U.K. who received plasma-derived coagulation
products and anti-thrombin III were advised not to donate blood, organs
or tissues, to inform their surgeons and dentists of their increased
risk so that special arrangements can be made for surgical and dental
instruments to control potential infection, and to inform their families
so that surgeons could be told in case of emergency surgery.

Now, in the United States, there was no licensed product made from U.K.
plasma. However, a small number of Factor XI deficient patients, and we
estimate the number to be on the order of 50 or less, were treated under
several IND protocols with Factor XI concentrate derived from U.K.
plasma. No Factor XI product used in the United States was manufactured
from any donor known to show clinical symptoms of variant CJD. Over
time, however, we may find some infected individuals who did contribute
to the manufacturing pools.

Now, with regard to Factor XI utilization, Factor XI is in the category
of a very rare bleeding disorder. Literature estimates are on the order
of 1/30,000 or 1/100,000,000. There is a much higher prevalence in
certain population groups, including Iranian Jews, Ashkenazi Jews, and
French Canadians.

The physical manifestations of the disease are rare, and the disease may
be unrecognized until bleeding occurs associated with surgery, trauma,
dental procedures, or menorrhagia.

Most of the Factor XI products studied under IND was used in one or two
situations per patient, to prevent excessive surgical or dental
bleeding. This very infrequent use is in contrast to the use of plasma
derivatives, like Factor VIII or Factor IX to treat the hemophilias.

We\'ll now have an in-depth presentation of the models and actions taken
in the United Kingdom and the United States. Doctor Soldan, from the
U.K. Health Protection Agency, will talk about the methods of risk
assessment and assumptions used to develop a risk assessment model in
the U.K.

Doctor Molesworth, also from the U.K. Health Protection Agency, will
discuss actions taken in the U.K., based on their model.

Then Doctor Stephen Anderson from the FDA will present an assessment of
possible risk of variant CJD from the Factor XI product used in the
United States. This will be followed by a discussion by Doctor Lynne
Sehulster from CDC about current public health recommendations on
management of surgical instruments used on patients with TSC or TSC
risk.

As these presentations are being made, we request the Committee to keep
in mind these proposals. We ask the Committee at the end here to comment
on FDA vCJD risk assessment for Factor XI manufactured from U.K. plasma,
with regard to the model as applied to Factor XI, and to please give any
additional information that is needed to improve risk assessments for
this Factor XI product.

CHAIRPERSON PRIOLA: Are there any questions for Doctor Weinstein before
we go on?

Okay, if not, thank you.

We\'ll move on to the next speakers, who are Doctor Kate Soldan and
Doctor Anna Molesworth, who are going to discuss U.K. risk assessment
methods and assumptions.

DOCTOR SOLDAN: Good morning, everybody. Firstly, thank you very much for
the invitation to come and speak to you today and share the U.K.
experience.

Can you hear me? Is that clear? Okay, can everyone hear now? Great.

Anna and I, as introduced, Anna and I work at the CJD section of the
U.K. Health Protection Agency Centre for Infections. I\'m speaking today
mainly in my role there as Scientific Secretary to the CJD Incidents
Panel, which is the committee that has guided our management of the vCJD
risk to plasma product recipients, and a role I\'ve held since October.

My colleague, Anna, worked throughout 2004 on the U.K.\'s notification
of recipients of vCJD implicated plasma products. Anna will present to
you the details of that process that we went through.

In our presentation today, we are going to give you an overview of both
the context and the process of the U.K. plasma risk assessment and
notification in the U.K. I\'ll start by setting the context and the
general approach to reducing the risk of iatrogenic vCJD in the U.K.

For us, the plasma products are one aspect of this risk, and our
approach is in the context of the whole iatrogenic risk in the U.K., so
I hope that in setting the context I will preempt to answer some of the
questions you may have about why we did what we did about plasma
products in the U.K.

Anna will then go on to present the methods and the assumptions of the
plasma product risk assessment. Anna will show the methods, or at least
the strategy, that we used for notification of patients considered to be
at risk.

And, we\'ll just end briefly on mentioning the ongoing surveillance of
vCJD in this patient group in the U.K.

You\'ll be familiar, I\'m sure, with the U.K. epidemic of vCJD, and this
is the latest observed data and modeling for the vCJD deaths to the end
of 2004, you see here that the quadratic model in statistics is the best
fit now for this observed incidence to date, with a peak in the middle
of 2000 and currently a declining incidence.

It assumes, generally, that the majority of these cases, and the course
for this curve here, reflects exposure to the BSE epidemic, the primary
epidemic.

Person-to-person, or secondary transmission is now secondary cause for
concern. There are, of course, many uncertainties in both the
transmissability and the extent of exposure via secondary routes, not to
mention susceptibility of those exposed, and this means that the
magnitude of any future epidemic arising due to secondary transmission
is highly uncertain at the moment. However, from modeling, for example,
on the transmission by contaminated surgical instruments, shows the
uncertain assumptions, iatrogenic transmission can lead to ongoing
levels of infection, even in the absence of a continuing primary
epidemic due to BSE.

So, this gives the background to the U.K.\'s public health response to
iatrogenic vCJD, which includes the epidemic I\'ve just shown you, and
also knowledge of a potential, but unknown, risk, both due to surgery
involving contact with tissues known to include vCJD infectivity, and
also due to blood.

It\'s recognized this great uncertainty regarding pre-clinical and also
sub-clinical vCJD in the population in the U.K., and an awareness,
unlike sporadic CJD, variant CJD cases are younger, and therefore in
some ways more likely to pose a risk to others.

There is knowledge of pre-symptomatic prion accumulation in certain
tissues, and as I mentioned there\'s a possibility of sustaining the
vCJD epidemic in the U.K. population by secondary means.

Also as a background to our approach, was the expectation that many of
the actions may need to be taken retrospectively as routes of secondary
transmission are identified after the diagnosis of the case.

To address these needs, and suit that background, in 2000 the Department
of Health established a U.K.-wide expert committed, called the CJD
Incidents Panel, and the role of this panel is to advise on situations
where there was understood to be some risk of transmission of CJD of all
types between patients through clinical interventions.

I\'ll spare you from showing you the network of all the committees and
organizations involved in the U.K. public health response, but simply
mention that this panel, which guides this response to iatrogenic risk,
works very closely with another committee, which makes recommendations
for infection control precautions prospectively in clinical care
patients in the U.K.

So the CJD Incidents Panel has played a key role in the plasma product
risk assessment and notification. Its thinking and its approach was
developed also, and, in fact, quite heavily, with surgical exposure in
mind. And much of the rationale is shared.

The panel understands that there\'s a need to take precautionary
actions, particularly, when science and the evidence is weak or, in
fact, lacking, and for surgical exposures it was recognized that the
means to eliminate risk, be that by single-use instruments, complete
decontamination for all patients, or identification of particular
patients which pose a risk, was not an available option, but some action
was needed, and the actions would very often require individual review
of individual cases.

One key principle you can see from all this is that in the CJD Panel\'s
thinking and actions has been of risk reduction rather than risk
elimination, and also the balance between risk reduction for public
health purposes with some consideration of disproportionate efforts to
achieve that and adverse effects for individual patients.

The panel advises on reduction of iatrogenic risk for a range of
patients, for all patients with symptomatic disease, and also a number
of groups of individuals who are asymptomatic and considered at risk of
CJD, including variant CJD.

Plasma product recipients at risk of variant CJD come into the
penultimate group listed here, along with patients exposed by
potentially contaminated surgical instruments, and also by fresh blood
transfusion.

The surgical exposure, the panel was guided in its actions and its
recommendations by risk assessment conducted by the Department of Health
that modeled the risk of transmission with repeated use of instruments
that had been used on different tissues in individuals thought to harbor
CJD infectivity.

The example model shown here is for CNS tissue, and with an assumption
of 10 percent transfer of residual tissue on the instruments. Then you
can see, that\'s the dotted line here, the risk ? you see the risk fall
away with repeated use of instruments. This is the risk from 100 percent
down to zero, and repeated use of the instruments. And, by the sixth
patient, you see here the modeled risk falls around or below a 1 percent
additional risk of infection.

In our risk assessment, the infectivity has been expressed in ID50s,
which is the dose that is thought to lead to 50 percent of those exposed
becoming infected. Based on those surgical models, the panel chose to
consider patients to be at risk of vCJD or CJD due to surgery if their
exposure equated to .02, ID50s, or a 1 percent additional risk of
infection of both the population risk due to the surgical exposure or
their potential surgical exposure.

This same threshold was used to determine the plasma product recipients
to be considered at risk in the subsequent plasma product risk
assessment and notification.

So, what happens to these patients who are considered to be at risk?
They are advised, given a package of measures to reduce the risk of
transmission. In fact, you have seen these already, but the patients are
asked not to give blood, not to donate tissue, and also to enable the
medical staff to take certain precautions with the instruments used on
them in surgical interventions.

In addition, clinicians were also asked to play a role in this in
ensuring that infection control precautions are taken when these
patients go for treatment, and also to review their previous medical
history to identify if there are any other incidents that may have
exposed patients that would also need similar control procedures to be
applied.

Just to show you the prospective infection control recommendations that
are made, what they actually lead to, they specify that in general
instruments in contact with high or medium-risk tissue, as shown here,
for this column of individuals the plasma product recipients would be at
risk of iatrogenic, and for those patients it is generally advised that
the instruments should be removed from use after use on the patient.
And, of course, this can be both costly and disruptive to services. So,
this is experience we are gaining in applying these guidelines
currently.

Now, I want to move on specifically to the plasma products, and where
theoretical risk assessment was conducted in 1997. This was updated in
2003, both to incorporate new evidence, and also to move towards an
assessment tool that could be applied to plasma pools containing
implicated donations for immediate actions in the U.K.

The CJD Incidents Panel considered these risk assessments and developed
and consulted on a mechanism for approaching these patients and the
package of advice that they should be given. And then, as you know, in
2004, with two reports of probable transmission of vCJD infection by
blood transfusion, that is of recipients transfused with blood from
cases, this precipitated the move in the U.K. to trace and notify
recipients of plasma products that were identified as at an increased
risk.

Here I\'ll hand it over to Anna to take you through that process.

DOCTOR MOLESWORTH: Hi.

So, where are we? We\'ve got, in 2004, two reports of probable
transfusion-associated transmission, and we\'ve also got framework for
handling ? for managing the risk in those patients, in terms of the
public health precautions that need to be taken.

When the first case was announced at the end of 2004, we immediately
addressed the risk of transmission of variant CJD infection to other
people who had been transfused implicated blood components, and we did
that at the end of 2004 ? 2003, and the start of 2004.

In addition to the components recipients, we also, obviously, had the
radical risk of transmission of variant CJD through plasma products, and
we had the DNV risk assessment, which had already been considered. We
had a framework, again, to operate within, and we also had had a tool
developed by the U.K. Department of Health which actually took the
results of the DNV risk assessment and had made the first steps to
translate that into assessment of individual risk.

At the start of 2004, we obviously were handed over the task of
implementing the public health precautions, and I\'m going to take you
through that. But, you see DNV aren\'t here to present the risk
assessment, and they are in a far better position than I am to actually
explain the detail. What I\'m going to do is just outline how it was
used in terms of the U.K. notification and take you through that in
further detail.

Okay. So we\'ve got the DNV risk assessment in three stages. It looked
to infectivity in blood, infectivity in plasma fractions, and then also
provided a tool for assessing batch risk and individual exposure to
variant CJD.

So, to start off with, DNV reviewed all the experimental research
available on the infectivity of blood and its components, and they
produced a value of infectivity in one unit of blood. This is taken
straight out of the DNV report. It gives you the various experiments
which they considered, which you can find in the DNV report, so I\'m not
going to go into detail, and also the proportion of infectivity, which
you\'d expect to find in the various blood components as a result of
these experiments, and the three main blood components being the red
blood cells, the buffy coat, and also the plasma.

Now, there were a number of experiments. The main experiments which DNV
focused on were the experiments by Brown, et al, in 1998 and 1999. in
terms of reviewing the infectivity in the unit of blood, they actually
focused on Brown\'s experiments in 1998, and in 1998 Brown conducted two
main experiments, the low-dose endogenous experiments and also
experiments which used spiked material.

The low-dose endogenous experiments looked at the distribution of
infectivity in the blood for mice who were inoculated intracerebrally,
but with a mouse-adapted human TSE.

The spiking experiments looked at the distribution of infectivity in
blood components in human blood, which have been spiked with bone
material from scrapie-infected and scrapie-diseased hamsters, so two
main experiments.

The one the DNV decided to go with, which proposed would be the most
suitable, were the low-dose endogenous experiments, and they looked at
the distribution of infectivity and they came out with this just over
half the infectivity which you\'d find in a unit of blood would be found
in the plasma component.

Okay. Then DNV actually assessed how that infectivity in the plasma
might be distributed within the different plasma fractions. Okay. So,
this is in two parts, there\'s a focus on this, which is again from the
DNV report, this is the outline of plasma fractionation process.
Effectively, you start with a very large plasma batch start pool, about
20,000 donations, and the plasma are separated into cryoprecipitate,
from which you get the main clotting Factor VIII, and cryosupernatum,
which the other products made from including the other blood clotting
factors, Factor IX, XI anti-thrombin, various immunoglobulins and
albumin, and these are the main products, and they are for ? they are
for the main intermediates, although plasma is also used to make other
products. The whole of the Det Norske risk assessment was based on the
major clotting factors, immunoglobulins and albumin.

Having been sent through the fractionation process, you get various
intermediate stages, and in each of these stages before you reach the
final product you get a series of processes involving precipitation,
centrifugation and filtration, heat treatment, depending on the actual
product involved.

And then, once you get to the final product, that\'s, obviously,
distributed into the vials of product, and used to treat a variety of
conditions.

Having an idea of this, obviously, Det Norske wanted to see how this
infectivity might be distributed, there again, refer to the experiments
conducted by Brown, et al in 1998 and 1999. All these are Brown\'s
experiments, and again, it\'s found in the risk assessment, and
effectively they decided to go with the low-dose experiments, the
mouse-adapted human TSE, and that was the rate of the infectivity was
distributed amongst different plasma fractions with, actually, a
combination of Brown\'s experiments in 1998 and 1999.

And, in this figure, just as in the previous one, I just want to draw
your attention to the huge variation between the different experiments
and the types of infectivity you might expect to see in the different
plasma fractions.

This is what they came up with, and I will actually go into more detail
of the assumptions further on in this presentation, but they derived
values for the infectivity in each component and fraction per unit of
blood. They said if a unit of whole blood, 450 mls, has got about 950
ID50s per unit, 53 percent of that goes into plasma, and then within
that the infectivity is apportioned to these variant intermediate plasma
fractions, the greatest infectivity being found in the cryoprecipitate,
and the straight cryosupernatant, and then other levels of infectivity
in the progressively ? the highest levels of infectivity being in the
lower fractions.

Okay, so that\'s what they came up with, and that was effectively what
we used for ? those were the figures that we used for our patient
notification exercise.

So, DNV conclusions, obviously, we don\'t know the level of risk of
variant CJD infectivity in the blood of people incubating disease. It\'s
entirely based on animal models, but they show that we may have
infectivity present in plasma, as well as other components, and if the
level of infectivity is as suggested by animal models then it may be
sufficient to cause infection, and therefore certain plasma products
could carry a risk of infection.

Okay. So then the next stage of the DNV risk assessment is they provided
this tool for assessing the type of risk you might expect to find in
product batches and had to translate that into individual exposure. Now,
we took this, this is what our Department of Health were working on, we
developed it slightly, but not a great deal. Effectively, this process
we used to calculate the potential risk of variant CJD in our implicated
product batches using this, the infectivity per unit in a product batch,
number of donations, number of implicated donations in the plasma start
pool, the fraction-specific infectivity, and the proportion of the
fraction used to make a batch, those were the key inputs.

Having got an idea of the individual batch risk, then what we needed to
do is, obviously, assess the individual exposure risk, so you get to the
total infectivity in a product batch, the dose that individual would
have received, from that, overall, the batch an individual would have
received, and that will give us an idea of the kind of levels of
potential infectivity that are out there, and, obviously, getting back
to Kate\'s 1 percent threshold, the potential exposure to .02 ID50 is
equivalent to our 1 percent risk of infection.

So that was the basis, that was the theoretical basis upon which we did
the notification.

Now, clearly, there are a great many assumptions and uncertainties in
that process. The main ones ? well, they can be summed in three
sections, the infectivity of blood relating to the processing, and also
the susceptibility of individual recipients to infection. Now, certainty
where there was uncertainty the most precautionary option was used, when
there was uncertainty throughout, basically, throughout this entire
process, we took a very precautionary approach, within the context of
the background risk from dietary exposure to BSE, and this approach is
basically traditionally used by the U.K. National Blood Services.

And, I guess that\'s with the view that measures could be relaxed,
should we get new evidence indicating that the risk had been
overestimated by several orders of magnitude.

Okay, so I\'m going to go through each of those ? each of these
assumptions.

Okay, relation to the infectivity of human blood. So, we are assuming
that blood from somebody, incubation variant CJD is infectious. I think
that\'s a reasonable assumption. We\'ve had two reports of
transfusion-associated infection. Statistical analysis indicate that the
case of infection in a recipient of blood from a variant CJD-infected
donor is unlikely to have occurred by chance, and we\'ve had two
instances of transmission of infection.

The other issue is right, okay, so we\'ll assume it\'s infectious, how
much infection do we actually have in human blood? There\'s a massive
range of levels of infectivity in human blood, I think it ranges between
about 300 and 400 ID50. Experiments from Brown indicated that actually
the level of infectivity might be towards the low end of the spectrum,
and that Det Nortske\'s factors took the figure of ten as an appropriate
level.

Then, additionally, experiments of Brown also indicated that the actual
intravenous inoculation of infectivity may be five times less efficient
than through the intracerebral route, so they reduced that down to two,
although it may be up to 100 times and this may again be an
overestimate, but again, even if we had two intravenous ID50 primarily
to human blood there\'s great variation around that estimate.

Okay. The second one, infectivity is constant throughout the incubation
period, and is in presence at the time of donation, and as far back as
1980. In the U.K. we use 1980, as that\'s the time when we feel that BSE
first entered the human, could have first entered the human food chain.
So, that\'s why we use the start date of 1980.

So infectivity is constant throughout the incubation period, and nobody
really knows, the experiments from Brown, which looked at pre-clinical
distribution of infectivity, showed that there was very little. You
couldn\'t detect the infectivity in pre-clinical stages, but that it
showed up as soon as the mice became symptomatic. So, the chances are
that that is probably not the right assumption, and the infectivity will
increase the closer you get to onset of disease.

This one is very important, that the infectivity in blood components and
plasma factions varies from the vary for whole blood according to the
ratios determined from endogenous low-dose experiments using blood from
mice innoculated with a mouse-adapted human TSE. So, we are saying that
Brown\'s experiments are directly applicable to the human situation. And
again, as I showed you before, there was wide variation in the levels of
infectivity found in the different plasma fractions.

We also did in it in clinically-ill mice in Brown\'s experiments, and
they are also using a mouse-adapted human TSE, which is
Gerstmann-Straussler-Scheinker syndrome, which although no relative
percentage of other forms of CJD we are not sure how that translates to
variant CJD.

Okay, and then the fourth one, leucodepletion doesn\'t reduce infective
geoplasma, basically, that was evident through the review of
experimental evidence, the infectivity may be present in components
without white cells.

Okay, so that\'s the relating to the infectivity of blood, and we got
the effects of processing, or processing-related issues.

In the U.K., we\'ve got this background risk from the BSE epidemic,
dietary exposure. We are only looking at the specific number of
implicated donations in the plasma start pool. We are only looking at
donations from people, from donors, who are known to have gone on to
develop variant CJD.

There\'s no cross-contamination during manufacture.

Every fraction manufactured could contain the potential levels of
infectivity found per unit fraction of blood. We are, basically, saying
that the figures that are presented to you from Brown\'s experiments, or
derived from Brown\'s experiments, those could end up in the plasma
fraction. We know that that\'s not possible because not the same amount
of every plasma fraction is used in the product of each batch, so there
might need to, again, be an overestimate.

We also assumed there was no reduction in infectivity through processing
beyond fractionation or through storage, which is unlikely. There are,
basically, three different approaches which were considered at this
level. There was no evidence for the apportioning of infectivity
according to protein content, which is one of the approaches considered
in the Det Norske report.

Experiments on naturally-infective plasma, the endogenous experiments
showed the infectivity falls below the limits of detection early in the
process, and that could be because of the low sensitivity of the test,
but also the very low levels of infectivity present. The alternative to
the endogenous experiments, the spiking experiments, we felt the
behavior of infectivity as shown by the spiking experiments may not be
the same as in endogenous infections.

Now, the U.K. ? the Incidents Panel, our Incidents Panel, decided that
either we could go with the spiking experiments, which did show
successive reduction beyond fractionation, or we could go with the
endogenous experiments, which dropped so low we couldn\'t detect it.
Either would be justifiable. We actually went with the measure of
infectivity in the plasma fractions of animals with endogenous infection
and assumed no additional clearance after that. So, there\'s no
clearance beyond fractionation. That\'s the worst-case scenario. It\'s
unlikely that that is the precautionary approach we took in the U.K.

Okay. So then we go on to the susceptibility of recipients. Okay. The
dose response for infectivity is linear, so, okay, we say we\'ve got one
ID50 is 50 percent risk of infection, the .02 is 100 percent of the risk
fraction, therefore, .02 is the 1 percent risk of infection.

The risk to patients is additive over their lifetime of exposure. Now,
animal models have suggested that the cumulative effect of regular doses
is actually less than the effect of a single cumulative dose, so to
speak, and actually, when Det Norske Veritas were developing their risk
model they decided that they would look at exposures, human exposures,
up to a period of one year, and then forget the rest. We took a more
precautionary approach, and we just said, cumulative exposures over a
lifetime, and that\'s what we looked at.

All recipients are equally vulnerable, well, we, obviously, did not take
into account genotype, of which all cases of CJD have been methionine
homozygous, although we have had this one instance of transmission of
infection to a heterozygote, no strain variation, no discrimination by
age. We took into account no host factors.

And then the final assumption was, obviously, that animal models are
applicable to humans, and, particularly, in relation to variant CJD.

Okay, so that\'s how we used the DNV risk assessment.

So then, it was how do we translate this into action? We\'ve got a
process for estimating batch risk, and individual risk, should we want
to take that approach, and we\'ve also got this framework. So, as Kate
was saying, the CJD Incidents Panel has advised that patients who are
exposed to a 1 percent or .02 ID50 or greater potential risk of
infection by surgical exposure, or exposure to plasma products, in
addition to the background risk from potential dietary exposure, should
be considered at risk of variant CJD for public health purposes. And, it
was a very important thing, this \"for public health purposes,\"
although we\'ve had these two cases, two instances of
transfusion-associated transmission, we\'ve had no case of variant CJD
in any patient regularly receiving plasma products in the U.K., and we
simply don\'t know how the risk of exposure to infectivity actually
translates to the risk of developing CJD.

Okay, so these patients are at risk for public health purposes, and we
needed to advise them of the special precautions that they needed to
take.

Okay. So, the first stage, the National CJD Surveillance Unit in
Edinburgh, handles the surveillance of variant CJD in the United
Kingdom, and our National Blood Services, obviously, consider the donor
population. They have a study called the TIMER review, which actually is
used to identify blood donors who subsequently develop variant CJD, and,
in fact, what happens is that all variant CJD cases are actively
investigated for history of blood donation or transfusion, and the
implicated donations are identified.

Now, when we launched this notification in September last year there
were nine donors, there are still to our knowledge nine donors who
subsequently developed variant CJD who donated blood for fractionation.

Having identified those donors, we identified plasma sent for
fractionation, and there were 23 donations of plasma sent for
fractionation, and then working with the product manufacturers we
identified the batches of plasma product or intermediate made from the
implicated plasma, and thereby the estimated dose equivalent is 1
percent risk. And again, we had to take 187 batches of product and
intermediate from these 23 donations from these nine donors, and that
situation still holds today.

Okay. The next step was, obviously, to estimate the infectivity
calculated using the process I\'ve just described to you, so that\'s
using the DNV risk assessment and also the batch specific manufacturing
data from the manufacturers, and what we managed to do was to look at
each of the products which had been implicated, so we had Factor VIII,
Factor IX anti-thrombin, immunoglobulins now being 4.5 percent, as well
as these other products. The intermediate excipient is used as a vehicle
or stabilizer in the final product batch, so with Factor VIII, the
actual factor concentrate here wasn\'t implicated, the albumin that was
used to stabilize that factor in the vial was implicated.

We looked at the infectivity for each of these batches, across 174 total
finished product batches, rather than intermediate, and we looked to
see, we looked at the sort of dose ranges that patients were likely to
have been treated with in clinical practice, and then so comparing that
with the infectivity to see how much of this product would actually be
required to cross the threshold.

And, as a result of that, we managed to stratify each of these
implicated products according to the likelihood of a patient who
received those products passing the 1 percent threshold. So, with the
Factor VIII, Factor IX anti-thrombin, that was high because a single
dose, or a fraction of a dose in the small ? a fraction of a dose in the
single-dose ? would be sufficient to cross this threshold.

With these products, with some of the intravenous immunoglobulins now
being 5 percent, there was a huge range in infectivity. It was feasible
that some patients, if they had been exposed to certain product batches
might have cross the threshold, but the majority of cases you would need
these volumes of albumin, say, to cross the threshold. So, in most of
these situations there wouldn\'t have been any risk, per se, in terms of
our public health action, but they were still an important group to
check, and with the low volumes required to have been so large that they
would not have been right in clinical practice.

And the advice that we gave was that we made efforts to trace the high
risk, we traced the high risk batches and the patients who received
them, because only a single-dose ? would be considered at risk, but the
medium risk batches, again, we\'d want to trace those products and
actually assess the individual exposure to risk, and with the low risk
factors the risk was negligible, and our advice was that the batches do
not need to be traced.

And so, that\'s what we did. But, of course, the next stage was,
obviously, assessing the ? was how we actually notified the patient
groups, and we identified three main groups of patients. We had patients
with bleeding disorders and congenital anti-thrombin III deficiency, as
well as patients with primary immunodeficiency, who are regularly
exposed to plasma products. Then you\'ve got the other group of patients
with a heterogenous group of other conditions, where they may, say
through treatment of severe burns, plasma exchange or certain
neurological conditions, be likely ? be exposed to these products in the
sort of one-off situation.

So, it\'s how do we best notify these people? Obviously, we developed
strategies for each patient group in collaboration with the patient
representatives, and also the clinicians treating them, so it really was
an iterative process to reach a consensus.

But, the main factors dictating the final choice were, obviously, the
likelihood of patients surpassing the threshold, the numbers affected
how we actually traced the products and, obviously, the potential impact
of the public health measures.

There were two main approaches. The population approach, which we took
for patients with bleeding disorders, which was that all patients with
bleeding disorders and congenital anti-thrombin III deficiency had been
treated with the U.K.-sourced pooled factor concentrates, or
anti-thrombin between 1980, when BSE first entered the food chain, and
2001, which was the last expiratory date of any product made in the U.K.
from U.K.-sourced plasma, should be considered at risk of variant CJD
for public health purposes.

And, this is what we termed the population approach, and it was based on
the fact that a single dose of implicated product in a small trial
fraction ? it should be the other way around, sorry ? would be
sufficient to place an individual recipient at risk, that not receiving
these products may not necessarily mean exposure hadn\'t occurred,
because future batches may be implicated. A large proportion of patients
were likely to be affected, and also that the use of a cutoff, this 1
percent cutoff, implied the degree of scientific uncertainty, which
given these other factors, and the context of care and the history of
previous notifications of other blood-borne pathogens in this patient
group couldn\'t really be justified, so that\'s why we went with the
population approach for this group.

For all other patients, we went on an individual approach, so patients
with other conditions, who had been assessed to be over 1 percent, to
have received a 1 percent level of infectivity, should be considered at
risk, and the decision to do that was based on the fact that for most of
these patients, most other patients, the products used to treat the
conditions were such that substantial quantities would be required to
place the recipient at risk, and, therefore, very few patients were
likely to be affected, and that\'s been borne out, really, by the
outcome of our notification, and also this approach was consistent with
the approach used for surgically-exposed patients.

Okay. So, those are the two approaches.

Very briefly, this is what ? this really summarizes who we will notify.
We\'ve got patients who received plasma products between 1980 and 2001.
Recipients of non-U.K.-sourced products, no action needed, they are not
in the equation here. Recipients of U.K.-sourced products are, or
patients with bleeding disorders, patients with bleeding disorders and
congenital antithrombin III deficiency between these dates, they were
all considered at risk and they were contacted directly by the
clinicians.

Patients with primary immunodeficiency, between these dates, \`96 and
2000, that was the dates in which the products were circulating, were
also contacted directly by their doctors. Not all of them were at risk,
they were individually assessed, but they could be handled by their
doctors because there were clinical networks that support these
patients.

It\'s with the other groups of patients, where it becomes, in a sense,
more difficult, because there is no clear clinical network or patient
support group to support these people, so the patients with
immunodeficiencies, certain neurological autoimmune conditions, patients
seen for severe bones plasma exchange, other patients who may have
received prothrombin complex concentrates, you know, with acquired
anti-thrombin deficiency or requiring rapid warfarin reversal, thus
anticoagulation, these are the groups we needed to trace through the
hospitals, and this is what we asked as part of the notification, was
that these groups, the hospitals actually trace the implicated product
batches down to individual patient level, and then we, at the HPA,
assess their level of risk and get back to them with the action they
need to take.

Okay, so that summarizes where the entire process underlying our work
last year on the risk assessment, and also the translation into public
health notification.

I\'ll just hand back to Kate to wrap up.

DOCTOR SOLDAN: Just to very briefly, really, mention ongoing
surveillance now has several strands. There is a study in place of
patients with hemophilia, and this protocol involves collection of
residual tissues taken during clinical curve, as well as requests for
post-mortem during life to be granted.

Also, another strand of monitoring this risk, of course, is the National
Surveillance cases, and review of that past medical history, to try and
identify any exposure through plasma products.

We are also working on developing follow up for other at-risk patient
groups, along the same lines as for the hemophilia patients.

And, of course, as always, all these methods have weaknesses and gaps in
ascertainment, heavy reliance in the U.K. on astute positions physicians
to pick up particularly unusual events in patients that they may think
to be associated with exposure to CJD.

I need to acknowledge, you can understand the process of risk assessment
and patient notification was no small undertaking in the U.K., and I\'m
sure this isn\'t a full list of contributors, but we do acknowledge the
contribution of many people in all of these organizations.

Thank you.

CHAIRPERSON PRIOLA: Are there any questions for either of the speakers
from the Committee?

Doctor Telling?

DOCTOR TELLING: So you mentioned that some major uncertainty relates to
the validity of using mouse-adapted scrapie and the effects of strain
and other effects have been more or less ignored in determining risk.
So, I\'m wondering whether the work of Houston and co-workers, who have
shown transmission of BSE in a sheep model by blood transfusion can shed
any light on modifying the risk assessment?

DOCTOR MOLESWORTH: Again, this is why we need Det Norske Veritas to
comment on this, but the work by Houston was incorporated into their
risk assessment. It was one of the experiments that they actually
assessed, and they decided to go with the work by Brown, but they did
incorporate an awful lot of other information. And, yeah, I\'m quite
sure there are various different scenarios which we could look at.

DOCTOR TELLING: Okay.

DOCTOR MOLESWORTH: Yeah.

CHAIRPERSON PRIOLA: Doctor Schonberger?

DOCTOR SCHONBERGER: You know, public health often uses human
epidemiology to make decisions, and I was wondering how you\'ve used the
tracing of recipients of the plasma products in your decision-making,
and also the results of the study of hemophilia patients in the U.K.,
which I understand does not show any lesions in these patients
indicative of prion infection. Is that not true?

DOCTOR SOLDAN: Well, on your second point, I mean that study protocol is
in place, but there\'s not really ? there\'s no power there, there\'s no
findings as yet that would lead you to say one way or another. I mean,
that protocol is in place, and being developed as we speak here today,
but, you are right, there\'s no findings to indicate infectivity, but
there\'s not been ?

DOCTOR SCHONBERGER: I don\'t understand why there would be no power. You
are saying that one dose, from 1980 onwards, would potentially put these
people at high risk, how many people have been studied?

DOCTOR SOLDAN: Well, what I was referring to was the collection of
residual specimens in post-mortem in those people, that\'s not ? we
don\'t have numbers of those events yet. We don\'t have residual tissues
collected and tested. We don\'t have post-mortem findings from those
patients.

So, the protocol is set up to do that, but as yet it hasn\'t yielded
very much.

DOCTOR SCHONBERGER: And, the follow up of ? is the statement that there
are no variant CJD cases amongst the group that have received these
products from known vCJD donors a true statement still?

DOCTOR MOLESWORTH: That\'s correct, as we all know, I mean, the National
CJD Surveillance Unit in Edinburgh would detect these cases. To their
knowledge, there have been no cases detected.

DOCTOR SCHONBERGER: So, cannot that type of data be entered into your
risk assessment, as to what the absence of cases, particularly, in
hemophilia patients which would have ?

DOCTOR MOLESWORTH: The whole basis of the risk assessment is
precautionary. I mean, we have no cases in recipients of plasma products
that we\'re preempting.

DOCTOR SCHONBERGER: Right, but can\'t you use ? I mean, the worst case
scenario would be assuming that those individuals were not infected,
what could still be the risk assuming ? in other words, one could look
at the absence of those cases and say there\'s no risk, we can forget
about it. The precautionary approach would be, well, we\'ve got those
observations, let\'s assume worst case scenario, that they\'ve avoided,
by luck or some other reason, getting the disease, what would then be a
risk consistent with the observation in humans? Has that kind of
approach been tried?

DOCTOR SOLDAN: I mean, the statistical monitoring needs to go on from
this point. We\'ve not yet got the person years of exposure monitored
that would exclude a level of transmission which is consistent with ?

DOCTOR SCHONBERGER: With what he observations have been.

DOCTOR SOLDAN: Yes.

CHAIRPERSON PRIOLA: Doctor DeArmond?

DOCTOR DeARMOND: Yeah, sort of following up on that, but from just the
basic data perspective. There\'s an assumption that there\'s two ID50
units in a unit of human blood, but can\'t that be measured? I remember
a couple of years I asked this committee, has blood been looked at in
detail, and I was told, or we were told by some representative from the
U.K., that blood was not allowed to be taken from these patients for
such studies.

But, it seems to me we should be able to look at that at this stage and
find out what the true ID50 is of human blood, of patients with variant
CJD. That would eliminate a lot of all these assumptions.

The other aspect has to do with the various purification of fractions.
The assumptions in none of your figures here of what it should be, the
assessment in, I guess, a whole unit of human blood is based, I guess,
on the animal studies.

DOCTOR MOLESWORTH: Yes.

DOCTOR DeARMOND: And, the question, even here the assumption is that the
animal studies represent ? the way they purify the fractions is
identical to the way fractions are purified in the human case.

On the other hand, there\'s the techniques for detecting abnormal prion
protein today are so sensitive, they are less than one infectious unit
based on bioassays. Those fractions can be tested today to get a better
marker of what infectivity is, what infectivity level may actually be
there.

So, this is very confusing to me as a neuropathologist, it\'s very
intense, based on a lot of assumptions, and I can see that there is some
real data that has to be obtained at this stage, and can be obtained at
this stage. It\'s more, what are your comments on that?

DOCTOR MOLESWORTH: My comments are I agree completely. I mean, it\'s
just based on the experimental data, it was updated in 2003 by DNV, but,
yeah, I mean, you\'ve got massive assumptions that human blood ? we
should have a far better idea of the infectivity in human blood, and
also the reduction in infectivity through processing.

I don\'t know myself how sensitive the tests are to very low levels of
infectivity, so I\'m not sure ?

DOCTOR DeARMOND: They are very good now, absolutely, the CDI assay is
very ? is superior.

DOCTOR MOLESWORTH: Yeah.

DOCTOR DeARMOND: It\'s a thousand-fold better than Western.

DOCTOR MOLESWORTH: Yeah.

DOCTOR SOLDAN: We don\'t as yet, am I right, we don\'t as yet have a
test sensitive enough for testing bloods, so though that\'s the
direction things are going, we don\'t yet have it.

DOCTOR DeARMOND: That\'s not true. There are ? this has been presented
at meetings in Europe and in the U.S., you can actually in sporadic vCJD
cases you can detect abnormal prion protein in blood. It\'s not very
much higher than controls, but you can detect it, but we have no clue as
to what it is in a unit of blood from a variant CJD case.

DOCTOR MOLESWORTH: Yeah.

DOCTOR DeARMOND: And, that should be known at this stage.

CHAIRPERSON PRIOLA: Well, there\'s certainly been no proved test for
detecting in blood.

DOCTOR DeARMOND: You mean approved test.

CHAIRPERSON PRIOLA: Yes, yes, yes, so there\'s nothing ?

DOCTOR DeARMOND: There is a proved test, but not an approved test.

CHAIRPERSON PRIOLA: Right, right.

Doctor Salman?

DOCTOR SALMAN: Can you comment on what the range you used for the
fraction-specific infectivity in your equation?

DOCTOR MOLESWORTH: In can\'t comment on the range for that, that comes
out of the DNV report.

DOCTOR SALMAN: So, it\'s only from the animal data, is that right?

DOCTOR MOLESWORTH: Yes.

DOCTOR SALMAN: But, you combined both the use of instruments and the
blood donors, in the one risk assessment, is that correct?

DOCTOR MOLESWORTH: No.

DOCTOR SOLDAN: No, there\'s been two sets ? there was a risk assessment
done on surgical ? contamination of surgical instruments, a separate
risk assessment did on bloods and blood products. Is that your question?

DOCTOR SALMAN: Yeah, but you used the same threshold, is that right, of
.02 ID50?

DOCTOR SOLDAN: Yes.

DOCTOR SALMAN: What\'s the justification for that, to be used for both?

DOCTOR SOLDAN: Well, when the surgical risk assessment was considered, I
mean, it was based on the model of which I showed you one example.

DOCTOR SALMAN: Okay.

DOCTOR SOLDAN: And, balancing the practicality of tracing recipients ?
sorry, tracing exposed patients with the reduction of the risk. So, the
cutoff was taken at a point which was felt to balance the number of
patients to be contacted and informed and managed in this way with the
reduction of the risk. And, the 1 percent threshold was considered a
pragmatic and public health sensitive threshold.

When the panel came to consider the plasma product risk assessments, the
same threshold was applied in order to be consistent with the surgical
exposure, and follow a consistent approach, in the absence of any real
evidence that a different approach would be better.

DOCTOR SALMAN: And, it seemed like you have not done the sensitivity
analysis to see how sensitive this type of threshold.

