U.S. FOOD AND DRUG ADMINISTRATION

CENTER FOR BIOLOGICAL EVALUATION AND RESEARCH

TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHIES ADVISORY COMMITTEE

16^th^ MEETING

THURSDAY,

OCTOBER 14, 2004

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

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

[PRESENT]{.underline}:

SUZETTE A. PRIOLA, Ph.D., Chairperson

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

JOHN C. BAILAR III, M.D., Ph.D., 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., Member

[PRESENT (Continued)]{.underline}:

PIERLUIGI GAMBETTI, M.D., Member

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

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

RICHARD T. JOHNSON, M.D., Member

FLORENCE KRANITZ, Acting Consumer Representative

KENRAD E. NELSON, M.D., Temporary Voting Member

STEPHEN R. PETTEWAY, Non-Voting Industry Representative

MO SALMAN, B.V.M.S., M.P.V.M., Ph.D., D.A.C.V.P.M., F.A.C.E., Temporary
Voting Member

JAMES J. SEJVAR, M.D., Temporary Voting Member

WILLIAM FREAS, Ph.D., Executive Secretary

[FDA REPRESENTATIVES]{.underline}:

DAVID ASHER, M.D.

STEVEN ANDERSON, Ph.D., MPP

JAY S. EPSTEIN, M.D.

JESSE L. GOODMAN, M.D., MPH

DOROTHY SCOTT, M.D.

ALAN E. WILLIAMS, Ph.D.

[INVITED SPEAKERS]{.underline}:

HENRY BARON, M.D.

LAWRENCE ELSKEN, D.V.M.

[INVITED SPEAKERS (Continued)]{.underline}:

LISA FERGUSON, D.V.M.

PETER GANZ, Ph.D.

LUISA GREGORI, Ph.D.

BURT PRITCHETT, D.V.M.

ROBERT G. WILL, M.D.

[C O N T E N T S]{.underline}

Introductions 6

Conflict of Interest Statement 9

Presentation of Plaques to Retiring Committee

Members 14

Presentation of Lawrence Elsken, D.V.M. 15

Presentation of Lisa Ferguson, D.V.M. 24

Presentation of Burt Pritchett, D.V.M. 37

Public Comments:

Dr. Steve Figard 64

Dr. Alan Rudolph 71

Dr. Johanna Bergmann 78

Dr. Quentin J. Tonelli 82

Dr. Stuart Wilson 87

Dave Cavenaugh 94

Presentation of Dorothy Scott, M.D. 100

Presentation by Henry Baron, M.D. 109

Presumptive Transfusion Transmissions of vCJD:

Consideration of Current FDA Recommended

Safeguards

David Asher, M.D. 118

Changes in Canadian CJD/vCJD Blood Safety

Policies, Peter Ganz, Ph.D.,

HealthCanada 186

Current Safeguards for Blood Products

Recommended by FDA, Dorothy Scott,

M.D., OBRR/CBER 198

Possible Effects of Prior CJD-Related Blood

Donor Deferrals on Blood Supply,

Alan Williams, Ph.D., OBRR/CBER 202

Questions for Speakers 218

[C O N T E N T S]{.underline}

OPEN PUBLIC HEARING 227

Presenters:

Peter Page, M.D., American Red Cross 228

Michael Fitzpatrick, M.D., America\'s 234

Blood Centers

Robert Rohwer, M.D., VA Medical Center, 240 Baltimore

Merlin Sayers, M.D., Carter Blood Care 248

Jonathan Goldsmith, M.D., Immune

Deficiency Foundation 253

Questions to the Committee 254

Committee Discussion and Vote 255

Adjourn 287

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

(8:08 a.m.)

DR. FREAS: Good morning. Again, if you\'d take your seats, we\'d like to
get started.

The reason why I\'m trying to move this meeting along is some of you
watched TV last night and knew that you didn\'t necessarily have to
answer questions. However, of our Advisory Committee members we won\'t
let them go home until they give us full and complete answers to every
question we ask.

Good morning. I would like to welcome everybody here. This is the 16th
meeting of the Transmissible Spongiform Encephalopathies Advisory
Committee.

I am Bill Freas. I\'m the Executive Secretary of this committee.

The entire proceedings today will be open to the public, and we welcome
public comment during our open public hearing sessions.

I would like to introduce now the members seated at the head table, and
I\'ll start on the right-hand side of the room. That\'s the audience\'s
right-hand side.

In the first chair we have Dr. Pierluigi Gambetti, Professor and
Director, Division of Neuropathology, Case Western Reserve University.

The next chair is empty right now, but it will soon be filled by Dr.
Kenrad Nelson. Dr. Nelson is a former Chair of FDA\'s Blood Products
Advisory Committee. He is also Professor, Department of Epidemiology,
Johns Hopkins University, School of Hygiene and Public Health.

In the next char we have Dr. Allen Jenny. He\'s a pathologist from the
National Veterinary Services Laboratory, USDA, Ames, Iowa.

In the next chair we have Dr. James Sejvar, neuroepidemiologist,
Division of Viral and Ricketttsial Disease, Centers for Disease Control
and Prevention.

In the next chair we have Dr. Nick Hogan, Assistant Professor of
Ophthalmology, University of Texas, Southwestern Medical School.

In the next chair we have Mr. Val Bias, Co-chairman, Blood Safety
Working Group, National Hemophilia Foundation, Oakland, California.

In the next chair we have Dr. Stephen DeArmond, Professor, Department of
Pathology, University of California, San Francisco.

Around the corner of the table we have Dr. James Allen. Dr. Allen will
be Acting Chair of FDA\'s Blood Products Advisory Committee, and
they\'ll be holding their meeting next week, and the information for
that committee is, of course, up on the FDA Website.

Dr. Allen is also President and CEO of the American Social Health
Association.

In the next chair is the Chairman of this committee, Chairperson of this
committee, Dr. Suzette Priola, investigator, Laboratory of Persistent
and Viral Diseases, Rocky Mountain Laboratories.

Next we have our Acting consumer representative, Ms. Florence Kranitz.
She\'s President and founder of the CJD Foundation, Akron, Ohio.

Next we have Dr. John Bailar, Professor Emeritus, Department of Health
Studies, University of Chicago.

Next we have Dr. Lynn Creekmore, staff veterinarian, APHIS Veterinary
Services, USDA, Fort Collins, Colorado.

Next we have Dr. Mo Salman, Professor and Director, Animal Population
Health Institute, College of Veterinary Medicine, Colorado State
University.

Next we have Dr. Arthur Bracey, Associate Chief of Pathology, St.
Luke\'s Episcopal Hospital, Houston, Texas.

Next we have Dr. Richard Johnson, Professor of Neurology, Johns Hopkins
University.

At the end of the table, we have our non-voting industry representative,
Dr. Stephen Petteway, Director of Pathogen Safety and Research, Bayer
Corporation.

I would like to welcome everyone for attending this meeting this
morning.

I would now like to read into the record the conflict of interest
statement required for this meeting.

The following announcement is made part of the public record to preclude
even the appearance of a conflict interest at this meeting. Pursuant to
the authority granted under the committee charter, the Director, Center
for Biologics Evaluation and Research, has appointed to this meeting the
following participants as temporary voting members. They are Dr. James
Allen, Allen Jenny, Kenrad Nelson, Mo Salman, James Sejvar, and Ms.
Florence Kranitz.

Based on the agenda, it has been determined that the committee will not
be providing advice on specific firms or products. 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 an d Drug Administration prepared general matters
waivers for participants who required a waiver under 18 U.S. Code 208.

Because of the general topics impact on so many entities, it is not
prudent to recite all of the potential conflicts of interest as they
apply to each member. FDA acknowledges that there may be potential
conflicts of interest, but because of the nature of the discussions
before the committee, these potential conflicts are mitigated.

We would like to note for the record that Dr. Stephen Petteway is a
non-voting industry representative for this committee acting on behalf
of regulated industry. Dr. Petteway\'s appointment is not subject to 18
U.S. Code 208. He is employed by Bayer and thus has a financial interest
in his employer and other similar firms.

In addition, in the interest of fairness, FDA is disclosing that Dr.
Petteway is a member of the Viral Safety Working Group at the Plasma
Protein Therapeutics Association.

With regards to FDA\'s invited guest speakers, the agency has determined
that the service of these speakers are essential. The following
interests are being made public to allow participants to objectively
evaluate any presentation and/or comments made by these speakers.

Dr. Lawrence Elsken is employed by the USDA Veterinary Services in Ames,
Iowa.

Dr. Lisa Ferguson is employed by the USDA Veterinary Services in
Hyattsville, Maryland.

Dr. Peter Ganz is employed by the Biologics and General Therapies,
Director of Health Products and Food Branch, Health Canada.

Dr. Luisa Gregori is employed by the Baltimore Research and Education
Foundation, a nonprofit organization. She is doing research on TSE
diagnostics and TSE removal.

Dr. Robert Will is employed by the National CJD Foundation Unit in
Western General Hospital in Edinburgh, U.K. He also consults and advises
with a firm that could be affected by the committee discussions.

In addition, there are regulated industry and other organizations
scheduled to speak at today\'s hearing. These speakers have financial
interests associated with their employer and with other regulated firms.
They were not screened for these conflicts of interest.

Members and consultants are aware of the need to exclude themselves for
discussions involving specific products or firms for which they have
been screened for conflicts of interest. Their exclusion will be so
noted in 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 upon written request by the Freedom of Information
Act.

That ends the reading of the conflict of interest statement. Before I
turn the meeting over to our Chair, I would like to ask you if you have
a cell phone, would you please check to make sure that it\'s in the
silent mode? Your neighbors would appreciate that.

Dr. Priola, I turn the meeting over to you.

CHAIRPERSON PRIOLA: Thank you, Bill.

I\'d like to welcome everybody, all the members of the committee, the
temporary voting members of the committee.

Since we have a very full schedule today and a set amount of time to get
things done, I\'d just like to begin by turning it over to Dr. Jesse
Goodman.

DR. GOODMAN: Well, good morning. I ran over here, and it\'s my pleasure
really to honor the people who have helped us on this committee because
it\'s important. Certainly CBER Advisory Committees are critical for us
in receiving expert advice, in having a public forum, and in having a
transparent process, and these kinds of tremendous public health
responsibilities I think are nowhere more obvious than with TSE and some
of the kinds of issues you consider in terms of safety of our products
here.

It is a lot of work to be on these committees and review the material.
It\'s a lot of responsibility because as we know, there\'s never an easy
answer to any of the questions we look at, and I notice the agenda
today, and I\'ve been helping to look at the materials that folks have
put together; that this is no exception. It\'s extremely challenging to
use the best science to do public health while you\'re running 40 miles
an hour at the same time and accumulating new data.

So really this morning I just want to honor those who have provided a
service to this committee, and I\'d like to ask Dr. Priola and John
Bailar, Steve Petteway, Pierluigi Gambetti, and Stephen DeArmond to come
up and join me at the microphone.

My understanding is that all of you have served for about three years on
the committee. So that is a real contribution not just to FDA, but to
the people of this country. So please join me in thanking these folks
for that and honoring them with a plaque and, I believe, a letter from
our Associate Commissioner for External Affairs, External Relations,
Sheila Walcoff.

So again, please join me in honoring these folks who have contributed so
much.

(Applause.)

(Whereupon, the plaques were distributed.)

DR. GOODMAN: So, again, thanks, everybody.

(Applause.)

DR. FREAS: We did have a photographer, and we may call you back during a
break for a picture, but the photographer apparently is not at the
correct hotel.

Thank you.

CHAIRPERSON PRIOLA: Okay. Thank you very much, Dr. Goodman.

Speaking for myself, it has been a real pleasure and privilege serving
on this committee, and I have learned a lot from doing so, and I think
that\'s true of everybody else here.

I think we should go ahead and get started with the informational
presentations. I just want to remind the committee that these are
informational presentations for our use only. It is really not a voting
topic. These aren\'t discussion topics. This is just to sort of update
the committee on the state of things in the testing world today
primarily.

So what I\'m going to do is have the speakers give their talks and save
the questions to the end in order to try to keep to time.

So our first presentation is from Dr. Lawrence Elsken from the USDA.

DR. ELSKEN: Well, good. That wasn\'t a very good start the first time
around anyway.

The relationship between license test kits and enhanced surveillance is
that the test kits are being used to increase the throughput and to
provide the enhanced surveillance that\'s ongoing at this time.

Just since I was first up, I thought I\'d briefly do the prions or
abnormally folded proteins, not a virus or bacterial. There is no known
host immune response. However, you can produce antibodies across
species. So there are polyclonal and monoclonal antibodies, which is an
essential component of the kits.

There\'s two forms of the prion protein, the normal, the PrPc on most
cells, although high concentration in neural tissue, and then the
infectious form, which is relatively resistent to disinfectant,
sterilization, and proteinases, and accumulates and kills neural cells.

There\'s at this time no effective live animal test for BSE. All the
tests currently use brain tissue, neural tissue. The first and gold
standard test is immunohistochemistry, IHC, which combines
histopathology with an antibody demonstration of the presence of a
proteinase-resistant protein.

Negative tests do not guarantee the absence of infectivity, and the
tests are not intended as a food safety test. So the histology,
immunohistochemistry is basically an ELISA where the fixed tissue is
reactive with an antibody to PrP. The tissue has been treated to remove
the proteinase susceptible normal form, and then there\'s an antibody
precipitate on the slide.

The rapid tests are in various formats, enzyme linked immunoassay,
ELISA, EIA and Western blots. The rapid tests are generally more rapid.
They are associated with occasional false positive initial reactions,
especially in the ELISA. The Western Blot test of the rapid test has a
lower throughput, is slower, and is more involved than the ELISA. It
provides another measure of confirmation that what you\'re looking at is
the infectious prion on a size basis, and it provides some information
on possible variants of BSE, and there are some recent publications on
that coming from Europe and Japan.

All of the approved tests have excellent sensitivity and specificity,
but they are only intended as screening tests, and I think I say that
twice more on upcoming slides.

The immunohistochemistry I think I\'ve already mentioned adds the
immunologic confirmation, and it can have positive results before
you\'re getting some of the classic spongiform lesions, and basically it
is our gold standard test so there can be no false positives. Again, it
can be negative and experimental inoculations. It generally requires
several days to complete the test.

And the lower section you can grossly see that the blue is the normal
and then the pink is where there is a precipitate reacting with the
abnormal protein.

This is just to let you know, well, we\'ll let industry know and the
general scientific public and the public in general that, yes, we will
consider licenses for rapid tests for BSE as a disease of animals at the
Center for Biologics.

So a brief background on why the USDA is licensing these kits is all
veterinary biologics are regulated and reviewed and licensed by the
USDA. Veterinary biologics include diagnostic test kits intended for use
in the diagnosis of disease in animals, and just our authorizations.

So what makes a regulated test? Because we do not regulate reagents or
media or bacterial growth or things like that.

The diagnostic test kit contains all the reagents required to do the
test, complete instructions for the test, instructions to interpret the
test, and claims, uses and limitations. They\'re used to diagnose the
existence of disease usually, although there are some tests coming on to
indicate susceptibility to disease agents, and as I said, reagents are
not regulated.

Our pre-license assessment includes accuracy and precision, diagnostic
sensitivity, specificity. The ruggedness and repeatability gets into to
demonstrate that at various labs it will produce consistent results, and
in the prelicense process, you\'re generating the predictive diets
(phonetic) for the test.

So the prelicense validation involves testing large numbers of known
positives and negatives. These are general slides just on diagnostic
test kits. So there aren\'t antibody test kits for the TSEs, but just in
general this is the format that we\'re looking at companies to follow,
and the gold standard in the BSE test has been immunohistochemistry.

The problem, if you will, with the TSEs and using neural tissues is that
unlike a serologic test where you can have animals and do repeat
sampling, you only get one sampling per animal on the TSE test kits. So
we have a little bit of problem with that second point determining the
onset of detection of disease.

The manufacturing controls is to minimize within serial. So bottle to
bottle and serial to serial variation. There\'s controls on the method
of production. There\'s controls on the inputs that are used to produce
the test kits, and there\'s a serial release process that we maintain in
the USDA where each batch, lot or serial of product needs to be
submitted to the USDA for testing and then released after that testing.

And the TSE test kits licensed by the USDA are all in 100 percent
confirmatory testing. So we\'ll be testing them as long as I can see.

And the serial test panel is usually generated by the USDA for use in
these test kits by all manufacturers. So there\'s a standardization
there.

We\'re also inspecting the manufacturing facilities. We do some more
extensive prelicense testing of the serials and the seeds and the
materials that go into the product, and we review and approve all
labeling.

We have a slightly different terminology for foreign manufacturer versus
domestic manufacturer. Foreign manufacture kits are issued permits, and
there\'s a responsible U.S. party. We\'ve issued three permits for BSE
test kits to Bio-Rad, France, Abbott Laboratories for Enfer, Enfer\'s
polyclonal ELISA. That\'s the only polyclonal product of the seven that
are licensed. And the Roche is a permittee for Prionics, Switzerland.

There\'s four U.S. manufacturers that have been issued licenses. IDEXX
is an immunoassay. Pierce, which is basically producing the Prionics
kit, has sublicensing the situation. And Pierce is also manufacturing
and exporting basically the Prionics kit back to Europe as a
manufacturer.

And then VMRD in Washington State has an export only
immunohistochemistry kit. Canada evaluated that and reported on that a
few years ago.

Okay. So for the format of the technique, all use obex tissue. You
purify the normal or abnormal, and abnormal together PrP protein.
There\'s a treatment to remove it. It\'s removed in an immunologic
sense. So it might be denatured. It might be digested with proteinase.
So that the normal PrP will not react anymore with the antibody that\'s
used as an indicator for the presence of the abnormal.

The Western Blot adds an additional step to separate protein basically
by molecular weight, transferred to nitrocellulose, and then react with
the antibody to the PrP. And then you develop the color.

Diagnostic Center development, there\'s a lot of things being done. Of
course, the ultimate goal always seems to be a \"cowside\" or an
animal-side test that will give you an answer in about a millisecond.

So this just basically has got a Website on there. If you have
additional questions or would like some more information, it\'s
available there.

The enhanced surveillance program or expanded surveillance program began
June 4th, 2004. The purpose is to determine if BSE is present in the
United States and to determine if risk management policies are adequate,
but it is for animal health and not food safety.

Guiding our decision of what animals to test, and our risk analysis has
been the experience in the European Union. As you can see, the emergency
slaughter, that EM slaughter category is about 1,000-fold more positive
animals than the healthy adult cattle as far as percent positive on
test.

And, again, the suspect category is astronomical.

So the experience has demonstrated that targeting surveillance efforts
at certain high risk populations is the most effective way to identify
BSE. Estimates that the U.S. high risk population is about 446,000
cattle. These are further broken down into about 246,000 on-farm deaths
with unexplained causes or causes consistent with BSE in a population
that\'s consistent with the possibility of being positive for BSE.

Two hundred thousand ante-mortem condemnations, and then your highest
risk would be your foreign animal disease investigations for CNS
diseases where there\'s reason to believe in an adult cattle.

So the majority of the samples for the enhanced surveillance program are
going to be coming from nonambulatory cattle, cattle with CNS disorders,
other signs associated with BSE such as emaciation and injury, and dead
cattle.

And USDA personnel will also sample all cattle condemned on ante-mortem
inspection by USDA\'s Food Safety Inspection Service.

And the risk analysis is basically the outcome of that, is that if we
sample about 250,000 high risk cattle and no positives are found, then
we can be 99 percent confident that there were less than five positive
animals in the entire target population.

For the much more extensive background on the enhanced surveillance plan
and inferences in the risk analysis, I provided the Website.

And just to update you as to where we are as of yesterday or earlier
this week, no positive BSE test results in the enhanced surveillance
program. We did have a not negative ELISA test result that caused a bit
of a stir early on in the program.

Cumulative tests are approaching 80,000. We\'re testing well over 5,000
a week at this point. So we\'re well on track to get the 280 or so
thousand samples within the 18 month goal.

And if you want to see week-to-week updates, we\'ve provided the Website
there where those are posted.

And with that I\'m finished.

CHAIRPERSON PRIOLA: Thank you, Dr. Elsken.

Our next speaker will be a recently retired member of this committee,
Dr. Lisa Ferguson.

DR. FERGUSON: Good morning. Actually that sounds odd, \"recently
retired.\" I wish I could retire completely because there\'s so much
more I would like to do, but anyway, glad to be here this morning.

I am going to go over a bit of the world situation in regards to BSE and
what some of our response has been to that. Larry and I are also doing a
bit of a tag team on surveillance. So I will hit on, again, a few of the
high points of what we\'ve done for surveillance because we recognize
there\'s lots of questions and confusion out there about what we\'ve
been doing since June 1st and why.

So let\'s talk about the entire world situation. Just total cases,
greater than 188,000 total cases since the beginning of this entire
thing. Just a reminder that the vast majority of those are still found
in the U.K., greater than 96 percent. Actually I think it\'s closer to
97 percent.

If you want to have a fairly up to date Website that lists current
reported totals of detected disease, the OIE maintains their Website
fairly frequently, and as countries report those numbers, OIE does post
those, and that is their Website right there. You can actually get it in
English, French, or Spanish. Take your pick.

Just to show you some of the numbers, I realize this is probably a busy
slide and too tiny print for folks to see, and I just now realized also
the red print doesn\'t show up real well, does it? Anyway, down there in
the lower right-hand corner, the total U.K. cases is close to 184,000.
Compare that with all of the rest of the world, which is non-U.K., about
5,000. That is, you can see some countries stand out with higher numbers
of cases. In general terms, those are countries that found their first
cases back in the late \'80s, 1989, 1990, with a few exceptions. Some of
the European countries that first identified their cases in 2000, 2001
like Spain and Portugal, actually their numbers have climbed up fairly
quickly.

The European Union posts very detailed summaries of their test results
on an annual basis on their Website, and just to look at their summary
testing in 2003. Now, the numbers that I\'m quoting here will be for the
15 member states. Their 2003 report also does include some numbers for
the ten additional member states that have recently joined the union,
but these are just for the EU 15. So they\'ve tested close to 10 million
cattle in 2003, and of that, the vast majority were apparently normal
health cattle presented for slaughter greater than 30 months of age. So
8.7 million of that were healthy animals presented for slaughter.

Out of that, about 1,300 positive cases. But the significant point is
you compare 2003 to 2002. You can also go back and compare to 2001, but
their number of cases and their overall prevalence decrease by about 35
percent as compared to 2002.

Now, prevalence, when I\'m using that term, that\'s number of cases per
million adult animals, and that\'s detectable prevalence. So that does
demonstrate that the control measures that they have put in place do
seem to be having some effect.

And let\'s look a bit and pull out just a few countries just to do some
comparison. So the total estimated adult cattle population in the EU 15,
about 39 million. Out of that, you know, 1,300 positives. So that\'s a
prevalence of about 35 percent. Compare that to 2002, which was 53.

But you look at individual countries. The numbers are slightly
different. As you can see, let\'s look at France. With a higher cattle
population, close to 11 million, 138 positives in 2003, and their
prevalence is still decreasing.

Portugal actually is interesting. Their prevalence seems to be
increasing a bit. The U.K., prevalence continues to decrease
dramatically every year.

We talk a bit about country status and how different assessments of
country status have been done. There is a wide variety of those out
there. One of the most commonly talked about and known is the European
Union has done what they call geographical BSE risk assessments, or GBR.
This was actually initially started in 1998 under the auspices of the
Scientific Steering Committee.

They completed that initial round of assessments in 2000 still under the
SSC, and the way this methodology was set up, it categorized countries
into one of four levels, Level I being BSE is very unlikely to occur;
Level IV being BSE occurs at a high incidence.

At that point in time, the U.S. was considered GBR, Level II in 2000.

The commission requested that several reassessments be done. They
didn\'t redo all of the assessments that they did initially in 2000. I
think they are in the process of redoing quite a few more of those
primarily due to additional findings of BSE in additional European
countries and elsewhere in 2001 and later.

These recent assessments have been done not under the auspices of a
Scientific Steering Committee. That committee is no more, but it\'s now
under the auspices of the European Food Standards Agency. Hopefully I
got that right. I always get it mixed up.

Anyway, in this initial or reassessments recently, U.S., Canada and
Mexico, all of North America, has been put in Level III. South Africa
also was put into Level III. Interestingly enough, our Australian
colleagues, they remain at Level I, and I\'d encourage folks if you\'re
interested in reading some of those and doing some comparisons, it\'s
actually very interesting to see how those conclusions were reached.

You can rad their entire report. It\'s posted on their Websites.

Level III actually is BSE is likely to occur or occurs at low incidence
level.

Now, the OIE, which is the world organization for animal health, also
has guidelines for evaluating country status, and they have five
categories of countries: free, provisionally free, minimal risk, low
incidence and high incidence, and the OIE a couple of years ago offered
the opportunity for countries to submit information, and the OIE would
put together an ad hoc panel to review this information and determine if
countries could be considered free or provisionally free.

Several countries submitted information, and there were some questions,
some concerns raised with the initial assessments, and they have kind of
redone the process a bit. They did finalize that process for four of
those countries, and at last May\'s general session officially
recognized four countries as provisionally free: Argentina, Iceland,
Singapore and Uruguay.

Now, there were some countries that initially put some information in,
but pulled out of the process and didn\'t finish the process. So just to
make the point with the OIE, that is determinant on a country sending in
information and specifically requesting that that be considered.

So what has USDA-APHIS done in regards to any of these reports of
disease? Various things. Our import regulations are contained in Title
IX, Code of Federal Regulations, Parts 93 to 98. Specifically probably
of interest to this committee, Part 9418 contains what we call the BSE
restricted list. These are those lists of countries that are either
affected with BSE or that we consider to present an undue risk of BSE.

After Canada found their first case in May 2003, we did put Canada in
that list of countries affected with BSE.

In November of last year, we did publish a proposal to change this
section of the regs. along with other sections of the regs., but our
proposed rule essentially was creating another categories, a minimal
risk category of BSE. The proposal outlined import conditions for
certain animals and products from countries that would be in that
minimal risk category. We also proposed placing Canada in that category.

That comment period was open until after the first of the year. After
the finding of the case in Washington State, we let the initial comment
period expire. We then reopened that comment period this spring. It is
closed again.

We have more than 3,300 comments, some very substantive comments that
we\'re continuing to review and analyze, but this is a priority for us
to somehow finalize this regulation here in the near future.

A brief summary of the Canadian situation. As everybody knows, two
indigenous cases identified. The case in May 2003, and then the cow that
stole Christmas, the December 2003 case actually diagnosed in
Washington, but this cow was confirmed to be Canadian in origin.

They\'ve done extensive epi investigations on each of these and have
taken additional measures; as probably folks know, in June 2003, did
institute SRM removal in the human food chain.

They have had a feed ban in place since 1997 essentially the same as
ours and put in place at the same time. As we are, they are also
considering additional animal feed restrictions at this point.

They have instituted increased surveillance. As we have done, their
surveillance has traditionally been targeted at high risk animals, and
their goal is to obtain 8,000 samples here in 2004, and they\'re ramping
up their surveillance and hope to then obtain about 30,000 samples in
2005.

And with comparing adult cattle populations essentially it would be
considered equivalent to the efforts that we\'re trying to do. They are
on track for their goal in 2004 with more than 6,300 samples today.

The committee has heard a lot of this information back in February, but
just to summarize again, actions that our colleagues in FSIS have taken
for public health preventive measures in response to the North American
situation. These were all published in the [Federal
Register]{.underline} in January 12th as interim final rules or as
policy notices.

Essentially, prohibit nonambulatory, disabled animals for human
consumption. These animals are contemned on ante mortem inspection.
Specified risk materials prohibited from the human food chain.
Mechanically separated meat prohibited from human food and also have
additional process controls on advanced meat recovery product, and if
samples are taken from animals presented for inspection for our BSE
surveillance, that carcass is not passed for inspection until negative
test results are received.

And then just to hit a few high points again, on our surveillance plan,
I can\'t stand not to talk about it. As Larry has said, our goal is
obtain as many samples as possible from the targeted high risk
population in a 12 to 18 month period. We did get started on June 1st,
and we are targeting the population where disease is most likely to be
diagnosed, and this is the most efficient way to find the disease if it
is present in the U.S.

Our assumption is if we can\'t find disease in this targeted population
or the most likely population, we would be even more unlikely to find it
in the non-targeted population or the healthy animal population.

We will be able hopefully to use the data that we obtained to
extrapolate the information to the broader cattle population. There are
several different ways to do that. We\'re looking at lots of different
options to be able to do that, but what we can take is, okay, the
statistic that Larry quoted: if we get 268,000 samples, we\'ll be able
to say, okay, in this targeted high risk population, that means there\'s
no more than five cases in that population. Then we can extrapolate that
to the broader either adult cattle population or entire cattle
population, depending on how you want to do it.

Just again a summary of what our targeted population is and those
entities that we\'re working with to obtain this. I would like to
emphasize there still seems to be a lot of confusion out there that
people think an inspected slaughterhouse is the only place where we can
have access to these animals.

There are lots of the animal disposal chain with rendering facilities,
dead stock facilities, non-inspected slaughter facilities, salvage
slaughter facilities. We\'ve been working with these type of facilities
all the way along, and that\'s where our targeted population generally
shows up. These are the animals. They\'re not clinically normal,
apparently healthy looking animals.

So we\'re working with these other facilities. These are nonambulatory
animals, animals that die on the farm for unexplained reasons, any type
of field central nervous system cases or on-farm suspects.

We work with veterinary diagnostic labs as they get odd neurological
cases, other cases that might fit a clinical picture, working with the
public health laboratories. As they get rabies negative samples, they
can forward those tissues on to us, and then as Larry mentioned, we are
working with our colleagues in FSIS and all the animals that are
contemned on ante mortem and slaughter are sampled.

Just to emphasize where we\'ve been in the past and where we are now,
these are summary charts through the end of May of this year, and the
past two years we are looking at approximately 20,000 samples a year. Up
through May of this fiscal year we had a bit more than 17,000 samples.

Just to show you what populations those were coming from in the past,
primarily dead stock downers. The yellow line are the total samples. The
purplish line were those nonambulatory animals, and the blue line were
dead stock.

Just our numbers again. Total numbers conducted since the start of June
through October 10th. All of these have had negative results. We did
have two inconclusives on the rapid screening tests. If they get a
reactive test, those samples are immediately forwarded to our National
Veterinary Services Laboratory for confirmatory testing. They are deemed
to be inconclusive on that initial rapid screening test.

Confirmatory testing is done then with immunohistochemistry or Western
Blot, depending on what type of tissue we have.

And just to show you our graph that shows we are making progress, these
are tests conducted per week. What we\'ve tried to project is to reach
our goal we need to be at about 5,000 samples a week at a sustained
level, and we\'ve been at that level with a little minor glitch there
over holiday weekends since essentially the first part of October.

So we feel like we\'re doing really pretty good, and we\'re on track to
meet our goal, and hopefully we\'ll have some very good data to analyze
here in about a year.

We do have lots of information up on our Website. I\'d encourage folks
to read through that, and if you\'ve got questions, let us know.

Thank you very much.

CHAIRPERSON PRIOLA: Okay. Thank you, Dr. Ferguson.

The last speaker for this informational portion will be Dr. Pritchett.

DR. PRITCHETT: Good morning. I\'m Burt Pritchett with the Division of
Animal Feeds and FDA\'s Center for Veterinary Medicine.

Before I update the committee on the status of our efforts to strengthen
the BSE feed regulation, I would like to just briefly review the feed
ban that is currently in place.

The current feed ban went into effect in 1997. It prohibits feeding
mammalian protein with some exceptions to ruminant animals. Those are
exceptions are blood and blood products, milk and milk products,
gelatin, porcine or equine material that has been obtained from a single
species slaughter facility, and plate waste.

In addition to prohibiting the use of mammalian protein and ruminant
feed, the regulation requires that those firms that handle prohibited
material and also make ruminant feed for feed ingredients intended for
ruminants, either maintain separate equipment or facilities or else use
clean-out procedures adequate to prevent cross-contamination.

It requires that records be maintained sufficient to track prohibited
material throughout receipt, processing, and distribution, and it
requires that products that contain prohibited material be labeled with
a caution statement \"do not fee to cattle or other ruminants.\"

FDA\'s latest action to strengthen the feed ban was to publish an
advanced notice of proposed rulemaking jointly with SUDA on July 14th,
2004. In the ANPRM FDA announced its intention to propose banning SRMs
from animal feed.

