UNITED STATES OF AMERICA

FOOD AND DRUG ADMINISTRATION

CENTER FOR BIOLOGICS EVALUATION AND RESEARCH

TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHIES

ADVISORY COMMITTEE

MEETING

FRIDAY, FEBRUARY 13, 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 as to its accuracy.

The Advisory Committee met at 8:00 a.m. in the Kennedy Ballroom of the
Holiday Inn Silver Spring, 8777 Georgia Avenue, Silver Spring, Maryland,
Dr. Suzette A. Priola, Chairperson, presiding.

[PRESENT]{.underline}:

SUZETTE A. PRIOLA, Ph.D. 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

LISA FERGUSON, D.V.M. Consultant

PIERLUIGI GAMBETTI, M.D. Member

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

ALLEN JENNY, D.V.M. Consultant

RICHARD T. JOHNSON, M.D. Member

RIMA KHABBAZ, M.D. Consultant

JEANNE LINDEN, M.D., M.P.H. Consultant

KENRAD NELSON, M.D. Consultant

GEORGE NEMO, Ph.D. Consultant

STEPHEN R. PETTEWAY, JR., Ph.D. Non-Voting Industry Representative

JAMES SEJVAR, M.D. Consultant

SIDNEY WOLFE, M.D. Consultant

WILLIAM FREAS, Ph.D. Executive Secretary

[FDA REPRESENTATIVES]{.underline}:

KAREN MIDTHUN, M.D. CBER

WILLIAM M. EGAN, Ph.D. CBER

GERALD M. FELDMAN, Ph.D. CDER

MELISSA A. GREENWALD, M.D. CBER

MARTHA O\'LONE, RN, BSN CDRH

MORRIS POTTER Center for Food

Safety & Nutrition

DOROTHY SCOTT, M.D. CBER

ALAN WILLIAMS, Ph.D. CBER

[AGENDA ITEM]{.underline} [PAGE]{.underline}

[INTRODUCTIONS]{.underline}:

William Freas 3

[CURRENT CBER SAFEGUARDS FOR BLOOD PRODUCTS]{.underline}:

Dorothy Scott 5

[QUESTIONS/COMMENTS]{.underline}: 19

[CURRENT BLOOD DONOR DEFERRALS & THEIR IMPACT]{.underline}:

Alan Williams 21

[QUESTIONS/COMMENTS]{.underline}: 33

[MINIMIZING RISK OF TSE IN AGENTS IN HUMAN TISSUE]{.underline}:

Melissa Greenwald 44

[QUESTIONS/COMMENTS]{.underline}: 50

[USE OF BOVINE-DERIVED PRODUCTS IN THE MANUFACTURE]{.underline}

[OF VACCINES & ALLERGENIC PRODUCTS]{.underline}:

William Egan 54

[QUESTIONS/COMMENTS]{.underline}: 66

[MINIMIZING RISK OF TSE AGENTS IN DRUGS]{.underline}:

Gerald Feldman 79

[QUESTIONS/COMMENTS]{.underline}: 90

[MINIMIZING RISK OF TSE AGENTS IN MEDICAL DEVICES]{.underline}:

Martha O\'Lone 95

[QUESTIONS/COMMENTS]{.underline}: 105

[FOOD AND COSMETIC SAFETY]{.underline}:

Morris Potter 107

[QUESTIONS/COMMENTS]{.underline}: 111

[OPEN PUBLIC HEARING DISCUSSANTS]{.underline}:

Bill Drohan - Clearant, Inc. 118

Chris Penet - Genencor International 122

Hal Baker - Pall Medical 126

Robert Rohwer - Public Citizen 130

Patrick Crotteau - Inamed 132

[QUESTIONS]{.underline}: 133

[COMMITTEE DISCUSSION]{.underline}: 138

[ADJOURN]{.underline}:

Suzette Priola 202

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

8:05 a.m.

SECRETARY FREAS: Good morning. I would like to welcome you back to this
our second day of the Transmissible Spongiform Encephalopathies Advisory
Committee meeting. I would like to go around and introduce to you the
survivors who made it through yesterday\'s session. They are, starting
at the end of the table, Dr. Richard Johnson, Professor of Neurology,
Johns Hopkins University. We know who she is, she is the star of the
show from yesterday, Dr. Lisa Ferguson, Senior Staff Veterinarian, U.S.
Department of Agriculture. She will be right with us. She didn\'t make
it.

Next is, and if you would raise your hand, Dr. Arthur Bracey, Associate
Chief, Department of Pathology, St. Luke?s Episcopal Hospital. Next, we
have Dr. Rima Khabbaz, Associate Director of Epidemiologic Science,
National Center for Infectious Diseases. Next, we have Dr. George Nemo,
Division of Blood Diseases and Resources, NIH. Next, we have Dr. John
Bailar, Professor Emeritus, University of Chicago. Next, Dr. Sidney
Wolfe, Director of Public Citizen Health Research Group.

Around the corner we have Dr. Nick Hogan, Associate Professor of
Ophthalmology, University of Texas. In the empty seat we will soon be
joined by Dr. Kenrad Nelson from BPAC, who is the chair of BPAC. Next,
we have the Chair of this committee, Dr. Suzette Priola from the Rocky
Mountain Laboratories. At the corner of the table we have Dr. Allen
Jenny from the National Veterinary Services Laboratory. Around the
corner we have Dr. James Sejvar from CDC. Sitting next to him is Dr.
Stephen DeArmond, Department of Pathology, University of California.

Next, we have Mr. Val Bias, Co-Chairman, Blood Safety Working Group,
National Hemophilia Foundation. Next, we have Dr. Pierluigi Gambetti,
Professor and Director, Division of Neuropathology, Case Western
Reserve. Next, we have Dr. Lynn Creekmore, Staff Veterinarian, APHIS,
USDA. Next, we have Dr. Jeanne Linden, Director, Blood and Tissue
Resources, New York State Department of Health. And at the end of the
table, Dr. Stephen Petteway from Bayer Corporation who is our industry
representative.

The Conflict of Interest statement that was read into the public record
yesterday at the start of the meeting pertains to today as well and with
no changes. So, Dr. Priola, I turn the meeting over to you.

CHAIR PRIOLA: Okay. Thank you, Bill. Today\'s agenda is really a
continuation in many ways of yesterday, so many of the discussion points
that were raised yesterday will probably apply somewhat to what we are
discussing today. But I think we want to particularly focus on one of
the points that came up yesterday, and that is that given the current
situation, we want to assess the current safeguards that FDA has in
place, see if there are any reasons based upon current scientific
knowledge to change those safeguards or address how changes could be
made to those safeguards, what the feasibility of that would be, always,
of course, keeping in mind the risk- benefit ratio, and also to consider
how to obtain or continue to obtain relatively pure and safe bovine
materials from other countries in a way that is similar to what we have
done for other countries that have scrapie in sheep and goat.

So with those points in mind, I think we\'ll go ahead with the first
speaker, Dr. Dorothy Scott.

DR. SCOTT: The title of my talk is current CBER safeguards for blood
products, our approach to products containing or exposed to bovine
materials. Now, I do want to talk about a few other things as well. Some
of these are in your package. One of them is not simply because it was
published after the package came out, but the \--

UNIDENTIFIED SPEAKER: We can\'t hear you. Turn your microphone on.

DR. SCOTT: But the other thing in particular I want to mention is
European policies that are relevant to this discussion that are a model
or at least present some potential solutions to some of the problems
that we think we may encounter. And after I speak, Dr. Williams will be
talking about safeguards for human blood with regard to variant CJD.
Next slide.

Just to very briefly review, and this doesn\'t apply to blood,
obviously, but to all of our products. There are various strategies for
minimizing the risk of BSE exposure to products, this includes how you
source your materials, the geographic source of the animals that you
use, the tissue source from the particular type of animal, the tissue
collection technique, which can be optimized to minimize the risk of
cross-contamination of low-risk tissues with high- risk tissues, and
herd source and monitoring may also be important depending on the
country that one is sourcing from.

In addition, there is a possibility for many products of TSE clearance
during manufacturing. And something that we won\'t be discussing much
today, but still is important is how equipment is cleaned between
batches, particularly batches with intermediate or high-risk material in
them. Next slide.

So, first, I\'m going to go through what we in CBER and particularly in
the Office of Blood have already done prior to the discovery of BSE in
this country, and the description of the presumptive transfusion
transmission of variant CJD. From 1993 forward, we have sent letters to
manufacturers recommending that they not source bovine materials from
BSE countries. But as BSE is detected in more countries, instantaneous
source switching becomes very difficult, because it takes time to locate
and contract new sources of material and also raw materials have to be
qualified.

You have to be sure that your new source provides you with the same
manufacturing or comparability of your product as the old source did.
And then as was pointed out yesterday in the open public hearing, there
can be availability concerns. In other words, it may be difficult to
source from other countries if there isn\'t very much there or at least
if it doesn\'t meet our needs, and I think that discussion was about one
of the bovine blood products. Next slide.

I just want to give you a sense of the scope of blood products that
contain or are exposed to bovine materials, and these are just some
examples, and I have divided them into four sub-categories. First is
active substance. So, in particular, some of our hemostatic products
contain bovine thrombin, bovine aprotinin, and bovine gelatin
derivatives. There also may be excipients or adjuvants of bovine or
ruminant origin. However, this is a very minor category.

Certainly raw starting materials and reagents are important. As you
know, we regulate not only blood-derived plasma derivatives, but
recombinant products. In addition, some of our plasma derivatives are
exposed to monoclonal antibody columns. So all of those require cell
culture reagents, and some of these that are commonly used are fetal
bovine serum, bovine insulin, and bovine serum albumin.

Manufacturing reagents may also have some bovine materials. In
particular, tallow derivatives, and I just mention polysorbate 80, which
is used for viral inactivation, that can also be sourced from plants.
Bone derivatives, typically gelatin, again. And equipment qualification
materials may contain bovine source material. And I am talking about
what is used for media fills. This is actually media that is used to
test the integrity of an aseptic filling system at the end when you are
filling your product into vials. Okay. Next slide.

So, just to summarize, what we have done is we have requested, as I
said, our manufacturers to source bovine materials from non-BSE
countries, and we have also encouraged them to use non-bovine materials
whenever possible. And indeed we have had some switches to non-bovine
materials. In addition, our IND and BLA product reviewers assess the
presence of ruminant materials in any of our new products, their
geographic source, their tissue source, and we make recommendations
accordingly. In the past, typically, these recommendations have been
sourced from a BSE-free country. Next slide.

This Committee has reviewed a couple of topics that are relevant to
these issues, and I\'m just going to mention two of them. One is this
Committee reviewed facility and equipment cleaning methods with respect
to TSEs, very recently July 18, 2003, and you concluded that the current
facility cleaning methods, and I\'m speaking of plasma derivative
facilities, e.g., the use of solutions of sodium hydroxide or sodium
hypochlorite followed by extensive rinsing cycles are adequate to
minimize the possibility that an infectious dose of the vCJD agent,
that\'s what you were considering then, but we don\'t really recognize
the distinction between that and the other TSEs in this context yet, may
be carried over from one manufactured lot into the next.

On inspections, which are typically held every other year for our plasma
facilities, raw material sourcing is confirmed, and facility equipment
cleaning methods are assessed. Of course, some companies are inspected
more often than every two years. Next slide.

In addition, in February of 2003, this Committee endorsed our
consideration of labeling claims for TSE clearance in the manufacturing
of plasma derivatives that would be based upon specific demonstration of
TSE removal during manufacturing. And we have encouraged such
submissions in the Office of Blood, and we have received some such, and
we are in the process of evaluating those. Next slide.

I can\'t show you any of those studies today, but I just want to say
that for plasma derivatives there have been a number of studies and most
of them have been published in peer reviewed literature. You can just
get a sense of them from their titles. In addition, by and large, these
were funded or supported by manufacturers. So the methods that are used
are typically down-scaled manufacturing processes. So you can just go on
to the next slide, which is more of the same.

But you can see that there is a literature that is accumulating now on
this, but, of course, when we receive a submission, we ask for a great
deal of additional detail. Next slide.

I also want to mention risk communication and that we have labeling with
regard to CJD for plasma derivatives and blood products. Just in
general, the labeling is intended, in a case like this or in the case of
viral transmission, to provide an estimate of the risk of transmission
of infectious agents. This is usually a general estimate, not a
numerical estimate. It may discuss, labeling may discuss, measures taken
to reduce risks.

Right now, our TSE-related labeling does not do that. In the case of
viruses, labeling may include results of clearance studies, and overall
this allows the public to make a more informed decision about
risk-benefit. Now, labeling claims for viral clearance typically undergo
a very thorough scientific and regulatory review prior to approval, I
should put. And labeling claims for pathogen removal in the past have
been based upon rigorous and specific scientific evidence. Next slide.

This is our current recommended labeling. This is through guidance for
blood products, because this product is made from human blood, it may
carry risk of transmitting infectious agents, e.g., viruses. And,
theoretically, the CJD agent. Now, you will notice that maybe this looks
a little passe to you. We do have CJD as sort of encompassing CJD and
variant CJD.

And based on some of the discussions we\'ve had and on the presumptive
transfusion transmission in the U.K., some people might question even
the use of theoretically. But that\'s a discussion, I think, for another
Committee session and not for this one. But I just want to point out
that this is the kind of thing that we expect to be bringing back to
you. Next slide.

Now, I\'m just going to mention some of the European policies that are
relevant to these topics. And the EMEA has proposed guidelines for TSE
clearance studies. This is part of a discussion paper, so they don\'t
have a guidance for this now. But they are struggling with the same
issues that we are that to do a TSE clearance study, you\'re still
dealing with a lot of unknown, since we don\'t know what form the agent
actually takes in blood.

These studies are difficult to perform. There is a question of how often
a bioassay should be done versus a PrPsc assay when you are assessing
the amount of clearance that you have, and there are a number of other
issues that make these studies difficult to know how to do, and not
necessarily difficult to interpret, but difficult to bridge over to what
may actually be relevant. Nevertheless, I think that we all need to do
the best that we can.

This is what they propose, and we already request this. The use of
actual production materials for scale-down clearance studies and
appropriate scale-down models. They have recommended that spiked
infectious material not be more than 10 percent of the final volume.
Obviously, that is going to affect the characteristics of the matrix
that you use. Studies should be in accordance with GLPs. Partitioning of
infectivity should be demonstrated, in other words, to make a claim. And
interestingly, infectivity reduction factors of less than one log should
be considered insufficient. This is a number that is a bit on the lower
side, if you consider the precision of some of the assays that are
commonly used. Next slide.

But I present this really as a model that has a lot of benefits.
Combined-step studies, in other words, throughput type experiments
should help support the decision to accept whether or not two or more
steps are additive. And combined-steps are important where a prior step
might alter the context or infectivity of the TSE agent. For example, a
solvent detergent treatment might alter the properties, the physical
chemical properties of the TSE agent that you are using and might affect
its removal by a subsequent step. So that\'s called \"conditioning.\"

They requested a rationale be given for the TSE strain selected in these
experiments. They don\'t actually mandate a particular type of spike be
used, but they recommend microsomal fractions. Others can be used. A
rationale needs to be provided. Next slide.

They suggest bioassays, but PrPsc assays used to identify steps that are
most like to remove infectivity, and they suggest that studies should
focus first on products manufactured by processes that appear to have
the lowest overall capacity to remove TSE agents. Next.

They state that all manufacturers must critically evaluate their
processes in light of published data, consider modification of processes
and that it is highly desirable that manufacturing steps with
potentially highest removal capacity are experimentally investigated. So
again, what I\'m trying to convey with this is that these studies
aren\'t mandated. Next slide. So far.

Now, I want to switch topics a little bit, but this might be one of the
more important topics to this Committee today. And that is the Note for
Guidance that, as I mentioned, you don\'t have in your packet, because
it was just recently published. It wasn\'t even up on the website when I
got back from the EMEA in Europe. But this is a Note for Guidance on
minimizing the risk of transmitting animal spongiform encephalopathy
agents via human and veterinary medicinal products, the topic that we
are discussing.

And this is a guidance, and therefore it has the force of law in the
European community. Very briefly, this has several detailed parts, but
initially they suggest or they say that a risk assessment for animal
sources in veterinary medicinal products must be made. And this has to
take into account the sourcing of animals. And when I say animals, I
mean cattle, sheep, goats, any animals that are susceptible via oral
feeding to a TSE agent.

Okay. So this doesn\'t cover just cattle. Animal sourcing, the source of
the tissue used, TSE clearance manufacturing, just what we have been
talking about. The route of product administration, the quantity of
animal material in the final product, the maximum therapeutic dosage,
and, presumably, and this is also the frequency of the dosage, since
some of our products are taken lifelong, and the intended use of the
product and its clinical benefit. Next slide.

Getting into the details, they recommend that source animals are sourced
from countries with the lowest possible GBR risk, and I will mention
what the GBR risk is. This is defined by the Scientific Steering
Committee on Geographic BSE Risk, unless the use of material from higher
GBR countries is justified. So a GBR I country is where BSE is highly
unlikely. This would be, for example, Australia and New Zealand.

A GBR II country is where BSE is unlikely, but not excluded. A GBR III
country is a country where BSE is likely, but not confirmed or confirmed
at a lower level. That is less than 100 animals per million cattle.
Okay. And a GBR IV country is more than that. This document also brings
up the concept of negligible risk herds and that those may be considered
in conjunction with the GBR classification.

So what is a negligible risk herd? Well, actually, the Scientific
Steering Committee published in 1999 what constitutes a negligible risk
herd for BSE. And such herds would be comprised of cattle that had no
meat and bone meal for at least eight years in that herd. And they
can\'t be fed any fish or poultry meat and bone meal. Diet records have
to be kept. Food tracing has to be possible. There can\'t be any other
domestic species on the property that are fed meat and bone meal,
particularly, pigs and poultry.

They can\'t import into the herd except from herds that are negligible
risk or better, that is GBR I. Every animal has to be traceable. All
animals have to be proven to have had no meat and bone meal through
their entire lifetime, and they can\'t be fed even tallow, gelatin, or
waste. And all brains of cows that are killed at an age of greater than
1 year-old need to be examined at slaughter. So that\'s a negligible
risk herd. And this is the website where that is. Next slide.

Now, on to the source tissue, this is subdivided into Categories A, B,
and C, and they state that sourcing from Category A tissue shall not be
used unless justified. In other words, they leave possible the opening
that one might actually have this as the only source for a certain
product, but it would be very difficult, perhaps, to justify it.

Category A high infectivity, SRM-like materials, lower infectivity
tissues include a lot of the tissues that we and others use in medicinal
products. So this is bovine blood, lung, liver, lymphoid tissues, and so
on. And Category C is things like skin, hair, and so on. I have a list,
but I\'m not going to go through all of that. It\'s four pages long.
Next slide.