DOCTOR SOLDAN: I\'m not sure I understand.

DOCTOR SALMAN: For the risk assessment, have you done any sensitivity
analysis on some of the parameters you use in the equation?

DOCTOR SOLDAN: Did the DNV risk assessment includes sensitivity
analysis?

DOCTOR MOLESWORTH: No.

DOCTOR SOLDAN: In think the range, it was always acknowledged that the
uncertainty was great, and ranges were given around some of the
parameters, but not on the cutoff.

DOCTOR SALMAN: Okay, thank you.

CHAIRPERSON PRIOLA: Doctor DiMichele?

DOCTOR DiMICHELE: Thank you.

In sort of pursuing the issue of getting tissue or getting evidence
prospectively, could you describe the surveillance program for
hemophilia that\'s underway, with respect to what tissue, in whom, are
hemophilia A and B patients being looked at similarly, and is this going
to be a voluntary or, you know, less voluntary program?

DOCTOR MOLESWORTH: Yeah, I can do my best. I don\'t know all the details
of it myself.

The U.K. Hemophilia Centre Doctors Organization has a study which is set
up to monitor exposure to variant CJD implicated plasma products in the
patients on their register, and that register was, I think, set up about
three years ago.

And, the patients currently on their register include hemophilia A and B
and von Willebrand\'s disease, they don\'t include anybody else, so we
are going ? we are working with them to expand that, that protocol.

In addition to monitoring ? to monitoring exposure to variant CJD
implicated products, and, obviously, the outcome of that exposure, the
long-term outcome in that patient group, they also have tagged onto that
the information relating to the outcome of tonsillectomies and, I think,
appendicectomies, that have been tested by the National CJD Surveillance
Unit in Edinburgh, and I don\'t know whether they test PrPsc-positive or
not. The actual intricacies of how that mechanism works I myself am
unclear on.

DOCTOR SOLDAN: In mean, I can just add a little bit to that I think. The
protocol involves, certainly, informed consent or dissent to tissues
removed during the course of clinical care to be referred for testing,
and also consent or dissent in life to investigations afterwards. So, it
is with consent.

CHAIRPERSON PRIOLA: Doctor Petteway, and then Doctor Belay.

DOCTOR PETTEWAY: Thank you.

Just a couple of questions relating back, again, to the assumptions made
on process and removal, and I wonder if there was an analysis done of
the process that was used by Brown, et al, when they did their studies
relative to the fractionation process as it were used to actually make
the products in that correlation.

And then the other is, you know, when you are informing someone of risk,
I think a lot of assumptions went into this, but one of the key
components of assessing risk for pathogens, certainly, for viruses, has
been removal or inactivation during a specific process. And, not to
include that probably doesn\'t allow you to inform whoever you are going
to inform of a more holistic sort of approach to risk.

And, I think, I mean, this is a very good approach, and I think you\'ve
done a great job, but leaving that out and not applying it probably
doesn\'t give you a good idea of risk for each product, and I just
wonder, you know, what were the components of that discussion, and why
did that get left out?

DOCTOR MOLESWORTH: In mean, issues like this were thrashed round and
round various committee tables over about a nine-month period. I can\'t
actually tell you why it ended up like that. I\'m not quite sure. I
think the important message is not so much to focus on individual risk,
but to look at the relative risk of each product in relation, so that I
would be happy saying that they clotting factors are higher risk than
the immunoglobulins and the albumin. But, in terms of the actual batch
specific infectivity as calculated, yes, there are huge numbers of
assumptions, and they cannot ? I mean, if you look at the assumptions
you know that they cannot be right in themselves.

We really did try and convey that message when we were notifying the
patients, we said you are at risk for public health purposes, but we
don\'t know how this translates to your risk of actual exposure to
infectivity or to developing CJD.

I mean, it\'s very difficult to get that message across.

DOCTOR PETTEWAY: In appreciate that, and that was, you know, the basis
of my question, and so you did clarify that as you made your
communications.

DOCTOR MOLESWORTH: Yes.

DOCTOR BELAY: I was just curious about the total estimated number of
patients that have been notified, and whether or not discrimination in
clinical care, for example, was a problem.

DOCTOR MOLESWORTH: Okay.

There were about 6,000 patients with bleeding disorders notified of the
situation, of whom about 4,000, we estimate, fell into that ? into the
at-risk category under the population approach.

And again, our U.K. Hemophilia Centre Doctors Organization is collecting
the data so they will be able to provide some more up-to-date figures on
the actual numbers who were placed at risk in that group.

In terms of patients of primary immunodeficiency, there are no patients,
to our knowledge, or to the clinical networks, who undertook the
assessment who have been placed at risk. So, not one patient with
primary immunodeficiency who received repeat doses of intravenous
immunoglobulin received sufficient to be placed at risk.

In terms of the other patients, we have ? we\'ve been collecting
information on those patients and performing the individual exposures,
we\'ve received, I think at the end of last year we\'d received about
19,000 ? 1,900 exposure assessment forms, of which I think it was about
?

DOCTOR SOLDAN: About a dozen.

DOCTOR MOLESWORTH: Yeah, about 12 patients who\'d been actually placed
at risk, most of whom had actually received the anti-thrombin III or the
prothrombin complex concentrates, and only about three of them had
received sufficient albumin to be placed at risk.

Okay, so we are dealing with very small numbers there.

DOCTOR SOLDAN: So, the bulk of the impact in terms of clinical care is
with those 4,000 hemophilia patients, and at after examining some of the
issues we\'re working through with quarantine of instruments and,
therefore, the services those patients may have, whether the services
would be in any way compromised by the need to quarantine instruments
after procedures on those patients. And, that\'s something we are
working through at the moment.

There doesn\'t seem to be a huge crisis as yet, but, of course, there
are certain areas of healthcare that are raising concerns about the cost
of quarantine and the implications for service.

But, there are ways to manage that, which we are trying to develop now,
in order to minimize the impacts, both on those patients and on other
patients.

DOCTOR BELAY: Do any of your at-risk patients include Factor XI
recipients, because that\'s what this Committee is considering today.

DOCTOR MOLESWORTH: Those patients, if they exist, will be encompassed
under our population approach to patients with bleeding disorders, but
remember, we ? the whole notification that we dealt with was based on
implicated products, products which had been implicated by a donation
from a known donor who subsequently developed variant CJD. Factor XI was
never implicated, it was only Factor VIII, Factor 9 and anti-thrombin
that to date have been implicated.

CHAIRPERSON PRIOLA: Doctor Allen?

DOCTOR ALLEN: Thank you.

When I first put up my hand I had wanted to get into this area of
recipient notification, and you\'ve answered some of the issues. Can you
tell us a little bit about the response of the people? You already
commented on the difficulty, obviously, of conveying what the actual
degree of risk is, and could you also comment on what the reaction of
physicians is, since you are using the primary care physician for
notification, as we would probably do in this country, and I think the
difficulty of trying, in my view, to bring primary care physicians up to
speed in terms of how to do the notification, and what to say, is
probably equally as difficult as notifying the patients.

DOCTOR SOLDAN: I\'ll start, Anna, maybe you can add some points.

I mean, I think this process is still very much in process for us, so
it\'s a little bit early to feed back to you the response from the
patient group on the whole. I mean, we are having early and ad hoc
responses, but we\'ve as yet not investigated, particularly, not
investigated patient response, and not greatly clinician response
either.

After the notification of recipients of blood components, which was a
much smaller group, that was the first notification of this type that we
did, we did a survey of the clinicians who did that notification, and
whether they found they were the appropriate people to deliver the
notification, and whether the patients found the information acceptable.
And, on the whole, that was the message that came back, that the primary
care physician was the appropriate person to deal with this situation,
bearing in mind it\'s going to be a chronic one, and also that in
general the patients accepted the information fairly stoically.

We don\'t as yet have any ? and, obviously, it\'s a much larger group,
and so in discussions we\'ve been consulting with social science
colleagues in order to do some study of the response of the patients in
this larger group.

CHAIRPERSON PRIOLA: Doctor Bracey and then Doctor Schonberger.

DOCTOR BRACEY: Actually, my comment related to what Doctor Allen was
commenting upon, and that is the great degree of difficulty in training
the communicator. We have experience here with CJD, tremendous problems
in terms of the vCJD travel restrictions in terms of training the
communicator, the primary physician. So, I would just caution that they
will be a tremendous undertaking.

DOCTOR SCHONBERGER: In wonder if you could clarify again how you are
handling the Factor XI recipients who, of course, as you say, have not
received product linked to a known vCJD donor, but I saw that you were
regarding them potentially at risk, but you are not ? can you clarify
how you are handling that again?

DOCTOR MOLESWORTH: This is correct.

Patients who receive Factor XI are included under our population
approach. All patients with bleeding disorders who received U.K-sourced
plasma between 1980 and 2001 are considered at risk, and, therefore,
they are being handled in exactly the same way as every other patient
within that umbrella, regardless of whether or not that patient received
an implicated product. So, they will be treated the same way as a
patient who received five vials of implicated Factor VIII, either be
approached by a clinician, they will be told there is this possible
potential risk of variant CJD infectivity that they may have received
through plasma products, and that they are asked to take these special
public health precautions to reduce the possibility of onward
transmission.

DOCTOR SCHONBERGER: But, that hasn\'t been done yet, and we don\'t know
how they\'ve reacted, is that ? I was trying to figure out what your
answer to Doctor Belay was.

DOCTOR MOLESWORTH: It has been done, that was the patient notification
that took place in 2004, but as Kate was saying, we have not ? we do not
yet know what the individual patient responses have been to those
patient notifications.

DOCTOR SOLDAN: It\'s, perhaps, important to clarify there that it\'s
only patients with bleeding disorders who come under that population
approach. So, a patient without a bleeding disorder anti-thrombin
deficiency, who had received Factor XI in the U.K., is currently
non-notified. Is that your question? Because they\'ve received no
implicated product, and they don\'t come under the population approach.

CHAIRPERSON PRIOLA: Doctor Epstein, do you have a comment?

DOCTOR EPSTEIN: Yes.

I have two questions, first for Doctor Molesworth. Could you just
clarify for me, when you look at the estimated threshold for receiving
.02 ID50, and then you determine whether a patient is or is not in the
at-risk category, is that based on their historic product use, or does
it include some effort prospectively to look at their likely product
receipt, say, over a year or over a lifetime?

DOCTOR MOLESWORTH: No, it\'s only based on the information that we
receive on exposure to the specific implicated product batches.

DOCTOR EPSTEIN: SO, how much implicated product did the patient receive
is the question you try to answer?

DOCTOR MOLESWORTH: That\'s exactly it, yes.

DOCTOR EPSTEIN: Okay.

And, looking at these numbers, am I correct to conclude that for
clotting factor and AT3 patients receipt of an individual dose would be
likely to exceed the threshold?

DOCTOR MOLESWORTH: Yeah, that\'s correct, and that was one of the
factors which fed into this population approach, was it because such low
doses were received, and because vials of this stuff were distributed
throughout the U.K., a large proportion of individuals were likely to
have been affected.

DOCTOR EPSTEIN: And then, my last question is, could you comment whether
the tissue surveillance studies that have provided a finding of,
roughly, three positive appendices out of 12,000 surveyed, suggesting
that there might be a higher level of latently incubating infection of
the population may affect these estimates that we\'ve been hearing? In
other words, in light of the tissue survey, has there been any effort to
reexamine the risk estimates, for instance, in pools of 20,000 you
might, first of all, expect a much higher frequency of contaminated
pools, and secondly, the risk of multiple positive units contributing to
a pool is not trivial if those rates are, in fact, real.

DOCTOR MOLESWORTH: I\'ll pass this on to Kate, but the main message I
think is important to get across, we\'ve got a different situation in
the U.K., because we have this background risk to exposure to variant
CJD, so that, we didn\'t consider the possibility ? I mean, yes, we
recognized that there will be in the future other donations who will
become implicated, but didn\'t factor that into this risk assessment,
because we are already sitting on this background risk, where everybody
in the population is being exposed. So, no, we didn\'t incorporate that.

If you want to say something more.

DOCTOR SOLDAN: Yeah, there\'s not much to add. I mean, the answer is no,
in light of the prevalent studies these risk assessments have not been ?
not as yet been redone.

CHAIRPERSON PRIOLA: In think we\'ll have one more question and then
we\'ll move on.

Doctor Nemo?

DOCTOR NEMO: I\'m still unclear on how you treat the Factor XI
recipients. Now, they\'ve never received any implicated lots, but what
public health message are you giving to them? Are they not to donate
blood as well?

DOCTOR MOLESWORTH: Yeah, that\'s correct, because Factor XI recipients,
under the population approach for patients with bleeding disorders, same
as any other patient with bleeding disorders who is incorporated in that
approach, not to donate blood, tissues, organs, to inform their medical
carriers and dentists, and also to tell their families.

CHAIRPERSON PRIOLA: Will both of you be here for part of the day, or the
rest of the day?

DOCTOR MOLESWORTH: Yes.

CHAIRPERSON PRIOLA: Okay.

So, if there are anymore questions from the Committee members,
especially during our discussion period, they\'ll be around to answer
them. So, keep those questions in mind.

So, with that, we\'ll move on to Doctor Anderson, from the FDA, who is
going to provide us with the risk assessment for Factor XI.

DOCTOR ANDERSON: All right, good morning. My name is Steve Anderson, and
I\'m the Associate Director for Risk Assessment, in the Office of
Biostatistics and Epidemiology, at the Center for Biologics Evaluation
and Research.

Today I\'m going to talk about a draft risk assessment that we have for
U.K.-manufactured Factor XI and potential variant CJD exposure.

All right. Now, generally, FDA follows this four-part framework for risk
assessments that we conduct in the Agency. The framework was initially
developed by the National Academies of Science. The four elements shown
in this slide consist of hazard identification, dose response, and
that\'s also known as hazard characterization in some certain other
frameworks, exposure assessment, and then risk characterization.

Now, just for brevity purposes, I\'ve put brief descriptions for each of
these components, but I think I\'ll hold off the explanations for each
until I get to those portions that I describe in the risk assessment.

So, I have a lot of caveats in my talk, because I think the main wall
about what we are going to be talking about here is quantitative risk
assessment, and if anything you take away from this risk assessment
process is uncertainty.

So, commonly, what we do is we use risk assessment as a process, when
uncertainty about a risk is particularly high. Uncertainty, again, is
pervasive throughout risk assessment, so everything that I say there\'s
a degree of uncertainty in the calculations, in the assumptions we make,
and in many of the components of the risk assessment that I\'m going to
describe.

Just for sort of a clarification, because you hear this term, risk
assessment, a number of times, I\'m going to be describing our risk
assessment, and our risk assessment, actually, consists of two
components. It consists of a model, in this case a computer model that
we\'ve done, that contain all the calculations that are contained in
this document, and then the document is a summary of those mathematical
equations, and it\'s organized according to the National Academies of
Science framework.

So, that\'s just for a simple clarification.

Now, more about quantitative risk assessment. I\'m just going to sort of
briefly go through some of these.

The purpose of quantitative risk assessment is to link the relevant data
together in a meaningful way. We are trying to estimate potential
exposure and risk, and I think one important thing here is that there\'s
going to be a heavy reliance and emphasis on exposure and less on risk,
because we are more ? although we have a high degree of uncertainty, we
are more certain, or there\'s less certainty, let\'s say, about
exposure, and a high degree of uncertainty about estimating risk. So, we
are going to emphasize sort of the potential exposure and exposure
assessment aspects in this model.

Also, risk assessment provides us framework to identify critical
elements where research will improve the model. It\'s also an important
process in understanding key elements, that what we say is the elements
that drive the risk, or heavily influence the final risk estimate. And
then, I think it\'s important to remember that this is an iterative
process, so, you know, the document that\'s been submitted and that you
are seeing is really sort of the first part of this whole process, and
we are going to probably be ? well, not frequently, but we are probably
going to be updating this model as new data and information, and we
conduct a peer review process on this model, go on.

So, this is really just a starting point or a jump-off point for the
next stages in the process, so let me move on to the draft risk
assessment for Factor XI and variant CJD.

Okay. So, what we\'ve got, actually, I\'ve got this long question here,
so given the probable ? the recent probable transmission of variant CJD
via transfusion of non-leukocyte-reduced RBC concentrates, or red blood
cell concentrates, the important question for me is here as a risk
assessor, what is the risk to U.S. recipients that received human
plasma-derived Factor XI product from 1989 to 1997 that was manufactured
from U.K. plasma? So, that\'s the question that gives this risk
assessment its scope and its shape. We are interested in this risk from
this product that was manufactured in the U.K., and was used in the
United States during this 1989 to 1997 period, as Doctor Weinstein said,
under investigational use.

Okay. So, Doctor Weinstein has also given us some background about
Factor XI. Again, it\'s a clotting factor present in low concentrations.
The deficiency is rare. Bleeding is less frequently observed than that
of other hemophilias, especially A and B, and bleedings associated with
surgery.

All right, so, all right, I\'m going to start sort of just walking you
through these components that we\'ve applied this risk assessment
framework to for the Factor XI risk assessment. So, I\'m going to start
with hazard identification.

Hazard identification is this in-depth review of the available data and
information. So, we\'ve done an exhaustive, or extensive, literature
review, pulled in all the information that we had available to us, and
what that information does for us is it establishes ? we try to
establish a causality between the hazard, which is the TSE agent in
blood, and then infection or illness, what\'s the possibility or risk
that we could have vCJD infection caused by this hazard of TSE or vCJD
agent in the blood, or what\'s the possibility of illness?

Sort of just rapidly moving on, these are the kinds of things, although
in the risk assessment you\'ll see there\'s much more detail that we
include, so we have two recent cases of probably transfusion transmitted
variant CJD in the United Kingdom over the past year and a half. Now,
that raises this possibility of transmission of variant vCJD via
plasma-derived products. And, I think it\'s important to emphasize this
last bullet point, which is, to date variant CJD transmission via plasma
derivatives has not been observed, and that\'s significant, and I\'m
going to discuss that a little bit more in detail in a moment.

Any time you see this bullet point sort of highlighted, this is pink or
orange, Factor XI risk assessment, I\'m specifically talking about the
risk assessment. I\'ll also be making some general points about risk
assessment in this talk, too.

So, in the Factor XI risk assessment, we considered vCJD transmission
via Factor XI as a potential hazard. So again, we haven\'t really
observed cases or transmissions via Factor XI of variant CJD, but there
is a potential, given the transmission in blood products. And again, we
are just indicating that the U.K.-manufactured Factor XI was used in the
U.S. during this period of time.

Quickly moving on, the next component of risk assessment is dose
response, again, called hazard characterization. All right, what is dose
response? Dose response relates to the amount of agent in a particular
dose to the probability of infection or illness. If you look at this
simple dose response model, what I have is a linear relationship, and
the power of dose response models is that you can, on the X axis we have
this probability of infection ? or, I\'m sorry, along the Y axis we have
this probability of infection, and along the X axis at the bottom we
have this quantity of agent. So, if we had a quantity of agent, say, two
organisms, that would be associated with the 50 percent probability in
this case of infection.

And then, we can use this to link dose that we get from exposure
assessment. So, if we knew that our exposure assessment said we were
exposed to two organisms, using this dose response we could say, well,
that person that\'s exposed to two organisms has a 50 percent chance of
infection.

Now, the issues for TSEs, and the challenges that we face, is that dose
response is very unclear for TSEs. First of all, human data are absent.
I think we\'ve had some conversations about that already and
discussions, and I think people recognize some of the limitations that
we have.

Human data is absent. Again, one of the most important things, I think
one of the Committee members mentioned, was that we really need to get a
handle on the quantity of agent in human blood or plasma. We know
there\'s possibly variation in the amounts, maybe people have early on ?
don\'t have the agent in the blood early on, but as infection
progresses, perhaps, the agent appears in the blood. The question for us
also, is it present throughout the entire incubation period or are there
sporadic occurrences in appearances of this agent in blood?

We also are thinking about genetics and susceptibility of humans, an
important factor, is there a threshold or not for this agent? Do you
need 100 ID50s, animal ID50s, to become infected, or do you only need
one? So, we don\'t really know that, and we don\'t know if you get
exposed to fractions of infectivity of an ID50 what does that
particularly mean as far as infection and a threshold?

And, another issue for us is, is there a cumulation of the agent in
humans? We certainly don\'t know that that occurs at this moment in
time.

What we do have is, is we have some animal data available to us, and we
do use this in our risk assessment. The question for us is, though, does
this animal data that I\'m going to talk about approximate the human
situation as well as we\'d like, and we don\'t know that until we have a
comparison in the human to make any assumptions about this. Our current
assumption in the models is that the animal data is comparable and
reflects the human situation on a one-to-one comparison.

The next thing I\'m going to talk about, this is more of a
clarification, since this term is going to come up constantly, I\'m
going to use this term, ID50, all the time. ID50 is a commonly used
terminology, and it\'s sort of a metric or the currency that we talk
about in TSE risk assessment. So, one ID50 we defined as a dose
necessary to initiate infection in 50 percent of the exposed population,
and I think it\'s important to sort of qualify what this term actually
means. The inferences are based on animal TSE data, so any ID50 that I
talk about is really, you can just put animal ID50 in front of that,
because that\'s what we are actually looking at.

Extrapolation of animal data, that the human outcomes is highly
uncertain. Assumptions in risk assessment, again, I just mentioned this,
animal data approximate infection and illness in humans at the same
rate. We don\'t know actually if that assumption is accurate or not.

And, I think an important thing to consider, too, is that exposure, if
you are exposed to this agent that may not necessarily lead to
infection, and then if you are infected with this organism ? I\'m saying
for saying organism, but with the prion, infection may not necessarily
lead to illness. So, I think that\'s an important issue, too, that
we\'ll talk about in some of the prevalence studies, because there may
be a number of infections that may never progress to full-blown illness,
and those may not be captured in some of the estimates of prevalence
that are currently being used by other researchers and risk assessors.

Just to sort of summarize this whole dose response issue for us, dose
response, we believe, provides a useful link in estimating risk based on
exposure. I think it\'s safe to say that dose response at this time is
really lacking for TSEs, or at least you can say is highly uncertain. We
can use the ID50 as a guide for us, but I think we have to have all the
caveats, but that is really an animal system measure that we are using
and applying to the human system. So again, there\'s going to be that
big sort of gorilla in the room, which is uncertainty about this
estimate.

So again, therefore, predicting probability of variant CJD for humans is
extremely uncertain. I\'m going to keep on sort of saying that time
after time.

Okay. Now, moving on to the exposure assessment, and I just wanted to
say, this is the largest component of our model and of our risk
assessment. So, what we are actually doing is we are conducting a model
of an exposure assessment, and then we\'re going to make some
conclusions about risk in a moment.

So, what I want you to take home from exposure assessment are sort of
two key factors, and those are, in exposure assessment we look at the
routes of infection and how a person might become infected or exposed to
a particular hazard. We know that, and that\'s well characterized for
Factor XI, people receive that product due to being part of the
investigational drug studies in the United States. The other component
of that that are really important for exposure are, what\'s the
frequency of exposure or the probability of exposure to the variant CJD
agent, and then the second component of this exposure assessment is
quantity. So, if we know that a person has been exposed, how much of
this particular agent have they been exposed to. That\'s an important
question for us to try to answer.

And, just sort of moving on, this is sort of just a brief outline of the
model as I\'ve laid out. So, what we have are three basic components,
Parts A, Module A, Module B, Module C, that I\'m going to show you in
just a second.

Module A, what we are trying to do is, we are trying to predict the
probability and the quantity of variant CJD ID50s in a plasma pool.
Again, we want to know the probability, and probability not only is
related to the possibility that we\'ll get a positive batch, but it\'s
also related to the amount of agent that you might see. So, I think
Doctor Epstein had asked the question that, you may have multiple doses,
perhaps, or multiple donations from several variant CJD donors in a
particular pool, if the prevalence of the disease is high enough in the
population, or the infection is high enough. So, I think that\'s
something very important to consider.

So, probability begins to ? as prevalence begins to move up, you are
going to see more of this affecting the quantity of agent that\'s
actually in the starting pool.

All right. And then, I think another important aspect that we carefully
consider is reduction going on during manufacture, so I\'m going to talk
more about that in a moment, and then dose per surgery. This is actually
how much of the dose of the product do they receive, and then how much
dose of the agent do they actually receive, of the variant CJD agent.
So, the quantity of variant CJD in the final product, and then we
consider the amount of product actually used by patients.

So, here\'s sort of a cartoon version, again, of our Factor XI risk
assessment, so I\'ve indicated this as part of our assessment in orange,
and if you go through this what I wanted people to sort of get out of
this is that we have these inputs going into the model, we have
probability of variant CJD in the United Kingdom, number of donations,
et cetera, and we have it going through a number of calculations, and
then we have outputs for each section. Those outputs feed directly next
into the next section, and then so on an so forth. So, what we\'ve got
are these three major modules that I just described, and ultimately what
we are getting out of this is, we are getting the exposure to variant
CJD IV ID50s, we are doing that by vial per unit of Factor X, and then
for three specific scenarios that patients might encounter as they are
being treated with this product.

So, that\'s sort of the quick overview.

All right. So, this is probably one of the most difficult things for us
to calculate, so Module A, the variant ? the probability and quantity of
variant CJD ID50 in a plasma pool. There\'s a high degree of uncertainty
with these estimates, so I\'m going to explain to you two approaches,
and there\'s sort of a disparity in the literature as to the estimates
that are coming off each approach, and I\'m going to talk about those in
just a second.

Again, what we are trying to do is calculate this probability that ID50s
will be in the pool or product, and that\'s directly related to this
estimate of prevalence. So, it\'s important to sort of get this estimate
of prevalence as accurately as possible, although a lot of uncertainty
again, and what we are doing is looking at the estimation of prevalence
of variant CJD in the U.K. population for this particular model.

All right. So, what we did was, we considered the various estimates
going about in the literature for mathematical models, and there are
several. So, there\'s Ghani, and I think one thing I should sort of
delineate is that these models are sort of linked to the actual cases
that are being observed. So, what you\'ll see is that early on the
estimates were extremely high, 236,000, but as we\'ve seen in the last
three years the actual number of cases that started to decrease, what we
are seeing is people\'s estimates of the number of symptomatic cases are
also going down.

So, if you look at Ghani\'s estimates from 2000 to 2003, we go from
70,000 to 236,000, he has several estimates in his paper, this is one of
the most extreme estimates, and that correlates to about as low as one
in 500 possible cases incubating in the population to about one in
800,000.

Okay. So, as you get up more and more into the more recent data, those
numbers are going down. He\'s estimating a median of about 100 cases and
that works out to about one in 500,000 in the population.

And then another paper, Llewyn estimated the possible number of
infections incubating in the population at one in 15,000 to one in
30,000.

And, I think one thing that I should say about these models that\'s very
important is, these models are predicting the number of clinical cases
that are expected to arise in the future, and what they don\'t capture
is the number of non-clinical, or asymptomatic, or latently incubating
people that will never become symptomatic, will never become ill. They
are infected, but they\'ll never become ill.

We don\'t know the size of that population, but these models don\'t
actually capture that, so that\'s one of the issues that we\'re trying
to resolve, and so what we\'ve chosen is another strategy, is to use
surveillance data. So, the most recent surveillance data that\'s come
out, and this is a study by Hilton, et al, and it\'s a surveillance
study of tonsils and appendices, and what they\'ve done is, they\'ve
identified three positive samples, samples from three different patients
were positive in a total of 12,674.

And, what they estimated in that paper is that gives you a rate of about
237 positives per million individuals in the U.K. population. If we walk
that down to estimates for our model, what we assumed was that we would
have one positive individual in 4,224, just a strict interpretation of
this data.

So, I wanted to provide somewhat of a rationale for us using this data,
and I think these data, for us, are very compelling, first of all
because they are surveillance data, they are not modeling data, there\'s
not much more modeling done o them. There\'s not much more analysis done
on them, so they really represent what we consider real data of possible
incubating cases. So, we think this data are actually capturing some of
the incubating cases that won\'t progress to illness, as well as those
cases that will progress to illness.

Now, we know this is somewhat of a conservative approach, but again, the
uncertain estimate of the prevalence I think sort of necessitates that
we take this approach and use these numbers.

Again, the modeling data sort of mostly estimate clinical variant CJD
cases and won\'t really capture those asymptomatic cases. And, I think
it\'s important to emphasize that the non-clinical or asymptomatic
infections probably have the similar potential for transfusion
transmission as somebody that\'s going to progress to clinical illness.
So, I think that\'s sort of our reasons for using this data.

So, you may want to circle this slide, because this is going to be a
point that we may want to discuss later on in the discussion.

Again, this is just a summary of the different types of data in the
United Kingdom that have been presented, mathematical modeling results
are out there in the literature and surveillance studies.

In the United States, I think I\'m going to not discuss this, because we
are going to discuss this point more fully in the second presentation
that I\'m going to be giving, so let me just move on from there.

All right. Now, I\'ve just discussed, in our Factor XI risk assessment
we\'re interested in the probability of exposure, and prevalence of
variant CJD determines the number of variant CJD donations per pool. So
again, if we take that Hilton data, and we look at it, again we are
getting one positive in 4,225 individuals, we\'ll round it up, or down,
and what that actually breaks down to is, we consider processing for
20,000 donations, so a pool of plasma donations in the United Kingdom,
the average size of the pools that were used to make Factor XI was about
20,000 donations, and in that what we would expect, just applying these
numbers, is that we would have approximately 4.7 donations on average
per pool. So, not just one, but we\'ve got almost five, so that\'s a
significant amount. Not only do we have nearly 100 percent of the pools
predicted to be contaminated, but we also have this larger number of
donations going on, so about an average of five times more infected
material going into those pools.

And, what I did was, I just wanted to show how we actually arrived at
calculations in the model, and what we did was, we just adjusted, these
are numbers per million, 237 per million, coming out of the Hilton
study, and the range on that, with their 95 percent confidence
intervals, was 49 to 692. We, basically, just divided these by 50,
because it\'s 1 million up here, 20,000 down here, that\'s dividing by
50, and we get a mean of about five donations or variant CJD donations
per pool of 20,000 donations, and the range on that went as low as zero
and as high as, potentially, 14, although this is a much less likely
event.

So, that\'s how we actually sort of took this data and adapted it for
our uses in our model, based on the 20,000 donations going into a plasma
pool.

All right. Our next question then is, we\'ve got this probability, and
we\'ve got a little information on quantity, we wanted to get more
information on quantity. So, in general, what\'s the quantity of TSE
agent in the starting plasma pool, the amount of infectivity per
donation in pool had to be calculated, so we estimated infectivity in
human blood derived from animal data. So again, we are using animal data
to draw these conclusions.

We also wanted to estimate the number of TSE donations per pool, and
we\'ve done that using the Hilton data, and it\'s just important to
remember, the higher the prevalence and incidence of the disease the
greater the chance of multiple donations in a pool.

All right. So, you may want to circle this slide, too, because these are
some of the major assumptions we are going to be talking about in the
talk. So, this goes to the Factor XI risk assessment, how did we
calculate the quantity of variant CJD ID50s that were present per ml of
plasma, and what we did was, we used animal studies, and we used what\'s
called a triangular distribution, because this is a probabilistic risk
assessment. We are not using just ten ID50s and calculating things out,
we are saying, minimally, there could be .1 ID50s per ml of blood, but
we are estimating, well, most likely from the data that we\'ve seen that
there are ten ID50s, but we actually suggest that there could be a
maximum of 1,000 ID50s.

I just wanted to sort of summarize some of the data sort of verbally, so
what we did was, I think some of this data is also described in the risk
assessment, but we also relied on Doctor Paul Brown\'s data to make
these estimations. That\'s why we are assuming our most likely is around
ten, because his estimates came up in 1988, I\'m sorry, 1998 and 1999,
with an estimate of ten to 20 ID50s per ml of blood, and then also Bob
Rohwer\'s group at the University of Maryland also did some more
studies, there\'s were in the range of two to 20 ID50s per ml of blood.
So, we have a heavy emphasis down towards the lower range, but we are
acknowledging that there are some experiments done by Paul Brown and
others that are sort of up at the high end. So, we still have to sort of
incorporate that into our estimate, so we did that with this
distribution.

All right. The second part is, what fraction of the infectivity in blood
is associated with plasma. We assumed based on experiments by Luisa
Gregori in Bob Rohwer\'s lab at the University of Maryland, that 58
percent was associated with plasma, very similar to the Paul Brown
estimates of around 50 percent or slightly higher than 50 percent. But,
we chose 58 percent as our estimate.

The other thing to do that we did was, we adjusted for the efficiency,
and there is a reduced efficiency for intravenous units versus
intercerebral ID50s. So, what we\'ve got up here at this point is
intercerebral ID50s. These were determined by injecting blood into
animals, but what they think is that there is a five to ten-fold
reduction in efficiency via the intravenous route, because we are
looking at blood we are interested in that intravenous infectivity, so
we adjusted any estimates downwards by about five to ten-fold, and
that\'s based on information from, I believe, Paul Brown\'s lab, and
also from a paper from Kimberlin in the late \`90s.

So, you may want to circle this, and we can come back to this and
discuss it as part of our assumptions that go into the model.

The next part of the model that\'s very important, and I would say that
what the sensitivity analysis showed us, I\'ll sort of tilt my hand
right now, is that the variant CJD prevalence was the most important
factor in determining risk. This is one of the second most important
things. So, we are sort of emphasizing this quite a bit, and that is,
what\'s the log of reduction that could occur during processing, and
this reduction is based on the various processing steps, and I believe
the previous presentation walked through several of those various steps
in the reduction levels achieved.

I think it\'s important to remember that there\'s variability in the
processing and the levels of reduction achieved. But, based on
information we had, we assumed for Factor XI, again, this is a Factor XI
risk assessment, that the minimum reduction could be as low as zero, the
most likely level of reduction could be as high as two logs, and this
would ? the counterpart would be about 99 percent reduction, and then as
high as four logs. So, about 99.99 percent reduction in the amount of
infectivity.

Now, sort of a caveat that I would put, or an explanation here, is that
we never assumed that infectivity is totally eliminated. We assume it\'s
greatly reduced, but we assume that there\'s never 100 percent
elimination, just to keep that sort of conservative aspect in our
estimates.

Finally, moving on to the last part of the risk assessment, what\'s the
dose that people actually receive of the product and of variant CJD
ID50s during their surgery or treatments with this product? And, what we
have to consider is package size, whether it\'s a vial or other type of
product, the vial size. If you have multiple vials coming from multiple
different pools, that has an influence on risk. The number of units in
those vials, the ID50 then per package, whether it\'s a vial, or unit,
or whatever your unit of interest is, how often the product is used, in
this case for Factor XI it\'s used individually or two or three times
during surgery. But, there are people that use other sort of plasma
derivatives that have multiple or chronic need for use of these
products, and they are at higher risk if there is a risk associated with
that product.

Again, utilization may vary by severity of the disease. We saw in some
of the Factor XI patients being treated, some were very mild, needed
very little of the product, some needed a lot. Again, those that
probably need a lot are at higher risk of variant CJD transmission than
those that received lower amounts potentially.

Again, in our estimates of utilization I think it\'s important to try to
be as precise as possible, since this is an important aspect of exposure
assessment.

Okay. So, what did we do for Factor XI? Okay, so for the Factor XI risk
assessment we looked at utilization of the U.K.-manufactured Factor XI
in the U.S. by patients. Now, what we did was, we looked at the
scientific literature to get an idea of the dosing. We looked at also
other sources of information for dosing, and what we came up with is
three possible scenarios. And, what we try to do is sort of have
representative scenarios, an extreme scenario, something that\'s more in
the middle, and then something that\'s at the low end, just to give you
an idea of risk, and that\'s what we are doing. This is sort of a low
estimate. A patient might receive one treatment, a 60 kilogram patient
might get 50 units. That would total about 3,000 units of product.
Scenario two, somebody might receive 9,000 units and then 15,000 units
if they get three or more treatments, or they are particularly a large
patient, heavier, et cetera.

So, these are the three scenarios that we use representing the extremes
that we saw in the literature.

Again, so to do the risk characterization part. I just wanted to say
some general comments again about risk characterization. This is the
integration of the exposure assessment component, or dose, and then the
dose response information to estimate risk. And remember, we don\'t have
a good estimate of the dose response relationship, so we are probably
going to apply a sort of more qualitative estimate to that, to our risk.

TSE dose response information again is, that information is lacking, so
it\'s not possible to precisely estimate the risk, and that\'s a severe
limitation here. I think it\'s important to emphasize, though, what I\'m
doing here is what we call a TSE risk assessment, but we are really
characterizing exposure. So, it\'s really sort of almost the end of the
exposure assessment stage, we go a little bit further, but not much. So,
I just wanted to give that clarification.

We can draw some limited qualitative conclusions about risk. So, if we
know the exposure is extremely high, you can say, well, you know, there
is a risk there. If it\'s extremely low, then we can say, well, there\'s
very little risk there. So, I think we can draw some sort of qualitative
comparisons by looking at these types of models.

I think you may want to circle this slide, too, because this contains a
summary of all of the different parameters that went in and the
different statistical distributions. So again, the number of variant CJD
donations per pool of 20,000 donations, we estimated a minimum of zero,
most likely of two, which works out to a mean of five donations per
pool, and then a maximum of 14, 20,000 donors in the pool, 200 mls ?
I\'m sorry, 20,000 donations in the pool, 200 mls per recovered plasma
unit, these are the variant CJD ID50s and on and on.

Again, we also have the log reduction in there, and that\'s an important
factor in driving the risk and the risk estimate, and then we also have
information on the yield of Factor XI from the pool. Again, these
numbers are all feeding into our risk of what the patients are actually
receiving.

So, this is the final result of actually all the effort of doing the
model. What we\'ve got is our three scenarios of 3,000 units, 9,000
units, 15,000 units. We also did a calculation for 1,000 vial, and what
the risk was for that, and then per unit of Factor XI. So, these are all
Factor XI, and then these are the exposure estimates based on our risk
assessment.

So, for instance, you see a number for 3,000, six times 10^-2^, or .06,
for 9,000 it\'s .17, and then for scenario three it\'s .28. I think at
this point I\'ll sort of just put an aside in and say that, so how do we
really interpret this information? And, I think it\'s important at least
to put some guide on this information. So, this is an ID50, and if we
sort of did a strict interpretation of the linear dose response for the
ID50, I think as Anna or Doctor Molesworth or Soldan described, what we
would get is, we would get .28 units would equivocate to about a 14
percent risk, so we would reduce this by 50 percent, because it\'s an
ID50, that would equate out to a risk of about 14 percent.