FDA also asked for public comment on feed controls recommended by the
international review team. This is the subcommittee of the international
BSE experts convened by the Secretaries, Foreign Animal and Poultry
Disease Advisory Committee, and we ask for comments on other new feed
control measures being considered by FDA.

The comment period for FDA\'s questions closed on August 13th. The feed
controls recommended by the international review team were that, one,
all SRM should be excluded from all animal feed, including pet food;
that cross-contamination should be prevented throughout the feed chain,
including transportation and on the farm; and that the current feed ban
should be extended to exclude all mammalian and poultry protein from all
ruminant feed.

With respect to a ban on SRMs in animal feed, FDA asked for comment on
the following. Should the list of SRMs prohibited in animal feed be the
same list that\'s now prohibited in human food?

What portion of the intestine should be considered SRM?

What are the economic and environmental impacts of an SRM ban?

And what methods can be used to mark materials that contain SRMs and
what methods can be used to verify non-feed disposal?

Dead stock and nonambulatory, disabled cattle, also known as downers,
are among the highest risk cattle population. So an SRM ban would
exclude these two categories from being rendered for us in animal feed.

In the ANPRM, FDA asked for information on the economic and
environmental impact of banning deads and downers. We asked if SRMs can
be effectively removed from deads, and we asked what methods could be
used to verify that feed does not contain rendered material derived from
dead stock.

In addition to the information requested on SRMs, FDA asked what the
risk reduction would be and what the economic and environmental impacts
would be of other new feed measures being considered. These other
measures include requiring that equipment and facilities used to handle
prohibited material be dedicated to the production of non-ruminant feed;
removing the exemptions in the current feed ban for blood and plate
waste; prohibiting the use of poultry litter in ruminant feed.

We asked if tallow derived from rendering SRMs and dead stock poses a
significant BSE risk, if the insoluble impurities level is less than
0.15 percent, and we asked what would be the risk reduction and the
economic and environmental impacts of the IRT\'s recommendation to ban
all mammalian and avian meat and bone meal from ruminant feed.

FDA also asked for views on whether these other feed controls are needed
if SRMs are banned from animal feed.

As announced in the ANPRM, FDA is focusing first on a proposal to ban
SRMs from animal feed. CVM has completed review of those comments that
pertain to an SRM ban. Approximately 1,500 individuals and groups took
the time and effort to express their views and provide substantive
information which we very much appreciate.

Approximately 1,400 of those were from individuals, mostly form letters.
One hundred were from groups. These were primarily trade associations
and individual firms in the meat rendering and animal feed industries,
livestock associations, consumer groups, state Departments of
Agriculture, and other regulatory agencies.

The agency is still working on the proposed rule to remove SRMs from
animal feed, and I don\'t know what the time frame is for publication of
the proposal. Once work is done on the proposal, CVM will review the
comments that address the other beef controls being considered.

Banning SRMs from animal feed is much more complex both from a
regulatory perspective and an industry perspective than banning SRMs
from human food because it requires new infrastructure for sorting,
transportation, disposal, and regulatory oversight.

Recognizing that this infrastructure might be lacking, the international
review team said in their report that a staged approach might be
necessary for implementation.

These diagrams help illustrate the infrastructure challenges starting
here with how slaughter byproducts are currently disposed of in the U.S.
Estimates used are from the environmental assessment that accompany
FDA\'s interim final rule on use of materials derived from cattle in
human food and cosmetics.

Slaughter data from 2003 show that we slaughter 28.2 million steers and
heifers that go to slaughter at a young age, and 7.1 million older beef
and dairy cows plus a small number of bulls in the older animal
category.

Both types of slaughter combined generate about 15 billion pounds of
inedible byproducts. This material goes to inedible rendering where
it\'s rendered into fats for industrial and feed use and meat and bone
meal which is used in feed for nonruminant species.

The USDA and FDA interim final rules published in 2004 identified as
SRMs, tonsils and small intestine from young animals, and brain, skull,
eyes, trigeminal ganglia, spinal cord, and the vertebral column,
including the dorsal root ganglia, from older animals.

Excluding these tissues from human food did not substantially change the
disposal of this material and did not require new infrastructure because
the tissues are eligible to be rendered for use in feed for non-ruminant
species.

Besides the slaughter byproducts, cattle mortalities, including some of
the downers no longer eligible to go to slaughter also go to rendering.
We have some differences in the estimates here which I will explain, but
according to the estimates that FDA used in the environmental
assessment, the combined cattle mortalities from those under 30 months
of age and those over 30 months of age adds another .7 billion pounds of
material that goes to inedible rendering.

Not all cattle mortalities are collected by the rendering industry. What
is not collected by renderers is disposed of by various other means,
mostly by on-farm burial, composting or landfill.

There is general agreement on the estimates of the number of cattle
mortalities in the U.S. However, estimates from Informa Economics,
formerly the Sparks Company, say that renderers collect around 50
percent of the mortalities rather than the 20 to 25 percent estimate
used by FDA, and that\'s indicated in the footnote there.

According to Informa estimates, an additional 500 million pounds is
rendered rather than being buried or composted on the farm or
landfilled. So using Informa estimates, about 16.2 billion pounds of
cattle mortalities go to rendering and about 1.5 billion pounds goes to
other disposal.

Assuming that an SRM ban gets proposed as a full SRM ban, we would still
have 13.5 billion pounds of inedible byproducts going to rendering for
non-ruminant feed.

I say full SRM ban because we received numerous comments suggesting that
we require removal a subset of SRM tissues to remove a percentage of the
potential infectivity at a fraction of the cost. For example, remove
about 90 percent of the infectivity by requiring removal of brain and
spinal cord only from cattle over 30 months of age.

Diverting the human list of SRMs from all animal feed will necessitate
special disposal of 1.4 billion pounds of material no longer eligible to
be rendered for animal feed. This is composed of tonsils and small
intestine weighing 28 pounds, from 28 million head or 804 million
pounds, and the longer list of SRMs from older cattle weighing 88 pounds
from 7.1 million animals for 624 million pounds.

In addition, a full SRM ban would require that the .7 billion pounds of
cattle mortalities also diverted to special disposal, assuming that the
SRM ban does not alter the proportion of deads that were disposed of by
rendering. This brings the total volume of material going to special
disposal to 2.1 billion pounds.

Options usually mentioned for non-feed disposal are landfill or
rendering for volume reduction and then landfill, incineration, alkaline
digestion, or biofuel productions.

So this is a brief overview of the challenges of putting an SRM ban in
place. There\'s a lot of work to be done, a lot of details to be worked
out before a final rule can be published and an SRM ban can be
implemented.

CHAIRPERSON PRIOLA: Okay. Thank you, Dr. Pritchett.

Are there any questions from the committee for any of the speakers this
morning: Dr. Elsken \-- yes, Dr. Bailar.

DR. BRACEY: Yes. I had a question regarding the testing. There certainly
is lots of work that has been done in terms of prelicense testing, but
in essence, having the test in the field is somewhat of a different
matter, and I assume that there is a proficiency program that actually
tests the performance of the laboratories performing the assay in the
field, and I\'d just like to get some comment on that.

DR. ELSKEN: Yes. There\'s an approval process for labs that are using
the rapid test. Actually Dr. Jenny could probably talk a lot more about
that process, but it involves proficiency panels and, you know,
procedures in place.

DR. FERGUSON: Actually before Al jumps in, I\'ll also add a few more
details. At this point we have seven state-federal labs that are working
with us. We will be bringing on an additional five labs so that we\'re
not talking a huge number of labs at this point in time.

We did initial approvals in proficiency tests in these labs. We are
doing ongoing proficiency testing. We\'re also looking at their raw
data, their OD value, just to see if there\'s anything that\'s really
funky or off the wall.

Al, do you want to add anything?

DR. JENNY: Well, yeah. We also do inspections of the labs, go visit,
check the facility, and look at their SOPs.

CHAIRPERSON PRIOLA: Dr. Gambetti, did you have a question?

DR. GAMBETTI: In one of the slides presented by Dr. Ferguson, it is
entitled \"Enhanced BSE Surveillance.\" It says all negative results,
and in parentheses two inconclusives. Apparently it sounds like that if
they were inconclusive, they couldn\'t really be called negative or
maybe I don\'t understand exactly the message here.

DR. FERGUSON: Yeah, okay. My wording probably could have been better. I
could have said all negative final results.

We did have two inconclusives on the rapid screening test with
confirmatory testing at NVSL. Those were determined to be negative.

CHAIRPERSON PRIOLA: Dr. Bailar.

DR. BAILAR: I have a question for all three speakers, especially Dr.
Ferguson, especially with respect to the international data.

Fundamentally about the quality of the data that we\'ve been hearing,
there\'s been a lot of statistical data presented, very simple data,
counts, proportions, ratios, and so forth. And I\'m wondering about a
general sense of the quality of the sampling, the testing that\'s used,
especially in other places; the possibility of covert diversion of sick
animals on the farm; even suppression of evidence.

What level of confidence can we place in the numbers we\'ve heard there?

DR. FERGUSON: I\'ll jump up and be the first victim.

I think in most instances we can have a pretty good level of confidence
in the information. I know especially the European information. They
have done quite a bit with testing, quite a bit with legislation and
mandating testing.

There are always opportunities for certain ways of diversion, but when
you set up a surveillance program, as long as you\'re maintaining access
to a wide variety of challenges or a wide variety of facilities, you
should be able to get a good idea and a good, representative sample of
whatever population you\'re looking for.

I think if you look at their numbers, especially from 2001, 2002, and
2003, they are getting a valid sample and getting, I believe, a
representative sample.

Mo is looking at me like he might have something additional to say, but
I think those numbers are very solid.

I\'ll go ahead and throw in the Japanese situation. There are always
questions about what\'s going on in Japan. I\'ll admit that we have our
own set of questions about how they have done surveillance in the past
and how they\'re continuing to do surveillance if it\'s really
meaningful or, you know, trying to get valid information about
detectable disease. They\'ve been testing everything presented at
slaughter, including veal salves and other animals, which raises
questions about how meaningful those tests would be, but they are
adjusting that and are doing more sampling in targeted, high risk
animals.

CHAIRPERSON PRIOLA: Dr. DeArmond.

DR. DeARMOND: Probably for you, again, Lisa. The question I have
concerns who is allowed to test. I don\'t understand regulations or who
can be approved. For example, can the State of California test cattle?
How would they be approved to do that, or a boutique slaughter ranch?
Could they test to assure that public that their cattle doesn\'t have,
and how could they be approved?

Is it even possible?

DR. FERGUSON: Okay. I\'ll do part of that, and then I\'ll let Larry do
part of it.

Our policy has been that testing for BSE is done under our auspices and
is done in state-federal laboratories. This is a regulatory disease, and
there are certain dramatic actions that would follow. If positives are
found, there are certain reporting requirements that are best dealt with
in a state-federal animal health regulatory situation.

And I\'ll let Larry talk about authorities on licensing.

DR. ELSKEN: Well, all of the licenses have been issued with restrictions
on distribution, and they are only allowed to be distributed to labs
that have been approved by NVSL, and we\'re inspecting and auditing
these records on an ongoing basis.

So I suppose a lab could develop their own immunohistochemistry or
histopathology, but on a statewide basis, but I don\'t know anything
about that.

DR. DeARMOND: Could I?

One other question concerns whether strains of BSE have been identified.
Is there any way of separating out BSE of Great Britain that is known to
be transmissible to human from perhaps some wild type BSE? Any data on
that or any way of \-- has anyone approached trying to sort out of that
problem?

DR. FERGUSON: There are reports of that, and I\'m sure other folks
sitting around the table can also address this. There are publications
from Europe about atypical strains that are very interesting. Actually
these do look different on a Western Blot. You have different molecular
characteristics so that you can look at that.

There are still lots of unanswered questions about whether these are
truly different strains. You know, are they the same? Are they truly
pathogenic? Are they transmissible to people? Do they cause disease even
in animals?

Those are all the unanswered questions that are still out there.

DR. DeARMOND: So basically the cases that you\'ve identified in the
Untied States, do they match the patterns for the protein as seen in
Great Britain?

DR. FERGUSON: Yeah. Actually the two cases, if you look at the blots, et
cetera, it does match the pattern in European BSE.

CHAIRPERSON PRIOLA: Hang on just a minute. Ms. Kranitz had a question.

MS. KRANITZ: I apologize if this has already been answered in Dr.
Ferguson\'s talk. I may have missed it, but my question is: what about
general random sampling of cattle not falling into the high risk area?
Is that being done?

DR. FERGUSON: No, at this point in time we\'re focusing our sampling on
the targeted high risk population, and that population where we\'re most
likely to find disease if it is present. We\'re focusing our resources
on looking in that targeted population.

CHAIRPERSON PRIOLA: Dr. Johnson.

DR. JOHNSON: Lisa, sorry to keep you on your feet.

DR. FERGUSON: Maybe I\'ll just stay up here.

DR. JOHNSON: Stay up there. That\'s right.

Now, particularly relevant to this question of alternate strains of
agent, it was particularly interesting in the Italian cases, the two
cases from which the different agent, the agent that will be a different
strain than the British BSE were from perfectly healthy cattle, but very
aged cattle, 15 and 20, as I recall, years of age. They really old, old,
retired milk cows.

And if one is looking for other strains, possible even less pathogenic
strains, are you going to target that area of looking at the healthy old
animals? You didn\'t mention that in your target population.

DR. FERGUSON: You mean are we going to target that population?

DR. JOHNSON: Yes, in the United States. That\'s right.

DR. FERGUSON: In the United States?

DR. JOHNSON: That\'s right.

DR. FERGUSON: Not at this point in time. Our goal is just to try to see,
okay, do we have disease here in the U.S., and then if we have some
positives to help put parameters around what a possible prevalence level
might be. Once we get that first cut, then we\'ll look at, okay, where
do we need to go from there.

DR. JOHNSON: It seems to me that\'s fine if you\'re looking for British
BSE. If you\'re looking to say is there other kinds of BSE that occur in
the United States, you\'re not going to answer that unless you look at
healthy older animals.

DR. FERGUSON: Well, actually we don\'t know that. There could be other
strains out there in the clinically ill older animals, which is what
we\'re looking at. You know, I don\'t know that I would necessarily lead
to the conclusion that the only way you would find, you know, these
strains as in the Italian paper are to look at 15 year old apparently
normal dairy animals. I don\'t think we have enough information to go
there just yet.

CHAIRPERSON PRIOLA: Dr. Hogan.

DR. HOGAN: I just have some simple questions. Who and how identifies the
cattle that will be tested? Is it only done by inspectors or is it
voluntary by the owners-managers?

DR. FERGUSON: Okay. Some of this gets to the point that I was trying to
make about the type of facilities that we\'re working with, and at this
point since our goal is to get samples from as many of the targeted
animals as we can, there\'s not a whole lot of a selection process going
on. So if our folks are at a rendering facility, essentially what
they\'re doing is looking to see, okay, is this animal greater than 30
months of age; is it not, and are getting a sample.

So it might be our permanent employees, APHIS employees at these
facilities. We\'ve hired a lot of temporary employees. We are working
with contractors in some instances. So it\'s a variety. It is all under
our supervision.

DR. HOGAN: How much does one of these tests cost?

DR. FERGUSON: Just the test kit and all affiliated labor and \--

DR. HOGAN: Well, like a per test cost. I\'m trying to evaluate how much
this whole program is costing. You know, is it 50 cents a test or is it
five dollars a test?

DR. FERGUSON: No, actually I\'ll just go ahead and throw out the cost
that we have used in our budget figures. For this effort we have
obtained 70 million in emergency funds. To run this effort we probably
will need some additional funds on top of that.

Now, that does pay for our personnel, equipment, et cetera. We figure
our total cost for labor, shipping, the test kit, paying the lab to run
the test is about 130 bucks a test. Just literally to the lab, we\'re
paying 12 bucks for a test kit and 12 bucks for the lab to run that kit.

DR. HOGAN: Thanks.

Last naive question. How long from the time an animal is identified
until test results are obtained?

DR. FERGUSON: With the rapid test kit we\'re getting essentially a
24-hour turnaround time. Someone is collecting samples through the day.
They pack those up, ship them off FedEx overnight. They\'re getting
results back the next afternoon.

Now, in some instances where there\'s not an issue with holding the
carcass, if that carcass has been buried, going into the landfill, et
cetera, we are still running some immunohistochemistry testing as you
saw in my slide, and that\'s not that same turnaround.

CHAIRPERSON PRIOLA: Okay. Dr. Allen.

DR. ALLEN: Let me follow up on that last question just with one brief
one, and then I\'ve got another question.

With regard to the 24-hour turnaround, I assume that that\'s with the
screening test only. If it\'s negatively, obviously that\'s easy. If
it\'s a presumptive, positive on the screening test, is the animal then
removed from the food chain?

DR. FERGUSON: Okay. Yeah, you are correct that that 24-hour turnaround
is on the rapid screening test. Let me emphasize that these animals are
not going into the, quote, food chain. These are all somehow in the
animal disposal end of the industry.

We are holding the carcasses, cold storage, whatever, somewhere, and
that carcass remains held. We do offer if we get an inconclusive on the
initial rapid screening test, we do offer the facility that will take
care of a disposal form if they don\'t want to continue to hold it, but
that is continue to hold.

If that goes forward on for inconclusive, immunohistochemistry takes
probably another four days to a week.

DR. ALLEN: A question for Dr. Pritchett and I guess in light of our
recent presidential debate, you know, maybe you can limit your response
to two minutes.

(Laughter.)

DR. ALLEN: I think this could take days of discussion.

You mentioned the economic and environmental impacts of some of the
additional animal food chain regulations if they\'re being implemented
and the infrastructure is developed and so on. A lot of different
players in here and huge economic impacts.

What are some of the different pressures that are bearing on this other
than the attempt to use scientific information to make the correct
decisions, and how do you see some of this coming out in the long term?

DR. PRITCHETT: Well, you\'re right. It would be nice to make the
decision purely on a scientific basis. However, my understanding is that
for this to go into effect, it\'s subject to review up through the
department level and then to OMB, and at that point, you know, a
decision is made on whether this rulemaking is too costly or needs to be
trimmed, some of the costs need to be trimmed.

So at that point we may be asked to reduce the cost.

DR. ALLEN: Yeah, thank you.

I think this is an area that needs a lot of open discussion and debate.
I think if you were to ask the general public, if you were to lay out
for them what all goes into or has in the past gone into animal food
products, much less the human chain when we talk about all the processed
foods and so on, I think many people would be appalled and public
response might drive some of the decisions.

You know, this issue of what\'s too costly is a total imponderable, and
the magnitude of all of this is obviously very difficult. I can\'t begin
to wrap my mind around 15 billion pounds of, you know, SRM or non-SRM
foodstuffs, animal body parts that might got into the animal food chain.
This is an area that obviously needs a lot of very, very careful
discussion and decision making.

CHAIRPERSON PRIOLA: Okay. We have a couple of final questions. Dr.
Salman.

DR. SALMAN: Yeah, this is a question to Dr. Ferguson.

If you could comment about the autolyzed samples, how is that being
tested now?

DR. FERGUSON: Okay. Autolyzed samples, actually we\'ve tried to
encourage our collectors to do their best to primarily collect viable
samples. If we get a sample that is too severely autolyzed to recognize
the tissue location, if you\'re essentially pouring it out of the tube,
we\'re considering that a no test and not running a test.

Now, if we get into a situation where we run and you have a valid sample
and you run an initial inconclusive and for some reason then when it\'s
forwarded on to NVSL for confirmatory testing, if you then have an
autolyzed sample at that point in time, we do have Western Blot testing
available to us that we can use on those types of autolyzed samples.

But for that initial cut, if you can\'t even tell where that\'s from,
we\'re not even running the test.

CHAIRPERSON PRIOLA: A last question. Dr. Bailar.

DR. BAILAR: We heard, I think, that the primary goal of the present
testing program is to find out if this agent or these agents are present
in the U.S. For that purpose, a focus on high risk animals is 100
percent appropriate, but I think that question has been answered, and
it\'s time to go on now to what I see is the second question, which is
how much.

And that question cannot be answered without testing animals that are
not perceived as being at high risk.

What are the chances of getting in some testing on a stratified sampling
plan of animals that appear to be healthy?

DR. FERGUSON: Actually, I would point out that there are ways to
extrapolate information from the targeted sampling that we\'re doing and
carry that over to a broader population. So those are different options
that we are looking at.

It can be as straightforward as just looking at ratios based on European
data and the sampling that they have done, to more complicated models,
to evaluate that and to extrapolate information from one subset of the
population to the broader population.

So all of that is still under consideration. I would also say that we
really at this point, I don\'t think we\'ve truly answered the question
whether we have the disease here or we haven\'t. That\'s what we\'re
going through this effort for. We will have pretty solid details
hopefully once the time we\'re done with this to help answer that
question.

We have given consideration to some testing of apparently normal
animals. That\'s a difficult decision to make, and it\'s a real
challenge to consider in a surveillance program. You have to look at,
okay, what is our goal, what are we trying to do.

We\'ve established our surveillance program in the most efficient, cost
effective way to get done what we want to do. We will consider other
options depending on available information and the data that we get, but
at this point in time, we\'re still focusing on a targeted high risk
population.

CHAIRPERSON PRIOLA: I think we had better move on to the open public
hearing section, but you can keep your questions in mind for later.

Bill.

DR. FREAS: As part of the FDA Advisory Committee process, we hold open
public hearings to the members of the public who are not on the agenda
who will have an opportunity to express their comments to the committee.
These include both written and oral presentations.

At this time I\'ve received three written requests for the public
record. They are in your red folders, and I have a cover sheet like
this. They\'re available on the outside table upon request, and they\'ll
also be posted on the Web shortly.

They are from a woman in the U.K. regarding a letter to her husband\'s
consultant on vCJD and questions for this meeting.

The second submission is an E-mail from Terry Singletary, and the third
submission is an E-mail from Ms. Sachau.

These letters are for your reading.

We also have five oral requests for presentations at this morning\'s
meeting. These presentations will be limited to a maximum of eight
minutes. The presenters are asked to make any statements that they have
regarding financial affiliations that they have with any products they
wish to comment upon.

The presentations will be limited to eight minutes. You have an option
if you\'re one of these speakers. You can either advance the slides
yourself up here or you can have the AV team advance the slides for you.
It\'s just when you come up to the podium, you have to let us know
whether you want to operate your own slides or whether you want to say
\"next slide,\" and have somebody advance them for you.

Dr. Priola, would you read the required statement for this meeting?

CHAIRPERSON PRIOLA: Both the Food and Drug Administration, FDA, and the
public believe in a transparent process for information gathering and
decision making. To insure 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 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.

DR. FREAS: Okay. Our first request is from Abbott Laboratories, Dr.
Figard will be the presenter.

DR. FIGARD: Good morning. My name is Steve Figard. I am an employee of
Abbott Laboratories, and I\'ve been working with Enfer Scientific out of
Ireland for the last three or so years, working with them on their
assay.

What I wanted to briefly do today is just give you an overview of how
the Enfer BSE assay works. The primary focus is on our recent work on
automating what we call the front end of the assay, which I\'ll show in
the next slide, and then give you a brief data review from an external
evaluation that\'s been ongoing in Europe at this point in time.

At this point I want to make a brief legal disclaimer. You\'ll see down
there at the bottom it says \"Enfer TSE kit.\" The kit has only been
approved in this country for BSE testing. However, it is used in Europe
for scrapie testing as well.

According to my regulatory people I have to make sure that you
understand that it\'s only used for BSE testing in this country.

Okay. You can break down the Enfer assay into four general areas. The
first is sample preparation in which the tissue, brain stem tissue is
cut. It gets put into an homogenization buffer and is homogenized, and
then that is clarified to some extent by a centrifugation on a plate.

The supernatant from that centrifugation gets transferred to a different
test plate. These are 96 well ELISA plates where the sample
simultaneously is digested by PK so that any normal prion is removed,
and then the protease resistant PrPsc get absorbed nonspecifically to
the polystyrene of the plate.

The plate then is washed with salt. It is treated with guanidine HCl and
sodium hydroxide, and this opens up the protein to allow greater access
for the antibody to subsequently come in and bind.

The immune reactions then include your standard ELISA plate reactions
with a primary polyclonal anti-PrP rabbit antibody. With the appropriate
washes in between, you then come in with a secondary HRP labeled goat
anti-rabbit IgG.

Then again, with the appropriate washing you add your substrate and read
signal, and the signal is a chemiluminescence signal.

Now, what we mean by front end automation is we\'ve addressed some of
the more labor intensive or difficult portions of the assay at the front
end of the assay, so to speak, during the sample preparation and the
initial sample treatment.

The first thing we\'ve done is I\'ll show you in the next slide how we
do the cutting, but we\'ve developed a new, safer cutting tool. We\'ve
got a new automated instrument that does homogenization much faster.
We\'ve replaced a bag with a tube that makes sample handling much
easier. We\'ve streamlined the sample process and, as I\'ll show, we
still have the same performance as we had before.

This is how it\'s currently done, and this slide gives me the
heebie-geebies every time I see it because it\'s obviously stages. The
person that is wearing these gloves doesn\'t even have the appropriate
safety gloves underneath. I assume you that in the lab both at Enfer and
whenever I\'m doing it in the R&D lab, I\'ve got the appropriate safety
gloves under there.

But we do use a razor blade, and what we have developed is this plastic
punch that works a whole lot better and certainly a lot safer, and you
simply place the punch on top of the tissue, rotate it back and forth
down through and you basically create a small plug that can then be put
into the tube.

By using or introducing this, we will be eliminating sharps. It\'s a lot
easier for disposal. The cuts are much more standardized in size and
weight. It\'s just as rapid and inexpensive as a razor blade.

Now, the plastic bag that the sample is normally put in now in the
manual assay is this bag, and there\'s this plastic mesh screen in the
middle, and you put the sample on one side, add your solubilization
buffer, and I\'ll show you in the next slide the stomacher that\'s used,
but this bag is a little bit tricky to deal with and requires a certain
amount of manual dexterity.

The new automated instrument uses this tube, and the sample is simply
dumped into this outer tube, and then this grinding shaft is placed
inside the tube. The grinding shaft at the bottom here has a surface
that will grind the material to help solubilize it. There are slits at
the bottom here that allows the solubilization buffer with the
solubilized material to go up into the center part, and then in the
automated system the fluid is withdrawn through the top of the shaft in
the middle there.

Before working on this assay, I had never heard of the stomacher, and
all this is is a machine that\'s apparently used in the food processing
industry fairly well, and it has got two paddles that you can\'t see
very well, but they\'re right in there, and they just bounce back and
forth and wallop this solution into subjection, so to speak.

(Laughter.)

DR. FIGARD: And you can get two bags into one stomacher at a time, and
it actually works fairly well, especially with soft tissue like brain
tissue.

We\'re replacing that with what we\'re calling an Enfer tissue disrupter
system, and of course, as scientists we can\'t get away without our
acronyms. So that\'s EDTS.

This will process eight samples in ten seconds. The individual tubes get
placed in the rack. They\'re set in there. You press two buttons. The
shafts come down, rotates the shaft in the tube very quickly, and you
get your solubilization of your tissue.

As compared to the stomacher, you can do two bags at a time. Each are
stomached for two minutes. So to get the same age samples takes four
minutes. So there\'s a significant saving in times with this.

You streamline the sample process in that once you put the sample in the
tube, you just basically play with the tube. You add your solubilization
buffer in the rack. You can then put it into the EDTS, and then our
final component of the automation includes this instrument, the Tecan
that we use to do automated sample pipe heading from the EDTS tube to
the centrifuge plate, and then after the centrifugation from the
centrifugation plate to the test plate.

We also use it to automate the addition of the Enfer Buffer 2, which is
our Proteinase K to the test plate, and it will take about five minutes
for one plate of 44 samples.

The EDTS rack fits \-- those eight tubes goes directly from the EDTS
right over to the Tecan and fits right in there. So there\'s no problem
with that.

We have other standard features of automation.

LGC is a lab in the U.K. that has done some of the specificity testing
for us. They had 6,894 confirmed negatives. We do test in duplicate.
We\'re dealing with an antigen that is very difficult to solubilize. So
getting a truly homogeneous suspension is not guaranteed.

In this first we had six what we call initial reactives that were
plus-minus. The rest were negative. Retesting, which is the standard
protocol, those six were double negatives, and so we had 100 percent
specificity here.

In a separate lab we had 200 positive samples from the over 30 month
population; 200 negative samples that were fallen stock and were
described as severely autolyzed.

Autolyzed samples, one of the main problems there is you can have levels
of protease inhibitors and any assay that depends upon a Proteinase K is
going to have the possibility of false positives. So autolyzed samples
in a negative population are very important to evaluate this.

The results are shown in this slide. All of the negatives were negative
down here. All of the positives were positive. So in this particular set
of samples we, again, had 100 percent sensitivity and specificity,
including the fact that we\'re having worst case negatives in the
sample, in the autolyzed.

If there\'s time for questions, I\'ll be happy to address the questions.

DR. FREAS: Unfortunately we have to move along right now and we may have
questions if time permits at the end of the open public hearing.

Our next requester is from Adlyfe, Incorporation. The presenter is Dr.
Alan Rudolph.

DR. RUDOLPH: Thank you very much. thanks to the committee for the
opportunity to speak.

Adlyfe is a new company in Rockville, Maryland. We were started by a
contract from DARPA, and we have funding from NIH as well, and we\'re
dedicated to diagnostic products for neurodegenerative diseases, and I
am currently the CEO of that company.

With regard to diagnostics for prion diseases, we have to recognize that
the aggregate nature of this protein represents some fundamental
challenges in detection of the material. These challenges are
represented both in the detection itself, as well as sample preparation
for a high hydrophobic as well as sometimes aggregated protein from
different materials.

We have developed a novel set of ligands which mirror the folding
process in which we\'re directly measuring misfolded PRP so that we
don\'t have any Proteinase K treatment, and we can directly look for the
disease in a variety of samples.

We\'re developing a kit and what we\'ll show you is the ability to
detect misfolded PrP and blood sample from positive BSE animals, which
we recently tested in the U.K.

We\'ve also done control challenge studies in hamsters and shown
ante-mortem presymptomatic detection of PrP misfolded protein in both
braining tissue and in blood samples.

The final two bullets on this slide talk about some of the issues for
the field of detection in general and our experiences over the year of
our lifetime in trying to move our product forward to the market. The
lack of controlled studies and matched samples to correlate the etiology
of disease from risk materials in these animals over the expected time
course of disease, which is relatively long, limits progress in new
diagnostics that may be ante-mortem, more sensitive, and able to detect
in blood materials.

The standardization of source materials is desperately needed to provide
accelerating testing, accelerated development of needed tests.

The principle we\'re operating on is a rather unique principle in which
we can look at the direct misfolding of PrP as it goes from a largely
alpha-helical confirmation to a folded beta-sheet confirmation, and then
subsequent aggregations of beta sheet, the typical types of plaques that
we see upon histological sections.

We\'ve created new ligands for sequence matched to regions of the
protein that undergo folding that have been tagged with fluorescent
labels that are sensitive to the position of those labels as a result of
the folding of ligands. So these small ligands associate directly with
PrP misfolded protein, fold themselves, transducing a signal associated
with the direct detection of misfolded PrP.

The sensitivity of the reaction comes through an amplification step. The
amplification step is generated by these small ligands essentially
nucleating other ligands in the solution to also fold, amplifying the
signal dramatically and giving us what I show you is sensitive
detection, enough to be able to detect it in blood plasma from BSE
positive animals.

That\'s simply read as a fluorescent shift as our ligands go from an
open alpha-helical conformer to a closed beta-sheet conformer in the
presence of PrPsc. That shift is measured in a diagnostic kit, 96-well
plate, and can be measured in standard diagnostic laboratory instruments
available in diagnostic laboratories.

This is the data that we collected this summer at the VLA in Weybridge
in U.K., with Danny Matthews. On the left in red are BSE plasma samples
from matched positive brain tissue that was 30 month and older animals
collected at the VLA, positive by Western Blot in brain, and you\'re
looking at the ratio of the fluorescence associated with our test
showing positive detection in BSE plasma.

In blue are animals that were suspect negative, Western Blot negative
and by our test also negative by BSE plasma with two notable exceptions.
In pink on either side of the blue areas are two samples that we were
given that were Western Blot negative, but came up positive in the
Adlyfe test. We then we back to the VLA, asked them to rerun the
Westerns, and they were, in fact, confirmed positive by a rerun of a
Western.