The additional source tissue considerations in this risk assessment
include the possibility of cross-contamination of low-risk tissues with
high-risk tissues. The stunning and slaughtering techniques that are
used, you need to use ones that assure that brain tissue doesn\'t
contaminate other tissues. Some of the stunning techniques actually do
that. And measures need to be adopted to avoid contamination during
collection of tissues. They also stated it is prudent to source from
young animals, and procedures should be in place to ensure auditing
suppliers of starting and raw materials of these ruminant materials.
Next slide.

This also has special sections for collagen and gelatin. I\'m not going
to go through all of these, but some of them, for example, sourcing of
amino acids or gelatin from GBR free countries, you have to use certain
processing techniques or show that other processing techniques are going
to lead to clearance of TSE agents. But for bovine blood derivatives, I
just mention that in particular they specify that all batches have to be
traceable to the slaughterhouse and to the farms of origin and that GBR
I and II source countries should be used, unless otherwise justified,
and that the stunning methods must also be described.

I think that may be the end. Yes. Thank you for your attention.

CHAIR PRIOLA: We have a few minutes for questions for Dr. Scott if
anyone has questions. Dr. Wolfe?

DR. WOLFE: Just a quick question. Dr. Scott, you mentioned that one of
the criteria for this low-risk would be examining the brains of all the
animals after slaughter. Is that before or after release of the product?

DR. SCOTT: It doesn\'t state. One would presume that would be before.

DR. WOLFE: But we don\'t know?

DR. SCOTT: That\'s correct.

DR. WOLFE: If we could find out, that would be useful.

DR. SCOTT: Right. I happen to have the document here, so I\'ll read it
again and let you know if I can see otherwise.

DR. WOLFE: Okay. Thanks. That would solve a lot.

DR. SCOTT: But I believe it doesn\'t.

DR. WOLFE: Okay.

CHAIR PRIOLA: Dr. Bracey?

DR. BRACEY: With respect to the examination of the brain, this would be
a microscopic examination?

DR. SCOTT: Presumably, this would be according to one of the approved
tests.

DR. BRACEY: Okay, with the test. Okay.

DR. SCOTT: Including, you know, histochemistry.

CHAIR PRIOLA: Okay. Thank you, Dr. Scott. The next speaker is Dr. Alan
Williams.

DR. WILLIAMS: Good morning. I\'m going to discuss FDA recommended
safeguards for minimizing the risk of variant CJD from blood products,
namely the deferral of blood and plasma donors based on potential risk
of BSE exposure. In several meetings of this Committee during 1998 and
early 1999 time frame, there was clearly much discussion about
increasing awareness of the BSE epidemic in the United Kingdom and cases
of variant CJD in the U.K. and in France, and the potential impact on
the safety of the U.S. blood supply.

That came in concert with recognition that there were no screening tests
potentially available to screen donors for prion disease, nor were there
any specific targeted measures to assess potential exposure to
contaminated materials. Next slide, please.

At the meeting of the January TSE Advisory Committee, the Committee felt
strongly that there was a need to begin to consider deferral based on
dietary exposure to BSE, but was uncomfortable, at that point, of making
a specific recommendation due to potential impact on availability of the
blood supply, which is fragile in the best of times. So at that early
1999 meeting, it essentially commissioned a survey on the travel
patterns of blood donors to determine information that would help to
make an informed policy decision regarding donor deferral.

That survey took place between February and May of 1999. It involved a
survey of 19,000 blood donors at 12 blood donor sites. It was conducted
in really very good collaboration between the American Red Cross,
America\'s Blood Centers, the AABB, the National Heart, Lung and Blood
Institute through the REDS study and other participants. We got about a
50 percent response rate to that survey, which collected information
about travel to the United Kingdom based on intervals from which we
could determine cumulative time of exposure.

Based on the results from those data which were presented at the June
\'99 meeting of the TSE Advisory Committee, the Committee recommended
and subsequently through draft and final guidance, FDA recommended to
industry in November of 1999 donor deferrals related to dietary risk to
BSE, and these recommendations included travel or residence in the
United Kingdom for more than or equal to six months between the period
of 1980 to 1996, reflecting the period of the BSE epidemic in the United
Kingdom, and the 1996 time frame representing when the Committee felt
that food chain controls in the U.K. were adequate to assure with
reasonable certainty that dietary risk had been minimized.

In addition, donors who had received bovine insulin sourced in the U.K.
after 1980 were also subject to referral. And product retrieval and
lookback procedures were recommended if a donor was later discovered to
have variant CJD. Now, based on the survey information the estimated
donor loss for these deferrals was 2.2 percent. And there really was
quite an intense discussion about, you know, what an impact 2.2 percent
loss would have. And that was very much a risk to donor loss
consideration, which resulted in that recommendation. Next slide.

Now, in further discussions and increasing awareness of the spread of
BSE throughout Europe, we continue to work with the results from this
survey as well as information that was being collected concurrently and
made estimates for what residual risk might still remain in the donor
population. And this is a pie chart shown at one of these meetings
reflecting the proportions of risk estimated to come from different
potential donor exposures.

You see, there is a residual risk for travel to the United Kingdom,
because clearly most donors who travel to the U.K. don\'t stay as long
as six months, and you have a cumulative consideration of donors who
have been there a few days up to a five month period for which the
deferral would not capture. Similarly, recognition of the epidemic in
Europe and travel to Europe was estimated to comprise 14 percent of
residual risk. Based on a risk-weighted model in which Europe, based on
the best data available, which was from Switzerland, would have a risk
proportion of approximately 5 percent to the risk in the U.K., so this
was a risk-based model.

In addition, about 25 percent of the New York Blood Center blood supply
was imported from Europe, and this was estimated to comprise about 11
percent of the risk at that time. Also recognized was that the
Department of Defense imported substantial quantities of beef from the
U.K. during the period of interest in norther Europe from 1980 to 1990
and in southern Europe bases from 1980 to 1996, and also added to the
risk equation. Next slide.

Based on those considerations and an additional hard look at the survey
data, FDA presented a series of options for potential additional
safeguards, and these were discussed at the TSE Advisory Committee in
June of 2001, and based on their recommendations, guidance was
subsequently issued to industry in draft, and then in final form in
January of 2002. And this added donor deferrals for risk to BSE exposure
in Europe based on five years cumulative exposure in Europe.

It tightened the U.K. donor deferral. It ratcheted it down from six
months to three months. And because of concern about donor loss and the
impact of an acute implementation, implementation was conducted in two
phases, with the first phase, namely the U.K. deferral, recommended for
completion by May of 2002 and the European deferral by October of 2002.
And again, based on the survey data, this was estimated to result in a
90 percent reduction of that total cumulative risk that you saw in the
pie chart with a loss of about 5 percent of the donor base in this
second recommendation, but then combined with the 2 percent realized in
the initial U.K. deferral about 7 percent total donor loss. Next slide.

I went over this mostly in discussing the last slide. Briefly, the U.K.
deferral was tightened up to three months residence or travel in the
U.K. cumulative between 1980 and 1996. The five year residence or travel
in Europe was specific to blood donors, for donors of source plasma it
was felt that using the same deferral for all plasma donors would have
undue supply impact, so this criteria was applied only to France, which
was felt to have 5 to 10 percent total consumption of UK beef, and at
that time it also had several recognized variant CJD cases.

The deferral for exposure on U.S. military bases in Europe was for six
months, and this had differing time frames between the northern and
southern distinction. I think in practice blood centers found it easier
to simply pool these and defer for the 1980 to 1996 time frame, but FDA
did create the option to try to preserve donor loss where possible.
There was also deferral for transfusion in the United Kingdom from 1980
to the present and again receipt for bovine insulin sourced in the U.K.
Next slide.

Now, the impact of these deferrals has been a topic of a lot of
discussion, and, in part, that is due to the fact that there is really
no precise way to measure a deferral, the impact of a deferral like that
after it has been put into place. The reason being that deferral happens
at many points. Once a deferral is implemented blood centers make this
known to their donor base. When donors call for appointments, often this
information is given over the phone. It is sent to the donors.

Clearly, it is advantageous to defer the donor at the earliest time
possible when appropriate. So a lot of the deferral happens before the
actual blood collection, and there is also self deferral at the blood
collection site, as well as deferral during the interview donor
screening process. And, in fact, while this gets a lot of attention, it
is actually one of the smallest components of the donor deferral impact.

The travel survey estimated a 5 percent overall donor loss from the
second phase of deferral with a higher loss in the coastal areas,
perhaps as much as double in the east and west coast, and specific to
the New York Blood Center, this would be a potential 10 percent donor
loss combined with the 25 percent loss from the inability to use
Euroblood in the future. In fact, this observation appeared to be
realized once the deferral was implemented, but something not realized
at the time was that geographic areas which had high concentrations of
military donors were very hard hit.

We did attempt to capture information from military donors in the very
short time frame that we had to run the survey, but, in fact, military
populations don\'t respond very well to surveys. We had about a 10
percent sampling rate, and we knew it would be excessive, but we really
couldn\'t create estimates. But, in fact, in subsequent discussions that
was, in fact, one of the biggest surprises from implementation of the
deferral.

So the observed onsite deferrals, as I mention, small components,
potentially, of the total deferral ranged from 0.1 percent to 3.5
percent as presented by blood centers subsequently. And this was
discussed in some depth at the June 27^th^ meeting of this Committee.
Next slide, please.

Okay. I\'ll just hold on that for a second. The New York Blood Center
presented its experience. As I mentioned, it was estimated that 25
percent of the blood that was imported from Europe would be lost and 10
percent deferral, based on the survey estimate. In fact, they realized a
13 percent travel deferral combined with a 25 percent. They anticipated
a lot of this loss in New York, and it secured alternate supply
agreements. It also implemented a very well designed and assertive
recruitment program and managed to get through the period and still
provide necessary blood supply for their hospitals.

However, it clearly did make a significant dent in the donor base, and I
think in holiday periods subsequently, all blood collectors have felt
the pinch of having sufficient blood supplies in the traditionally
shortage times. The American Red Cross implemented a deferral that was
slightly different than the FDA recommendation. The primary difference
being deferral for six months cumulative time spent in Europe as opposed
to five years, which was the FDA recommendation. This was implemented in
October of the previous year.

This also followed an extensive recruitment campaign, and losses within
the Red Cross onsite deferrals range from .2 to 1.1 percent overall. But
again, some areas like the Norfolk area and the Alabama collection sites
were particularly hard hit because of high military populations. Now,
America\'s Blood Centers also presented at that meeting and showed a
range of .3 to 4.6 onsite deferral and presented information from a
survey conducted prior to the implementation of the deferral at blood
systems, which estimated a 3 percent overall loss, but as high as 7.7
percent in areas of northern California, again related to the military
populations.

ABC maintains a blood monitoring system on its website called a
stoplight system with red representing one day supply, yellow two day,
green three day supply, and clearly that system has shown that really an
uncomfortable percentage of ABC sites have been at a one and two day
supply over the past couple of years, and I think this factor was
mentioned by Colonel Fitzpatrick in his discussion yesterday reflecting,
you know, that there is, in fact, a long term impact of trying to
maintain the blood supply in the face of laboratory and donor deferrals.

And then finally, the military presented their experience. They
anticipated and realized an approximately 18 percent loss of donors due
to these donor deferrals. They combined this with a major recruitment
effort, and due to a very high penetration rate of donation within base
staff, their donations actually rose subsequent to this deferral by 9
percent.

I think it is important to mention that while the blood supply has been
termed as being generally adequate for patient needs, and this was
reflected in a GAO report in July of 2002, there have been a lot of
discussions, for instance, at the Advisory Committee for Blood Safety
and Availability, that the blood supply is fragile and some of the
holiday and summer periods that are being experienced really show not
just regional shortages, but also potential national shortages, and
there have been national appeals made in both holiday periods over the
past two years.

So there is concern about the, you know, ultimate degree to which the
blood supply is resilient and could be made up by additional
recruitment, and this recruitment more and more requires resources that
could be placed in other areas. So there is concern really across the
board at the difficulty of maintaining adequate supply in the current
situation.

I wanted to mention briefly, I think the donor survey that I referred to
probably could not have been conducted, certainly not conducted as well
without the presence of the NHLBI supported Retrovirus Epidemiology
Donor Study. This study ran its first phase, a long phase, until, I
think it just ended, near the end of 2003, and it is embarking on a new
funding period. That was crucial in supporting that survey, and I\'m
also just going to show a brief bit of data which I think will help
assess the ultimate impact of these deferrals.

Briefly, the first phase involved five REDS participants and Westat,
Incorporated, which is the coordinating center. Next slide.

And one of the key data collection elements within REDS is that all
donors and all donations at the five sites report additional demographic
information, which has really been a gold mine of information for
relating to test results and many other factors. Next slide.

One graphic that I did want to show you, and this resulted in a
discussion with the REDS group, that, perhaps, given this database, we
should give a hard look at some of the long term changes in the donor
base resulting not only from the donor deferrals related to BSE
exposure, but due to implementation of new laboratory tests and so
forth. This is just a fairly simple graphic of the percentage of repeat
donors providing donations from 1991 to the year 2000.

78 percent of the blood supply made up of repeat donors in 1991 to a
high of 82 percent in 1993, dropping back down to close to 76 percent in
2000, and we don\'t have the \'01 and \'02 data, but one could presume
that these figures may even be lower because we anticipated that the BSE
deferral would hit hard at repeat donors. So I think there needs to be
additional analysis of this sort to look at the long term impact of
these sorts of interventions and assess the dynamics with respect to the
blood supply.

One final note is that BSE, we could create a policy resulting in
intervention to protect the blood supply from U.K. exposure and,
theoretically, BSE exposure in Europe. We are not prepared at this point
if there should be a recognized BSE outbreak in Asia. We don\'t have any
data related to donor exposure, and I would hazard a guess that right at
the moment we don\'t even have the infrastructure that we had in 1999 to
conduct a survey as we did like that at that time.

So I think there is a message there that we need preparedness to conduct
ad hoc data collections as we can and be able to use those data to drive
policy decisions and maintain a logical balance between the science
related intervention and the ultimate impact. Thank you.

CHAIR PRIOLA: Thank you, Dr. Williams. Are there any questions? Dr.
Bracey?

DR. BRACEY: More of a comment with respect to the adequacy of the blood
supply. Indeed, we have had difficulties, particularly, in the holiday
period. If you track the numbers, the information is right on target in
terms of having a one or two day supply. But in truth, in January in
large areas such as Dallas, there was about six hours worth of supply.
And, in fact, there were cases delayed throughout the state of Texas and
various other regions.

One of the things I think that has been discussed, but I\'m not sure
that action has been taken, is the application of resources to donor
recruitment. Largely, it is left up to the individual region. In our
region, the regional blood center has invested resources into putting
ads on prime time developing a promotional campaign. Some years ago, it
came to my attention that Canada, its health system, funded such
activities, and I don\'t know if there has been discussion of such in
the States, but I think that as we look at improving the blood supply,
we need to look at the resources to make the blood truly a national
resource and to get away from this point of fragility.

And then one last comment is that with regard to the utilization, I note
that our colleagues in Europe are looking at addressing utilization. If
you look at product use review, you\'ll find that as much as, in the
worst scenarios, 40 percent or in the best case, perhaps, 20 percent of
transfusions are unneeded. So I think a major effort that we might also
look at is educating \-- developing an educational program regarding the
use, so that we can approach best practice.

CHAIR PRIOLA: Dr. Sejvar?

LT. SEJVAR: Yes, just a question about the decision or the rationale
about the cumulative time spent in various areas with respect to
deferral. What was the basis or the rationale for the decisions on the
time and has adjusting those time frames been looked at in terms of its
impact on blood supply?

DR. WILLIAMS: The basis for the cumulative time spent in an endemic area
really is just an assumption that there is a direct proportion between
time spent and potential for dietary consumption of beef and,
theoretically, beef which may be contaminated. We looked at whether
there might be reasonable stratification for those who did not eat beef.
In fact, in the survey responses that we got, we found enough
conflicting information that we felt it would not be, you know,
sufficiently specific to use in donor criteria determination.

So basically, it\'s a rather simple correlation between time spent
relationship to dietary exposure. And I mentioned the risk-weighing
between potential exposure to U.K. beef in different parts of Europe,
both indigenous BSE as well as imported U.K. beef. As far as reviewing
the policy, this Committee meets every six months, and we do
periodically raise the deferral criteria for discussion. And I think,
you know, one consideration that was made was cutting off the potential
U.K. exposure period at 1996. I think as other countries implement
similar safeguards, there will be consideration of them.

CHAIR PRIOLA: Dr. DeArmond?

DR. DEARMOND: I was very amazed a couple of years ago when we learned
that the military was one of the major sources of blood. I can\'t
remember what the figure was 10, 15 percent of the total donations come
from young military.

DR. WILLIAMS: That sounds a little high. I think it\'s closer to 3
percent.

DR. DEARMOND: Oh, gee. So, but it was considered to be a major loss when
any were excluded. And you mentioned that there has been some rebound
since then. And that is because they keep turning over rapidly, and the
population that was exposed to beef, I presume, are out of the service,
and now we have got new people with the same fervor to donate.

Has the war had any impact on this, because so many of the recruits are
in Iraq and Afghanistan and other places?

DR. WILLIAMS: I can\'t comment specifically on that. I haven\'t heard a
presentation from DoD specific to that. I guess one might presume that
the more troop movement there is around the world, it would affect the
deferrals, but I haven\'t heard specific information on that.

DR. NELSON: The war has had a major impact, not because of BSE, but
because of leishmaniasis. They are deferred for a year just based upon a
potential leishmaniasis risk if they have been in Iraq.

CHAIR PRIOLA: Dr. Linden?

DR. LINDEN: This is really just a comment informationally. Dr. Williams
mentioned how hard hit New York was, in particular, because of the loss
of Euroblood. And I just want to mention that something that we did as
the Health Department is that we printed up little cardboard flyers
encouraging blood donation and giving the 800 numbers for the two major
blood centers in our state, English on one side, Spanish on the other.

And we distributed them by the Department of Motor Vehicles in routine
mailings that were already being sent anyway. And the cost to print
these was something in the range of \$8,000 or \$9,000 per million. So
for less than \$50,000 we were able to do five million mailings, because
the cost of the mailings themselves was zero. And this is an ongoing
effort. We don\'t have any data on whether this was successful or not,
but I just wanted to mention this is a strategy that we tried to employ.
And I know Dr. Wolfe asked me about this yesterday, and we would be
happy to share information about our experience with anybody else who
might be interested in thinking about that kind of strategy.

DR. WILLIAMS: One brief follow-up comment to Dr. Bracey\'s comment.
There was just a meeting of the Advisory Committee for Blood Safety and
Availability, which is an HHS Committee, on the role of Government in
the blood supply and maintaining the blood supply. Had some very
interesting discussions, including, you know, model systems overseas as
well as potential government role in recruitment and maintaining the
blood supply, creation of reserves, that would be a very interesting
transcript to look at if you\'re interested in that subject.

CHAIR PRIOLA: Dr. Bracey?