So, if we had 100 individuals that all received this dose, you might
expect 14 of those to potentially become infected with the disease. Now,
that doesn\'t mean that they are going to become ill, and I think we
also have to remember that this is an animal ID50, and there are all the
caveats of uncertainties that come along with this estimate. And
remember, this is based on animal data, the units of infectivity per ml
of blood are based on animal data. We also have the logs reduction, and
that\'s based on data ? some data, but a lot of uncertainty there, and
on and on. And, we have all these assumptions going into this model that
have extreme uncertainty. So, I would caution anybody sort of looking at
this and trying to do a direct interpretation.

I think I wanted to draw people\'s attention to this, which we didn\'t
actually try to do, but 1,000 units, as the earlier presentation, this
equates out to .02, so this would equate out to about a 1 percent risk,
if we are using the U.K. approach to this.

And again, I think the other aspect of this that\'s very important is to
look at these, we not only have these measures of central tendency so we
are using the mean, but we are also giving you the fifth percentiles and
the 95^th^ percentiles. These express the uncertainties within the
model.

Now, the other big uncertainty that\'s not really ? that we can\'t
express because we don\'t know the uncertainty there, is again, this
sort of translation of what\'s an animal ID50 in comparison to a human
ID50. So, we can\'t capture that in these estimates, so that\'s not
there.

And, other estimates of things that aren\'t in the model and their
uncertainties aren\'t there either. So, there is extreme uncertainty
again in these estimates.

All right, so let me go to the next slide, which talks about models and
uncertainty. I just wanted to say that I think you have to keep these
models in perspective. I do this all the time, and, you know, I try to
keep this in perspective. I don\'t say, this is an absolute, people are
going to get ill, blah, blah, blah. That doesn\'t mean ? necessarily
mean that. A model reflects a mathematical approximation of reality. Our
model may be inaccurate and may not actually approximate reality very
well. As we get more data, it will, and we\'ll have less uncertainty,
but there is extreme uncertainty.

Now, the predicted risk, you have to remember on this model, is a
product of uncertainty in the data and the assumptions, so we not only
have the data that are uncertain, but we also have assumptions that we
make are uncertain.

What we are doing is, we are using a probabilistic model approach. We
use statistical distributions to capture the uncertainty that we know
about, again, there\'s unknown uncertainty in here that we have to
consider, and then what we do is, we use what\'s called the Monte Carlo
method, it randomly chooses values from the distribution, so we have
distributions going up and down the model, and what we are generating at
the end is another distribution, which is an aggregate distribution, a
product of all those distributions. So, it\'s just important to keep
this process in line, as to what we are actually doing.

So, we repeat this, we choose randomly from each of those distributions,
repeat this process thousands of iterations, and we get this huge
aggregate distribution at the end for the risk.

Let me just remind people that this is the estimate, these are the
distributions we are generating, these are summaries of them, so that\'s
what we are doing, we are actually generating a summary of the
distributions that the model generates.

All right, so let me just sort of quickly move on. Uncertainty arises
from this lack of information. Uncertainty also arises, another point is
a model uncertainty, so the model could be highly uncertain, it could be
incorrect, so there\'s uncertain there. Express uncertain outcomes from
the model using measures of central tendency, and then the uncertainty
with confidence intervals.

Then, sort of moving on quickly, we\'ve mentioned sensitivity analysis,
and that was mentioned as a question in the previous talk. We actually
did do sensitivity analysis. I wanted to explain what that is, so
sensitivity analysis determines what factors in the model have the
greatest influence, and we actually do that by varying parameters in the
model by percentages, for instance, 25 percent, 50 percent, and so on.

And then, we observe those ? the impact of each of those portions of the
model on the risk estimate, so this can be done for multiple outcomes,
so we could do this looking at our ID50s for any of those particular
scenarios. We can do it for potential illness if we had a dose response
curve, et cetera, and infections as well.

And, what it does is, sensitivity analysis identifies factors in the
model where additional information would improve the risk assessment, so
we know those things are really driving the risk estimate and they are
highly uncertain. So, if we get more information and we prove particular
aspects of the model, we can improve the final estimates.

So again, for the Factor XI risk assessment, we specifically did a
sensitivity analysis, two major factors influenced risk. There were
certainly more, but the number of variant CJD donations per plasma pool,
of large influence on the risk.

I wanted to put in, this doesn\'t necessarily apply to Factor XI in the
U.K., but it does apply here, that for the United States the risk
reduction measures that we have in place are the donor deferrals that
get at this prevalence and try to prevent individuals that are
potentially infected with variant CJD from getting into these plasma
pools.

The second factor that sort of drives risk, second most important, is
the log reductions of the variant CJD agents during the manufacture of
the product. Again, we have risk reduction measures, and we look at the
processing, and then try to predict the levels of reduction, but again,
you know, a good risk management strategy, I think that was being
alluded to earlier, is that if you can get the reduction even greater
than you\'ll reduce the risk even further. So, we think that this is a
very valuable step in reducing risk.

So, and I think it\'s important that these processes be validated so we
know, you know, what the level of risk ? you know, what level of agent
is being reduced and quantify the level of reduction that\'s occurring
during these processes.

Let me just sort of quickly move on. There\'s model validation. I think
we were sort of getting to some of these issues about epidemiological
data and not having epidemiological data. In emerging situations, and I
would consider variant CJD much like that, epidemiological data on
outcomes may not be available. Certainly for this new emerging issue of
hemophilia infectors and plasma derivatives in risk we don\'t have any
indication of cases coming from that, so it\'s very hard to sort of
estimate those risks. So, we do that using these risk assessments.

Now, lacking that data, formal model validation may not be possible, and
we sort of acknowledge that up front. But, it\'s important, I think, to
anchor the components of the model with data, so maybe the endpoints we
are uncertain of a little bit, but if we can get some of this
intervening stuff that are used to predict that risk, then we can have a
more certain estimate of the final outcomes, and that\'s very important.

So, for instance, we have ? we are gaining more information and at times
know the levels of TSE clearance for specific products, we know about
utilization, those pieces are incorporated into our model. But again,
and this is what gave us sort of the impetus to put in the surveillance
data for the variant CJD prevalence, is that empirical data and
epidemiological data are much preferred over risk assessment estimates
and model estimates.

I\'d probably get fired for that from the risk assessment group for
saying that.

So, the objectives of risk assessment, I think it\'s a useful tool in
decision-making. What we are really doing here is, we are determining,
is there a risk with this risk assessment, what\'s the magnitude of that
risk? So, I think it\'s a very useful tool for sort of starting, at
least, visualizing what that risk is, and then what the impact of risk
reduction measures are, and we can get to that in future risk
assessments as we develop this risk assessment further.

An important part, as people were mentioning, I think, you know, about
the amount and quantity in human blood of this agent, you know, to
identifying gaps and research priorities, and this can be a useful tool
for saying, hey look, if we had this information we would know more
about the risk. So, it\'s very important as a tool for doing that, so we
have to really consider that carefully in looking at the results of
these risk assessments.

So again, the uncertainties, I think everybody on the Committee
certainly knows about all of these things, you know, prevalence in the
U.K. and the USA, amount in the blood, and plasma, et cetera, so we have
a number of data gaps and a number of data needs.

Conclusions of the risk assessment, so potential exposure to variant CJD
manufactured in the U.K. and used under IND was estimated in the risk
assessment that we\'ve done. It\'s possible that the product
manufactured from U.K. plasma may have been manufactured from plasma
pools, and the model actually predicts that, that it was manufactured
from plasma pools that may have contained or did contain plasma
donations from an individual that was incubating variant CJD.

Again, to date, no recipients of plasma derivatives in the U.K. or
elsewhere have been diagnosed, again, but given the potentially
prolonged incubation times those cases may be out there, but may yet to
be identified.

And, I wanted to acknowledge the people that are part of this process. I
don\'t do this process alone. I have a lot of help from other people and
the area experts. So, there were a number of people at the Centre, and
this is a limited list, a lot of people that aren\'t listed here also
contributed.

So, I thank you for your time.

CHAIRPERSON PRIOLA: Are there any questions for Doctor Anderson from the
Committee?

Doctor Salman?

DOCTOR SALMAN: Well, I appreciate all the precaution and the explanation
of the model. I think it\'s very well done.

My question, and it\'s maybe very general, is, as you explained in the
beginning the first step in the risk assessment process is the hazard
identification. And, it seemed like, by just looking at that, you came
up with a conclusion it\'s almost there is no hazards. And so, the
process after that, and I think you explain it very well, is mainly
characteristic or characterizing the exposure, rather than risk
assessment per se.

My concern is the table you presented, because that really is not
characterization of exposure, that merely is you are talking here about
risk assessment, okay, and I think we need to be aware, as you said, is
the gaps in the data and the assumptions you went with in all the
process.

Most of the time is, when you have the first step, hazard
identification, to lead you to that, there is no risk, then you stop
there, but I think it\'s, and you did it, I would say, very nicely, is
you followed that to maybe characterize the exposure, and I think we
need to differentiate between the two.

The other thing is, the data presented in that table, I believe, is
related to the variability rather than the uncertainty.

DOCTOR ANDERSON: Well, it\'s actually probably a little bit of both, so
you are correct.

DOCTOR SALMAN: The 5 percentile and the 95 percentile, that\'s related
to actually the variability within your point estimates, rather than the
uncertainty in your point estimates.

DOCTOR ANDERSON: I guess what we can do is, it actually captures both,
and what we could do is, we could go to another level of modeling, which
is to separate variability and uncertainty and really even hone in on
what those components are, and how they contribute to those estimates.

But, we didn\'t do that, and, perhaps, later on we will. But, you are
correct.

CHAIRPERSON PRIOLA: Doctor Gaylor?

DOCTOR GAYLOR: Yes. I\'ve gone through the risk assessment each step in
great detail, as Doctor Anderson knows, and I agree with the framework
that the FDA has used here. It appears that they\'ve included all the
important factors and elements, and as has been said over and over, the
problem is not the framework of the risk assessment, but the data, the
numbers that we plug into it. They are both assumptions and data
uncertainties.

You had a slide near the end of your talk where you had two major
factors that influence risk. I would add a third one to that, and
that\'s the ID50 per milliliter of plasma is another major factor.

And so, I agree with the approach. The bottom line that I come up with
at this point, with the estimates that are available, and assuming that
the animal ID50 applies to humans, you come up with risk estimates
varying from near zero up to as high as 50 percent. That\'s a pretty
wide range, and you say, well, how useful is that going to be to the
regulators and decision-makers, but that\'s where we are at. The risk,
based on the data, and the assumptions, could be quite high, could be as
high as maybe 50 percent, but equally likely as zero percent. So, we
have a wide range of uncertainty here.

DOCTOR ANDERSON: But, I think, if I can just comment, I think one of the
things we can do, in effect, is reduction, and so we can reduce the
level of the agent that people are being exposed to, and then we can do
further validation studies to see, are we actually affecting, do we ever
get down to near zero as far as the amount of agent that\'s in these
products, even if it comes from a contaminated batch or a batch that has
a donation or five donations in it.

So, I think one of the areas of focus for us is really to sort of
emphasize that. You know, log reductions really can have a potential
impact, and I think that\'s ? we don\'t have control over the prevalence
of a product that was manufactured in the U.K., and the other way we
control it here is, the donor deferrals. And so, I think the value of
the risk assessment is, we can look at those different mitigations and
then try to predict what impact they\'ll have on risk, and then you can
determine, well, is that an important benefit or not.

And so, I think that that\'s sort of the value. I agree, we are highly
uncertain as to our risk estimate, so ?

CHAIRPERSON PRIOLA: Doctor Gambetti?

DOCTOR GAMBETTI: In want to compliment you, because it looks to me a
very complete and clearly presented study.

There is one point that I would like to have some clarification.
According to your calculation, it looks like you have the likely
scenario is five donors were affected by variant CJD in that pool of
blood from which Factor XI had been extracted.

At the same time, you also made the statement that no symptomatic, or no
patient with variant CJD, was demonstrated to be one of the donors. So,
is that the assumption that we are making here, that all those five
potential donors remained asymptomatic?

DOCTOR ANDERSON: Potentially, or they could become symptomatic at a
later time and not be caught by the system.

DOCTOR GAMBETTI: We go from \`87 to \`99, so the least time here,
assuming the incubation time, the common figure for the incubation time
for variant CJD, is about ten years, so there would be time, at least
for some of those to have become symptomatic.

DOCTOR ANDERSON: And, some have, and they\'ve been traced back, but not
to Factor XI.

DOCTOR GAMBETTI: In beg your pardon?

DOCTOR ANDERSON: Some patients have been identified and traced to other
products, just not Factor XI, specifically.

DOCTOR GAMBETTI: So, there could be less than this five?

DOCTOR ANDERSON: Again, I would say that that\'s an assumption based on
the current prevalence estimate that we are using, based on this
surveillance data. But again, I don\'t really know of those five what
proportion of those will actually progress to clinical disease.

So, it could be that all five of them will, but what I suspect is that,
you know, 90 percent of them won\'t and maybe one will. So, I think
there\'s a large sort of population out there that\'s potentially
infected in the U.K., but they won\'t ever progress. And so, that\'s
part of this calculation at this point in time, and so I think the U.K.
and others are using an estimate of what happens if we get one infected
donation per pool, but we are sort of saying, well, that\'s fine if you
are predicting based on the number of clinical cases, but if you want to
expand that and include the non-clinical or latent cases then we have to
allow for this possibility that there could be more than one infected.

DOCTOR GAMBETTI: In agree, I agree, that is correct, but at the same
time ?

DOCTOR ANDERSON: So, we don\'t know what that estimate really should be,
and it could be five, or it could be less, and we acknowledge that there
are limitations to the surveillance data.

DOCTOR GAMBETTI: No look, my question, I understand all this, my
question centers on the fact that probably those hypothetical five are
all, or most of them, remain asymptomatic, so probably come from that
pool of patients who never really developed the disease, so it\'s a
special pool of patients that may be different from those who have gone
and developed the disease. And, probably with those five we are dealing
with the pool of patients who never developed the disease.

Is that right? Is that the assumption?

DOCTOR ANDERSON: I would say that that\'s at least my working
assumption, so, yeah, that\'s my thinking on it.

CHAIRPERSON PRIOLA: Doctor Allen and then Doctor Hogan.

DOCTOR ALLEN: I guess my question is sort of a corollary of Doctor
Gambetti\'s. The Hilton data, obviously, were very important in your
establishing your presumed risk up front. Have you, or have our British
colleagues, examined the similarities between the population that went
into the Hilton data and the population of blood donors in the U.K.?

DOCTOR ANDERSON: I think I would leave that to ? can either of the ?

CHAIRPERSON PRIOLA: Would either Doctor Molesworth or Doctor ?

DOCTOR BIRD: If I could just comment on that.

CHAIRPERSON PRIOLA: Could you identify yourself, please?

DOCTOR BIRD: Sheila Bird, from the Medical Research Council\'s
Biostatistics Unit.

The majority of the tissues in the Hilton study were from people aged
ten to 30, at the time of operation in 1995 to 1999, and so rather than
use a multiplier of the total U.K. population it may be more appropriate
to use a multiplier which is closer to either 12 million or 24 million,
in respect of that particular age range. And, the problem with the
surveillance at present is that we have very limited surveillance data
for people over the age of 50. So, that might take down your estimate of
five.

DOCTOR ANDERSON: Right.

DOCTOR BIRD: If you bear in mind that that surveillance was targeted at
the high-risk, in terms of clinical cases, age group of 10 to 30.

DOCTOR ANDERSON: Right.

DOCTOR BIRD: There are also data from John Collinge, who tested, I
think, about 2,000 tonsil specimens, and I think there were no positives
in that.

So, mentally, you might roughly expand that to three positives out of
about 15,000.

DOCTOR SOLDAN: If I could just add to that, that the average age of
blood donations, of blood donors in the U.K., is around 40 or over. So,
the 20,000 of our donors in the pool ?

DOCTOR ANDERSON: And then, for plasma donors is it less?

DOCTOR SOLDAN: No, well, it was the same donors, so we were the same
donors fractioned for plasma, so I think that\'s a very important point.

And also, just to comment on that, that again the use of that three,
that two of those samples were of an atypical pattern, which I know you
are assuming to represent infection equivalent to the one that was
typical.

CHAIRPERSON PRIOLA: Doctor Scott, do you have a comment?

DOCTOR SCOTT: Yes, and I think that Doctor Soldan is referring to the
possibility of false positives, which is referred to in the Hilton
paper, because it was an atypical pattern of staining in two out of
three of the positives.

The other thing I wanted to point out is that, I gather from the paper
that the finding of the three positives out of approximately 12,000 was
after they began only looking at appendectomy samples and maybe a few
tonsil samples, of people aged 20 to 29. And so, that\'s really the
group we are looking at, which isn\'t going to completely overlap or
perfectly overlap the population of donors as we\'ve just heard.

So, we do agree that that is something that potentially could be
adjusted if we could get more information.

CHAIRPERSON PRIOLA: Doctor Hogan?

DOCTOR HOGAN: This issue comes up all the time when we talk about
corneal donors versus infections, and you use the surveillance data and
come up with the five in the donor pool, how did you come up with the
number of two most likely out of five to donate? That is, you are sort
of assuming that five ? all or half of these patients will donate.
What\'s the prevalence data in terms of donation in the U.K., how many
individuals out of how many population donate, and could that affect
this calculation?

Do you understand my question?

DOCTOR SOLDAN: Well, I\'ll refer whether it would affect your data to
the risk assessment team, but it\'s about 7 percent in the U.K.
population, it\'s roughly around 7 percent of the eligible age group
population in the U.K. donate blood, but how that would affect ?

DOCTOR ANDERSON: Right, but I think the actual distribution, we just
look at particular types of distributions when we do this modeling, and
actually, whether it was two or whether it was five, there\'s a wide
swath of things coming down around five, actually. So, it happens to go,
because that\'s the average that we\'ve plugged into the model as well,
of five, so two ends up being the most likely. We had put that in
because we are defining the other distributions by most likely. But, I
put in that sort of qualifier of the mean as well, just to clarify that
point.

DOCTOR HOGAN: My only point is that you can\'t assume that people with
the disease will be donors. I know you have to assume that for your risk
model, but there\'s a lot of people that wouldn\'t even do it for
various reasons, wouldn\'t even be in the donor pool.

DOCTOR ANDERSON: Right, but you would assume there\'s not some
pre-selection, you would assume it\'s just a random sample of the
population, and it may be only 60 percent of the population is qualified
to donate, let\'s say, but you would assume that\'s a random sample of
the population.

CHAIRPERSON PRIOLA: Doctor Belay?

DOCTOR BELAY: Yeah, Mo raised this question, actually, but I didn\'t
have the answer for it. You repeatedly said the ID50 was derived from
animal studies, and you selected to use the icID50, and adjusted it for
intravenous ? the intravenous route.

DOCTOR ANDERSON: Right.

DOCTOR BELAY: Now, my question is, why did not ? why didn\'t you use the
ivID50 directly, is it because the data are ?

DOCTOR ANDERSON: There aren\'t a lot of data ? a lot of the data aren\'t
generated for ? it\'s generated for icID50, so we had to actually take
all that data and convert it to ivID50.

DOCTOR BELAY: ivID50 is not available, it\'s not tested, or not
published?

DOCTOR ANDERSON: I don\'t believe there\'s any data in the published
literature where they did, specifically, ivID50, except they were
probably trying to get at that with the Houston study that was earlier
mentioned.

CHAIRPERSON PRIOLA: There are probably some old Kimberlin studies in
mice or hamsters that are done, he did a lot of that.

DOCTOR ANDERSON: Okay.

CHAIRPERSON PRIOLA: There might be some data there for iv, but it would
be probably 20 years ago.

Doctor Bracey?

DOCTOR BRACEY: Yeah, just a point of clarification. In terms of the
comment about the ID50 and the most likely being ten, and that being
based on the data from Brown, somehow I recall that that data related to
animals that were symptomatic, and, in fact, that earlier when the
animals were tested that were asymptomatic there, in essence, was no
transmission. Could you comment on that?

DOCTOR ANDERSON: Well, our assumption for the model is that an
individual or animal will be ? will have agent in their bloodstream
throughout the entire incubation period. So, that\'s a conservative
assumption, but we acknowledge that the animal studies actually show, or
certain animal studies show that probably for the first half of the
incubation period there\'s probably not infective agent in the blood,
but for the second half of the incubation period in animals there is
infectivity in the blood. So, several experiments do show that, but
again, we don\'t have the human data, so what our conservative
assumption is for the entire incubation period that agent is in the
blood.

DOCTOR BRACEY: Right, I think it\'s a significantly conservative
projection, in that, again, when the animals are in the asymptomatic
state there hasn\'t been proof of that transmission.

DOCTOR ANDERSON: I think it\'s important also that what this risk
assessment is, is more, you know, a public health tool. So, we weren\'t
specifically targeting this towards clinical predictions, et cetera, but
really as a public health tool. So, we do have a tendency to err on the
side of sort of conservative estimates.

CHAIRPERSON PRIOLA: Okay.

I think we\'ll move on to the final speaker, and that\'s Doctor
Sehulster, who is going to talk about recommendations for surgical
instruments used on TSE patients.

DOCTOR SEHULSTER: Well, good morning, Committee Members and guests in
our audience. Can you hear me now? Okay.

In the interest of time, I know we are running very, very late, I\'ll
try to keep my comments very brief, and, basically, much of what I will
review this morning is already available on the internet, either from
the WHO website or from two pages within the CDC website. Much of the
material from CDC is already cleared guidance that is either available
as a question/answer format in that first page of CDC, or in the
guidelines for infection control in dental health care settings, and so
they do cover very briefly CJD transmission issues in dentistry.

And, basically, what we do in terms of instrument management and
developing a strategy for surgical and dental instrument management,
basically, can be summarized into three major elements.

The first would be patient status, and now we recognize that certainly
this is helpful, especially if you know the risk factor history or the
medical status of the patient, certainly the decision-making process is
easier for the confirmed or suspected patient with CJD. It gets a little
tricky when you are dealing with a great deal of unknowns, as we\'ll see
a bit later.

The other element to consider is potential tissue infectivity level and
certainly from the WHO conference in 1999 the consensus is that we can
divide tissues into either high-level infectivity or low-level
infectivity, and certainly those that do not fall in those two
categories are thought to be little or no infectivity.

And finally, the other element of consideration is the instruments used
in the procedures, and the potential for those instruments to make
contact with tissues, particularly, of the high-level infectivity group.

Now, with respect to patients who are confirmed or suspected of having
CJD, at least in the U.S. where fortunately for our purposes we are
looking primarily at classic CJD, the material from Table 2 in the WHO
document, basically, identifies the high-level infectivity tissues to
brain, spinal cord and the eyes. Again, this is in the confirmed or
suspected patient.

Low level infectivity tissues are a bit more broad. We have either
spinal fluid, kidneys, liver and lungs, lymph nodes, spleen and
placenta, and we do recognize that in dealing with variant CJD other
tissues in the lymphoreticular system are certainly of concern.

Now, in the U.S. the primary procedure of concern is that of
neurosurgery, but not all neurosurgeries are considered a high-risk
procedure, and in this regard we focus our attention on persons,
especially those who are suspect or confirmed cases of CJD to the
neurosurgical procedures performed on these persons.

If there are neurosurgeries that are performed for the purpose of
diagnoses, or to obtain a non-lesionous biopsy, these are also
procedures that may present with a high clinical suspicion that there\'s
a potential for CJD transmission.

One thing to consider is the demographics of CJD patients, certainly in
the U.S., when evaluating the potential for the neurosurgery to pose a
risk to subsequent patients if nothing extraordinary is done for the
instruments. And certainly, we would say in our estimation that biopsies
in neurosurgery performed, for example, on a pediatric patient, say,
less than ten years of age, may not really fall into the category of a
procedure of concern, whereas, a diagnostic neurosurgery on a person in
their 60s or 70s may raise the question, should you take precautions
when managing the instruments?

This table, again, captures the essence of guidance that we have on the
CDC website. It\'s formatted to resemble the table that is in the WHO
document, and frankly, to simplify it what I did was, in trying to
determine decontamination options Annex III refers back to the WHO
document, where they list the different methods and the strategies for
instrument reprocessing. And, I think what is very obvious is that when
you have a confirmed or suspected CJD patient when you are dealing with
high infectivity tissues or low infectivity tissues it\'s prudent to use
the procedures outlined in Annex III.

After that point, things get a little bit fuzzy, in terms of consensus
of opinion, and certainly in reviewing the WHO document we note that for
persons who are family relatives of inheritable forms of TSE there is a
different sub-opinion, and so this is one of the reasons why I have put
Annex III, but listed it as a point of debate because there really is
continuing debate on this particular guidance.

And then, when you have tissue contact for those organs and tissues with
no or little infectivity routine reprocessing procedures are appropriate
for that group.

Now, in the WHO document, they certainly, as you recall, mention that
the absolute safest approach to instrument management is to consider all
instruments, particularly, those that are in contact with high-level
infectivity tissues as a single use, and to dispose of them by
incineration. But, that is not a very practical approach for many
facilities, and so, consequently, they list a series of methods for
decontamination that can serve as alternatives.

And, what I\'ve done in this and the next slide is to just remind the
group of the operational parameters of these methods. In our estimation,
the first three of the methods, and there are about five or six, we deem
appropriate for use in the U.S. healthcare system, and so what you see
are, basically, a combination of chemical and physical methods to effect
prion inactivation.

And, this particular method, that that combines sodium hydroxide as an
immersion chemical, autoclaving instruments while immerse in sodium
hydroxide appears as the first of these methods, and we certainly
recognize that this can be a hazardous process, not only for the
sterilizer equipment, there are occupational health issues, and there
have been concerns about how the instruments come from this process, and
what is the effect on the instruments.

The second and third methods, again, I\'m not going to reiterate the
fine details, suffice it to say that method number two is still an
immersion type method, the difference being, though, that the
instruments are taken from the immersion chemical ? excuse me, the items
that are put into either sodium hydroxide or sodium hypochlorite, they
are transferred then to water, again, immersed in water following that
chemical exposure, and put into gravity-displacement autoclave.

The third method, I\'m a little ahead of myself, the third method is the
one where after exposure to chemical the instrument is taken from that
chemical, dried, and then put into the autoclave for the time and
temperature described.

Those were methods that are suitable for heat-resistant instruments.
Obviously, we have a large category of heat-sensitive instruments
available in healthcare, and so the question becomes, how do we deal
with the heat-sensitive methods?

The guidance is directed at, again, the confirmed or suspected CJD
patient, and the most conservative approach is to discard the
instrument. Again, if that is not a feasible option, the other method
you can use is to either immerse or to at least flood the surface of the
instrument with sodium hydroxide or sodium hypochlorite, let stand for
an hour, and then after rinsing and cleaning the instrument use a
low-temperature process that you have of choice.

One of the things that has come up repeatedly are questions about,
again, the effects of these chemical and autoclaving methods on
instruments, and we are especially grateful to our colleagues in FDA who
have undertaken research to examine these issues, because we get asked
these questions quite a lot. The group at FDA looked at different kinds
of instruments, the quality of materials involved, and then the effect
on these instruments when exposed to either sodium hydroxide, sodium
hypochlorite, and again, in conjunction with the physical reprocessing.

And, basically, I think in a very simple view the sodium hypochlorite
will potentially have greater effect, a greater negative effect, on the
instruments compared to that of sodium hydroxide. What they found with
sodium hydroxide, primarily, was that you had more of a cosmetic effect,
a discoloration, but the overall function of the instrument was less
adversely affected compared to that effect for sodium hypochlorite. The
consequence is that the combination method with sodium hydroxide and
autoclaving can be an effective tool with minimal damage to the
instruments.

Now, those are our methods and operations that are helpful when you know
in advance the status of your patient and can devise your reprocessing
strategy accordingly. There were, however, a number of episodes that
came to our attention over the past few years, where a patient was
undergoing a neurosurgical procedure, it was determined after the
procedure that the diagnosis was, in fact, CJD, and this dilemma is, now
what do you do with the instruments, and how do you manage subsequent
exposures and potentially notification to patients?

I\'m going to limit my comments strictly to the instruments, because
notification, as you\'ve seen this morning, is a very, very delicate
thing. But, as a result of this the Joint Commission for the
Accreditation of Healthcare Organizations determined it was appropriate
to issue what they call a sentinel alert, and major points of the
sentinel alert were that, be aware that there atypical clinical
presentations of patients, and that they don\'t always fit the mold for
the classic symptoms.

One of the elements that worked against facilities was a lengthy time
between the collection of the biopsy specimen and when the final
pathology report was released. This interval is very difficult to be
dealing with, and so, consequently, the advice of the Joint Commission
was to take whatever measures you can do to shorten that interval to the
shortest possible time.

And then, this gets back to the process or the practice of quarantining
instruments. The Joint Commission Advisory again suggested that
neurosurgical instruments should not be reused while the diagnosis is
pending.

In that regard, the Joint Commission recommended to healthcare
facilities that they have policies and procedures in place so that they
can determine a strategy ahead of time and act accordingly. And, they
also made a formal recommendation that instruments be quarantined as
they are waiting a diagnosis coming back.

Now, this is where we get more into the practical advice. This is not
crystallized into a formal recommendation, but these were just some of
the ideas that came out of discussions with healthcare facilities at the
time. And, with regard to quarantine, quarantining, basically, is just
setting the instruments aside until you have information to take action
with. This really is a useful method, but there are some factors that
need to be in place in order to make it a very practical approach.

The first is, again, this is if that time interval between the surgery
and the final diagnosis being returned is very short, the shorter the
better.

Some facilities cannot do a quarantine approach because they lack the
inventory, sufficient copies, sufficient duplications of instruments, to
allow a set of neurosurgical instruments to be set aside without
affecting the flow of the work in the surgical unit. So, if you are
going to do a quarantine approach, it\'s beneficial to have sufficient
inventory on hand to allow you that buffer, as it were.

More importantly, though, and this comes from research in Europe,
particularly, using steel instruments, is if prion infected material is
allowed to dry it becomes much harder, much more harder to inactivate.
And so, the important factor in quarantining is that the instruments
ideally should be kept moist during the entire period of quarantine, so
that you can be working with a factor that facilitates and enhances the
success of your prion reprocessing.

Now, what to do about exposing potential exposures to patients, in the
event that the instruments somehow are returned back to central sterile
supply, and you are trying to determine a strategy for management in
this case. I think ideally most people take the approach, well, we will
reprocess the instruments at this point, move forward with a
prion-specific form of decontamination, so that downstream from this
event all the subsequent surgical patients have the benefit of a prion
inactivation process on those instruments.

One of the things that, perhaps, helps in tracking which instruments
were involved in the surgery of concern is to implement an instrument
tracking approach, where you identify either the tray or key surgical
instruments, so you can focus your risk management and risk assessment
process to those patients who are directly affected, instead of all your
surgical patients.

And finally, one element that appeared in a situation that happened in
the past few months is the fact that if you have neurosurgery
instruments, you\'ve got your tray of neurosurgical instruments,
there\'s going to be some instruments in that tray which you may have
common to other surgeries. It\'s prudent to restrict those instruments,
that in your neurosurgical tray, to that tray, and not spread them all
over into other trays for other surgeries. So, we would advise in a
practical sense to keep those instruments in the neurosurgery trays and
keep them there.

Now, one of the things that we are certainly aware of is the fact that
much of the information about prion inactivation comes from an area that
doesn\'t exactly match what we do in central sterile reprocessing in
healthcare. And, there are groups in the world today who are starting to
take a look at this, in terms of evaluating decontamination processes,
cleaning and terminal reprocessing, and the effect on prions, so that
you have a closer fit to the practices we have today.

There are one or two papers that have started to look at this, as I
mentioned. They are taking a look at the effects of different chemicals
used as cleaners. The two most common categories would be those of
enzymatic cleaners or alkaline cleaners, and the low temperature
reprocessing arena has not been represented in previous studies up until
now, where groups are starting to look at how prion inactivation can be
effective using, say, peracetic acid systems, or hydrogen peroxide gas
plasma. The evidence is slowly coming in, and it is very interesting to
evaluate.

Other areas that we feel bear some interest is to look at the effect of
repeated cycles of cleaning and conventional autoclaving and see what
effect that has on prion decontamination, and then there are questions
that always need answers that may be very difficult to do, and that is
to see if there are processes we do in central sterile reprocessing that
could inadvertently spread prion contamination to other equipment, and
what measures do we need to take to minimize this from happening. So,
these are areas where we desperately need research and answers.

And finally, with dentistry, the guidance, or I should say, the
statements that are in the CDC dental infection control guidelines is
interesting, because our Division of Oral Health had looked at case
control studies and the studies that tried to look for prion presence in
polt and the facial nerves, and the statements are offered for
consideration without recommendation, which means that they feel more
information would be beneficial to evaluate before they come out with a
hard and fast statement.

But, at the moment, what they are suggesting is that, again, if you have
single-use items, or items that might be difficult to clean, to consider
them disposable and do so accordingly.

As with surgical instruments, the idea is to keep instruments moist.
Again, these are if you are working with a known or suspected CJD
patient, or in the case of Europe, a variant CJD patient, to keep
instruments moist until such time as they can be cleaned and
decontaminated.

Again, because of the lack of evidence that has documented transmission,
they suggest the method that is listed in the WHO for autoclaving 18
minutes at 134 degrees Centigrade, and they also do not recommend, as
some dental practices may do, do not flash sterilize the instruments,
and as you know flash sterilization is a process whereby the temperature
is higher than the conventional reprocessing, but the cycle time is
shortened.

And again, this summarizes the current position of the Division of Oral
Health. They feel that in dentistry today the risk of transmission for
CJD in dental treatment is low, and at this point we\'ve not had
documentation of quantities of prions in human oral tissues, and also to
date there have been no published reports of an association of CJD
transmission with dental treatment. But again, they are continuing to
evaluate the literature, and they are leaving the door open for, as what
they might call a mid-course correction, as more information comes to
the literature.

And just finally to close, one of the areas that I think really does
have a fair amount of debate ongoing is the management of the healthy,
at-risk patient, and at this point ?

EXECUTIVE SECRETARY FREAS: Doctor Sehulster, you have run considerably
over, if you could just wrap it up we\'d appreciate it.

DOCTOR SEHULSTER: Okay, this is my last slide.

Just to say that, at this point we have a group of interest, again, the
blood relatives of familial CJD patients, the groups that have either a
risk factor history, such as human growth hormone, or dura procedures,
are more problematic to assess, simply because it\'s been our experience
that the patient recall of these elements in their medical history is
not as strong as we would like it, and, consequently, it\'s difficult
for these persons in all cases to be identified previous or prior to
their surgeries.

So, this is something that we are continuing to look at, and as we get a
heightened awareness of prion risk factors and the epidemiology of prion
transmission, this may be another area where guidance might be modified.

That\'s it.

CHAIRPERSON PRIOLA: Okay, thank you, Doctor Sehulster.

I think in the interest of time we are considerably over, we should take
a break, we\'ve been sitting here for over three hours, and I think we
need about a ten-minute break, and we\'ll come back to the open public
hearing, and then committee discussion on the questions posed, and,
hopefully, move on to Topic 2.

So, everybody back at about 11:35.

EXECUTIVE SECRETARY FREAS: If Doctor Coker could come to the front table
during the break I\'d appreciate it.

(Whereupon, at 11:28 a.m., a recess until 11:40 a.m.)

EXECUTIVE SECRETARY FREAS: If I could ask everybody to take their seats,
we are going to go ahead and resume the meeting.

CHAIRPERSON PRIOLA: If the Committee Members could take their seats we
need to get started again, please.

EXECUTIVE SECRETARY FREAS: As part of the open public hearing, or as
part of the Public Advisory Committee process, we hold open public
hearings so that members of the public who are not on the agenda will
have an opportunity to make comments to the Committee.

Ms. Chairperson, at this time I\'ve received one written submission, and
that written submission is in the red folders on the Committee Members
table, and also in the viewing folder on the public table outside the
auditorium.

I have also received four requests for oral presentations, one request
this morning and three in the afternoon. These presentations will be
limited to a maximum of five minutes. The presenters are asked to state
any financial involvements that they may have with any firms or products
they wish to discuss.

The first presenter will be Doctor Samuel Coker, Ph.D., Principal
Scientists and Technical Director of Pall Medical, and he\'s going to be
discussing studies of the new Pall \"smart\" filter technology. But,
before he does so, our Chair has the standard required announcement for
this open public hearing.

CHAIRPERSON PRIOLA: 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 a
group\'s payment of your travel, lodging or other expenses in connection
with you attendance at the meeting.

Likewise, FDA encourages you at the beginning of your statement to
advise the Committee if you do not have any such financial
relationships. If you choose not to address this issue of financial
relationships at the beginning of your statement it will not preclude
you from speaking.

So, with that, can we have Doctor Coker?

DOCTOR COKER: Thank you very much for the opportunity to address the
Committee.

I am an employee of Pall Corporation, so I have a financial interest in
the company.

Thank you very much. This presentation is actually in response to the
concern that the Committee has regarding the possibility of the second
wave of variant CJD, and also for the encouragement for new
technologies, as well as approaches they may be taking to address the ?
to reduce the transmission of vCJD through blood transfusion.

So, what I\'m going to present to you is the exciting new technology
from Pall Corporation that may have reduced the transmission of vCJD
through blood.

Some of the work that we\'ve done will address specifically the removal
of variant CJD. As most of you have heard this morning, the transmission
of variant CJD had already been confirmed, at least in two cases in the
U.K.

There is still a serious concern about the second possibility of a
second wave of this serious disease. The approach that was taken at
Pall, for ? filtration technology, what we had done basic is to use our
core technology to develop a \"smart\" filter that will specifically
remove, not only the white cell but also any pathogens, especially the
infectious prion. This particular technology is not a ligand-based
technology, it\'s based on the technology that we developed at Pall
Corporation.

Some of the validation work that I will be sharing some of the
information with you, basically, is based on standard validation
protocol that have been used in other various validation programs.

Most of the work actually will revolve mainly about the low titer,
because this morning there was the concern about endogenous infectivity,
and already by some of these models, in this particular model what we
did, basically, was to use a scrapie infection, infected a lot of
hamsters, collect blood from the hamsters that are endogenously infected
with this particular scrapie.

Once they are infected, we collected the blood from the scrapies and
processed them into the red cells. The red cells are then filtered with
this new technology, and some of the results that we have are shown
here, using the Western Blot to monitor the level of infectivity before
and after filtration.

As you can see, the level of infectious prion before filtration is
actually very, very low, and this is after you\'ve concentrated the
blood by about 50 fold. At the end of the filtration process itself, all
of the infectious prion had been removed from blood, and this is what
happens with the Western Blot.

The next part of the studies did take this particular blood that had
been processed with this filter and inject it directly intracerebrally
into a series of hamsters and monitor them over a period of time, and to
see whether they develop any scrapie disease at all.

And, basically, what we found was that the animals that received the
unfiltered material, which is on the right-hand side here, two of them
developed clinical signs of the disease.