So the only two false positives we\'ve seen in our testing were then
reconfirmed as real positives.

We\'ve had considerable experience with animal testing in a variety of
animals under a variety of modes of infection. We\'ve done a number of
hamster studies in which we\'ve inoculated directly intercranially to
create disease. We have PrPsc directly in those animals at three weeks,
where typical ELISAs take nine weeks for detection, showing that we can
detect early pre-symptomatic in brain, and we have seen blood plasma in
those animals at five to six weeks positive for PrPsc.

We\'ve also done an oral gavage which mimics more closely the route of
infectivity thought to be taking place in these animals, and we have
also seen similar results in an oral gavage study in the ten-week
hamster model.

We have also done sheep scrapies in endemic populations of sheep both
from the Pullman herd, USDA, as well as the Ames, Ohio herd. In one case
of that testing we did get confirmation by the third eyelid test. These
were symptomatic animals, and in the other case we were looking at live,
on-the-hoof sheet plasmas and showing positive detection in sheep
plasma.

And then most recently expanding our testing in bovines. So we\'re up to
about 190, 200 infected animals that we\'ve looked at, and about 100
control animals, and we\'re considerably expanding our testing.

With regards to threshold of detection, we believe we\'re in the
fentomolar range. There\'s considerable historical and published data on
what kinds of levels one might expect in blood, and using that, we
believe we\'re in the fentomolar range for detection, and it has been
pointed out here already that the conventional diagnostics using
antibodies, first, don\'t distinguish between native and PrP misfolded
protein, therefore probably underestimating infective doses, and usually
operate in the picomolar range. Thus, they\'re only applied to late
stage disease in tissue samples for late stage animals.

We believe based on our testing that our testing is at least a couple of
orders of magnitude more sensitive than the current ELISA test enabling
the sensitivity for detection of blood plasma.

We\'re developing a kit that\'s a high throughput diagnostic kit. These
are sequence specific ligands. They\'re not producing antibodies. They
can be produced synthetically, and therefore, the costs can be
dramatically reduced and large scale production of components of the
test, and we are producing kits for validation and starting to work with
the appropriate agencies to look for validation and regulation of our
test both in the United States and in Europe.

So in summary, what I\'ve shown in the eight-minute slot that I had was
a more sensitive detection to PrPsc that could enable a greater
surveillance of risk materials, reducing the risk of transmission of
disease, certainly a major concern in a blood supply.

We can detect directly misfolded PrPc in risk materials. We have mostly
looked at central nervous system, brain, cortical areas. We have also
looked at blood. We have not looked as much into the spleen. We have
those samples, and we\'ll begin to analyze those as well, and those
could be good sources for early detection.

We\'re in discussion with a number of strategic partners to move forward
on both diagnostic applications, as well removal applications or other
detection such as in surgical instruments, and we\'ll certainly exploit
this unique ligand that we have created to directly detect the
misfolding of proteins in neurodegenerative diseases.

Thank you very much for your attention.

DR. FREAS: Thank you for your presentation.

The next request we have is from Altegen, Incorporated, and it will be a
presentation presented by Dr. Bergmann and Dr. Preddie.

This is Dr. Bergmann.

DR. BERGMANN: Good morning. I will tell you about a new test and the
background of the test for the detection of human exposure to BSE in
serum.

The prion protein transcriptional unit contains two messenger RNA
species. One translates the constitutive PrP; the other, a small protein
we call prionin. Prionins are usually not expressed in normal subjects,
but the prionin gene can be induced in the TSE specific manner.

Prionin genes are present in all mammals investigated so far. Prionin
have species-specific, unique antigenic epitopes. Pure synthetic bovine
prionin converts human native PrP in a cross-species manner and
recombinant PRP to conformers with a 27 to 29 kilodalton Proteinase K
resistant core under physiological condition within minutes of contact
in the test tube.

(Pause in proceedings.)

DR. BERGMANN: Sorry. The animation is gone in this slide. Thank you.

The gel, the upper gel in the panel shows the product obtained with
human PrP after five, 15, and 25 minutes. The lower gel, the left one
shows again products with human PrP after 30 and 90 minutes. The lower
right panel shows the products obtained with recombinant PrP. This is
commercially full size recombinant PrP after 30 minutes, and they are
crossed right link.

We suggest that prion proteins are the illusive converting factor in TSE
called Protein X and add that prionins play a role in TSE initiation.
The model which follows shows how prionins provide means for the
detection of human exposure to TSE.

Prionins once expressed are immune modulated. They are treated as an
auto-antigen. The anti-prionin IgG in serum can be easily detected with
a specific antibody trap ELISA. The immune response declines with time
and in some cases prionins escaping the immune control react with PrP
cellular form and converts it to PrPsc in a complex.

In this complex prionins are chaperoned to the brain where at the
neuronal membranes the complex dissociates. PrPsc is deposited
externally and the prionin enters neuronal membranes and initiates
neural degeneration.

Prionins entering \-- this unfortunately didn\'t transmit correctly.
I\'m sorry \-- prionins entering a subject from an external source in
the vCJD case of the bovine prionin entering a human are again immune
modulated. After decline of immune regulation, again, the prionin can
escape and induce the host, the human prionin gene. The human prionin
once expressed again is immune modulated as described before.

Those prionins escaping the immune control react with host prion protein
to form complex species and different disease pathologies. Most
importantly, the subject has two different antibodies with distinct
specificities, one for the bovine prionin, the other for the human
prionin.

These two antibodies can be detected with the anti-prionin ELISA, and in
a cross-species way distinguish between the two if the infection comes
from a cross-species way distinguish between the two if the infection
comes from a cross-species.

This is shown by data obtained with zero from a suspected vCJD patient.
Five months after the first diagnosis of the disease, the serum
contained anti-BSS, anti-bovine prionin antibody, not later on.

The antibody against the human prionin was present throughout the
observation period of 20 months in declining fashion.

Blood from donors was tested for the presence of anti-bovine prionin
antibody. In samples obtained in Country 1 in the year 2003, all samples
were negative for the antibody. Samples obtained from Country 2 in the
years 1996 to 1998 collected, in those samples four were positive out of
571. Actually Country 2 is the same country the vCJD patient came from.

This shows that the tests can detect contamination with BSE related
bovine material.

Conclusion: prionins are TSE related proteins. Transmitted prionins
elicit an immune response. This immune response can be detected with an
anti-prionin ELISA.

Endogenous prionins are related to TSE initiation. They elicit an
autoimmune response, and this autoimmune response can be detected by the
anti-prionin ELISA. Again, the ELISA can distinguish between these
immune responses if there is a cross-species contamination.

We suggest that the anti-prionin ELISA should be used routinely and be
added to the array of tests already in use to test blood donations to
increase the safety.

Thank you.

DR. FREAS: Thank you.

Our next request is from IDEXX, Incorporation, and the presenter will be
Dr. Tonelli.

DR. TONELLI: Thank you.

I am, of course, an employee of IDEXX Laboratories.

What I\'d like to do today is bring you through IDEXX\'s diagnostic,
post mortem test for BSE. I\'d like to point out that this is truly a
second generation post mortem test for prions, and that it detects
prions directly and does not require a Proteinase K step.

We are USDA approved, and we have successfully completed the 2004
European validation studies and are in the final stages of approval in
Europe. At this point with the samples that we\'ve looked at, we\'ve
seen both 100 percent sensitivity and specificity. The advantage of this
test is certain in that it\'s much easier to use in all of the up front
sample preparations, centrifugations, Proteinase K steps are removed.
It\'s simply to generate a homogenate and put it into the ELISA test.

We can combine speed and performance with the ease of use as well.

The key to this is a polymer. We use a chemical polymer to capture the
rogue protein PrPsc in the presence of normal PrPc from a simple tissue
in water homogenate. Again it removes all of the Proteinase K steps, the
centrifugation steps and so forth. It really allows for a much easier
automation as you can imagine.

Now, the basis of this is really you can see it\'s a Seprion technology,
but it\'s all around the use of polyionic and ionic compounds to capture
the rogue protein. As you know, there\'s quite a bit of history of
polyanions binding the prions, and what we\'ve been able to do with our
partners is to develop conditions where we can specifically capture
PrPsc in the presence of PrPc. The detection occurs with an anti-prion
antibody.

So this is the application. We have this ligand for binding, and some
examples of the types of binding could be the types of polymers that
work in the situation, a pentosan sulphate and detran sulphate, et
cetera.

We do use some matrix busters. We use trypsin and DNAse just simply to
break down the viscosity of the sample. It does not digest PrPsc, and
you can see that clearly on Western Blots.

And then there are surfactants to enhance and allow this binding to
occur.

This just simply shows the overall protocol, but again, it\'s very
simple in terms you generate the homogenate by whatever method you like.
The method that we have approved in the U.S. is a bead beating method
that\'s used in other methods as well, and you can take the sample as
you wish. You can dissect it out. You can take it with a syringe. You
can get your sample however you wish, and then homogenize it, and then
it simply goes into a microtiter plate, is diluted and run in a typical
ELISA.

On the ELISA automation, we use a commercially available tecan Evo
automation platform. It\'s very simple. In fact, it\'s even simpler than
it performs here. There\'s no incubators. There\'s no heating or cooling
steps. It\'s simply liquid handling and liquid addition, and our current
protocol, we can do nine plates of samples in just under five hours,
which is almost double, I think, throughput of most other assays that
are out there.

This is what information we can show you at this point from our EU
studies and samples as well that we\'ve run in other parts of the world,
and there\'s a negative distribution of the population and our cutoff,
and you can see that we are quite a way from, quite a number of standard
deviations away from the cutoff population, which indicates that we
should see and have seen excellent specificity.

And think there are 14,000 or so samples in this assay, and these are
samples that come from a variety of sources. They\'re normal slaughter
samples. They\'re downer animals. They\'re autolyzed samples, just a
whole variety of samples that are in that negative population.

The Phase 1 European trials where we run 150 negatives and 50 positives.
Again, I think all of the tests had to run through this first, and we
got, of course, 100 percent agreement there.

This is just to show you the agreement with another EU approved test
with the IHC positive samples. You can see overall there\'s pretty good
agreement between the two tests. Remember you need to meet an IHC. IHC
is the gold standard, and so you have to meet that as the standard of
positivity.

This is just simply a dilution series against a positive sample in the
negative brain against an EU approved test to show equivalent
sensitivity in this application.

And this is just to give you some idea of autolyzed samples. These are
normal samples that were just held to 37 degrees and run over a period
of days, and you can see they are negative samples, and they stay
negative.

We have positive samples as well, and the positives stay well. In fact,
in some cases they get a little more positive. I think that\'s because
the viscosity of the sample is being reduced over that period of time.

So in summary, we\'d just like to give you an idea that the test does
have strong performance. We have see no false positives in the 15,000 or
so samples we\'ve run so far in that sample set. We have 100 percent
correlation with the European approved product. We have USDA approval,
and we\'ve successfully completed the 2004 EU validation studies.

The benefits of this, I think, are a couple. One, it\'s easy to use.
It\'s fast and efficient, a lot less hands on time, and no extra
equipment. We don\'t have to automate any of the front end stages. It\'s
simply automating the assay itself.

Because there\'s no PK step, there\'s really less chance for error. You
don\'t have to worry about the PK. Youdon\'t have to worry about the
conditions and so forth, and there is an automated platform.

Thank you.

DR. FREAS: Thank you.

The next request is from Microsens Biotechnology.

DR. WILSON: Thank you for allowing me to speak.

I just wanted to tell you about our progress towards a feasible blood
test for TSEs and present you with some recent data.

In line with a lot of people these days we don\'t like this Proteinase K
step. We don\'t like it because there\'s no guarantee that all of the
rogue prion (phonetic) is proteinase resistant. This is becoming
reported now with atypical scrapie and BSE, which has got implications
for food safety, but also when we started this work, we didn\'t know
what state the rogue prion in blood was likely to be, whether it\'s
likely to be resistant to Proteinase K or not.

So Quentin Tonelli from IDEXX has already described the Seprion ligand
use in post mortem field and has told you that it\'s a polyionic polymer
that can specifically capture the rogue prion protein and avoid the need
for Proteinase K.

So this polymer does have a pedigree in the post mortem field.

Just a couple of slides showing proof of principle really. This work was
carried out by a group at the Veterinary Laboratories Agency in the
U.K., Roy Jackman\'s group, and it simply showed that if you take the
Seprion and coat it onto magnetic beads and interrogate BSE infected and
uninfected brain samples, you can elute the captured material, run it on
a Western Blot, and plate it with an anti-prion antibody. You only get
prion material in the infected brain.

So this ligand really does only bind. Of course, there\'s no protease
involved here, no Proteinase K. So it really does bind specifically to
rogue prion without the use of Protinease K, but the material that is
captured is protease resistant, as you would expect in that if you
pretreat the brain with Proteinase K before capture or treat the
captured material after capture, the signal doesn\'t decrease, but you
get a lopping off of a bit of the protein. So the mobility does
increase.

Okay. So that\'s all I wanted to say aobut the ligand and its pedigree.

What has surprised us when we\'ve been looking at blood perhaps is that
there\'s an awful lot of rogue prion in blood, but the rogue prion in
blood in our experience isn\'t the same as the prion that we find in
brain.

So we spent a bit of time doing spiking studies and came to the
conclusion that these really aren\'t adequate to mimic the blood borne
infection, and in fact, we\'ve only made significant inroads into
detecting blood borne prion when we actually achieved some animal
models, scrapie models.

I\'ve presented this slide before, and it shows our results when we were
investigating scrapie infected and uninfected sheep, and there\'s not
many results in this slide because these samples are as valuable as
hen\'s teeth, and at that time we had five infected animals and a few
controls. This just shows one day\'s experiment really, looking at five
infected animals and the two controls.

At that time we were looking in five mLs of blood, looking at the
non-red cell fraction, and you can see clearly distinguishing a signal
from the scrapie infected animals.

The labels always drop off this slide. I\'m not quite sure why, but this
set of animals here is from an exposed flock, and you can see that we
get a range of signals scrapie exposed animals. These are asymptomatic
animals that six months later went on to pretty much all of them
developed clinical disease.

We\'ve got a set of controls here from unexposed New Zealand derived
animals, and you can see clearly that the negative animals give very low
signals compared to some of the asymptomatic animals.

Again, that\'s using five to ten mLs of blood.

We went on to use the same assay on some human samples. We were lucky
enough to get some suspected iatrogenic CJD patient and a suspected vCJD
patient. We already knew that the assay \-- of course, you could work on
post mortem sporadic CJD and vCJD samples, and it worked on vCJD spleen,
and we could use it to spike the spleen into the plasma. As I said, we
don\'t like those spiking studies at all.

When they put the panel of samples through the assay with a load of
control samples, the only sample that came up positive in the assay was
from the suspected iatrogenic CJD patient. Tragically that patient has
gone on to develop full-blown disease.

The vCJD suspect did actually recover, so obviously wasn\'t a vCJD
infection at all.

Now, I know that me standing up and telling you what we can do is not
very convincing unless we can have some sort of independent evaluation,
and the way we tried to do that is to work on a blind panel. We
requested a blind panel of scrapie infected and uninfected bovine blood
from the VLA archive. We received those samples in August 2004.

Unfortunately the samples were frozen. They came as frozen blood. So we
had to develop new protocols to be able to handle that frozen material.

We ran some of the samples through our test and broke the codes. The
protocol was fairly simple really. There\'s a bit of front end
treatment, lyse the blood, DNAse-treated. There\'s a black box step
there that I can\'t say too much about at the moment in time, and then
capture on Seprion-coated magnetic beads. The beads are washed and then
the captured material is eluted and put through an in-house ELISA.

And these were the results once the codes were broken. Now, what these
results show is that our assay actually works. We\'ve got quite a good
sensitivity, missed one Western Blot positive sample.

Our specificity is letting us down a bit for false positives, at least
not picked up by the Western Blot. True, those were from New Zealand
derived animals that you wouldn\'t expect to find positive. Two were
from clinical suspects.

This animal here is a clinical suspect, but hasn\'t yet been confirmed
by Western Blot. So if that animal turns out to be positive, we would
have these results for sensitivity, specificity, positive predictive
value and negative predictive value. If it turns out to be negative the
results would be like this.

So once we knew that the assay was working, we could go back to those
samples now and put them back through the assay, through a revised
protocol. I don\'t know if I mentioned it. If I did mention it, I\'ll
mention it again. Here we\'re only using 125 microliters of blood, whole
blood, frozen blood, and you can see that once we\'ve revised the
protocol we\'re getting much better results.

We\'ve managed to remove three of the false positives. We have one false
positive left which is from a suspected animal. It was clinically
suspected to have disease. It wasn\'t confirmed by Western Blotting. We
need to go back and now look at the brain of that animal, and we have
now picked up the animal that we missed that was actually confirmed to
be positive.

So we\'ve improved the assay significantly in the short amount of time
that we\'ve been working on it.

This is just for your interest. It just shows you some repeats of what
we now know to be blood from a positive animal and two negative
controls. You can see that if we repeat the assay on three consecutive
days, we do get very similar assay signals. So it\'s a very reproducible
assay.

So in summary, we\'ve used the Seprion ligand technology which has the
post mortem pedigree to detect PrPsc in sheep with scrapie and in
preclinical animals, and we\'ve been able to use the assay to identify
an iatrogenic CJD patient.

Now, when we did this work, it was with large volumes of blood, and
since then we\'ve been able to adapt the assay to use smaller volumes of
blood, which of course is going to be more feasible as a blood screening
tool, and at the moment we\'re investigating a second blind panel with
our revised protocol, and we\'ll decode those results in the near
future.

Thank you.

DR. FREAS: Thank you.

Is Jean Halloran from Consumer Policy Institute in the audience?

(No response.)

DR. FREAS: Okay. Her comments if she is not here will be in the
afternoon open public hearing. There will be another open public hearing
in the afternoon.

Is there anyone else in the audience at this time who would like to
address the committee? Please state your name.

MR. CAVENAUGH: Thank you very much.

My name is Dave Cavenaugh. I\'m on the government relations staff of the
Committee of Ten Thousand, an organization of people with Hemophilia who
have contracted HIV and hepatitis from the blood supply and is very much
concerned about this entity we have.

This morning\'s agenda was devoted to the science of the testing of
cattle for BSE and this afternoon\'s will be on the science of clearing
of plasma. I can only suggest of the many things that I\'ve seen about
the process from the patient view, from the testimony that has been
given, the first piece of the three written testimonies is from the wife
of a person with hemophilia, HIV, Hepatitis C, and presumptive CJD.

And I strongly recommend it to you. It poses several questions for this
panel specifically about the safety of the U.S. blood supply.

My question to you to please consider as you go through the day is how
does the disease get from the cattle being sought for testing to the
humans donating blood. I don\'t mean scientifically. I mean what are the
processes.

The third piece of written testimony, the last two pages of it are
statements made in testimony by the man who shot the cow in Washington
State, and it just opens up \-- I\'m sure you\'ve all read it by now in
some capacity or another \-- the questions about the rigor of the
decision about what gets tested and what doesn\'t, the relationship
between the USDA agent and the staff of the slaughterhouse, the kind of
slaughterhouses that have this experience and don\'t, and the variation
that is reality in life.

You have a U.S. cabinet department now searching for a goal of 20,000
per year tests of only one small subcategory of the U.S. cattle supply,
if you will, of 33 million head a year. In the face of the fact that
there are over ten known strains of scrapie, that there is TSE across
six different species of animals in the face of the fact that we do not
know how the disease gets to humans in the sense of how the cases in
England that have been deemed to be vCJD, clinically, scientifically it
has not been proven that they got it from beef or how they got it from
beef.

You know, we have to proceed without an answer to that. We have to say
presumptively, okay, it\'s diet related, and now because of the two
publications last December and this summer it\'s possibly very likely
blood related even though we\'ve had years of evidence that nothing
happened.

Our organization has for years talked about but we have Rohwer\'s rat,
which is in a study some years ago by Robert Rohwer here methods of
transmission, including intracranial injection, but also vein-to-vein
transfusion in 22 hamsters, in the latter one did transmit venously, and
you know, we can\'t say it\'s not in the blood.

Now, the first person writing the testimony from the U.K. talks about
people who have come to this country from England after the ban on
European travel and donated blood freely, not getting screened. How are
we looking at how potential incubators are kept from donating to the
blood supply?

The case that she speaks of was a man who was exposed to contaminated
plasma in 1996, eight years ago. Now he has some symptoms. We know that
there\'s an incubation period issue with this disease. We must be
prepared to work in the unknown.

Perhaps the first and clearest step would be set aside some 30 percent
of those USDA cattle to be drawn at random, as was discussed briefly
this morning so that we have a better screen. We\'re still testing only
one percent of our cattle at present, and they\'re gearing up. That\'s
wonderful. They only tested 2,000 per year before, and that was the most
recent year before the current effort.

So I just ask you to keep your eyes on the fog. There are unknowns here
at the front end of the cattle testing process, in the middle of the
cattle-to-human and in the human donation process, in addition to the
cleaning, clearing of the plasma.

Thank you very much.

DR. FREAS: Thank you.

Is there anyone else in the audience who would like to address the
committee at this time? Dr. Epstein from CBER.

DR. EPSTEIN: Yes. Thank you very much.

I just wanted to clarify. Mr. Cavenaugh, you seem to be suggesting that
there\'s a potential case of vCJD in a hemophiliac treated in the U.K.,
but we have conferred with U.K. authorities, and to our knowledge there
is no such case.

That\'s not to say that there are no neurological diseases in
hemophiliacs in the U.K., but obviously this is an alarming statement.
The entire world, certainly the U.K., and certainly the U.S. are very
attentive to monitoring for that possibility, but I think it\'s very
important to have a clear record that at least at this point in time
there is no presumptive case of vCJD in a patient treated for
hemophilia, and Dr. Will, perhaps you would corroborate that statement
on my part.

DR. FREAS: A quick comment.

MR. CAVENAUGH: There was some reason for the U.K. Department of Health
to transmit letters to 6,000 people with hemophilia that they were at
the highest risk for CJD and to their physicians indicating the
commencement of several different procedure changes, such as bans on
sperm donation, on requirements of non-reuse of surgical instruments.

If we don\'t have a diagnosis because the man is still alive, thank God.
If we have symptoms that have been seen in a compendium of 27 cases of
vCJD of the 143 that have died, that match in the eyes of this nurse and
residents, it\'s worth looking at. Caution is what I\'m urging.

DR. FREAS: Dr. Epstein.

DR. EPSTEIN: Okay. Well, I think that\'s a helpful clarification. We are
aware of the risk assessment that was done in the United Kingdom on
certain products and the fact that those product recipients have been
notified. It remains the fact that there are no products licensed in the
U.S. made from U.K. plasma.

Additionally, there are no products that have ever been distributed in
the U.S. from which there was a product made including plasma from a
person who later developed vCJD.

We do hope, however, to review the U.K. risk assessment. We are engaged
in a preliminary risk assessment of U.S. products made from U.S. plasma.
Preliminary results do suggest that the risk of the U.S. products is
significantly less than the estimated risk of U.K. products, and we do
expect to present a more complete discussion and review of that issue at
the next TSEAC meeting in February 2005.

So I think your comments about the need for careful watching are well
placed, and we do share that perspective.

DR. FREAS: Thank you.

There will be another open public hearing in the afternoon. At this time
we\'re going to close the morning\'s open public hearing and get on with
the meeting.

CHAIRPERSON PRIOLA: Okay. Our next speaker is going to present some \--
it\'s another informational topic. Dr. Scott.

DR. SCOTT: Good morning. This presentation follows on from a February
2003 meeting of this committee where you discussed, we discussed
labeling claims for TSE clearance in plasma derivatives.

The committee voted at that time that the FDA should consider evaluating
submissions from industry concerning TSE clearance, and that these
studies from industry could support a description of those same studies
in labeling.

So what I\'m going to do is give you some of the background that you\'ve
already had but not in as exhaustive a detail as you saw at the February
2003 meeting, more concerning the rationale and how we went about this
after the committee voted.

Then I will review the committee vote and the committee\'s concerns
about labeling, followed by what we did and what we have approved
actually as labeling for such a claim.

The rationale for offering TSE clearance labeling is several fold.
First, it encourages studies of specific manufacturing processes to
determine their capacity for TSE clearance. Although the risk of
transmission by plasma products still remains theoretical, that is, we
know of no confirmed cases of people receiving plasma products that have
come down with variant CJD or CJD, the incubation period, as has been
discussed many times, may be prolonged and, of course, blood transmits
disease in animals and in humans.

Additionally, we only have one other handle on limiting the risk in
these products, and that is donor deferrals for blood and plasma donors,
but these deferrals do have their limitations, and that will be
discussed extensively this afternoon, particularly the supply impact is
increased, and the incremental benefit is decreased as deferrals become
more stringent.

I\'m particularly talking about especially the geographic donor
deferrals that we have for risk of exposure to BSE.

Published studies can be useful, and they show that TSE clearance is
condition and process dependent, that is, one size does not fit all. For
example, depth filtration may clear TSE infectivity, but different depth
filters and different intermediate products have different levels of
clearance. So I will be emphasizing this again.

Therefore, published studies for one product can\'t be extrapolated
perfectly to another product using another process.

Published studies also are not detailed enough for rigorous regulatory
evaluation. I don\'t think any journal would accept a submission that
was a couple inches thick.

Additionally, offering this TSE clearance labeling should result in
scientifically sound data that permits an estimate of risk reduction by
manufacturing, and very important, it improves risk communication to the
public. In particular, this allows labeling to describe risk reduction
measures.

I just want to review some aspects of TSE clearance in the manufacturing
process. Manufacturing processes for plasma derivatives are highly
individual. There are many variations on the Cohn-Oncley process of
alcohol fractionation. There are now other fractionation methods that
are used, and there are multiple variations in downstream processing and
purification of products. Most of these variations have to do with
getting rid of aggregates or getting rid of viruses or anything that
could cause an infectious disease.

Therefore, rigorous demonstrations of clearance have to be based on the
specific manufacturing process, but published studies can prove useful
in identifying steps that have a potential for TSE clearance. So for
selection of steps to study, I\'ve already said the amount of clearance
depends upon the process being studied and the precise characteristics
of the intermediate material that you\'re looking at before and after it
undergoes a step in manufacturing.

Some of these variables are a pH alcohol concentration, ionic strength,
prior conditioning by other steps, and I\'ll come back to that last.

I just want to mention a caveat which was alluded to in one of the
speakers from the open public hearing, and that is that experimental TSE
models might not be optimized because the nature of the infectious agent
in blood and plasma has not been fully characterized.

To review the vote, the TSE Advisory Committee was asked whether the FDA
should consider evaluation of TSE clearance studies intended to support
new labeling. The vote was 12 votes yes, one vote no.

We had presented a wording that was somewhat generic in nature, and the
committee didn\'t like that. First of all, it was thought that the
wording that we had in this labeling that we presented \-- and we have
something very different now, and that\'s why I\'m not reviewing this in
more detail \-- but that the wording \"remote\" and \"theoretical\" was
difficult to interpret, especially by patients and health care
providers.

It was also felt that the wording should match the specific details of
the clearance in the product and not be just the generic wording saying
that these studies were done and resulted in some clearance.

Some committee members felt that vCJD and CJD information should
definitely be separated from other information about viruses, and it
should at least be separated in terms of formatting in paragraphs.

There was also a concern about the perception of a double standard. That
is, some products with have TSE risk reduction labeling and some will
not. This, of course, is entirely dependent upon the data we receive and
the quality of that data when we evaluate it.

Lack of labeling would not mean that a product is deemed unsafe or even
that a product lacks risk reduction measures, but it would tell you that
so far those studies had not been both submitted and fully evaluated by
FDA.

These are what we considered to evaluate TSE clearance studies in
submissions that have arrived to us. There needed to be a rationale for
the animal model selected and the selection of the spiking agent. The
spiking agent needed to be characterized and all of the studies needed
to be done using actual manufacturing intermediates.

The process used on a lab scale had to be accurately scaled down. The
experiments need to be robust and reproducible, and an assay needs to be
used that\'s well characterized for TSE infectivity, although there is a
possibility that binding assays or solid phase assays could be linked to
bioassays; that bioassays would not have to be done in every case.

An estimated amount of log\'s clearance of the TSE by processing steps
had to be provided, including a reduction factor and a clearance factor.
Mass balance needs to be demonstrated.

Now, there are cases where this is difficult, and we do accept at least
explanations and discussion of where you cannot look at mass balance.
For example, if a TSE infectivity is removed by a solid column, it\'s
very difficult to assay that column matrix for infectivity later. These
are technical limitations of these kinds of studies.

There needs to be a demonstration where it\'s relevant that orthogonal,
or non-orthogonal that should read, or similar clearance steps are or
are not additive.

There also needs to be an accounting for the conditioning of infectivity
where a prior step, such as solvent detergent treatment may affect the
physical state of the TSE agent and, in turn, affect the clearance step
downstream.

In addition, our current thinking is that steps with less than three
logs of clearance are not considered to provide meaningful amounts of
clearance if they are based upon partitioning because partitioning in
general is not an extremely robust method.

So here\'s a new labeling. It has already been approved for one product.
We have other submissions in hand. In the description section, which is
the first part of package inserts for plasma derivatives, it reads that
additionally the manufacturing process was investigated for its capacity
to decrease the infectivity of an experimental agent of TSE considered
as a model for the vCJD and CJD agents.

The purpose of this sentence is to characterize the studies as
investigational and to introduce a concept that models for vCJD and CJD
were studied.

Also in the description section the following statement provides some
specificity. Several of the individual production steps in the product
manufacturing process have been shown to decrease TSE infectivity of an
experimental model agent, and then there\'s a listing of the TSE
reduction steps which states the process that was looked at, for
example, depth filtration and the number of logs of clearance.

And then finally the statement these studies provide reasonable
assurance that low levels of CJD, vCJD agent infectivity, if present in
the starting material, would be removed.

So the purpose of this whole statement is to state that clearance was
observed and to give an idea of the specific amount of clearance for
each step, very similar to viral inactivation labeling that these
products have, and it provides an estimation of the effectiveness in the
context of low levels of infectivity.

In addition, the labeling in the warning section is retained. So the
plasma derivatives all carry this warning because this product is made
from human blood. It carries a risk of transmitting infectious agents,
e.g., viruses and theoretically the CJD agent.

So this captures the still uncertain but still potentially possible
risk, and the reduction of risk, if it\'s based on scientific
demonstration is reflected in the description section.

As I mentioned, we have submissions under evaluation. These come in as
prior approval supplements or are provided in new biologics license
applications, and I also want to say to the audience that future
improvements in risk assessment, understanding of the nature of plasma
infectivity and improvements in study methods could provide a basis for
additional labeling requests or recommendations.

So the story isn\'t over. I think that you will be hearing in a moment
where industry is on these studies and we do think that we\'ve had a
fair amount of interest in these labeling claims.

Thank you very much.

CHAIRPERSON PRIOLA: Okay. Thank you, Dr. Scott.

Our next presenter will be Dr. Henry Baron.

DR. BARON: Thank you.

Good morning. My name is Henry Baron, and I am the Chairman of the TSE
Task Force of the Plasma Proteins Therapeutics Association, or the PPTA.

PPTA member companies have generated an abundance of prion reduction
data since the last TSEAC meeting of February 2003 that Dr. Scott just
referred to, and within the 15 minutes of time allotted for this
presentation, there certainly is not enough time to present all of that
data.

So what I\'m going to be showing you is selected data on certain product
categories that are of particular interest to the FDA at this time, and
those are clotting factors and immunoglobulins.

For all of the studies that I\'m going to be showing you the data from
today, the prion strain that has been used as a spiking agent is the
263K hamster prion strain. It\'s a well known, well characterized prion
strain widely used throughout the domain of prion research.

Now, the first category of products that I\'m going to show you data
from are Factor VIII/von Willebrand factor products, and as you can see
different spiking preparations have been used. I\'m going to show you
data from three products here. Different spiking preparations have been
used for these evaluation: microsomal membranes, purified pathogenic
prion protein, detergent treated brain homogenate, and crude ten percent
brain homogenate.

These studies also have been performed with different prion detection
methods. The confirmation dependent immunoassay, Western Plot
immunoassay, and animal bioassay in hamsters, and for each of the
studies, at least two to three independent runs have been performed per
spike preparation.