DR. BRACEY: Just one other comment. In terms of the donor base, there
are issues related to the repeat donor base. But also, I think, if you
look at the impact of recruitment, it has largely been on the European
donors, it has been under \-- there is under representation of
Hispanics. There is under representation of African Americans. And as
the demographic of the nation changes, I think, we really need to focus
on those resources to bring that up to speed.

CHAIR PRIOLA: Dr. Rohwer, did you have a comment you wanted to make?

DR. ROHWER: Yes, Alan, in your last slide it looks to me like the
fall-off in repeat donations occurred before the implementation of the
geographic deferrals, and I\'m just wondering what conclusion you are
actually drawing from that.

DR. WILLIAMS: The only conclusion I am drawing from that slide is
probably that is a multifactorial dynamic. I think probably what, in
fact, impacted that in the earlier time point prior to 2000 maybe is the
implementation of some of the laboratory tests and changes in current
laboratory tests that impact some of the longer term repeat donors. It
has a marked effect there, because your repeat donors tend to be the
ones who come back more often, whereas the first-time donors, a
proportion of them that actually become repeat donors, I forget the
figure, but it\'s close to 20 to 30 percent, I believe.

So the impact is much more felt on repeat donors. And if they are
suddenly deferred because implementation of a new lab test, they are out
of the picture, and it shows an impact. But I think what I\'m saying is
it would be interesting to continue the data and look at the time points
related to the other deferrals.

CHAIR PRIOLA: Dr. DeArmond?

DR. DEARMOND: On that chart you show that you kind of pump and then drop
off, but the values vary from 82 percent to, what, 76 or something. It
was like a 6 percent change. Is that statistically significant? Because
if you had the entire chart from 0 to 100, it would be a little blip in
there and is this truly a trend or just within statistical variation?

DR. WILLIAMS: Well, I guess, the first answer is this is not a sample.
This is actual observation at five sites, so it\'s a population. So
there is not statistical inference. This is actual observation. 2
percent loss of repeat donors in the current blood supply represents
200,000 people. You know, whether it is statistically significant, it is
medically significant. So I think, yes, when you look at populations of
this size, even small percentage changes can have major impact.

CHAIR PRIOLA: Okay. Dr. Linden?

DR. LINDEN: But, Al, these numbers, though, are percentage given by
repeat versus first-timers, right? It\'s not loss in numbers. And I know
there have been a lot of efforts to reach out to first-timers. I mean,
like the efforts I was describing of doing, you know, general mailings.
There have been a lot of efforts in schools to reach out to younger
donors. I know there is a lot of discussions in our state about going to
16 year-olds instead of 17 year-olds.

So couldn\'t this partially reflect increased efforts to reach out to
new communities? I know there have been a lot of efforts to reach out to
Hispanic communities in New York. For example, there were not previously
efforts to really go to the entire borough of Brooklyn, and all of a
sudden we were, you know, now going to Brooklyn. So if the percentage of
repeat donors is decreasing, it may be success in increasing the number
of first-timers. I\'m not sure that\'s necessarily a bad thing. And, you
know, if you\'re talking about a 2 percent change, that\'s really not a
huge number.

DR. WILLIAMS: I think that\'s a good point, Jeanne. It is
multifactorial. It would encompass both loss of repeat donors as well as
an increase in proportion of first-times due to recruitment efforts. It
needs to be modeled.

CHAIR PRIOLA: One last question. Dr. Bailar?

DR. BAILAR: It seems to me that I have been reading in the newspaper for
at least 40 years that you are running out of blood. Appeals for people
to come in and donate. It sounds like the situation is a little bit
worse than it used to be. On the other hand, how often do your
facilities actually run out? I\'m not counting being able to import
blood from something on the other side of town.

DR. WILLIAMS: That\'s also a very important question. Monitoring systems
that have been in place so far, basically, have been covering counting
inventory, days\' supply available, et cetera. There haven\'t been many
data collected reflecting, you know, impact on patient care or patient
morbidity, that sort of information. Though some of that has been done
within the HHS Monitoring System. Some of it has been done with the
TransNet System that FDA has developed and piloted, actually looking at
impact on patient care.

And running out of blood, no, I don\'t think that instance happens where
you don\'t have the blood to meet an emergency need, you know in the
worst case. What has happened and, you know, is considered as having an
impact on patient care is when you get delays in elective medical and
surgical procedures. That does happen. It was documented both with the
TransNet Program and the HHS monitoring in the holiday period of last
year. And use of Rh-positive blood for Rh-negative patients, again, you
know, arguably not an ideal medical practice, but it happens frequently
in times of shortage.

So there are gradations in the impact that it has. Running out of blood,
no, that hasn\'t occurred and I think that\'s compatible with the
generally adequate statement of the GAO. But one has to consider what
would happen in a crisis if you needed a large amount of blood in a
large area and, you know, would we have the reserve support that we need
if we\'re only carrying a one to two day supply in the blood center
shelves.

CHAIR PRIOLA: Okay. I\'ll tell you what, let\'s move on to the next set
of talks, and then we can come back to this. The next speaker is Dr.
Melissa Greenwald.

DR. GREENWALD: So good morning. I am Melissa Greenwald for the Division
of Human Tissues in the Office of Cellular, Tissue and Gene Therapies.

UNIDENTIFIED SPEAKER: We can\'t hear you. Use the microphone.

DR. GREENWALD: The microphone is on. It\'s on. So I\'m just a little bit
shorter than everyone else who spoke before me. I\'m from the Office of
Cellular, Tissue and Gene Therapies at CBER, and I\'m going to be
talking about the ways we have been trying to minimize the risks of TSE
agents in human tissues. Next.

So the human tissue safety will be discussed in the context of three
general approaches to reduce the risk of TSE transmission, careful
screening of donors for TSE and for risks of TSE. We would require
testing if and when it\'s validated, control of recovery and processing
to prevent contamination and cross-contamination, as well as using steps
during manufacturing to inactivate our clear TSE agents. However, there
is really no current validated methods for human tissues to do this.
Next.

So FDA\'s regulatory approach in general, and especially in human
tissues, has a whole range of different methods, and we have current
regulations or rules, we have current recommendations or guidance, and
then we also have a set of proposed regulations, as well as proposed
recommendations. Next.

Our current regulation that we\'re operating under right now is 21 CFR
part 1270, human tissues intended for transplantation, which was
published in 1997. This requires screening and testing of potential
donors for HIV, hepatitis B, and hepatitis C, and does not include
requirements to screen or test for TSEs. It requires written procedures
and record keeping, has inspection and enforcement provisions, and
1270.31(d) specifically requires validated procedures to prevent
infectious disease contamination or cross-contamination by tissue during
processing. And I highlight this, because I will show you a guidance in
a minute that refers back to that. Next. All right.

We have three current guidances right now. The first one is the Guidance
for Industry: \"Screening and Testing of Donors of Human Tissues
Intended for Transplantation,\" which was published in 1997, and this
recommends that you defer donors with risk factors for CJD, but doesn\'t
include variant CJD risk factors. Next.

The Guidance for Industry: \"Validation of Procedures for Processing of
Human Tissues Intended for Transplantation,\" it clarifies 1270.31 where
we were talking about not contaminating tissues during processing. So we
explain that infectious disease contamination does include viral,
bacterial, fungal, as well as TSE agents. And there are currently
validated methods available to prevent contamination by viruses,
bacteria and fungi, but for human tissues there are no validated methods
yet to prevent contamination by TSE agents. Next.

There is a new guidance document that was published just this past
December, Guidance for Industry and FDA Staff. It\'s a Class II Special
Controls for \"Human Dura Mater,\" and this was published by the Center
for Devices and Radiological Health. It discusses additional deferral
criteria beyond those for CJD and variant CJD, but we\'re focusing the
talk today just on those diseases. It states that donor screening for
CJD and variant CJD should follow the published blood donor criteria,
including the travel history questions that were recommended. Next.

It also recommends deferral of donors who have classic CJD risk factors,
and those are listed, people with degenerative or demyelinating diseases
or other neurologic diseases, such as senile dementia or Alzheimer\'s
Disease, and those who have died in a neurological or psychiatric
hospital. Next.

So now, we go into the realm of our draft regulations and guidances. So
in draft form that was published in 1999 was our Suitability
Determination for Donors of Human Cellular and Tissue-Based Products:
Proposed Rule. It includes requirements, would include requirements to
screen, including a medical history interview, for risk factors for and
clinical evidence of relevant communicable diseases, and those would
include hepatitis B, C, HIV, and TSEs. It also requires testing for
relevant communicable diseases, including HIV, hepatitis B and C, and
syphilis. Next.

In the Current Good Tissue Practices for Manufacturers of HCT/Ps:
Inspection and Enforcement was proposed in January of 2001. This rule
would include requirements for controls over facilities, personnel,
equipment, environment, incoming materials, labeling, storage, process
controls, process validation, record keeping, adverse reaction and
product deviation reporting as well as tracking. Next.

Contained in the GTPs also are provisions for inspection and
enforcement, a requirement to archive appropriate specimens from each
donor of dura mater, specific requirements for dura mater to be
processed using a validated method to reduce TSEs, prohibition of
pooling, and an exemption or alternative form of any of the GTP
requirements could be requested by a firm, but they would have to submit
that request to us in writing with valid data to be reviewed. Next.

But because FDA was concerned about CJD and variant CJD, we did publish
a draft guidance document in June of 2002 to discuss risk factors of
that even though our regulatory frameworks that require screening and
testing were not in place yet, just to give manufacturers guidance on
what we were thinking at the time if they wanted to implement screening
measures. And this guidance document was presented to TSEAC in June of
2002. Next.

It recommends donor screening recommendations for variant CJD, and they
are based on the blood guidance to reduce the risk of transmission of
CJD and variant CJD. That was published in January of 2002, and, really,
the recommended donor screening criteria for human tissues are the same
as those that are listed in the blood guidance document. Next.

And just for everyone\'s information, I have listed those requirements
in an abbreviated form, but Doctor Williams, you know, listed them out
last talk, and I won\'t go back over them. Next.

So we are anticipating a Donor Eligibility Draft Guidance Document to
accompany the Donor Eligibility Rule when it publishes, and we
anticipate that we would be publishing those two documents within a
relatively close time frame. And then, you know, our current thinking is
to plan to finalize the donor eligibility guidance as a document that
would include the CJD and variant CJD measures that were described in
the 2002 guidance document. But until the Donor Eligibility Rule
publishes, really there are no requirements for vCJD screening. Next.

And we have published an Interim Final Rule this past January that
requires all establishments that manufacture HCT/Ps to go ahead and
register and list. This was implemented for manufacturers? tissues who
had previously been regulated under 1270, and then beginning in January
to put people on notice that we\'re going to require it for everyone,
whether they are regulated by 1270 or not.

However, this does specifically exclude manufacturers of human dura
mater and heart valves, which will continue to be regulated as medical
devices until all the final rules are in place. And we do plan to revoke
the Interim Rule when the Donor Eligibility and Good Tissue Practices
Final Rules are published, when both products will be regulated with
HCT/Ps. Next.

So that is the information we have about tissues, and does anybody have
any questions?

CHAIR PRIOLA: Dr. Wolfe?

DR. WOLFE: In this transition period where dura mater are sort of
floating in cyberspace between CDER and CBER, is there any requirement?
I mean, do we know? I mean, I have asked this question now to the, I\'m
sure, boredom of the Committee for about seven or eight years. Do we
know now whether there are companies in the United States that are
actually processing dura mater, and are they complying with at least the
guidance as it is now?

I mean, what\'s going on? I mean, I realize this is still in CDRH, but
what \-- I mean, how many people are getting dura mater graphs? The last
time I heard, it was down from thousands to a few hundred, and at one of
the meetings one of the companies said that he was not aware of any
companies still making this. Do we have any information on that?

DR. GREENWALD: Dr. Durfor from CDRH is coming up.

DR. WOLFE: Oh, yes.

DR. GREENWALD: He has talked to the TSEAC before about this issue.

DR. DURFOR: Yes. My name is Charles Durfor. I work for the Center for
Devices and Radiological Health. I don\'t have information, at this
time, with regards to the incidence of dura mater implants or the
numbers sold. That is just not available to us, and it\'s not something
we collect. I also, unfortunately, don\'t have the most recent
information in terms of inspections, because I am not in the Office of
Compliance. But, we have enacted, and just to call back to your
attention, a document that is in your package, the Special Controls
Guidance document, which has been put in place in December, and I do
know that our inspectors do rely upon this document and do talk very
closely and carefully with each of the facilities.

And I apologize that I did not come in terms of updated, in terms of the
extent of compliance actions and NIAs and such as that, but it is our
belief that the safety of dura mater has not changed, and that the
record in the United States is very good.

DR. WOLFE: Would it be possible just to find out how many facilities are
currently making dura mater, have been inspected and what the results
are, because that\'s really \--

DR. DURFOR: I believe that, certainly, it would be possible to get to
you.

DR. WOLFE: Okay.

DR. DURFOR: And as much as would be publicly releasable, we would be
happy to give it to you.

CHAIR PRIOLA: Dr. Schoenberger, do you want to make a comment or just a
moment, doctor.

DR. SCHOENBERGER: Dr. Sejvar may remember. We just wrote an MMWR article
updating the outbreak in Japan, which had reached 97 cases and was
continuing. In the process of writing that MMWR article, we did call
around, and I think the Miami Tissue Bank was the primary supplier in
the United States, and they had told us that they sold around 900, was
it, last year?

LT. SEJVAR: I\'m blanking on the exact number, but during our search for
publication of the MMWR, which came out in October, I guess, we found
one distributer in the United States, and that would be the Miami Tissue
Bank, which is distributing human cadaveric dura mater. And I believe
that Larry is correct on that number. It\'s less than 1,000.

DR. WOLFE: Per year?

LT. SEJVAR: Per year, yes, and I can actually check the MMWR over the
break and get at least the information that we came up with through our
search.

CHAIR PRIOLA: Dr. Gambetti, did you have a comment?

DR. GAMBETTI: I may have missed it. I may have missed that, but in the
current recommendation for deferral of dura mater donors, in that slide
it\'s written classic CJD risk factors, classic CJD risk factor. In
other words, individuals with classic CJD risk factors are deferred.

DR. GREENWALD: Yes, sir.

DR. GAMBETTI: And what are these risk factors?

DR. GREENWALD: They are all listed.

DR. GAMBETTI: Could you explain them?

DR. GREENWALD: They are all listed in the guidance document. I didn\'t
list them all out, because we\'re talking about variant CJD mostly for
this meeting, but, you know, people with a the family history of CJD and
people who had had a dura mater implant and, you know, things along
those lines.

MR. COLYN: Dr. Greenwald, at this time, are you able to give any
guidance?

CHAIR PRIOLA: Excuse me. Could you, please, identify yourself?

MR. COLYN: Yes. My name is Jim Colyn. I am with LifeCell Corporation in
Branchburg, New Jersey, and my question is to Dr. Greenwald. Is it
possible, at this time, to give any guidance as to when we can expect
the Donor Eligibility Rule to become a final rule of the current Good
Tissue Practices?

DR. GREENWALD: Sir, as we have said in public many times before, until
it\'s published, I have no information about when. I\'m very sorry.

MR. COLYN: Thank you.

CHAIR PRIOLA: Okay. Thank you, Dr. Greenwald. Let\'s move on to the next
talk, and it\'s Dr. William Egan.

DR. EGAN: May I have the slides, please? Let me put my glasses on. I
can\'t see them. I guess I don\'t need any prescription. Good morning.
In the next several minutes, I hope to inform and update the Committee
on the status of vaccines and allergenic products relative to TSE risks,
and in particular BSE risks.

I will note, to begin with, that allergenic products within the Center
for Biologics are also regulated by the Office of Vaccines. This status
update will touch on several areas, including estimating risk, managing
risks, and communicating risks. Next slide, please.

A variety of bovine-derived materials are used in the production of
vaccines and allergenic products. Now, until the end of this talk, I
will be concentrating on vaccines. Comparatively, at least from the
point of view of BSE risks, TSE risks, the allergenic products are
relatively simple. The complexity is with the vaccines.

Bovine-derived materials that are used in the manufacturing of vaccines
include fetal calf serum, beef muscle and organ extracts, the organ
being primarily pancreas for enzymes, gelatin and processed gelatin, and
a variety of small molecules, such as the amino acids, hemin, glycerol
and lactose. Being animal-derived, certain risks are inherent in the use
of these products, primarily the potential for adventitious agents,
various viral adventitious agents that may be in bovine products, but
also the BSE agent, the subject of this meeting. To the extent possible,
the Office of Vaccines Research and Review encourages manufacturers to
develop and use non-animal sources for many of these materials or the
use of a synthetic media. Next slide, please.

These various bovine-derived materials are used in a variety of
manufacturing steps, and these include the production of master cell
banks and master seed banks, both viral and bacterial, the production of
working seed and cell banks, cell cultures and bacterial fermentations,
reagents that are used for immunogen purification or processing, and
finally vaccine formulation, stabilizers or other excipients. The next
slide, please.

CBER\'s policy and necessarily OVRR\'s policy regarding the sourcing of
bovine-derived materials is clear and has been clear. The policy is and
has been that bovine-derived materials from BSE countries should not be
used in the manufacture of FDA-regulated products, and BSE countries are
designated as those or have been designated as those that are on the
USDA, Department of Agriculture\'s, APHIS list.

Now, previous recommendations were restricted to bovine material. The
most recent is broader, and includes ruminant, and previous
recommendations mentioned only countries in which BSE was known to
exist, and the language has now been changed somewhat to risks for BSE
based on the broadening of the inclusion criteria in the USDA/APHIS
listing. In any event, the basic message has been clear and simple. The
next slide.

And these just list some of the various letters and guidances that have
been put out over the years beginning in 1991 when a survey was called
for, what are all of the bovine-derived materials that are used in the
production of biologics, and all of these are available on the Office of
Vaccines\' website and that address will be given a little later. It is
in the handout. May I have the next slide, please?

Although the rules are clear, the recommendations are clear, in early
2000, based on a review of a regulatory submission, it became clear to
the Office of Vaccines that these recommendations were not being
followed in their entirety. As a result of this finding, a complete
inventory of all licensed vaccines with regard to sources for
bovine-derived materials used in manufacture, including preparation of
master and working cell and seed banks, was undertaken. We surveyed all
products, and a number of instances were found where CBER\'s
recommendations were not followed.

Risk estimates were made for the various situations by CBER scientists
and by manufacturers, and CBER recommended a set of corrective actions
and these were discussed in a joint session with the TSE Advisory
Committee and the Vaccines and Related Products Advisory Committee.
Could I have the next slide, please?

Some of the issues that came to the fore and that were discussed with
the Advisory Committee included use of fetal calf serum from the United
Kingdom in the establishment of cell banks and viral seed banks, use of
European-sourced beef broth, use of European-sourced low molecular
weight materials, for example, hemin, use of European-sourced
manufactured gelatin derivatives. May I have the next slide?