At the end of that, when we look at the brain to see the presence of any
infectious prion material, we identified a third one that did not show
clinical sign of the disease, but was actually carrying the proteinase
K-resistant form.

When we look at the hamsters that received the blood that had been
processed with a new filter from Pall Corporation, none of them
developed clinical signs of the disease, and there was no presence of
infectious prion in the brain. So, this is demonstrating that most of
the hamsters are adequately protected from developing scrapie.

The next part of work is to now take this observation and move straight
forward to human variant CJD, to see whether the animal model of scrapie
can allow us to extrapolate to what happens in human. So, we use a
mouse-adapted human vCJD material, and, essentially, what happens was,
you take this transgenic mice, you inject intracerebrally with human
variant CJD, and at the end of that we collect the brain material,
extract the human vCJD and spike it into red cells.

We repeat the experiment again, we measure the level of infectious
material in the blood before filtration and also at the end of the
filtration process itself, and, basically, what we found was, before
filtration that was the presence of ? using the Western Blot, we could
see the presence of infection prion. This is the human form, not the
scrapie, and at the end of the filtration process all of the infectious
prion had been removed from blood.

The next part of my study, now will demonstrate that you can remove the
infectious prion, the next question is, what is the quality of the red
cell at the end of the process? So, I\'ll be sharing with you some of
the work that we have done to demonstrate that the red cell at the end
of the processing still maintained all the above physical and
biochemical properties, so the process that we\'ve developed has very
little on the quality of the cells.

We look at the level of white cell removal also with this particular
filter, and that\'s something I need to stress, is that this particular
filter, not only removed the infectious prion, but also has the
additional benefit of removing all of the white cells. The white cells
are removed to the level of ? releases, which is the most stringent
requirement currently.

We look at the level of red cell hemolysis over a period of time, as you
can see here, the most stringent requirement from the Council of Europe
was a level of about 0.8 percent hemolysis. When we look at the red cell
over the study period, the level of hemolysis is well below the required
guidelines.

We also look at another form of red cell preparation, this is CPDA
blood, again, the level of hemolysis at the end of the study period is
still well within the required guidelines.

We look at what we call in here is about physical measurements of the
ability of the cell to deform or to carry out its normal function of
oxygen transportation, and again, there were physical properties very
well maintained.

All of these data suggest that, not only do we remove the infectious
prion, but also that the quality of the cells at the end of the
processing is very well maintained.

So, in summary, what we\'ve demonstrated to you is to use a low titer
infectivity study, using endogenous infectivity, and we\'ve been able to
demonstrate that we can remove infectious prion from blood below the
level of sensitivity of the Western Blot, and when these filter
materials were injected into hamsters, the ones that received the filter
material did not develop any clinical signs at all of scrapie, and when
we look at the brain material there was no presence of infectious prion.

We repeated the experiment using human material, and we were also able
to demonstrate conclusively that the new filter removed, not only a
scrapie, but also human vCJD material.

So, in conclusion, using this particular filter may help address the
concern that the Committee may have in regards to the transmission of
vCJD.

Thank you very much for the opportunity.

EXECUTIVE SECRETARY FREAS: Thank you for your presentation.

Is there anyone else in the audience at this time who would like to
address the Committee on issues related to the discussion this morning?

Yes, Doctor Cavanaugh.

Please, give your name and state any affiliations.

MR. CAVANAUGH: Thank you for the promotion, it\'s Mr. Cavanaugh.

I\'m Dave Cavanaugh, Government Relations Staff for the Committee of
10,000.

Our bylaws prohibit us to receive any financial backing from any
fractionator organization or any other manufacturer of supplies being
discussed here.

I\'m trying to gather some of the earlier and later presentations we\'ve
heard this morning. Unfortunately, I\'m not an expert on Factor XI, so I
can\'t exactly speak to that.

We have one published article about presumed blood-borne transmission
yielding a symptomatic case of vCJD in England, another found in the
spleen from a non-CJD symptomatic person later last year.

From that, the U.K. wrote 6,000 letters to people with hemophilia,
warning them that they were at risk, telling them to see their doctors,
and tell them that, and their dentists, and not telling them what to do
about it, not counseling them about stigma.

I don\'t know if in the U.K. with national health your doctor can fire
you, but in the early days of AIDS back here that\'s what happened,
people went to their regular doctor, got a positive test, and were told
don\'t come back. They are experiencing stigma over there, it\'s a very
different situation, I\'m not going to draw any parallels, because I\'m
uninformed on it, but it\'s a smaller country and they have a larger
amount of symptomatic CJD, so it\'s not an easy time for them.

What I take out of that is the need to say here, with some alarm, blood
donors get vCJD from eating infected meat. USDA is inspecting 1 percent
of the cattle in this country per year, aiming at the most symptomatic.
We learned from the U.K. hemophilia experience, if you will, that
long-term infections become a factor of experience, or blood experience,
that we are talking about an eight, nine, ten-year incubation period.
Please, don\'t be complacent that non-symptomatic humans or animals are
not infectious with CJD.

Thank you.

EXECUTIVE SECRETARY FREAS: Thank you very much for your comments.

Is there anyone else in the audience who would like to address the
Committee at this time?

Seeing none, Doctor Priola, In turn the meeting over to you.

CHAIRPERSON PRIOLA: Okay. This is the part on the schedule where the
Committee discusses and votes on the issue presented to them by FDA, and
if everyone would look at the end of the Topic 1 handout, that\'s what
FDA has asked us to comment on, and that is, please comment on the FDA
variant CJD risk assessment for Factor XI manufactured from U.K. plasma
with regard to, (A) the model is applied to Factor XI, and (B) any
additional information that is needed to improve risk estimates for this
Factor XI product, and there was already quite a bit of discussion
during the question period after each of the major speakers this
morning, are there any other comments, discussions, things the Committee
would like the FDA to know, in regards to this risk assessment model?

Doctor DeArmond?

DOCTOR DeARMOND: In think the models are fine, and as Steve Anderson
pointed out, one of the features that they do help with is identifying
parameters that we should be investigating in a more direct way with
more empirical type, more real type data.

And, I think the risk assessment as a predictor of areas that we should
look at is really good, and the conclusions they come to, though, are,
as they say, just rough estimates at this stage, because there are
numerous assumptions built into them.

And, for me, it\'s still the key issue is that we have to get some data,
and the data should be easily obtainable. That\'s the thing that\'s so
irritating, is that blood samples can be looked at, the techniques are
much better, the end products of extracting each of these factors, the
coagulation factors, they can all be searched out.

In fact, I didn\'t mention earlier, we have a paper coming out that
these new CDI assays are even better than the neuropathology, that is,
looking at vacuolation scores, and immunohistochemistry. They are
superior to that. We can find no vacuolation in some cases, no
immunohistochemical staining, but there\'s a strong confirmation of
dependent immunoassay signal.

So, the techniques have improved dramatically in the last couple of
years, and we should be able to get these answers.

So, my conclusion again is, the model is great, and it\'s giving us ?
it\'s telling us key points in the system where we have to get some
data, and we can get the data.

CHAIRPERSON PRIOLA: Doctor Petteway?

DOCTOR PETTEWAY: Thanks.

Yeah, I\'d just like to agree with Steve and add to that. From the
plasma protein companies we\'ve evaluated, we think the model is very
good, too, and it makes sense.

But, it\'s the issue of understanding risk based on establishing the
initial load and threshold, and I would encourage the Committee to
encourage the FDA to see if they can provide some support to get the
data that Steve is talking about. There are more sensitive assays
available today to investigate human blood, human CJD blood, or vCJD
blood, whether it\'s asymptomatic or symptomatic. And, it seems to me
the problem is actually getting the samples and getting those
connections made.

And, that data, if available, would provide a great deal of clarity, as
far as these models and estimating exposure and risk.

CHAIRPERSON PRIOLA: Doctor Salman?

DOCTOR SALMAN: I think the model is academically and scientifically very
reliable. I have no problem with that.

I have some concern about labeling the model as a risk assessment model.
I still think it\'s an exposure or characteristics of the exposure, and
I think as the table, and taking that table to the public and show the
variability in the type of risk, that maybe it could come negative on
the FDA with their wonderful work, because it will show like there are
so much variability, and I think it\'s that by itself, because of the
data collected are not appropriate for this type of risk model.

So, I\'m in favor of encouraging the FDA to go and seek the more
reliable data that can be associated with the model, but I also think
the model is a very good prototype for evaluation of any type of risk
related to this type of issues.

My concern is, to take this model only for Factor XI, I think Factor XI
by itself is not a high level of risk as compared to the other things at
least what we understand from the U.K. data.

CHAIRPERSON PRIOLA: Doctor Allen?

DOCTOR ALLEN: I agree with the previous speakers. One, we do need to get
additional data to the extent possible, and factor that in to refine the
model.

The model itself I think has been a elegantly developed as is possible,
given the current information. There are a number of assumptions, they
are well stated. Some of them we don\'t necessarily fully agree with,
the point I mentioned before about the comparability between the
population that goes into the Hilton data and the actual blood donors
during the decade of the \`90s.

And, I think as long as the model is applied to the population that was
exposed through Factor XI in the past, I agree, I think the probable
risk is very, very small, and that then comes ? and we are not talking,
as I understand it, about ongoing exposure at the present time, so then
the question becomes, I will vote to accept the model, the question is,
what\'s going to be done with the model and how are we ? you know, what
are the decisions that are going to result afterwards. That\'s not part
of our question here, but, obviously, that to me is of the greatest
concern right now.

CHAIRPERSON PRIOLA: Doctor DiMichele?

DOCTOR DiMICHELE: Once again, I would echo what everyone else has said
about the model. It seems very sound.

I think the only thing, and this was a little bit of a discussion that
was going on at the break, the only thing that could certainly add to
this model would be some sort of an epidemiological sort of Kaplan-Meier
assessment of risk, you know, to the sort of time-based risk out of the
U.K., sort of and maybe applying two different models, one looking at
those patients who are known to have potentially received contaminated
product, and those who received plasma-derived product in the high-risk
period but were not known to be contaminated by donations from those
individuals who so far have come down with CJD.

And, I think if we could have some sort of an epidemiological
Kaplan-Meier ongoing risk assessment to then put into this model, not
only for this, but for all plasma derivatives which is going to come up,
I think it would be very, very helpful.

And, I don\'t know whether, you know, we can have a model that\'s
generated here, or whether maybe something could be generated out of the
U.K.

CHAIRPERSON PRIOLA: Mr. Bias?

MR. BIAS: I think I agree with everyone else that the model looks very
good. I\'m still alarmed with the number of uncertainties that we have,
in terms of what data we put in the model. And, I would encourage the
FDA not to allow us to get carried away with the model, now that we have
a model, that we really go after the data, that we not alarm patients.
We will not have the same reaction from a U.S. population that\'s
exposed as the U.K. has had, I can almost guarantee you they won\'t be
stoic in terms of their response.

In addition to that, with the way patients are served in this country,
with about 70 percent of the bleeding disorder population being in
organized hemophilia treatment, I wonder what happens to that 30 percent
that is outside. And, since we have, virtually, no contact with their
primary care physicians, how we would even communicate effectively with
them as to what they might tell their patients. It seems that we might
be creating a little hysteria, so I would just advise caution to the FDA
as they move forward with the model.

CHAIRPERSON PRIOLA: Doctor Schonberger.

DOCTOR SCHONBERGER: Yes. I\'d like to echo what others have said as
well. I think Anderson did a tremendous job in putting all this
together, and I also appreciate the U.K. colleagues for coming here and
sharing what they\'ve done.

But, as one who has been impressed with all the unknowns associated with
the model to date, I\'m very hesitant to take on the negative effects
that have been mentioned, both by the speaker from the public talking
discrimination and labeling of a whole group of people based on this
kind of model, and your concerns that you just expressed on the
Committee, of creating alarm, potentially unnecessary alarm.

And, there are three factors that ? three observations, I call them
epidemiologic observations, that make me wonder whether the 50 percent
risk down to zero percent risk, whether the 50 percent risk is really
very likely to occur, and that we may be much closer to the zero percent
risk that fits this model.

And, these are the facts that most persons with hemophilia would be
receiving many fold times the exposures that the Factor XI recipients
would be exposed to, perhaps, even a couple logs or a couple of orders
of magnitude more. And yet, we\'ve had no hemophilia patients with vCJD
reported from the U.K., or for any other country as far as I\'m aware.

Second, the risk of plasma derivatives, of their transmitting the prion
disease, in my mind is still theoretical, because I don\'t really know
of any such transmission that has been convincingly demonstrated.

And third, which relates to this business of asymptomatic to
symptomatic, you know, could we really be seeing a group of asymptomatic
individuals and we\'re just waiting for a long incubation period?

And, for that, I agree that the data is not ideal, but we can look at
all the data that are available to us, and to date there\'s been at
least one iatrogenic prion disease from an exposure to a known source of
prion disease, that has first appeared within varying times, depending
on the route of transmission.

So, for a known source where the route of transmission was the central
nervous system, the first case showed up about 1.3 years after that
exposure. Okay?

For the other known type of transmission, which would be intramuscular,
like the human growth hormone, or the other gonadotropin hormones, they
showed up first in a period of between five and 12 years, the first
case.

Now, their mean incubation period might be longer, but you start seeing
the first case, you know, within 1.3 years in a central nervous system,
maybe five to 12 years intramuscularly.

And, what we are dealing with is something we hadn\'t seen before, which
would be intravenous. So, the question then becomes, how does
intravenous transmission relate to IM versus IC, and I think most of us
would think it\'s somewhat intermediate.

And so, we would think then that enough time, given the relative
efficiency of these routes of transmission, has past, that we should
have seen a case already in the hemophilia patient if we really had to
be concerned about this risk, because what are you dealing with, we are
talking about treatments between 1989 and 1997, if my calculation is
right that should be about seven and 16 years have past for hemophilia
patients that would have been treated at that same time, and in the U.K.
hypothesis they were talking about even blood between 1980 and 1987 as
being \"high risk\" at 1 percent level, which adds even more time.

So, the other sort of reassuring thing is that I think the longer one
has to wait to see that first case, it\'s probably true that the lower
the overall impact that problem is going to have.

Another bit of data about what, you know, that would influence our
preventative measure, is what\'s the chances of it spreading through the
surgical arena to other patients if we are wrong? And, we don\'t have
all the data we would like, but even there we do know that the normal
type of procedures that are used in the United States, the routine
sterilization procedures, will have an effect on the titers on those
equipment. I mean, you know, it may not be perfect, but you are going to
get several logs of decline just from your normal, you know, the regular
sterilization.

And, it may be sufficient for a contamination, for example, of a
low-dose contaminated material like blood, if you had surgical equipment
contaminated with blood, the routine may actually be sufficient to
eliminate even the low risk that might occur or spread.

And, there\'s where we could use some more data, not just the data on
the model, but the data on what is the effectiveness of the routine
sterilization procedures used in the United States on lowering the
infectivity of these instruments. And, my understanding is that, Dave
Asher, if he\'s here, is that we talked about, at some point, trying to
look at that issue and get some data on that, which would then affect,
you know, these kinds of concerns that are being raised on the negative
side of sending out 6,000 letters and alerting people, because just the
very fact that you are sending out 6,000 letters may convey a higher
risk to the recipients of those letters than actually we can document or
feel exists. And, that would be a concern that I would have.

But, now that the U.K. has done what they\'ve done, I don\'t see how we
cannot inform those 50 people, our Factor XI people, about at least what
has happened in the U.K., so they are not caught totally off guard that
this has happened, and then give them some additional information, more
of the type that we\'ve heard here around the table, that at least in
the United States at this point stay tuned, we are not as alarmed, and
we don\'t think it\'s, perhaps, as necessary to be informing all your
physicians and so on about the situation, but be informed. And, if you
want to, fine, but this is the danger, you can get the kind of
discrimination you were talking about, or the alarm, but put it into a
context that shows that we are not all that concerned.

CHAIRPERSON PRIOLA: Doctor DeArmond?

DOCTOR DeARMOND: Well, Larry, my wife was an epidemiologist, who has
been angry at me since we got married because she wanted to work at the
CDC in Atlanta, and I didn\'t want to go to Atlanta.

But, she says the same thing to me. I always talk about testing, and she
says, the epidemiology shows there is nothing there. So, you can\'t
create panic. And, she\'s always emphasizing, don\'t create panic. That
can be as dangerous as not telling the truth about a true infectious
process.

And so, I don\'t know what the use of this model is going to be, and how
far you are going to push it, and that goes to your question, are you
going to really tell the public that there is a danger, when the
epidemiology, which is really even more important than detecting the
prion protein, because it tells you the final product, does disease
actually emerge.

If the epidemiology is negative and stays negative, there\'s ? I agree
with you, you don\'t want to create panic, and you have to have a very
soft letter to the Factor XI people.

CHAIRPERSON PRIOLA: Doctor Johnson.

DOCTOR JOHNSON: Sue, I\'m not sure what the vote is on.

CHAIRPERSON PRIOLA: Well, it\'s not really a vote, it\'s more a
discussion. So, I think there\'s a consensus coming around the Committee
that the model is basically valid and solid, but that you need more data
to be more comfortable with the predictions for exposure, not infection
or disease.

That\'s all this is, a discussion, not a vote.

DOCTOR JOHNSON: Well, because there\'s really two issues that have come
up, and they need to be separated. I think everybody agrees the model is
interesting. I think most of us would think it might be over-estimated,
but that\'s all right. I mean, if it needs to be worked with, it needs
better data.

The second issue is, what should be told to the 50, or all the 10,000
hemophiliacs in the United States, or the 50 who received the British
material.

CHAIRPERSON PRIOLA: Right, and that\'s ?

DOCTOR JOHNSON: And, I think that\'s a very different question that we
should focus on.

CHAIRPERSON PRIOLA: ? well, it is a very important question, it is very
different, and it\'s also not the purview of this Committee to do,
because this Committee advises the FDA, and I believe that\'s a CDC
issue.

So, discussion of that issue in this Committee isn\'t really pertinent
to what we are doing. It\'s an incredibly important question, but it\'s
not one that we have to deal with.

That\'s correct, right, Doctor Epstein?

DOCTOR EPSTEIN: Notification?

CHAIRPERSON PRIOLA: Yes.

DOCTOR EPSTEIN: Yes, we have specifically not brought that question to
the Committee today, because we see this as a process taken in stages,
and we felt that the first stage should be to do our own risk
assessment.

The thinking of the Committee will feed into a dialogue among the Public
Health Service agencies, where we will consider the questions that you
are putting on the table, which are, should patients be notified, what
spectrum of patients should be notified, and what are the public health
messages?

So, all of that, you know, will follow in due course, but the place to
start is to understand the assessment of risk and the limitations to our
ability to make that assessment. So, we are only at that stage here
today.

DOCTOR JOHNSON: Well, I assume that the 50 people who received it under
IND there will be a, basically, ethical mandate that they be informed in
some way.

DOCTOR EPSTEIN: Well, I think there are many individuals who might share
that view, but it\'s still, there\'s a process we would have to follow
and actually make a decision, you know, whereas treaters may feel,
perhaps, ethically obliged, or obliged for whatever reason, they still
want to know what\'s the correct public health message.

So, it\'s really not going to happen until we make some decision about
the significance of potential risk and what kind of public health
strategy is appropriate in our country.

So, you know, there may be that desire, and we understand that, but
things really won\'t move forward until, you know, some decisions are
made.

CHAIRPERSON PRIOLA: Are there any other comments?

Doctor Gambetti.

DOCTOR GAMBETTI: In tend to agree with Steve and others that although
the model is excellent, Steve, there are some information, or it would
be highly desirable that additional information be added, so that we can
reduce this gap and, therefore, be more useful to the recipients of the
Factor XI about the risk, if any, of that transfusion.

However, I think ? and so I tend to agree with the fact that, perhaps,
we should withhold any information before we at least try to improve the
risk assessment.

I think it would be very useful if we could be more precise, if on
improvement, what exactly, what practically, could we do to the current
model, or information available on which the model has been built, to
improve the risk assessment? Are there practical things that can be done
in a reasonable amount of time to have better assessment, or is this a
kind of vague wish that the system ? the model is improved?

In other words, Steve, do you think, do you see practical things that
could be done in a short ? relatively short amount of time to improve
the quality of the assessment?

DOCTOR DeARMOND: No. I just don\'t think so, because you have ? the time
frame is the order of months to a year, or less, weeks, to months, to a
year, and it would be quite a bit to get the other data at this stage.

And also, a lot of it has to be through the cooperation of Great
Britain, and that seems to be a complicated issue also.

DOCTOR GAMBETTI: So, I guess we have to base our judgment on the model
that we have right now, and decide what to do in terms of informing the
recipients about the risk, based on what we have seen to date.

CHAIRPERSON PRIOLA: Doctor Telling?

DOCTOR TELLING: Yeah, notwithstanding the issues of timing here, but
there are, I think, practical things that can be addressed in terms of
the animal models that are being used to study these issues. And, I\'m
thinking in particular about the BSE transmissions that have been
performed in the U.K. by Houston and co-workers, and also, more
particularly, the similar animal models using non-human primates that
Corinne Lasmezas is using to study new variant CJD.

However, I think you are right, these are not answers that we are going
to get in the space of a few weeks or a few months.

CHAIRPERSON PRIOLA: Doctor Gaylor?

DOCTOR GAYLOR: The negative epidemiology does not necessarily mean zero
risk, as we are all well aware, but I certainly would encourage trying
to use the human data to the extent we could to at least maybe get a
more realistic upper limit on what that risk might be.

CHAIRPERSON PRIOLA: Doctor Belay?

DOCTOR BELAY: I think the risk assessment is the best available data
that we have now, and there are numbers in that final table that are
associated with the output for the model.

So, I was wondering if this risk assessment, if there is a way of
validating the risk assessment, and I don\'t know if this is feasible or
not, or whether or not a risk assessment could be validated. So, the
real question is whether or not the numbers given at the final table the
last table, whether or not they are close to the truth or they are
totally off the chart.

What would happen, for example, if we take the model and apply to the
hemophilia population? Would it be consistent or at least close to what
we\'ve observed in the human population, because the absence of vCJD
cases in the hemophilia population, would, for example, the final output
be 90 percent, which would be, for me, off the chart? Would it be 30
percent, 40 percent?

So, are there ways that FDA could use to validate the risk assessment?
What would happen, for example, if you apply the model to red blood cell
recipients? We\'ve already observed at least two transmissions of vCJD
in patients who have received white blood cells.

I\'m not sure whether or not this is feasible, but I just wanted to
suggest it.

CHAIRPERSON PRIOLA: Are there any other comments before we move on to
Topic 2?

Okay, let\'s go ahead and move on to Topic 2.

Oh, I\'m sorry.

EXECUTIVE SECRETARY FREAS: Before you go on to Topic 2, can I just check
to see if there are any other FDA centers here who have any comments
about earlier topics?

COMMANDER O\'LONE: Hi, good afternoon. I am Commander Martha O\'Lone,
and I have addressed some of you before on behalf of the Center for
Devices and Radiological Health. I just wanted to make one comment based
on the discussion this morning.

I want to thank CDC, especially Doctor Sehulster for coming and talking
about the concerns we have with decontamination of medical devices, and
I just wanted to reiterate that we are encouraging manufacturers to
provide us with both detection and decontamination validation for
devices, because we do not have anything at this time that has been
cleared or proved for medical devices. So, our hands are still tied
without that data.

CHAIRPERSON PRIOLA: Okay, thank you, Commander O\'Lone.

So, I should double check with CBER, FDA, do you have the discussion
that you need or hoped to get from the Committee on Topic 1? Okay.
Apparently, they do, so let\'s move on to Topic 2, and the first speaker
is Doctor Dorothy Scott.

DOCTOR SCOTT: I\'m going to briefly provide an introduction to the
second issue. We seek the Committee\'s advice on the design and input
parameters of a risk assessment model for potential vCJD exposures from
products made from U.S. plasma, so this is in contrast to what you
initially saw, which was a risk of exposure from a U.K.-plasma
manufactured product. And, you\'ll see when Steve makes his presentation
where those differences lie in the assumptions that we try to make.

I\'ll briefly undertake the rationale for vCJD risk assessments for
plasma derivatives made from U.S. plasma, and also provide a short
overview of TSE clearance and how it is important to these models.

Then, Doctor Anderson will brief you on the risk assessment model for
products made from U.S. plasma, and that will include the model itself,
very similar to what you\'ve already seen for Factor XI, the data and
assumptions, the uncertainties, and it\'s use of ranges and
distributions, and the potential for sensitivity analysis.

Why should we do a risk assessment for U.S. products? We\'ve already
been over this many times. There\'s been a probable transfusion
transmission of vCJD reported in the U.K. Although, as was just
mentioned, there are no cases to date of variant CJD in any plasma
derivative recipients, including those in the U.K.

New information on vCJD prevalence and actual transmission by blood
allows a risk assessment to be undertaken, and these risk estimates that
we get provide a basis for reexamining the adequacy of current measures
to protect blood and plasma-derived products.

And, the model also provides a framework to update risk estimates, and
it contributes to public health decisions potentially. As we saw in the
U.K., they had a risk assessment for plasma derivatives in the early
2000s by Det Norske Veritas, and they were able to use that framework
then when they did C transmissions to try to make ? well, to actually
make public health decisions. So, we think it\'s a good thing to have in
place, in spite of its current uncertainties.

What can it do for us? Well, I think Steve Anderson will keep his job
for a while. It provides that framework. It can help us rank product
classes that may have greater or lesser margins of safety. It can give
us an estimation of the likely best case and worst case risk of exposure
to vCJD via products. Again, this will change as we get more
information.

It helps us think about how to estimate the need for additional risk
reduction measures for our products, and it also helps us get at the
levels of TSE clearance in manufacturing processes that are likely to be
meaningful. And finally, it provides some level of risk communication to
the public.

There are a lot of things it can\'t do, and this has a great deal to do
with all of the uncertainties you\'ve just heard, so I apologize for any
repetitiveness. It won\'t tell us the actual prevalence of vCJD agents
in blood or plasma donors. It won\'t tell us the timing of the presence
of infectivity in blood, of people who have vCJD who are incubating it,
how much infectivity is there we won\'t know from the risk assessment.
The effectiveness of blood donor deferrals for geographic risk of
exposure to BSE also cannot be provided by a risk assessment, but this
is important information, potentially, as you\'ll see. It can\'t give us
clearance data itself. It can\'t tell us if there\'s an effect of
cumulative low-level exposure to the vCJD agent, and it won\'t tell us
anything about the susceptibility of recipients to infection.

However, the good news is, a lot of this can be learned, and is being
studied, and we may have, if not some answers, some better ranges to
work with.

I just want to mention that there are two published risk assessments
from Europe. The first is the Det Norske Veritas risk assessment
commissioned by the U.K., and I\'ve provided the websites, and the
second one is a French risk assessment.

So, the question for the Committee, quite similar to your first set of
questions, please comment with regard to the U.S. risk assessment model
that Doctor Anderson will present, and please comment about what
additional information is needed to improve these risk estimates that
might result from the model.

I\'m going to go on to the second talk. I\'m going to preface Doctor
Anderson\'s talk with an overview of TSE-clearance studies in products,
because of their importance to the risk assessment.

You\'ve seen this morning that for the Factor XI risk assessment the
second-most sensitive factor or variable was TSE clearance. This is why
I wanted to provide more or less a summary of what we know and what we
don\'t know, and where improvements might be made.

Clearance during manufacturing is an important factor in the overall
risk estimation, and it can be tested in scaled-down studies, that is,
in lab experiments that recapitulate the manufacturing process.

And, the viral clearance studies paradigm is applied to these kinds of
studies, even though TSEs may not be, or behave exactly the same as
viruses.

The paradigm, very briefly, involves scaling down the manufacturing
process steps, so they can be studied in the lab, and validating the
scale down, proving that the lab process is the same, or very close, to
the manufacturing process.

I\'ll show you the two models that are now used, but one of them, the
most commonly used, is to spike at a manufacturing step with a high
titer of the infectious TSE agent. Usually, this is a model agent, often
a rodent brain preparation. Reduction factors are determined for each
step that is studied, and these may or may not be summed from
non-orthogonal processes to give a total log ten reduction value.

Typically, the sources of infectivity that are used are brain
preparations from experimentally-infected animals, with human or animal
TSE agents, or blood from experimentally-infected animals, and this is
what is referred to as endogenous experiment, or type of experiment. The
forms of the infectious agent will be brain homogenate or subcellular
fractions of that, sometimes membrane-free infectious material, which on
occasion behaves differently for certain manufacturing steps, or blood
and blood fractions.

It also needs to be considered that the form of the infectious agent
might be altered during manufacturing, and this is known as
conditioning, and this has to be taken into account when undertaking or
planning these studies.

The outcome measures of these can be in vivo infectivity, that is,
typically, considered the gold standard, but it is laborious. You can
use up a lot of rodents this way. It\'s expensive, because of the time
and the number of animals. It\'s also long term, because these have an
incubation period, especially when you are looking at low titers of
infectivity, it can be quite long. But, they are considered very
relevant.

In vitro, various ways of measuring the abnormal prion protein, are
used. These need to be linked somehow to in vivo infectivity, so that we
know this recapitulates that.

This is a spiking model that\'s commonly used. Here you take the TSE
preparation, it will have a high titer of the infectious agent, on the
order of 10^7^ or 10^8^ infectious doses or ID50s rather.

This is just an example to remind people have these are done. In this
case, we are looking very upstream in plasma processing, where the spike
may be put into plasma at a 10 percent or less concentration, and then
the manufacturing step is undertaken. In this case, you end up with
cryoprecipitate, which becomes Factor VIII, and the supernatant which
may become other products.

This is called the exogenous model. You can use a high titer, which
means you can measure large amounts of clearance here. The problem is,
nobody is really certain how much this kind of infectivity, or what
physical chemical similarity it has to the infectivity that is contained
in blood. That is one of the major caveats with this model.

The endogenous infection or clearance model is difference, because here
you use plasma or a blood fraction from a TSE-infected animal, and
that\'s your starting material, not a spike material. It undergoes the
manufacturing step. You can only study low titers of starting material,
because, of course, the titers of infectivity in blood are low. It\'s
deemed by many to be highly relevant, because it is, actually, the form
that is expected to be contained in human blood or plasma. Limited by
the fact that you have such a low titer here, you can\'t measure all the
clearance that might be occurring in any given manufacturing step.

There are many published TSE clearance studies, and many still to come.
The steps that have been studied and found to show some clearance in
many people\'s hand include certain alcohol precipitations, but it
depends a lot on the pH ionic strength and the amount of alcohol, as
well as the starting matrix, how much clearance you get. PEG
precipitation, salt precipitation, depth filtration, nanofiltration,
column chromatography, under some circumstances have all been reported
to result in clearance in these kind of experimental studies.

In all of these cases, the clearance relies on partitioning, and
there\'s always been a question, certainly in viral studies, how robust
a step that is. In other words, you are not inactivating the agent, you
are partitioning it out. You are getting it away from your final
product.

The additiveness of different steps needs to be demonstrated. Scale down
again is very important, and the relevance of the model is something
that\'s under heated discussion.

Again, I want to point out, as I have before, that manufacturing
processes for any given set of products are highly individual, and
rigorous demonstrations of TSE clearance have to be based on the
specific manufacturing process.

This is an example, I\'ve shown it before, but it just demonstrates that
you can do depth filtration for example, but the amount of reduction
that you get, or TSE clearance that you get, differs depending on the
starting material, or the matrix as we call it, as well as the type of
depth filter, perhaps, and you see you get anywhere from no clearance to
a very high level of clearance, so you cannot say depth filtration will
give you four, it might give you one, it might give you five. It all
depends on the specifics, and this is just simply the same case over
here.

This Committee in February of 2003 endorsed our consideration of
labeling claims for TSE clearance in plasma derivatives, based on
demonstration of removal during manufacturing in scale-down studies.
And, we encourage that these submissions be made to us. We have received
some such submissions, evaluations are in progress, and we have approved
a labeling claim based on TSE clearance studies.

This, of course, is voluntary. We ask that the best current methods are
used, but the problem is we have a lot of science and evolution, so the
best current method when you start your study might not be the best
method when you finished your study.

The model selection is not restricted at this point, but it has to be
justified. Certainly, three logs of clearance is something that we think
is probably meaningful for non-robust steps. By that I mean partitioning
steps, but there is some discussion about whether a whole series of
processes can be considered that results in a high level of clearance
even if any one step does not.

So, in summary, TSE clearance is a critical variable that\'s considered
in risk assessments for variant CJD, and it can be tested, at least, on
a laboratory scale with the caveats, especially those concerning the
relevance of the spike. And, improvements in ways of studying this would
be very useful.

We can get data for the risk assessments from this information, and that
is especially if there\'s been a specific study of the product that\'s
under discussion for the risk assessment.

I just want to remind people that there are a lot of studies that have
been done on TSE clearance. I found 16, I apologize if I\'ve missed any,
but I think that things continue to move forward and we are very
grateful for all the work that\'s already been done.

And so, now I\'ll pass on the podium to Doctor Anderson again.

DOCTOR ANDERSON: Okay.

I\'m actually aware that I\'m between you and lunch, so what I\'m going
to do is actually, I think I\'ve taken my longer period of time to
explain the basics of risk assessment, and I\'ve indoctrinated you, now
you are all experts, so I\'m going to move quickly through the slides,
because there are a lot of similarities in what I\'m presenting with
what I just previously presented for Factor XI, and I\'ll point out the
differences and walk you through those mostly.

And, what we are doing here is, we are doing a preliminary risk
assessment, and this is more of a concept model for U.S. plasma
derivatives and variant CJD risk.

You\'ve seen this structure before. I\'m going to follow it in
explaining to you what our concept model and plan is for doing a risk
assessment. Again, here\'s the question, It looks very similar. We have
the sort of preliminary part of the question, but our question that we
want to focus on is, what is the risk of potential exposure to variant
CJD agent in the U.S. populations. So, what we\'ve done is, we\'ve moved
over and we are talking about U.S. risk, specifically, in this talk, for
individuals that have received U.S.-manufactured human plasma derivative
products.

What we have underway are several risk assessments, actually. We have a
risk assessment underway for Factor VIII, Factor IX, immunoglobulins and
serum albumin. Now, I\'m providing sort of an overview of our concept
model and assumptions for the risk assessment, but I think it\'s
important to say that we haven\'t really completed the risk assessments.
So, please don\'t ask for results, because we don\'t have any at this
point in time.

Again, the hazard identification step is really what I just presented in
the previous talk. I\'m going to walk through that, just sort of walk by
that very quickly. Again, the dose response issues are the same as in
the previous talk as well.

Human data not available, animal data are very limited. Again,
predicting the probability of illness is extremely uncertain in these
models that we are going to generate.

Now, what I wanted to do was actually ? we\'ve actually divided this
model up, so before for Factor XI we had a three-part model, what we\'ve
done is added an additional component, and what we are doing is, we are
not only looking at variant CJD prevalence ? potential prevalence in the
United States, but we are also looking closer at plasma donation, and I
think we were getting at that issue earlier with the U.K. risk
assessment. We didn\'t have that information for the U.K., but we do
have some of that information for the United States, and we are
integrating that into our model to improve the predictive capabilities
of the model.

So, let me just go back and explain, again we\'ve added a component
where we are looking at vCJD in the U.S. population, or potential vCJD
in the U.S. population, and the potential for plasma donations that may
contain the variant CJD agent. Again, we are looking at probability and
quantity. We are looking for plasma donations, what are the
characteristics of plasma donors, individuals that have variant CJD, we
want to look specifically at what we had talked about earlier, age
specificity of variant CJD, age-specific characteristics of blood
donors, because that has a direct bearing on risk. Again, reduction, and
then the dose that people receive of these products.

All right. So, there\'s a model. Again, our outputs are, we are looking
at annual exposure to variant CJD agent. This is very similar to the
model that we\'ve seen before.

Now, I\'m going to walk through more slowly module A and module B,
because those are sort of new and probably the most important
components, and sort of just breeze by the last two components of the
model, concept model at this point.

So, for predicting potential variant CJD cases in the United States, we
are looking at variant CJD risk in the U.S. plasma donors, specifically,
and we think that the sources may ? I\'m sorry, that there may be two
potential sources of exposure to BSE agent and that may lead to variant
CJD infection and illness.

The first one is dietary exposure to the BSE agent from U.S. domestic
beef consumption. The second one is dietary exposure to the BSE agent
during extended travel to the U.K. and Europe.

What we\'ve done is, essentially, we\'ve eliminated number one, and
it\'s nearly zero for our purposes of this model. We did a number of
worst-case evaluations of the risk, so dietary exposure to the BSE agent
from U.S. domestic beef consumption, we evaluated USDA BSE surveillance
data in cattle, and then what we did was, we estimated that the risk,
the potential number of vCJD cases coming from that particular route of
exposure at this point, given the information that we have we assumed it
was negligible based on our analyses. So, what we did was, we just
assumed that zero cases would potentially come from this source.

Now we move on to the, perhaps, greater potential source or vCJD cases
in the United States, and that would be through dietary exposure to the
BSE agent during extended travel to the United Kingdom and Europe.

Our approach, first of all, was the model estimates variant CJD
prevalence in the United Kingdom population, then what we go on to do is
look at a concept called relative risk of exposure to the BSE agent, and
what happens is, we are pegging everything, all of our analyses, to that
variant CJF prevalence for the U.K., and we\'re saying that that\'s,
essentially, the maximum risk, where we assign that a value of one. And
then what you do for relative risk is, the relative risk for France and
Europe, I\'m going to talk more about this in a minute, but are
considerably less. It\'s estimated that France has a relative ? the U.K.
has a relative risk of one, France has a relative risk of .05, Europe
has a relative risk even lower, of .015.

Then what we do is, we calculate variant CJD risk for the United States
plasma donors, using this information on extended travel to U.K., France
and Europe. I\'m going to show you how that\'s done in a moment.

The calculation of U.S. donor variant CJD risk is based on prevalence of
variant CJD in the U.K., relative risk for U.K., France, Europe for BSE
and variant CJD. The percentage of donors with the travel history, so
the percentage of U.S. donors that have actually traveled to the U.K.
for extended periods of time, and then to France or Europe for extended
periods of time.

Then, we are also interested in this component of the duration of U.S.
traveler stay, how long did they stay. Presumably, people that stayed
for very long periods of time in the United Kingdom, for, you know, more
than three months, a year, would presumably have more risk than somebody
that spent three days there.

What we do is, we actually just add ? we calculate this for each country
that a percentage of the donor population in the U.S. may have visited.
So, if we know that a donor visited the U.K., what we do is, we have a
calculation where we calculate the prevalence of variant CJD, so
whatever that prevalence is times the relative risk, which for the U.K.
is one, the percentage of donors in the U.S. that actually traveled or
were in the U.K., and subject to potential exposure to the BSE agent,
and then the duration. And, we prorate the duration of exposure based on
the amount of time they spent in the United Kingdom.