Product A in which consecutive salt precipitation steps were evaluated
shows you data for microsomes and purified PrP scrapie ranging between
2.5 to 3.2 logs for this spike and up to 2.8 to 3.3 logs for the
purified PrP scrapie spike.

Product B in which the three percent PEG precipitations that was
evaluated. Multiple runs were used with this spike, and this was
evaluated by bioassay as well as by Western Blot immunoassay. The data
shown here represents the lowest removal factor in the range of data in
the different runs: 2.2 logs by infectivity assay; 3.0 logs by Western
Blot assay.

And Product C. Now, I\'d like to make a point here. These two products
are Factor VIII/von Willebrand factor products of relatively low purity,
and when you\'re dealing with these lower purified Factor VIII/von
Willebrand factor products in which it\'s essential that you have a
large concentration of the von Willebrand factor, you\'re going to get
removal levels in this range. You\'re not going to get a whole lot more.

Now, for some of these products there were other steps that also have
removal factors in this same neighborhood. So the additive removal
factor would be higher, but with these lower purity products, you\'re
not going to get a whole lot more than this.

This Product C here is a heparin-affinity purified Factor VIII/von
Willebrand factor product in which a PEG precipitation step was
evaluated using microsomes and detergent treated brain homogenate. Here
in two runs, 3.5 logs. The removal was demonstrated for the microsomes,
4.2 log removal for the detergent solid lines.

If you look at a more highly purified Factor VIII product now, such as
this monoclonal antibody affinity purified Factor VIII product, you\'re
going to get higher numbers. Again, the 263K hamster prion strain
evaluated using brain homogenate for the monoclonal antibody column and
using solvent detergent treated brain homogenate for a DEAE step.

And again, two independent runs were done for spike preparation. The
result is you have here, represent the average and monoclonal antibody
column, is going to give you a good removal factor of 4.1 logs with DEAE
Sephadex, again, 3.5 logs.

So with the more highly purified product like a monoclonal antibody
purified Factor VIII product, you will get a higher removal level.

Factor IX products now, again, spike preparations used, microsomes,
purified PrP scrapie, and detergent treated brain homogenate. Again,
CDI, Western Blot used as prion detection methods, and at least two
independent runs per product.

Product A, the manufacturing stage studied here were Planova filters in
series, 35 nanometer pore size and 50 manometer pore size, and the
result \-- and this, again, represents a mean \-- 4.1 log removal for
this Factor IX product for these two filters studied in series.

Product B, nanofiltration, the YM 100 filter was evaluated using
microsomes and purified PrP scrapie. Here is the results for the two
runs, 3.3 and 3.7 log removal to give you a mean of 3.5 logs. Purified
PrP scrapie, relatively similar results, 3.6, 3.6.

Product C, another Factor IX product in which salt precipitation was
evaluated. Again, microsomes in purified PrP scrapie, and again, we\'re
in the same neighborhood for the same microsomes, 3.8, 3.6 logs, a mean
of 3.7, and for the purified PrP scrapie, a little bit less removal with
a mean of about 3.0 log removal.

Now I\'m going to switch over to immunoglobulin products, and I\'m going
to just show you data from two products, and I\'m going to show you
specifically a set of data that address an issue that has been often of
concern to the regulatory environment, and that is the feasibility of
adding removal factors from independent steps, and whether it is
appropriate to offer a calculated removal factor based on evaluation of
independent steps as opposed to evaluating the steps, coupled, this
whole series of steps, spiking here, and then evaluating what comes out
here at the end.

The result in this experiment which evaluated cryoseparation, Fraction I
and Fraction II separation, you can see that the additive removal factor
for adding up the individual factors for these three steps is 7.1 logs,
and it is comparable to the removal factor done when the three steps
were studied consecutively, 6.8 logs.

And another immunoglobulin product showing the same kind of data, and
this one a depth filtration. Two different depth filtration filters were
evaluated in series, and you can see that when the two filters were
evaluated in series, you get a log removal factor of 7.2. When you did
them individually, 4.5 plus 2.8 gives you a log removal factor of 7.3.

So I think these are two sets of data which show you that the additive
calculated removal factors, adding up the factors for different steps do
correlate very well with the evaluation when you do the steps in series.

Now, the numbers that I have shown you are just numbers at this time,
and in order for them to have any kind of meaning, they have to be
considered in the context of whatever we consider the risk of vCJD to be
in the donor population. I\'d like to spend the next few minutes
discussing this issue.

To date there have been 15 blood donors diagnosed with variant CJD in
the United Kingdom, of which nine contributed to roughly 20 pools used
to manufacture plasma derivatives. So from 1980 to 1998, the incidence
of variant CJD donors amongst the donor population was 50 divided by
1,907,000, which was the number of donors in the U.K. in the year 1997,
times 18 years, and this gives us a number. This gives us a number which
would give you the incidence of variant CJD donors per million donors
per year in the United Kingdom.

Now, I would like to also look at some data which shows the exposure to
BSE in the United Kingdom as compared to that in the European Union, and
what you see here is that up to the end of the year 2000, which was the
year in which \-- excuse me \-- up until the end of 1999, up until the
year 2000. In 2000 active surveillance at the slaughterhouse level was
implemented in Europe.

You had 180,000, roughly, cases of BSE in the U.K. The number of BSE
cases in the European Union up to that time was 1,777. So basically what
this is showing you is that in the European Union, there was a 100-fold
lower exposure to BSE as opposed to that which occurred in the U.K., and
all of the U.K. vCJD infected donors contributed prior to the
introduction of active testing for BSE.

However, I think it\'s important to note also that since 2000 when
active surveillance, systematic testing at the slaughterhouse level
occurred, there was a fourfold increase in the BSE detection due to this
active testing.

So I think that what the PPTA is doing now, we\'re showing you this data
because we\'d like to use this data to develop an alternate assessment
of the risk of vCJD. By using this data we are going to calculate the
vCJD, the potentia; vCJD incidence in the donor population in the
European Union, and then use those numbers as a model to assess the risk
in the United States considering the European Union to be a worse case
scenario for BSE exposure and variant CJD than the United States.

And we hope to be able to present this data, this risk assessment at the
next TSEAC meeting in February.

And finally, I\'d like to make some concluding statements. I showed you
a good deal of data from different PPTA member companies in which
different investigative approaches, different spikes, different assays
were used, and the use of these different investigative approaches gives
confidence that the current systems are working to assure efficient
prion removal.

And these efforts made by PPTA member companies really represent an
enormous investment in applying the precautionary principle and
providing reassurance in the safety of plasma products, and this is an
ongoing effort. This is not something that\'s going to stop in any
recent time.

And finally, we feel that balanced approaches are really needed to
insure both the safety and the availability of lifesaving plasma protein
therapies.

Thank you.

CHAIRPERSON PRIOLA: Okay. Thank you very much, Dr. Baron.

I think that we\'ll take our 20 minute break here until 11:00 a.m.
because we had to absorb a lot of information here. All of these
speakers should be available for much of the day for questions if the
committee has them.

So we\'ll reconvene at 11.

DR. FREAS: Our official photographer is here, and so I would like to ask
those who have received their plaques to come up during a break and get
their picture taken. Otherwise you cannot leave the committee without an
official photograph.

(Whereupon, the foregoing matter went off the record at 10:46 a.m. and
went back on the record at 11:10 a.m.)

DR. FREAS: If the committee would return to the table.

Thank you.

CHAIRPERSON PRIOLA: Okay. If we could get started here, most of the
committee is back at the table.

And our next set of talks deal directly with the topic that the
committee has been asked to discuss and vote on. So our first speaker
will be Dr. David Asher.

DR. ASHER: Thank you, Dr. Priola.

Now we turn to our decisional \-- gang, can I ask that we take side
conversations out into the hall, please? We\'re running considerably
late already.

Thank you. So thanks very much.

Now we turn to our decisional issue of the day, soliciting advice and
posing questions for the committee to vote or to have an opinion from
them. After offering the charge, I will review briefly the history of
FDA actions to help protect the supply of human blood and blood products
against contamination with TSE agents.

Note recent events of concern introduce the scientific program intended
to help the committee and then pose the questions. We seek advice on
whether recent information regarding variant CJD information of which
you\'re aware warrants consideration of additional measures to maintain
the safety of FDA regulated human blood and blood products.

For more than 20 years, FDA has taken precautionary actions and offered
guidance to blood and plasma establishments based on the assumption that
the infectious agent might be present in the blood of persons with TSEs
or during an incubation period of TSEs.

In 1978, Elias Manuelidis and colleagues reported the first convincing
evidence that guinea pigs with an experimental TSE had infectivity in
blood, a report later confirmed and extended many times in other animal
models. Especially informative have been studies by Paul Brown, Robert
Rohwer and their colleagues. Both of them spoke at our last meeting, and
I\'m glad to say that they\'re both attending today.

In 1983, FDA, learning that a blood donor had been diagnosed with CJD,
encouraged voluntary withdrawal of indate components and plasma
derivatives. Nine similar withdrawals followed during the next 12 years.

In 1987, FDA recommended precautionary deferral of some donors with a
history of increased risk of CJD, those who had received human cadaveric
pituitary growth hormonem, and later added history of dura mater
allograft or a family member with CJD.

In 1995, FDA recommended precautionary withdrawals of both blood
components and plasma derivatives from increased risk donors, but three
years later for reasons summarized on the slide in your handout FDA no
longer recommended withdrawal of plasma derivatives when a donor was
recognized post donation to have had classic forms of CJD or to be at
risk for them, although retaining previous policy for whole blood and
components.

However, there was a greater concern about donors with the new variant
CJD, and FDA has continued to recommend withdrawal of plasma derivatives
from any pool to which a donor with vCJD contributed, something that has
not been necessary in the USA, although the U.K. as we will hear has not
been so fortunate.

In January of 2002, FDA recommended enhanced precautionary vCJD
policies. Those are still current and are the topic of today\'s
discussion.

Last year we became aware that two Canadian born cows, one resident in
Washington State, had been found with BSE; discussed that issue at
previous meetings. We also received very troubling news from the U.K.
regarding vCJD and blood safety, that a recipient of red cells from a
healthy donor later diagnosed with vCJD had himself come down with the
disease.

Professor Robert Will was kind enough to share information about that
case at our last meeting, and he is here again to speak about a second
presumptive transfusion transmitted vCJD infection, the overall
situation regarding vCJD in the United Kingdom and other countries and
related information.

Not least of which is the recent notification of certain recipients of
derivatives made from plasma of U.K. donors that may be at increased
risk for variant CJD, and that was referred to in the earlier discussion
this morning.

In the handout, you will find a summary of current FDA CJD/vCJD blood
safety guidance. Many of you are already very familiar with those
policies, and for those who are not, Dorothy Scott will review them
later in the program.

The FDA, aware of uncertainties surrounding TSE risks, effectiveness of
risk reducing measures and potential to contribute to shortages of life
sustaining blood products, is committed to reviewing its blood safety
policies frequently. In addressing TSE risks, the agency has tried to
take a proactive approach consistent with the findings of the Institute
of Medicine regarding government decision making, and that took place
for HIV and the blood supply.

As part of that effort, we have tried to review policies regularly and
publicly with the TSE Advisory Committee, and in an abbreviated form
with the Blood Products Advisory Committee, especially when new
information suggests that risks should be reevaluated.

Since our last meeting in February of this year, significant new
information has become available.

FDA has been more concerned about variant CJD than other forms of CJD
for reasons listed here. Not only was the neuropathology different, but
also there was much more scrapie type prion protein in lymphoid tissue,
an obvious potential source of infectivity in blood, and there was a
more general concern that because vCJD was an emerging disease,
different in so many respects from other forms, that the relatively
reassuring epidemiological information that had failed to show actual
evidence of transfusion transmitted classic CJD might not be predictive.

The reports of two cases of blood borne vCJD in less than a year has
increased our concern.

There has been some good news as we heard earlier this morning. The BSE
outbreak may have peaked in many cases, and no further cases have been
detected so far in North America since the two were recognized last
year.

And the number of diagnosed vCJD cases worldwide is smaller than some
models had earlier predicted.

However, troubling uncertainties remain. Evidence from cases of vCJD
thought to have been acquired by people in the U.K. who then left the
country suggest that incubation periods after dietary exposures might be
nine years or more and after transfusion six years or more.

It is clear that as in animal models, blood of an infected person is
likely to be infectious for some uncertain fraction of the preclinical
incubation period, at least 18 months in one U.K. case and three years
in the other.

Furthermore, results of a recent survey of scrapie type prion protein in
tissue from routine appendectomies in U.K. suggested that more than 100
persons per million in the U.K. might be in the preclinical incubation
period of variant CJD.

We conclude that until uncertainties are resolved better, there\'s
reason for continued concern about the safety of blood donors who were
potentially exposed to the BSE agent.

Relevant published information about both the first case of presumed
transfusion transmitted vCJD was summarized for us by Professor Will at
the last meeting of the committee, and he will discuss the second case
today. I summarize information, published information, for you in the
handout.

Taken together, the new information has a number of implications.
Variant CJD must be presumed transmissible by blood or at least by
non-leukoreduced red blood cells. The heterozygous prion protein
encoding genotype, methionine-valine at Codon 129, while probably
providing some protection against vCJD as it does for other forms of
CJD, does not convey absolute resistance to infection with either CJD or
vCJD agents.

A second save of variant CJD affecting persons not homozygous for
methionine at the 129 locus is possible. The number of persons
incubating variant CJD in various countries is uncertain, but may be
significant especially in the U.K. where dietary exposure to the BSE
agent was greatest.

The number of persons have vCJD agent in blood may, therefore, be
significant. The FDA therefore sees no reason to doubt that recommending
geographic BSE blood donor deferral policies was prudent and justifiable
and probably remains so.

FDA has recommended CJD and vCJD blood safety policies to reduce the
risk that a donor might be incubating CJD of any kind, while not
deferring so many donors as to compromise the supply of blood products.
We have acknowledged that the policies cannot eliminate all conceivable
risk.

We intentionally are not now offering specific options for the committee
to consider, but it might be useful for you to direct your attention to
the general kinds of precautionary deferral already in place in order to
consider which, if any, are amenable to enhancement, enhancements that
might reduce risk sufficiently to justify the inevitable loss of
otherwise suitable donors who are a precious resource.

One, deferrals for potential dietary or other exposure to BSE agent,
possible enhancements to current geographic deferrals, ignoring the
taking of individual dietary histories which are generally thought to be
very unreliable would be to reduce the time that a suitable donor might
have spent in various countries or to add new countries to the list.

Regarding nondietary BSE exposures, we are not aware of any other U.K.
bovine derived injected product similar to insulin that was in general
use.

Two, deferral for history of exposure to human blood or blood products
from donors potentially incubating variant CJD. The enhancement would
extend deferrals to donors transfused in places other than the United
Kingdom.

To aid the committee and inform the industry and public as well as our
own agency, we have enlisted the aid of a number of speakers. Professor
Will as mentioned will review variant CJD and recent events of concern.

FDA\'s Steven Anderson will again compare blood risks of classic and
variant CJD, U.K. and U.S. situations and will comment on the
development of risk assessments for recipients of coagulation factors.

Luisa Gregori will summarize her work with Robert Rohwer and colleagues
investigating the effects of leukofiltration on endogenous infectivity
in a hamster scrapie model and possible implications for human blood
safety.

Peter Ganz was to come from Ottawa. Has Peter been able \-- okay, good.
Peter Ganz has kindly agreed to come to share with us as much as he can
regarding variant CJD and Canada\'s approach to blood safety.

Dorothy Scott will summarize and comment on current FDA policies, and
Alan Williams will estimate risk reductions and donor losses from
previous and current deferral policies and those that might be expected
from other possible policies.

In our open public hearing, Dr. Peter Page, I believe, will report on
the latest results of the American Red Cross study that was summarized
briefly at our last meeting by Dr. James Sejvar of CDC, and has been
incorporated into Steve Anderson\'s analyses.

And we\'re always grateful for other contributions to the open public
hearing, as well.

After the program, the committee is asked:

One, to consider whether CJD/vCJD deferral policies currently
recommended by FDA to protect the safety of the blood supply remain
justified; and

Two, if so, in considering recent additional information about BSE and
vCJD, they are still adequate.

If the committee considers any current policy to be inadequate, FDA
solicits its advice in suggesting enhancements to existing policies or
possible additional policies that might reduce the risk further without
jeopardizing an adequate supply of life sustaining and health sustaining
blood products.

We ask you please to vote on the first two questions and to discuss the
third. As always, we are very grateful to you for your help, and we
thank you.

CHAIRPERSON PRIOLA: Thank you, Dr. Asher.

Are there any questions from the Committee for Dr. Asher? Dr. DeArmond?

DR. DeARMOND: It\'s more of a comment. If we can believe this ‑‑ the
letter that this person wrote in Great Britain about the son donating
blood in the U.S., it seems that the deferrals are fine, but the
enforcement of or the actual practice of making sure somebody from a
high-risk country doesn\'t donate blood is the bigger problem at this
time.

And it\'s ‑‑ this is all anecdotal, and I don\'t know how you follow up
and make sure that this isn\'t happening. But it was a little disturbing
to realize that Europeans from high-risk countries can come in and
donate blood relatively freely, which means, again, people are not
following the deferral policies.

DR. ASHER: The donor in question ‑‑ and I don\'t know if the audience
has seen the document ‑‑ as I recall the situation, is alleged to have
given false information on a donor questionnaire in order to donate I
believe plasma. And I don\'t know ‑‑ but perhaps as Alan Williams coming
in ‑‑ I don\'t know, aside from spotchecking, what one can do to protect
against donors who intentionally give false information or leave out
information when questioned on a blood donor situation. The whole system
runs on honor.

CHAIRPERSON PRIOLA: Okay. Thank you, Dr. Asher.

Our next speaker is Dr. Bob Will, who is going to update us on the
transfusion transmission of variant CJD in the UK.

DR. WILL: Good morning. I\'m very grateful for the invitation to come
and speak about what is a very difficult issue, both in the UK and
elsewhere. I\'m going to concentrate on the blood issue, but at the end
I will say something about the plasma issue in the UK and the
notification of recipients that has just taken place, and perhaps try
and balance that with some views from other European agencies.

You have seen this before from David Asher. This is the number of cases
of variant CJD worldwide as of today. UK, 149; France, 7; Republic of
Ireland, 1; Italy, 1; USA and Canada, and all the ones in blue had
potential exposure to BSE in the UK because of a residential history.

I think there\'s just a couple of things I should probably say about
this in view of some of the questions this morning. As far as the other
cases outside the UK are concerned, we believe that none of them were
blood donors. As far as the UK cases are concerned, we still believe
that the most likely hypothesis is that these cases were caused by
dietary exposure to high-titer bovine tissue in the human food chain.

And one reason for that is that the great majority of these cases had no
significant past medical exposures. Only five of them had ever received
a blood transfusion to our knowledge, and a case control study of risk
factors, medical risk factors, has shown no significant additional risk
from medicinal procedures in this group compared to controls.

So we do not believe that the evidence that we have today suggests that
these individuals have developed variant CJD through medical
interventions. Although I am not in a position to discuss this in
detail, we have also recently completed a case control study with Hester
Ward, which does give some evidence in support of the dietary
hypothesis.

The number of deaths from variant CJD worldwide is shown here. There
should be an additional orange bit here to represent a case in the
United States that I believe has died this year. It shows this pattern
of deaths in the UK with a clear decline, and, as I\'ve said before, we
believe that clinical onsets are probably a more accurate view of what
is happening in terms of temporal trends in the number of cases.

And you can see this peak in 1999 of clinical onsets, and then a clear
decline. The data for the years 2003/2004 are incomplete, but it clearly
looks as though there has been a decline in the epidemic of variant CJD
in the UK, although I must stress that all of the tested cases to date
of clinical cases have been methionine homozygotes. And all of the
mathematical models, which I\'m going to present shortly, assume that
only methionine homozygotes could be infected, and we no longer believe
that that is the case.

This doesn\'t show very well, but this is the numbers of variant CJD
onsets, and Roy Anderson modeling of infections of BSE with an
incubation period from the peak of the presumed exposure to the peak of
the presumed epidemic of variant CJD of about 12 years, which I think is
biologically plausible from what we know about other prion diseases.

Now, modeling of what will happen in the future of the variant CJD
epidemic has been carried out over many years, and I think I presented
this the last time. The first study done by Simon Cousens in 1997 was
designed to show the great uncertainty about the number of future cases
of variant CJD that there could be at the very start of what was
potentially an epidemic.

And what has happened with time? This is just a selected number of these
models ‑‑ is that the projections of the future number of cases have
become more and more conservative with time, with recent projections
suggestions cases of perhaps 4- or 500 in the UK over the next 40 to 50
years.

However, as I\'ve already said, there are a number of assumptions in all
these models, one of which is that methionine homozygotes would only be
affected. There is also the presumption that there was a unimodal UK
population exposure to high-titer bovine tissue in the food chain, and
Byrd and Cooper have suggested that there may have been a bimodal
distribution of exposure.

So there is great uncertainty about the future still in relation to the
variant CJD epidemic in the UK, although I must say that from my point
of view, personally I think the very fact that we\'ve had a peak and a
decline in the MM homozygote population means it\'s less likely that
we\'re going to have such a large epidemic as was originally feared.

The issue of secondary transmission of variant CJD has been a matter of
concern for many years, notably since spleen was found to contain PrP by
James Ironside and colleagues many years ago. And also, this has
subsequently been shown to contain infectivity at a lower level than
brain in a variant CJD case.

This is the original study of appendices from samples in the population
in which they found 1 out of 8,318 positive, suggesting an estimated
prevalence of prion protein in the population of about 120 per million,
although with very wide confidence intervals.

And, of course, the concern about this is that these tissues can be
positive for a long time during the incubation period, presumptively in
humans for many, many years, and that individuals who contain
infectivity in the periphery could be acting as blood donors. And it\'s
for this reason that there has been such concern in the UK and elsewhere
about the whole issue of the possibility of secondary transmission of
variant CJD through blood.

And this is a slide that you have seen already from David Asher showing
the more recent study by David Hilton and colleagues in which they
looked at large numbers of appendix and tonsil samples, totally
anonymized. That was the ethical guidance that was received. Three
appendix samples were positive for PrP, leading to an estimated
prevalence of 237 per million, again with wide confidence intervals.

Or, because of the age distribution of the sample that they studied,
3,808 individuals age 10 to 30 years might be incubating variant CJD in
the UK. So there is a disparity between the observed epidemic and the
projections in relation to these tissue studies.

Now, I\'m just going to talk about the Transfusion Medicine Epidemiology
Review, the TMER study. And just the background is that variant CJD was
identified in 1996, it was thought to be a new disease, and we\'re now
confident about that, its future infection with a BSE agent. Some cases,
in fact, is blood donors.

And, importantly, I think ‑‑ this will be discussed in the next talk ‑‑
sporadic CJD is known is to be transmitted from person to person but not
through blood transfusion. And the concerns about variant CJD is it\'s a
new infectious agent with a different pathogenesis. Therefore, there may
be different outcomes in relation to blood.

The study involves the National Blood Service in England, the Scottish
National Blood Transfusion Service, the Welsh Blood Service, the
Northern Ireland Blood Transfusion Service, the Surveillance Unit, and,
importantly, the Office of National Statistics. And in brief, because I
don\'t want to go on about this at length, the methodology of this study
is really very simple.

What happens is that every time we identify a case of variant CJD that
is classified as probable or definite, the details of that individual
are circulated to the relevant blood transfusion service in relation to
their residential history, and a search is made to determine whether any
of them had acted as blood donors.

If they have been identified as blood donors, the recipients of the
blood are identified, and the details are then circulated to the Office
of National Statistics in order that if any of these individuals die we
receive a death certificate.

The ethics of this study, when we originally started it, were that the
individual recipients of potentially contaminated blood would not be
informed that they had received such blood. Although as you will know,
that decision was reversed last year.

Now, this is the current situation. We have 149 cases of variant CJD,
but 147 we have details of. Two of them are currently going through this
system, although we know from the families that these two individuals
were not said to have been blood donors.

The number who are eligible to donate ‑‑ that is, over the age of 17
years ‑‑ is 137. There are reported to have been blood donors and
actually ‑‑ cases where actually donor records were traced ‑‑ 19,
including one in whom the family had said they had definitely not been a
blood donor, interestingly; 16 ‑‑ from whom components were actually
issued was 16; and we have 50 recipients of labile blood products.

In terms of the blood donors, this is the year of death, and the total
number of vCJD cases, the total eligible to donate. And all I\'m really
trying to show you here is that a number of donations were given over a
period of many years, although a low number each year.

And this is the use of these transfusions. This is the products that
were transfused to the recipients, mainly red blood cells and mainly
non-leukodepleted red blood cells, because this was introduced
relatively late.

Now, I talked about this earlier in the year, but just to briefly go
through this. Last December we received a death certificate from one of
the recipients, which was received on the 8th of December, which
mentioned dementia. All the previous death certificates we had received
on recipients who had died had not mentioned any neurological disorder.

And this clearly raised the possibility that this was a case that could
have developed variant CJD. The donor to this individual had donated two
units at different times in 1996 when they were healthy ‑‑ a 24-year
old. One unit went to a patient who died of cancer after five months.
Platelets were included in a platelet pool, which has not been traced.
And plasma from both donations were included in different plasma pools,
and the donor died three and a half years later of pathologically
confirmed variant CJD.

When we received the death certificate mentioning dementia, we had also
received tissues on this case, and also had had a referral from the
relevant clinician.

In 1996, the recipient, who was then age 62, was transfused with five
units of red cells, one from the vCJD donor, and in brief developed
symptoms and signs that were relatively typical of variant
Creutzfeldt-Jakob Disease. The MRI scan was normal, but the patient died
13 months after the onset of symptoms, which is more or less the average
for variant CJD. And the post-mortem confirmed variant CJD Codon 129 MM
with a Type 2 prion protein in Western Blot.

And I think I\'ll just briefly show you slides from James Ironside of
the pathology in this case, showing the so-called florid plaques on H&E,
and with immunostaining appearances that are totally typical of variant
Creutzfeldt-Jakob Disease in the recipient.

And the Western Blot pattern showed the Type 2B pattern, which is seen
in variant CJD and not in other forms of CJD. And this is just a graphic
representing the distribution of the different glycosylation types of
PrP. And this is the two samples from this case here in amongst the
cluster of variant cases and the other sporadic cases over here. So we
are confident that this is a case of variant CJD.

The statistical analysis is always difficult when there\'s only a single
observation. However, Simon Cousens did do an analysis which looked at
the chances of an individual developing variant CJD through dietary
exposure in the small population of recipients, and he came up with an
analysis of 1 to 15 to 30,000. So we felt that this was a possible case
of transfusion transmission of variant CJD, and that case was published
in The Lancet earlier this year.

It did cause a lot of concern, and this was one of the newspaper
headlines. And one of the reasons I thought I\'d put this up is that you
may have gathered we received the death certificate on December 8, 2003,
and we immediately informed the Department of Health about this issue
and there was an announcement by the Minister of Health on
December 18th.

We have never and have no intention ever of trying to suppress any
information about variant CJD or any other form of CJD. And I think I
can assure you that if anything was happening we would make sure that it
entered the public domain.

The second case was really as a result of a change in policy after this
discovery, because the decision was made that as of December 2003 there
were 17 recipients of the blood transfusions from a vCJD donor who were
alive. And the decision from the Department of Health and the Health
Protection Agency was to inform all recipients of the risk, together
with their general practitioners and the hematologists who had been
involved with the blood transfusion.

In 2004, one of these recipients died of a ruptured abdominal aortic
aneurysm. There was no history whatever of neurological illness. But
because the clinicians were aware of the context in this case, a
post-mortem was carried out, which included specific examination of the
brain and peripheral tissues to determine whether there was any evidence
of infection with variant CJD.

The recipient had received a blood transfusion in 1999. The blood had
been donated by someone who was age 27 and was healthy at the time, and
18 months later the donor developed symptoms of variant CJD and died in
2001 with pathologically confirmed variant CJD.

And as far as the recipient is concerned, James Ironside and colleagues,
John Bell, carried a post-mortem examination in this recipient, who I
stress had no neurological symptoms or signs. Using immunocytochemistry
and Western Blot for PrP, the brain, spinal cord, tonsil, and appendix
were negative. However, the spleen and one cervical lymph node were
positive, consistent with infection with prion disease.

And just to put it in context, a very important question is using the
same technique, so I must stress using the same techniques. What other
experience do we have of the neuropathology and the general pathology
systemically of other forms of human prion disease and controls? And at
that stage, there were 56 other human prion disease cases that had been
examined that were non-variant, and 85 non-cases, and all of them were
negative in the same tissues using the same techniques.

So we believe that this is good evidence, the fact that they\'re stating
at all that this is consistent with variant CJD.

And this is the spleen showing the immunostaining, which, of course, is
much less marked than the previous sample. It may be that this
individual was pre-clinical, was incubating the disease, and there may
have been accumulation of PrP subsequently in these tissues.

And this is the Western Blot, and the recipient spleen tissue and in
controls, case sample 1 here, case sample 2 here. Variant CJD is a
control on the right showing the same pattern which is typical for
variant CJD.

The statistical analysis, again, is very difficult. Simon Cousens,
again, agreed to do this. And in the absence of transfusion
transmission, the chances of one or more in the recipient population, as
I\'ve said, making assumptions about age, is 1 in 30,000; the chances of
two or more cases, about 1 in a billion, assuming that they\'re both
transfusion transmitted.

However, we also can look at the appendix/tonsil data, which I presented
earlier, and if you use that, if it were 5,000 individuals in the UK
infected, the probability of two or more cases is about 1 in 80,000. So
on both counts it looks as though statistically it is far more likely
that these two cases are transmitted through blood than through dietary
exposure. And I think for the purposes of public health, we have to
assume that blood transfusion is a mechanism of transmission of variant
CJD.

This was published, again, in The Lancet. And one important issue was
that this individual was Codon 129 heterozygous. So this is a patient
who we believe was infected with BSE who had a heterozygous background,
and this contrasts with our previous experience in variant CJD cases
where 100 percent of tested cases have been MM.

And this suggests that the projections in relation to the future
epidemic of variant CJD in the UK will have to be revised to take this
factor into account, although I must stress we do not know that the
individual heterozygote was going to develop clinical disease. And
there\'s also a possibility that this individual could have been left in
a carrier state. Of course, that\'s still very important for public
health.

And just to summarize the current situation, we\'ve had 32 deaths from
variant CJD. There are two variables here ‑‑ the time from transfusion
to the onset of clinical symptoms in the donor, with the presumption
that the sooner before clinical illness the more likely you are to
contain infectivity. And then, the survival ‑‑ that is, the followup
period in this axis here in years.

And you can see that in those that die the great majority died within a
very short time, within a year or two of the transfusion, of course,
because of the primary illness for which the transfusion was given. And
we have some survive ‑‑ some individuals who live for longer before
dying. One is the CJD case, and the other is the PrP positivity in
spleen, five and six and a half years after the transfusion.

And here we have the surviving recipients, now 18. And you can see that
these individuals have survived for a variable period, some up to 17 or
18 years. But the donation was given some 16 years prior to the onset of
clinical symptoms in the donor. And the leukodepleted cases are here.
And one of these individuals was an individual who received a blood
transfusion from the same donor as the pre-clinical case.

The final thing I wanted to comment on ‑‑ and I hope I\'m not going over
time yet ‑‑ is the blood donations from variant ‑‑ nine variant CJD
donors contributed 23 units for plasma fractionation. And with the
identification of the second pre-clinical case, the authorities in the
UK became concerned about this issue, although, as I\'ll say in a
minute, for some years now we have been importing from the USA primarily
plasma for the production of fractionated products.

And the decision was made in September to ‑‑ on the basis of a risk
assessment that some recipients should be informed that they may be at
additional risk for developing variant CJD because of their treatment
with plasma products. And this caused major concern, as one can easily
understand, epidemic fears after thousands given CJD alert. And 6,000
get Mad Cow Disease warning. It is feared we may be facing a CJD
epidemic.

The basis of this policy to inform these individuals was made by the CJD
Incidents Panel and based on a risk assessment carried out by Der Norske
Veritas. And I thought what I\'d do is just go through some of these
issues in brief, although I must stress that I am not a risk assessor or
qualified to comment on mathematics.

The CJD Incidents panel has defined an at-risk threshold for public
health purposes as the possibility of being exposed to a one percent or
greater potential risk of infection on top of the general risk to the UK
population that is thought to have resulted from dietary exposure to the
BSE agent. That was the basic premise.