For all of these cases, risk estimates for the various situations were
made, and these risks were based on the likelihood that cattle that were
used might be infected, the amount of bovine-derived material that might
be present in the final product, the inherent infectivity of the bovine
materials, using experimental limitations to material where no
infectivity had ever been detected. So although no infectivity had been
detected for fetal calf serum, rather than use zero we used what risk
could be ruled out. May I have the next slide?

Also, many of the cases were, because these products, all sources, were
not known, and if a source was not known, we simply assumed the worst
case, namely that it came from the U.K. in 1989. Now, the Joint
Committee had several recommendations consistent with those that had
already been communicated by the Office of Vaccines to the
manufacturers, and these were to find and utilize new sources of bovine
materials from non-BSE countries for materials used in production, to
rederive working cell banks and working viral and bacterial seed banks
utilizing bovine-derived materials sourced from non-BSE countries. Next
slide, please.

But it was also felt that master viral and bacterial seed banks need not
be rederived. The risk to changing the product during a potential
rederivation far exceeded the risk that might attend the product, and
finally that these issues were of public concern and the public should
be appropriately informed about the risks and which vaccines were
affected.

I mean, our own feeling in the Committee was that recipients of these
vaccines have a right to expect that they are produced according to the
recommendations of the FDA, and if they are not, then they should be so
informed. May I have the next slide, please, and present an update from
that meeting, what has occurred since.

Now, with regard to the recommendations about this being a public
matter, a website containing the transcript of the meeting, various risk
assessments, and a listing of the affected vaccines was developed within
a few months and put up. This website still exists and is periodically
updated, and the website address is noted in the slide. Also, an article
outlining all of the issues was published in MMWR. New sources of the
affected bovine-derived materials were found and placed into production.
Working cell and seed banks were rederived, qualified and placed into
production and, at the moment, most of the affected vaccines are now out
of date, the ones that went on into the market. They are out of date.
Next slide, please.

Now, why have I gone into this history? Well, for two reasons. One is to
update the Committee on what has been done relative to their
recommendations, and, namely, all were taken and acted upon. But second,
and of considerable importance, to present a lessons learned. Although
the CBER policy, based on source country control, was clear, is clear,
it can be problematic as countries, as new countries are put on or added
to the list.

As this happens, we must contend with several facts, that licensed
products that have been released remain on the market, and that products
that are in various stages of manufacture will go to market. Secondly,
manufacturing time-lines are quite long, greater than one year in almost
all cases. So from the time that a manufacturer decides to put a new
source of material into a vaccine and that vaccine gets into the market,
more than a year or more is generally taken. This is because of
production time-lines and the controls that are necessary prior to
release.

The status of master and working cell and seed banks becomes uncertain.
Will they need to be rederived, under what circumstances. Consider a
cell bank that was established with fetal calf serum from a country
newly placed on the USDA list, and consider that that cell bank was
derived 20 years previous to the country being placed on that list.
Consider the fact that it was 10 years previous to being placed on the
list, five years previous to being placed on the list and so on. Are
there cutoffs that are scientifically justified?

Finally, what is the status of products, cell and seed banks that are in
development, and that could be anywhere from preclinical investigations
through to we\'re reviewing the biologics license application. And I
think it\'s apparent that risk-benefit decisions will need to be made
and continue to be made. Source country, of course, and the risk for BSE
in that country is one factor in that decisional process, but it\'s not
necessarily the only one.

I mean, consider the possibility right now that cell banks and seed
banks that we discussed in 2000 were rederived using fetal calf serum
from North America, which we again need to rederive them and keep doing
this on a continuing basis. This is simply not possible. May I have the
next slide, please?

Let me now discuss North America. Bovine-derived materials from cattle
that are, in the words of the recommendations, \"born, raised or
slaughtered\" in the United States and Canada are used in U.S.-licensed
vaccines and vaccines that are currently under development. The
materials that are being used are inherently low-risk materials,
primarily or for example, fetal calf serum.

Based simply on the number of BSE cases in North America and the
additional safeguards that have been put in place by the United States
and by Canada, the risks that these materials might pose are several
orders of magnitude less than those that were previously considered by
this Committee in 2000, and where the risks were deemed to be both
remote and theoretical. So we\'re orders of magnitude below that. The
Office of Vaccines Research and Review has not requested manufacturers
to replace existing Canadian or U.S. sources of bovine-derived material.
May I have the next slide, please? Can you go one more? I think I got
these out of order. Yes, thank you.

Towards the end of last year, the U.S. Department of Agriculture
published a proposed rule in October, and this rule would allow the
import of certain live ruminants and ruminant products from Canada and,
as was said there, other minimal risk regions for BSE, but for the
immediate this rule would only be concerned with Canada. So this makes,
you know, the decisions a little more, whatever one wants to do, a
little bit more tenuous at the moment. Go back now, please.

In looking towards the evaluation of TSE risk, and it appears that we
will still need to be making these risk-benefit decisions, there is much
that we still need to know. And I would just like to point out now for
this Committee two areas that I think are important.

I think we need data on the ability of various cells, cell lines, to
propagate the BSE agent. There are a limited number of cell lines that
are used in the manufacture of vaccines, Virocells, MRC5 cells, WI-38
cells, that is primarily it, and we need to have more data on the
ability of these cell lines to propagate the agent if present. The
studies that were recently published by Dr. Priola certainly need to be
carried out with these cell lines. And in this regard, I will mention
that the Office of Vaccines is collaborating with Dr. Asher, the
collaboration being that Dr. Asher is doing all the work, to address, in
part, this issue.

Secondly, I think one might also fruitfully look at the ability of some
of the manufacturing steps that are used in vaccine manufacture to clear
the agent, a BSE agent, at present. Now, not all vaccines are the same,
and not all are amenable to purification procedures. A live viral
vaccine, such as Varicella, is quite delicate and difficult to purify in
any rigorous manner. Others such as hepatitis B are relative hardy and
there are a number of purification processes that are used in its
manufacture, but the ability of these filtrations, chromatographies to
clear an agent that is present is unknown.

Now, let me come to allergenic products if I may have the last, this
slide. And as I mentioned, these are regulated by the Office of
Vaccines, and similar issues were encountered with the allergenic
products, except on a much reduced scale and primarily, it was with
molds, certain molds that are propagated in culture media that do
utilize bovine components, and the master stocks were prepared in this
way.

Subsequent to our meeting, joint meeting with the TSE and the Vaccines
Advisory Committees, this issue was discussed with the Allergenic
Products Advisory Committee, and in that case the mold master stocks
were rederived using bovine components from non-BSE countries. Unlike
viral master seeds, the Committee felt that there was little hazard to
the product in its rederivation and accordingly, they were rederived. If
I can have the next slide. Okay.

Finally, let me mention one issue with regard to risk communication. In
addition to OVRR\'s website and published articles, several vaccines
employ human serum albumin as a stabilizer, this is present in milligram
amounts, and as a blood product the labeling carries the statement that
is presented here on the slide about a minimum risk, potential risk, for
transmission of viral diseases or the agent of CJD.

Now, if recombinant human serum albumin were substituted for the
blood-derived, and this is in every case licensed human serum albumin
that\'s used, such a statement would not be necessary, it not being a
blood product. That concludes my update. Thank you very much for your
attention.

CHAIR PRIOLA: Dr. Wolfe?

DR. WOLFE: This will sound analogous to yesterday\'s discussion about
the difference between a recommendation in that case, that it would be
nice if states had mandatory reporting for CJD, which some do and some
don\'t, and a regulation or a law. And really, in part of your, I think,
very nice presentation about looking backwards and what lessons can be
learned, looking backwards, would you think that it might not have been
better in May of 2000 to have a regulation, a rule, as opposed to some
recommendation?

I mean, one of the problems with recommendations, policies, guidances,
again whether it is reporting, some do and some don\'t, and in this
case, as you showed in your slide, you put out this May 2000
recommendation and some companies complied and some didn\'t.

So looking backward and, again, it\'s not just simply a regulation, but
it has to have some teeth and some enforcement to it, would it have been
better to have that be a rule, as opposed to just a recommendation?

DR. EGAN: Yes. I should probably ask the Office of Chief Counsel to
comment on this.

DR. WOLFE: Your own personal \--

DR. EGAN: But I won\'t, and I will give you a personal response. The
Public Health Service Act allows us to recall vaccines if we feel that
there is a danger, that there is a risk, so we have that authority to do
that. We have lot release with the vaccines, and we could choose not to
release them to market. We could recall them from the market.

DR. WOLFE: But the release, you might not even know that it had been
sourced from there, which is the case here, right?

DR. EGAN: Well, that is correct. So I think there are authorities that
allow us, when we find something, that we can recall it if we feel that
there is a risk. But if we have a regulation, a law, based on, you know,
risks and benefits, one could use discretion in whether one wishes to
recall or not.

So I think my bottom line is that we\'re talking about six of one and a
half a dozen of the other, and it all comes down to recognizing,
realizing a situation, making some judgments about risks, assessing them
and then deciding what to do, whether one does it under the Public
Health Service Act, recalling it, or using that as the basis for the
action or using a law as the basis for the action.

DR. WOLFE: So you\'re saying if you had it to do over again, you would
just do a recommendation and not put out a rule or a regulation in May.
Is that it?

DR. EGAN: My own personal feeling, based on the authorities that exist
under the Public Health Service Act, and these authorities are much more
extensive for vaccines than they are for other products that are
regulated by FDA, and this had to do with the Vaccine Injury
Compensation Act that added this into the Public Health Service Act. So,
I mean, my own feeling is it\'s six of one, half a dozen of the other.
It could be either way, but it\'s judgment in both cases.

CHAIR PRIOLA: Dr. Bailar?

DR. BAILAR: I think we\'re probably all concerned about the diminishing
number of countries that are known to be or considered to be BSE-free,
and maybe it\'s time to start thinking about alternatives. The policies
at present are written as if risks start and stop at national
boundaries, which is just nonsense, and there might be other ways to go
at this, such as distance or marketing and shipment patterns. I wonder
if there has been some thought to alternatives to this national-based
approach.

DR. EGAN: Well, there has certainly been a lot of thought that has been
given to it both within the Office of Vaccines and within the Center for
Biologics and within FDA as how to approach different things, and I
think, maybe, you know, for some issues, one solution is best and it may
be a law. For other situations, you know, that prohibit things by
source, I don\'t know. For others, other approaches may be better.

I think that we do have to consider sourcing, where it comes from. There
is a difference between calf serum that came from the U.K. in 1989 and,
you know, calf serum that\'s coming from Michigan, not to pick on any
state, that we have to consider the tissue that\'s used. I am loath to
use any high infectivity tissue no matter where it comes from, and
between fetal calf serum, you know, which has no demonstrated
infectivity, as hard as people have tried, and neural tissue there is,
you know, nine orders of magnitude difference. That may, you know, swamp
out any geographic consideration.

There is also the amounts of material that will wind up in a product. In
most of the cases with vaccines, we\'re talking about very, very, very
small amounts of material that might wind up in the product, in a
product that may be given once or twice.

But yes, I agree completely with you. I think that all of these things
need to be considered in our decisions, and I think what was noted
yesterday just like, for example, fetal calf serum, industry currently
uses about 500,000 liters per year, 65 percent of which is coming from
North America. So I think to say that everything had to come from New
Zealand and Australia, it\'s not clear that there would be enough at
least for the near future unless they ramped up those industries.

CHAIR PRIOLA: Dr. Nemo?

DR. BAILAR: One sick cow in Australia could do us in.

DR. EGAN: Yes. Well, at least if one had a strict country source rule.

DR. NEMO: Do you know if your recommendations have created any
particular hardship for vaccine manufacture, particularly smaller
manufacturers that may just decide well, this isn\'t worth it, you know,
we\'re not going to pursue development of this vaccine for an orphan
disease, let\'s say? Have you seen anything like that?

DR. EGAN: To date, I don\'t think we have put anybody out of business
because of this, but it \-- certainly, I can\'t elaborate too much, but
it has had an impact on certain vaccines that were under development.

CHAIR PRIOLA: Dr. Gambetti?

DR. GAMBETTI: In view of most of what was said yesterday and of the fact
that you are saying that the number of countries that are so-called
BSE-free is decreasing, and, therefore, it becomes more and more
difficult to obtain products that are used for making vaccine and so on,
I wonder what your thoughts are about really starting switching from
classifying countries according to whether they are or we perceive them
as BSE-free or not with country instead with a kind of classification of
countries that perform extensive testing.

What I feel I see is that we actually, on the basis of what we have seen
here in this continent, in North America, that the more testing you do,
eventually you will find cases. So at a certain point, I think what I
was saying is that we should probably switch from countries that are
classified BSE-free based on lack of import or lack of evidence of
import to countries that instead do very extensive testing and,
therefore, they have BSE under control.

DR. EGAN: Yes. I understand your point, and this issue about there being
a penalty for finding out what the truth is and then learning how to
deal with it, as opposed to not trying to find out what it is, yes. I
mean, I think those are important considerations, and I think some of
the other things that were talked about the other day about
certification of herds, having, you know, closed herds that are
extensively monitored, you know, each animal is monitored through
testing are certainly things that should be taken under advisement.

And I guess one of the things that I\'m hearing from the Committee is
that we are needing to look more closely at these risk-based types of
decisional models rather than simply, you know, the strict geographical,
and I think we\'ll need to consider those in greater depth.

CHAIR PRIOLA: Dr. Johnson, did you have a comment?

DR. JOHNSON: I was going to bring up the issue that he just brought up,
and that was the select herds. But could those be developed in
sufficient number in whatever country it was to fulfill the needs? I
mean, are we talking about \-- is this pie-in-the-sky?

DR. EGAN: Well, the answer may be yes and no. For higher risk materials
that are used in smaller amounts, that may be very, very doable. For
fetal calf serum, the closed herd may be in Australia and then, you
know, anything in between. But for things like some beef extracts that
were used in bacterial fermentation, it\'s probably sufficient to \-- I
haven\'t thought about this in great depth, but to have small herds for
that. But I think that is, again, another thing to be explored.

DR. JOHNSON: If you do this, it\'s going to make the product terribly
expensive, isn?t it, if you go to the herd or every cow is tracked and
none has ever been fed any kind of meal and et cetera, et cetera.
Aren\'t these going to be pretty expensive cattle?

DR. EGAN: Yes. You know, I don\'t know the economics of this, but I
suspect not.

DR. JOHNSON: You suspect not?

DR. EGAN: Yes, but economic impact would, you know, certainly have to be
considered.

DR. LINDEN: Is that right, Lisa?

DR. FERGUSON: Well, I guess I suspect that the economic impact would
probably be pretty big, and I think, you know, for a realistic type
thing, setting up those type of herds, as you said, for high-risk
product, if you\'re using, you know, brain-heart infusion artery or
something like that, that it could perhaps make some sense to do that
for fetal calf serum, for BSA. I\'m sorry, it\'s just not going to work.

And even trying to set up, let\'s say, the national herd of Australia, I
think what we have seen previously, and sometimes in especially the
fetal calf serum market, this stuff moves around and you can really
create some interesting effects in a market when you put out that type
of a regulation, and you see products being labeled as what it really
isn\'t and moving through various channels depending on the economic
drivers.

So you know, we need to be real, real cautious. I guess some other
alternatives to look at, I mean, if we\'re talking about beef extracts,
what actually is going into that beef extract? Is it a chunk of muscle
meat? Do we really think that\'s a risk or is it spinal cord? So those
types of things, I think, all probably need to be thrown into the mix.

DR. EGAN: Yes. And, you know, with regard to the fetal calf serum,
usually they are made in pools of about 1,500, 2,000 and, you know, the
keeping track of where every single cow that was blood raised and
slaughtered that went into that is rather difficult.

CHAIR PRIOLA: We\'ll have Dr. Creekmore and then Dr. DeArmond.

DR. CREEKMORE: Actually, I think my question has been answered in a
variety of ways, but the basic question was how do we currently source
bovine-derived products in North America? Are there cattle that are
specifically produced for the purpose of some of these products, or in
general is it the population at large?

DR. EGAN: To the best of my knowledge, you know, within the material
that is sourced in the United States is just general.

DR. DEARMOND: I would disagree with the idea that this would not be
economically feasible. In fact, that\'s just not knowing the history of
the United States. We have been founded on this competitive free market
system where the person who builds a better mousetrap often will get the
money and will sell the product.

And indeed, some drug companies already have their own herds that they
keep because of the cost of having a failure. A drug company will go out
of business if something goes wrong. And again, the example is this,
it\'s kind of a silly example, but the silicon breast implants destroyed
a company and products that were used for a lot of other things, and it
wasn\'t even a product that was dangerous, as we learned later.

In my opinion, and in the way of knowing the free marking system as it
works with some federal help with tax benefits, these cattle can be
raised and they can be raised, if you look at the cattle industry, you
begin with small herds, young cows, young calves that are fed off of
land, and those are then moved to other sources of food. And when you
look at the Japanese, by golly, they hand feed the animals and massage
them, and they can still sell their product and even give them beer on
top of that.

I mean, this can be done, and it\'s the way the enterprise system works.
It isn\'t the way government works, but it\'s the way things are done
successfully in the U.S., and we could get guaranteed herds of cattle
that could be used for any number of products.

DR. EGAN: As I said, I haven\'t done the economic analysis. I mean,
that\'s well out of my \--

DR. DEARMOND: But you don\'t have to, because we know the success of the
system. Whenever you have a crisis, somebody comes up with a new method
of doing things, and it becomes economically feasible.

DR. EGAN: And I think, as I have said, I think it probably is. And I
think a relevant example of what you\'re saying, it\'s not cattle, but
it\'s chickens. For some of their, you know, vaccines, I think Merck,
for example, bought SPAFAS, created SPAFAS, bought SPAFAS, and these are
closed herds of chickens for the eggs that are used in the production of
some \-- these are specific pathogen-free eggs, herds that are monitored
continuously. They are closed and monitored for that purpose. So, I
mean, it\'s done with other animals for vaccine purposes.

CHAIR PRIOLA: Dr. Nelson, did you want to make a comment?

DR. NELSON: This is kind of a side comment. I have reviewed for the IRB
some new like HIV vaccines, and in the 15 page consent form, there is a
paragraph that we can\'t assure that you won\'t get Creutzfeldt-Jakob
Disease, and nobody who reads that knows what the hell that means. You
know, it\'s a legal or whatever, but, you know, it\'s, I guess, a
fallback against some legal action, but a lot of the vaccines contain
statements about Creutzfeldt-Jakob based on bovine serum albumin or
fetal calf serum in the cell culture system. You know, I don\'t know how
effective that really is in terms of educating the public, warning them,
or even knowing what people are signing when they accept a vaccine.

DR. DEARMOND: I hate to say this against my daughter who is a lawyer,
but it sounds like a lawyer wrote that statement, not a scientist.

DR. EGAN: Well, I mean, you know, sometimes it\'s one, sometimes it\'s
the other. We have had discussions about this, this area, putting in
some statement about a risk that you estimate to be you are one in
10^-20^ relative to some other risk, for example, getting bacterial
infection accompanying the injection, that may be 15 orders of magnitude
greater.