We go ahead and do this for several populations. The first line is for
people that visited the United Kingdom, second line is for France, third
line is for Europe. And, we\'ve got another set of calculations for
military populations that may have been posted to the U.K., France and
Europe as well. So, I just wanted to give you a basic flavor for the
types of things we are considering in the model with this equation.

Again, the prevalence you\'ve seen, this is our assumed prevalence based
on the Hilton study of one in 4,225 individuals that may have variant
CJD in the United Kingdom. The periods of time that we\'re interested in
for establishing relative risk of U.K., France and Europe, are the
periods of a three-month stay in the U.K. from the period 1980 to 1996,
just to note in 1996 we are not as concerned after that point because
food chain controls were put in place and high-risk tissues are thought
to have not entered the food supply after that point.

In France and Europe, we are looking at a stay, if a person stayed in
Europe or France for more than five years from the period of 1980 to
present. This correlates with our blood donor deferral policy. We are
linking our model to our current blood donor deferral policy.

The model, again, uses this concept of relative risk, and we evaluate
all travel in relation to the U.K. U.K. again, is one or 100 percent,
and everybody else\'s risk is calculated in relation to the relative
risk for the United Kingdom.

So, I actually should have presented this slide a little bit earlier,
after having gone through all this. The relative risk for U.K., France
and Europe for BSE and variant CJD is a soon to be one for U.S.
citizens, specifically, anybody that stayed in the U.K. for a period of
over five years, a traveler, et cetera, would have a relative risk of
one. That\'s an assumption we made in the model so far.

And then, anybody that stayed for a period of less than five years from
1980 to 1996, we did a proration of this risk, so if they stayed in for
four years it was 80 percent of this risk, three years 60 percent, et
cetera, on down to three months. So, we apportioned the risk equally in
the years between ?- 17 years between 1980 and 1996 for the U.K.

For France and Europe, it was a little bit easier, anybody that stayed
in France for a period of greater than five years had a relative risk of
.05. Anybody in Europe had a risk of .05.

Now, this concept of relative risk is just based on exposure, the number
of variant CJD cases that have been observed in France, and then also, I
believe, France received approximately 5 percent of its beef supply from
the U.K. during the times of the BSE epidemic. So, that\'s how we are
getting this relative risk of .05 or 5 percent.

And, it\'s much lower because Europeans have a lower incidence or
prevalence of variant CJD, very few cases across Europe compared to even
France, and then also the amount of beef products that they received is
much less. So, the relative risk there is much less.

All right, so the next component is the percentage ? we had to figure
out the percentage of donors that actually traveled to these countries
for a duration or a period of time that they would have been exposed.
So, this slide is actually incorrect, I didn\'t give an updated slide,
but this is approximately 7.2 percent of U.S. residents had a history of
travel to the U.K. and Europe during the 1980s and 1990s. Three percent
of those individuals were military and dependents, hence, we are
treating those separately in the equations that we are doing. They also
tend to spend approximately two years, one year, they have more sort of
defined periods of time that they were in the United Kingdom or in
Europe.

Of blood donors that were questioned, 1.7 percent traveled to the U.K.
during the time period 1980 to 1996 for a three-month period, and then
.2 percent for a five-year period since 1980, and then .7 percent
traveled to Europe since 1980 for a five-year period.

The duration of travel. So, we have information from U.S. surveys that
were conducted in blood banks and blood organizations, and we have
information on travel history and duration of travel, and Alan Williams
has presented this, from the FDA, has presented this in previous
meetings, so I\'m not going to in depth into it, and he\'ll probably
actually touch on it this afternoon as well in his talk.

But, travel history and duration of travel was taken from that
information and incorporated, so we could get the number of days and
years that people resided or traveled to these three areas of the world,
U.K., France and Europe. That was included in the model.

What we assumed was that blood donor travel history is the same for
plasma donors. Again, plasma donors are known to have less of a
probability of having traveled, or less of a history of travel to U.K.
and Europe than blood donors, but right now we have the best information
for blood, so we are assuming they are the same.

Just sort of moving on quickly, talking about plasma donation, so a
plasma donor walks in, we want to know something about their age of
donation, because that\'s related to variant CJD rates, so most of the
individuals that donate are under the age of 35, I believe that\'s about
70 percent of donors, and that\'s really the group that\'s largely
affected or most affected by variant CJD. So, the median age, remember,
for variant CJD is 28 years, so there\'s a lot of overlap and a lot of
potential for risk in the U.S. from these groups, because they so
overlap in their demographics.

The probability of variant CJD donation per plasma pool, we\'ve
calculated that. The quantity of ID50s, again, what we are doing here
is, the quantity of ID50s we are getting in from the previous model, our
estimates of quantities of ID50s from blood and animal studies, and then
the probability of donor deferrals. So, this all goes into the plasma
donation.

The probability of donor deferrals is quite important, because we think
that that\'s an effective risk reduction strategy and probably knocks
out about 90 percent of the risk or more. So, that\'s an important
component of all this.

So, just to give you an idea. This is some of the representative data we
are using. This model uses estimated age-specific source plasma donation
rates. So, we characterize all donors by these characteristics, and, for
instance, this is about 70 percent of the donors fall under age 34.
People over 35 represent about 20 to 30 percent.

Some of the other data we use for the model is the age-specific variant
CJD rates. Again, we are plugging this all in to see the overlap between
these two age demographics of donation and variant CJD rate in these
populations.

The probability that a variant CJD donation will be in a plasma pool or
the probability of variant CJD per plasma pool, what we are doing here
is, we are using a mathematical equation, a binomial distribution, to
estimate the number of variant CJD donations per pool. Basically, the
assumption is, is that the risk is very low, the variant CJD prevalence
in the United States is very low, so the chances of getting one or more
donations in a pool is very small. The chance of even getting one
donation in a pool is small, but it is possible.

So, this equation, basically, gives us the probabilities. We can plug it
in for zero donations, which, you know, would probably be something like
99 percent or more, but you\'ll have a few pools that will have
donations, and then we can run the probabilities, plug in one, run the
probability, two, what\'s the chance of having two donations, three
donations, very small probabilities once you get past one, of having
more than one donation per plasma pool, unlike the situation with Factor
XI this morning.

All right. The quantity of agent, I\'m just going to say this is data
from this morning, so I\'ll refer you to that from the earlier
presentation., all assumptions that you\'ve seen before.

Again, the probability of donor deferral, we assumed that the universal
donor questionnaire, with the questions on travel history, are about 90
to 95 percent effective in eliminating potential donors that may have
been exposed to BSE through travel history to the U.K., France or
Europe.

All right, so processing, I\'m not going to say much about this, because
this is very similar to Factor XI. The effects of processing do reduce ?
potentially reduce the amount of variant CJD infectivity. I think it\'s
important to emphasize the processes, like Dot had just mentioned,
processes are going to vary for each different product. You use
different sort of methods of purification. So, specific reduction is
going to be based on processing steps, and I haven\'t presented a
complete picture here.

What I\'m going to do is present some of the information for Factor
VIII. So, high purity product, for instance, is an immunopurified
product, and then intermediate uses some other steps, like alcohol
precipitation, chromotography, et cetera.

And, the levels of reduction we\'re assuming for Factor VIII at this
moment in time are given here. So, a minimum of three, most likely of
five, a maximum of six logs of reduction for Factor VIII, and then a
much lower profile two, three and four, for intermediate purity Factor
VIII.

We get on to utilization. Again, we\'re interested in probability and
quantity of exposure that influence ? probability and quantity that a
person will be exposed to the variant CJD agent is really influenced by
the amount of product that they are using. So, if it\'s a one time or
sort of an incidental use for surgery, like Factor XI, there\'s less of
a risk, but we\'ve got a number of patients that use these products,
Factor VIII for instance, constantly. It\'s a chronic use type of
situation, and there are also degrees of severity of disease, so very
severe disease for, I believe, about 60 percent of the population, and
the remaining population is less severe disease, and these patients that
are taking the most product are the severe patients and would be at
higher risk if there is a risk for variant CJD exposure.

I thought I would just present this, this goes back to Doctor Salman\'s
question about variability and uncertainty. This is actually a good
example of variability, so we are looking at utilization of products.
This comes from a paper by Jeanne Linden\'s group in New York, where the
mean utilization of Factor VIII was predicted at 200 ? and you can say
about 240,000 units, but there are percentiles around that utilization
as well that we can do. So, that represents ? we know that information,
so this is true variability.

So, episodic, just to note, if you are treated on an episodic basis
about two and a half times less amount of product you are using and
being exposed to. Again, what we are doing is, we are not only doing
Factor VIII, but Factor IX, immunoglobulins and albumin in this larger
risk assessment. So, the concepts for utilization for these products is
very similar. We are interested in probability and quantity of exposure,
and that\'s influenced by utilization, processing, and a number of
different specific, product-specific steps that go into the manufacture
and use of these products.

Again, I think I\'ve just covered most of those points in what I said.

Many of the concepts in this model are very similar. You know,
probability of variant CJD, the probability of contaminated pool,
effectiveness of screening questionnaire, all of those are sort of the
common components of these models, and then what\'s going to vary are
the plasma pool size, the reductions that we see, product package size,
amounts dispensed, and then utilization by patients. Those things are
going to vary, but these are going to pretty much stay the same.

So, to sort of move on. Again, more data are needed, and we\'ve talked
about these data needs, and I think I\'ll leave that for the Committee
to discuss, and then I just again wanted to thank all these people. I
have a limited list of people. Hong Yang, though, has been doing most of
the modeling, and so she\'s done an extreme amount of work just in sort
of, you know, developing this model and getting the Factor VIII and
several other models up to snuff.

And then, we have a lot of people providing technical assistance, and a
lot of people that I haven\'t mentioned. Again, I have to say that I\'m
really pleased by the compliments that we\'ve received, but, you know,
it is Steve Anderson sort of the face of this, but underneath it all
there is this whole effort by a large number of people that really need
recognition as well.

So, I thank you for your time.

CHAIRPERSON PRIOLA: Okay, thank you very much, Doctor Anderson and
Doctor Scott.

We are going to have a discussion and vote period after lunch, but I
want to give you an opportunity to ask any pressing questions right
after these talks.

So, Doctor Salman, do you have a question?

DOCTOR SALMAN: Thank you, Doctor Anderson, it was a very good
presentation, but just a couple points for clarification.

In your model D, you are saying the output will be annual predictions?

DOCTOR ANDERSON: Right, based on utilization of the product, but it
could be different because things like albumin are used more for a
surgical procedure.

DOCTOR SALMAN: So, I assume, just listening to the methodology, you are
taking the entire cumulative data, and then you try to divide them by
the number of years? How you will get annual prediction, that\'s what I
don\'t know how you will get this.

DOCTOR ANDERSON: I\'m sorry, what?

DOCTOR SALMAN: How you will get the annual predictions, when you are
dealing with a cumulative data of several years, unless if you assume
like the exposure are equal among all these years, is that right?

DOCTOR ANDERSON: Right now, the model is assuming ? you mean for the
U.K. prevalence, for instance?

DOCTOR SALMAN: U.K. prevalence or any of this.

DOCTOR ANDERSON: \>From the period from 1980 to 1996.

DOCTOR SALMAN: Yes.

DOCTOR ANDERSON: We haven\'t done, right now we are assuming equal risk
throughout those entire years, from 1980 ? for each year. Right now,
it\'s equal. I think what we need to do in the model that\'s taking a
lot of time is, we\'ll actually link it to the BSE prevalence. So, it
will be different, and we\'ll link it to the BSE prevalence and
epidemic, and then, you know, it will be a more realistic representation
of the risk.

DOCTOR SALMAN: And, that\'s taking me to the second question about the
BSE, you are taking relative risk, which I think is a good indicator for
France versus U.K., and versus Europe, but these are whatever is the
output from the surveillance data. There are other countries,
specifically, in Europe, in which they have much, much higher cases, but
they have poor surveillance, and you are actually penalizing countries
in which they showed result, where the other countries they don\'t show
results, such as East Europe. I can tell you, if I\'m traveling in East
Europe I will be at much higher risk there to be exposed to the BSE
agent as compared to France or Switzerland.

DOCTOR ANDERSON: Right. I mean, I would agree with you. Right now we
haven\'t gotten to the refinements in the model. I mean, right now we
are making large blanket assumptions, but, eventually we\'ll refine
those estimates.

I think a good source to potentially do that could be the
geographic-based risk assessments, but, you know, the information on
those countries that aren\'t doing surveillance are really poor, but you
can also consider other factors in risk, as far as do they have food
chain controls in place, do they have surveillance, et cetera, and then
link it to what\'s been determined by the GBR, the geographic-based risk
assessment.

DOCTOR SALMAN: I really believe, like if you take the GBR classification
that will be much better, and associate that with your calculation of
relative risk.

DOCTOR ANDERSON: I just want to say, I mean, I like getting these ideas
from people, because it tells us what direction we should really be
going, and what you are saying is, we need to refine these estimates as
much as possible. It does take a great deal of work to do that, but we
are putting that effort in.

So, it just takes time, you know, we\'ve got bundles of data out there
to sort of go through and integrate in.

CHAIRPERSON PRIOLA: Are there any other questions from Committee Members
before we break for lunch?

Okay, so let\'s break for lunch until 2:00, and come back with questions
and discussion.

(Whereupon, the above-entitled matter was recessed at 1:04 p.m., to
reconvene at 2:00 p.m., this same day.)

A-F-T-E-R-N-O-O-N S-E-S-S-I-O-N

2:19 p.m.

EXECUTIVE SECRETARY FREAS: Okay, Doctor Priola, with your permission we
are going to resume and starting with the open public hearing.

And, I would like to ask, I have not received any requests to speak in
the second open public hearing, is there anyone in the audience who
wishes to address the Committee at this time?

Yes, Doctor Baron.

DOCTOR BARON: Thank you.

My name is Henry Baron. I am an employee of ZLB Behring, a major
producer of plasma protein therapeutic agents, and I\'m also the
Chairman of the TSE Task Force of the PPTA, the Plasma Protein
Therapeutics Association, and I just wanted to make a comment about the
risk assessments and the exposure assessments that we\'ve seen today.

I think that there was unanimity, as far the fact that the models being
used to generate an outcome in these assessments appear to be valid.
I\'m no expert about that, but it certainly ? they certainly look like
good models to me.

Where the problems seemed to occur were in the data gaps that led to
some of the assumptions, and if there were two assumptions that had a
huge impact on the final outcome of the assessments those were the ones
involving the estimation of the prevalence of vCJD in a given donor
population, and the estimation of the amount of infectivity in the blood
of a vCJD patient. And, these are the two areas with the highest degree
of uncertainty.

Now also, clearance factors were indicated as a critical variable as
well by Doctor Scott and also by Doctor Anderson, and I think that
there\'s less variability there, even in view of some of the caveats
demonstrated by Doctor Scott, because of the fact that even though
people are doing these studies in very different ways the data seems to
converging in the same direction.

But, I would like to bring us back for a second, if the Committee would
consider this, to a question that Doctor Gambetti asked when looking for
ways to fairly rapidly address one of the main data gaps, and that was
the one that involves the amount of infectivity potentially present in
the bloods of vCJD cases. And, he asked the question to Steve DeArmond,
who seemed to give an unqualified no, there doesn\'t seem to be anything
that we can really do in a short amount of time.

And, I would just like to suggest that there could potentially be
something that could be done in a short amount of time if the FDA could
make it an aggressive part of its agenda to try to obtain samples of
blood and/or plasma from known vCJD patients in the U.K., these samples
could be analyzed in a relatively fast amount of time by one of the
laboratories currently implementing and employing the CDI immunoassay,
which has an extremely high degree of sensitivity as far as human prions
are concerned.

So, I think that this is not an approved test, as you had asked earlier,
Doctor Priola, it\'s not an approved test, but it is, nonetheless, the
endogenous infectivity experiments which have been used to be the basis
for the current estimations, or the current assumptions are not approved
tests either. It\'s a research tool, but it\'s a highly-effective and
highly-sensitive research tool, that I think could give us some
reasonably realistic and relevant answers about the potential or the
amounts of potential infectivity in blood.

And, that\'s what I wanted to say. Thank you.

DOCTOR SCOTT: I would just like to comment on that. I think it would be
useful for everybody to understand what these sensitivity and
specificity of those tests are for blood of infected animals.

DOCTOR BARON: As far as blood of infected animals is concerned, there
has been no study done with the CDI, as far as I know. Now, Steve
DeArmond might have some further comments to make upon that.

The sensitivity of those tests, as far as brain material is concerned,
is that the CDI detects less than one ID50 per ml of brain homogenate,
so you would have an answer at least as far as the ability to detect
less than so much infectivity, as demonstrated in tests with brain
homogenate.

As far as the animals are concerned, the problem is also what antibodies
you are using with the test. The test that we\'ve employed for the human
prions uses antibodies that capture antibody, that only reacts with
human PRP.

Steve, do you have any further comments that you would make?

DOCTOR DeARMOND: Not specific. All I can say is, there are multiple new
ways of enhancing the sensitivity of the detection tests that our lab
have, but Aguzzi\'s lab and other labs are using, and the most
remarkable part about it is that they show positivity even when the
pathology is negative, that is, there\'s no vacuolation and when
immunohistochemistry is negative.

And, what I was trying to say this morning is that today, because of
these newer developments, and as I say, it\'s not just our group, it\'s
multiple groups have done this, we are in a new era of detecting
abnormal prion protein.

DOCTOR BARON: If I could just add that while we haven\'t tested human
blood, because we haven\'t had access to those samples, what we have
done is, we\'ve taken variant CJD brain tissue and formulated it into
different preparations, including microsomes, caveolae-like domains, and
purified PRP scrapie, and spiked that at the human plasma, and I can say
that human plasma does not interfere with the ability of the CDI to
detect those preparations of human prions.

EXECUTIVE SECRETARY FREAS: Thank you very much, Doctor Baron.

Is there anyone else in the audience who would like to address the
Committee during this open public hearing?

Seeing noone else, Doctor Priola, In turn the meeting over to you.

CHAIRPERSON PRIOLA: Okay, so this is the discussion part of Topic 2,
where the FDA wants the Committee to consider and comment on the U.S.
risk model in regards to assessing risk for TSE contamination and
exposure via U.S. plasma derivatives.

So, the comments are just as in the ? just as for the first topic, that
is, do we have any comments on the model per se, and is there any
additional information that is needed to improve the risk estimates for
the various plasma derivatives?

Doctor Bracey?

DOCTOR BRACEY: In have one question, and that is, unlike the U.K., there
seems to be sort of a greater variance in terms of variability, in terms
of how plasma products are made in the U.S., and, perhaps, Doctor
Petteway could comment on that. Are there, I understand that there has
been a move, perhaps, by some to increase the number of apheresis
donations, and, therefore, perhaps, the volume in a given lot of product
might be greater.

What is the trend, and what is the uniformity, and, you know, is the
U.S. product that different?

DOCTOR PETTEWAY: Well, in general, cone fractionation uses ethanol, pH,
temperature to precipitate proteins along a train that\'s then purified.

There\'s a significant difference in the way that those steps are
coupled together and not coupled together. One company may take three
steps and make three fractions, fraction I, II and III, all in one
process step, and that has one set of consequences for partitioning.
Another company may separate the fraction I part of it from the fraction
II plus III.

So, in general, for the data that we have, where different companies
have used different processing to look at removal, as Hank Baron said,
they all converge and they all coincide, and as you move down the trunk
you remove prion.

That said, I think as Dorothy Scott said, they also differ significantly
beyond the trunk. So, the trunk is one aspect, but, perhaps, some of the
most important removal steps are in the purification processes, and they
are very different from company to company. So, they really have to be
looked at independently.

And, if you are going to look at them as a composite, then you have to
look at, say, for all immunoglobulin products, then you have to look at
a composite of data from different companies.

And, actually, I think that industry has presented that sort of data
here before.

CHAIRPERSON PRIOLA: Doctor Hogan?

DOCTOR HOGAN: Yes, I\'m going to come back to this question again, and I
really don\'t know the answer to this, I\'m not an epidemiologist or a
statistician, but if you are looking at prevalence rates, that\'s a
population-based figure, and I still think you need to think about, or
add to your model, or at least consider, what percentage of a certain
prevalence might donate. That is, if only 7 percent of the 28-year olds
are going to donate, why would you expect 100 percent of those patients
to have CJD, vCJD, would donate?

So, I don\'t know, is that a useful tool to put into your model, or am I
just confabulating?

CHAIRPERSON PRIOLA: Doctor Anderson, do you want to comment on that?

DOCTOR ANDERSON: Can you repeat that?

CHAIRPERSON PRIOLA: Could you go to the microphone?

DOCTOR ANDERSON: Sorry.

DOCTOR HOGAN: Essentially, what I\'m asking is, when we look at corneal
donor data ?

DOCTOR ANDERSON: Sure.

DOCTOR HOGAN: ? and there\'s two ways of looking at it, that everybody
that has CJD donates, or the percentage of people in a specific
population would donate, that is, the corneal donor population is less
than 1 percent of the total population.

DOCTOR ANDERSON: Right.

DOCTOR HOGAN: So, you don\'t look at all corneal donors, you look at 1
percent of the population.

DOCTOR ANDERSON: So, the question is, is there a way for us to narrow
down the population that we are looking at that\'s at risk for variant
CJD in donations?

DOCTOR HOGAN: That is, you say there\'s a prevalence rate of vCJD, what
percentage of that population, given the ages or whatever, might be
expected to donate? You can assume 100 percent for worst case scenario,
but what\'s the real world?

DOCTOR ANDERSON: Right. We are trying to adjust for that as much as
possible by including age specificity for variant CJD rates and then
donation rates. But, I can\'t, beyond that, really sort of narrow it any
further. I mean, we are open to suggestions in doing that.

CHAIRPERSON PRIOLA: Doctor DiMichele?

DOCTOR DiMICHELE: In think I might know the answer to this question, but
I feel like I need to ask it anyway.

There\'s also an issue that we are going to be discussing later on, and
that\'s the whole issue of Euroblood and the four million units that
sort of have come into the United States, primarily, in the New York
area.

And so, I was just wondering if transfusion acquired variant CJD needs
to be included in the model.

CHAIRPERSON PRIOLA: Doctor Anderson?

DOCTOR ANDERSON: We can do that, and that\'s probably something that we
can consider in the future. We are not considering ? I mean, I haven\'t
incorporated that concept yet in the model, but certainly something that
we can do.

CHAIRPERSON PRIOLA: Doctor Belay?

DOCTOR BELAY: Related to that, I was a little bit worried about the
90-95 percent effectiveness of the donor deferral policy. That seems to
be the assumption in the model.

My recollection was the 90-95 percent was removal of the person time
exposure in the U.K. or other European countries, rather than the risk
of exposure.

So, the actual risk of exposure that\'s reduced by the donor deferral
policy could actually be smaller.

DOCTOR WILLIAMS: You\'re correct. They are really two different
concepts. The deferral for geographic risk by our calculations, given
the overall potential geographic exposure, removed 91 percent of that
risk.

I think what Steve was referring to in the model was, actually,
something like the predictive value of the question itself, to remove
those folks who, for instance, for the U.K. had a three month or greater
geographic exposure.

I believe the model does not cover that residual 9 percent risk for
those who had a shorter geographic exposure.

EXECUTIVE SECRETARY FREAS: Those comments were made by Doctor Alan
Williams.

CHAIRPERSON PRIOLA: Any other comments from the Committee on this issue?

Is there a consensus of the Committee that this model is ? the Committee
is as satisfied, in general, with this model as the one presented
earlier this morning for Factor VIII, since they are relatively similar
with these differences, donor addition and what not? I see nodding.
Okay.

One more chance, any other comments?

Doctor Belay?

DOCTOR BELAY: Yes, Doctor Steve Anderson maybe already is thinking about
this issue, but I didn\'t see it on the slides so I just wanted to
mention it, and that is, I think the risk assessment should be
stratified by the time that the donor deferral policy actually came into
effect. In other words, the risk before 1999 and after 1999 is
dramatically different, and the risk assessment should accordingly be
stratified during at least the two time periods, although there are some
nuances and differences in terms of the time period that the different
donor deferral policies were instituted.

DOCTOR ANDERSON: Right.

I can tell you right now that we are focusing on one year, which is the
current year or one of 2003, 2004, and trying to get the model set for
that period, and then the idea would be to sort of move back and look
at, you know, previous time periods, like before these mitigations were
put in place and the donor deferral policies, et cetera, and look at the
risk for these products at those times at well.

So, right now we are just sort of starting where we have the most
information and developing the model, then we\'ll sort of probably do a
retrospective look at previous years as well.

DOCTOR BELAY: Right.

Obviously, the bulk of the risk would be pre-1999.

DOCTOR ANDERSON: Sure.

CHAIRPERSON PRIOLA: Doctor Schonberger?

DOCTOR SCHONBERGER: One other refinement, perhaps, is the issue of when
they actually were visiting the U.K., and you talked about refining it
per the epidemic of BSE, or having it proportional to the epidemic of
BSE, but Doctor Belay has also mentioned preventative measures that
could influence exposure of humans. I think the U.K. instituted their
preventive measures for humans, at least, was around 1999, figure a
couple years to make it effective, so that, in fact, even though the
peak may have been \`92-\`93, it may well be that the peak human
exposure, given the preventative measures, may be a year or two earlier
than that.

So, you might want to take that all into consideration.

DOCTOR ANDERSON: I think we\'d really like to do that, but we don\'t
have travel ? that type of travel history. We are getting this from
survey data, so, you know, that type of survey information would have to
be collected, and that\'s a pretty large undertaking.

DOCTOR SCHONBERGER: Yeah, I can imagine.

DOCTOR ANDERSON: So, we don\'t have a year of attribution for the
travel, which is unfortunate, and that would certainly help in doing the
types of things that you are talking about.

DOCTOR SCHONBERGER: Yeah, that came up in part because of this recent
Japanese case that was only there for a month, and it happened to be
1989, which of all the years that might be the year, because that was
the first time that the U.K. was starting t put in the preventative
measures to protect human exposures.

DOCTOR ANDERSON: Right, and prior to, I think, you know, yesterday or
the day before, we weren\'t really thinking about under three months as
a risk.

DOCTOR SCHONBERGER: Yeah, exactly.

DOCTOR ANDERSON: I think we\'ll have to reconsider that as well.

CHAIRPERSON PRIOLA: Doctor Belay?

DOCTOR BELAY: Last point. I think this current risk assessment focuses
on blood derivatives, right?

DOCTOR ANDERSON: On blood?

DOCTOR BELAY: Blood derivatives, not blood components.

DOCTOR ANDERSON: Correct.

DOCTOR BELAY: Yeah, but we know blood components, particularly, before
1999, could potentially be highly risky, because ?

DOCTOR ANDERSON: Right.

DOCTOR BELAY: ? there was no donor deferral policy.

DOCTOR ANDERSON: Right.

DOCTOR BELAY: So, in fact, in most of the patients who potentially would
have been exposed as a result of blood transfusions would probably be
exposed to blood components collected from people who have visited to
the United Kingdom before 1999.

How are you addressing this issue?

DOCTOR ANDERSON: We aren\'t addressing that at this point in time. I
mean, that\'s something we can certainly do in the future. Yeah, I
can\'t really add much more to that. So, it\'s definitely something that
we can consider in the future, but at this moment in time we are not
doing a risk assessment on that topic.

DOCTOR BELAY: That\'s, obviously, a real risk than a theoretical risk
for blood derivatives, that\'s basically what I\'m trying to point out.

CHAIRPERSON PRIOLA: Doctor Allen?

DOCTOR ALLEN: This gets very difficult, and I think what I hear you
saying with your cautious statements is, we really need to look at how
reliably we can collect the data, how much effort has to go into
collecting and analyzing that, and what are we really going to use it
for as we move further back.

And, I think those are very important considerations, you know, from an
epidemiological perspective what you\'ve heard expressed is right on
target, but I think unless you\'ve got a good way to reliably collect
the data it makes it very difficult to ?

DOCTOR ANDERSON: Yeah, you are correct, because then we went into issues
of, you know, recall-wise as you go further back. I mean, who can
recall, you know, where they traveled, you know, a year ago, two years
ago, three years ago, and the further and further you go back what you
ate, the types of behavior, the activities, things that you did, that
all becomes much more difficult, you know, the further back we go.

And so, that\'s some of the challenges that we are going to be facing if
we sort of go in that direction. So, I think it\'s important to do,
because, you know, we have had these deferrals and other policies that
we\'ve put in place relatively recently, in the last three or four
years, but again, just collecting the data and the information, and
getting our hands on it, is really difficult.

DOCTOR ALLEN: And, what you\'ve just expressed is the real conundrum
that faces all of us sitting around the table, as well as the Blood
Products Advisory Committee, the FDA in general, in terms of how do you
set policy that is reasonable, because, you know, I\'m very concerned
that we not do anything that is going to be disruptive to the supply of
blood. On the other hand, we want to make it as safe and good as
possible.

And, we need to be very clear in terms of every step that we take to
enhance the safety of the blood supply, that it really is effective, so
that I think this kind of model, the studies that will emanate from it,
are extremely important, but we always have to be trading off.

DOCTOR ANDERSON: Right.

Well, we are well aware, I mean, of the issue of balancing this safety
versus supply, and so, you know, we can incorporate supply issues into
the future models as well, because, you know, we have developed some
minimal supply models, and, you know, do more of a risk-risk tradeoff
type of model, as we\'re considering other deferral policies, et cetera,
or other policies that might affect supply.

So, that\'s something that we can do in the future.

CHAIRPERSON PRIOLA: Doctor Telling?

DOCTOR TELLING: Could we review what we know about the etiology of this
Japanese case? I think it would be useful for the Committee to visit
this, it seems to me germane to this discussion.

CHAIRPERSON PRIOLA: Comments on the Japanese case?

CHAIRPERSON PRIOLA: Comments on the Japanese case?

DOCTOR SCHONBERGER: In just wrote an e-mail on it a couple days ago,
I\'ll try to remember what I actually said, but I think the patient was
in his 40s, that the onset was like in 2001, December I think, and the
patient died three years later in December of 2004, 36 month duration.
What we\'ve learned is that there was a visit to ? oh, just got my memo
here ?

DOCTOR ALLEN: Instant messaging.

DOCTOR SCHONBERGER: What I wrote here was that the CJD Surveillance
Committee in Japan confirmed the case as vCJD as of February 4, 2005.
The month of onset was December, 2001, and the month of death was
December, 2004, so that\'s good. I am aware of only four vCJD cases, I
wrote, with a longer duration of illness, so it\'s not the longest
illness that ever occurred here. The vCJD case patient had been
classified officially earlier by the Surveillance Committee as a
probable sporadic CJD case, because of the report of the patient\'s
developing an EEG finding more characteristic of sporadic CJD. So, this
report indicated that late in a very long vCJD illness an EEG, more
similar to that of the classic CJD, does not rule out vCJD, a fact that
may not have been previously appreciated.

The patient is classified as definite, based on pathological Western
Blot and immunocytochemistry findings. There\'s been genetic analyses
performed, and they revealed no PRNP mutation. It also revealed the
presence of the codon 129 met/met homozygosity characteristic of all
food-borne vCJD cases to date. A presumed exposure of the case patient
to the U.K. in 1989, which was a one-month exposure, they did not say ?
have a history of what he ate or anything, but it suggested an
incubation period of, roughly 12 years.

This probably, if it\'s true that that was the source, then I was saying
that it suggests that one does not need cumulative exposures lasting for
a year or more as some people have postulated was responsible for some
of the cases.

And, more information from Japan should be forthcoming, and the source
of this information is Doctor Yoshikazu Nakamura from Jichi Medical
School, who is a member, as I understand it, of the CJD Surveillance
Committee in Japan, and he helped us write a couple articles on dura
mater, the dura mater epidemic that they are having, so we had just
e-mailed him and asked whether he knew about this case, and that\'s what
he answered.

CHAIRPERSON PRIOLA: Doctor Bird, did you have a comment that you wanted
to make about something that came up earlier?

DOCTOR BIRD: Yes, I did, just to remind the surveillance data from the
United Kingdom relate to tissues that were removed at operation 1995 to
\`99. So, although the paper was published in 2004, it was a
retrospective study, relevant to the period 1995 to \`99, which is
important.

CHAIRPERSON PRIOLA: Thank you.

Are there any other comments from the Committee for FDA? So, is FDA ?
oops, sorry, Glenn?

DOCTOR TELLING: You mentioned the John Collinge had done some studies on
tonsil biopsies, what time periods did those tissues cover?

DOCTOR BIRD: I\'m not absolutely sure, because as far as I\'m aware
those results haven\'t been published, but I think they are fairly
similar towards the end of, you know, 1999-2000, so it\'s about the same
sort of time period. But, it was a prospective collection of tissues for
the prion unit.

CHAIRPERSON PRIOLA: Is FDA satisfied with the discussion on Topic 2?
Okay.

I know we have a break scheduled here, but we just got back from lunch,
so with the Committee\'s permission we\'ll go ahead to the speakers and
take a break after that.

So, this will start a new topic, Topic 3, which has to do with the risk
reduction aspect of all these models. That\'s the potential deferral of
blood and plasma donors as a consequent of a history of transfusion in
Europe, and the first speaker is Doctor Alan Williams.

DOCTOR WILLIAMS: Thank you. It\'s my pleasure to chair this third
session.

This session can really be viewed as a continuation of the last TSE
Advisory Committee meeting held October 14^th^, where the Committee
heard an extensive set of presentations regarding to development of FDA
policy related to interventions related to potential BSE vCJD exposure.
And, although the Committee voted that the measures currently were
adequate and did not recommend any additional changes, there were some
threads of discussion in the course of the meeting that we wanted to
pick up on and continue in a little more focused fashion in this
session.

Specifically, some more discussion about history of transfusion in
countries other than the U.K., specifically, France and other BSE
countries of Europe.

Fortunately, I don\'t really need the slides for this intro, but the
goal of this session is that FDA seeks the advice of the Committee
whether the recommended donor deferral for history of transfusion in the
U.K., which is currently 1980 to present, should now be expanded to
include history of transfusion in France and other BSE countries of
Europe.

We have several data presentations in this session. The first speaker
was scheduled to be Doctor Jean-Philippe Brandel, who is a Neurologist
with the Epidemiosurveillance Network, however, he, unfortunately, was
not able to travel, and his talk will be shared by two FDA speakers. The
first will be a presentation on vCJD in France by Doctor Pedro Piccardo,
who is with FDA, and the second will be risk of vCJD transmission by
plasma-derived medicinal products, risk assessment in France, and this
will be addressed by Doctor Steve Anderson.

The next talk will be deferral ? I\'m sorry, estimates of blood-borne
vCJD risk in the U.K. and other European populations. This will be by
Doctor Sheila Bird, with the Medical Research Council, Biostatistics
Unit, Institute of Public Health, at Cambridge University, and then I
will round out the speakers by addressing some of the risks and benefits
of deferring donors transfused in France and other BSE countries of
Europe, potential impact on blood and plasma supplies.

Because I do want you to see the questions, I\'m going to just take a
second and flip to those slides. The first question for the Committee
is, based on the available scientific information does the Committee
recommend deferral of blood donors transfused since 1980 (A) in France,
or (B) in other BSE countries of Europe?

Then, as a separate question considering the potential for infectious
agent clearance, as part of the fractionation process, a separate
question, based on the available scientific information does the
Committee recommend deferral of source plasma donors transfused since
1980 (A) in France, or (B) in other BSE countries of Europe?

Thank you very much.

CHAIRPERSON PRIOLA: Okay, thank you, Doctor Williams.

I think we\'ll move on to the first part, so Doctor Piccardo will be
giving part one, and the second part will be given by Steve Anderson,
about variant CJD epidemiology in France.

DOCTOR PICCARDO: Okay.

So, as was said, unfortunately, Doctor Brandel cannot be here, so I have
to present for him. Unfortunately, for me, I did not have the chance to
talk with Doctor Brandel about these slides, so I will make the best I
can, try to be objective on this presentation.

The whole issue is about an overview of vCJD, the situation of vCJD in
France. Okay.

So, there are nine patients with vCJD in France, eight died, five were
diagnosed with definite vCJD and three with probable vCJD, and one of
the cases is probably vCJD and is still alive. The age of onset is ? the
mean is 33, and between 17 and 52, and the mean duration of disease in
months was 20 years.

What you see here is the distribution of cases according to year, and
according to onset, and this is between 1994 and 2004, and according to
death between 1996 and 2004. I think that the only thing we can conclude
from this slide is that probably because of the small amount of cases is
that there is no pattern or no trend.

Okay. So, the diagnosis of vCJD patients in France, the five definite
cases had typical neuropathological data, just to remind you that to
make the diagnosis of definite you need the neuropathology, and florid
plaques, and the Western Blot analysis showed a type 2B according to a
specification of Parchi and Gambetti. As you know, different ? I mean,
there are basically two groups that have a slightly different version of
how to classify PrP, and one is John Collinge\'s group, and the other is
Parchi and Gambetti, so this was classified as 2B, type 2B, according to
the Parchi and Gambetti specification, and there are four probable
cases, and to make it probable cases you need the clinical consistent
with a vCJD case, plus the MRI that showed the typical posterior
thalamic sign, and positive tonsillar biopsy shown by positivity for PrP
by immunohistochemistry or Western Blot analysis.

Genetic analysis was done in all these cases, and in nine out of nine
cases were met/met homozygous for the 129 polymorphic site on PrP, and
there were no mutations detected.

Actually, this slide was not provided by Doctor Brandel, but we decided
to include just a few slides to exemplify what we mean, and this is the
MRI of a patient with vCJD, sorry, with sporadic CJD, that show high
signal on the basal ganglia, and this is the classical or typical MRI
for a patient with vCJD, that shows this high signal, pulvinar signal,
or in the posterior thalamus.

And, what you see here is, basically, a case of sporadic CJD with a
typical vacuolation, and usually patients with sporadic CJD show PrPres,
or PK-resistant PrP that could be of approximately 21 or approximately
19 kV of the non-glycosylated isoform. Patients with vCJD that show in
the pathology this typical florid plaque, usually show a pattern that is
slightly different that is notorious for the presence ? for the
over-representation of the de-glycosylated PrP isoform as shown here.

Actually, this slide was provided by Doctor James Ironside, and this
slide was ? these two slides were generated at the Indiana Alzheimer\'s
Disease Center, working for the WHO.

The other thing is that patients with vCJD, with clinical vCJD, that are
positive, usually there is immunhistochemistry positive for PrP in
tonsils.