On this basis, the levels of likelihood of surpassing the threshold have
been categorized as follows, and there are three levels. Number one is a
high ‑‑ the amount of potential vCJD infectivity is high enough for the
threshold to be surpassed following the administration of a very small
dose, e.g. one treatment with Factor VIII, Factor IX, or antithrombin
where one vial of product used has been implicated.

Medium ‑‑ the amount of potential vCJD infectivity is not low enough to
be ignored, but substantial quantities of the material in question would
need to be administered before the threshold is surpassed. Several
infusions of intravenous immunoglobulin G or large doses of albumin of
4.5 percent from pools that have contained a variant CJD donation. And
all of the individual lots and batches have been traced.

Finally, low ‑‑ the amount of potential vCJD infectivity is so low that
the likelihood of surpassing the threshold can realistically be ignored.
Factor VIII products where the albumin excipient used the manufacturing
process, and not the plasma concentrate has been implicated,
intramuscular normal immunoglobulin for travel prophylaxis.

So that\'s how the categorization was done, and this was the actions in
relation to each of ‑‑ each implicated batch of plasma, according to the
likelihood that recipients would have surpassed the at-risk threshold
for public health purposes, I stress.

High ‑‑ the batches should be traced. Individual recipients considered
at risk of variant CJD for public health purposes, and these individuals
‑‑ the intention was to inform them of this risk.

Secondly, medium ‑‑ this involves tracing batches and assessing the
potential additional risk by looking at the volume of material that had
been given. And if the threshold was exceeded, those individuals, the
intention is or will be to inform them. But if the threshold is not
reached, they will not be informed.

And finally, low ‑‑ the batches do not need to be traced. Individual
recipients do not need to be informed. That\'s albumin 20 percent,
intramuscular, normal immunoglobulin, anti-D, and etcetera. And there is
a flowchart, which you won\'t be able to see very well. I must apologize
about this, but this is a flowchart released the 7th of September for
vCJD of plasma products that may be affected.

Recipients of UK sourced products down here, which are listed ‑‑
hemophilia, von Willebrand Disease, etcetera. Patients will be
contacted. Patients with primary immune deficiency will be contacted. A
number of individuals will not be contacted, including those recipients
of non-UK sourced products, which has been the position of the UK for
some years now. And then there\'s the middle group in which an
individual risk assessment has to be done.

Now, the CJD Incidents Panel recommendations ‑‑ there is also some text
after this, and I will just read the cite again. I\'m sorry, this is not
a good way of presenting it, but I think it\'s very important to get
this precise and accurate. For each of the major assumptions underlying
the risk assessment, the most precautionary option was chosen.

The uncertainties underlying the assessment of risk are great, and
several precautionary assumptions are involved. Therefore, the at-risk
threshold for public health purposes is not a precise guide for advising
individuals about their potential additional risk of developing vCJD.
Very important.

So this is a public health move, because these individuals have been
advised not to, for example, act as blood donors or tissue donors, to
avoid recycling of infection within the UK population.

Now, again, I\'m sorry about this for people in the back, but this is
the ‑‑ some of the tables form the Der Norske Veritas risk assessment,
which is on the website here. This is a possible infectivity level that
is transferred to patients from plasma pools containing a donation from
variant CJD patient, and this is the infectivity in ID-50s per year for
a range of products.

And one of the ones that comes out here is Factor VIII with ‑‑ down at
the bottom with one ID-50 after one year\'s treatment, which is why I
think the policy to inform these individuals was introduced.

However, as I\'ve said, all the risk assessment ‑‑ the risk assessment
contains a lot of variables with a lot of ‑‑ a range of potential
outputs, and they have decided to use all the worst-case assumptions.
And just to show you some of the variation ‑‑ I\'m sorry this hasn\'t
projected very well. But this is two alternative approaches in the risk
assessment, for example, infectivity by a high approach or by worst-case
scenario.

And there is quite a lot of difference. There\'s, you know, two logs
difference in many of these assumptions. And I\'m sorry, this one is
just as bad ‑‑ two alternative approaches for the dose of each product
containing an ID-50. And, again, there\'s marked variation within this,
within each product, depending on the assumptions that are made.

And I think finally, which might be more visible, this is a comparatant
of the estimates of infectivity in plasma fractions, which, of course,
is a very important baseline for making risk assessment. And there are a
whole range of possibles here depending upon the assumptions that you
make with cryoprecipitate here, Factors I, II, III in dark, and Factors
IV and V, these light areas here.

So there\'s a huge range of possible assumptions you can make about the
levels of infectivity before you start. And there\'s also, which I
won\'t go on because of Hank Baron\'s talk, the estimated clearance
fractions in plasma products ‑‑ again, with some variability between two
sets of assumptions.

Now, having said all that, I thought I\'d better just put it in the
context of other European views from official bodies. And this is the
French Agency for the Protection of Public Health and Medications. And
this states ‑‑ this is from 2003, although I do believe that there is a
further version of this from this year, which has come to more or less
the same conclusions I think.

The conclusions or recommendations of the report established in December
2000 remain valid. None of the items dealt with ‑‑ discussed in this
report needs to be modified. No new measure to propose in relation to
further reduce the risks of transmission of vCJD by blood products.

And, of course, one of the reasons for this is that the situation in the
UK is unique. We have a very relatively high incidence of variant CJD
compared to any other country. We do have evidence from the tonsil and
appendix study that there may be people incubating the disease, and this
may not be true for many other countries.

The measures that were recommended by AFSSAPS in 2000 were as follows ‑‑
reinforce measures potentially reducing the infectious load, e.g. plasma
leukodepletion in addition to leukodepletion of cellular labile blood
products, which has been applied in France since April 1998, and the
addition of nanofiltration steps during the manufacture of some
plasma-derived medicinal products, continue the validation of processes
reducing the infectious load during the preparation of both labile blood
products and plasma-derived products, and maintain close scientific and
epidemiological surveillance.

Then, there is the European Medicines Evaluation Agency, which in June
2004 provided a report which had considered the first presumption
transfusion transmitted case, but not the second I must stress. And I\'m
just going to read three of the conclusions from this report.

It is recommended that donors who spent a cumulative period of one year
or more in the UK between these periods are excluded from donating blood
plasma or blood stroke plasma for fractionation. There is no
recommendation to recall batches of information that would have excluded
a donor based on his/ her stay in the UK becomes available
post-donation, since this is a very conservative precautionary measure.

Secondly, this is an issue to do with the manufacturing process and to
do with clearance factors. The rationale for this position is that if,
in the future, further cases of vCJD occur in countries collecting blood
and plasma for the manufacture of plasma-derived medicinal products, a
process previously shown to be able to reduce TSE infectivity will
provide reassurance on the safety of past products and could help to
justify continuing fractionation, which seems to be perhaps
understandably slightly a different position from that taken in the UK.

And, finally, it is, therefore, recommended that donors who have spent a
cumulative period of one year in the UK are excluded. Countries are
highly encouraged to choose their national cumulative period limit for
plasma-derived medicinal products according to a nationally calculated
benefit risk balance, which will take into account the endogenous risk
of BSE and the risk of shortages of blood and plasma for the manufacture
of medicinal products.

Just to finish, the UK precautionary measures that have been taken ‑‑
withdrawal and recall of any blood components, plasma derivatives, or
tissues obtained from any individual who later develops vCJD, which was
taken in December in 1997.

Important of plasma from the U.S. for fractionation to manufacture
plasma derivatives, announced May 1998, implemented October 1999. And
perhaps one thing I should say is that the concerns that have been
expressed this morning, and a bit later in the morning, are that it is
clearly important that from the UK\'s perspective and from the plasma
recipients in the UK, that the blood that is obtained in the United
States is itself at low risk for variant CJD. And the implementation of
measures to ensure that such appropriate screening take place is very
important.

Look at depletion of all blood components announced July 1998,
implemented autumn 1999, importation of clinical, fresh-frozen plasma
from the U.S. for patients born on or after the 1st of January 1996.
That is, individuals who are presumptively not exposed to dietary BSE,
announced August 2002, introduced in spring 2004. Of course, promotion
of appropriate use of blood and tissue as an alternative throughout the
NHS.

And, finally, transfusion recipients deferred as blood donors in 2004,
of course, again with the idea of breaking the potential cycle of
reintroducing infection in the UK population.

So, conclusions. I think vCJD now should be regarded as transmissible
through blood transfusion for public health purposes, and I think the
scientific evidence is now fairly convincing.

One important issue is that precautionary measures in relation probably
would have taken years in advance of evidence of
transfusion/transmission in the UK, and, of course, in many other
countries including the USA, which Dr. Asher showed the long evolution
of such measures here.

Predictions of the future number of cases of vCJD in the UK may have to
be revised. And we believe that humans with ‑‑ who are heterozygote at
Codon 129 PRNP can be infected with BSE, although we do not know whether
they will have any clinical expression of disease. And I think difficult
decisions will arise if vCJD blood donors are identified in other
countries.

I don\'t have a slide of acknowledgements, but I shall just state that
the Transfusion Medicine Epidemiology Review has really been the
responsibility of Pat Hewitt and Charlotte Llewelyn from the National
Blood Service, who have worked very hard on this for years. And also Jan
McKenzie at the Surveillance Unit.

And the final comment, which I think is very important and I always make
it, we could do none of these studies without the cooperation of the
families of cases.

Thank you.

CHAIRPERSON PRIOLA: Thank you, Dr. Will.

Are there any questions for Dr. Will from the Committee?

DR. BRACEY: In terms of the patients that expired ‑‑ the 32 ‑‑ are there
any autopsy or necropsy specimens that haven\'t been studied but could
be studied?

DR. WILL: Well, it\'s a very important question, and it relates to the
ethics of the study. When we flag people with the Office of National
Statistics, we have to go through an ethics process, quite rightly, and
the ethics guidance from that is that any individuals who are identified
through that process cannot be contacted, and neither can their
clinicians.

So we know that the 32 individuals died, but we have no further
information on them, including post-mortem results.

Now, whether that ethical position should be reviewed in the light of
recent scientific developments is a very important issue. One thing I
can say, however, is that we do know that none of those 32 individuals
themselves acted as blood donors. So it\'s a very important question
that is under consideration.

CHAIRPERSON PRIOLA: Dr. Nelson?

DR. NELSON: Hearing you describe trying to trace these cases led me to
one question. Does the UK have a computerized registry of donors that
could be used to facilitate the lookback? Because it seems this would
help.

DR. WILL: Well, my understanding is that computerized systems for the
blood transfusion service were introduced in the UK many years ago. But
I can\'t exactly remember the right date, maybe around ‑‑ actually, I\'d
better not say. All I can say is that this means that for the variant
CJD donors, all of whom are young by definition, we have good access to
data and can get followup data.

We are carrying out a similar study in sporadic CJD, but the absence of
records in the \'80s and \'70s and prior to that has made that
extraordinarily difficult, because many of these individuals are in
their sixties and seventies when they die, and it is found they may have
donated blood 30 or 40 years ago.

So the answer is: we have ‑‑ there is a good computerized system for
tracing donations within the UK, but it is time-limited. It doesn\'t go
back forever.

CHAIRPERSON PRIOLA: Dr. Bracey?

DR. BRACEY: Yes, another question in terms of the ‑‑ I guess the 17
recipients that are still alive, 16, whatever the number is. Very
interesting information has been presented in terms of some potential ‑‑
obviously, they\'re still under investigational research assays that
could be applied to blood. Has there been any thought in terms of, you
know, doing those sorts of minimally-invasive assays in that group?

DR. WILL: Well, again, a very important question. Current ethical
guidelines do not allow us to contact those individuals. However,
clearly, it may be that some of those individuals would want to
contribute to scientific research. And we are actively considering
exactly how to proceed with this in the light of proper ethical
guidelines.

CHAIRPERSON PRIOLA: Dr. Salman?

DR. SALMAN: Yes. The question is about the sporadic CJD. What type of
results you are obtaining to parallel the results you are getting with
the new variant CJD?

DR. WILL: Well, I don\'t have the figures to hand. All I can say is that
the number ‑‑ in that lookback study, we have a very limited number of
individuals in which we\'ve been able to trace the names of the
recipients and find out what has happened to them subsequently.

To date, in that study with very limited numbers, we have no evidence of
transmission of sporadic CJD in the light of what we have found with the
variant cases using the same methodology. But I have to say I think
there is a study going on in the United States that\'s very much more
powerful than our study that was reported at the February meeting in
which they had fairly large numbers with quite a long followup period.

So our data is very limited, unfortunately, for the methodological
reasons I\'ve explained.

CHAIRPERSON PRIOLA: Dr. Sejvar?

DR. WILL: I\'m sorry?

PARTICIPANT: When will those be reported?

DR. WILL: Oh. They\'re going to reported again today.

DR. SEJVAR: I\'m sorry. You may have already, you know, mentioned this.
But given the ethical considerations, how was the pre-clinical second
transfusion case identified or come to autopsy?

DR. WILL: After the identification of the first presumptive transfusion
transmitted case, the decision was made to inform the patients and the
doctors of the surviving recipients. So it meant that when the
individual died of an unrelated illness there was clearly an incentive
with consent from the relatives to carry out a detailed post-mortem to
see whether there was any evidence of infection with variant CJD. And
that\'s how it happened.

CHAIRPERSON PRIOLA: Okay. If there are no more questions, we\'ll move
on. Our next speaker will be Dr. Steve Anderson.

DR. ANDERSON: I was going to say good morning, but it\'s already
afternoon. So good afternoon.

My name is Steve Anderson, and I\'m the Associate Director for the
Office of Biostatistics and Epidemiology in the FDA\'s Center for
Biologics Evaluation and Research.

So today I\'m going to talk about comparing transfusion risks for
variant CJD and CJD transmission via blood. And at the end of the talk
I\'m going to mention some of the risk assessments that we\'re currently
developing to look at some of the TSE risks for blood products in the
United States.

Animal data have suggested that both variant ‑‑ that both CJD and BSE
can be transmitted via blood. Now, I\'ve listed a couple of examples
here of animal systems and the types of agents that have been tested.
For instance, sheep and BSE ‑‑ that\'s both been done by Houston and
Hunter in the same group, as well as scrapie.

Dr. Rohwer\'s group has looked at hamsters and scrapie. And I believe
you reviewed his work in the February 2003 meeting and in the previous
meeting as well. And then there was work done in mice with CJD and
showing transmission via blood in all of these animal systems with these
particular prion agents.

Now, I\'m not ‑‑ I have slides on the particulars that Dr. Will just
spoke of, so I\'m actually just going to sort of flash them and say you
already ‑‑ we already know about these two particular patients in
December 2003 and July 2004. And he has explained far more than I know
about them.

I\'m not going to discuss any of the particulars of the surveillance
program, the TMER study that Dr. Will just discussed, but will mention
it at the end of the talk when I talk about the little example
comparison that we\'ve done.

Now, I just wanted to remind people about CJD and blood epidemiology.
Just to remind people that the incidence ‑‑ it\'s a very rare disease.
The incidence is about one death per million population per year. It
occurs largely in older individuals and has a long incubation period.

The current evidence suggests that CJD transmission via transfusion is
considered a low risk. Now, I think it\'s important to mention as well
that if the transfusion risk was significant, one might expect to see an
increase in the CJD rate annually, or the disease might increasingly be
seen in younger and younger individuals.

However, the CJD rate has been essentially stable for the last 10 to 20
years in the U.S., and I believe in other countries in Europe where
monitoring has been taking place.

And we\'re going to receive a talk this afternoon on the American Red
Cross-CDC lookback study, so I\'m not going to go much into the details
of this. The current lookback study just tracks 368 individuals who
received blood from donors that later were diagnosed with CJD. I\'ve
just received an update that it\'s 118 of the recipients, instead of 116
of the recipients, have lived longer than five years post ‑‑ greater
than equal to five years post-transfusion.

And approximately 28 percent of those individuals, or 102 recipients in
the study, are still alive. And to date, there have been zero observed
CJD infections observed in the study. And I think that\'s an important
concept to reinforce, that if ‑‑ it is possible that this event could
occur, but at the very least we\'re looking at something that\'s a very
potentially rare event.

And our interest as well is in ‑‑ as a risk assessment person, we\'re
interested in the hemophilia populations that are potentially at risk as
well. Those that use ‑‑ frequently use blood or plasma derivatives might
be at higher risk for contracting CJD, variant CJD, or a number of
potentially other prion diseases.

CDC has done a study, and they\'ve talked about this at the previous
Advisory Committee meeting ‑‑ again, the CDC study was 12,000 hemophilia
patients that they looked at, and they also looked at 40 decedents.
Again, no observable CJD to date in that patient population.

And the UK also did a similar study, although smaller than this one.
They specifically, I believe, looked at 33 autopsies of hemophilia
patients in a post-mortem study. Again, no indication of variant CJD or
CJD in that population.

I\'m just going to breeze through to get to the comparison. So for our
comparison, again, this is just an example. There are a lot of
comparisons that we can use. We could look at comparisons among the
animal data ‑‑ the human data and the animal data.

What we\'re doing here is we\'re looking at a comparison between the
variant CJD populations that are under surveillance that have given
blood, and we now have recipients that have received those blood
products, and then the American Red Cross-CDC lookback study.

Again, the numbers ‑‑ for our interest, I\'m going to ‑‑ we\'re going to
keep with 116, since that\'s what I had in the slide ‑‑ 116 in zero
observations, and so far 15 in two observations for the variant CJD
study.

And if we set this up in a simple matrix and look at it, I\'ve done a
very rudimentary statistical analysis, and I\'m glad to see that Dr.
Will has done ‑‑ and the UK risk assessment people have done a nice and
actually more precise analysis than what I\'ve got here. So this is
pretty crude and rudimentary.

But what we\'re seeing ‑‑ what we would say is that the ‑‑ based on this
information, there\'s a small probability this would be actually less
than or equal to 1.2 percent that variant CJD cases occurred by chance.
And as Dr. Will just stated in his talk ‑‑ and I\'ll sort of try to
remember those numbers ‑‑ I believe his population estimates were much
more precise, and he estimated that across the population the chance
occurrence of two of these types of events occurring through, say, a
source like food exposure would be something like one in a billion.

And based on the tonsil study, you could adjust that as well, and that
would be ‑‑ I believe he quoted a number of 1 in 80,000. So I think the
conclusion that you draw from these types of analyses is that it seems
clear that these variant CJD cases are arising because of transmission
transfusion of variant CJD from donor to recipient.

And I think there are a lot of caveats to doing these types of analysis.
That\'s why we haven\'t really done a lot of in-depth analyses, because
the power in the ‑‑ the statistical power of these studies is really
limited, and there are a lot of limitations.

The size of the groups that we\'re looking at are relatively small, only
15 patients in the case of the variant CJD surveillance. The incubation
period of the disease is long. And I think that\'s important given that
most blood recipients are very sick individuals, and they usually have a
high mortality rate two or three or five years out. So their chances of
survival are ‑‑ often exceed the incubation period of these long
incubating prion diseases.

All right. So as a risk assessment person, I tend to look at weight of
evidence approaches when I\'m doing my risk assessments. Now we\'ve got
two pieces of important information. First, we had a clue early on that
animal transfusion transmission was possible, and now we\'ve got these
two cases.

So what we\'re working with now is that it seems like variant CJD
transmission transfusion is a reality essentially, and we\'ve got to
treat it like that. This is a very important public health issue that we
need to monitor and evaluate very carefully.

So what we\'re doing at FDA is we\'re developing risk assessments for
blood products in the United States. Specifically, we\'re starting with
Factor VIII, and we did present a preliminary risk assessment for Factor
VIII products at the February 2003 meeting of this Committee. We\'ll
probably move on and do Factor IX, and then other important blood
products as well as we complete the initial analyses on Factor VIII and
Factor IX.

I think the important thing to take away is that these risk assessments
evaluate TSE risk for blood products. They help us identify risk
reduction measures. And not only that, but evaluate the effectiveness of
those risk reduction measures. So it\'s part of a plan of reducing the
risk, and the public health risk that could arise from variant CJD or
CJD possibly transmitted through these products.

I will end with that.

CHAIRPERSON PRIOLA: Any questions for Dr. Anderson from the Committee?
Dr. DeArmond?

DR. DeARMOND: How far along are your ‑‑ the risk assessment of Factor
VIII?

DR. ANDERSON: I would say it\'s probably midway through. And we\'ve got
some initial results from that, and we would say ‑‑ I think Dr. Epstein
alluded to before that the estimates, preliminary estimates anyway, are
that the risks in the United States are significantly lower than they
would be for the UK.

DR. DeARMOND: What sort of Ns ‑‑ how many individuals, or how are you
doing that assessment?

DR. ANDERSON: We\'re looking specifically for Factor VIII, looking at
the hemophilia populations. So we\'re starting out with actually back
calculations for the potential number of individuals in the United
States that could have variant CJD or CJD, and then could donate blood
into a plasma pool. And from there we\'re looking at the plasma
processing steps and the reduction steps to the TSE agent in there.

And then, finally, looking at how patients utilize those products, and
trying to determine their, you know, annual risk and individual risk. So
that\'s a quick ‑‑

CHAIRPERSON PRIOLA: Dr. Nelson?

DR. NELSON: Are you considering the source of the donors of the Factor
VIII or blood products? In other words, clearly, there is a greater risk
of a UK donor, even in the past. And how are you adjusting your analysis
for that factor?

DR. ANDERSON: We\'re actually including that. We have ‑‑ in our back
calculations, what we\'re doing is we have actually a fair number of
populations in the U.S. that are potentially at risk. So there\'s the
background risk essentially, potentially in the United States, of BSE
risk. So that\'s put into the model.

And then there are all the populations that have traveled and meet the
criteria for the deferrals that are in this study as well ‑‑ military
and their dependents, and immigrant populations as well. So it\'s a
pretty ‑‑ we\'re trying to include as much of that information as
possible.

I think the important question that came up was: can we measure evasion
or people not honestly answering questions? And we could put that in if
we had a better measure of that parameter, but we don\'t have that
exactly in it now, so ‑‑ I believe our ‑‑ the effectiveness of the donor
deferral policy, we have a range of 75 to 90 percent effectiveness on
that.

DR. NELSON: The REDS study may have some data on that. And, actually,
you know, they have looked at people who have ‑‑ who test positive who
on retest how many have ‑‑

DR. ANDERSON: Not honestly answered the questions.

DR. NELSON: Yes. But I don\'t think they\'ve done it for geographic
risks and BSE risks yet. But I think that might be a priority, actually.

DR. ANDERSON: We\'ll consider it, certainly.

CHAIRPERSON PRIOLA: Dr. Gambetti?

DR. GAMBETTI: Could you just remind us on the ‑‑ how, really, the CJD
was excluded in that study of the American Red Cross and CDC study ‑‑
and CDC on transmissibility of CJD by blood transfusion? In other words,
was only ‑‑ I understand that there\'s a considerable number of cases
still alive, but was any autopsy performed on those ‑‑

DR. ANDERSON: For the lookback or for the hemophilia?

DR. GAMBETTI: The lookback study.

DR. ANDERSON: I think I\'ll let ‑‑ Larry, do you want to answer that?
Sorry.

DR. SCHONBERGER: The lookback study is basically looking at death
certificates, cross-checking the recipients that are identified who have
received a component from a CJD donor, going to the hospital, getting
all the identifiers, and then cross-checking with the death index to
find out: a) whether the recipient died, and then, b) much as was done
in the UK, find out whether there was any neurologic disease identified.

And the actual numbers ‑‑ he had it in one table ‑‑ greater than three
years, which the 116 was greater than or equal to five years.

DR. GAMBETTI: Five. Five.

DR. SCHONBERGER: But in the next table it was ‑‑ comparison was greater
than three years. And that would give you another ‑‑ make it 128
patients, just to give you some sense of how the numbers would change as
you increase the period of followup or decrease that period.

The hemophilia situation was done differently. That ‑‑ I think DeArmond
was ‑‑ had volunteered to take any death from a hemophilia patient, with
or without any neurologic symptoms, but any death where there was a ‑‑
where they would volunteer to donate the brain tissue for detailed exam,
looking, in essence, for a pre-symptomatic lesion of CJD in the brain.

And, DeArmond, you may want to comment. I think most of them were AIDS.

DR. DeARMOND: This is before we understood about the spleen and other
organ involvement in some of the acquired forms of CJD, variant CJD. But
these ‑‑ we looked at the patients that had neurological symptoms, and
they died either of a Hepatitis-related ‑‑ Hepatitis virus-related
neurological disorders ‑‑ that is, hepatic encephalopathy or
AIDS-related disorders. And we didn\'t see any abnormal prion protein or
vacuolation that would suggest a prion disease. It\'s a relatively small
population.

DR. SCHONBERGER: Right. So these are people, then, who didn\'t have a
clinical diagnosis of CJD who are hemophiliacs, and then having their
brain studied by Dr. DeArmond to make sure there was no sort of silent
lesion.

DR. DeARMOND: In fact, they did have lesions, but they weren\'t lesions
‑‑

DR. SCHONBERGER: Of CJD.

DR. DeARMOND: ‑‑ of CJD. They were the AIDS-type lesions, progressive
multi-focal leukoencephalopathy and things like that.

CHAIRPERSON PRIOLA: Okay. Thank you, Dr. Anderson. We\'ll move on to the
last talk of this late morning/early afternoon session, and that\'s Dr.
Luisa Gregori.

DR. GREGORI: Thank you. This presentation will focus on removal of TSE
infectivity from blood using leukofilters.

It is known for some time in the literature that TSE infectivity in
blood is concentrated in a buffy coat. If we take whole blood ‑‑
infected whole blood and spin it around to prepare the three major
components ‑‑ plasma, buffy coat, and red cells ‑‑ and then each
component is titered, we find that there is a level of about 30 percent
of infectivity found in plasma, 45 percent in buffy coat, and the rest
is the red cells.

This type of distribution was quite a surprise result for many people,
because we are used to seeing that TSE infectivity is cell-associated.
And this 30 percent here with infectivity was kind of strange, but I\'ll
come back to that point later.

Some one of the first things that we were interested in is to identify
the cellular component that is involved with TSE infectivity. The first
component, the first cell type that we looked at, were platelets. We did
this work with ‑‑ in collaboration with Holada and Vostal at the FDA.
They are platelets experts, and they came to our lab. And two to five
platelets from infected blood, and we noted that these platelets and
look at the infectivity, and we found that there was no infectivity
platelets.

So we kind of said, \"Okay. Platelets are out.\" Red cell ‑‑ they are
not really ‑‑ there is no evidence in the literature indicating that red
cells might be in a ‑‑ carry infectivity, and we have a study now
ongoing in our laboratory that I think will definitely confirm, and that
red cells are not involved with TSE infectivity.

So that pretty much leaves out the white cells. So the question is:
white cells are the only component that carries infectivity. This is one
of the bases for the leukofiltration. Red cells seems to be the ‑‑ at
that time looked like it was the major carrier of infectivity, so the
deal was if we remove white cells, and then we remove infectivity from
blood.

That\'s despite the fact that there was quite a significant portion of
infectivity found in plasma, as I mentioned earlier. But people was
thinking that that infectivity in plasma was perhaps contamination from
white cells or cell debris or something like that.

One study ‑‑ actually, more than one study that was reported in the
literature shows that if plasma from infected blood is centrifuged at a
high speed, and the supernatant is tested, there is no significant
removal infectivity, indicating again that that type of infectivity
might be in a soluble form or in ‑‑ not cell-associated I should say.

There were also two studies done, present in the literature ‑‑ one by
Paul Brown and co-workers, and one by Prowse and Bailey, looking
specifically at leukofiltration. This study has been around for some
time. I\'m not going to describe them in details. All I want to do at
this point is summarize their findings.

For the first study, they used infected plasma from mice infected with
TSE and they filtered plasma through a plasma platelet filter, and they
found that there was no removal of infectivity by the leukofilter. The
second study was done in a very different manner. They tested four whole
blood commercial filters, and they challenged the filters with a unit of
human blood spiked with PrPres from hamster brain.

And then they looked at the ‑‑ what was filtered at the leukoreduced
blood in terms of PrPres removal by Western Blot. And in that case also
they found no removal of PrPres by any of the leukofilters they tested.
So that was the first indication that there might be something going on
in there that perhaps leukofiltration might not be removing all the
infectivity in blood.

However, many countries had decided to adopt leukofiltration and
implemented it as a universal leukofiltration. And one of these
countries was Canada, and Tony ‑‑ Dr. Giulivi came to us and he wanted
‑‑ he\'s from Health Canada, and he wanted us to do a study to see if we
could show whether we could test whether the leukofilters did remove TSE
infectivity.

We were also considering that leukofiltration could not be considered
the perfect solution until we actually demonstrated and make a
validation study. So we were very glad that Tony came to us, because we
could do this experiment with Health Canada.

The validation we decided to do ‑‑ we had to decide what kind of
challenge to use for these filters. We couldn\'t think of any spike that
we can prepare that would be a valid spike. So we decided to do without
spike. We will do endogenous TSE infectivity in blood, and this will be
the challenge.

We also, for the same reason, we did not want to scale down the study,
so we did a full unit of scrapie hamster whole blood. And at that point,
then, we used all of the same protocol and treatment used at the blood
centers in Canada. The Canadian ‑‑ Health Canada has adopted two systems
of leukofiltration, one for whole blood and one for red cells and
platelets.

The whole blood is shown here. Here is where usually human blood will be
collected. We did not put human blood. We collected one unit, about
450 mLs, of hamster infected blood. This obviously was pooling, because
that ‑‑ one hamster has four mLs of blood. So that\'s about 130 to 140
animals. So the blood was pooled. This was leukofiltered. This is a Pall
leukofilter, this online filter.

And we collected leukoreduced whole blood here, and this, then, we
continued to prepare red cells and PPP fraction. So this was the first
leukofiltration unit that we tested.

We also tested a second one, as I said. This is ‑‑ has two filters and
is a more complicated ‑‑ this is another unit of hamster blood. We first
centrifuged this unit, and then the supernatant, as it\'s called,in
platelet-rich plasma was passed through this filter, the platelet
filter. And the red cells was passed through the red cell filter. And
then we continued to prepare all the rest of the fractions and
components.

We did not titer this, so I\'m not going to show you data about ‑‑ I\'m
referring to this particular filtration, but I\'ll focus on the
filtration that I showed you earlier on whole blood leukofiltration.

The first thing that we had to demonstrate to ourselves and to
everybody, that the leukofilter that is specified and designed for human
blood would perform the same way with hamster blood. We didn\'t know
that at that time when we first started.

So to demonstrate ‑‑ to make this demonstration, and to verify that we
could actually do this type of experiment, we used the AABB ‑‑ the
American Association of Blood Banks specifications, and we tried to meet
all their specifications. So we collected one full unit, about 250 mLs
of hamster infected blood in a few hours. These animals were all at the
same clinical stage, and they were obviously pooled.

The blood was processed within eight hours from collection, which is one
of the AABB specifications. So we were able to meet the time
specification.

We also looked at removal of white cells that should ‑‑ it has to be at
least three logs of white cell removal. Also, the AABB specification
indicates that a leukoreduced red cell component must contain at least
85 percent of the original red cells and cannot contain more than 5
times 10^6^ white cells.

So we measured the white cells in hamster blood before and after
leukofiltration, and all of the other fractions. The method that we used
is a cell counter calibrated for hamster blood. This cell counter is a
HemaVet and has the capability of doing five-part differential.

We also measure the cell count in the leukoreduced fractions by manual
count and by flow cytometry. The flow cytometry was done in Health
Canada, and they stained white cells with propidium iodide. We did not
measure cell fragmentation in microvessels generation. This was one of
the concerns that the Scottish National Blood Service had, and they
published a paper sometime ago indicating that the leukofilters do not
produce this effect.

This is the activity of cell removal. As I said, we had to ‑‑ we had to
show what kind of white cell removal we obtained with this filter that
was used with hamster blood, and also all of the other recoveries. So
here are the ‑‑ this is a lot of numbers. I\'ll just focus on a couple
numbers here.

Those are the fractions that we tested pre ‑‑ whole blood
pre-filtration, whole blood post-filtration, PPP, and red cells. This is
platelet-poor plasma. And this is the recovery for the white cells, the
recovery for the red cells, and the recovery for platelets.

The first thing is the recovery of ‑‑ no, the removal of white cells
after leukofiltration. It\'s 2.9, and 3 was our target, so we are close.
The removal of white cells ‑‑ the contamination of white cells in the
red cell component has to be less than 5 times 10^6^, and it was.