You know, you can\'t put in everything, because then nothing has meaning
or importance. But it\'s a difficult area about, you know, what to put
in, things that really are of large risk.

DR. DEARMOND: Is that an FDA requirement that such a warning be listed
or is that just a legal fallback, BSE?

DR. EGAN: Well, with regard to serum albumin, human serum albumin, in
the vaccines, yes, we did tell the manufacturers to put that in.

CHAIR PRIOLA: Okay. I think we\'ll move on to the next speaker. Thank
you, Dr. Egan. The next speaker is Dr. Gerald Feldman.

DR. FELDMAN: Good morning. As this slide demonstrates and as the Madame
Chairperson had mentioned, my name is Gerry Feldman, and I represent the
Center for Drug Evaluation and Research, and my purpose for the next 10
or 15 minutes is to provide to you, members of the TSE Advisory
Committee, an overview of the scope of involvement of bovine components
in CDER-regulated products, as well as the mechanisms by which the
Center for Drug Evaluation and Research attempts to minimize risks
associated with those bovine components. So if I may have the next
slide.

Bovine components in CDER-regulated products fall into three categories,
as you have heard already from the numerous speakers that have presented
already. We categorize them as active ingredients, excipients or
inactive ingredients, and reagents or raw materials that are used in the
production of the final product, and I will in the next slide begin to
describe what those actually are. So if I may have the next slide.

As active ingredients or parts that are injected for the purpose of
treating a disease, we have as examples, glucagon, which is derived from
the pancreas of cows, aprotinin, which is derived from the lung of
bovines and other animals, heparin, collagen and amino acids, and a
number of these components have already been described and discussed at
various TSE Advisory Committees over the years, and I will allude to
those in a few minutes.

In the next slide, we have those materials that are used as excipients
or inactive ingredients, and they include gelatin, which has been
described and discussed on numerous occasions in this Committee, amino
acids, which were described and discussed in October of 2001, I believe,
at this Committee, and glycerine and Polysorbate 80, which are
tallow-derivatives, which have also been discussed at this Committee.
You will notice that amino acids also appeared as an active ingredient.

And you will find, as you will see in the next slide, that amino acids
also form the final category of reagents or raw materials that are used
in the production of a wide variety of regulated products. Also included
in this group are bovine serum albumin or fetal calf serum or other
sources of serum, which has been discussed at great length by Dr. Egan,
human transferring, which is another blood component.

And I provided this list, as well, Protein A, which is not usually
considered a bovine-derived component and, in fact, it is not. It\'s a
bacterial component. But unbeknownst to the majority of people in the
industry, we have found, as well as scientists who use it, Protein A can
be and usually is derived over a human IgG column for purification
purposes, which brings into play the discussion of risks involved with
human plasma-derived components, so we also address the risks involved
with using Protein A for the purification of monoclonal antibodies,
which are a CDER-regulated product. So if I can have the next slide.

The assessment of risk that CDER utilizes is similar to what has been
discussed already in the Center for Biologics and will be discussed by
the Center of Devices in a couple of moments, and that is we look at the
source country, the country from which the animal, in these cases the
cows, originally come from, were born in or raised or slaughtered. We
look at the source of the component, from what tissue or organ it came
from. We also examine the proposed use of the component, whether it\'s
going to be used as an active ingredient, an excipient or starting
material.

In addition to that proposed use of material, we also examine and use as
a basis for our assessment of risk how that component is going to be
used, in other words, what indication it is going to be used for,
whether it\'s a serious and life threatening disease or something that
is not serious or life threatening, as well as how it is going to be
administered, whether it\'s an oral, topical or IV injected product.

Finally, we look at what is known regarding the inactivation by the
manufacturing process of potential TSE infective agents both in terms of
the manufacturing process of the component, e.g., high temperature for
glycerol derived from fat or gelatin, as well as whether or not there is
anything known regarding the manufacturing process of the final product.
For example, when that glycerol or amino acids that have already
undergone acid hydrolysis are used as a raw material for the production
of a recombinant protein, what is known regarding the process by which
that final product is purified or manufactured that may impact on either
the presence or infective capability of the TSE agent.

So these are the components that comprise our assessment of the risk in
bovine components, and the next slide demonstrates our efforts to manage
that risk, and these include communication of the risk through industry
letters, FR notices, industry guidance that have been described at great
length in previous presentations.

In addition, the Office of New Drug Chemistry has a series of MAPPs or a
Manual of Policies and Procedures in place for internal use that,
essentially, describe exactly how our own reviewers will go about
assessing the risk. Step one, if there is a bovine component, what is
the source country, what is the source tissue, etcetera, etcetera. This
comprises part of the application review both for products that are in
IND or NDA development, as well as under license application or have
already been licensed and are marketed in this country.

The use of bovine components is also accurately tracked both by the
Center for Drug Evaluation and Research, as well as the Center for
Biologics Evaluation and Research, such that any component that is used
anywhere in the process of manufacture of a regulated product is put
into a computer database, so that we can, at any time, pull out what
component or what country is using what component for what type of
animal, for what type of tissue and whether or not a country that is on
the APHIS list is a source for any of those components.

And all this impacts, or is utilized to assess our own risk assessment
plan on a continuous and iterative process, such that as new data is
derived at or demonstrated or published, we look again at our risk
assessment and at the mechanisms we use to manage those risks.

So overall, as you will see in the next slide, the management of the
risk that CDER utilizes is a generalized prohibition of use of raw
materials originating from countries with known BSE or considered at
risk for BSE, and this is identical to what Dr. Egan had just mentioned
a few moments ago. And in fact, you will not find anything new in my
entire presentation over what you have already heard over the course of
this morning\'s presentations.

There are specific exceptions to this generalized prohibition. As you
know, gelatin, tallow derivatives, for instance, amino acids, which was
discussed previously in October of 2001 and, as Dr. Egan had also
mentioned, there have been no actions taken against either Canada or the
U.S. in terms of the products that are made using bovine components from
either of those two countries. So this prohibition of use of raw
materials originated from countries with known BSE or considered at risk
does have specific exceptions.

Also, as a method to manage the risk in CDER-regulated products, we
strongly recommend, where possible, where feasible, that bovine
components be changed to non-animal-derived ingredients in reagents,
but, as Dr. Egan alluded to, it is not always possible, feasible or
wanted to do that. Although, if it is done, that is highly preferable.
The next slide, please.

So the management of risk that we utilize in the Center for Drugs is
similar to the management of risk that takes place in the other sectors.
Also separate the components out by how they are used and where they go,
such that for active ingredients we have certain exceptions that may not
exist when we\'re talking about a raw material. So the general
restriction for active ingredients in compliance with 1996 FDA policy is
that no bovine-derived components from BSE positive or high-risk
countries are utilized. However, there are no restrictions for other
ruminant sources.

But specific exceptions do exist, as was referred to in the earlier
presentations, milk-derived components, for instance, or hide and
hair-derived components are also specifically excepted for use for any
bovine source material, and there are also other exceptions that the
Committee is already aware of. The next slide, please.

It refers to the management of risk for excipients and, again, the
restriction is the same as for the other types of components, but here
there are other exceptions. Gelatin, for instance, with specific caveats
that denote that the gelatin may come from BSE positive countries
providing certain limitations are present.

However, unlike that for active ingredients, gelatin cannot be used for
injected products if it does come from a BSE positive country. It can
only be used as an oral or a topical use if it comes from a BSE positive
country, even though the head and the vertebral column are removed.
Tallow derivatives are also some of the components used as excipients
either for stabilization of the final product or something like that,
and there, too, there are caveats with exception. As you know, the
tallow derivative must be derived from a validated process that has been
demonstrated to remove or inactivate the TSE agent, as has been
discussed in this forum over the course of the last several years.

And in the next slide, we present the management risk for raw materials
or reagents. The restriction is identical here as it is for the other
types of components, but here, too, there are specific exceptions. As
Dr. Egan referred to, master cell banks, because of the inherent
problems with changing or rederiving them, which could and quite often
does change the final product that is used, the Center for Drug
Evaluation and Research has not recommended going back and rederiving
the master cell banks.

Amino acids are another exception that has been discussed at this
Advisory Committee. The Center for Drugs does allow the use of amino
acids even from BSE positive countries as a raw material for the
production of the recombinant proteins. However, amino acids are not
allowed to be used as an active ingredient if they do come from a BSE
positive country. There, the amino acids are required to be sourced from
plants. So here, too, is another specific exception for specific use of
the component.

And in the next slide, which is my last slide, I present to you the
ongoing activities in CDER for managing the risks associated with bovine
components. As I mentioned, and as Dr. Egan mentioned, there has been no
official action taken against the United States or Canada in terms of
the use of bovine components derived from either of those countries.

Yes, there are pending regulations, as has been referred to by previous
presenters on the current TSE and BSE policies. There are also pending
revisions to the gelatin guidance based on the last TSE Advisory
Committee where recommendations had been made regarding changing that
guidance document and the Center for Drugs is reviewing those
recommendations and will be revising that gelatin guidance accordingly.

And finally, and I think most importantly, we continue the tracking of
all materials that are used anywhere in the process of, in the
production of the final product that may come from any animal, in fact,
and from any country and this is done both by contacting the companies
directly, by our biannual inspections of all companies that have
licensed products before us and by continuing with any curative
reevaluating the products that are regulated by the Center for Drugs,
such that we hope to have and continue to have and continue to maintain
an up to date and well characterized database from which we can track
all components in all countries and all uses of the bovine components,
and all other animal components that are used in the production of drugs
used and marketed in the United States.

And with that, I thank you for your attention and open it up to
questions.

CHAIR PRIOLA: Questions for Dr. Feldman? Dr. Nelson?

DR. NELSON: Yes, I too am concerned about the geographic exception. I
wonder how the Europeans have dealt with this for vaccines that are
licensed, you know, made and licensed and sold in Europe. Do they also
have a geographic exception or do they have registered herds or some
safety measures other than just excluding the use of materials from
areas that are BSE positive?

DR. FELDMAN: I think that\'s a question better directed to Dr. Egan from
the Office of Vaccines, but before you do answer, Bill, in terms of the
components that are used in drugs and recombinant proteins made by
European companies, most companies have been using components first from
the United States, Canada, Australia and New Zealand for the production
of those types of products.

In fact, I can tell you that when Japan came out to the APHIS list with
its first diagnosis of BSE, we contacted all the companies that were in
our databases that suggested that they use Japanese components and were
told unilaterally that companies who had used those Japanese components
also had in their system the ability to use North American and
Australian and New Zealand components.

So the switch from Japanese to U.S., Canada, Australia and New Zealand
components was easily made and very rapidly made. I don\'t believe there
were products on the market at that time that had to be recalled, but
manufacturing was switched almost immediately. There was no down time in
changing those components. And now, I\'ll let Dr. Egan respond to Dr.
Nelson\'s question.

DR. EGAN: Yes, the Europeans have done things similar to what we have.
And so following, you know, our discussion of the sourcing issues and
vaccines with the TSE Advisory Committee and the Vaccine and Related
Biological Committee, the Europeans looked at this as well, and they
came up with a similar set of recommendations and things to do. So their
fetal calf serum is actually sourced primarily from Australia and New
Zealand and the United States and Canada.

And they source most of the bovine components from outside of Europe.
Now, in part, this is because, you know, the vaccine industries are kind
of global and, you know, GSK or Aventis Pasteur have been making
vaccines for the world, you know, they are here in the United States,
Canada, Europe and so they try to find that highest common denominator.

CHAIR PRIOLA: Well, Dr. Egan, before you sit down. With the current
discovery, of course, of the BSE case here in Washington in December and
the one in Canada earlier and the other cases there, Europe has made no
change in their sourcing, in that they still come to North America for
sourcing their vaccine components? That hasn\'t affected that?

DR. EGAN: Yes, I believe that they said there is no particular risk from
materials in Canada.

DR. FELDMAN: If I can add one thing, if you would, to what Dr. Egan just
mentioned. When Canada found its first case of BSE, we did not implement
any action against or directed towards bovine components that may be
sourced from Canada. We didn\'t contact some companies to determine what
was happening and other companies contacted us to see what we were going
to do regarding the presence of Canada on the APHIS list.

And because most of the countries, as I already said, had in place
mechanisms for switching quickly to another source, those companies that
did use Canadian drug components quickly switched to U.S. source only or
U.S./Australia/New Zealand source components only, not at our request,
but on their own volition. Probably and undoubtedly for reassuring the
general public that they are not using materials derived from BSE
positive countries.

CHAIR PRIOLA: Dr. Epstein?

DR. EPSTEIN: Yes, I believe that there are countries whose laws prohibit
importation of materials from BSE countries similar to our own. And I\'m
aware that at least in one case in Korea they are rejecting U.S. plasma
on that basis. I\'m not sure how extensive this phenomenon is at the
present time, but it would not be correct to say that there are no
countries presently rejecting U.S. or Canadian source material. There
are.

CHAIR PRIOLA: Dr. DeArmond?

DR. DEARMOND: I think though there is a danger in assuming that we\'re
absolutely pristine. We know we\'re not. And I would agree with
Pierluigi and experience in Europe. If you test more, you\'ll find more.
And the fact that we\'ve been bringing in which I never had understood
before was that one to two million head of cattle every year being
imported in here and we\'ve identified one case of BSE, and that\'s only
because it was a downer and I don\'t know how other heads of cattle were
slaughtered at one point or another for some other purpose that we have
not \-- and it was never identified that they had the disease.

So we don\'t even know the extent of the disease in the country. And I
know when I\'m interviewed by newspapers, radio stations about the
extent of BSE and in the past I\'ve always said well, there isn\'t any
BSE in the United States. And then they say, but how do you know? We
know that people don\'t tell us everything. And I said well, you know, I
can\'t judge that. I can\'t judge that somebody is hiding it. But by not
testing we are in de facto hiding the extent of the problem. So we need
to know this. We really need to know this data and we need to know the
full extent of it.

CHAIR PRIOLA: Dr. Gambetti?

DR. GAMBETTI: Serum plasma of this product from bovine origin for these
purposes are obtained at which point or when from the time of slaughter
or out of special animal that are producing this materials? The reason
I\'m asking that is because maybe those animals could be tested, so you
know already whether the animal producing this material will affect it
or not. So in a sense, that would give assurance that that particular
plasma serum is not BSE contaminated.

DR. FELDMAN: My understanding and somebody, please, correct me if they
know otherwise, is that the majority of serum used is derived at the
place of slaughter. However, I am aware of several companies that used
closed herds that they started on their own, so that they have a
pristine source of serum for their own purposes. I am not sure of any
other sources or any other uses or other sources by other companies or
other countries for that matter.

CHAIR PRIOLA: Okay. Thank you, Dr. Feldman. Let\'s move on to our next
speaker, Martha O\'Lone, Commander Martha O\'Lone.

CDR O\'LONE: Good morning. I am Martha O\'Lone and I am a Commander in
the United States Public Health Service. Thank you, Dr. Priola. And I am
also a nurse with over 20 years of neuroscience nursing experience.
Currently, I am assigned to the Center for Devices and Radiological
Health as a medical device reviewer in the Infection Control Devices
Branch, and I\'m also the chair of the Center for Devices and
Radiological Health, TSE Working Group.

And today, I\'m going to talk about the steps that we are taking at CDRH
to minimize risk of TSE. So before I do that, I thought that I would
cover our mission, which for the Center for Devices and Radiological
Health, is to promote and protect the public health. And we do this by
ensuring that medical devices are safe and effective for their use and
we also have a responsibility for protecting the consumer and the
country from radiation that is unnecessary in medical, occupational and
consumer products. Next slide, please.

My objective for today is to provide an overview of our CDRH measures to
minimize risk of TSE agents in medical devices. And I thought that
because we have such a broad range of devices and we have to take,
therefore, a broad approach that I would discuss implanted medical
devices, and then include information about neurological devices and
general surgical instruments to give you a picture of how we look at
TSE-risk. And before I finish, I will talk a little bit about in vitro
diagnostic devices in relationship to TSE. Next slide, please.

So the way that we carry out our mission at CDRH is through these
procedures and approaches. First, we have our premarket review and for
the devices I\'m talking about most of them are Class II or Class III
devices, and we use 510(k) IDEs, PMAs to review those products. As far
as post market surveillance goes, we have device tracking and we also
have the opportunity to have medical device reporting.

And prior to yesterday, I had already planned to make a plug for medical
device reporting and say that this is the responsibility of every
practitioner to try to let us know what is going on with medical devices
in the community. And we do take those seriously. I was very surprised
when I came to the FDA as a nurse who had been practicing for a long
time in clinical centers to find out that each report is looked at very
carefully. So the more reports we have, the more information, the better
we can pursue this.

As far as scientific research, we did talk last July about the fact that
we have our Office of Science and Technology and they have been looking
at TSE and doing some research on decontamination of devices, along with
Dr. Asher. They have worked on other things with concerns for TSE. Also,
our staff and my colleagues have looked at TSE as far as what research
has been available to us and attended seminars and tried to maintain
education throughout our staff, as far as what is going on with this.

Even for the engineers of my division, I will sit up there and talk
about what TSE is, so they have an idea of what is going on in the world
before it becomes a problem for devices that we review. Field
inspections, our Office of Compliance carries out inspections. They also
are able to track through that and find out what is going on with
devices, for the devices that are tracked. Let me think what else I
wanted to tell you here just for a second.

And one of the things that they do to inspect is look at quality systems
and the general manufacturing practices that the people have to make
sure that they are accurate. And they do include in that, even though we
don\'t have any particular directive, at this very moment, they do look
at problems that are occurring in science and look at TSE if it is
warranted.

The biggest thing that we do for risk management right now is risk
communication, and we talk with industry, and we have done that through
letters and guidances starting back in the early \'90s, and we have also
talked with health professionals. Not only clinicians in practice and
academia, but also with our sister agencies, CDC, NIH, EPA, USDA, to
make sure that we are all providing a consistent message and we keep up
on what is going on with the other agencies.

As far as communication to consumers, we do have our websites available
and we do communicate with foreign governments through letters also.
Guidances, we have available for both manufacturers and for our
reviewers to look at and our public meetings. Next slide, please.

So for implanted medical devices, I thought that I would review what
I\'m talking about here just briefly. For the purpose of this
discussion, I\'m going to talk about the devices that we have with human
and bovine tissue. For the implanted medical devices that are human, we
can look at whether or not it goes into the blood or into the CNS. For
human devices that would go into blood contact areas, we would look at
cellular wound dressings, bone void fillers, human collagen, pericardial
valves and human dura mater would be for the CNS.

And we do look at CNS contacting-risk as being the highest risk based on
the WHO Guidance for biologicals and the title that I have just now
forgotten. And for animals we are looking again at the absorbable
hemostatic agents, the pericardial valves and collagen implants as being
blood contacting and then dura substitutes as being a higher risk with
the CNS contact. Next slide, please.