Now, talking about, once again, specifically, about these nine patients
that were recognized in France, these patients had no specific medical
risk factor, so therefore there was no history of human growth hormone
treatment, or dura mater graft, or neurosurgery, were not blood
recipients, or treatment with albumin, immune globulins or clotting
factors. Well, no other risk factors, for example, there was no family
history of dementia or CJD, or contact with CJD patients, or contact ?
frequent contact with animals or animal products that ? are considered
to at risk, there were no professional risk factor, no special diet, and
traveling the U.K., except for short stays for three patients.

And now, what about, once again, we go out of the nine cases, two cases
with vCJD happened to be blood donors. The first patient provided 14
donations between 1993 and 2003, that result in 13 transfusion of red
cells and one transfusion of platelets, and the recipients, five are
still alive, and nine are dead.

The second patient provided two donations in 1984, and the two ?
resulting two transfusions of red cells, and two transfusions of plasma,
and seven donations between 1996 and 2002, that resulted in five
transfusions of red cells and three transfusions of platelets.

Okay, what about risk for vCJD in France? And, the sources of exposure
to BSE of the French population could be bovine carcases and other beef
products imported from the United Kingdom, endogenous BSE in French
cattle, or travel to the U.K. It has also been recognized that the
distribution of the incubation period and age-specific susceptibility
happens to be similar or the same to that seen in the U.K. population.

And, continuing with the risk factors, the predicted number of vCJD
cases in France by birth cohort and gender, according to this
publication, the total number of vCJD cases would be up to 33 cases, and
67 percent in the post-1969 birth cohort, and the number of cases would
be equal to the number of infection, meaning that very few cases would
be censored by death, meaning that if they are patients they will tend
to die in that birth cohort due to vCJD, and not to other causes. And,
no expected cases attributed to travel in the U.K., which is something
that is not very clear to me.

And now, I\'ll pass on the podium to Steve Anderson, who is going to
present the risk assessment, the French risk assessment.

DOCTOR ANDERSON: All right, I\'m going to talk about the risk assessment
that was done in France. You\'ll notice these slides are a little bit
starker than the other slides.

Okay, this risk assessment, there were actually several iterations of
the risk assessment and reviews and comments made on the document. The
report is a December, 2000 document, \"Risk Analysis of Variant CJD
Transmission By Blood and Blood Products, and Recommendations,\" again,
a number of different iterations to this French document.

The French document and risk assessment actually estimates numbers of
cases of variant CJD based on the Ghani model, statistical model, and I
discussed that a little bit earlier. I presented earlier a few starker
estimates from that, but they are using a more realistic hypothesis or
sort of the middle level hypothesis, that there is a mean incubation of
the disease of 30 to 60 years, and you can predict 150 to 6,000 cases in
the United Kingdom.

Earlier this morning, I think it was at the 230,000 range, at the upper
end.

Again, there\'s a 20-fold lower level of exposure to the risk of BSE.
That sort of relates to the relative risk that I was talking about for
our risk assessments, 20-fold is about a 5 percent level compared to the
United Kingdom, and that\'s based on consumption of bovine products, and
then the number of cases of variant CJD in the U.K. versus the number of
cases in France.

So, what they estimate is, the total number of cases in France would be
six to 300 in the next 60 years, and if you remember what I told you
this morning, is that since the number of cases in the U.K. are sort of
decreasing Ghani\'s most recent estimates suggest the number of cases in
the U.K. are also decreasing, but what the French are doing is, they are
keeping this assumption based on the earlier, more sort of conservative
estimate, and using that in their estimate of risk for France.

And, what they are doing here, here are some of the estimates of the
blood of these 300 ? I\'m sorry, assumptions that they are using in
their risk estimates on the blood of these 300 subjects, currently
asymptomatic, is infected throughout the incubation period. That\'s seen
in several risk assessments. Blood donors are random sampled the French
population. We also assumed that these are very sort of standard risk
assessment assumptions. Asymptomatic subjects are restricted to the
general population, and the prevalence of pre-clinical incubating
disease is approximately in the blood donor population is 8.3 per
million.

And then what they do, what that works out to is a maximum of one blood
donation is predicted per 120,000 that could be infected with variant
CJD agent.

And, this is the risk for the transfusion product, assuming no
significant reduction in infectivity occurs from the donor to the
recipient. This is for blood product.

Working assumptions on infectivity of blood. They are using animal
models as well. I think the important thing here is, not to sort of get
confused, you are seeing a lot of numbers here, 20 to 30 infectious
units, that would correspond approximately to ten to 15 ID50s, because
their one infectious unit is defined as a minimal infectious dose
capable of transmitting the disease at 100 percent level, essentially.
So, this is what they are assuming, 20 to 30 infectious units per ml of
blood.

And, they don\'t do a correction for the intracerebral route, which is
probably a more efficient route compared to the intravenous route, so
they are assuming intracerebral and intravenous are equally infective
and capable of transmitting the disease.

The infectivity in blood, again, they are assuming, very similar to
what\'s in the literature, 50 percent of the infectivity is in plasma,
30 percent in buffy coat, so this is the number they are working with.

Now, they also do leukodepletion in France and so infectivity in the
plasma, what they do is estimate it at not more than ten infectious
units per ml, and that\'s intravenous, and that corresponds,
essentially, to five ID50s per ml of blood.

Here are some further working assumptions in their risk assessment, just
calculating residual infectivity in plasma-derived medicinal products.
Some of the things that they follow are the volume of the plasma pools,
every single pool is infected by at least one donation. The extraction
yield for the protein, for instance, if it\'s Factor VIII then you have
a range of, you know, 120 to 160 units per liter of plasma, they are
assuming, you know, the lower end of that as far as the yield from these
proteins that they are purifying.

The extraction yield for the proteins is at the lower end. Cumulative
reduction factors resulting from the manufacturing processes, so you can
? I believe these processes they believe are additive, although they
don\'t add for reduction factors that have similar mechanisms, so they
only allow for adding reduction factors for different processes. It
can\'t be two ethanol precipitations, it\'s got to be, you know, two
specific processes, like ethanol precipitation and chromatography, et
cetera.

Total dose of the product received by a yearly patient is at the maximum
dose regimen, so if it were a hemophilia A patient they would assume
that they are receiving the maximum dose, if they had severe disease and
were, say, on prophylaxis. So, that type of sort of the worst case for
the treatment scenario.

Now they walk us through a number of different reduction steps that
could occur during the processing of these different products that I\'m
going to show you a list of at the end, near the end of the talk. So,
for cryoprecipitation, and these are of the assumptions that they are
making for the levels of reduction associated with the process, so, for
instance, cryoprecipitation and the cryoprecipitate, they assume zero
levels, zero logs of reduction. But, up here for ethanol precipitation
of fractions I and III in the supernatant the reduction factor is
approximately three logs. Again, you can just go through these, four
logs for ethanol precipitation of II and III in the supernatant, et
cetera. So, they have a number of assumptions for different types of
processes and allow for the variation in the processes, and their level
of reduction accomplished with each.

Again, just going through more of the processes. For instance,
absorptions in chromatography, for instance, two to three logs of
reduction, et cetera, so these are very sort of straightforward
hypotheses. They don\'t allow for any reductions due to, I believe this
was detergent, enzyme or heat treatments.

So then, they go through a number of example calculations. They are
going to present one here for Factor VIII. The smallest pool necessary
for fractionation is approximately 4,000 liters. That, I think, sort of
corresponds to about 20,000 donations, 20,000 donations of recovered
plasma that is.

The extraction yield is about 100 units of Factor VIII per liter of
plasma. The cumulative reduction factor, they assume a range which could
be as low as four logs, and it\'s between four and seven logs or a max
of up to seven logs, so between four and seven logs of reduction in
their model for Factor VIII.

Again, the yearly dosage that somebody might receive on Factor VII, they
assumed the maximum dose regimen would be as high as 500,000 units, and
given that theoretical residual infectivity in that product, if they
receive all infected, contaminated product, would be 2.4 x 10^-2^, or as
low as 2.4 x 10^-5^.

All right. So, what they do here is, they present sort of a tour de
force of all these models, and they are just presenting results. So, for
Factor VIII, they are presenting this sort of as three logs of
reduction, greater than three logs of reduction the risk is 10^-3.21^,
Factor IX it\'s 10^-5^, as far as levels of infectivity. Now, this is,
remember, levels of annual infectivity, so what would be sort of typical
for annual usage of these products.

And, what they are trying to show here, I think, is that there\'s a
hierarchy of risk, some products are certainly riskier than others, as
far as ? and that is dependent on the types of processes and the
utilization of these products and the number of other product specific
processes.

So again, just albumin, again, down at the ^-3^ logs of ID50s, as far as
risk, Hepatitis B down to ^-3^, you have some that are even lower, and
^-7^ et cetera. So actually, what they\'ve done is, a lot of simple
calculations, but on a lot of products, and they give you at least this
general range of risk for each product, so you know sort of a hierarchy
of which products are the riskier, and which are less riskier.

So, what they are saying here in their conclusions, that the residual
infectivity value given for each product must be considered as sort of
indicative, or you might say relative, and it\'s not an absolute value,
and although absolute values are imprecise the risk hierarchy, again,
they are focusing on this risk hierarchy. The interesting thing out of
this model is that they give you the risk hierarchy that you get from
this model for the different products is more robust, and you can take
more meaning from those, at least the relative risk from one product to
the next.

And, none of the plasma-derived products has been judged as bearing a
risk that would warrant its withdrawal.

Risk assessment in France, the measures taken in France, so they have
permanent deferral for blood donations for previously transfused
individuals, permanent deferrals for people that lived in the United
Kingdom or British Isles, equivalent to one year between 1980 and 1996,
and they also have mandatory plasma leukoreduction, plasma for
fractionation undergoes this process, and you get just ? I\'m not sure
exactly what that means ? oh, removing down to or a minimum of 10^4^ or
10^6^. These are two different types of process, plasma for
fractionation, removes less cells, plasma for therapeutics remove more
of the leukocytes per liter of cells.

Some of the other measures taken in addition, improvement of ? and I\'m
not sure what LFB processes are, I assume those are the manufacturing
processes for the production of these products, and they recommend TSE
validation studies for the fractionation steps that are performed for
these various different products, and then revision of the
recommendations on the use of plasma-derived medical products.

Boy, they keep on going.

And then, they go into nanofiltration, which is a new technology for
reduction of risk. Before 2000, they talk about for Factor XI and Factor
IX, using these 15 nanometer filters, now you are using a combination,
you are sort of hitting the products first with a larger filter, and
then following it up with a smaller size filtration device, and that\'s
just an improvement over the previous purification schemes for those
products.

TSE validation for these processes, these are the numbers and the levels
of reduction that they are achieving. So, for albumin precipitations of
fractions I, II and III, you are getting greater than 2.8 logs of
reduction, et cetera. For the rest of these, and then they are looking
at polyvalent IV immune globulin in Factor IX, and through
nanofiltration with a 15 nanometer filter you are getting greater than
2.7 logs of reduction.

So, these are validated processes, and then they use those in their risk
assessment to estimate risk. Validation again for Factor VIII, with
nanofiltration you are getting the greatest, greater than 3.3 logs, von
Willebrand factor, 3.9, et cetera.

All right, and that\'s it.

CHAIRPERSON PRIOLA: Okay.

Doctor Allen, I\'m not sure it\'s entirely fair to ask too many
questions, but go ahead.

DOCTOR ALLEN: Going back to one of the earlier slides, it talked about a
mean incubation period of 30 to 60 years.

DOCTOR ANDERSON: Yes.

DOCTOR ALLEN: I wondered if the context seemed to be that, perhaps, that
was a population-based incubation period with, perhaps, the out years
ranging from 30 to 60 years? I don\'t know.

DOCTOR ANDERSON: Um ?

DOCTOR ALLEN: I mean, 30 years as the low end of the incubation period
is incredible.

DOCTOR ANDERSON: Right, and that would give you the lower estimate, but
if they used a shorter incubation period I believe the numbers would go
up, and they\'d get more cases, basically.

CHAIRPERSON PRIOLA: Do you know why they picked that 30-year lower
limit?

DOCTOR ANDERSON: I think in the study they just presented a number of
different scenarios, like 30 to 60, you know, ten to 20, et cetera, if I
remember correctly. And so, and there were different case predictions
from those studies.

DOCTOR JOHNSON: The mean age of onset of variant CJD is 29, it didn\'t
work, and I think the longest incubation period on record are the kuru
patients at 40 now. So, I don\'t know where they got 60. Those numbers
seem just way off base, I agree.

DOCTOR ALLEN: Yes. I guess I was assuming that if they looked at a
fairly short, you know, controlled incubation ? controlled exposure
point, and then you follow the population through that, they are saying
by the end of 30 years ? I don\'t know, I just had trouble ? I think
there\'s probably a problem in interpretation here.

DOCTOR JOHNSON: At the end of 30 years they\'ll all be gone, or maybe as
long as 60 years.

DOCTOR JOHNSON: Yeah, that was ?

DOCTOR JOHNSON: Yes.

CHAIRPERSON PRIOLA: Doctor Belay?

DOCTOR BELAY: You say they permanent defer from donating blood patients
who have been transfused?

DOCTOR ANDERSON: They did, yes.

DOCTOR BELAY: Did they do that for plasma donors, did they defer them
from donating plasma, do you know?

DOCTOR ANDERSON: I don\'t know off hand.

DOCTOR BELAY: Jay, do you know?

DOCTOR ANDERSON: I don\'t think we know.

DOCTOR BELAY: That\'s one of the questions that we are asked in the
document.

DOCTOR ANDERSON: Yeah, and I don\'t know what their policy is off hand.

CHAIRPERSON PRIOLA: Doctor DiMichele, did you have a question?

DOCTOR DiMICHELE: It was, actually, for Doctor Piccardo, and it was just
the slide went by so quickly, I was wondering if we could re-clarify the
second donor, how much that donor had actually donated, and the
implications with respect to the recipients?

DOCTOR PICCARDO: That I can read to you.

DOCTOR DiMICHELE: Okay, yes, please.

DOCTOR PICCARDO: Second patient?

DOCTOR DiMICHELE: Yes.

DOCTOR PICCARDO: Two donations in 1994, and that was two transfusion of
red cells, two transfusions of plasma, and the recipients are two are
still alive, one dead, one to be confirmed. You don\'t have to take
notes, I\'ll be happy to give you this.

DOCTOR DiMICHELE: Oh, okay.

DOCTOR ALLEN: Can you?

DOCTOR PICCARDO: Definitely, I will give you these. Okay? Do you want me
to keep on reading, or should I just make the copies?

DOCTOR DiMICHELE: Okay, I\'m sorry, of all of them, how many recipients
are potentially still alive then from the two donors?

DOCTOR PICCARDO: \>From the two donors, two, two are alive.

DOCTOR DiMICHELE: Oh, so just two.

DOCTOR PICCARDO: Two, yes.

DOCTOR SCHONBERGER: The first had five alive.

DOCTOR DiMICHELE: Five alive, yeah.

DOCTOR SCHONBERGER: So, there\'s five there alone.

DOCTOR PICCARDO: Let me see, of the second patient, yeah, second
patient, recipients two still alive, recipients two still alive ?

DOCTOR DiMICHELE: Okay, so a total of seven, okay.

DOCTOR PICCARDO: No.

DOCTOR DiMICHELE: A total of nine? Okay, never mind.

DOCTOR JENNY: Were any of the recipients of that blood tested? Do we
know?

DOCTOR DiMICHELE: So, it was nine?

DOCTOR PICCARDO: I\'ll make you copies.

DOCTOR DiMICHELE: In think there was another question.

CHAIRPERSON PRIOLA: Yes, Pedro, Al Jenny had a question for you.

DOCTOR JENNY: Do we know if any of the recipients of the blood from
those individuals were tested when they died, after they died?

DOCTOR PICCARDO: In don\'t have that information. If any of the
recipients have been tested you say, that is the question?

CHAIRPERSON PRIOLA: It might be unlikely, because isn\'t it true that
often ? I mean, the transfusions are given to people in dire straits
frequently.

DOCTOR PICCARDO: Or, who are dying.

CHAIRPERSON PRIOLA: Right, so by the time these look-back studies are
done that\'s probably not.

Doctor Johnson?

DOCTOR JOHNSON: Yeah, isn\'t the 1994 case the one in which there was a
series of letters back and forth in [Lancet]{.underline} about the
body-building auto mechanic who was taking injections of pituitary
hormones? I mean, I know they said no pituitary hormones, but isn\'t
that the same case, that\'s the 1994 case in France, I think, the first
case, the first French case. It was reported then, there was a letter
afterwards saying that he\'d been taking some kind of pituitary hormone
extract that was approved by the FDA of France for a while and then
taken off the market.

DOCTOR BELAY: I don\'t know, the question is whether or not the first
case in their slide refers to the very first vCJD case or the first vCJD
blood donor, I don\'t know.

DOCTOR JOHNSON: I know there was a pituitary hormone.

DOCTOR DeARMOND: But, wasn\'t the pathology variant CJD in all of those
cases?

DOCTOR JOHNSON: Yes.

DOCTOR BELAY: Yes.

CHAIRPERSON PRIOLA: Doctor Bird, do you have a comment?

DOCTOR BIRD: Just a clarification, that the two French vCJD cases who
had been blood donors were the 8^th^ and 9^th^ case, so it was certainly
not the first vCJD patient in France. The blood donor cases are
France\'s 8^th^ and 9^th^ cases.

EXECUTIVE SECRETARY FREAS: Could I just clarify one thing for the
record. If we get permission we, of course, will give the slides to the
Committee member and to the public, we cannot give it just to the
Committee members unless we have permission, because it\'s not in the
public domain at this time.

CHAIRPERSON PRIOLA: If there are no more questions ? whoops, there, Mr.
Bias.

MR. BIAS: I don\'t know if this is a question, it sounds like we are
asking a lot of questions, we are not getting a lot of answers, so I\'m
not even sure we are going to be able to answer the FDA\'s question,
based on the information we\'ve been given here.

But, it was nice of them to tell us how many logs per product that you
needed to remove ? or that they consider safe, so you won\'t have to
figure that out. That\'s good.

I don\'t know if I have a question, it\'s just that there seems to be a
lot of missing information, and I\'m not exactly sure we are going to be
able to give you a confident answer without getting some of those
questions answered.

I was also disappointed, and I guess LFB is the fractionator in that
country, but we\'ve written them several times about product lines that
are finished or partially produced there and then shipped to the United
States for sales, and we\'ve been able to get very little information
out of them as the manufacturer, which doesn\'t bode well in terms of
building confidence in terms of this question that the FDA is asking.

CHAIRPERSON PRIOLA: Let me ? what\'s your name, sorry?

DOCTOR WEINSTEIN: Weinstein.

CHAIRPERSON PRIOLA: Doctor Weinstein.

DOCTOR WEINSTEIN: Could you clarify that, because there aren\'t any
licensed products, as far as I\'m aware, LFB plasma derivatives, was
this personal importation, is that what you are referring to?

DOCTOR ANDERSON: Are you talking about the ZLB?

DOCTOR WEINSTEIN: We are talking about LFB, the French company, a
different company, LFB, not ZLB.

MR. BIAS: But, still my comment is, we don\'t seem to have all the
information we need to answer your question.

CHAIRPERSON PRIOLA: Doctor Schonberger?

DOCTOR SCHONBERGER: Well, I was just going to comment that if in France
they don\'t accept as donors people who have received blood in their own
country, it\'s not clear that we should be. That\'s my comment, I guess.

CHAIRPERSON PRIOLA: The gentleman at the microphone, could you identify
yourself, please?

MR. JACKMAN: Yes. My name is Dennis Jackman. I\'m with the ZLB Behring,
and I\'m trying to answer Val\'s question, possibly, in some ways
referred to as ZLB incident, actually, there was a donation from a
single French donor in 1996, who then subsequently developed variant
CJD. He was the 8^th^ so-called French donor that went up in one batch
of a European product which had been recalled, and there was
notification given around the world on that.

Beyond that, what LFB has done, I think you are trying to get answers to
questions beyond that, whether other products might have been imported
possibly under personal importation or other aspects, that would be
something only LFB would know, and so we can\'t answer that any further.

So, just to clarify, I hope that clarifies a little bit.

MR. BIAS: Thanks, that clarifies it in terms of ZLB, and your excellent
service to the community, it doesn\'t clarify it in terms of them
answering questions that we might have about their processes over there,
which makes the FDA\'s question loom pretty large if we can\'t get
answers out of them.

CHAIRPERSON PRIOLA: Doctor Bracey?

DOCTOR BRACEY: In noted that when the Netherlands had the rejection of
people that had been previously transfused, there was a loss of about 8
percent of the donor base, and I think it would be important for us to
know in France what the impact on the donor base has been, so that we
can make an assessment of the tradeoffs.

CHAIRPERSON PRIOLA: Okay, if there are no other comments or questions
we\'ll move on to the next speaker, and that\'s Doctor Sheila Bird, who
is going to talk about estimates of blood-borne variant CJD risk in the
U.K. and other European populations.

DOCTOR BIRD: Thank you very much, Madam Chairman.

I\'d like to talk about the BSE cascade through human dietary BSE
exposure, primary exposure, to blood-borne vCJD exposure.

When we think about human dietary exposure, we have to consider U.K.
exports of bovine carcasses, 60 percent of which went to France, U.K.
exports of contaminated feed for cattle, and U.K. exports of infected
livestock.

These last two featured large in the European Union\'s Geographic BSE
Risk Assessment, which was concluded in 2000, by which the European
Union regarded that all member states bar two were GBR III, in other
words, BSE likely or proven at a low level. And, that classification
applied to member states that had not had any clinical BSE cases. But,
that geographic BSE risk assessment was part of the underpinning for the
obligatory post-mortem BSE testing that was introduced on the 1^st^ of
January, 2001 in the European Union.

You\'ve heard earlier this afternoon about the work of Marc Chadeau and
Annick Alperovitch, just published in January of this year, which
suggested that in dietary exposure in France is about 1/20th of the U.K.
dietary exposure, and that that dietary exposure in France was mainly
through U.K. exports of bovine carcasses, 60 percent of our exports
having gone to France, and, therefore, that would suggest that in other
member states they would account for two thirds of the cases that one
might be projecting for France.

U.K. human dietary BSE exposure raises the issue that we would in
dietary cases expect a male predominance of 58 to 60 percent of dietary
vCJD cases being male, on account of male\'s greater consumption of
contaminated ? of the likely implicated foods.

And, indeed, as you see here, variant CJD cases presumed dietary in the
United Kingdom have been 152 to the end of 2004, nine in France, as you
heard earlier, and there have been seven other vCJD cases, two in the
Republic of Ireland, one in Italy, one in Saudi, one in Japan just
announced on Friday, one in Canada, and one in America.

When it comes to blood-borne vCJD exposure, we need to consider U.K.
versus France, versus other exports of pre-clinical or sub-clinical
infections of variant CJD. By pre-clinical, I mean patients who might
ultimately go on to develop clinical disease. By sub-clinical carriers,
patients who potentially, even if no matter how long they lived, might
never actually manifest clinical disease, and not only exports of
individuals, but exports of contaminated blood and blood products.

I\'d like to take you through a brief history of vCJD and BSE from 1980
to 1999, to remind you that BSE was announced in November, 1986, variant
CJD on the 20^th^ of March, 1996, although the first onsets of variant
CJD were in 1994, and the first diagnoses in 1995.

The United Kingdom\'s BSE projections have been too low, largely because
we assumed that later cases would be due only to maternal transmission,
rather than continued exposure to contaminated feed. We were wrong,
France protested, and the projections in various ways were revised.

Variant CJD projections, again, as you\'ve heard, have been generally
newsworthy, initially they were vast, and have been coming down until
the latest surveillance data, which have put them up again, and I\'ll
talk a bit more later about the geographic BSE risk assessment.

This shows abattoir removal of spinal cords, so abattoir workers were
the guardians of the public health. The BSE controls after November,
1986, remember, that highest infectivity is in brain, spinal cord and
the dorsal root ganglia, which nestle closely against the vertical
column. So, the first action of the ? Food Committee was to introduce a
slaughtering compensation policy to ensure that the carcasses of BSE
affected cases, clinical cases, did not go into the human food chain,
which they had been doing for about two years, and in August, 1988 also
we introduced the ruminant food ban.

It was over a year later before the specified bovine offal\'s
legislation was introduced, which removed brain and spinal cord, and
some other tissues, from all slaughtered cattle, irrespective of BSE
infected or not.

Over the next six years, there were some amendments to our specified
bovine offal\'s regulations and inspections by the State Veterinary
Service, particularly, in 1995, which eventually persuaded us that we
were not doing a good job at the abattoirs and, in fact, we could not do
an adequate job, so that the use of mechanically-recovered meat from
vertical column walls ended in December, 1995.

Variant CJD announced in March, 1996 the recovery of head meat was ended
in March 1996, our over-thirty-month scheme, whereby cattle slaughtered
over the age of 30 months would not enter human food or animal feed
chains introduced from April, 1996, and from August, 1996 a reinforced
feed ban, which was supposed absolutely to protect our cattle from
contaminated feed. It has not. We have had BSE cases in cattle born
after the 1^st^ of August, 1996.

And, the rest of the European Union introduced its reinforced feed ban
from January, 2001 and they, too, have had BSE cases in cattle born
after January, 2001.

Human surveillance of CJD was reactivated in the United Kingdom in 1990.
The remit of the CJD Surveillance Unit was to alert to any changes in
the age-specific incidents, occupational distribution or dietary
correlates of CJD that might alert to humans having been affected by
exposure to BSE.

Presentation, if it happened at all, was considered more likely to be
atypical, but, therefore, couldn\'t be described in advance.

And, of course, the CJD Surveillance Unit sadly fulfilled its remit
spectacularly well, ten cases of variant CJD were announced on the
20^th^ of March, 1996, characterized by young age at onset, longer
clinical course, distinctive neuropathology, and methionine
homozygosity, which applies still for all clinical cases.

The very next day, the French were going to ban British beef. Our
Ministry was still reluctant to release data, and they phoned calls to
pass on data from the dam-to-calf experiments that had already ? that
were already showing 10 percent maternal transmission risk in the last
six months prior to BSE onset in the dam.

That information was used by Roy Anderson and colleagues in their
seminal paper in [Nature]{.underline} on the transmission dynamics and
epidemiology of BSE, according to which mean BSE incubation period was
five years, and they estimated the U.K. had had 1 million BSE
infections. We now know that was an underestimate by a factor of three,
we had over 3 million.

In order to be BSE affected, what you observe as clinical cases is a
convolution of the BSE incidence curve, the incubation period, and the
age-specific slaughter or export pattern.

Now, the BSE incidence curve depended upon access to contaminated feed,
to maternal transmission, and possibly to another exposure, though no
other exposure has been definitively identified.

Age-specific slaughter pattern for cattle is different for dairy versus
beef herds, and it was assumed, wrongly, that it was irrespective of
whether the cattle were BSE infected or not.

So, BSE projections in the United Kingdom were essentially back
calculations from clinical cases, and that procedure led to serious
underestimation of our BSE infections. The back calculations assumed no
under reporting of BSE cases after the thought on compensation policy in
1998, wrong, no diversion of BSE cases into the over-thirty-month
scheme, implausible, no differential survival of BSE infected, wrong,
and no exposure except maternal after August, 1996, wrong.

Beware, therefore, that variant CJD projections, which have, of course,
been very newsworthy, have also, essentially, until recently, been back
calculation from clinical cases. That we cannot rely upon with this
disease. The projections have been reined in from vast 200,000 to under
about 400, and are now on their way up again because of the surveillance
data.

Our own work considered dietary BSE exposure by birth cohort, because we
were interested as to whether differential dietary exposure of itself
would explain the young age of variant CJD cases. It does not.

These were the dietary results for the U.K. Shown separately here for
the 1980s, exposure in terms of bovine oral ID50 units in the 1990s,
you\'ll see that exposures were actually greater in the 1990s than in
the 1980s for each of the birth cohorts. The youngest birth cohort was,
of course, being added to by birth. The oldest birth cohort being
depleted by deaths. But, it was, in fact, the middle birth cohort, those
born in 1940 to \`69, who had been most exposed to BSE infectivity, but
most of the cases had not occurred in that birth cohort.

The work just published by Marc Chadeau and Annick Alperovitch used,
essentially, the same approach, but based on U.K. exports of bovine
carcasses to France, and this shows the cumulative exposures for the
U.K., dietary exposures for the U.K. versus for France, and you can see
that the French exposure is, indeed, about 1/20 of that of the United
Kingdom.

The reason that I say that dietary exposure does not sufficiently
explain the young age of the variant CJD cases, this slide shows for the
first 112 vCJD onsets in the United Kingdom the period of birth for
those born 1940 to 1969, and you\'ll see that there were 21 of those 47
were actually born 1965 to \`69, whereas, the age distribution predicted
by our dietary exposures was shown in the middle column, which you can
see is a very poor fit to the age ? the periods of birth of the actual
cases, and only became a good fit when we incorporated the idea put
forward by Valleron, again, vive la France, that age-dependent
susceptibility decreased for exposures beyond the age of 15. And so, the
work that Annick Alperovitch and Marc Chardeau have just published for
France incorporated our estimate of a .06 exponential decay in
susceptibility, and then one can get the age distributions to match that
of the cases.

So, we think it is not dietary exposure, and this raises the specter
that sub-clinical BSE infections may be differential by birth cohort.
What\'s happened to those exposures in the older birth cohort that have
not materialized as clinical cases, and we do not know that they are not
blood or operation transmissible, even although they may not materialize
as clinical disease.

And so, I\'ll go rapidly over this, because you have seen this already,
that the French projections, that France will have a further central
estimate of about 33 variant CJD cases, and on that basis the United
Kingdom might be expected to have about 20 times more, around an
additional 600.

Let me turn now to this rapid post-mortem testing, introduced first in
Switzerland. Switzerland tested all of its fallen stock, and 5 percent
of its normal slaughter, in 1999. In that year also, the United Kingdom
tested 4,000 cattle in the over-thirty-month scheme, and found 16 of
them, to our horror, positive. So shocked were we, that the next year we
tested 10,000 and found 40 positive, unfortunately, confirming what
we\'d seen the year before.

France and Ireland had also started testing of risk stock and found that
their late-stage BSEs were being considerably underestimated by their
veterinary surveillance.

In 2000 also, there was a comparison of four tests for rapid-post-mortem
testing, three of which were approved for use throughout the European
Union, in the program that started on the 1^st^ of January, 2001, which
obliged all member states to test all cattle born ? coming for slaughter
at 30 months or above, and to test risk stock age 24 months and above.

That surveillance, from the very first year, showed that BSE positivity
is ten to 15 times higher in risk stock than in normal slaughter bovines
? in bovines slaughtered over the age of 30 months, and in order to
understand BSE in the country you need to consider the threesome of the
clinical cases, plus their BSE test positives in risk stock, plus their
BSE test positives at normal slaughter, and both of those surveillances
should be comprehensive, unlike they appear to be in the United States
for risk stock.

Because here, compare in the first four months only of 2004, the
European Union\'s BSE surveillance in member states, the old member
states other than the United Kingdom, which had about 36 million adult
cattle compared to the U.S.\'s 45 million, and in four months the
European Union tested 400,000 risk stock, and you are talking about
having tested 200,000 in eight months in a larger herd, which suggests
that on a European basis you are testing between one in four and one in
five of what we would consider risk stock.

In white, for the member states other than the United Kingdom, you can
see that the BSE positive rate in risk stock was 245 per million tested
risk stock, whereas, in normal kill the rate was 16 per million tested,
in other words, about 15 times less.

Whereas, in the United Kingdom in the first four months of 2004, still
our test rate in risk stock was about four times higher than in other
member states throughout the European Union. And, in the new member
states who had just started rapid-post-mortem testing at this time, they
had no clinical cases, but they had 12 cases, late-stage BSE test
positives.

And, indeed, the implications of the U.K. testing in this
over-thirty-month scheme in 2000, when we had 40 positives in just over
10,000 tested, in that year between 600,000 and 700,000 cattle five
years of age or over, had gone through the over-thirty-month scheme. So,
although we were credited with 40 BSE test positives in that year, we
probably had 2,700 go through the over-thirty-month scheme. So, unless
your testing is comprehensive, you need to multiply up, adjust for your
sampling fraction.

Briefly on scrapie, where the European Union in 2002 set up a TSE
testing scheme in 60,000 adult sheep per member state, and 6,000 fallen
sheep per member state, and also did genotyping of a sample of 500 adult
sheep per member state, again, within the first year of that
surveillance we found four TSE positives in what had previously been
considered to be the scrapie-resistant genotype. So, this post-mortem
testing is revising our understanding of scrapie epidemiology. Also,
it\'s leading to a reappraisal of the ARQ/ARQ genotype, which accounted
for nearly 40 percent of the positives, although it had been considered
to be only a moderately-susceptible genotype. So, one fails to
understand TSEs adequately by looking only at clinical cases.

And so, to post-mortem testing in humans, you\'ve heard already about
the two blood-borne cases in the United Kingdom. Let me remind you that
the first of those was detected, essentially, because we had a study
that was flagging recipients of vCJD implicated blood, and the death
certificate, copy of the death certificate was sent to the CJD
Surveillance Unit and had a sort of query dementia, an astute physician
had been concerned about the clinical course of this patient, had
persuaded the family to agree to a post-mortem. The post-mortem was not
done on the basis this was query CJD. Had we not had that surveillance
and that study in place, we could have missed this case, methionine
homozygote, born pre-1940.

And, the second patient, the aortic aneurysm, abdominal aortic aneurysm
case, again this was a patient who had received vCJD blood, the general
practitioner had been alerted to this fact. It\'s not clear whether the
patient had been, but there was a medical legal post-mortem. So again,
another special reason for there to be a post-mortem which discovered
this sub-clinical case in a patient who was heterozygote at codon 129.

And again, the testing for abnormal prion and tonsils, appendix, that
you\'ve heard about, this was unlinked anonymous testing of stored
tissues, those stored tissues relate to 1995 to \`99, even although the
results were published in 2004, and the subjects whose tissues they were
were mainly, predominantly, age ten to 30 years at operation.

A positive was found in the first 8,000 tested, when we had expected
that there would only be likely to be one positive in 40,000, on the
basis of that calculation from clinical cases. So, this study was not
done to be powerful in terms of an estimate of prevalence, this study
was done to give the opportunity to falsify the assumptions that went
into the back calculations from clinical cases. And again, spectacularly
fulfilled its remit, unfortunately, because we have three positives in
just over 12.5 thousand, two of them atypical and subject presently to
genotype.

So, there is a conflict, again, just as in the animal studies, between
clinical cases and surveillance, essentially, tissue testing or
post-mortem testing. And, that conflict is reflected in the latest
estimates published by Clarke and Ghan in the [Journal of the Royal
Society]{.underline}, again, in January of this year, where based on
back calculations in variant CJD cases only they would be projecting
only a further 70 cases in the United Kingdom. If you take into account
the surveillance data, then the numbers are hugely uncertain, affecting
conflict between cases in surveillance, anything from 32 to 4,000
additional cases.

And, a model which makes the assumption that we are dealing with
sub-clinical carriage would estimate that we could be dealing with, in
terms of prevalent infections in 2004, anything ? a central estimate of
about 5,000 prevalent infections, but a range from 1,000 to 13,000. So,
vast uncertainty. We don\'t know whether these sub-clinical infections
would be transmissible in blood. We would be prudent, of course, to
assume that they could be.

Therefore, I suggest that the United Kingdom in particular needs to
limit human vCJD transmission, but we also need to acquire key data, and
in order to do that we need to consider attributable testing for
abnormal prion, particularly, at autopsy, people who come to autopsy
under the age of 55. And, we also need to approach those who have been
alerted that they are at vCJD risk recipients, to ask them to consider
giving permission in life for post-mortem testing in the event of their
death, because otherwise we will not have evidence from vCJD informative
tissues, and I would on that caution you about the interpretation of the
hemophilia data in the United Kingdom, what we need to ask is how many
men with hemophilia were subject to post-mortem from 1995 onward, or had
testable operative tissue, and should we be doing, essentially, unlinked
anonymous testing in those to find out whether there was sub-clinical
carriage of variant CJD. That has not, to my knowledge, yet been done,
but your discussions today persuade me of the importance of doing so.

Reminding you again of the rural analogy, experimental BSE in scrapie
transfusion risks in sheep, infusing when the transfusion was made
halfway through the incubation period in the donor sheep, have given
rise to transmission rates of between 10 and 20 percent in sheep.

And then, if we look at the vCJD transmission risk in humans in the
U.K., and we consider only those who are five-year survivors, we have
had 17 five-year survivors of vCJD implicated blood transfusions, two of
whom we already know are clinical or sub-clinical carriers, but five of
those 17 there was no autopsy, and so if you reduce that denominator
from 17 to 12 you are looking at the current evidence in man is of a
transmission risk between 10 percent and 20 percent, which reemphasizes
the need, in my view, that we in the United Kingdom should be testing
without consent at autopsy for sub-clinical variant CJD, because then we
would be able to have surveillance data by age group, by gender, and by
genotype, and if we did identify sub-clinical variant CJD then we could
alert the recipient network, in terms of recipients of blood products or
tissues surgical network, needle stick network, maternal transmission
network, and those recipient networks would then be alerted in order to
prevent onward transmission and to contribute key data to document their
exposure risk.

And, that comes from their giving permission in life for post-mortem
testing in the event of their death, because, ultimately, at the bottom
of this slide what we need to consider are how many post-mortem detected
sub-clinical variant CJDs do we have in those who were vCJD exposed at
least five years previously, divided by the number who were subject to
post-mortem and/or who were exposed at least five years ago. So, we need
a relevant numerator and a relevant denominator, and you need to be
hearing about that in all future talks, or asking why we can\'t provide
you with numerators and denominators.

So, in terms of detectability, if you take a worst-case scenarios of 10
percent transmission risk, if we, for example, conducted 500,000 tests
on operative tissue, and if in 2004, as opposed to in 1995 to \`99, it
was still the case that about 1 in 5,000 of those was positive, we would
be looking at 100 sub-clinical vCJDs, 10 percent of those might have
been donors with an average of about four recipients, 40 recipients,
about a quarter of those 40 recipients will survive to about five years,
for at least five years, so we would have ten recipients of implicated
blood who were five-year survivors, and if you had a 10 percent
transmission risk one of those might, indeed, develop vCJD. So, we would
have one viable blood-borne vCJD transmission. That\'s not the worst
case, it\'s just a worse case, and even if screening were to cost us 200
pounds per tissue, that\'s about \$400, then the cost of that sort of
surveillance is a 10^th^ only of the cost of the over-thirty-month
scheme to prevent one cattle to human variant CJD, dietary, vCJD, over
the next 60 years, no species barrier for human-to-human transmission
species barrier in the second case.