And, lastly, the other AABB specification is that the recovery of the
red cells must be more than 85 percent of the original red cell content,
and we obtained 86 percent. So from this observation and data we
concluded that this study could be titered, because the cell recovery
and white cell removal was according to the specification of the AABB.

And, therefore, we proceed into the titration of the two fractions ‑‑
the pre-filtration, the whole blood pre-filtration, and aliquot of the
whole blood post-filtration, the leukoreduced whole blood.

The titration was done using the limiting dilution titration method that
I\'ll talk in a minute. More than ‑‑ about 100 animals were titered ‑‑
were used for each titration. That\'s about 5 mLs. The titration was
completed after 566 days post inoculation, and the brain of every animal
was analyzed by Western Blot.

This is something that we routinely do in our laboratory for validation
studies, and the purpose of this Western Blot is to ‑‑ there are two
purposes. One is to confirm the clinical scoring; and, second, is to see
if any of the animals that are sacrificed at the end of the study were
actually incubating TSE.

Occasionally, we find that some animals were pre-clinical, and we can
pick up the PrPres by Western Blot in their brain. In this particular
study, there was none of those animals pre-clinical, so there was a
complete match between the Western Blot results and the clinical scoring
on the animal.

This is a slide you might have seen before. This is the limiting
dilution titration method. This is a method that was developed in our
laboratory, and this is used in the titration of solutions with very low
level of infectivity.

The way it works is rather simple. We have an animal that is the donor.
This animal has somehow been infected, so the ‑‑ we take the blood from
the donor animal, and then we inoculate this blood ‑‑ let\'s say, we
take 5 mLs of ‑‑ this one animal has only 4 mLs, so this has to be at
least two animals to do this.

(Laughter.)

So the incubation ‑‑ we inoculate 5 mLs, 50 microliters each, into 100
animals. Then we wait the time for the disease to take its course, and
then, at the end, we count the number of animals that are infected.
Let\'s say in this case there are 44, so there were 44 infected in 5 mLs
of blood. That\'s 8.8 infectious doses per mL.

This number then has to be corrected for the distribution that takes
into account the probability that one animal received two doses of
infectivity. And that usually increases the value a little.

So this is how we did our titration. That\'s how we do all our
titrations for blood or blood components. This is just to show you the
distribution of incubation time of all the animals that were in this
study. This is whole blood in red. This is the post-leukoreduced whole
blood in blue. Those are ‑‑ here in gray are the animals that were
sacrificed at the end of the study. And they were all normal. And the
square ‑‑ the triangle one are the animals that died of not scrapie
during the incubation.

This is the results. I noticed earlier that in the handout that you have
this table didn\'t come out. I apologize; it was not intended. But this
table is in the publication, The Lancet publication, so you can see it
there.

The whole blood ‑‑ those are the two fractions that we titered ‑‑ whole
blood and leukoreduced whole blood. This is the volume we inoculated,
the total number of animals that we inoculated, the animals that came
down with the disease.

This is the titer that we found for whole blood and pre- and
post-leukofiltration. This has been adjusted for Poisson distribution.
So what this means ‑‑ and this is the fraction distribution of
infectivity, what this means ‑‑ it means that 58 percent of the total
infectivity that we started with was still present in the leukoreduced
whole blood.

Or another way to put it is that about 40 percent of infectivity was
retained by the filter. And this is about the same percentage of
infectivity that we found ‑‑ we find if blood is separated by
centrifugal force in the buffy coat.

So we think that these two results are pretty much consistent with the
removal ‑‑ with some part of infectivity being present in white cells,
either in buffy coat or stuck to the leukofilter. That also ‑‑ we also
think that the post-leukoreduction infectivity is most likely in plasma,
and that, therefore, the infectivity in blood is present at least in two
forms ‑‑ one associated with white cells and one in plasma.

There were also some other conclusions that we draw from this study
about the ‑‑ we were worried that the infectivity may wash off or be
liberated during leukofiltration. We did not find this to be the case.

The implication is that leukofiltration we think is necessary but not
sufficient to remove all blood-borne TSE infectivity. In this specific
case, we have almost 6,000 units in one unit of hamster blood that I
showed you, about 6,000 units of infectivity. At the end, we find more
than 3,000 in the leukoreduced blood.

So it ‑‑ post-leukoreduction infectivity is not cell-associated, and,
therefore, we think there is a need for additional methods to remove TSE
infectivity.

And I close with this.

CHAIRPERSON PRIOLA: Thank you, Dr. Gregori.

Are there any questions for Dr. Gregori from the Committee?

It was very clear. Thank you.

Are there any other ‑‑ do any of the Committee members have any other
questions for any of the speakers this morning before we break for
lunch? It appears we need to break for lunch.

(Laughter.)

So we\'ll reconvene here. We\'ll take an hour. We\'ll reconvene here at
1:40.

(Whereupon, at 12:43 p.m., the proceedings in the foregoing matter
recessed for lunch until 1:50 p.m.)

DR. PRIOLA: I guess we\'ll go ahead and get started with the afternoon
session. And our first speaker will be Dr. Peter Ganz from HealthCanada.

DR. GANZ: Good afternoon. I\'d like to thank the TSEAC Committee and FDA
for giving HealthCanada an opportunity to share some of our recent
thinking in the area of variant CJD in risk-reduction measures for the
blood system. And thanks for a very, very broad title on the agenda.
I\'m actually going to focus the talk primarily on variant CJD and not
CJD and I also note that Dr. Ron Rogers, we\'ve had a couple of
presentations previously at this Committee concerning BSE and some
broader TSE issues in Canada over the years. So I\'m not going to
retread old territory.

And again, I\'m not going to spend a lot of time. I know that you\'ve
had a very good overview of many of the variant CJD issues in previous
presentations, so I\'m not going to spend too much time on background
material.

In terms of worldwide numbers of cases, as Dr. Will remarked, there was
a case in Canada and again what\'s of interest is that if there had been
deferral measures at the time that would not have been an individual who
would have been eligible to donate and that one case is one that is not
indigenous to Canada.

Very generally, risk mitigation efforts in Canada certainly mirror those
elsewhere. Globally, there are very, very general TSE control measures
that have been in place since 1996 and as I mentioned, I think last
year, Dr. Ron Rogers sort of summarized some of those control measures
very generally for this Committee. There are food chain control measures
that have been implemented. And also, there\'s a very, very active
surveillance system, not just for animal TSEs but surveillance for CJD
very, very generally. And Canada is very, very active internationally on
the surveillance front.

For the blood system, a couple of points I\'d like to try and make with
regard to background. Since 1996, HealthCanada has carried out a number
of various risk assessment exercises and had consultations and
internationally regarding variant CJD risk issues and managing those. In
a nutshell, the summary of all of the risk assessments and consultations
has been operationally that HealthCanada exercised our precautionary
principle, primarily, because we were dealing with theoretical risks and
put in place geographic travel and residency deferrals that were again
based on theoretical risk of transmission. And again, those needed to be
balanced against the loss of available blood supplies.

Also, for the blood system and again, I want to emphasize quite clearly
that for reasons and benefits not related to reducing variant CJD risks,
HealthCanada issued a regulatory directive in November of 1998,
requiring that blood system operators implement universal pre-storage
leukoreduction and in fact, as of June 1999, all blood in Canada has
been leukoreduced. And again, I am, I guess cognizant of the recent
publication which we sponsored that by Gregori, I guess there will be
another presentation later indicating that at least in [The
Lancet]{.underline} article that 42 percent of the total TSE infectivity
from blood may be reduced by leukoreduction. So perhaps in hindsight,
this might be a valuable measure.

Now when we went forward with the series of directives that we had put
in place, we had a commitment that was made that we would periodically
review any new scientific data and consider amending deferral measures,
based on new information. And again, we\'ve had some presentations
already today concerning data from experiments in animal model systems
indicating that there can be transmission via blood and again we\'ve had
summaries already, fairly detailed summaries indicating the two more
recent published studies showing CJD infection in individuals who
received blood components donated from patients who died of variant CJD.

Now with regard to deferral measures in place in Canada, again in August
of 1999, we issued a directive and primarily focused on reducing risk
from individuals who lived and resided in the U.K. for greater than six
months. We did a number of theoretical risk assessments and I believe
Dr. Tony Giulivi at one point from our program area did discuss this at
either BPAC or TSEAC and based on some of the theoretical risk reduction
numbers, we feel that that particular measure reduced our theoretical
risk to levels greater than 80 percent. However, the cost of doing that
at the time was about 3 percent of our donor base in Canada. And that
was originally predicted and there have been some follow-up surveys and
I believe that the actual numbers are pretty close to 3 percent which
was really the buffer in the blood system in Canada that we could
accommodate. So between our first directive and leading to the present
day, there\'s been a huge effort on the part of our blood system
operators, Canadian Blood Services and Hema-Quebec to recruit new donors
to basically replenish our donor base.

In September of 2000, based on, at the time there were three deaths due
to variant CJD in France. We felt that the risk wasn\'t equivalent to
the U.K. risk, but there was still a risk and we felt that it would be
prudent to look at again, geographic deferral for France. That was
implemented and again, there was \-- the donor base erosion was again
\-- it was somewhat less, around 1 percent, depending on which part of
Canada, whether it was Province of Quebec or elsewhere. And again, there
was a slight reduction of 5 percent or so of what we believe in
theoretical risk reduction.

In August of 2001, we again broadened the geographic deferral slightly,
and in fact, asked our operators following a very successful and
unprecedented donor recruitment effort, asked them to consider whether
or not it might be possible to yet further reduce geographic risk
reduction, geographic deferral in the U.K., France and also to consider
a broader Western Europe deferral and again, that was done and was
carried out. And in fact, within the Province of Quebec, based on their
donor demographics and that\'s the area serviced by Hema-Quebec, we have
a one-month deferral for the U.K. So we\'ve tightened the deferral here
yet further.

All in all, we feel that we have a greater than 92 percent theoretical
risk reduction with these kinds of measures and again, there have been
obviously consequences in terms of numbers of donors deferred. Also,
very importantly, we decided with the directive in August to include
individuals who have ever had a transfusion in the U.K. and that
includes labile blood components such as platelet, red cells or plasma.
And again, that\'s irrespective of the travel and residency deferral.

So that\'s really where we are today in terms of blood system deferral
measures. And again, as I indicated in a couple of slides earlier, we
are looking at what are the options for reducing risk yet further and
are there such options available.

And again, I want to emphasize we don\'t look at deferral measures very
lightly in the sense that it is a rather onerous process to do for the
operators and does have consequences for blood supply globally,
generally.

One option obviously is to maintain the status quo. The risk reduction
measures that are currently in place in Canada could be considered as
adequate and we would just assume that we have \-- we\'re at the stage
now with our current directives that our system is as safe as it can be,
given risks.

A second option is to consider more stringent travel residency donor
exclusion policies such as reducing the time spent in the U.K. to less
than three months, reducing the time span in Western Europe to less than
five years and also to look at whether or not we can reduce yet further
the travel residency requirements for France to less than three months.
So that \-- those are options we\'re looking at.

Another option is to \-- whether or not it might be prudent and again
this touches a little bit on Dr. Asher\'s slide earlier is to consider
in terms of human to human risk, whether or not one could consider
excluding individuals who ever received a transfusion in Western Europe,
including France since 1980. So that would be a consideration to broaden
our transfusion deferral which is currently for U.K. broaden it to
include France and Western Europe.

So those are the options that we\'re currently looking at and also I
want to emphasize yet again that any kind of changes such as those in
option 2 or 3 would have to consider the potential to create blood
shortages, because the risks that we\'re looking to manage are
incremental.

We\'ve had a number of consultations on these various points, certainly
with the blood system operators in Canada, Hema-Quebec and Canadian
Blood Services. Obviously, a first step to these considerations and
moving forward with these would be to look at our existing donor
demographic data, particularly concerning options 2 and 3 and I guess
ascertain whether or not those data are good enough data for decision
making or whether or not a more recent donor demographic survey would be
warranted.

The impact of proceeding with option 3 on the blood donor base and
that\'s the option to debar individuals who have ever received a
transfusion of labile components in Western Europe, including France,
appears to be minor, at least based on the number of deferrals that were
currently, that are currently in place for United Kingdom transfusions.

We\'ve \-- similar to the U.S. and many countries, our Expert Advisory
Committee on Blood Regulation met late in September and we had an
opportunity to discuss a couple of the new recent findings and some of
these issues with our advisory committee and I think that there was, and
we\'ll have minutes available on our website in a couple of weeks, but
basically we \-- there was, I think, some good discussion around a
number of these options and I think that there was some reasonable
strong opinion that we \-- that option 1, the current status quo was
probably not acceptable and that were opportunities to move forward.

What about the way forward? Well, certainly we\'re at very early stages
with considering these issues and that we have committed to further
consultation not only with the members of the general public and
interest groups, but also with the blood operators. We are currently in
a situation where both operators are going to look at their donor
demographic surveys yet again, the ones that were carried out initially
and again, with regard to trying to tighten the very general geographic
deferrals which include the U.K., France and Western Europe. Based on
the old donor demographic survey, it appears as if that latter option
would have a significant impact on the donor base. In other words, the
numbers, particularly for the U.K. for most of Canada, if you were
trying to reduce from a three month to a two month deferral, we\'d be
looking at cost of about 4 percent of our donor base for just a one
month tightening in that area and for some of the other options within
that broader option, again, the cost to the donor base seemed to be
fairly significant.

With regard to an option to debar donors who\'ve ever received
transfusion of labile component in Western Europe and France, we again
need to \-- initial discussions with operators indicate, again, based on
what we\'re deferring now for U.K., it appears as if that would cause a
minimal impact in terms of donor base and so that also is being looked
at.

I think this is pretty well my concluding slide, but certainly in the
discussions to date and our thinking to date, is that the impact of
moving forward with deferring donors who have ever had a transfusion in
Western Europe would result in debarring a small number of donors
against the benefit of having \-- risking the Canadian blood supply
being reduced by a small degree below the level that\'s affording with
the current three directives that we have in place.

So that is my last slide and certainly some of this will appear in
either on our website in terms of meeting minutes and we\'d be happy,
certainly, to update as time goes by.

Thank you very much.

DR. PRIOLA: Thank you, Dr. Ganz. Are there any questions from the
Committee for Dr. Ganz?

Dr. Bailar.

DR. BAILAR: I appreciate this presentation very much, but there was one
comment in passing that really pushed a button. It doesn\'t have much to
do with the burden of Dr. Ganz\' presentation here. We do not know
nearly enough about possible infective loads in blood products or
anything else, nor do we know nearly enough about infective doses.

To illustrate the problem, imagine that you have a unit of blood that
has 100 infected doses in it. Reducing that by 42 percent isn\'t going
to help. There will still be 58 ineffective units. The need here really
is for multiple log reductions, not things you would measure in percents
this way.

The gap here, I think is in knowledge about both \-- about the relation
between exposers and infective doses and I hope that FDA and others will
be working on this pretty hard so that we\'ll have a better
understanding of how they are related.

The problem is in fact much more general that reduction in risk is
simply not linear. It isn\'t even close to linear with respect to
reductions and exposure.

Forty-two percent is fine, but it\'s a bare beginning.

DR. PRIOLA: Any other comments from the Committee?

Dr. Epstein?

DR. EPSTEIN: Thank you very much, Peter. I appreciate you coming down.
Can you just clarify \-- I noticed that you\'ve maintained consistency
in the deferral period for exposure in France and exposure in the U.K.
despite what most people believe to be a disparate risk from food
exposure in those two geographic areas and I\'m just wondering whether
that\'s been done because of a pragmatic decision just to keep things
simple or whether it reflects some other equivalent measure of risk or
benefit?

DR. GANZ: Good question, Jay. Again, I think part of the reason there
was at one point we had made the policy decision that if there was a
jurisdiction that had variant CJD deaths that the deferral \-- that we
would have a deferral, based on incidents of variant CJD death. So
that\'s originally how that came about and they were, as I say, at the
time three deaths in France and deaths in the U.K., and hence there was
an agreement that there should be a deferral measure based on that.

Subsequent risk analysis I think showed that you\'re absolutely correct.
There are differences in risk in those two areas, but we\'ve maintained
the deferral period because we were able to, based on blood supply.

DR. PRIOLA: Okay, thank you, Dr. Ganz. We\'ll move on to Dr. Dorothy
Scott, who is going to discuss current safeguards for blood products.

DR. SCOTT: This should be very brief. I\'m going to review the current
safeguards for blood products recommended by FDA and this is really a
lead in to tell you for what Alan Williams is going to tell you and that
is how these safeguards evolved over time. That will give good context
for moving forward and responding to the questions that we\'re asking.

This probably seems like a primer to a lot of you, but I\'m just putting
it out there at the beginning. These are the donor deferrals for risk of
what we call classical CJD. They include, of course, diagnosis of CJD.
Also, the two iatrogenic risks in the U.S., receipt of human pituitary
growth hormone injections and dura mater transplant. In addition, people
are deferred for a family history of CJD in one or more family members.
And blood components are withdrawn if there is a posed donation finding
that the donor as CJD or, in fact, these risks.

This is donor deferrals for variant CJD risk. Again, it should go
without saying, but of course, we have to say it, for diagnosis of
variant CJD, for risk of exposure to products that may contain or in
theory could contain BSE and for risk of geographic exposure to BSE. So
I\'ve put these in two different categories.

Risk from products may include the receipt of transfusion in the U.K.
from 1980 until the present, or injection of bovine insulin that was
sourced from the U.K. between 1980 and the present.

The geographic donor deferrals I\'ll go into in the next slide, but this
includes travel and residence in certain countries with BSE or exposure
to British beef on military bases in Europe. The current donor deferrals
are for greater than or equal to three months\' residence in the U.K.
between 1980 and 1996; five years or more in France between 1980 and the
present. That\'s because France also had BCJD cases and they had a
fairly large importation of British beef; or six months or more on
certain military bases between 1980 and 1996, and that\'s because of the
British Beef to Europe Program.

In addition, there\'s a deferral for five years\' residence or travel in
Europe from 1980 to the present, again, reflecting the risk of exposure
to BSE. And this deferral is for blood components for transfusion only,
therefore source plasma or plasmapheresis plasma is not included in this
donor deferral, except for France, as you saw in the previous slide.

The decision to do this was based on the demonstrations that model TSE
agents are partitioned or removed during plasma fractionation and that
was evidence from published studies, but more than that, the European
risk of variant CJD has been low and it appears to continue to be low.
They had a very small BSE epidemic relative to that in the U.K. as
we\'ve already seen.

In addition, the magnitude of risk reduction achieved by fractionation,
in general, is likely to be greater than that achievable by donor
deferral. And finally, there were concerns that if there was a deferral
for travelers to Europe or if they were prevented from donating plasma,
that there could be effects on nationwide and worldwide plasma supplies.
This is obviously uncertain, but there was a potential.

For the implementation of geographic donor deferrals, those who were on
the Committee probably remember that it really had to be thought out
over several different meetings. The concerns about blood and plasma
supply were addressed through conducting surveys and estimates of the
risk benefit prior to making these recommendations. Certainly, they came
before the Committee as well for advice. Phased implementation of donor
deferrals which is important for blood especially because some centers
have been relying in part on blood from Europe. Blood supply monitoring
occurred both by blood supplier organizations and by HHS after the
deferrals were implemented and in some cases that still continues.

And we also made a recommendation to perform pilot studies if a blood
bank or blood organization wanted to implement more stringent deferrals
than those that we recommended.

Finally, product disposition. This is an additional safeguard. This is
post-donation discovery of a risk factor or disease. For BCJD diagnosis,
all products including plasma derivatives are withdrawn. Of course, this
hasn\'t happened yet. For CJD diagnosis, all components in unpooled
units of plasma are withdrawn. But if the plasma is already pooled, it
moves forward into fractionation. And for risk factors, likewise, all
components in unpooled plasma are withdrawn is a post-donation discovery
of a risk factor occurs.

So that is the review of the current donor deferrals and the disposition
of components and then I\'ll leave it to Dr. Williams to go into greater
depth about the effects of these donor deferrals.

DR. WILLIAMS: Thank you. What I\'m going to do is give a little bit of a
retrospective of the policy development process since around 1999,
primarily for the benefit for some of the new members of the Committee
who weren\'t part of this process all along. And show some of the data
that helped underlie some of the decisions that were made and I hope
leave you with the thought that as a Committee, you should feel free to
consider where new data may be needed to make decisions into the future
and feel free to speak up and when those data are needed as the
Committee in 1998, in fact, did under the chairmanship of Paul Brown.

So as I mentioned the talk is entitled \"Development of FDA
Recommendations for Deferral of Donors Based on Risk of BSE Exposure.\"

Next slide.

The goals overall, and I think these have held true throughout the
response to this epidemic is that an effective response is needed to the
spread of variant CJD in Europe and the potential threat that it holds
to the blood supply, that there needs to be an optimal balance between
variant CJD risk reduction, interventions and blood supply, certain
preservation as you\'ve heard several times already. There needs to be
an implementation plan that\'s sensitive to the dynamics of the donor
recruitment process and the realities of sharing blood around the
country. You can\'t necessarily assume because you lose proportion of
donors in part of the country that that immediately fills up by supplies
from elsewhere although certainly the ability to identify needs and
share blood supplies has improved quite a bit in the past several years.

And there\'s a need for both a coherent, scientifically explainable and
uniform national policy.

Now ideally, one would be able to have a risk model based on data, but
to do that in this situation would require data that we largely don\'t
have. That would be the likelihood of dietary exposure within a country
with endemic BSE, knowledge about the length of the incubation period,
both the mean and the range; the prevalence of an asymptomatic carrier
state. This is an updated slide from some time ago. Presence of a
variant CJD agent, whether it occurs in blood during the incubation
period or carrier state. Of course, now we know that and hopefully,
rarely that is the case, but we know that\'s no longer theoretical; and
the susceptibility of the recipient population, whether based on genetic
make up or other factor.

Because of the very limited data, database model, empirical model isn\'t
possible and the prior comment, notwithstanding, we did base most of the
analysis on a linear risk model under several assumptions and this is at
the risk of exposure to BSE for variant CJD is linear and related to the
duration and the likelihood of a dietary exposure. This is a concept
that this Committee has discussed previously numerous times and has
several assumptions that underlie the use of survey data to support
policy making. These are that the data regarding travel and residence in
a BSE endemic country as a valid surrogate for dietary exposure to BSE
and the subsequent potential to transmit variant CJD via blood.

The major data collection activity that served to support policy making
was a blood donor travel survey actually commissioned by a prior TSE
Advisory Committee to measure travel and duration of travel within not
only the U.K. but countries in Europe which were known to have endemic
BSE at that time. This was based on a probability sample of accepted
donors at 12 blood centers in late 1998, early 1999 and involved 19,000
mail surveys meant to be simple, a single page mailing, together with a
cover letter. We had a 50 percent response rate to that mailing and the
survey collected travel and residence data from the U.K., limited
European data and some basic demographics on the respondent population.

The data was requested by the Committee and has been presented
extensively at previous meetings. And throughout this talk what I\'m
going to do is just mention some of the high points from some of these
discussions.

Overall, what\'s the prevalence of any U.K. travel or residence between
1980 and 1996? That figure is 22.8 percent overall for the donor
population to defer. Any donor who has ever been in the U.K. is 22 plus
percent of the donor population. Similarly, for any European country,
recognized as having endemic BSE in 1999, that about be about 35.5
percent.

Now in some of the calculations, we needed both a numerator and a
denominator, so what we had available was duration of time spent in a
BSE endemic country and we converted that to person days exposure.
That\'s derived from the total estimated cumulative times spent by
donors in a defined geographic area. And then from the other side we
knew what the prevalence was of donor travel to that area and we could
establish a cutoff value, for instance, three months, six months, one
year, five years and define and estimated proportion of donors who spent
time in the area and if they were deferred what the donor loss would be.

Some of the characteristics of the blood supply which had to come under
consideration is, for instance, 80 percent of the blood supply in the
U.S. comes from donors who have donated before, so any deferral that
either targets the older donor population or for some reason targets
donors who have donated before, that\'s a costly deferral because these
are largely individuals who donate several times a year and you lose
subsequent donations from deferred individuals.

The blood supply itself is stressed. It\'s an aging donor base and just
simply through economics there are fewer large work site collections
than there used to be. So recruiting donors and actually collecting
blood is a more dispersed operation and generally more difficult than it
was 10 or 15 years ago.

From the other side, we know that the blood supply is at least somewhat
elastic. There have been losses due to previous events such as
implementation of antihepatitis B core testing and change of hemoglobin
determinations from ear stick to finger stick that deferred somewhere in
the range of 3 percent of donors, so we know that we recovered from
those changes in operations and predicted that we would at least have
that much elasticity.

However, we know that periodically in the summer and in the holiday
periods there are spot shortages and even regional shortages of the
blood supply.

Also, a concern, we know the public response to crises, we know the
public response to appeals, but we don\'t know what the long term impact
is of deferrals as far as those donors who responded to the appeals or
other associations with the deferral process.

And as mentioned earlier, there needs to be a capability of monitoring
supply impact. That\'s been the basis of several discussions of this
Committee to be able to assess what the downstream impact is of an
intervention.

So an example of some of the calculations that were done in the first
consideration was for the six month deferral for travel residents in the
U.K. There were a total of 252,804 person days of exposure in the survey
population. If there was a cut point at six months, we removed 217,000
of those person days, resulting in an 86 percent theoretical risk
reduction based on that linear model.

We knew that the donor loss related to that was 2.2 percent and just an
arbitrary index based on the ratio of percent person days removed to
percent donor loss, this had an index of 39.

Looking at the next possibility and in fact, the U.K. deferral currently
in place, the denominators are same, the numerators are somewhat higher.
A little higher proportion of risk removed specific to the U.K., a
little higher donor loss, 3.4 percent. As you can see, a little lower
index of efficiency.

Going down to one month, again, 97 percent of U.K. risk removed.
Considerably higher donor loss, 6.4 percent and the index reflects that
as 15.

And then just one example of a combination, were the current deferral to
go from its current three month in the U.K. to one month, the additional
risk, theoretical risk or risk removed based on the total U.K. risk
model would be an additional four percent removal. This would have an
additional three percent donor loss with a very low relative efficiency
factor. So some gain in risk reduction, but at very high cost in terms
of donor base.

And this is simply a graphical representation of some of the data I just
showed and you can see as time spent decreases the slope of the curve
reflects the fact that your risk reduction is much lower for each
increment of donor base lost.

As a result of the extensive discussion on these data in June of 1999,
the Committee made its recommendations and subsequently the FDA issued
guidance in November of 1999, recognizing that there would be an
estimated 2 percent donor loss with respect to a six-month U.K. deferral
and made that recommendation for exposure between 1980 and 1996,
recognizing that the U.K. had put in very strong food supply safeguards
and the Committee was comfortable with the 1996 cutoff; also receipt of
bovine insulin in the U.K. And it\'s not mentioned, product retrieval
recommended if the donor was later discovered to have variant CJD.

Now subsequent to that guidance, there was evidence of the epidemic
expanding in Western Europe, as well as new data became known with
respect to supplies of U.K. beef to DOD European bases. There was
recognition in concert with the expanding BSE epidemic that part of the
country\'s blood supply was sourced in Western Europe, the so-called
Euroblood imported by the New York Blood Center. And there was some
residual risk from the U.K. as was potential European exposure.

The analysis then took a slightly more sophisticated tack in large part
due to assistance from Larry Schonberger and colleagues at CDC who went
to a weighted risk model and assigned the U.K. a value of one, given
that that was the BSE epidemic focus. Based on U.K. imports and
observations of BSE in France and several, I think two variant CJD cases
in France, France was assigned five percent relative risk weighting. And
other parts of Europe for various factors were assigned a .015 percent
risk factor.

In considering France in relation to the U.K. throughout these
calculations, we did not specifically assess travel residents in France,
but did the relationship that any travel to U.K., compared to any travel
to France had a relationship of 12.7, so we used that as an adjustment
factor.

Specific to the DOD bases overseas, we knew that U.S. bases were
supplied with about 30 percent of their beef supply came from the U.K.,
so we assigned that a 35 percent factor compared to 1 for U.K. itself.

Again, based on subsequent discussions, FDA issued revised guidance in
January of 2002 and I\'m not going to walk through these because Dot
showed these to you in the prior talk.

And this was the impact on that theoretical pie chart representing the
risk. The DOD risk was entirely removed, based on the interventions put
into place. The \-- I\'m sorry, not entirely. There\'s a small residual
left there.

The U.K. deferral was reduced, not quite half. You can see there\'s
still a residual U.K. risk exposure there. And similarly, the European
deferral was reduced, but not entirely removed.

Euroblood was just eliminated, so that risk was entirely removed.

The incremental risk reduction based on this later guidance was 72
percent so that the total risk removed with the two recommendations
considered in concert was estimated to be 91 percent of the total
geographic dietary risk exposure.

Some advantages and disadvantages regarding the FDA recommendations. The
deferrals were tied to BSE observational data and there was a ratio in
the deferral of 3 months for U.K. exposure to 60 months or 5 years in
Europe. This represents a worst case situation for all of Europe except
for France. Remember that proportion was .015. So a conservative
relationship, but still we maintain that 3 month to 60 month ratio.

We knew that the impact in the New York area with a loss of Euroblood
was going to be severe, but collectors were encouraged to take
aggressive donor deferral measures. Many did and in fact, the New York
area blood supply actually did pretty well with an aggressive
recruitment campaign by the New York Blood Center, some assistance from
other centers, but the impact was dealt with.

As Dot mentioned, there was a pilot provision, allowing flexibility for
sites to put their pilot programs into place and assess the donor
impact. And the provision for deferring donors who had been transfused
in the U.K. provided some protection for the potential for human to
human passage of variant CJD and some, at least embryonic evidence that
there might be some adaptation of strains in passage between species or
within species. And the deferral continued to recognize food chain
protections.

At the time the transfusion transmission of variant CJD remained
theoretical. Of course, that has changed now. A big disadvantage is the
complexity of this deferral itself. Any time you\'re trying to get
survey response answers or get individuals to give a medical history,
you need to keep your questions simple and to the point and this is a
complex screening paradigm and we recognize this.

The estimated four to six percent loss exceeded experience of the past.
And it was hoped that the ability of the rest of the U.S. could
compensate for the severe impact of donor loss in the New York area and
in other coastal areas.

There were considerable discussions of the impact of this deferral. As I
mentioned, the projected loss was about five percent nationwide.
Importantly, the actual loss was not directly measurable. We just don\'t
have a means to do that. While donors certainly are deferred on site and
with respect to a direct question about their travel and geographic
exposure, in fact, many donors self-defer long before ever coming to the
Blood Center and Blood Centers frequently and talking on the phone to
donors, encourage them to self-defer if they have a particular exposure.

So you\'ll see data reflecting deferrals, but most of that is on-site
deferral data and really doesn\'t capture the full picture.

There were known to be some disproportional impacts of travel deferrals;
coastal cities thought to have about 150 percent effective loss and
rural U.S., about 50 percent of the total loss. New York Euroblood area
was not only impacted by the loss of the blood from Europe, but also by
the travel deferral which particularly hit the coastal and financial
centers of the coastal areas.

TSEAC recognizes these potential impacts and requested supply monitoring
and assessment and I think to the extent that those systems could be
brought to bear, we did get a reasonable assessment of how this deferral
impacted the blood supply and now with the development of the HHS BASIS
model for monitoring, I think those capabilities have improved.

That said, seasonal and regional blood shortages still persist and I
think anyone in the blood collection community will still tell you
things are tough out there in terms of bringing donors in and retaining
them, maintaining supply.

What are some of the future potential challenges? Well, obviously, the
recent documentation of transfusion transmission during variant CJD.
Asymptomatic incubation period is very worrisome. The deferral for U.K.
transfusion in 2001 was precautionary. It begs the question as to
whether additional deferrals of individuals with previous transfusion in
France or Europe or elsewhere may be indicated.

We tried to squeeze the survey data for one more piece of analysis to
see if we could address that and this is combined with the data shown
here, different data from the NLRBI-sponsored REDS program which
assessed the percentage of donations given by transfused allogeneic
donors within a nine-year period. And you can see this changes, reduces
a little bit over time, but overall, there\'s about a 5 percent basic
prevalence of prior transfusion anywhere within the U.S. donor base.

A quick age-specific breakdown, as you might expect. This is higher and
older donors ranging from 10 to 11 percent and much lower in the young
donor population in the U.S. donors.