So to minimize the TSE-risk for implanted medical devices, pretty much
we have to use the tools that we have. We have our premarket review and
when we are aware that a device has animal tissue in it, we do look at
that on a case by case basis. We do consider the source. We have
guidance about BSE-free countries and about ? now even more defined
guidance about the actual herd and other information that came out in
our human dura guidance. We, in our premarket review, have other factors
to look at like manufacturing and sterilization.

The guidances that we have for the human guidance, I did include in your
packet, the human dura guidance and that is consistent with what CBER
has talked about this morning. We do the same things as CBER does. We
look at the tracking and all of the elements that they have listed
earlier. For the guidance for animals, we have had that guidance since
1998, and that animal tissue guidance came out and talked about, again
the source and went into great detail about what we would ,be looking
for in animal tissues.

One of the things that we did with that guidance was also announced to
the public that we have an animal tissue biomaterial database that we
maintain, so that we are aware of where the devices are and what has
been coming in since that time. As far as post-market surveillance, we
have still our device tracking with that, and we also have the
opportunity to go after and inspect for just regular routine practices,
as I mentioned.

As far as inspections go of manufacturing facilities, it is routine, so
for a PMA every site is approved before by inspection before it is
allowed to bring the products to market. And then afterwards for 510(k)s
and follow-up with the PMAs, you would have quality system reviews, and
also general manufacturing practices would be checked. We do have the
ability to go in and do further assessment if it is needed, if it is
warranted in our inspections, so that is something that is available to
us.

One of the main things that our Office of Compliance has done, who is
the one that performs the inspections, was in January of last year,
2003, 25,000 letters were sent to manufacturers, suppliers and importers
to remind them of the items that we have in our animal tissue guidance.
And this was highlighting the importance of maintaining records of
animal sourcing and manufacture. And that also gave us a more up-to-date
database that we have a very good idea of the manufacturers that we have
for all animal tissues and especially we can look at that for bovine or
whatever else we would like to look at. Next slide, please.

So minimizing TSE-risk for neurological- general surgical medical
devices, in addition to the devices that I discussed with tissue, these
devices are of potential concern in the transmission of CJD. And
according to CDC, iatrogenic transmission of CJD agents has been
reported in over 250 patients worldwide, and that is something that they
have currently on their website. But it is important to know that in six
of these cases, they were linked to the use of contaminated equipment,
and four were associated with neurosurgical instruments, and two were
stereotactic EEG depth electrodes.

And although there hasn\'t been additional data since this 1976 time,
CDC and FDA are still concerned about the potential for transmission of
TSE agents with the reuse of surgical instruments. We consider this risk
in our premarket review of devices that are known to be used with high
infectivity tissues, such as inside the CNS and for general surgical
instruments and medical devices that are not specifically labeled for
use in CNS or other high-risk tissues.

And as I discussed in the July 2003 TSEAC meeting, we are also
considering the risk for devices that are used in reprocessing medical
devices such as sterilizers. Next slide, please.

The approaches that we use to minimize TSE-risk for these medical
devices are again the premarket review of the neurological medical
devices to the general surgical devices. And each submission again is
considered on a case-by-case basis in the review. And in each
submission, we are carefully looking for labeling for reuse to see if
there are any reprocessing instructions after exposure to TSEs. And as
we\'ve discussed in July, if they did have those kinds of instructions,
we would want to see validation as we had asked for in general for all
medical devices for reuse in our 1996 labeling guidance.

Currently, CDRH has not cleared or approved any medical device with
claims that it can be reprocessed or used to reprocess medical devices,
such as scalpels, forceps after exposure to or potential exposure to
TSE. And we continue to work with CDC on recommendations. The current
information from the CDRH/CBER research that was discussed in July has
been incorporated into the CDC website. And the initial research on
decontamination of medical devices exposed to TSE that was completed by
CBER, which is Dr. Asher, and CDRH, which was Dr. Brown, was presented
last July, and there are ongoing steps now to look at additional parts
of the study. So the next slide, please.

Now, the reason I\'m bringing up in vitro diagnostic devices is really
more of a solicitation. The CDRH Office of In Vitro Diagnostics would be
the appropriate part of FDA to review a test to aid in the diagnosis of
variant CJD or infected and at risk for developing CJD. And just like
CBER, CDRH has the mechanisms to meet with sponsors early and to try to
establish a least burdensome pathway to market, as well as procedures
for expediting review of new and break- through diagnostics with
significant public health impact, which, of course, a device like this
would be.

So for sponsors of tests that would aid in the diagnosis of variant CJD
or for patients infected and at risk for developing CJD, I would urge
them to contact the Office of In Vitro Diagnostics as listed on this
slide. Next slide, please.

And in conclusion, I have discussed and tried to be succinct about the
steps that we have to go through to take action to minimize TSE risk,
and I think that we have continued to work on that, and I want to thank
the CDRH TSE Working Group, which has been very diligent over the years,
to continue to pursue this issue and for their hard work recently in
response to the finding of one cow in the United States.

I did include the guidances at the end of my slides, just in case you
were not familiar or wanted to see what I was referencing. So thank you
very much. Are there any questions?

CHAIR PRIOLA: Dr. Nemo?

DR. NEMO: I would assume that in the diagnostic tests we\'re talking
about, if it were a screening test for the blood supply, then that would
come under the auspices of Jay\'s group?

CDR O\'LONE: Yes, it would be in CBER. And I was going to explain that
in my speech, but then I thought you might have thought that is what we
do, so I just left it out.

DR. NEMO: Yes.

CDR O\'LONE: But that\'s exactly right.

DR. NEMO: Okay.

CDR O\'LONE: Any other questions?

CHAIR PRIOLA: Dr. Asher? Hold on just a minute, Dr. Gambetti. Dr. Asher?

DR. ASHER: If there were to be either a diagnostic test or a blood
screening test submitted to the agency review, George, I can assure you
that both Centers would review it jointly.

CHAIR PRIOLA: Dr. Gambetti?

DR. GAMBETTI: As far as the danger of contaminated surgical instrument,
especially for human medical treatments, I want to underline that there
is another very important issue for ? to have a good National
Surveillance Center, and it is very important that that Surveillance
Center render a diagnosis on a case that had surgery as soon as
possible. The situation has presented itself several times of the
patient that was not suspected to or having CJD and now to be CJD after
surgery, when the instrument that had been used on other patients
already.

CDR O\'LONE: Right.

DR. GAMBETTI: So that\'s very important that diagnosis be made and that
the diagnosis be made quickly. That\'s why the Surveillance Center is
really trying very hard to have not only as many cases to examine not
only as many cases as possible, but to have also turn-around extremely
short, as short as possible.

CDR O\'LONE: Thank you. And I would note that Dr. Edmiston, who is the
chair of our General Hospital Panel, who came last July, had discussed
that risk problem as well, the need to be able to turn around and decide
what they should do as far as a potential exposure or a known exposure
of instruments after a CJD case.

CHAIR PRIOLA: Any other questions? No. Thank you, Commander O\'Lone. Our
last speaker of the morning is Dr. Potter.

DR. POTTER: Thank you and good morning. As we all know, the focus of
this meeting is on medical products. Do you want me to talk into this
thing?

CHAIR PRIOLA: Yes.

DR. POTTER: All right. I\'ll see if I can remember to do that. The focus
of this meeting is on medical products, but I just couldn\'t bear the
thought of having you all here assembled and not say anything at all
about food, and Suzette and Bill very graciously gave me a few minutes
here at the end to remind you what we have been doing and what our
intentions are to enhance the safety of cosmetic and food products,
including dietary supplements, food ingredients, food additives.

The Committee has discussed to a considerable extent the difference
between guidance and regulation. And what we have been using up to the
present to enhance the safety of food and cosmetics is a series of
letters to manufacturers, announcements in the [Federal
Register]{.underline} and guidance documents to encourage and cajole the
industry to assure the safety of their sources and the efficacy of their
effectiveness of their processes.

Since 1992, the agency has recommended that firms manufacturing or
importing foods that may contain bovine tissues or their derivatives
assure the safety of their source. Also, since 1992, FDA has advised
dietary supplement manufacturers and importers to assure that no dietary
supplement ingredients come from cattle born, raised or slaughtered in
countries that are at elevated risk of BSE.

Since 1994, we have recommended that firms manufacturing or importing
cosmetic products that contain bovine tissues or their derivatives take
the necessary steps to assure the safety of those products and
ingredients. And in 1997, FDA published guidance on the production of
gelatin for its many oral and cosmetic uses that recommended removal of
skulls, spinal column and spinal cord and made recommendations on safe
sourcing of bones and hides.

During the last Advisory Committee meeting on July 2003, you heard
evidence of the effectiveness of the gelatin process in activating
prions and evaluated possible changes to our gelatin guidance. We are
considering your advice as we review the gelatin guidance in light of
our pending regulatory changes. As we review the guidance and as we
draft the Interim Final Rule, we will likely find it appropriate to
bring back to the Committee a new draft gelatin guidance to ask for
additional advice and comment.

Yesterday, Mary Porretta from FSIS outlined the USDA response to the
documented presence of BSE in the United States, and briefly in January
USDA published regulations that prohibit the inclusion in human food of
non-ambulatory disabled cattle, SRMs from cattle older than 30 months,
plus the small intestine and tonsils or at least the ileum and tonsils
of cattle of all ages and mechanically separated beef. FSIS has also
established new standards for advanced meat recovery to limit central
nervous system tissue in that product.

On January 26^th^ of this year, FDA announced its intention to publish
parallel regulations to provide the same level of increased protection
for food and cosmetic products regulated by FDA. If I could have the
slide now, please? Thanks. And with these new regulations in place, the
flow of FDA food and cosmetic products comes down through animals
inspected in past for human food and comes down into edible trim and I
think advanced meat recovery used for, among other things, foods that
contain just a small amount of beef and are therefore regulated by FDA,
instead of USDA, like pizza toppings and soup and some frozen dinners
and perhaps some baby food.

Edible fat gets rendered into edible tallow for food use and food
additives, ingredients, titrate supplements, soaps and cosmetics also
use a tremendous amount of tallow. You see it showing up at present in a
couple of boxes here on this slide as this current supply of edible
tallow is inadequate for all of the purposes that tallow and tallow
derivatives are used for.

Edible byproducts include brain, spinal cord and eyes from cattle under
30 months of age, and from cattle of all ages the liver, kidneys,
hearts, spleen, thymus, testicles, pancreas, placenta, esophagus, bile,
mesentery stomachs and probably a few other body parts. These get used
in dietary supplements and other food and food ingredients, including
soups, stocks, flavorings, extracts, collagen, amino acids, bones, as
you recall are transformed into gelatin, hides for gelatin, collagen
come down the inedible side, because of the way slaughterhouses are
constructed. I think tracheas are probably harvested over there as well.

Now, we are still in the drafting process for the IFR. Because it is an
Interim Final Rule, it will go into effect when it is published, and
will continue the process that has been ongoing for the last dozen years
of concentrating the flow of regulated foods and cosmetics down this
right hand side of the slide. And with that, I will end this discussion
of food and cosmetics, and will hope that this sort of finds the
Committee for future meetings when we can focus on this more interesting
aspect of what FDA does.

CHAIR PRIOLA: Thank you, Dr. Potter. Dr. Wolfe?

DR. WOLFE: Am I understanding the lower right hand corner correctly?
Does it actually say that for cattle under 30 months that it is okay to
use the brain, cord and eyes for dietary supplements?

DR. POTTER: Right. Those are not included in the definition of
specified-risk materials.

CHAIR PRIOLA: Dr. Khabbaz?

DR. WOLFE: As you know, it is not exactly easy to figure out what
country these things come from, but given that at least Dr. Brown\'s
study shows that whereas the brain itself may not start getting affected
until over 30 months, the other parts of the body are affected under 30
months. This seems like a literally crazy idea to encourage dietary
supplement manufacturers to include brain as long as the animal is under
30 months.

DR. POTTER: The IFR process does have a comment period.

DR. WOLFE: I will comment in writing myself.

DR. KHABBAZ: Yes, Morrie, I have a question, again, regarding
supplements. And I\'m always looking at that because I have the same
reaction saying everybody buy product supplements and you went through
the list and I think I looked around and many people in the room were
kind of, you know, rolling their eyes. I\'m thinking of people who, you
know, by choice avoid bovine material and by choice, you know, don\'t
eat many products here and then go and consume supplements. I mean, have
there been discussions about labeling as to origin and what goes into
supplements?

DR. POTTER: That gets a bit beyond things that I know very much about.
Labeling issues are fairly difficult. I think part of the problem is how
far back does one label amino acids and fatty acids, things like that
may be derived from bovine products. But at some level a can of motor
oil has relationship to a prehistoric fern and we don\'t consider it a
vegetable product. And I wonder, you know, on a label that contains
fatty acids or amino acids, is it informative to include all of that
information. Tough questions.

DR. DEARMOND: It is a reasonable question though, because there is a
number of things. I watch the golf channel and they are always
advertising some supplement that has got growth hormone or something
else to improve your golf game.

DR. WOLFE: Or brain.

DR. DEARMOND: Or brain. It probably does. I am very surprised at that
lower right hand corner, too. But then you said the labeling is very
difficult and yet I called one of those companies, because I was on this
Committee, and I said where do you get those hormones and they couldn\'t
tell me. It has got to be \-- reasonably they should know that and it
should be labeled.

CHAIR PRIOLA: Dr. Johnson?

DR. JOHNSON: Excuse me. I think there are two different issues in the
lower right hand corner. Sid and I come from different cultural
backgrounds. My grandparents were Swedish immigrants in the Midwest and
they ate brains very likely with scrambled eggs for breakfast.

DR. NEMO: That\'s why you got involved in food.

DR. JOHNSON: Yes, that\'s why I got involved. There are a lot of
Midwesterners who, in fact, eat brains, cow brains and pig brains and
all kinds of brains as food. Then there is a different issue and that is
the supplements like the one I have in my hand, which is called \"Body
Fortress,\" and this is not from some quacky store. This is from the
local vitamin shop in suburban Baltimore and it contains raw brain, if
anybody would like to try some? There is a lot of this on the market
shelves. The problem is you need a magnifying glass. I\'ve got one right
here.

DR. NELSON: It wouldn\'t be licensed if they had ephedra in it though,
would it?

DR. FERGUSON: That\'s okay. Actually, it says raw gland complex (heart,
brain, carotid, eyes, stomach and kidney).

DR. JOHNSON: Even better.

DR. WOLFE: I want to thank you for the kind offer.

DR. JOHNSON: You know, you can barely read that.

DR. WOLFE: This does sound like a no-brainer.

DR. JOHNSON: This is sold. I mean, there are lots of them on the shelf.
If you go into your local store, your local shop, grocery store or
whatever it is, but you need a hand lens and you will find out there is
all kinds of brain being sold in there as a supplement. Which I think is
quite different than the stuff that is in the meat counter that is
marked calf brains, which is for people who want to eat brain. This is
for people who don\'t know what they are doing.

DR. WOLFE: Well, it\'s also ? unlike calf brains, this is regulated by
the FDA.

CHAIR PRIOLA: Okay. I want to refocus the discussion now, back on the
medicinal product, which is the basis of this meeting. But I\'m sure
this will come up in the future. It has in the past and it has now. So
we\'ve been asking questions of the presenters. Are there any other
questions or comments the Committee members would like to make before, I
think, we will just go right to the open public hearing part, unless
there are any other comments or questions.

DR. WOLFE: We\'re going to need to leave.

CHAIR PRIOLA: Well, our lunch is scheduled for 11:30. Is that right?

DR. WOLFE: We\'ll need to check out.

DR. WOLFE: Are we going to need to really have lunch?

CHAIR PRIOLA: You really need to check out? You\'ll get charged? Oh, I
guess so. All right. That\'s a good point. Thank you. Do you want to
take a 10 minute break, so that you guys can all check out? Thanks for
reminding me of that.

DR. WOLFE: Okay.

CHAIR PRIOLA: And then we\'ll come back for the public open hearing.
Sorry.

(Whereupon, at 10:54 a.m. a recess until 11:11 a.m.)

CHAIR PRIOLA: If the Committee members could come back and take their
seats?

SECRETARY FREAS: We are going to begin with the open public hearing, at
this time. This is the opportunity for the public to address the
Committee on matters related to the agenda topics. The public is welcome
and encouraged to participate. Our presentations will be limited to six
minutes and again, the Chair has been asked to read a statement
regarding disclosure of Conflict of Interest issues at this open public
hearing.

CHAIR PRIOLA: Both the Food and Drug Administration, FDA, and the public
believe in a transparent process for information gathering and decision
making. To ensure such transparency at the open public hearing session
of the Advisory Committee meeting, FDA believes that it is important to
understand the context of an individual\'s presentation. For this
reason, FDA encourages you, the open public hearing speaker, at the
beginning of your written or oral statement to advise the Committee of
any financial relationship that you may have with any company or any
group that is likely to be impacted by the topic of this meeting.

For example, the financial information may include the company\'s or 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.

SECRETARY FREAS: Normally, I would like the participants to the
microphone in the order in which I have received their requests. I would
like to make a little change, if I could, just because we are set up
right now for overheads and I would like to do the overhead projection
first and then go on to the others, if that\'s okay with you. Okay. So
our first presenter with overheads will be William Drohan from Clearant,
Incorporated. He will \--

MR. DROHAN: Right. I will.

SECRETARY FREAS: Oh, okay. He doesn\'t. Yes, go ahead.

MR. DROHAN: Yes. I\'m Bill Drohan and I represent Clearant, a
biotechnology company in Gaithersburg, Maryland. I would like to thank
the Committee for an opportunity to present today. Also, in terms of a
Conflict of Interest, I am a full-time employee at Clearant, so my
salary goes to the Universities of Virginia and California where my
daughters go to school. So I am compensated fully.

Our company has developed a technology, which basically allows us to
deliver gamma radiation to biologics under conditions where we can
actually recover the activity of the biological material. We have been
able to demonstrate that we can inactivate bacteria, viruses and, more
recently, prions.

About 14 months ago, we published a paper in [Vox Sanguinis]{.underline}
in which we presented data in which we could inactivate one to two logs
of prions while recovering the majority of the activity of a 25 percent
albumin solution. This was done in the hamster scrapie model that Bob
Rohwer presented yesterday and, in fact, was done in collaboration with
Dr. Rohwer.

In lieu of time, I have made two overheads, and the first one basically
describes the delivery of gamma radiation to fetal bovine serum. It\'s a
non-reduced gel. It\'s an SDS PAGE gel and what one can see in lane,
let\'s see, this would be lane three, is an unradiated fetal bovine
serum sample as a control. About 50 percent of fetal bovine serum in the
United States is radiated to 25 kilograys, and what you can see in lane
four is the result of that.

What we have done has been to deliver additional doses of gamma, between
25, and if you look in lane 10, 105 kilograys of gamma, and what I hope
to convince you in this overhead is that there is little change in terms
of the size of the proteins, little change in the high molecular weight
proteins, nor accumulation of small molecular weight, which would
indicate a lack of degradation.