Now, clearly, if transmission risk were 100 times less than my worst
case, then we couldn\'t afford to reduce them, but we are in the
scenario that, perhaps, we need to consider that detector now.

Thank you.

CHAIRPERSON PRIOLA: Thank you, Doctor Bird.

Are there any questions for Doctor Bird from the Committee?

Ms. Kranitz?

MS. KRANITZ: If I understood you correctly, if you suspect that there is
maternal transmission in BSE, what do you feel the risk is of maternal ?
human maternal transmission?

DOCTOR BIRD: It is a risk which we need to be alert to. We know that
vCJD is blood-borne, and whenever you have a blood-borne disease you
have to consider the possibilities of maternal transmission.

It is early yet to think in terms of the finding of a clinical case. If,
for instance, only one in ten vCJD mothers was anyway capable of
transmitting, who delivered a baby in the last six months of her
incubation period, then we probably have had fewer than ten such
deliveries in the United Kingdom as yet, and the incubation period for
vCJD, as you\'ve heard, is probably on average 11, 12 years, and so
it\'s too early yet for us to know.

And, we could be looking at, you know, one potentially at-risk child so
far, which is not, you know, a core that statisticians hail, a
denominator of one, and so it\'s really very uncertain at present. We
have to be alert to the possibility, and we can\'t rule it out.

CHAIRPERSON PRIOLA: Doctor Telling?

DOCTOR TELLING: So, we hear a great deal about with respect to scrapie,
a great deal about, albeit apocryphally, the potential for environmental
transmission, or at least mainly apocryphally.

What about your rather alarming numbers for the existence of the BSE
epidemic after these measures were put into place, what about the role
of environmental contamination in sustaining the epidemic in the U.K.?

DOCTOR BIRD: In the U.K., we think in terms now of the third wave of our
BSE epidemic, the first one before the ruminant feed ban in August,
1988, and then the second epidemic between August, 1988 and the
introduction of the reinforced feed ban on the 1^st^ of August, 1996.

So, the BSE cases that were born after the 1^st^ of August, 1996 are
what we think of as our third wave of the BSE epidemic, and in terms of
such cases the United Kingdom is now probably at about the peak of BSE
cases coming through from that third wave, and there are about 60 to 80
a year. So, it\'s very low level.

There are at least a third of those cases that you can definitely say
were not due to maternal transmission, and the current ? I mean, the
U.K. veterinary epidemiologists are trying to set up a sort of case
control study, not only in the United Kingdom, but would apply to born
after the reinforced feed ban also in other European member states, to
see whether it is still some residual contamination at feed mills or in
transport of materials in ships or whatever.

So, one can\'t rule out the potential, but the geographic distribution
of the third wave of cases is distinctive from both of the first two
waves, which argues a bit against environmental contamination.

DOCTOR TELLING: Can I ask a second question?

CHAIRPERSON PRIOLA: Go ahead.

DOCTOR TELLING: So, a second question relates to scrapie genotype,
scrapie susceptible genotypes, and I ask this because there was a lot of
attention given several years ago to the possibility of BSE infection in
sheep, and I notice you talked about the ARQ genotype.

What is your thought about the possibility of those cases actually being
BSE in sheep?

DOCTOR BIRD: Well, in the European Union any TSE positive in the scrapie
resistant genotype had to be reported and has been subject to
experiments and passaging in mice. And, as many of you will be aware,
that surveillance program covered goats as well as sheep, and in France
they detected a field case of BSE in a goat, and that detection was in
2002, but the definitive results of the mice studies have just come
through. And so, about a week ago was the announcement that, yes, this
is a field case, the first that we are aware of.

I don\'t know, I\'m afraid, to what extent there has been passaging of
any of the positives in the sheep. There have also been some odd
positives in the sheep, not necessarily just in the ARQ/ARQs, and that
particular genotype is highly variable between member states, the sheep
in different member states.

CHAIRPERSON PRIOLA: Doctor Johnson?

DOCTOR JOHNSON: Yeah, I just thought it needed to be clarified for Ms.
Kranitz and others that this is variant Creutzfeldt-Jakob Disease
that\'s being discussed, and that there\'s a lot of epidemiological data
that would show that there\'s no vertical transmission, or horizontal
transmission, of the sporadic disease that we see here in the United
States.

CHAIRPERSON PRIOLA: Doctor Belay?

DOCTOR BELAY: I\'m just trying to understand the last slide that you
showed us, where you said potentially there could be one avoidable vCJD
transmission via blood.

How are you proposing to identify the donors? You said testing operative
tissues, are you saying that anybody that goes into some kind of surgery
should be tested? I\'m trying to understand.

DOCTOR BIRD: Well, for example, if we would ? if in the United Kingdom
we were doing attributable testing when somebody had their appendix
removed, or when they had their tonsil removed, and if we found 100
positives in 500,000 such tests, then we would know who those positives
were.

Remember that in the United Kingdom patients who have received at vCJD
risk blood have been alerted, and so, I mean, if we found a tonsil
positive or an appendix positive they would be in the same category of
requiring to be alerted in terms for the public health.

We are not doing attributable testing at operation at present. I\'m
raising the issue as to whether we should be.

DOCTOR BELAY: So, you have to notify the patients that they are positive
and that they should not donate blood?

DOCTOR BIRD: That\'s correct.

DOCTOR BELAY: All right.

DOCTOR BIRD: Yes.

CHAIRPERSON PRIOLA: Doctor Salman?

DOCTOR SALMAN: This is, again, for clarification. As far as your birth
cohort, are you saying like due to this type of study, like the dietary
is not as important a factor in the transmission of new variant CJD? Is
that what you are saying?

DOCTOR BIRD: No, I\'m saying that dietary exposure is a very important
factor, and for the ? so, for example, this was based on the dietary
exposure, the average age at onset in the youngest birth cohort was 21.8
years of our 64 cases ? yes, the 64 cases, and based on the dietary
exposure data we simulated onsets, and the average age of our simulated
cases was 21.3 years. I mean, very good, directly from the dietary data.

But, when we did exactly the same thing for the middle birth cohort, the
agreement was insufficiently good, that was illustrated, so in the older
birth cohort it\'s not just dietary exposure, and we suspect that there
is an age-related susceptibility to, as it were, progression of that
exposure. Okay? So, we are getting less clinical cases than their
dietary exposure would suggest.

DOCTOR SALMAN: That\'s in the old cohort.

DOCTOR BIRD: In the ?

DOCTOR SALMAN: Old cohort only.

DOCTOR BIRD: ? exactly, in people who were born before 1970, and it\'s
even more pronounced in what I\'ve called the oldest birth cohort, those
born prior to 1940.

DOCTOR SALMAN: I have another question, and this is merely just, I
wonder what\'s your speculation about Germany, why Germany would not see
any case of new variant CJD, why you think that, and giving the number
of BSE cases, giving the exposure, giving the dietary there, giving the
number of tests they are doing, or testing they are doing, and no
clinical cases, what\'s your ?

DOCTOR BIRD: Germany has had ? Germany has a large herd of cattle, and
it has done ? and it has a low BSE rate per million tested in its risk
stock. So, it has a much ? it has had a much lower level BSE epidemic
than France has had.

DOCTOR SALMAN: I thought the opposite, actually, just recently for the
last couple years Germany is much higher than France.

DOCTOR BIRD: So here, for example, Germany, now these are the data in
2003, for the whole of 2003, Germany has about 6 million adult herd,
cattle herd, it had 13 clinical BSE cases, 20 cases in risk stock, and
23 cases in normal slaughter. It\'s BSE positivity rate in risk stock
was 80 per million tested, whereas, France\'s rate was 300 per million
tested.

DOCTOR SALMAN: But, the denominator, as you said, the denominator for
France is 11 million, as compared to Germany\'s 6.2 million, the adult
cattle.

DOCTOR BIRD: Yes, but that would mean that if France was operating at
the same level as Germany, then in its risk stock France should have had
less than 40 cases. France has had 87 cases. It has considerably higher
level of epidemic in its own herd than Germany has. Germany has a very
low level of BSE.

CHAIRPERSON PRIOLA: Any other comments, questions, for Doctor Bird?

Okay, thank you very much.

We\'ll move on to the final speaker in the session, and that\'s Doctor
Alan Williams.

DOCTOR WILLIAMS: Thank you.

Both the slides and the speaker will be somewhat less colorful, but
there are a couple of additional concepts that we wanted to bring to
your attention to support the discussion.

First of all, just very quickly, because most of you have seen this many
times before, just to review the current FDA recommended policies with
respect to donor deferral.

In guidance to industry issued in January of 2002, which updated prior
guidance, FDA recommended that individuals who had greater than or equal
to three months residence or travel in the U.K., between the period of
1980 to 1996, be deferred indefinitely. Similarly, individuals with
greater than or equal to five years residence or travel in Europe for
whole blood donors, but specific to source plasma donors, donors of
source plasma, this would only apply to France based on some of the
relative risk considerations that you\'ve heard earlier several times.

In addition, deferral for individuals who spent greater than or equal to
six months on certain U.S. military bases in Europe that were supplied
with U.K. beef in the commissaries, deferral for transfusion in the
U.K., from the period of 1980 to the present and receipt of bovine
insulin sourced in the U.K. after 1980.

Now, at the October meeting you received a comprehensive review of
certain FDA recommendations and their development, and the Committee did
not provide additional recommendations but there were discussions in a
couple of areas that I wanted to probe just a little bit in this talk.

The first is the predictive value of the donor questions to exclude TSE
risk. This is, again, an instance where the donor screening process is
the only intervention currently available to potentially reduce risk
from an infectious disease agent, so it\'s an important question, just
how well these screening measures work for us.

Second is to consider the feasibility of deferral for history of
transfusion outside of the United Kingdom.

So, first to address the donor question itself. Of course, there are
very limited data, as in many things in this field. True validation of
the donor screening process is complex and expensive for many reasons,
one of which is the outcomes depending on what the gold standard is,
your outcomes tend to be very rare, particularly, if you are trying that
to a specific post-transfusion adverse event.

Secondly, most of the deferral of donors actually takes place before
that donor appears at the blood center, based on educational
information, conversations with the blood center, and just overall
knowledge of the donors themselves. So, then what you see as far as
on-site deferral of donors based on administered questions is really
only a fraction of the total deferral that occurs.

Thirdly, it\'s a difficult venue in which to conduct studies, because
the finding of alternate information related to a donor\'s eligibility
has operational implications. So, it is a difficult area in which to
conduct studies, but that said there have been many successful
epidemiologic studies conducted with the blood community.

Another factor is understanding of the questions, and I just wanted to
acknowledge that in collaboration with the Donor History Task Force,
which is sponsored by the American ? the AABB, formerly known as the
American Association of Blood Banks, there\'s been major progress over
the past five years to take a hard look at the donor questionnaire
itself, which for many years had simply been additive in terms of adding
new questions without any thought for their coherence as an overall
questionnaire.

Each of these questions has been looked at for content and subjected to
cognitive study, either by one-on-one cognitive interview, or focus
groups, or both. So, I think there\'s been a major improvement of this,
and in terms of the full-length donor questionnaire I think there are
major improvements occurring.

Trying to get at the very difficult estimate of what would be the false
negative donor response rate to some of the risk questions, there are
several studies that begin to address this, but none of them really give
a complete picture.

The NHLBI sponsored Retrovirus Epidemiology Donor Study in the \`90s
conducted some anonymous mail surveys post donation to donors who had
been accepted for donation, had donated, and then received a mail survey
afterwards, which, basically, reasked some of the screening questions.

And, the study found that through that survey one could document between
a 2 and 3 percent overall deferrable risk, i.e., positive responses to
questions by donors after successful donation that would have resulted
in their deferral, had they given the same answer at the time of
deferral. That\'s a cumulative factor.

For individual risk, this ranged from .1 to .5 percent, but all of the
risks were represented, including things like IV drug use, and clearly
for some of the less well focused questions, like needle stick or body
piercing type questions, that rate goes higher in proportion to the
vagueness of the question.

There were parallel findings and some similarly designed studies,
Canadian Blood Services did one, also there was one done in Hong Kong,
several other types of study formats. Blood centers frequently, in the
course of notifying donors of positive infectious disease test results,
combine that with a study to determine what risk factors the donor might
have had that contributed to that positive test result, and there are
numerous studies for known infectious agents like HIV, HCD, HTLV, et
cetera, that show that a high proportion of donors who successfully
donated and were found to be test positive, in fact, had the risk
factors that should have requested in their deferral. So, there clearly
is a level of false negativity, although it\'s very hard to quantitate.

One other thing I\'ll mention, it\'s not on the slide, but getting at it
from a different area one can look at risk factors measured in the
general population versus risk factors which result in deferral in the
first time donor population, and one example that\'s been used before is
the Dallas Household Survey of HIV Risk Factors, when those risk factor
prevalences were compared between general population surveys, albeit
limited, to first time donor deferrals, the risk reduction was about 20
fold. So, I think in keeping with the estimates put forward by Steve
Anderson in his model, a 95 percent efficacy rate of the screening
process, is a reasonable estimate.

There\'s one additional measurement, which does provide some
information, and I think this information addresses some of the
confusion that arises when you ask a very complex donor screening
question. Manufacturers are required to report to the FDA any deviations
which are discovered after the collection of a product that was, in
fact, distribution. These are known as Biological Product Deviation
Reports, used to be known as error and accident reports.

But, keep in mind in looking at the information that these are only
reported to the FDA when an implicated product is issued, so that if an
error was discovered in the course of a collection, but the product was
still in house, that would be useful information, but that\'s not sent
to FDA and collected.

The most common cause of BPDRs is what\'s known as post-donation
information, information that becomes known after the fact, after the
donation, and the most common PDI for 2003 was variant CJD travel,
reflecting the complexity of the question.

Where does the post-donation information come from? Generally, it comes
from subsequent donation, where a donor who had a false negative screen
at one time is found at a subsequent donation. Some time it\'s from the
donor calling back to the blood center, and sometimes, occasionally,
from a third party.

When was the deferral known by the donor? Generally, it was known at the
time of donation, but not provided for one reason or another. This
isn\'t necessarily, you know, lack of truthfulness on the part of the
donor, it may reflect the quality of the question or attentiveness of
the donor or some other factor. About 92 percent of the time it was
known at the time of donation but not provided, and about 8 percent of
the time not known at the time of donation.

I don\'t need to reflect on all of these numbers, this is simply total
BPDRs reported to FDA for 2001 through 2004, the percentage of those
which are post-donation information, and the percentage of PDIs which
are due to variant CJD travel. I put this up mainly just so you can get
a feel for the numbers that are involved. They are in the thousands, but
I think another eye opener is just anything considered in the context of
blood donation or plasma collection gets large really fast, just simply
due to the large number of donors. There are approximately 9 million
whole blood donors, approximately, the same number of plasma donors, so
the deferral itself results from 400,000 to 500,000 donors deferred in
each category. So, it\'s really major impact of some of these deferrals,
and the numbers that you see reflected in PDI 1/100th of those total
numbers.

So, in summary, estimates of the predictive value of donor screening are
crude, I\'ll say very crude. However, based on available data false
negative self-report of donor eligibility may be in the 3 to 5 percent
range of donors deferred on site and may be higher in relation to
complex questions.

Okay. Switching to a different concept, the current FDA recommendation
is deferral for transfusion in the U.K. from 1980 to present. There have
been a handful of recent developments, not that many since the last
discussion of the Committee. There have been two probable variant CJD
transmissions by transfusion, which I think most importantly reflect the
capacity in humans, similarly to the animal models, to have an
incubation period with circulation in the blood prior to clinical
disease, and the numbers here, I think as Dave Asher summarized, would
be on the order of 18 months and 36 months for the two cases.

There were recognized prior donations by variant CJD cases in France.
I\'m not sure this is contributes that much scientifically, but simply
opens your eyes if some of the variant CJD cases were donors.

There\'s also known to be donor deferral for any previous transmission.
France, the policy goes back to 1998. We don\'t know what the donor loss
is related to this, but I would propose that it\'s probably not too much
different from the losses estimated by the Netherlands, and as you\'ll
see some estimates for the U.S.

The Netherlands put the policy into place in December of 2004, with an
estimated 8 percent donor loss.

So, what are the range of possible policy extensions, if any? First,
would be a consideration of transfusion in France since 1980, again,
looking at that relative risk relationship.

Second is transfusion in any BSE country in Europe since 1980.

And, the third, any transfusion since 1980.

The donor loss estimates, I believe you saw quickly at your last
meeting, they are based on, again, the survey data for travel among
donors. We used as an assumption, because the longest period of travel
that we had available was five years or greater, we used this as an
estimate of long-term, lifetime exposure.

For U.K. travel, that was .4, there should be a percent there,
estimating that about 5 percent of donors were transfused, we estimated
donor loss already taken place of about 2 per 10,000 donors.

Similar calculation for France, we did not collect any data specific to
France, but what we did do was get lifetime travel to countries and then
established a ratio between travel to France versus travel to the U.K.
That ratio was .7 for France to U.K., so we simply inserted that with a
donor loss estimate of 1.4 per 10,000.

In considering source plasma donors separately, there are no even crude
calculations of donor loss, but we would expect it to be somewhat less
because history of transfusion is an age-specific relationship, and the
plasma donor population is somewhat younger than whole blood donors.

Estimating history of transfusion anywhere in Europe, exclusive of the
U.K., similarly, .7 percent times 5 percent estimated transfusion
history, loss of about 3 per 10,000 and the same comment for source
plasma donors.

So, overall, the donor loss, again, if you multiply by 9 million
individuals it can create a larger number than one might think, but
compared with some of the other donor deferrals comparatively smaller.

For overall transfusion, and I know you saw this slide at the last
meeting, one reason I wanted to show this is probably more than
considering history of transfusion between countries, it\'s important to
understand the distinction of donations versus donors. These are data,
again, from the NHLBI RED study, this is percentage of donations given
by transfused allogeneic donors, overall has dropped a little bit over
the years, but we use the figure of, roughly, 5 percent of donations
come from transfused donors.

It hasn\'t been calculated on a donor basis, but if you look on a donor
basis it\'s going to be, roughly, in that 7 to 7.5 percent range,
because you get different rates of donation for donors of different
ages. So, it\'s important to keep those two constructs in mind.

This one, similarly, percentage of donations, and this just gives an
example of the more frequent history of transfusion among older
individuals, as high as 11 to 11-1/2 percent, and among the college-aged
group well under 2 percent for an overall mean of about 5 percent.

Now, in considering the three potential extensions for transfusion,
it\'s important to consider the Euroblood program, as was mentioned
earlier. The reason it\'s important is, certainly one could, you know,
recommend a policy independent of considerations of the Euroblood
program, but it would potentially set up an asynchrony if one were to
defer for time spent in Europe with individuals in the U.S. who were
transfused with blood derived from Europe who may not be traceable. So,
I did want to give you some observations about the Euroblood program.
All of these were derived from testimony provide by the New York Blood
Center and the Greater New York Hospital Association in the 2001 era,
when the deferrals were being discussed.

The program began in the early 1970s, and at its peak represented about
1/3 of the New York area red cell supply, and approximately 2 percent of
the total U.S. red cell supply.

Euroblood was provided to over 200 New York metropolitan area hospitals
over the 30-year period of existence, approximately, well over 4 million
components.

In the absence of a massive look-back effort, Euroblood recipients
currently living in the U.S. are largely untraceable. A couple of
comments related to that. One is that it is known that the five-year
mortality following transfusion is well above 50 percent, may, in fact,
be as high as 80 percent, so many of these individuals are not living,
and that mortality we\'d actually say is generally unrelated to
transfusion. It\'s simply that it\'s people who aren\'t well, who
generally receive transfusion.

And a second is, look-back efforts are notoriously inefficient, that
even if you conduct a look back two to three years after an implicated
unit of blood is identified, your likelihood of finding the recipient
goes down over time, and it tends to be a very inefficient process.

A final comment is, the Euroblood program ended in the months prior to
the October, \`02 implementation of FDA deferral recommendations, which
was Phase II, and the pan-European deferral for travel and residence.

That brings us to the questions.

CHAIRPERSON PRIOLA: Are there any questions for ? yes, Doctor Bracey.

DOCTOR BRACEY: Can you give us an update on the status of the U.S. blood
supply? In recent years, we have experienced shortfalls. Anecdotally,
those of us in practice noticed that there have been shortfalls. What is
the most recent status of the blood supply?

DOCTOR WILLIAMS: I can only give an observation and, perhaps, defer to
Jerry Holmberg or others who might have more information.

It seems that we got through the holiday period this year without a
national appeal. That had not been true for the several years previous,
particularly, last year, as a very tough December and January for blood
supply, probably due to the low level of the flu infection this year,
combined with some of the warmer weather, perhaps, the impact this year
was not great in keeping donors home.

But, I think I would be one of the first to say that the blood supply
overall tends to be marginal and fragile, so that I think any policy
that we consider is carefully balanced against loss of blood and loss of
donors.

As far as actual measurement, this is now undertaken by Jerry
Holmberg\'s shop at HHS, and he\'s going to comment further on that.

DOCTOR HOLMBERG: Yeah, just ?

CHAIRPERSON PRIOLA: State your name for the reporter?

DOCTOR HOLMBERG: Is this on? Can you hear me?

My name is Jerry Holmberg.

As far as the shortages over the last year, I agree with what Alan has
said. We have sporadic shortages, for instance, New York is currently
experiencing a shortage, and has gone out on appeal, I think, last week?
Just for O-negs, however, there is a shortage currently.

And also, the New England area most recently experience some shortages
because of the snowfall, but overall the country is pretty well
supplied. We are talking about a three to five-day supply.

DOCTOR BRACEY: Is there any estimation in terms of the extent of donor
loss that the system would be able to endure?

DOCTOR HOLMBERG: Well, I just did a quick calculation based on what Alan
was projecting there, if we talk about three per 10,000, of course,
that\'s not calculating in the people that received Euroblood during
that period of time, and we\'re talking 2,700 donors. So, I don\'t have
a direct answer for you, but I think that you have to calculate in also
the fact that, you know, what about those recipients of the Euroblood?

CHAIRPERSON PRIOLA: Mr. Fitzpatrick, did you have a comment?

MR. FITZPATRICK: Mike Fitzpatrick from America\'s Blood Centers, just
for perspective, anybody that wants to can go to our website, you can
make a comparison between the status of our inventories now and two
years ago.

Our members are seeing about a 20 percent difference. They have about a
20 percent greater inventory now than they did two years ago, and we
attribute that to recovery from 9/11, the vCJD deferrals all coming at
the same time, and some very vigorous recruitment efforts.

But, to say that raising ourselves from a one to three-day supply, to a
three to five-day supply, provides an adequate supply for the country, I
think is a false statement. I think we had recommended previously that
we need a seven-day supply in the country, increasing to a seven-day
supply is an arduous task, and to go from a period of drought that we
have been in to a period of adequacy, if I can use that word, and I\'m
not sure that\'s the right word, sends a message that we are succeeding,
but we certainly are not in what anyone would call an ample inventory
method. There are shortages of Os throughout the country, and we\'ve
seen requests for Os throughout the country. There are surpluses of As
and Bs, and we made it through the holiday period in a much better
situation than we\'ve had in the past, and we haven\'t seen cancellation
of elective surgeries. But, in looking at the trend line in those
inventories just today, it\'s starting to dip down a little bit. So, it
may be a momentary improvement that we have to sustain.

CHAIRPERSON PRIOLA: Doctor Johnson?

DOCTOR JOHNSON: Yeah, I have two further questions about the Euroblood.

First of all, what countries primarily did it come from? Was it randomly
through Europe, more Eastern Europe? My feeling is a lot of it was
German blood, right?

DOCTOR WILLIAMS: I\'m sorry, I should have mentioned that.

It was sourced from Germany, Switzerland and the Netherlands,
exclusively.

DOCTOR JOHNSON: So that, at no time when Euroblood was being given have
there been recorded cases of variant CJD in any of those countries, is
that correct?

DOCTOR WILLIAMS: It sounds correct, yes.

DOCTOR JOHNSON: The second thing is, do people know if they\'ve gotten
Euroblood? I mean, the question is going to be, did you ever get
transfused in New York City, and you are going to eliminate everybody,
right? I mean, if some guy got knifed in the lower East Side, or upper
West Side, whatever, and you said did you get Euroblood or did you get
American blood, he\'s not going to know, is he?

DOCTOR WILLIAMS: I think it\'s very unlikely a patient would know that
they received Euroblood. I think one other characteristic that probably
is important to know is, it was likely Group O red cells that comprised
Euroblood, but in terms of specifically notifying a patient that that
unit of blood was collected in a U.S.-licensed New York Blood Center
facility in Europe, no, I don\'t think that was transmitted.

DOCTOR JOHNSON: It seems to me that with no cases of CJD ? variant CJD
in the donor countries that we ought to take Euroblood off the table and
talk about France, as a personal opinion.

CHAIRPERSON PRIOLA: Other questions for Doctor Williams?

We have another comment?

DOCTOR HOLMBERG: Yes. Alan, just a point of clarification, on the
deferral that the Netherlands put into place, was that for people that
had been transfused in France, or was that overall transfusions in their
country?

DOCTOR WILLIAMS: Transfusion ever anywhere.

DOCTOR HOLMBERG: Including the United States?

DOCTOR WILLIAMS: Yeah, I believe so.

CHAIRPERSON PRIOLA: Doctor Bird?

DOCTOR WILLIAMS: I\'m sorry?

DOCTOR JOHNSON: What are the Netherlands using for blood?

DOCTOR WILLIAMS: I can\'t answer that.

DOCTOR JOHNSON: It\'s donors who have never been ? so, they can take
donors, but they can\'t have been transfused.

DOCTOR WILLIAMS: Right, that would cost, by their estimate, 8 percent of
the donor supply, but, you know, far and away the majority of donors
have not been transfused, so they would still be eligible for donation.

MR. FITZPATRICK: Mike Fitzpatrick. We had some ? I\'m sorry.

CHAIRPERSON PRIOLA: In was going to ask Doctor Bird to go first.

DOCTOR BIRD: Just a point on Switzerland, although they have not had any
variant CJD donors, Switzerland has been concerned about an increase in
its numbers of sporadic Creutzfeldt-Jakob disease, and some work by the
Medical Research Council\'s Prion Unit suggests that when you put BSE
into mice there can be a bifurcation as to whether it materializes as
variant CJD-like disease or a Type 2 sporadic CJD. So, there\'s a little
bit of sort of basic science there that we are just a little bit
concerned as to whether variant CJD is the only manifestation of BSE in
humans.

CHAIRPERSON PRIOLA: Thank you.

Go ahead, Mr. Fitzpatrick.

MR. FITZPATRICK: Mike Fitzpatrick. We corresponded with Doctor van der
Poel from the Netherlands prior to the meeting about this topic. They
have a very robust blood program in the Netherlands, and when they put
in the deferral for all transfusion recipients they anticipated about a
10 percent loss. By his correspondence with us he says they have been
able to absorb that and meet their needs.

CHAIRPERSON PRIOLA: Okay.

If there are no other questions from the Committee for Doctor Williams,
I would suggest we take a brief break of about ten minutes, and then
come back for the open ? five to ten minutes, come back for the open
public hearing, and then the final discussion and vote.

(Whereupon, at 4:34 p.m., a recess until 4:44 p.m.)

EXECUTIVE SECRETARY FREAS: If you would take your seats, please. There
are many Committee members that need to catch flights tonight, so I
really would appreciate your cooperation in getting to your seat

CHAIRPERSON PRIOLA: If we could have all the Committee members take
their seats, please, so that we can start the open hearing portion of
this afternoon\'s session.

EXECUTIVE SECRETARY FREAS: Okay.

For this afternoon\'s open public hearing, we have three speakers lined
up, and before we begin these three presentations, that will be limited
to a maximum of five minutes, the Chair has a statement that has to be
read, if I could please ask everybody to take their seats, we\'d
appreciate it.

CHAIRPERSON PRIOLA: Okay.

Both the Food and Drug Administration, FDA 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 any
group\'s payment of your travel, lodging or other expenses in connection
with your attendance at the meeting.

Likewise, FDA encourages you at the beginning of your statement to
advise the Committee if you do not have any such financial
relationships. If you choose not to address this issue of financial
relationships at the beginning of your statement it will not preclude
you from speaking.

EXECUTIVE SECRETARY FREAS: The first request we have to speak in the
afternoon is Allene Carr-Greer, Deputy Director, AABB, Regulatory
Office. She\'s going to make a statement on the potential deferral of
blood and plasma donors for history of transfusion in European
countries.

MS. CARR-GREER: I am an employee of AABB, and AABB is an international
association dedicated to advancing transfusion and cellular therapies
worldwide. For those who don\'t know, our members include more than
1,800 hospital and community blood centers and transfusion and
transplantation services, as well as approximately 8,000 individuals
involved in activities related to transfusion, cellular therapies and
transplantation medicine.

For over 50 years, AABB has established voluntary standards for and to
credit institutions involved in these activities. AABB has a focus on
improving health through the advancement of science and the practice of
transfusion medicine and related biological therapies, developing and
delivering programs and services to optimize patient and donor care and
safety.

AABB believes that deferring donors who were transfused in France or
other European countries would not significantly affect the blood
supply. However, we are concerned about the increasing number of reasons
for donor deferrals, some of them a very low risk benefit ratio. And, a
few minutes ago Alan touched on some of the complexities involved in
donor questioning and predictive value on negatively and positively the
predictive values of questioning donors about history and trying to
recall memory.

Continual addition of new questions distracts donor attention from the
more significant risk questions, and decreases the likelihood that donor
questioning will elicit important and significant information. Although
each added deferral in and of itself may not impact supply, the additive
effect will almost certainly adversely affect supply, so that the risk
benefit must be carefully considered.

And, today\'s discussions I think have been really thoughtful
consideration of models for risk assessment, a great deal of discussion,
of course, about some of the assumptions that went into that, and I must
say I was struck by some of the descriptives that the speakers
themselves were using in presenting their material, when talking about
risk assessment and uncertainties. And, after a while, I jotted down a
couple of the statements, and we were hearing such things as, using a
huge number of assumptions, extreme uncertainties, unknown
uncertainties, and most recently I heard vast uncertainty.

It would be useful for FDA to examine all of the existing donor
suitability criteria to determine whether each of these criteria is
still necessary in light of current scientific knowledge and testing
capabilities.

We believe FDA should consider whether it\'s essential for the blood
banking community to focus efforts on this particular deferral issue, or
whether there might be other concerns that would yield more benefit, and
would greatly and positively impact donor and patient safety.

Thank you.

EXECUTIVE SECRETARY FREAS: Thank you very much for your statement.

The next requester is Doctor Michael Fitzpatrick, Chief Operating
Officer, America Blood Centers.

MR. FITZPATRICK: Good afternoon, and I am gainfully employed by
America\'s Blood Centers.

I\'ll make a departure from the written statement on occasion, but you
have it before you. The first paragraph tells you about us, we are the
network of the not-for-profit community blood centers in the United
States, 76 members, including Hema-Quebec in Canada, and these centers
serve more than 150 million people providing over 7 million collections
annually.

When the FDA announced deferral of the criteria to reduce the risk of
transfusion-associated vCJD in 1999, based on the application of a
precautionary principle and the hypothesis that the prion responsible
for vCJD could be transmitted by transfusion, the Committee reviewed the
two cases of vCJD that had been associated with transfusion from
individuals who later died from vCJD and did not recommend additional
deferral actions, and that was October of last year.

Today, FDA asked the Committee to review the issue again, and asked
whether individuals who received blood transfusion in Europe should be
deferred as blood donors. The rationale for the timing of this
discussion is not clear to us as we prepared the remarks. It has been
made clear throughout the day, but as Doctor Williams stated himself,
there have been only a few changes to what has occurred.

The incident of vCJD has declined since the peak in 1999, total number
of cases around the world about 160, it remains very small, only four
new cases of vCJD were diagnosed in the U.K. in 2004. We do have a new
one in Japan, but that remains to be evaluated, down from a peak of 29
in 1999.

The most telling fact this morning to me, as has always been, that no
recipient of any plasma-derived coagulation factor in the U.K. has
developed variant CJD, despite the fact that most of them have been
exposed to thousands of donors who were at risk during the most peak
periods of the epidemic.

If we review the model used by FDA to decide on the scope of the
geographic deferrals for people that lived in the U.K. and the rest of
Europe, it was predicated on balancing risk reduction with donor loss,
and predicted a statistically-derived 90 percent reduction of the risk
while deferring about 2 to 3 percent of the individuals who were already
donating.

The recommendation to defer all European transfusion recipients, in
order to decrease the almost unquantifiable residual risk, and from the
modeling today I think we can see that it is difficult to quantify,
provides what amounts to an immeasurable contribution that would be
statistically insignificant.

While most centers could absorb the minimal donor loss associated with
deferral for transfusion in the rest of Europe, we are concerned about
standing at the top of that slippery slope that is always discussed.

Broader deferrals for a history of transfusion will cost us as many as 5
to 10 percent of our donors. This is an unnecessary donor loss and
unreasonable stigmatization of volunteer blood donors. It also sends
recipients a very mixed message.

ABC, the Red Cross, AABB and FDA have frequently said over the past few
years that the blood supply is safer than ever. Yet, now we are
considering sending the message to recipients that the act of accepting
the lifesaving, safe transfusion would defer them from ever passing on
the gift by becoming a regular blood donor, but recipients have become
of the best donor recruiters in the Nation and regularly donate
themselves, as you saw from Alan\'s statistics.

If deferred for no known or real risk, they will have survived their
illness through transfusion to now live under a cloud of doubt,
wondering if the blood they received was safe, and when and if they will
begin to show signs of variant CJD or some other unknown disease,
that\'s preventing them from being a donor. We feel that\'s an
unwarranted stigmatization of a recipient.

I want to note a specific comment about geographic deferrals made in the
briefing documents. We talked about post-donation information related to
geographic exposures continues to comprise a high proportion of
biological product deviation reports submitted to FDA, indicating that
improvements in donor eligibility determinations are still needed.

In our opinion, and as we have stated in the past, post-donation calls
are a sign of success of the system, not a failure, and a success of the
screening process. Donors go home, think about the questions, or think
about the question at their next donation, look at their passports, talk
to their wives, and call back with more precise information. They want
to tell us if they should be deferred.

Immense resources have been used to update deferral questions, screen
and defer donors, and respond to questions from the deferred donors and
their friends. Adding a new layer of deferral will only require more
resources, which possibly could be utilized in CGMP compliance and
developing new screening techniques.

Deferral of transfusion recipients will not reduce the presumptive risk
of transmission of CJD by transfusion in a measurable way.

And again we ask, as we did last time, that FDA initiate discussions of
what could constitute an exit strategy. I was extremely impressed by the
modeling that we saw today, and the thought, and the process that has
gone into that modeling, and to me that modeling could be used as a
first step, because the modeling is predicated on the assumption that
there is a risk that is high, and we need to do something to prevent the
risk.

Now that we have that modeling, perhaps, we can reverse that thinking,
or use both lines of thought. Perhaps, there is not a risk, and,
perhaps, we can use this modeling to show that there isn\'t a risk, and
at some point have a strategy that says we have dealt with the epidemic,
the peak has passed, and now it\'s time to move on, and you have models
to show that it is not being transmitted in the rates and proportions
that we thought.

So, I would suggest that we use those models and begin discussions with
FDA on how we can assist to use those models to determine how to
implement recognized safety measures, how to decide when and if people
can donate again, and discuss the possibility of removing European
countries which have had no human cases of variant CJD, all but France
and Italy, from the deferral criteria.

The U.K. presentation was very telling, because we saw their use of
modeling in advance to determine what actions they would take if
something happened. I think we\'ve seen that same emphasis from FDA
today, to look at what to do if something occurs. We\'ve seen that we
have very little data to go on to support those models, but we would
love to assist and work with FDA to use those models to determine both
what should you do if the data changes and you should change the
deferral criteria, and what should you do if the data does not change
and we should remove the deferral criteria.

Thank you for the opportunity.

EXECUTIVE SECRETARY FREAS: Thank you very much, Doctor Fitzpatrick.

The third requester for this afternoon is Doctor Richard Davey. He\'s
Chief Medical Officer, New York Blood Centers.

DOCTOR DAVEY: I\'m Doctor Davey, and I\'m employed by the Blood Center,
actually a former member of the Committee, and I do appreciate the
opportunity to speak to the Committee today on behalf of the New York
Blood Center.

The New York Blood Center is the largest independent blood center in the
country. We collect over 450,000 units of whole blood and 50,000
apheresis platelets annually, which is about 5 percent of the Nation\'s
blood supply.

As you\'ve heard for over 30 years, the New York Blood Center imported
blood from three European countries, Switzerland, Germany and the
Netherlands, under our Euroblood Program. This blood was collected
entirely from volunteer donors under the New York Blood Center\'s FDA
license.

During the period from 1980 until the termination of the program in
2002, we imported about 4,700,000 units of red cells from these European
blood centers. The data from \`80 to \`84 I had to estimate, but I think
that number of 4,700,000 is pretty accurate.

In 2001, as you know, this Committee recommended the extension of the
prohibition of blood donation in the United States from those who had
resided in the United Kingdom to other European countries. This resulted
in the termination of the Euroblood Program in New York. We are
encouraged, as Mike has also said, that since that time the number of
vCJD cases has remained small, and the incidence of both BSE and vCJD
has declined, and there has not been, as you\'ve heard, not a single
case of vCJD identified within the three countries that participated in
the Euroblood Program, again, Germany, Switzerland and the Netherlands.

Very briefly, I\'d just like to touch on a couple consequences of the
extension in 2001 to the donation restrictions beyond the U.K.

As you know now, because of out of over 300 million Europeans, and tens
of thousands of Americans who have lived or traveled in Europe, are now
prohibited from blood donation in the U.S.

Another couple points. Actually, the viral marker rates, the blood we
imported from Switzerland in 1999, and this is typical, was ? this is
for HIV, HCV and HBsAg, was 0.15 percent, the average marker rate in the
U.S. is about 0.5 percent. So, when you look at that, it\'s not clear
sometimes, and to my mind they are replacing blood drawn from altruistic
volunteer donors in Europe with blood drawn in the U.S. has really added
a lot to blood safety.

Very briefly, I think as Alan mentioned, the blood that we did import
from Europe was very rich in Group O, since we don\'t have that anymore
it\'s thrown the ABO balance, at least in New York, somewhat out of
balance, and now we are chronically short of O, and have too much A.

The cost of collecting blood in New York is much higher than blood
collected and imported from Europe. We\'ve had to pass those costs on to
our hospitals and, of course, to third-party payers.

Just another point, there are some differences in the way these
restrictions have been applied in the U.S. For instance, I lived in
Geneva for a year when I was detailed from the NIH to the World Health
Organization in 1990-\`91, so I can donate blood in New York, but I
can\'t here in Washington. I can donate blood in Seattle, I can\'t
donate in Los Angeles. I can donate in Houston, I can\'t donate in
Atlanta. It puzzles me why my risk of vCJD seems to fluctuate as I move
around the country.