Now using some of these data with a number of assumptions, combined with
the survey data, we tried to extrapolate some potential impacts for
transfusion in other parts of Europe. And I think it\'s important to
state some of the assumptions that were made. There was an observation
of 5 percent prevalence of transfusion history. U.S. donors, overall, we
extrapolated that to be the same for donors who had extended period of
travel or residence in Europe.

The only way we could get at that was from the survey data, those donors
who had at least a five-year or travel residence history. Now that\'s a
conservative estimate of what would be a lifetime transfusion exposure.
Conservative, but it\'s the only data we have available.

Also assuming that the rate of transfusion among residents and travelers
to Europe parallel the U.S. experience and again, the prevalence of
travel to France was .7 in relation to travel to Europe.

So putting all of that together, the history of transfusion within the
U.K. and this is a deferral that was already accomplished by the 2001
guidance, would result in deferral or did result in a deferral of
approximately 2 donors per 10,000. Similar calculation for history of
transfusion. Any part of Europe excluding the U.K., approximately 3
donors per 10,000 and then specific to France with that correction of
1.4 per 10,000. So many assumptions, many extrapolations, but it gives
us a ballpark estimate of the types of deferrals that might be
experienced.

This is, I believe, my final slide. As subsequent meetings are held, the
Committee is going to be faced with, I\'m sure, new challenges. One
could be the spread or in fact the recognition of BSE or variant CJD in
geographic areas that hadn\'t been previously recognized. There are no
donor exposure travel or residence data available for donors beyond the
U.K. and European BSE countries. So just to make the Committee aware of
that, should something break in Asia or elsewhere, there are no data to
support those discussions.

Despite many of the limitations, many assumptions, I think it\'s fair to
say that the survey data did provide a framework for risk to donor loss
estimates. That supported policy making. And I know Dr. George Nemo is
here from the National Heart, Lung and Blood Institute. Their REDS
Program was just recently renewed. I anticipate that they may well have
a survey component to that program and I think as a Committee, you may
wish to consider relevant new data collection activities that would
support future deliberations on the topic.

Thank you very much.

DR. PRIOLA: Dr. Allen.

DR. ALLEN: Thank you, Alan, for summarizing that. It was very helpful.
You indicated and I will confirm from personal experience that it is
cumbersome to go through the questioning in the donor deferral or donor
data collection room. Recalling exactly where you\'ve been, when and
trying to add it all up is \-- takes time. It confuses the people
collecting the histories and it certainly is cumbersome at best.

Is there \-- do you have any data from other sources, from blood
collection centers or others in terms of the impact on the blood
donation process because of this? I mean we can talk about the number of
donors deferred. You talked also about that some people just don\'t even
bother coming in because they don\'t want to have to go through that,
even though they may be eligible to donate.

Do you have any information on the impact overall of this?

DR. WILLIAMS: I think, obviously, probably the blood collection
community is better positioned to comment on their experiences. I think
one thing I can say with a comment is that as part of its biologic
product deviation reporting requirement to the FDA, any \-- what\'s
known as post-donation information needs to be reported to the agency.
And the travel deferrals, specifically the U.K., European travel
deferral and the malaria travel deferrals are far away the leading cause
of this post-donation information.

That being a donor was accepted as a donor based on history given at the
time of screening and in subsequent to the donation event, recalculated
or was reminded by a spouse or in some other manner, transmitted
information to the Blood Center that hey, wait a minute, I wasn\'t
really eligible.

The travel deferrals are a leading cause of that information and I think
reflect that. The comment that FDA has worked very proactively, I think,
with blood collection community, particularly the American Association
of Blood Banks, to try to streamline and improve the donor history
process and we\'ve had many discussions at the Blood Products Advisory
Committee about progress in doing that.

The questionnaire that\'s in place in some centers now and soon to be
rolled out at other centers, for the first time uses questions that have
been cognitively evaluated either by focus groups or one interview by
the National Center for Health Statistics or focus groups conducted by
other sources. So I think we are taking steps to improve the
questionnaire and streamline it and make the questions the best that
they can be, but it still remains an imperfect process.

DR. PRIOLA: Dr. Nelson?

DR. NELSON: Yes, one deferral criteria that I really hadn\'t thought
much about and I wonder its impact and you didn\'t really mention it and
that is having received insulin from \-- bovine insulin from the U.K.
and I don\'t know the impact of that. I think maybe one percent or more
of the population is diabetic and that\'s increasing and I wonder if
people would know where the insulin that they got came from and is that
\-- how does that \-- did you ask about the prevalence of diabetes in
your \-- among \-- in your survey?

DR. WILLIAMS: No, we didn\'t collect that at all and I agree with the
implication of your statement. Rather than those who actually received
U.K. bovine insulin, it\'s probably those who weren\'t sure and answered
conservatively probably had the bigger impact, but we don\'t have
specific data on that.

DR. NELSON: And even \-- I was in the hospital recently and
post-operatively now there are many places in order to control
post-operative hyperglycemia which is suppose to improve wound healing
and all the rest, people get insulin post-operatively. They may be one
or two units to control and who knows where that comes from.

Are there data, of the insulin that\'s used in the U.S., how much of it
comes from bovine, U.K. bovine sources. I mean I have no idea.

DR. SCOTT: You can be reassured that none of it comes from the U.K. now.
What has happened is that there are some people with diabetes that feel
that this kind of insulin is the best kind of insulin to regulate their
disease and so they personally have imported it and continue to import
it and it\'s really that group that we intend to capture.

DR. PRIOLA: Dr. Bracey.

DR. BRACEY: Yes, just a couple of comments. Being from the hospital
side, clearly, the inventory or supply is fragile. We continue to
experience shortfalls and then for us that do collect, as mentioned
before, these travel questions are really, really difficult. I mean if
you \-- it is the number one reason for BPD. I mean it\'s not a week
that goes by when I see some of these things coming across, so there are
issues.

I was reading in the materials about the export of blood from Britain to
other places and how much of that activity has taken place? Is that
going to be a significant concern?

DR. WILLIAMS: I\'ll comment specific to the whole blood. That collection
brought in by the New York Blood Center prior to the guidance was
sourced, I believe, in Netherlands, Switzerland and either Austria or
Germany. That was the whole importer of whole blood and specifically red
cells, Group O red cells.

With respect to any other products, I\'d leave it to Jay or someone else
to address.

DR. EPSTEIN: There have been very small scale distributions of products
under IND that were manufactured from non-U.S. blood, by aside from
those which probably dozens to at most hundreds, there have not been any
plasma-derived products made from non-U.S. plasma. The red cell products
are only in exactly the ones that Alan has already outlined, the
Euroblood products from Germany, Switzerland and the Netherlands.

DR. PRIOLA: Dr. DeArmond?

DR. DeARMOND: The Department of Defense personnel in Europe during the
time that was dangerous, what\'s known about them because they accounted
for 40 percent of the deferrals. As I recall, they had a
disproportionate effect on blood donation since they tended to be high
level donators.

Do we know anything about the deaths of those individuals? Has any
follow-up of the military personnel or DOD personnel been made and is
there any plan to do any such thing?

DR. WILLIAMS: I think as far as variant CJD exposure and morbidity or
mortality related to that, I don\'t know specific studies, but I would
have to assume that there haven\'t been any specific variant CJD events
in that population.

With respect to the deferrals, that was one population that we didn\'t
capture very well by survey. We attempted to, but in turns out military
staff, despite all their great points, do not respond well to surveys.
So we got about a 10 percent response rate in the military population
and really had very little data to go on and in fact, those areas that
depended greatly on military bases, particularly in the Carolinas and
some areas like that, were hit very hard by the deferral, simply by the
loss of those populations.

DR. DeARMOND: I guess that means we can\'t do autopsies on all those
individuals.

DR. PRIOLA: Mr. Bias.

MR. BIAS: My question was, Dr. Scott had mentioned pilot programs for
looking at the deferral issue. Has any blood collector taken the FDA up
on that offer? What are some of the obstacles related to that?

DR. WILLIAMS: That was an element of the guidance because there were
numerous discussions about what risk reduction was appropriate and what
level of deferral could be sustained, specifically, the American Red
Cross had determined its own deferral policy. And in fact, had largely
implemented it by that time. It was slightly different than the FDA
recommendation and I think the Agency basically wanted to create an
environment where if that had a severe, not sustainable impact on the
blood supply that there would be room to revert to the recommended
regulatory policy. And I\'m only aware of that one organization that\'s
used a different deferral policy.

To some extent some of the differences remain, although a large part of
the policy now is harmonized. I see Dr. Page here. He may have a
comment.

MR. BIAS: One more comment. One thing that has changed since we\'ve
implemented these policies is that we do track people\'s travel a little
bit more significantly since 9/11 and I\'m wondering if there\'s any way
to correlate the information so that we can take that out of the
process, since we know where people are going and know where they\'ve
come from supposedly. I\'m sure not all can support that data, but it is
something to look toward in the future since we are now tracking that
information.

DR. WILLIAMS: I agree. Any source of data can be valuable. We, in fact,
tried to do some of that based on immigration figures and some travel
data that were available. It remains to be seen how useful it might be
in practice, but I think any aspect could be useful, yes.

DR. PRIOLA: Dr. Bracey?

DR. BRACEY: Yes. This is somewhat tangential, but one thing that I\'ve
noted that is happening a lot in the U.K. is a look at the other side
and that\'s the demand side. We do know that if one looks at blood
transfusion practice across the United States and in fact, across the
globe, there\'s a lot of questionable transfusions.

And I\'m not sure we\'re really putting enough effort into supporting
studies to improve practices along those lines. And I would hope that
one of the things that we can do as a Committee is to sort of stimulate
some thought and discussion about recommendations along that line.

DR. PRIOLA: Any other comments or questions for any of the speakers?

Okay, so I guess we\'ll move on to the open public hearing portion of
the afternoon.

DR. FREAS: To date, I have received four requests to speak in the
afternoon open public hearing. The first request is from the American
Red Cross, Dr. Peter Page, would you come to the podium?

Excuse me, we have to read one statement that I forgot about, each and
every time we have an open public hearing.

Please pay attention to this statement.

DR. PRIOLA: Thank you, Bill. 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 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 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.

DR. FREAS: Thank you, Dr. Priola. Dr. Page?

DR. PAGE: I\'m Dr. Peter Page, Senior Medical Officer at American Red
Cross, headquarters here in Washington, D.C. I\'m a full-time salaried
employee and I have no expenses related to this meeting.

Dr. Roger Dodd is the investigator on this study and would ordinarily be
presenting, but he\'s out of the country now, so I\'m going to try and
present the data on the Red Cross study which has been referred to
earlier.

It was designed in 1994, actually with input from the FDA by the Red
Cross and the Centers for Disease Control and was implemented in 1995.
In order to attempt to assess the risk of transmission of classic CJD by
blood components from whole blood donations.

In 1997, the coordinating responsibility for the study transferred to
the AABB and the now former NBDRC, National Blood Data Resource Center,
which discontinued being in existence a year or so ago. So late in 2003,
the study management returned to the American Red Cross and Dr. Roger
Dodd, primarily.

In September of this year, a cooperative agreement on the study was
reached with the CDC which provides funds to ensure that this study can
continue and that agreement is for five years.

The way the study works is this. Upon a U.S. Blood Center learning that
a blood donor has been diagnosed with CJD, and the source of this
information is usually a concerned family member of the CJD patient, who
knew that they were a blood donor an thought that the Blood Center might
want to know and have a concern with regard to recipients, so when a
Blood Center learns this, they can track the prior donations from the
patient who develops CJD and determine what blood components were sent
to which hospitals and so that they can \-- the recipients can be
identified by the hospital transfusion service.

The recipients are not notified, however. This is consistent with FDA
guidance and as you\'ll see in a minute, has been reviewed and
considered by the Red Cross IRB and the CDC IRB.

So we then have the name of the recipients of prior donations from
patients \-- from donors who ultimately developed CJ.

Each year since 1995, the names of these patient recipients who got the
components are checked against the national death index or NDI Plus from
the National Center for Health Statistics for multiple causes of death
to see if any of the transfusion recipients died with CJD.

This takes awhile. The data that we have here are up through deaths
through the end of 2001. We have just submitted a request to them for a
follow-up through the end of 2002 and I don\'t have that data here yet,
but we should be getting it shortly.

So there is a delay in the data and the data I have is not going to show
that much more since when it has been presented earlier.

As I mentioned, the Institutional Review Boards have reviewed and
approved the study. Changes have been made to the protocol following the
reporting of the possible transmission of variant CJD through
transfusion and FDA\'s new guidance.

No notification is necessary for the study. That is, no notification of
recipients is required, but medically appropriate notification and
counseling may be provided at the discretion of the health care
providers. Initially, we were precluded from doing that.

Both the CDC and the Red Cross IRBs must be consulted when a case of
variant CJD occurs in the United States or a test becomes available or
if classic CJDs should be associated with blood transfusion. Those have
not happened, but we will certainly do that.

Now the results, just to recap what has been provided before and the
numbers are only a little bit larger. We\'ve had two new patients
enrolled in the last year, so we have 28 donors who became CJD patients
who are enrolled in the study. Their prior donations blood components
went to 368 different recipients of blood. As of February 2003, we
learned that the end of 2001, 102 of those 363 recipients were still
alive; 241 had died. Of the 241, none had a diagnosis of CJD.
Two-hundred-forty have diagnoses that are not CJD and one is still being
researched and is pending, one of the deaths. And there are 25 other
recipients that we are trying to identify and follow up on.

The overall follow up in person years is that of the alive recipients
who are 966 person years of follow up without CJD. Of those recipients
who have died of other causes, we have 430 person years of follow up,
totalling almost 1400 person years.

The first line on the study is the total of what\'s below it, but it
relates to the long-term survivors, surviving recipients of the
transfusions, long term here being more than five years.

You can see on the first line in yellow that we have 116 recipients who
have lived more than five years, of whom 84 are living and will
hopefully continue to live so that we can increase that number of follow
up for over five years. But you will see that since many of the donors
who have developed CJ have been long-term donors who have donated a
while ago, we are lucky in that respect to have at least a few
recipients with longer-term follow up. There are 27 from 11 to 15 years;
13 from 16 to 20 years; and 4 with over 20 years of experience, 3 of
whom are still alive. And we will continue to follow up.

So in summary, no cases of CJD, classic CJD have occurred in 342
recipients of blood components from donors who subsequently developed
CJD, representing almost 1400 person years of follow up. This long-term
follow up of these survivors will allow for more accurate estimate of
the risk, if any, of transmission of CJD by blood components.

The real reason we wanted to speak here was not so much to update the
data, since it\'s not that much more from previous presentations, but to
advertise the program and make physicians, Blood Centers and families of
CJD patients aware that the study continues to exist and is looking for
more recipients to enroll. It has involved Red Cross as well as non-Red
Cross Blood Centers.

So when a CJD patient has been a volunteer blood donor, we would hope
that family members or friends would contact the appropriate local blood
collecting center to make them aware of it. Many volunteer blood donors
are proud of their donation history and make it known to their family
and friends.

Blood Centers learning of a blood donor having developed CJD are
continuing to participate in the study by contacting the Holland lab and
Roger Dodd\'s study. I believe that this information will be on the
website. We have requested that, so you can get the fax number for
contact and Karen Fujii, Ed Notari and Shimian Zou \-- and Shimian Zou
is here today \-- will be glad to talk to you about how to input.

I want to acknowledge that most of the work in this study was done by
Marian Sullivan, who is no longer part of this project as she\'s got
other employment and Dr. Larry Schonberger is the key co-investigator
who provided funding and other support and we also appreciate the many
Blood Centers, Red Cross and non-Red Cross, including the military blood
program who have participated. The staff members are listed there and
I\'ll just end by leaving the contract information up.

Thank you very much for your attention.

DR. FREAS: Thank you, Dr. Page. I think, as always, for the open public
hearing, we\'re going to hold our questions until the end.

The second request I have to speak in the open public hearing is from
the America\'s Blood Centers, Dr. Michael Fitzpatrick will be the
presenter.

DR. FITZPATRICK: Good afternoon. I\'m Mike Fitzpatrick and I am fully
employed by America\'s Blood Centers on a full-time basis.

Just to \-- before I preface and read the written statement which the
Committee has and was available outside, a couple of comments. One in my
former life as head of the Department of Defense program, I can respond
to one of the questions. There\'s an active surveillance program that
the military participates in, just as civilian physicians. Prior to my
retirement a year ago, there had been two suspected cases of
neurgenerative disease and deaths that were fully explored and were
negative. One was classical CJD and the other was not variant CJD, so
there\'s an active surveillance program for the active duty and retiree
members.

Most of the folks that were in Europe during that time are retired, like
I am now, and so are in the civilian health care sector or are on the
retiree sector.

Moving on, as you read the statement you may consider that ABC is a
salmon swimming upstream today. Our members and our organization take
blood safety very seriously. We do not take variant CJD lightly or the
deferrals that have been put in place. But we want to raise a point to
the Committee and to the audience. The precautions that have been put in
place were put in place a number of years ago based on theory and
probability and assumptions and on very little data because there was
very little data available at that time.

There is more data available, but not as definitive of an amount of data
that we would like at this point in time for you to look at. And there
is the definite concern about a second theoretical wave of cases.

Our concern, my concern especially today is that I\'ve heard lots of
discussion about more stringent requirements to reduce the risk.
However, I\'ve seen no data to show that there is an increased risk over
what was done several years ago. And in theory, the things that have
been put in place appear to be working. Two transfusion-related cases
have been reported in the U.K.. And there is a possibility of a carrier
population, but that population is defined. There are stringent controls
now over what enters the food chain and the exposure of people to the
agent has been greatly reduced and we need to keep that in mind.

BSE cases in countries other than the United Kingdom have not
materialized as we thought they would. We will have just France and
Italy. So with that thought in mind, I\'d like to move on to the written
statement.

We are, as you can see from the first paragraph, a network of 76
members, collect about half the blood in the country and we have one
international member, Hema-Quebec in Canada is a member providing blood
to a fourth of the Canadian hospitals.

It\'s been almost eight years since the implementation of the safeguards
to protect the bovine and human ends of the food chain from BSE, and the
human form of that disease variant CJD. The FDA announced donor deferral
criteria in August of 1999, five years ago, based on the application
precautionary principle and the hypothesis that the prion responsible
for variant CJD could be transmitted by transfusion and Dr. Williams
walked everyone through how we go to that point and left out a lot of
the pain in getting to that point, but the FDA and Dr. Williams are to
be complimented for arriving at that deferral criteria and those models.
There was a great deal of pain in getting to that point, and they led
the way on that.

Two cases of variant CJD have been associated with the transfusion of
blood from individuals who later died from variant CJD. This causal
relationship is based on mathematical models of probability and not
biological data. We\'d love to have biological data for that, but it\'s
not evident.

The lack of biological data continues to confound the issue in our
donors. We must note that the identification of these two cases has not
changed the picture. We knew many years ago through the animal models
that it was theoretically possible to transmit the agent for CJD by
transfusion.

Five years ago, FDA developed the model based on potential exposure to
the agent. This model continues to be used to defer hundreds of
thousands of donors who do not understand why they are being deferred
when it appears that both the human and bovine epidemics are over or on
the decline phase of those, as you can see from the BSE statistics, the
bovine form seems to be under control and we have a limited number of
human cases.

The toll of the human epidemic currently stands at 157 diagnosed cases
since 1994. There\'s only been one new human case in the past year.

We believe it\'s time to begin the discussion of an exit strategy for
this deferral. Immense resources, people and dollars continue to be used
to update deferral questions, screen and defer donors and respond to
questions from deferred donors and their friends.

These resources could be better utilized in CGMP compliance, developing
new screening techniques, better procedures and recruitment of new
donors. One severely affected population is the dependence of the
military stationed in Europe during 1980 to 1996. Many are just now
achieving the age of donation and like my own daughter who was born in
Germany in 1998, lived there for two years, eating formula and baby food
are indefinitely deferred.

I just had an event on Capitol Hill, rolling out the Ad Council campaign
and one of the staffers there who was a teen in Europe, stationed there
with her parents, asked if she would ever be able to donate. We proposed
that FDA initiate discussions of what would constitute an exit strategy.
The questions that need to be asked are, what requirements should be
fulfilled before discontinuance of all or part of the deferrals? What
benchmarks need to be met, just as we have used for SARS and testing for
West Nile virus. Should we consider discontinuing the U.K. deferrals a
certain number of years after implementation of recognized safety
measures? Could we decide that former U.S. military dependents have had
less exposure than originally thought and should be deferred for a
shorter period of time. Could we discuss the possibility of removing
countries which have had no human cases of variant CJD from the deferral
criteria? We raised these questions not as a point of reducing safety of
the blood supply, but thinking not only of what can be done to mitigate
risk, but what is our total plan after we see that we\'ve accomplished
that in a disease that has what appears to be a defined population of
carriers and suspect donors.

I want to thank you for the opportunity to address the Committee and we
hope to be able to work with the FDA on this in the future.

DR. FREAS: Thank you, Dr. Fitzpatrick. Our next request is from the
Consumer Policy Institute, Jean Halloran. Is she here this afternoon?

Okay, we will go on \-- my next request is from Dr. Robert Rohwer from
the VA Medical Center, Baltimore.

DR. ROHWER: Thank you for giving me this opportunity to make a comment,
but before I begin my prepared remarks, I\'d like just to second
something that Dr. Bailar raised a few minutes ago. It was our own
interpretation of our experiment that the conclusion should be that
leukoreduction by itself probably does not provide any risk reduction
and that as he pointed out there\'s 60 percent of the infectivity that
still remains in those preparations after a leukoreduction and by
definition an infectious dose is the dose required to cause an
infection. It\'s an empirical definition and as a consequence there is
in that unit, there\'s still 3,000 infectious doses remaining.

So at least for a collection that\'s made close to clinical disease,
there\'s still likely to be enough infectivity to cause an infection and
I think we\'re seeing that in the sheep transfusion experiments of
Houston where larger amounts of blood are being transfused and the
transfusion frequency in that model seems to be quite high. The
incubation times also seem to be quite short.

The issue that I actually came prepared to talk about goes back to the
very beginning of our discussion on blood today and involves how we go
about doing validation studies and the standards that we should apply to
labeling claims for those studies. And I\'m going to read that
statement.

The FDA has recently approved a labeling claim for removal of TSE
infectivity during plasma processing that is based on single-stepped,
scaled down studies using high concentrations of brain-derived TSE
infectivity. We participated in a number of those studies ourselves and
are responsible for that data.

It has been a consistent finding by our laboratory and now by several
others that brain-derived infectivity partitions with the precipitates
during alcohol fractionations conducted by either the Cohn or the
Kistler-Nischmann processes and is largely removed from the IgG and
albumin fractions.

Brain-derived TSE infectivity is mainly associated with insoluble
complexes of prion amyloid, cell debris and other particulate matter.
The size, distribution of these particulate associations can be reduced
by using a post-mitochondrial microsomal supernatant at a loss of 99
percent or more of the total infectivity. Nevertheless, the infectivity
is still largely associated with particulates and continues to
fractionate in a similar way and that\'s now been clearly shown in a
number of studies.

In contrast, we have shown in this leukoreduction experiment and also
other work that I\'ve presented at other times to the Committee in the
past, we have shown that blood-borne TSE infectivity is nearly equally
distributed between at least two compartments. Forty to 45 percent is
associated with white blood cells. Fifty-five to 65 percent is with
plasma, red blood cells and platelet.

We have also shown that the infectivity is not intrinsically associated
with purified platelet and we have preliminary evidence that this will
also be true for red blood cells.

This means that over one half of the infectivity is associated with
plasma. We know almost nothing about the physical form of the plasma
associated fraction. We\'ve been working very hard to find out more
about the nature of this material, but it\'s very, very difficult to do
this because of the type of titration experiments we have to do to
develop this basic data on this very low titer material.

As an example, there has to date been no convincing demonstration of PRP
amyloid in either blood or plasma. If an infection-associated form of
PRP is present, we do not know if it is in a fibular conformation or
some more elemental configuration, or whether it is free in solution or
associated with other molecules. There\'s been no conclusive proof that
the most elemental form of the infectivity even contains prion protein.
That\'s my own personal bias showing through there.

Depending upon its actual form and associations, plasma-associated TSE
infectivity might fractionate very differently from brain-derived
infectivity which is largely cell associated and/or highly condensed and
aggregated.

The concentration of TSE infectivity in the blood of a hamster in
symptomatic disease is one billionth that in the brain of the same
animal. As a consequence, there is insufficient infectivity in blood for
it to be spiked into a process sample for a TSE-removal measurement like
those that have been reported to date and were discussed this morning by
Hank Baron.

There is, therefore, no obvious way to use blood to demonstrate the same
five or six log 10 levels of removal per step that can be achieved with
brain-derived infectivity. Nevertheless, at 10 infectious doses per mL,
there is sufficient infectivity in a unit of blood, approximately 5,000
infectious doses or in the plasma-derived from a unit, approximately
3,000 infectious doses, to demonstrate up to 3 log 10 of clearance if
hamster plasma itself is fractionated.

Even though the maximum level of removal that is possible could be three
or four orders of magnitude less for a measurement on endogenous
blood-borne infectivity than for a brain-derived spike, there would be
far less uncertainty about the relevance or the removal of blood-borne
infectivity than for brain-derived infectivity. For example, high levels
of removal of brain-derived infectivity would be irrelevant if the same
fractionation steps removed a much lower amount of blood-borne
infectivity.

Since concentration of blood infectivity is too low to be used as a
spike, it cannot be used to test individual downstream steps in
isolation. Rather, one must start the process with TSE infected blood
and carry it through the successive steps of the process, measuring the
distribution of infectivity between the fractions at each step until one
reaches the final product or runs out of infectivity.

One might well run out of infectivity in the first few process steps.
This would be a reassuring result. From that point in the process,
brain-derived spikes would have to be used to test removal. But at least
one would have shown to the limit of practical measurement that
relevant, endogenous infectivity was also removed at some point during
the process.

If there were significant discrepancies between the findings using
blood-borne and brain-derived infectivity, it would serve as a warning
that the downstream steps necessarily tested with brain-derived spikes
might falsely represent the true removal capabilities of the process.

We have shown in our leukoreduction studies that hamster blood behaves
very similarly to human blood in most parameters so far tested. We have
also developed a very sensitive and precise method which we call
limiting dilution titration for measuring the concentration of TSE
infectivity in low concentration samples.

This method is capable of quantitating less than one infectious dose per
mL if more than one mL liter of blood is inoculated. We strongly
recommend that any blood or plasma-based clearance study include a
demonstration that endogenous blood-borne infectivity can be removed to
the limit of detection from the unit of equivalent \-- from a unit
equivalent of blood. This must be done by conducting the process
sequentially from the beginning, using whole blood or plasma from a
TSE-infected mouse or hamster.

Maximum measurement sensitivity can be obtained most efficiently by
inoculating the pace and pellets concentrated from blood. If infectivity
remains to the end of the process, there would be no point in also
testing a brain-drive spike. If endogenous blood-borne infectivity is
removed to the limit of detection in the early steps of the process,
subsequent steps would, of necessity, have to be tested with
brain-derived spikes. In this case, regardless of the limitations of
brain-derived infectivity spikes, it would have been established that at
least a one blood unit equivalent of relevant blood-borne TSE
infectivity had been removed by the process.

We also strongly recommend where brain-derived spikes are used, that
they are carried through multiple steps in succession with measurements
at each step instead of testing one step at a time, respiking at each.
This is at variance with the guidance for viral validation studies, but
I believe that that guidance is not really appropriate for testing the
heterogeneous material that makes up the typical TSE infectivity sample.

While we consider it reasonable to expect that the cell associated
component of blood-borne TSE infectivity will fractionate much the same
way as the cell associated and amyloid associated infectivity from
brain, over half the infectivity in blood appears to be in some other
form. The behavior of this form in the same fractionation schemes cannot
be predicted with the same confidence and this uncertainty should be
acknowledged in any claim for removal from blood or blood products
unless directly tested using endogenous blood-borne infectivity from
TSE-infected animals.

Thank you.

DR. FREAS: Thank you, Dr. Rohrer. I have one more request, that\'s Dr.
Merlin Sayers from the Carter Blood Care.

DR. SAYERS: Thanks for this opportunity to speak. My name is Merlin
Sayers and I\'m Chief Executive Officer for Carter Blood Care. Carter
Blood Care is the community independent blood program providing for the
blood and component needs of the Dallas-Fort Worth Metroplex and the 26
surrounding counties. We draw something like 275,000 volunteer donors a
year and provide service to 150 hospitals and medical institutions.

I have no financial declarations to make. This is a ruthlessly
not-for-profit presentation and I think you\'ll appreciate that when you
see the quality of the slides and you hear the anecdotal nature of the
dotter that I\'m going to talk to you about.

I have to say by way of a preface that I really don\'t want to dilute
the lofty academic quality of the presentations here, but until Alan
Williams spoke, we really had not heard anything from the volunteer
donors\' point of view and it\'s worthwhile bearing in mind that some 12
million of those individuals, their candidacy for donation and the
confirmation of their own self-assessment of good health is
significantly influenced by your deliberations and the responses that
you make to the questions raised by the FDA.

So let me tell you what has happened at the Dallas-Fort Worth Metroplex
and Carter Blood Care. This illustration shows between 2000 and 2004 to
date, the number of donors who have been deferred for variant CJD
criteria at Carter Blood Care. Something like 5,000 donors. And that
probably, as Alan Williams pointed out, only represents a third of the
total number of individuals who have been deferred or lost as a result
of these variant CJD criteria. Those that are not shown on these
histograms are those individuals who recognize the information that they
read in the press, or recognized and understood the information that we
gave them and they essentially voluntarily self-deferred.

Now in spite of all our efforts to ensure that donors do not actually
come to the Blood Center to realize that they are deferred for
geographic reasons, in spite of the fact that we have really taken
significant steps to try and make sure that donors self-defer before
they arrive at registration, this next illustration is going to show you
\-- can you put up the next one for me, please \-- that there are still
first time donors between 2000 and 20004 who are presenting themselves
to donate.

You might well ask why would those individuals present and I strongly
suspect that for some of these very significantly motivated individuals,
there is an element of confusion in understanding particularly the
geographic deferral criteria. And they only recognize that they are
indeed candidates for deferral when some of the more arcane aspects of
those deferrals have been explained to them at the Blood Center.

So what is our experience then with these individuals that are now
permanently deferred for geographic reasons? Let\'s have the next
illustration, please.

What we have here is an accumulative fashion the number of previous
donations by donors who are not deferred for the variant CJD criteria at
Carter Blood Care. This is cumulative and obviously it refers only to
those individuals who had previous donation histories. And as Alan
Williams pointed out, many of those individuals were obviously
individuals who had had long and devoted previous donation histories.

Before moving on, let me make one point very clear and that is that this
presentation is not an appeal for a less safe blood donation, for a less
safe blood donor selection system. Let me be quite emphatic about that.

Let me also make the point that nowadays it\'s not just a question of
replacing these individuals with dedicated donor histories. It\'s not
just a question of replacing the individuals who are lost to deferral.
Increasingly, donor recruitment has become a question of how best to
manage what is tantamount to increasing incredulity on the part of the
donors. For many, many individuals, donation has become a confusing and
a dismaying experience and if national experience is any extension of
the Dallas-Forth Worth experience, some 250,000 donors are now
permanently deferred for geographic reasons and in many of those
instances, significant questions have been raised in their minds which
we, as blood donors have great difficulty in answering.

We are confronted with donors how deferred who want to know if they
should tell their family, if they should tell their dentist. They want
to know if they should tell their family physician? They want to know if
they should reveal their new permanent deferral status to individuals
who are conducting health insurance exams. Some donors want to know if
that means their new self-deferral status now confirms the fact that
they are no longer on the National Marrow Donor Registry.

Now action which is prompted by observance of the precautionary
principle may well be understood in these relatively sterile
circumstances, but it is not reassuring to a donor to invoke the
precautionary principle when he or she is told that his or her blood is
no longer sufficiently safe for transfusion.

If there is no exit strategy that\'s developed, and if screening does
become part of international practice and it certainly sounds as if the
National Blood Service overseas will move to screening, once an
appropriate screening test is available, then my request is should
screening be part of our conduct here in the States? If donors are
screened for prion-based disease, then as early as possible, as soon as
is reasonably possible, re-entry programs for donors deferred for VCJD
risks should be developed and introduced.