Does this basically have any impact on biological activity? There is
another overhead there, if I could encourage someone to change the
overhead. What we have done in an admittedly preliminary experiment is
to look at the ability of the fetal bovine serum treated to 105
kilograys to sustain the division of Chinese hamster ovary cells, a cell
line that you well know is involved in the production of many biologics.
And what one can see, hopefully, is that at 55 or 105 kilograys, the
doubling time for the ability of those cells to become confluent is
unchanged.

The reason that I bring this to the Food and Drug Administration is that
we believe that this technology, the inactivation of prions in
biologics, especially fetal bovine serum, can be considered one of
perhaps a portfolio of different approaches to ensure the safety of
biologics as they are manufactured.

Certainly, diagnosis is important. Certainly, prion removal is
important, but we think this technology along with other ones
demonstrates that the prion protein can actually be inactivated by this
technology. We also encourage those who are funding this type of
research to continue to do so. We have benefitted from dialogue with
George Nemo and his group at the National Heart, Lung and Blood
Institute. We are currently funded by that Institute.

And in a final point, I would like to mention that in the presentation
that Bob Rohwer made yesterday, he demonstrated that there are 5 to 25
infectious units per ml in the serum of morbid animals. That is truly a
low level of infectivity if you compare it with the level of infectivity
one sees in the viremic stage of other infections, such as HIV,
hepatitis C and parvovirus infections.

Being able to develop diagnostic tests, which basically effectively can
pick up that level of infectivity, we think, is hard to do. It\'s
certainly worth doing, but a challenge. Well, if you look at the level
of infectivity, technologies like inactivation of the prions at 100
kilograys where you might get two, three or four logs could be
clinically relevant in terms of the safety of those products. Thank you
very much.

SECRETARY FREAS: Thank you for your comments. Is there anybody else,
before we put the overhead projector away, who needs an overhead
projector for this morning\'s open public hearing? If not, we will go
back to the order in which the requests were received, and the next will
be a PowerPoint presentation from Chris Penet from Genencor
International.

MR. PENET: Thank you, Dr. Freas. It\'s a pleasure to be here to present
an update to the Committee on some enzyme work that has been done in
collaboration with Genencor and the Health Protection Agency Branch of
the Ministry of Health in the United Kingdom.

Genencor\'s role in this has been in the later stages. The HPA had
stated this work previously. They were known as the Center for Applied
Microbiological Research or CAMR. Genencor got involved in the second
phases, which I will play out as we go through. It is a co-funded
program with the HPA at this point. First slide, please.

I also will point out that I was not supposed to be the original
speaker. The original speaker was supposed to be Dr. Neil Raven from the
HPA. Unfortunately, he was not able to join us this morning, but this is
the background of why the HPA or CAMR was interested in looking at
solutions to decontaminating medical instruments, as they were charged
by the Ministry of Health to look into more environmentally and user
friendly processes versus some of the science that was coming out of
Europe and using high caustic and high pressure treatments. So they were
charged with finding an effective and applicable, practical process to
be able to do this, and I won\'t go through all the points. Most of them
have been touched on by this Committee in the past. Next slide, please.

But this is the basic of the science that they had looked at. They
originally started out in the late 1990s looking at basically every
enzyme that was available in the marketplace. They screened over 40
different enzymes through analytical techniques, such as Western blots,
but then realized that they needed to take that analytical data to the
next level to be able to ensure infectivity was being actually reduced,
and so they started combining their analytical work with in vivo studies
using mice.

And I don\'t have the data for all the different enzymes they looked at,
but the Properase enzyme, which is a commercially available product, was
\-- and again, the original work was funded by the EC and the CEAC
Committees and the European community. Properase was one of the enzymes
that they saw some efficacy in reducing infectivity by about three logs,
and then the MC3 product is when Genencor got involved and designed,
based on genetic engineering, a more efficient enzyme for them to look
at.

They basically were looking at mouse-passaged BSE strain 301 that was
then treated with a pH 12 at 60 degrees C for 30 minutes with the
different enzymes, and then injecting them back into the mice for
monitoring the infectivity reduction.

The next slide is just a quick look, and you have seen many of these
Western blots before, where the enzymes have been able to decrease
analytically the prion protein, but the next slide is the one that shows
the key data that they wanted to present.

This orange line back here is the Properase enzyme that was originally
identified. All the other lines are different dilutions of the untreated
mouse brain homogenate being treated back into the mice, and then this
is the engineered enzyme, which is now showing roughly 500 days of
survival of the mice compared to the first enzyme that they saw, which
was back at about 175 days, and the straight material showing the mice
being killed off in less than 150 days. Next slide, please.

So basically, where they are at in the process is that two enzymes are
shown to be able to completely remove the immunoreactive material
analytically, but there is a significant difference in the levels of
observed infectivity through the mouse model. And at the choice for the
mouse model is a relevant combination of the agent and the animal, which
is showing a significant reduction in infectious dose. Next slide.

So basically, the HPA has added this point in working with the Ministry
of Health is they were showing, approximately, a seven log reduction in
the infectious dose with the BSE model and with in vivo studies. We have
some further studies underway looking at injection versus wire
implementation into the mouse cranial area. The interesting thing is
it\'s compatible with current disinfection practices.

There are many products out there today that have enzyme-based
pre-soaks, if you will, in formulations, so we\'re not talking about a
major cost, hopefully, to the sterilization units. It\'s a safe,
environmentally friendly process and the interesting thing has been able
to engineer an enzyme specifically for the prion inactivation.

And there is also ongoing work looking at the MC3 enzyme for rendering
bone meal, the prion for bone meal. And actually, that\'s where the CAMR
work originally started, was looking at a process to be able to reduce
the backlog of infected bone meal that was built up in the U.K. from
their outbreak in the mid \'80s and early \'90s. And I believe that was
the last slide, and these are just the acknowledgements of the HPA and
the Genencor people. Thank you.

DR. DEARMOND: Can we ask a question?

SECRETARY FREAS: I would prefer waiting until all these people have an
equal opportunity, and then if you have questions, we can call somebody
back. Our next presenter on the agenda as received, in the order in
which they were received, is Harold Baker, Technical Director and
Principal Scientist, Pall Medical.

MR. BAKER: Good morning. I am Hal Baker and I am here today as a
representative of Pall Corporation. Pall Corporation is a world leader
in the field of filtration, separation and purification technology. We
provide leading edge products to meet the needs of global customers in
transfusion medicine, biotechnology and pharmaceuticals. I earn my
livelihood as the senior vice president for the Medical Division, and
our Medical Division is conducting animal studies on the removal and
detection of infectious prion from red cell concentrates.

We\'re doing this investigation in cooperation with the New York State
Institute of Basic Research. We\'re grateful to Dr. Freas and Dr. Priola
for granting us the opportunity to share with you briefly the latest
results of this work. Now, my plan was to have our principal scientist,
Dr. Sam Coker, briefly walk you through a PowerPoint presentation
providing information on study design and results today and,
unfortunately, he got snarled in LaGuardia traffic today, so I\'m going
to briefly read a statement where I have gone through his presentation
and pulled out some of the key information that I would like to share
with you today.

The occurrence of a variant CJD in the United Kingdom, together with
recent animal data, and the evidence that the distribution of vCJD may
differ from the classical Creutzfeldt-Jakob disease has raised the
question of the possibility of transmission of the causative agent by
blood transfusion from infected individuals with no clinical symptoms of
the disease. In the present study, we are evaluating the use of a
prototype of a new leukoreduction filter for the removal of infectious
prion from red cell concentrates. I will tell you briefly about the
study design.

Units of whole blood were collected into blood bags containing 63 mls of
CP2D anticoagulant. Red cell concentrates were prepared from whole
blood, then resuspended in AS3 additive solution according to standard
blood bank protocol. 10 percent scrapie brain homogenates in buffered
saline were prepared from brains of hamsters infected with
hamster-adapted scrapie. The scrapie brain homogenate was clarified by
ultracentrifugation, and the scrapie brain homogenate was added into the
red cell concentrate. The scrapie brain homogenate-contaminated red cell
concentrates were filtered at room temperature with a prototype prion
reduction filter.

The presence of the scrapie brain homogenate in the red cell concentrate
was determined before and after filtration, using a Western blot assay
with 3F4 and 7D9 prion-specific monoclonal antibodies. In addition to
the Western blot, different dilutions of aliquot at the pre- and
post-filtration scrapie brain homogenate red cell concentrate were
injected through the intracerebral route into scrapie-susceptible
hamsters.

Preliminary results have shown removal of the infectious prion from full
units of red cell concentrates to a level well below the limit of
detection of the Western blot assay. After 26 weeks, none of the animals
injected with filtered scrapie brain homogenate red cell concentrate had
developed any clinical symptoms of the disease. But some of the animals
in the control group are beginning to show signs of scrapie disease, and
the disease is confirmed in one of them.

The present results show that the prototype of a new leukocyte reduction
filter are encouraging in removing infectious prion from red cell
concentrates below the level of detection of Western blot. The use of
this type of filter may help reduce the risk of transmitting infectious
prions through blood transfusion. However, additional in vivo studies
with the red cell concentrate from scrapie infected hamsters and other
forms of TSE in clinical and pre-clinical stage of the disease are
needed and are currently planned.

By combining white cell filtration technology already widely in use in
most countries to reduce donor leukocytes in red blood cells with the
ability to reduce infectious prion below the level of detection of
current methodologies, Pall Medical is taking one preventative step to
eliminate concerns about circulating prions in human blood.

This new technology development program is based on our surface
modification chemistries that have demonstrated an affinity for prions.
We look forward to the opportunity to keep you apprised of progress.
Thank you for your time today.

SECRETARY FREAS: Thank you. The next request is from Dr. Robert Rohwer.
He would like to speak to you as a private citizen instead of an invited
speaker.

DR. ROHWER: There has been a lot of discussion around the table about
closed herds as a potential source for sourcing of bovine materials, and
wearing my hat, not my academic hat, but my hat as a consultant to
Western Agricultural Services and the Prather Ranch, I wanted to make
people aware of one such herd that does exist in North America.

It has been in existence for over 30 years. They have feed records that
go back to prior to the emergence of BSE in Europe, prior to 1980. These
have been meticulously kept. This is a herd, which has been \-- I guess
it would be called a hobby herd originally. It has now been taken over
for the express purpose of maintaining these animals in their pristine
state. They have never been fed anything, except food that has been
raised on the premises of this property. They have never received any
meat and bone meal, for example. It has been closed with respect to
breeding in the sense that new genetics are introduced only as semen, so
no animals are brought into this property.

About 10 years ago, we designed and built a slaughter facility on the
premises, so the animals never have to leave the property before the
relevant bovine materials are taken off the animals for medical use and
medical purposes. The company that is primarily using the tissues from
these animals at the moment is Collagen Corporation, but there are other
companies that are using tissues from these animals and, as far I\'m
concerned, the herd is rather tragically underutilized. So I guess I\'m
also speaking in the role of an ad hoc business development officer for
this concern.

But nevertheless, a herd like this does exist in North America and if
there are people here who are interested in using these materials, they
should get in contact with me and I\'ll get you in contact with those
folks. It\'s not a big enough operation that this is something that
could solve the fetal bovine serum problems and that type of thing, but
for focused high value products and use, it is an option.

SECRETARY FREAS: Thank you, Dr. Rohwer. Is there anybody else in the
audience who, at this time, would like to address the Committee?

MR. CROTTEAU: Hello. My name is Patrick Crotteau. I am vice president of
Quality Systems for Inamed Corporation, and I would like to thank Dr.
Rohwer for the endorsement. Collagen Corporation was acquired by Inamed
Corporation in 1999 and we maintain and manage this ranch for the
sourcing of collagen for injectable uses. So again, just to correct Dr.
Rohwer, the Collagen Corporation has been acquired by Inamed. We do now
manage the ranch.

SECRETARY FREAS: Thank you. Is there anyone else at this time? If not,
Dr. Priola, I turn the meeting over to you.

CHAIR PRIOLA: So what we have scheduled for the rest of the day is
lunch, first of all, which is important, and then a discussion in the
afternoon over the issues of current safeguards, possible future
safeguards in relation to medical products that are regulated by FDA.
Are there any questions or comments that anyone would like to make
before we break for lunch and come back at 12:30? I know you had one.
Dr. DeArmond and then Dr. Johnson.

DR. DEARMOND: So I had a question for the, let\'s see, Genencor
International, the protease, the protease person, Properase.

MR. PENET: Yes.

DR. DEARMOND: Oh, I see. So you run this at a pH 12, and the question
that we\'re always asked, because the main issue is not being able to
eliminate infectivity. It\'s being able to prevent destruction of all of
the equipment that people want to deal with, and pH 12 can be
destructive itself.

Have you looked at a variety of stainless steel and other equipment to
see whether they maintain their edge and things like that?

MR. PENET: That is currently underway. That is part of the ongoing
studies, but we\'re also looking at further engineering of the enzyme to
get as much efficacy at a lower pH as we are at 12. We realize 12 is
still on the ragged edge, as well as 60 degrees is as well, but, you
know, it\'s the first set of results and obviously using mouse models,
it takes a while to do that and we\'re just getting into the formulation
aspects of it. We\'re not promoting that the enzyme itself is actually
going to be the solution. We really do believe it\'s enzyme plus
chemistry plus process to get there, but that\'s work that is ongoing.

DR. DEARMOND: Great.

DR. JOHNSON: Yes. I want to ask Bob Rohwer about how many other herds
are like this. I noticed that our local Wholesome Foods Store or
whatever they call themselves, the natural food store, had a full page
ad out this week in Baltimore saying that all of their meat comes from X
packing plant, which never uses bone meal and is a closed group, and so
on and so forth. I have no idea.

Is that common? Are there multiple herds like that around? And is there
a greater source, that is, for safer serum and whatnot?

DR. ROHWER: I\'m sorry, Dick, I can\'t really answer that
authoritatively. I am very familiar with this herd, because I helped
develop it. But I know that there are claims for closed herds, but I
don\'t think it\'s a controlled definition and \-- Lisa, you can correct
me on that if I\'m wrong, but my feeling is you can use that term
freely, and so it means different things to different people.

In some cases, it just means they are closed to breeding or the breeding
is controlled and tracked, but it doesn\'t mean, it has nothing to do
\-- and typically, it means nothing about feeding. Feeding is not part
of the definition. And so in this particular instance, this was kind of
unique. The origins of this herd are extremely unique, and I would be
sort of surprised if there are others like it, yes.

DR. FERGUSON: I think, you know, what you see in certain supermarket
chains, there are claims about natural beef.

DR. ROHWER: Yes.

DR. FERGUSON: Organic beef, etcetera. At this point really, truly, what
does that mean? It\'s a bit difficult to say. I think as Dr. Rohwer just
mentioned, definitely with those it\'s probably not a true closed herd,
in the definition that a scientist would think of a closed herd. Also,
you probably have to look real carefully at, you know, what are their
practices and what really does that mean.

I would also just point out that in certain European countries, there
have been cases of BSE found in closed \"organic herds,\" organically
raised beef herds. So you just need to be real cautious on your
definitions.

CHAIR PRIOLA: Dr. Jenny?

DR. JENNY: Yes. The definition varies from state to state and industry
to industry, and so if you were going to try to do something like this,
you would have to standardize what you\'re talking about. I know there
are a few organic herds that are very careful and actually analyze their
feed, but a lot of them depend upon certification coming from the feed
manufacturer and, you know, the certification is as good as the quality
control process behind it.

CHAIR PRIOLA: Okay. If there are no other questions or comments, let\'s
adjourn for lunch and return at 12:30 for discussion.

(Whereupon, the meeting was recessed at 11:38 a.m. to reconvene at 12:37
p.m. this same day.)

A-F-T-E-R-N-O-O-N S-E-S-S-I-O-N

12:37 p.m.

SECRETARY FREAS: Since many members do have flights to catch this
afternoon, we would like to go ahead and resume the meeting.

CHAIR PRIOLA: Okay. So it looks like most of the Committee members are
back in the room and are at the table, so I would like to resume, so
that we can get out on our deadline, so that those of us who have
flights can actually catch them this afternoon. I think what we have to
do this afternoon for the discussion is to focus on the topic of medical
products and how, in light of the variant CJD, the probable case of
variant CJD transmitted by a blood transfusion, the recent discovery of
the BSE cow in Washington, how we have to take those into account when
we consider risk-based sourcing of bovine material that is used in
medical products, how the safeguards for FDA-regulated medical products
have already addressed those concerns, how those safeguards, based upon
the current science, might be improved.

As an example, in terms of blood donation, we have to consider that now
that we have, again, a case of a probable vCJD transmission via blood,
does the FDA have to begin to consider deferring donors now with a
history of transfusion? Are broader and more restricted deferrals
necessary? Is leukoreduction a good safeguard? In terms of vaccine
production as another example, do we have to start worrying about
testing cell lines now for susceptibility to BSE agent or variant CJD
agent, etcetera?

So as a reference, you could go back to Dr. Scott\'s talk earlier in the
day around the slide on the top of page 6 of your handouts, give some
topics that you can think about and address and discuss, some of which
we already have. So I would like to open up this discussion for
comments, questions. Dr. Wolfe?

DR. WOLFE: This is not meant as a diversion and it will probably take
about 30 seconds is all, and in just trying to summarize some of the
things that happened yesterday, which is that even though our charge is
to sort of say did this Committee, which I think they did an excellent
job anticipating the possibility of transfusion case, which now has
happened, and I think that we look good in retrospect.

But aside from that, the issues of: (A) Traceability of cows; (B) The
feed ban and; ?) The testing, which were all discussed yesterday, even
though this is not our topic, our comfort at making any kind of
recommendations are going to be very different if we can be assured in
the future that these have been seriously addressed.

I mean, the traceability was a big problem and even though the
International Committee told them to stop looking for cows, by the time
they told them to stop looking, they probably would have been able to
find more cows with what was an excellent disease outbreak
investigation, hampered only by the traceability problem. And secondly,
the feed ban still has got some holes in it and, as was pointed out
yesterday, if you look only at the feedlots, the feed manufacturers and
don\'t ever look on the farms, you may miss some stuff that\'s going on.
And then third, the testing. I mean, I think that at least a number of
people on this Committee were probably not aware of the fact that no
normal cows have been tested at all, and whereas one might not want to
test every cow as in Japan or even every cow over 30 months, some
consideration needs to be given.

That is really all I wanted to say, and I think that from what I heard
from other people here, we would support just the idea of encouraging
those three things, some of which are USDA, some of which are FDA, the
feed ban, to just make as rapid progress as possible, because that will
ensure the larger picture that we\'re worried about.

CHAIR PRIOLA: Dr. Johnson?

DR. JOHNSON: Well, viewing it as titres and when you\'re looking at
10^8^ in one organ and 10^1^ in another, you just realize that volume
for volume, some things are important and some are pretty trivial by
comparison. So it seems to be the brain and the spinal cord that are the
big concern. What would be the problem, just logistically and
economically, of removing the brain and spinal cord from rendering, just
bury it and not process it back into the food chain, be that food chain
human or animal.