I raise these points just as an illustration that extensions of the
precautionary principle, while they are made in good faith, might have
far-reaching and unintended consequences.

Now, a little bit more about Euroblood. If we prohibit donations from
those who have received blood transfusions in Europe, we will by
abstention implicate recipients of Euroblood in the United States.

If we assume a transfusion episode of about four units, which I think is
accurate, about a million people, maybe slightly over a million people,
were transfused with blood from European sources in the U.S., between
1980 and 2001, almost all of the New York Metropolitan Area. Most of
these recipients are now deceased, because of the diseases they were
transfused for, and also actuarial loss of life.

Living recipients are aware that they are receiving life-sustaining
transfusions, but to the point of one of the speakers earlier, they
don\'t know, as any blood transfusion recipient doesn\'t know, or
shouldn\'t know, whether the blood came from Manhattan, from New Jersey,
from Geneva, or from Amsterdam.

Actually, I did do a couple quick stats, if I could take one moment. If
we look at, perhaps, a million recipients of Euroblood in the time
period we are looking at, due to death fewer than 100,000, maybe far
fewer, are still alive. If we look at New York, about 3 or 4 percent of
people donate blood, let\'s say 5 percent, there are maybe 5,000 living
recipients of Euroblood that are donating blood. Again, these are
recipients of blood from the Netherlands, Germany, Switzerland, their
risks are unknown, vague and low, at very best.

So, also as Alan Williams pointed out, if we did take the route of
identifying and notifying the recipients of the millions of units of
European donors, and subsequent requirement for our hospitals to trace
and notify those recipients, that would be an exercise in actually
mind-boggling complexity, scope and expense. This is in addition to the
chilling message for these recipients, that while there\'s no
established figure to determine risk they may be harboring a fatal
neurologic disease. Of course, they can no longer be blood donors.
Counseling these individuals would also fall to the hospitals, and those
are really ill-equipped institutions to perform these tasks.

I think personally that the bright line around the United Kingdom, which
this Committee established years ago with this unfortunate experiment of
prion disease and transmission is unfolding, remains a reasonable basis
for the application of the precautionary principle. Extension of these
restrictions to donors and recipients from other countries opens up a
slippery slope of extensions to increasing numbers of countries donors
and recipients.

We must be mindful of evolving data for sure, as well as the
consequences of actions based on limited or absent data.

In conclusion, blood safety remains a compelling priority for all of us.
We must consider, however, that not having enough blood, or burdening
health organizations with unmanageable issues of notification and
deferral, also has major and compelling implications for the safety of
the American blood supply.

Thank you.

EXECUTIVE SECRETARY FREAS: Thank you very much, Doctor Davey.

Is there anyone else in the audience now that would like to make
comments to the Committee related to this issue before the Committee?

Seeing none, Doctor Priola, In turn the meeting over to you.

CHAIRPERSON PRIOLA: Okay.

So, it\'s now time for the Committee open discussion and vote on the two
questions posed to us by the FDA.

The first question is, based upon the available scientific information
does the Committee recommend deferral of blood donors transfused since
1980 in France or in other countries of Europe? So, this question
precludes the Euroblood issue, and I think from comments that Doctor
Johnson made, and Doctor Hogan, and, perhaps, others around the table,
that there is some hesitancy in even considering Euroblood in these
deferrals because of the implications, is that right? Does anyone have
any comments on that?

Doctor Bracey?

DOCTOR BRACEY: I\'d just like to comment in terms of the Committee\'s
moving toward this discussion.

I think one of the things that happened at the last meeting is that the
discussion of this item came up toward the end of the day. There was
lots of information, and there was some uncertainty. We\'ve heard lots
of information today which for me alleviates the concern. I think
there\'s, as has been stated by many others, minimal gain to be had by
extending the range of deferrals, and in my mind I think we\'ve had a
thorough discussion, and I think that, in fact, the safety to be gained
from adding other countries would be minimal.

CHAIRPERSON PRIOLA: Doctor Johnson?

DOCTOR JOHNSON: Yeah, was it correct that the French have eliminated
donors in their own country who have had transfusions? So, we would be ?
I find it very convincing that we could look pretty silly if the
catastrophe occurred, that someone got blood that even the French
wouldn\'t use on their own.

DOCTOR BRACEY: Well, that\'s a point, but I think if we look at all of
the issues, as far as donor management, we see that there\'s been a very
cautionary approach taken by a number of countries, particularly, the
European countries.

If we were to ask the question, well, why did we pick three months for
the U.K.? We picked three months because we recognized that that would
eliminate a certain number of donors.

If we ask the question, well, what if we went to two months instead of
three months, would we ? you know, what would be the incremental gain?
What is that incremental gain, as opposed to adding France to the mix?

So, I think if we really were to sort of look at the added safety, that
in the final analysis I think it would be quite minimal, and I think
that even though in France the donors, in essence, are not allowed to
donate after ? if they\'ve been transfused, there really is no basis to
support that.

CHAIRPERSON PRIOLA: Doctor Allen?

DOCTOR ALLEN: These are very difficult questions. I would absolutely
concur that we were not asked about Euroblood, In think there\'s
compelling reasons not even to consider the Euroblood program. So, you
know, as I said, we are not asked that question, so that\'s good.

With regard to France and the deferral of their own donors in France, I
would venture to say that if you go back historically that decision
probably emanates from the failure to act rapidly in the HIV era, and as
you may or may not know there were some French blood banking officials
that rightly or wrongly were actually jailed because of that HIV
incident.

So, you know, there are probably lots of decisions, or lots of reasons
that go into some of these decisions.

The evidence, as far as I can ? nonetheless, I agree with you that if
France defers and the United States doesn\'t, and something happens, it
creates a very uncomfortable environment here. It seems to me that the
risk is minimal. It\'s not zero, it clearly is minimal.

Making this additional deferral for France or for other BSE countries in
Europe, complicates the selection of donors, and that tends to
discourage people from coming. Doctor Williams presented information
about inaccurate data that are collected when you are trying to ask
donors and they are trying to recall. It does create additional
regulatory burden, because the person ? the donor that answers one way
this time, and a different way three months or four months later,
whenever they come back in to donate, then creates the need to go back
and notify the FDA if the blood has already been released and
transfused, and, you know, we do create additional problems for
ourselves with these kinds of things.

You know, the issue of adding France alone, if the addition of France
can be rolled into the question of, did you ever receive a donation in
Great Britain, may not be difficult. I think the addition of other BSE
countries in Europe makes it very complex.

One might ask the question then, should you just defer anybody that\'s
received a transfusion anywhere in Europe? And, that simplifies things
from one perspective, it complicates it in others.

I personally am not sure exactly, In want to hear the rest of the
discussion, where I\'m going to come down. I probably am leaning
slightly towards the inclusion of France only, but it isn\'t clear to me
that we are really gaining a lot in terms of reducing risk, and there
are clearly going to be some significant tradeoffs on this one.

CHAIRPERSON PRIOLA: Doctor DeArmond?

DOCTOR DeARMOND: Well, it seems like there\'s probably just a small ?
relatively small population of people who have received a transfusion in
France.

The thing that kind of bothered me a little bit in the presentations
today was ? the presentation by Doctor Bird, of the sort of unknown
cases of variant CJD ? of BSE in France and, perhaps, the kind of
extended period of variant CJD cases occurring, kind of not in a
cluster, but just sporadic, suggesting that there\'s an underlying
problem there.

If we can understand that, and, in fact, I\'d like to hear more comments
about her data, does it say that France does have some sort of special
problem with BSE and variant CJD?

And, I don\'t know, the rest of Europe didn\'t seem to be a problem,
especially the Euro donors group.

So, I would kind of go along with the comments you made, Richard, about
considering France and not considering the other countries, for the two
reasons, they don\'t accept their own donors, their own transfused
patients, and there seems to be a problem with BSE and variant CJD there
still.

CHAIRPERSON PRIOLA: In think with respect to Doctor Bird\'s
presentation, maybe she can clarify this, the overall point was that
there\'s underestimation if you just base it on clinical cases, so not
to just single out France, but any country where there\'s BSE or variant
CJD surveillance there will be under-representation.

DOCTOR DeARMOND: Could you, I would like to know, I got a different
perspective.

DOCTOR BIRD: No, I think the important thing, from my point of view in
terms of France, is that the French team ? that the majority of the
exposure of the French population came from exports of bovine carcasses
from the United Kingdom to France, and that 60 percent of our export of
bovine carcasses went to France. So, there\'s a very clear reason as to
why France would be next in line.

There hasn\'t been much discussion here about Ireland, what we think of
as the Republic of Ireland, which is not part of the United Kingdom,
it\'s a separate country, and which has two countries ? two variant CJD
cases, and had a very high rate also of BSE in its cattle.

DOCTOR DeARMOND: So, you didn\'t implicate France, that France has a
special problem, except in the case of importation from Great Britain.

DOCTOR BIRD: Primarily, in respect to importation from the United
Kingdom, yes.

CHAIRPERSON PRIOLA: Doctor Nemo, did you have a comment?

DOCTOR NEMO: Yes, just from the availability standpoint, if you look at
the history of transfusion in France, it\'s 1.4 per 10,000. If you look
at, say, an average blood center that collects 200,000 units a year,
that only comes out, I think, to a couple, two to three, donors a month
that you\'d lose. So, it\'s not ? I think if my back-of-the-envelope
calculations are correct ? so, it\'s not a major loss as far as France
is concerned.

CHAIRPERSON PRIOLA: Doctor DiMichele?

DOCTOR DiMICHELE: Well, I just wanted to say, you know, AABB, we do have
our statement where we think we can absorb, you know, a loss from
deferral due to France, but I would say that, you know, a donor lost is
more than a donation lost. You know, anyone whose feelings are hurt when
they are rejected, you begin to lose their neighbors, their friends,
their family, their work site, and, hopefully, they were more than a
once-in-a-lifetime donor to begin with. So, it is a greater loss than
just, you know, a couple of units a month.

Thank you.

MS. CARR-GREER: I was just wondering if the U.K. was deferring
individuals who had been transfused in France?

DOCTOR BIRD: The U.K. defers any donor who has received a transfusion.

DOCTOR DiMICHELE: In the U.K.?

DOCTOR BIRD: The U.K. would not accept a blood donation from anybody who
had received a transfusion, period, is the answer now.

DOCTOR DeARMOND: Is that ever and in any coun ? from any country in
Europe?

DOCTOR BIRD: That\'s correct, but, of course, we\'ve only done this as
of 2004, whereas, France had made its decision in 1998, and part of our
reason for delaying, it obviously had been a consideration in the U.K.,
was concern about the impact on the blood supply, but then confronted
with blood-borne vCJD the action was then taken pretty quickly.

DOCTOR SALMAN: Is this transfusion in Europe? What if there was a donor
who was transfused in the United States, for example?

DOCTOR BIRD: I think I am correct in saying that the U.K. would not
accept as a donor somebody who had received blood transfusion, full
stop.

DOCTOR SOLDAN: Well, perhaps, we have to clarify this for the Committee
afterwards, because I\'m not convinced, and we need to just check that
for you to be absolutely certain. That\'s a key point, because my recall
is that it may only be U.K. transfusions, but we\'d like to check that
for you.

CHAIRPERSON PRIOLA: That would be fantastic, thank you.

Doctor Bracey?

DOCTOR BRACEY: One of the issues that I think we need to get somewhat
concerned about is this issue of taking that first step, because,
clearly, if you ask the question, you know, what is the minimal
biological risk, of course, the minimal biological risk is not to
receive ? is to receive the blood of a patient who has never been
transfused.

As we begin to take these small incremental steps and compare our
policies to the policies of other nations, I\'m just afraid that this
may just be the first step, and then, well, then comes the next step.
That\'s my concern.

And again, if we do this, in essence, because it\'s been done in France
for, in essence, trying to develop some sort of uniformity, I\'m just
concerned about taking that first step and then, perhaps, there\'s
another step that follows.

CHAIRPERSON PRIOLA: Doctor Hogan, did you have something you wanted to
say? No?

Okay, Doctor Salman?

DOCTOR SALMAN: Well, my concern, if we start with France now, somebody
will say, what about the Netherlands, and tomorrow another country in
Europe decide to do the same thing as France, when we will stop. Either
we have some risk assessment process that is going on and have from that
some outcome before we can decide, or maybe we ? like with all the day
we spend on reviewing risk assessment models, and now we are saying is,
we go with this and exclude France or exclude other countries, so
what\'s the purpose of risk assessment modeling we are reviewing?

CHAIRPERSON PRIOLA: Doctor DiMichele?

DOCTOR DiMICHELE: I\'m going to play the devil\'s advocate again.

I think that, you know, when we are talking about deferring blood
donors, I think the situation is a little bit different than what we\'ve
been talking about with respect to plasma derivatives. I think the
plasma derivative issue is a very different kettle of fish, with respect
to risk assessment.

I think we have evidence that ? or certainly some evidence, I mean,
maybe no incontrovertible evidence, but some evidence that this organism
can be transmitted through a regular blood donation.

I would have to say that there\'s some people who are breathing a lot
easier with our having deferred people transfused in the United Kingdom
from our donor base, you know, now having, you know, found out quite
later, after having made this decision, that there have been a few cases
of transfusion transmitted diseases. And, although I understand that
this is an ongoing risk assessment, and I would actually second Mike
Fitzpatrick\'s statement that there has to be an ongoing risk assessment
as we make these decisions, so that we can reverse them should the time
come, I would agree with those individuals who have said that in light
of the fact that we know that this organism, this prion can be
transmitted, or like I said, have fairly good evidence that it can be
transmitted through blood transfusion, and given that there is the
likelihood or the possibility that this situation could evolve in France
as it has in the U.K., and given that France does defer its own
transfused individuals from donating blood, I don\'t really see how we
could not defer France, and people who have been transfused in France,
at least as a precautionary measure.

CHAIRPERSON PRIOLA: Doctor Epstein, do you have a comment?

DOCTOR EPSTEIN: Yeah, I just wanted to comment that FDA\'s thinking in
posing the question specific to France was not based on the policy in
France to defer transfusion recipients, it was based on the epidemiology
of BSE exposure based on importation, primarily, of U.K. beef, and it
was based on the relative proportion of vCJD cases, about 5 percent of
that in the U.K., and that does make France stand out among non-U.K.
European countries.

So, I just wanted to clarify that we didn\'t really see the driver here
as the French policy decision, though it\'s certainly a matter that the
Committee can discuss.

DOCTOR DiMICHELE: Yeah, but on the other hand I would have to say that
the French saw their epidemiology as being a little bit of a risk
factor, and that\'s probably why they made their decision.

So, I mean, in essence, it does come back down to the epidemiology.

DOCTOR EPSTEIN: Right, but the question is whether a policy decision
should be based on the scientific risk assessment or looking at European
policies per se, and I\'m just trying to get us refocused on thinking it
through from the standpoint of risk.

DOCTOR DiMICHELE: Well, what I would then say is that I would agree with
you then that the epidemiology is the issue, and that the deferral in
France of their own transfusion recipients, I think, is just
confirmation that, you know, there is some concern about that
epidemiology, and some concern that should be taken here in the United
States. I guess I\'ll reframe it that way.

DOCTOR EPSTEIN: I think we\'d be more comfortable hearing it framed that
way.

CHAIRPERSON PRIOLA: Doctor Salman?

DOCTOR SALMAN: Well, if we try to make it on the epidemiology of what
happened with BSE in France, I think again I would emphasize, this is
really unfair because there are plenty of countries now in which they
have BSE cases, whether detected or not that\'s another issue.

Furthermore, when you look on the Eurostat, which is the most important
statistical-based figures from Europe, there are plenty of countries in
which they received U.K. meat, received MBM, meat and bonemeals, they
have more cases if we go with that type of prediction.

So, I don\'t think we can pinpoint only on France, whether the French
decided to go with that issue, I agree with Doctor Allen, is mainly
because of their previous experience with the HIV, that\'s their reason
to go that way.

So, if we go with the issue about epidemiology of BSE, In think there
are plenty of other countries I can pinpoint in which like they should
be included with France.

CHAIRPERSON PRIOLA: Doctor Belay?

DOCTOR BELAY: But clearly, the French question is different because they
have more vCJD, period, and that reflects what people have been saying
in terms of the BSE exposure in France, whether it\'s from within
France, BSE within France, or it\'s foreign material, imported material
from the U.K. is higher than other European countries, and that\'s what
the vCJD situation is telling us.

CHAIRPERSON PRIOLA: Although In suppose you could extend Doctor
Salman\'s argument and say in those countries where there is poor BSE
surveillance there\'s probably not much better vCJD surveillance.

DOCTOR BELAY: That\'s correct.

CHAIRPERSON PRIOLA: Doctor Bracey?

DOCTOR BRACEY: Perhaps, back to the issue of the Japanese case. Here\'s
a case where a person was not in the U.K. for three months, they
acquired the infection, so again, when we look at reducing risk are we
really treating other countries in a fair manner, you know, when we
decide for the U.K. that it is three months, because we want to maintain
our donor base with a loss of 2 to 3 percent? I mean, where\'s the
science in that decision? That was the decision, based upon loss of
donors. Should we go to a month for the U.K.? Would that decrease the
risk relative to France?

CHAIRPERSON PRIOLA: Doctor DiMichele?

DOCTOR DiMICHELE: In think you bring up an excellent point, and what I
was going to say is, that\'s not an issue that\'s on the table right
now, but I would have to say that, you know, this case in Japan is going
to have to be watched very carefully, and if there is further evidence,
yes, I would agree with a deferral, a stricter deferral.

I mean, and it\'s going to be difficult, but I\'m not sure what else we
can do until we, you know, begin to understand how to test for this, you
know, how to nip it in the bud as we have for other infectious diseases.

You know, fortunately, this case is not like West Nile, which, you know,
we were able to get control of very quickly, but, you know, I don\'t
know what else to do, I mean, the population still has ? I mean, this is
a terrible disease.

CHAIRPERSON PRIOLA: Mr. Bias?

MR. BIAS: Well, I guess ? boy, hard decision when you open up this door,
it\'s a very difficult decision. But, I guess what I\'m ? the reason
I\'m sitting in this seat, and wasn\'t sitting here years ago in a seat
like this, was because the Committee needs a human face. I\'ve been
independent on the blood supply my entire life, and I probably have
everything that\'s been through the blood supply as a result of that.

So, before we make this decision, very few decisions can be made based
on science alone, when we are talking about infusing it into people\'s
arms. So, I would ask you all to keep that in mind as we make this
decision.

I wouldn\'t make a decision that France is not willing to make
themselves, and if they are deferring then I think we have to hold that
line.

I think we got a model of a risk assessment tool, and I think we ought
to use it, at least try to use it, or try to get information so that we
can use it, before we start opening up the doors.

And then, I guess my final comment would be, is to think about that
person on the end if we are wrong, and what we tell them, or what we
have done to protect them. Are the blood banks talking about labeling
blood or notifying that patient that you are getting European blood, or
are they simply saying we are going to give you blood, and you are not
going to know?

And, I think that regardless of whether we get to make that decision at
this Committee that has to be part of our thoughts, because once we make
this decision it will be very difficult to reverse.

This is my fourth or fifth meeting, and at every one of these meetings
I\'ve heard the appeal from the blood collection industry to reduce the
deferrals, to open up the gates because of the lack of cases, and every
time I\'ve heard the science say to us over and over again that we have
one, two, three, four uncertainties that we\'re all concerned about,
that we just don\'t know the answer to yet.

So, I would actually consider that as we make this vote, not taking one
side or the other, but there are people here to be considered, and I
would ask the Committee to consider that.

CHAIRPERSON PRIOLA: Doctor Rohwer, do you have a comment?

DOCTOR ROHWER: Yeah, thanks.

I would like to have this opportunity to stir this up a little bit more.

I think the science behind deferring transfusion recipients is just
about the smartest thing you can do scientifically, and let me give you
the arguments.

Let me remind you that we have iatrogenic transmissions of this disease,
at least 250 of them are known from human growth hormone and dura mater,
so that\'s a fact, it does happen. And, the largest exposure that we
have to human-derived tissues is probably through the blood supply and
the use of blood.

This use of human-derived tissues is as close as we come to an analogous
situation to what happened to BSE in cows. There we had a disease that
was being recycled in that population for probably a decade at least
before the first case was recognized. It\'s now estimated that there
were probably somewhere like 100,000 animals that were already infected
by 1985, that then showed up in that peak that we saw six, seven years
later.

And so, the risk from these diseases is really the risk ? the public
health risk from them, and I\'m talking about a population risk more
than an individual risk, from the silent propagation of an infection
with a very long incubation time, that doesn\'t reveal itself in
symptoms until the last moments of the disease.

We also have heard today, or just since ? during this last year, that
the prevalence of this disease may be much higher than we had ever
expected from the tonsil/appendix survey, and something that hasn\'t
come up today, but that has concerned me considerably about that study,
is we have no idea what the ascertainment rate is for those tissues. It
can\'t possibly be 100 percent, and we know that it\'s imperfect because
the second transfusion case had neither an appendix or a tonsil signal,
they found it in the spleen.

So, we are not getting them all that way, and we have no idea whether we
are getting 1 percent, 10 percent, or whatever.

We also have all this new data about infectivity in muscles, which is
extremely alarming to me personally, because it suggests that we may
have completely underestimated the exposure. It may have been much
greater than we actually thought. It didn\'t come, necessarily, just
from SBOs and MRM and things like that.

So, and finally, we have these two transfusion transmissions that have
already occurred, and this is giving us a warning that we may be on the
same path to iatrogenic transmission that we saw with, you know, in 1985
there was one case of human growth hormone transmission as well. Now,
we\'ve got 150 or something like that on the books.

Finally, let\'s consider what has worked in terms of the management of
these diseases. We have a proven management method in the feed ban that
was implemented in Great Britain. It took an epidemic that was expanding
exponentially and stopped it in its tracks over about a four or
five-year period. We are down, we heard down, down to 80 or something
cases a year in Great Britain, from a high of 1,000 cases a week in
1993, I think, 1992, and that\'s amazingly effective.

The only analogous tool that we have right now for doing the same thing
with these transfusion ? with a potential for transfusion transmitted
infections, is to defer transfusion recipients. It doesn\'t prevent a
person from getting the disease from having been in the United Kingdom,
or Europe, or something like that, but it does prevent the propagation
of the disease, if, in fact, that\'s an issue, and we just don\'t know.

So, it is precautionary in that sense, but in terms of the science it
seems to me, and always has seemed to me, that this is absolutely the
most effective thing you could do to prevent a ? to stop an incipient
epidemic that may be incubating in our midst from going anywhere.

CHAIRPERSON PRIOLA: Thank you, Doctor Rohwer.

Any other comments from the Committee?

I\'m not sensing consensus in the Committee either way, so should we
take a vote and see how people stand on this issue?

DOCTOR DeARMOND: An unofficial vote.

DOCTOR JOHNSON: How about a motion to vote?

CHAIRPERSON PRIOLA: Well, I don\'t know if ? well, yeah, we can have a
motion to vote.

DOCTOR JOHNSON: So moved.

EXECUTIVE SECRETARY FREAS: We don\'t need a motion.

CHAIRPERSON PRIOLA: Yeah, I guess my comment would be that if you vote
and then you have to reverse, then you are not sure enough to vote yet
about how you want to do this, you know, whether you want to vote for
deferral or not for deferral in France and/or other European countries.

So, should we take a vote? Let\'s go around and vote.

EXECUTIVE SECRETARY FREAS: This will be an official vote, and there are
16 voting members at the table, and, of course, at the end we\'ll ask
the industry for their recommendation.

I\'m going to start with you, Doctor Schonberger.

DOCTOR SCHONBERGER: In agree with the argument that Doctor DiMichele put
forward, and I vote for the deferment of people from France for
donations of blood.

EXECUTIVE SECRETARY FREAS: Next, Doctor Hogan?

DOCTOR HOGAN: I\'m going to vote for it, but I\'m concerned about how
much everyone said, how much really we are significantly decreasing the
risk. However, I\'m compelled by Doctor Rohwer\'s argument, and that\'s
that we have to be extremely cautious.

EXECUTIVE SECRETARY FREAS: Doctor Bracey?

DOCTOR BRACEY: I\'ll vote against the exclusion.

EXECUTIVE SECRETARY FREAS: Doctor Jenny?

DOCTOR JENNY: I\'ll vote for it, but I still have concerns about that we
don\'t have enough information. I would have been ? the person from
France that was to be here, I think, could have helped this discussion a
lot.

EXECUTIVE SECRETARY FREAS: Doctor Gaylor?

DOCTOR GAYLOR: May I abstain?

EXECUTIVE SECRETARY FREAS: Yes, you may abstain, yes.

Doctor Nemo?

DOCTOR NEMO: In vote for.

EXECUTIVE SECRETARY FREAS: Doctor Johnson?

DOCTOR JOHNSON: Aye.

EXECUTIVE SECRETARY FREAS: Doctor Allen?

DOCTOR ALLEN: Yes, but not strongly.

EXECUTIVE SECRETARY FREAS: Doctor Priola?

CHAIRPERSON PRIOLA: In vote no.

EXECUTIVE SECRETARY FREAS: Doctor Telling?

DOCTOR TELLING: I have no concern for voting for the deferment.

EXECUTIVE SECRETARY FREAS: Mr. Bias?

MR. BIAS: I vote for.

AUDIENCE: What was your vote?

DOCTOR TELLING: I voted for the deferment with no concerns.

MR. BIAS: I vote for the deferment.

EXECUTIVE SECRETARY FREAS: Doctor Creekmore?

DOCTOR CREEKMORE: In vote for.

EXECUTIVE SECRETARY FREAS: Doctor DeArmond?

DOCTOR DeARMOND: We\'re talking about a small number of people that
would be affected. France defers them, and I like Val Bias\' argument
that we have to consider the patient receiving transfusions, and they
are the second largest number, they have the second largest number of
vCJD cases, so I vote for.

EXECUTIVE SECRETARY FREAS: Doctor Belay?

DOCTOR BELAY: I vote yes for the deferment.

EXECUTIVE SECRETARY FREAS: Doctor Salman?

DOCTOR SALMAN: I vote against it.

EXECUTIVE SECRETARY FREAS: Doctor DiMichele?

DOCTOR DiMICHELE: In vote for it, and continue to urge, though, that we
continue to evaluate every decision.

EXECUTIVE SECRETARY FREAS: May we get the industry opinion?

DOCTOR PETTEWAY: In think the decision in October is still the correct
one, I vote no.

EXECUTIVE SECRETARY FREAS: Okay, that was an opinion, not a vote, for
point of clarification.

So, we have two no votes, one abstention and the rest were for the
deferral.

Oops, my math is not that good, it\'s three no votes, one abstention,
and that should leave 12 yes votes.

CHAIRPERSON PRIOLA: Let\'s move on to the second part of the question,
should we recommend deferral of blood donors transfused since 1980 in
other countries of Europe?

So, let\'s go around and vote on the second part of the question then.

EXECUTIVE SECRETARY FREAS: Going around the table the same way, Doctor
Schonberger?

DOCTOR SCHONBERGER: No.

EXECUTIVE SECRETARY FREAS: Doctor Hogan?

DOCTOR HOGAN: No deferral.

EXECUTIVE SECRETARY FREAS: Doctor Bracey?

DOCTOR BRACEY: No.

EXECUTIVE SECRETARY FREAS: Doctor Jenny?

DOCTOR JENNY: No.

EXECUTIVE SECRETARY FREAS: Doctor Gaylor?

DOCTOR GAYLOR: No.

EXECUTIVE SECRETARY FREAS: Doctor Nemo?

DOCTOR NEMO: No.

EXECUTIVE SECRETARY FREAS: Doctor Johnson?

DOCTOR JOHNSON: No.

EXECUTIVE SECRETARY FREAS: Doctor Allen?

DOCTOR ALLEN: No.

EXECUTIVE SECRETARY FREAS: Doctor Priola?

CHAIRPERSON PRIOLA: No.

EXECUTIVE SECRETARY FREAS: Doctor Telling?

DOCTOR TELLING: I vote no, but with the caveat that I\'m concerned about
the increased rise in cases in Switzerland, which has the second highest
incidence of BSE in Europe, and the fact that new variant CJD may
manifest in more than one molecular form.

EXECUTIVE SECRETARY FREAS: Mr. Bias?

MR. BIAS: I\'m going to abstain.

EXECUTIVE SECRETARY FREAS: Doctor Creekmore?

DOCTOR CREEKMORE: No, with the comment, though, that I think we should
remain vigilant, we should be continuing to investigate that situation,
and consider using this risk analysis tool for both continuing to look
at these other countries and also, as has been mentioned before, as we
get down the road making decisions about changing policies we\'ve
already made.

EXECUTIVE SECRETARY FREAS: Doctor DeArmond?

DOCTOR DeARMOND: No, but with the same caveats that Glenn and Lynne had.

EXECUTIVE SECRETARY FREAS: Doctor Belay?

DOCTOR BELAY: No.

EXECUTIVE SECRETARY FREAS: Doctor Salman?

DOCTOR SALMAN: No.

EXECUTIVE SECRETARY FREAS: Doctor DiMichele?

DOCTOR DiMICHELE: No, with ? and I concur with careful reevaluation.

EXECUTIVE SECRETARY FREAS: And, industry\'s recommendation?

DOCTOR PETTEWAY: No.

EXECUTIVE SECRETARY FREAS: Okay.

We have one person abstained, and then it was unanimous no votes with
caveats.

CHAIRPERSON PRIOLA: Okay.

So, we can move on to the second question, which is, based upon the
available scientific information, does the Committee recommend deferral
of source plasma donors transfused since 1980 in France or in other
countries of Europe, and I guess this is with the caveat that there is
probably some degree of TSE clearance in sourced plasma products.

Discussion from the Committee, comments?

Doctor DeArmond?

DOCTOR DeARMOND: As I recall, or I can\'t remember the details, of where
plasma byproducts are obtained. Are they mostly from industry in Europe,
or do we have a large industry here? As I recall, it\'s mostly European,
but I don\'t remember.

CHAIRPERSON PRIOLA: Doctor Petteway, do you want to comment?

DOCTOR PETTEWAY: By byproducts, you mean where is the plasma obtained
for U.S. products? It\'s U.S. plasma.

DOCTOR DeARMOND: And, where is it processed into the sub-fractions?

DOCTOR PETTEWAY: It depends on the company, yes.

CHAIRPERSON PRIOLA: But, the source of it all is U.S. blood.

Doctor Allen?

DOCTOR ALLEN: I\'m concerned by the degree to which it\'s believed that
the prion infectivity is in plasma, I think the figure that was
mentioned was about 50 percent.

On the other hand, the processing seems to clear, and if one looks at
the epidemiological data that has been cited several times,
particularly, within England and looking at the absence of any apparent
cases in people who have received regular infusions of clotting factor
and other products, you know, I\'m convinced that it seems as though the
risk is within acceptable limits at the present time, and I\'m assuming
the FDA will, of course, continue to monitor the situation carefully.

CHAIRPERSON PRIOLA: Doctor DiMichele?

DOCTOR DiMICHELE: In would just like to ask a question for
clarification.

I think I understand that all of the deferrals so far for transfusion
and for other reasons for the blood product industry also applies to
source plasma, except for the clarification of greater than or equal to
five years residence, travel in Europe, applying only to France for
source plasma, is that correct?

CHAIRPERSON PRIOLA: In believe so. Would someone from ? Doctor Williams
will answer that.

DOCTOR WILLIAMS: Yes, that is correct.

DOCTOR DiMICHELE: That is correct?

DOCTOR WILLIAMS: That is correct.

DOCTOR DiMICHELE: Okay.

So, there\'s already a special precaution for France in source plasma
that doesn\'t apply to, from what I\'m understanding, I mean, there\'s
already a special exclusion, or in the absence of exclusion of Europe
for blood donors there is an exclusion ? no, wait a second ? there is ?
what I want to say is, is that France is out for source plasma anyway,
with respect to five years of residence and travel, I think, from what
I\'m understanding here then.

So, there has already been sort of a caution relating to France already.

Am I reading this correctly?

AUDIENCE: Yes.

DOCTOR DiMICHELE: Yes, okay.

So, I would have to say that, you know, this is a tough question,
because I think that the epidemiology of it isn\'t quite clear. In one
way we are being told that certainly source plasma donors are the
younger donors, they are the ones we have to worry about with new
variant CJD by and large, rather than the older donors. We know that 58
percent of the CJD is in plasma, so we can\'t say that plasma is not a
source of concern.

By the same token, most of it is going into plasma derivatives, you
know, and, you know, we are a little less concerned about plasma
derivatives.

On the other hand, I would have to say that there\'s already a caution
for France, so I would have to say that this would have to be considered
seriously.

CHAIRPERSON PRIOLA: Other comments from Committee members?

If there are no other comments or questions, should we take a vote on
this second issue then? Okay, let\'s do that.

EXECUTIVE SECRETARY FREAS: Same order?

CHAIRPERSON PRIOLA: Let\'s reverse the order, so that Steve doesn\'t
have to wait so long.

DOCTOR PETTEWAY: Appreciate that, I vote no for both A and B.

EXECUTIVE SECRETARY FREAS: Okay.

Doctor DiMichele?

DOCTOR DiMICHELE: In don\'t think I quite answered my own question yet.
Oh, gee, I don\'t know that I\'m ready for this vote, if I have to ?

EXECUTIVE SECRETARY FREAS: You may pass and we\'ll come back and get
you.

DOCTOR DiMICHELE: Okay, well, yeah, I think I have to abstain, because
I\'m just not sure.

EXECUTIVE SECRETARY FREAS: Doctor Salman?

DOCTOR SALMAN: No.

EXECUTIVE SECRETARY FREAS: Doctor Belay?

DOCTOR BELAY: I vote yes.

EXECUTIVE SECRETARY FREAS: Doctor DeArmond?

DOCTOR DeARMOND: Well, based on the epidemiology I\'d have to say no.

EXECUTIVE SECRETARY FREAS: Doctor Creekmore?

DOCTOR CREEKMORE: I\'d like to pass.

EXECUTIVE SECRETARY FREAS: That\'s an abstain.

DOCTOR CREEKMORE: Or abstain.

EXECUTIVE SECRETARY FREAS: Okay. If it was a pass we\'d come back and
get you.

Mr. Bias?

MR. BIAS: Can you state the question one more time?

CHAIRPERSON PRIOLA: It\'s, based upon the available scientific
information does the Committee recommend deferral of source plasma
donors transfused since 1980 in France?

MR. BIAS: Yes.

EXECUTIVE SECRETARY FREAS: Doctor Telling?

DOCTOR TELLING: Yes.

EXECUTIVE SECRETARY FREAS: I\'m sorry, Mr. Bias, your answer was?

MR. BIAS: Yes.

EXECUTIVE SECRETARY FREAS: Okay.

And, Doctor Telling, yours was yes, too.

Doctor Priola?

CHAIRPERSON PRIOLA: No.

EXECUTIVE SECRETARY FREAS: Doctor Allen?

DOCTOR ALLEN: No.

EXECUTIVE SECRETARY FREAS: Doctor Johnson?

DOCTOR JOHNSON: Yes.

EXECUTIVE SECRETARY FREAS: Doctor Nemo?

DOCTOR NEMO: No.

EXECUTIVE SECRETARY FREAS: Doctor Gaylor?

DOCTOR GAYLOR: In abstain.

EXECUTIVE SECRETARY FREAS: Doctor Jenny?

DOCTOR JENNY: Abstain.

EXECUTIVE SECRETARY FREAS: Doctor Bracey?

DOCTOR BRACEY: No.

EXECUTIVE SECRETARY FREAS: Doctor Hogan?

DOCTOR HOGAN: No.

EXECUTIVE SECRETARY FREAS: Doctor Schonberger?

DOCTOR SCHONBERGER: Yes.

EXECUTIVE SECRETARY FREAS: My count, five yes votes, four abstain, and
the rest would be no votes.

The yes votes were Doctor Schonberger, Doctor Johnson, Doctor Telling,
Mr. Bias and Doctor Belay.

There are 16 people voting, so it\'s 5-7-4.

CHAIRPERSON PRIOLA: Yes, so seven no.

EXECUTIVE SECRETARY FREAS: Seven no.

CHAIRPERSON PRIOLA: Five yes, seven no, four abstain.

As to the second part of the question, deferral for source plasma donors
transfused since 1980 in other countries of Europe.

DOCTOR PETTEWAY: No.

Oh, Doctor Petteway already voted.

EXECUTIVE SECRETARY FREAS: Okay.

DOCTOR DiMICHELE: No.

EXECUTIVE SECRETARY FREAS: Doctor Salman?

DOCTOR SALMAN: No.

EXECUTIVE SECRETARY FREAS: Mr. Belay ? Doctor Belay?

DOCTOR BELAY: No.

EXECUTIVE SECRETARY FREAS: Doctor DeArmond?

DOCTOR DeARMOND: Using Doctor Schonberger\'s epidemiology argument, I
still say no.

EXECUTIVE SECRETARY FREAS: Doctor Creekmore?

DOCTOR CREEKMORE: No.

EXECUTIVE SECRETARY FREAS: Mr. Bias?

MR. BIAS: No.

EXECUTIVE SECRETARY FREAS: Doctor Telling?

DOCTOR TELLING: No.

EXECUTIVE SECRETARY FREAS: Doctor Priola?

CHAIRPERSON PRIOLA: No.

EXECUTIVE SECRETARY FREAS: Doctor Allen?

DOCTOR ALLEN: No.

EXECUTIVE SECRETARY FREAS: Doctor Johnson?

DOCTOR JOHNSON: No.

EXECUTIVE SECRETARY FREAS: Doctor Nemo?

DOCTOR NEMO: No.

EXECUTIVE SECRETARY FREAS: Doctor Gaylor?

DOCTOR GAYLOR: No.

EXECUTIVE SECRETARY FREAS: Doctor Jenny?

DOCTOR JENNY: No.

EXECUTIVE SECRETARY FREAS: Doctor Bracey?

DOCTOR BRACEY: No.

EXECUTIVE SECRETARY FREAS: Doctor Hogan?

DOCTOR HOGAN: No.

EXECUTIVE SECRETARY FREAS: Doctor Schonberger?

DOCTOR SCHONBERGER: No.

EXECUTIVE SECRETARY FREAS: Unanimous no.

CHAIRPERSON PRIOLA: Okay.

With that, that concludes the meeting. I appreciate everybody\'s
efforts. These were not easy questions.

Thank you all for being here, and I\'d like to thank all our speakers,
especially the speakers from the U.K. Their input was greatly
appreciated.

(Whereupon, the above-entitled matter was concluded at 5:49 p.m.)