Unless these re-entry programs or unless an exit strategy is developed,
we are going to be increasingly confronted with permanently deferred
donors whose answers to questions are not well understood and those
individuals will continue to become a significant disincentive and
deterrent to other individuals in the community who do not want to
expose themselves to similar deferral criteria.

Thank you.

MR. FISK: Thank you, Dr. Sayers. We\'re getting behind on the agenda. Is
there anyone left in the audience who would like to make a brief comment
before the Committee? Okay, we\'ll time you for two minutes \-- we\'re
really behind on the agenda.

DR. GOLDSMITH: That\'s fine. Thanks very much. My name is Jonathan
Goldsmith. I\'m the Medical Director for the Immune Deficiency
Foundation and that is who employs me.

I just wanted to say a couple of things on behalf of our Medical
Advisory Committee to the Committee to try and improve the long-term
safety of plasma derivatives. And also in terms of some of the comments
that have been made today in terms of uncertainties in the blood supply.

We have come out with a statement that makes the following two points.
One, there should be a minimum documented level of prion protein removal
from all IGIV manufacturing processes. And second, that manufacturers
should investigate additional methods to reduce potentially contaminated
prion proteins and not be content with the methods that are in place
today.

Thank you very much.

MR. FISK: Thank you. Is there anyone else in the audience who would like
to make a brief comment?

Seeing none, we\'ll close the open public hearing session. Thank you for
your participation.

(Off the record.)

DR. PRIOLA: I think we\'ll take about a 20 minute break until \-- no,
not a five minute break. Let\'s take a 20 minute break until quarter to
4 and we\'ll come back and discuss and vote on the questions.

(Off the record.)

DR. FREAS: We have several members that must make airline connections
and this is unavoidable, so if you would find your seat, we\'d
appreciate it.

DR. PRIOLA: If we could have all the Committee Members return to the
table, so we can open the discussion. So they put up the questions that
we\'re to discuss and consider and vote on up on the screen. And the
first two questions, if you read through them are basically yes or no
questions which we can discuss them and it makes it very easy to vote
on.

The first one is \"are the measures currently recommended by FDA to
reduce the risk of transmitting CJD and vCJD by blood and blood products
still justified?\"

So to open the discussion, I\'d like to go to Dr. Salman first.

DR. SALMAN: Thank you. First of all, I want to say that there\'s no such
thing as zero risk, so we have to accept some risk in anything we have
to do, including blood transfusion.

I believe like the FDA has taken so much precautionary measures to
reduce the risk of transmitting new variant CJD way before we have any
type of evidence of the transmission and I think now we have not to talk
about hypothetical situations. We do have some evidence that at least
two cases have been transmitted through the blood transfusion. However,
as Dr. Will presented, proportionally, even the mode of transmission of
these two cases occurred and we agreed on it, is proportionally, this
type of transmission is much less likely as compared to the dietary
transmission for the new variant CJD.

I think as the current recommendation or the constraint that is applied
by the FDA is sufficient to reduce the risk to minimum risk as much as
possible for the \-- for any type of blood or blood products and to
transmit the new variant CJD agents.

So I think you can see my response to the first question. However, I
want to say especially related to the question in 3. So we need to be
careful as far as like how far and for how long we have to accept this
type of rules and measures and my opinion and currently and my
estimation, currently, we don\'t have enough data and evidence to say
well, either to stop it or to have a time frame to say when we will stop
it, so I believe like we need to accumulate as much as possible data
before we could maybe stop this type of measure.

DR. PRIOLA: Dr. Gambetti?

DR. GAMBETTI: I agree. I think though that there are few pieces of
information that are missing or I missed in order really to make a
complete judgment on this issue. One is the information on the French
cases of variant CJD.

We heard a lot about the transfusion, donation, blood donation history
of the British cases, but I haven\'t heard information on the history of
blood donation by the French cases. These would, may give us an idea on
whether the disease, although the cases are much fewer, but whether the
disease may be spread, may spread through blood transfusion in France as
well, especially in view of the possibility of banning also cases that
receive transfusions from the donor, deferred cases that receive blood
transfusion in France.

Another issue that I think is peripheral because I see not much
enthusiasm about requiring leukoreduction as another measure to reduce
risk of transfusion and I agree, 50 percent or so reduction infectivity
is not very impressive and I don\'t think it\'s justifiable. Certainly,
disease base, that\'s not justified additional measure based on that,
but I haven\'t heard anything about what \-- if leukoreduction is
required, what would be the cost involved? In other words, what will be
the costs of these additional steps that I agree is of questionable use.

I haven\'t heard anything about donors in this country that \-- who had
surgery in the U.K. and therefore could have been exposed in view of the
results of the study on the lymphoreticular system being affected in
presymptomatic patients. An individual could be exposed due to surgery
by contaminated instruments to variant CJD.

So I think this additional information may be useful to make a final
vote on these three issues.

DR. PRIOLA: Dr. Nelson.

DR. NELSON: Yes, this question is simple. It says should we continue the
deferral criteria that are currently in place. That\'s question number
one. I don\'t see how we could not do it, given the fact that there are
now two probable causes and given the fact that what we\'re dealing with
is two incubation periods, one from the exposure, the dietary exposure
and the second one to that person becoming infective and then donating
and the recipient then becoming,d enveloping symptomatic disease.

I don\'t think we know where this is going to go, but I can\'t see any
public health rationale for not keeping the current criteria in place.
However, I do agree with Dr. Fitzpatrick, that at one point if the risk
is minimal or low or doesn\'t materialize, at one point we need an exit
strategy. But I don\'t think that\'s now, after this second case. It
just doesn\'t make sense to me. So I\'d vote yes on this one.

DR. PRIOLA: And most of Dr. Gambetti\'s point get more to the second
question.

Dr. Allen?

DR. ALLEN: Thank you. Just a couple of brief points. I think we\'ve
heard a lot of very important, very useful information today. I think
all of us would agree that we still have an awful lot more to learn,
that the tests are coming along, but they still don\'t lt us answer all
the questions or begin to answer all the questions that need to be done.
We don\'t have an agent that we can easily work with and identify in all
kinds of different specimens. So there\'s a lot more that needs to
continue to be done.

Very specifically, with regard to the question of leukoreduction, if we
want to use the hamster model, it clearly reduces by a percentage basis
the risk of infectivity. It doesn\'t eliminate it. Dr. Bailar talked
about the proportional reduction that would be necessary. So I don\'t
think leukoreduction for elimination or reduction of TSE is a
justification.

Many blood collection centers, however, are doing leukoreduction for
other reasons and that\'s perfectly fine, but I wouldn\'t even want to
consider doing it for the basis of this alone.

DR. PRIOLA: Mr. Bias?

MR. BIAS: I\'ll try not to repeat anything anybody else has said. I
would agree. We just don\'t have enough science here to change our
current recommendations in terms of lessening them or coming up with an
exit strategy.

I was reading the news and getting a lot of information and when the
U.K., second case from the U.K. came out and I wanted to just speak
briefly to something that I read and we got a lot of information during
the open public hearing from the blood collectors about reducing some of
the stringent deferral issues and I agree that this is probably not the
time to look at that. But I was surprised when I got the PPTA
information that they were actually touting in the last paragraph their
reduction of logs from plasma products.

When you look at those tests and we\'re not able to draw any conclusions
from the reductions of logs around this table, so my caution to all of
us is that once we open that door and we start reducing standards, the
industry is going to take that ball and run with it and I\'m just not
prepared to face those consequences as a person who\'s dependent on the
blood supply at this time.

DR. PRIOLA: Dr. DeArmond?

DR. DeARMOND: The reason I think that we should keep the deferrals as
they are is the second case in Great Britain, the MV case. That opens up
the possibility as Bob Will says that there is a second wave of patients
that may come along.

Alternatively, that case is very mysterious and raises the other
possibility that MV may be protective and actually has kept the disease
from getting to the brain and has put it into places where it can be
destroyed. But we don\'t know anything about that.

But it\'s a possibility of a second wave that means what we have is fine
and it needs to be here until we see that, whether a second wave
materializes.

DR. PRIOLA: Dr. Bracey.

DR. BRACEY: I must admit that prior to having the second case, I was
leaning more towards trying to see if we could develop an exit strategy,
but I think that would be premature now. And in fact, what really
bothers me the most is again what I mentioned before and that\'s making
sure that the current checks and balances that we have are working. I
think it would be important for us to get some \-- an update on the
frequency of BPDs related to this because again, we have two cases. We
know that it is transfusion transmitted, but what we do know also is
that there are people that are escaping the filter and we should track
that and make sure that that works before we pull away any restrictions
we have.

DR. PRIOLA: Dr. Creekmore.

DR. CREEKMORE: I agree with Dr. Bracey and many of the others that have
spoken here. I think it\'s too early to make a decision about lessening
the restrictions, especially with the second case that has been
described.

DR. PRIOLA: Should we go ahead and vote on that first question? It seems
that there\'s pretty much a consensus.

So the question is \"are the measures currently recommended by FDA to
reduce the risk of transmitting CJD and vCJD by blood and blood products
still justified?\"

DR. FREAS: I\'ll call your name. Dr. Gambetti?

DR. GAMBETTI: Yes.

DR. FREAS: Dr. Nelson?

DR. NELSON: Yes.

DR. FREAS: Dr. Jenny?

DR. JENNY: Yes.

DR. FREAS: Dr. Sejvar?

DR. SEJVAR: Yes.

DR. FREAS: Dr. Hogan?

DR. HOGAN: Yes.

DR. FREAS: Mr. Bias?

MR. BIAS: Yes.

DR. FREAS: Dr. DeArmond?

DR. DeARMOND: Yes.

DR. FREAS: Dr. Allen?

DR. ALLEN: Yes.

DR. FREAS: Dr. Priola?

DR. PRIOLA: Yes.

DR. FREAS: Ms. Kranitz?

MS. KRANITZ: Yes.

DR. FREAS: Dr. Bailar?

DR. BAILAR: Yes.

DR. FREAS: Dr. Creekmore?

DR. CREEKMORE: Yes.

DR. FREAS: Dr. Bracey?

DR. BRACEY: Yes.

DR. FREAS: Dr. Johnson?

DR. JOHNSON: Yes.

DR. FREAS: And Dr. Petteway, can we have your opinion, not your vote?

DR. PETTEWAY: Yes.

DR. FREAS: Thank you. It\'s unanimous.

DR. PRIOLA: We can move on to the second question which is \"do the
recent scientific data on vCJD warrant consideration by FDA of any
additional potentially risk-reducing measures for blood and blood
products?\" And this gets back to what Dr. Gambetti introduced a few
minutes ago and one of the things he discussed was leukoreduction.

Now I remember reading somewhere in the briefing materials and you
alluded to it as well that a lot of blood producers are already doing
that.

And what\'s the prevalence of that? Is that now a very common practice?

DR. NELSON: I think the American Red Cross and Dr. Page can talk about
this, but I think virtually all of the or most of the blood is
leukoreduced and there\'s been a statement of the AABB and others to
promote this, based on CJD risk.

DR. PRIOLA: Based on other infectious or transmissible \--

DR. NELSON: Based on post-transfusion febrile reactions and other
things.

DR. BRACEY: Not a scientific survey, but I would say that there probably
are as many as 30 percent of facilities that aren\'t leukocyte reduced,
using leukocyte reduced blood. In fact, largely for economic reasons,
folks have begun to move away and some centers, for example, in North
Carolina, the Red Cross began to back off of its policy of 100 percent

\-- offering that.

There are mixed data. It is rather expensive. I can tell you that for a
medium sized or I should say a large size hospital, it adds about \$1
million added cost to the total budget of \$200 million.

DR. PRIOLA: Dr. Page?

DR. PAGE: Dr. Page, American Red Cross. The American Red Cross provides
just less than half the red cells transfused in the United States. We
originally did have a policy of 100 percent leukoreduction of all red
cells, except for autologous. We backed off from that for reasons that
were alluded to, but as it turns out now, customers are ordering and we
provide over 90 percent of our red cells as leukoreduced in any event.
And the remaining, less than 10 percent include the autologous. So our
customers have largely wanted to get universal leukoreduction. It is
correct that some don\'t and I believe it\'s largely a matter of price.

I don\'t want to speak for ABC which is the other part, but I believe
they\'ve done a survey in that regard.

DR. PRIOLA: From ABC, then Dr. Johnson.

DR. BIANCO: Yes, I\'m Celso Bianco. I\'m from America\'s Blood Centers.
Dr. Bracey is correct. The American Red Cross with about half of the
supply

\-- here we are talking 7.5 million units or 7 million units in each
half. Leukoreduces about 90 percent of the blood. Our members of ABC
leukoreduce about 65 percent of the blood. And so if we try to do a
calculation for the whole country, it\'s about 80 percent is
leukoreduced. And it\'s interesting that in certain regions, the blood
is totally leukoreduced. In other regions the hospitals and physicians
will only order leukoreduced products for a certain population of
patients like hematologic patients. They are the ones that benefit the
most.

DR. JOHNSON: I think we really have nothing to do with this. I don\'t
think they should use leukopheresis. The BAC problem is a justification
for it. If they\'re doing it for other reasons, that\'s fine.

I do not think we should recommend leukopheresis. I think 40 percent
decrease is \-- when you talk about it in terms of many log reductions,
you\'d really like to see trivial and we should not bother with that. If
we\'re going change anything in terms of tightening them, they would
either be, seem to me to be the other options other than leukopheresis,
there may be others, but the only ones I see are decrease in the time
over seas in other countries or decrease in the number of countries on
the list.

My opinion would be that that probably is not the time right now to do
that and therefore my answer to number two, would be no.

DR. PRIOLA: Dr. Rohwer, did you want to address the leukoreduction data?
It\'s your data.

DR. ROHWER: I just wanted to make a couple of other points. We don\'t
believe that leukoreduction by itself can significantly reduce the risk
from blood-borne TSE infectivity. However, we\'re also strong believers
in the idea that removal is a very good option for significantly
reducing the risk from TSEs in blood and leukoreduction would be an
essential part of any removal strategy because it\'s required to get rid
of this cell-associated component of the infectivity.

What\'s needed now is a strategy for getting rid of the
plasma-associated component of the infectivity. We\'re working very hard
with a company called PRDT to develop such a product, to develop such a
device. We know that the Pall Corporation is also working very hard to
develop a strategy that they would combine with leukoreduction to do the
same thing and there may be other people out there also working on this
possibility.

But there are several very attractive features to a reduction strategy,
one being that as you go farther and farther back in the disease, before
the clinical stage, it\'s going to get harder and harder, presumably
harder and harder to detect infectivity with a diagnostic and addressing
the disease in that way seems to me to be problematical at best, whereas
a reduction strategy, if it worked, would work hopefully equally well on
very low concentrations as well as higher concentrations, realizing that
none of the concentrations will ever get very high in blood itself.

So I guess what I\'m \-- the message I want to leave is that well
leukoreduction by itself does not seem to be the answer. Don\'t throw
out the idea that a reduction strategy might be a very good one.

DR. PRIOLA: Dr. Hogan?

DR. HOGAN: I agree. I think any time you can an 80 percent compliance
with anything, as they\'re currently doing with leukoreduction, that\'s
pretty good. It\'s already happening. Secondly, I think it\'s irrelevant
if you\'re only reducing half the risk anyway, so I think that just
should be tabled.

Secondly, the issue of changing the deferral from three months to one
month, let\'s say for U.K.. I think that 3 percent calculation that Dr.
Williams showed is too much. You\'re going to lose too many donors. So I
think again, I think the current criteria, given the data that we have
are adequate. We have two cases, one of which is very atypical,
heterozygous and no neurologic disease, maybe his incubation period was
40 years. He was 82 if my calculations looking at the old paper are
correct.

I think we need to leave it well enough alone.

DR. PRIOLA: Dr. Bailar?

DR. BAILAR: Perhaps I should add a little bit to what I said earlier
about a 42 percent reduction and the continuation of a very substantial
risk. The linear model does have some important uses. In particular, it
can be a very good basis for proceeding if two conditions hold. One is
that the infectivity is low, that the risk is not lumpy, that is that
there\'s a little here, a little there. It\'s pretty uniformly spread,
not one unit here with 5,000 units and then thousands of units with
none.

So if the infectivity is low and reasonably uniform and if
susceptibility is uniform, if there is no tiny, but immensely
susceptible subgroup, the linear model can be right on target.

Having said that, I find the second question a good bit more troubling
than the first one. The fundamental problem, as I see it is that we have
a very limited kit of tools for identifying risk. We need to expand that
kit of tools. I\'m glad to hear that a lot of people are working on it,
but right now we have a few screening questions and for VCJD we don\'t
have much except geography and time. That\'s a pitifully small base on
which to try to reduce risk, but we use it as we can, but we shouldn\'t
kid ourselves that this is really going to do everything we want and do
it cheaply.

I\'m still thinking about how to vote on this second issue, but I\'m
sure that whatever we say, FDA will continue to monitor this situation
and we\'ll be pushing for improvements in the things I had mentioned,
that we really need to do to estimate risk.

DR. PRIOLA: Dr. Bracey?

DR. BRACEY: I think that in light of the fact that we now know that this
is most likely transfusion-transmissible that it really does warrant
that the FDA would consider additional risk-reducing measures. However,
I don\'t feel that increasing the number of donors deferred to let\'s
say 6 percent is reasonable. We simply wouldn\'t be able to tolerate
that. But there a number of interesting questions, the question of the
previously transfused donor, the question of issues related to the
differing criteria that we have for source plasma versus recovered
plasma.

So in a nutshell, I think that we really do need to ask is there
anything else that\'s within reason that we can do to reduce risk in
light of the second case.

DR. PRIOLA: Dr. Schonberger?

DR. SCHONBERGER: As I listen to the discussion, I wanted to raise the
issue that people are talking about a 40 percent reduction in risk, but
my understanding is that \-- or a titer \-- but my understanding is that
that relates to whole blood and most of the transfusions in this country
are not whole blood, but rather red blood cells and those red blood
cells are often washed and plasma eliminated as much to a rather high
degree.

So it\'s not clear to me that the 40 percent reduction is appropriate
for most of what is being used in the United States.

DR. NELSON: A washed unit still contains one million blood cells.

DR. SCHONBERGER: But that\'s what \--

DR. JOHNSON: When you talk about 40 percent reduction, you\'re talking
about a 40 percent reduction of risk only if the unit contains one
LD-50. If it contains 20, you\'re reducing it to 8, which is still 8
times more than it takes to kill you. So it\'s only if it happens to be
right on the line that you get a 40 percent \-- so we\'re not talking
about a 40 percent decrease in risk. We\'re talking about a 40 percent
decrease in infectivity which is an unknown decrease in risk that we
know is less than 40.

DR. EPSTEIN: I think it needs to be clarified that most red cells for
transfusion are not washed, that that\'s done in selected instances, for
example, frozen units that are thawed or certain units for selected
patients, for example, with donor antibodies, that the typical packed
red cell unit does contain plasma, about 20 to 30 mL, at least 10 mL. So
even if you take 3,000 round number residual infectious units in a
leukoreduced whole blood, and if there\'s really only 10 mL is what 20
percent of the unit, right. So you\'d still have at least 600 infectious
units in a pack of red cell.

DR. BIANCO: You still have a lot of units, but at 10 mL here, would be
since the amount of plasma unit is about 220 to 250 mL, it would
represent only five percent or less of the total content of plasma. So
it may improve the calculation, that you are reducing by one log. But
the significance of reducing by one log as we heard may not be relevant
in this case.

DR. PRIOLA: Dr. Rohwer?

DR. ROHWER: There is one other important point to keep in mind and that
is we titered the blood by the most efficient means of titration which
is to put it directly into the brains of recipient animals and there is
some current confusion about what the efficiency of infection is by the
intracerebral route versus the IV route, for example.

And it had been sort of dogma for a long time that in rodents it was
about 10 fold less efficient by the IV route, but there\'s been some
recent work by Corinne Lazmezas in France using monkeys and assaying
blood in a same species transmission by the IV route in monkeys where
based on incubation time it looks like there wasn\'t any difference
between the IC and the IV route.

This is something that needs to be looked at much more exhaustively than
we have done in the past. We\'ve not actually done these experiments in
our laboratory, but we tend to do them now.

DR. PRIOLA: Dr. Hogan.

DR. HOGAN: Was that, in that monkey study, they used brain-derived
material, right? Not blood-derived infection?

DR. ROHWER: You\'re right. What did I say, did I say blood?

DR. PRIOLA: So do we want to vote on issue 2?

Dr. Gambetti.

DR. GAMBETTI: Steve, I think that this Committee should briefly, but
consider the possibility of deferring cases that receive blood
transfusion in France in a similar way as the people who receive, donors
who receive the transfusion in U.K. are deferred.

DR. PRIOLA: So this gets back at your original comment. Is there any
data or tracking of the blood transfusion patients in France? Dr. Will,
do you have some comment on that?

DR. WILL: My understanding is that of the seven cases in France, none of
them have been blood donors. That is what I gather. The basis of that
evidence, I\'m not quite sure about because of course, whether they
actually tracked to find out as we do whether they all had been to any
blood donor centers in France, I don\'t know. But they\'re very
confident that my understanding is that there were no blood donors in
France.

It\'s also my understanding that in France already transfusion
recipients are not acting as blood donors. I think that\'s correct.

DR. DeARMOND: Bob, were they recipients? Were those seven in France
recipients? They weren\'t donors, but were they recipients?

DR. WILL: I don\'t know the answer to that question. From our experience
that I\'ve already mentioned we have \-- more or less age-matched the
French cases, the same age distribution so the chance of receiving a
blood transfusion are relatively low. In our series it\'s 5 out of 149,
so France \-- I don\'t know the answer, but I suspect it\'s not very
likely.

DR. PRIOLA: Dr. DeArmond.

DR. DeARMOND: It seems to me without having any data of the patients in
France acquired vCJD by blood transfusion rather by ingesting some beef
product, I don\'t see why we would add more to the deferral. It isn\'t
even at the level of a true theoretical risk at this stage. It would be
nice to have a little more data on that.

I think the deferrals are doing enough in the United States to prevent,
to at least keep the risk of having contaminated blood products to a
minimum and the United States is not Great Britain. We don\'t have the
mass quantities of people who were exposed who might be percolating with
the disease and at least there\'s no evidence that we have that here
yet.

So I would say that we don\'t have to add any additional piece of
deferral.

DR. CREEKMORE: I\'m jumping in on a totally different sort of issue, so
is there any more on that before I get us off on another tangent?

The way I read number two it says, \"do the recent scientific data on
vCJD warrant consideration\" not necessarily warrant adoption, but
\"warrant consideration by FDA of any additional potentially
risk-reducing measures.\" And I think for FDA to continue to consider
other reasonable risk-reducing measures is a good thing and that as long
as they are reasonable and they are considered within a cost benefit
framework, similar to what was presented in the presentation by our
Canadian colleague, so that we can continue to look at what are some
other potential options and what are the costs and benefits and use that
for the decision making process.

DR. PRIOLA: Dr. Johnson?

DR. JOHNSON: I was going to say exactly what you were going to say
except that I already said I was going to vote no on 2. And then I read
it again and I don\'t want to vote no that they shouldn\'t think any
more at FDA. I mean that really is kind of \-- that\'s a loaded \-- the
way that\'s written is loaded.

I would vote \-- I don\'t think we\'ve heard anything today that should
be instituted, but FDA should consider anything that comes along.

(Laughter.)

They should keep an open mind at FDA.

DR. HOGAN: My sense is even if we voted no, they\'d still consider it.

(Laughter.)

DR. PRIOLA: Dr. Allen?

DR. ALLEN: This is beating a dead horse. We can ask Jay for
clarification, but I think the FDA will continue to monitor the data.
They should. We need all of the new information as it becomes available.
I haven\'t heard anything today that would make me want to seriously
recommend that they consider anything additional and on that basis, I\'m
going to vote no, but with the understanding that the FDA doesn\'t sit
back, as I know they won\'t, if we make such a vote.

DR. EPSTEIN: I can certainly confirm that we won\'t stop thinking.

(Laughter.)

I think our objective in asking you question 2 is to see if there was
anything on the front burner, in other words, is there something obvious
that we ought to be trying to develop now as an additional safeguard.

DR. PRIOLA: So with that in mind, do any of the Committee \-- Dr. Jenny.

DR. JENNY: I think the one thing we need to think about is what do we
need to know to make an educated decision down the line. Is there data
that we want to get that will make a difference whether that decision is
made or not in the future?

DR. PRIOLA: Dr. Allen?

DR. ALLEN: From my perspective, in terms of epidemiological data, do we
add France, do we add any other \-- do we change the deferral window,
that sort of thing. I \-- if there\'s any good information that becomes
available, yes, we ought to consider it. I don\'t think it\'s likely
however, that that\'s going to be the source of new and better
information on which to base decisions.

I think we\'re going to see the next quantum leap which is going to be
very important and it will come eventually in terms of the development
of tests and using the state-of-the-art tests as they become available,
the understanding of our database better and in being able to make more
precise recommendations. But I think testing and technology is where the
next big advances are going to come.

DR. PRIOLA: Dr. Sejvar?

DR. SEJVAR: I guess just a quick comment. I guess kind of looking at
issue 2 from the other side and this arises just because of how
intriguing the second transfusion-related case in the U.K.
Neurologically asymptomatic, homozygous, excuse me, heterozygous and
just brings up this issue of an asymptomatic carrier state.

It kind of leads one to wonder well, are there people who are going to
either be resistant or essentially not able to pass the infectivity. And
obviously, at this point we have to go on the assumption that yes, this
is going to be transmissible no matter what the state of the host, but
maybe those are additional research questions that could be sort of
looked at. I don\'t have any particular recommendation per se, but I
mean it\'s intriguing.

DR. PRIOLA: Dr. Nelson?

DR. NELSON: I guess the data that I\'m more concerned about is the
appendix and tonsil and other data that suggests that there may be quite
a few people who, whether they\'re infectious or not or whatever, but
they may be, have been exposed and may or may not develop symptoms, but
the numbers \-- the terms of further research and so I would think that
those \-- that kind of study might be pretty important. I already
mentioned Dr. Will and it would be interesting, this is an anonymous
study now, but it would be interesting to try to link those positive
appendices with data that might obtained post mortem from such patients.
And it\'s now anonymous, but we might be able to link people by genetic
markers, HLA or something else to find out that when such a person dies
and has an autopsy, where is the prion? Is it there? Because it\'s
possible we may be missing some manifestations, particularly we might be
missing infectivity as opposed to frank CJD.

I think the surveillance is probably pretty good in the U.K. on variant
CJD, but infectivity is what we\'re really concerned about here.

DR. PRIOLA: I suppose one other thing to consider about the met-val
heterozygosity is that\'s 50 percent, I believe, from Dr. Will\'s side
of the population and so when you have it in a met-val population, it
may very well transmit more easily into the met-val population and
that\'s because the PrPs are compatible. I don\'t know if that will turn
out to be true, but it\'s possible.

I can\'t remember if it\'s true in transgenic mice. I think it varies
from lab to lab, if I remember.

DR. DeARMOND: It\'s actually the opposite. The MMs are very susceptible
because they have a higher incidence of CJD beyond the percentage of the
population and the MVs almost behave as if they\'re protective.

DR. PRIOLA: I think I\'m just referring if you have the infectivity come
from an MV and it goes into an MV, then you\'ve got that match, that\'s
all. So it\'s another thing to consider and another reason to be
cautious for me.

Dr. Bailar?

DR. BAILAR: I think the Committee has read question 2 in different ways.
Other people will surely do the same. Do we have the option to re-word
the question?

(Laughter.)

DR. PRIOLA: We always have the option to reword the question. It depends
upon whether or not the Committee considers the word \"consideration\"
to imply that the FDA will continue to investigate this, even if we vote
no and it seems the FDA has said that that will be the case.

DR. BAILAR: Yes, surely they will continue to consider. I think the
question that they might have meant to ask is whether anything warrants
action.

DR. PRIOLA: Dr. Epstein, could you clarify?

DR. EPSTEIN: Yes, I think the distinction we were trying to make here is
that if an intervention is proposed, we might need to assess it further
before moving to action. So what we were really looking for is between
questions 2 and 3, whether the Committee Members felt there was a
specific action that we ought to further develop as possible or feasible
for implementation.

I mean, for example, had it been the sense of the Committee that there
really seems to be a value for leukocyte reduction, let\'s get on this,
you would answer question 2 affirmatively.

So again, I mean you have the option to reword the question, but I hope
I\'ve adequately explained what we\'re looking for. This is something
that really rises to the level of consideration at this time, and FDA
would then take that advice and see if it\'s feasible to develop that
recommendation.

DR. PRIOLA: Dr. Bailar?

DR. BAILAR: If we could take that as de facto revision of the question,
I think I would vote no.

DR. PRIOLA: Does the Committee agree we can vote?

All right, so we\'ll vote on the second question, \"do the recent
scientific data on vCJD warrant consideration by FDA of any additional
potentially risk-reducing measures for blood and blood products?\"

DR. FREAS: For the record, there are currently 14 voting members around
the table. I\'ll go around and poll from the opposite side of the table
this time.

Dr. Johnson?

DR. JOHNSON: Vote no with the reservations expressed.

DR. FREAS: Dr. Bracey?

DR. BRACEY: I would vote yes.

DR. FREAS: Dr. Creekmore?

DR. CREEKMORE: No, with a revision of the question.

DR. FREAS: Dr. Bailar?

DR. BAILAR: No, with the revision.

DR. FREAS: Ms. Kranitz?

MS. KRANITZ: I vote the same, no, with the revision.

DR. FREAS: Dr. Priola?

DR. PRIOLA: No.

DR. FREAS: Dr. Allen?

DR. ALLEN: No, with the caveats.

DR. FREAS: Dr. DeArmond?

DR. DeARMOND: No, except as long as they keep thinking.

(Laughter.)

DR. FREAS: Mr. Bias?

DR. BIAS: No, with the revision.

DR. FREAS: Dr. Hogan?

DR. HOGAN: No.

DR. FREAS: Dr. Sejvar?

DR. SEJVAR: No.

DR. FREAS: Dr. Jenny?

DR. JENNY: No, with the revision.

DR. FREAS: Dr. Nelson?

DR. NELSON: No and I hope my vote won\'t be used in some sort of a
political debate in the future.

(Laughter.)

DR. FREAS: Dr. Gambetti?

DR. GAMBETTI: No, with the revision.

DR. FREAS: Out of the 14 voting members, we have one yes vote and 14
qualified no votes.

Dr. Petteway, would you please give your opinion?

DR. PETTEWAY: No.

DR. FREAS: Thank you.

(Laughter.)

DR. PRIOLA: So I would just like to make sure that by the revision we
mean that it\'s understood that the FDA is going to continue what
they\'re already doing which is the risk analysis for geographical
deferrals and time frame deferrals and what not. Is that \-- that\'s
what we mean by the revision. Okay.

Well, with that no vote, we basically \-- we don\'t have to say anything
about 3 because I think the FDA is pretty clear on what we mean by the
vote on 2 and that impacts on question 3.

So are there any other \-- before we adjourn, are there any other
comments from \-- Dr. Hogan?

DR. HOGAN: We wouldn\'t even be here if it hadn\'t been for the
excellent activities of the CJD Surveillance Unit and I would like to
personally thank Dr. Will for all of the work that he and his colleagues
are doing and I would urge them to continue to watch these human
experiments because I think that\'s where we\'re going to get most of
our information and I think it will be interesting.

DR. PRIOLA: Thank you, Dr. Hogan. Dr. Epstein, do you have a comment?

DR. EPSTEIN: Yes. I was just curious. There was one yes vote to the
question, as amended and I just wonder what specific safeguard that
individual had in mind?

DR. BRACEY: Well, the specific safeguard I had in mind was the history
of previous transfusions as beyond the U.K. Part of the concern was
information, well, you know, the increase infects herd infection rate in
Portugal. I\'m just concerned about that issue.

MR. BIAS: I would agree with that. Sometimes when we come to these
meetings, I\'m like what\'s going on with the rest of the globe here,
because we only get the information on Europe and the United States and
Canada. So some information on that would be interesting to digest as
well.

DR. PRIOLA: Are there any other comments from the Committee or the FDA?
Anyone else like to contribute?

Okay, I thank everybody very much for coming. Have a safe trip back. I
thank all the presenters and speakers for doing such a marvelous job and
this meeting is adjourned.

(Whereupon, at 4:32 p.m., the meeting was concluded.)