DR. WOLFE: Or the food supplement chain.

DR. JOHNSON: Food supplements, and I will even give them up for
breakfast.

CHAIR PRIOLA: Dr. Ferguson?

DR. FERGUSON: Yes, just to answer some of this.

DR. JOHNSON: I waited for you to come back before I answered the
question.

DR. FERGUSON: Sorry. Thanks. Some of the implications of those type of
recommendations, it\'s somewhat straightforward to think of that in a
slaughterhouse environment where, you know, it\'s easy to remove those
and that\'s not necessarily a problem. You know, you can divert those
one way or the other.

Where the issue comes in is in the dead stock and more the animal
disposal end of things, and I think perhaps what a lot of folks in the
Committee don\'t necessarily recognize is, you know, that\'s another
component of rendering, where they are picking up dead stock and they
are not set up to remove specific parts from that animal.

DR. JOHNSON: Yes.

DR. FERGUSON: That hide comes off, the whole carcass goes in the
grinder, and you go. So that is where the issue comes in and at least my
understanding is sort of where the industry is, at this point in time,
if those type of requirements were put in place, essentially, what a lot
of the renderers would say is, I\'m not going to pick those up. So then
we\'re stuck with a large pile of dead animals that we have to deal with
in some way, shape or form.

CHAIR PRIOLA: Dr. Nelson?

DR. NELSON: Are the new plans for the Department of Agriculture to test
dead stock, in addition to those that can\'t walk very well and have
fallen over?

DR. FERGUSON: Well, I think if you look at the slides that I presented
yesterday, we already have been testing dead stock. For the past two and
a half years, we have been including dead stock in our testing
population.

DR. NELSON: So are you confident that there is no BSE in that
population?

DR. FERGUSON: Okay. Again, our surveillance is not meant to identify
specific sub-populations and the prevalence in that sub-population. Our
surveillance is geared to identify presence of disease in the U.S. at a
given level.

DR. NELSON: But is all dead stock, with the new plan, now to be tested
in the future, or just up to 40,000 animals?

DR. FERGUSON: You mean the Surveillance Plan?

DR. NELSON: Yes.

DR. FERGUSON: Well, first of all, again, you know, there\'s a lot of
options still under consideration for surveillance with, you know, many
different recommendations have been forwarded to us both from the
International Review Team and lots of things swirling around out here.
As we\'re continuing with our 40,000 goal, that does include dead stock
as part of the targeted high-risk population. I mean, I can put the
slide back up again, yesterday, that says these are what we include in
our targeted high-risk population, non-ambulatory dead stocks, CNS,
etcetera, etcetera. So those are included in the population.

CHAIR PRIOLA: And I think in terms of sourcing for materials to be used
in human and veterinary medical products, the high-risk category,
Category A, spinal cord and brain, they are not used anyway, if I
understand correctly. They are not sourced unless it\'s absolutely
justified, and if they are sourced, it\'s from a low-risk BSE country.
So those are at least some of the safeguards that are in place for that,
from the FDA\'s point of view, if I understood Dr. Scott\'s presentation
this morning.

DR. JOHNSON: But even if it\'s a downer cow like the cow in Washington,
we kept hearing the comment that don\'t worry, the brain and the spinal
cord didn\'t go into the human food chain, it went to a rendering plant.
But it seems to me that, you know, they may only be making vitamin
supplements and mascara and stuff like that out of that and not making,
you know, sauteed brain, but it\'s still in the food chain in an
indirect way. Isn\'t that right? I mean \--

DR. FERGUSON: Well, I think the offal from that type of a facility,
which would have included the, you know, stuff from this animal, that\'s
not edible rendering. That\'s inedible rendering, you know, so that\'s
not going to be in a dietary supplement, per se.

DR. JOHNSON: Soap.

DR. FERGUSON: Yes, soap.

DR. JOHNSON: Cold creme.

DR. FERGUSON: I don\'t know. Actually, I don\'t know where cosmetics
manufacturers \-- if they obtain their product from the edible rendering
chain or the inedible rendering chain.

CHAIR PRIOLA: Well, that\'s something that I don\'t know that we have to
address here with the cosmetics. I want to steer away from the dietary
supplement, cosmetic thing, because we all know that\'s an issue, but I
would rather stay focused for a moment on the medical products, because
that is sort of the charge of the Committee today.

DR. NELSON: I don\'t know. What would be the problem with testing all
dead cattle or downer cattle, and is that under consideration as a
possibility?

DR. FERGUSON: Well, there are lots of things under consideration as a
possibility, and I guess I would just encourage the Committee any time
we\'re talking about surveillance, you know, let\'s decide what we\'re
trying to do with our surveillance. This is the point that I was trying
to make yesterday. You know, it\'s not just a matter of oh, test all of
this or test all of that. You know, what you need to do is decide what
is the question you\'re trying to answer, and then you set up your
program to do that.

And, you know, I guess, internally within the Department, you know, we
have set up lots of different questions that we could try to answer, and
those are all the different things that are being considered. You know,
it ranges from continue with our, you know, one in a million and a 95
percent confidence interval in a targeted high-risk population, it could
go up to one in 10 million, a 99 percent confidence level, again
continue in the targeted high-risk population. But you need to decide
what question you want to answer, and then you decide how you\'re going
to do it.

DR. NELSON: Well, it seems to me that once you have found that the rates
are higher than one in a million in the one downer cattle that has been
detected, then you have got to readjust and find out what now are you
going to do. And, you know, after blood donors were found to be HIV
positive, they decided to test them all, and I can\'t see any real
difference here between particularly edible products and BSE testing of
cattle.

CHAIR PRIOLA: Dr. Bailar?

DR. BAILAR: Well, this brings me to something about which I have had a
growing concern over a couple of meetings, and especially the last two
days, which is the strength and reliability of the many risk assessments
that we have heard about. This is, fortunately, an uncommon condition
here, so we don\'t have a lot of positive data, but we do have a fair
amount of reliable laboratory data and more on the way.

But overall, as an old-time risk assessor in other contexts, I am very
deeply troubled by the fact that we really don\'t know what the risks
are. We see risk assessments. We have seen some here that are presented
with an air of some authority and go to two or three decimal places. I
am not sure that any of the ones we have seen here are correct within a
couple of orders of magnitude.

There are too many unknowns, uncertainties in the risk assessments, and
I think it would be useful for FDA to make a major effort to improve the
database to identify the uncertainties in each of the risk assessments,
see how much slack there is in them, and try to come out with not a
single figure, but with a plausible range of risks, because at our
present state of knowledge, I think that\'s the best we could possibly
do. The risks may be much greater than we think. They may be much
smaller. I have no way to tell.

CHAIR PRIOLA: Dr. DeArmond?

DR. DEARMOND: Yes. Following up on that, I think what has been learned ?
since at least it became newsworthy on December 23^rd^ ? that somehow
there is a BSE cow in the United States, the confidence level of what
has been done dropped dramatically. First of all, that there was one
here, that it snuck in from Canada that we learned a couple of days
later, but also that now there is huge numbers of cows that have been
coming in, and that the only criterion so far for testing is that they
are downers.

So we have missed probably many of them. We don\'t even know. I think
the confidence level dropped that I have had, is we have no idea now,
and that the sentinel one says we don\'t know an awful lot about what\'s
going on.

CHAIR PRIOLA: Dr. Gambetti?

DR. GAMBETTI: Yes. I agree, I agree with what was also said yesterday. I
just really cannot resist the temptation to add something or repeat
myself again. European countries went through the same procedure,
decision process. They always had to \-- they had to deal exactly with
the same problem, so we don\'t have to reinvent the wheel. They have
done it already and they make a decision.

The least I think we can do is analyze what led them to that decision.
You know, the European, at the time, if I remember correctly, at the
time it was decided to test animal above 30 months of age, some of the
countries were, essentially, BSE immune. But once they started testing,
those countries also found a certain number of cases. So I really urge
all of us to analyze the data and see whether really, on the basis of
what the data tells us, whether really we should adopt this same
procedure.

DR. FERGUSON: Actually, I think that\'s a good point, to analyze the
European data and to talk with the Europeans in regards to their
experience, specifically in testing the clinically normal animals over a
certain age. They took that decision to include that population in their
testing for consumer confidence reasons, essentially, and they sold that
decision for consumer confidence reasons.

I think if you look at the data, you know, that\'s not where they are
finding disease. I think their percentage of positives in the clinically
normal population is .003 percent. And if you speak with them, you know,
most of the European regulators and the experts, you ask them if they
would back off of that decision, most of them would back off of that
decision. And I think some of that is shown in the report that we got
from the International Review Team, is, you know, testing clinically
normal animals at slaughter is not scientifically justified.

I think they would all agree that a targeted surveillance program, you
know, looking in your highest risk population if you\'re wanting to find
the disease, that\'s the way to do it. And, you know, that\'s one of the
things, again, in 2000, 2001, it wasn\'t just that they said test
clinically normal animals. It\'s that they said okay, we\'re also going
to test the targeted high-risk animals that they hadn\'t necessarily
been testing before.

CHAIR PRIOLA: Dr. DeArmond?

DR. DEARMOND: Well, there is something in that statement that I find
difficult. Certainly, consumer confidence is a very important aspect,
and we have to acknowledge that, because, even myself as a consumer, I
don\'t want to eat contaminated beef and I certainly don\'t want my kids
to. If I eat it, it doesn\'t matter. The incubation time is going to be
longer than my life.

But that is a very important part. And then if the other idea is
testing, because they don\'t want to identify it, they have identified a
low level, but they have already been listed now as on the more
endangered, they have a problem in their country, so people aren\'t
going to buy their beef as they used to. And I sometimes wonder in the
United States whether we\'re not doing that. We don\'t want to find any
problem here, even if it\'s .1 percent, because people will then list us
as a Class III or IV country, in terms of beef. But that is contrary to
science.

I think the science is to look and to get data. We don\'t have data,
which you want to analyze data. We have no data. We have one cow, and a
lot of possibilities that there are more of them because of the
uncertainty, and we need to analyze data. We need to get more. To
analyze data, we have to have data to analyze. So we have to test more.

CHAIR PRIOLA: Dr. Wolfe?

DR. WOLFE: We already have lost, not a large chunk, but at least a
number of countries, just because of this cow are not buying U.S. beef
and it isn\'t that they aren\'t buying downer cows or dead cows anymore.
They are not buying healthy cows, and I just think ? I agree with both
what Pierluigi is saying and what you\'re saying, Steve, is that not to
do any testing at all in normal animals, whether it is a combination of
consumer confidence, both consumers in this country and consumers in
these other countries, doesn\'t make an awful lot of sense.

Within the scope of Europe, there are, at one end of the spectrum, the
United Kingdom where they had a huge number of cow cases and human
cases, but the other end of the spectrum includes European countries
that are much more like the United States, where they had one human case
and it didn\'t even arguably come from that country, or they had one
that did come from the country.

So I think that if one looked at all of the policies there, and they
differ, even though there is a EU, they have different policies, that we
might find something that is instructive and, you know, we could maybe
modify something. But I think not to look \-- you know, I\'m sure that
some of them may be sorry for what they did, but maybe it\'s only in
retrospect. You can\'t, in the absence of data, make a decision saying
well, if it comes out this way, I\'ll be glad and if it comes out this
way, it won\'t be good. That is not a scientific approach to this
problem.

CHAIR PRIOLA: Mr. Bias?

MR. BIAS: I guess I\'m the guy without any letters after my name that is
just looking at it from a consumer perspective. One of the things I see
is we need to decide whether we\'re regulating the beef industry or
whether we\'re enabling the beef industry, and I realize that these
changes will be costly and I think that they will be very difficult for
the industry to adapt to, but over time they will, just as the blood
industry had to adapt when HIV hit the market.

Now, in retrospect, which is always 20/20, you could say if we had
implemented certain blood tests early on in the HIV crisis, they would
have been very costly to our system, but they probably would have saved
us billions of dollars in health care costs, in hindsight, and lots of
lives.

So I would urge everyone to take a new look at this. This industry will
survive whatever changes are imposed on them. That is what capitalism is
about. They will adjust. It will take them time. It will be painful. It
will be costly, but as the Federal Government, we can\'t enable them,
when it\'s the safety of the American population\'s health that\'s at
stake.

We have to make certain decisions, and it will take them some time to
make these adjustments. And in some cases, it will be costly, and in
some cases, we\'ll have to help them make these adjustments. But if we
say that, you know, brains and spinal have to be removed and sent to a
different place, and the rancher says well, I\'m not going to pick that
up, well, they are out of business. That\'s the way life works.

It\'s, you know, sort of we have to make a decision about which side of
this coin we\'re going to be on. And right now, just on the information
that was provided for us yesterday, I\'m not feeling a lot of
confidence, and I think many of the other members of the Committee
aren\'t feeling that confidence either.

So before we make a mistake, maybe we ought to plod it out and start it
slowly, and maybe we ought to give them the benefit of the doubt, give
them the opportunity to make some changes, but let\'s go forward. Let\'s
not go backwards. Let\'s not stop ourselves with speculation. Let\'s
figure out what it is.

CHAIR PRIOLA: Dr. Creekmore?

DR. CREEKMORE: I guess I would put out there that testing is important
and it\'s a part of the equation, but all of us have some knowledge
about how tests work, and we know that testing will detect animals at a
certain point in the disease process through the clinical course. But,
you know, testing isn\'t something that is the magical bullet that is
going to detect every animal.

And I guess I would ask the public health professionals out there, you
know, how do you view the other safeguards that were put into place, in
terms of the things that are really, truly protecting human health? You
know, from the animal health side, the SRM, the new SRM Rules, the feed
ban are the really critical components to me to protecting animal
health.

CHAIR PRIOLA: Dr. Bracey?

DR. BRACEY: Again, thinking about this from the perspective of the blood
industry, when we are given a risk, perhaps sometimes even a theoretical
risk, we consider the test, but if we are told that the risk is at the
level of about one in a million, which is what we have heard from some
of the projections, which may be off, and there is a test, then, in
fact, we do offer that test.

I am somewhat concerned about, as has been voiced before, in essence, a
double standard. That is, we\'re very concerned about what we\'re going
to give intravenously, but for some reason or another we\'re not equally
as concerned about what we\'re going to consume by the oral route. I
mean, to me it\'s just a double standard, and I could not defend having
such a double standard.

The other point is that in terms of looking at only the sickest animals,
although the window may be short, you know, we have been looking for
emerging diseases, and if we test only the sickest animal, we\'ll see it
too late. Maybe it won\'t show at 12 months, but we have heard that
already it\'s shown at 20 months for some animals.

So again, I think that having these cutoffs are somewhat arbitrary, and
I would propose that we consider looking for emerging disease, rather
than disease after it\'s manifested.

CHAIR PRIOLA: Dr. Bailar?

DR. BAILAR: Other parts of FDA do regulate on a basis of lifetime risk
of one in a million. Is that an option here?

CHAIR PRIOLA: What do you mean by an option?

DR. BAILAR: Well, I know a little bit about how they regulate possible
carcinogens in food, for example, and the standard there is, at least it
used to be, a lifetime risk of one in a million. In this context, is
there a possibility of regulating on the basis of a lifetime risk of one
in a million? I don\'t know.

CHAIR PRIOLA: Dr. Jenny?

DR. JENNY: Are you saying one in a million people being infected?

DR. BAILAR: Right. I\'m talking about human risk, over a 70 year life
span, of one in a million.

CHAIR PRIOLA: Well, I think in some ways with the blood deferrals that
have been put into place over the last seven years, that\'s what they
are doing. They are actually putting forth recommendations based on a
theoretical risk that\'s significantly less than what you just said. So
they are able to do that, in that regard. Dr. Nelson?

DR. NELSON: Well, I think we probably have a fair handle on
transfusion-transmitted CJD, but I don\'t think we have a very good
handle on vaccine-transmitted CJD or other biological, other products. I
mean, I don\'t know how we would identify a case unless we had a huge
cluster of cases that somehow were related to a product, an injectable
product, or a food. I mean, we might see, because I think the risk is
probably fairly low, and, you know, the risk of \-- well if we found
variant CJD, I suppose we would go back and look, but I think it would
be difficult to know.

CHAIR PRIOLA: Dr. Johnson, did you have something to add? Oh, did you
want to finish?

DR. JOHNSON: I would have to say that the risk of \--

CHAIR PRIOLA: Well, hang on just a minute. Dr. Bailar had one more
comment, then I\'ll give it back to you. Sorry.

DR. BAILAR: I have a related question, again, from ignorance. In
devising new regulations, is the focus at FDA on the best estimate of
risk, on the highest plausible level, maybe an upward 95 percent
confidence bound, the lowest plausible level or what?

CHAIR PRIOLA: Well, someone from FDA would have to answer that. I know
we\'re not advising in that regard, but perhaps you could give us the
information.

DR. MIDTHUN: Karen Midthun, Acting Deputy Director for Center for
Biologics. I mean, obviously, this is a question that impacts on a
number of centers at FDA. I think that we look at all those factors when
you come out with a regulation if that\'s what we\'re to do, you know,
to assess, you know, what are we trying to \-- what\'s our goal here.
And I think, in general, you do try to, you know, limit the risk, but
within, you know, what\'s feasible and also within what\'s known.

DR. NELSON: I think, you know, BPAC, we have been \-- I mean, as close
to zero as possible. There is no guideline of one in a million or
anything. We have recommended procedures, you know, where the risk is
probably one in a million. I think that there isn\'t any magic figure
over which you accept a certain risk. I don\'t think that, you know. And
applied to this debate, it becomes interesting.

DR. BAILAR: I don\'t have any particular difficulty with the notion of
accepting a small risk as long as we know what the risk is and make the
rational decision that the benefits of accepting it outweigh the risk
and the costs of it. But the situation I see now is that we really
don\'t have a good idea of what the risks are of any of these things.

CHAIR PRIOLA: Dr. Johnson?

DR. JOHNSON: Yes, I would agree with that. We don\'t know. We do know
that we all do have a risk and it\'s one per 100,000 per lifetime,
about, or about that number. And do we know anything that absolutely
increases that? Yes, living in England between 1980 and 1996 does and
we\'re not even sure it\'s eating meat.

It may be exposed to rendering product by some other method. All you can
say is living in England during that period does it. Getting a dura
graft does it, having pituitary hormone does it, and we\'re pretty much
in the dark beyond that. So I find it very difficult to know how to say
we don\'t know that blood transfusion increases the risk at all. I mean,
there is one case and that\'s only in England. So I think it would be
very hard to come down to a number. I don\'t know how we would do that.

CHAIR PRIOLA: Dr. DeArmond?

DR. DEARMOND: Yes. I don\'t want to sound like a broken record here, but
our problem is we have no data. We don\'t. We can\'t make a risk
assessment, at this stage, and the events over the last couple of months
have told us that we really don\'t know, and we don\'t know how many of
these animals that are killed before they are downers for all the
variety of products that are derived from them might have the disorder.
We have no idea. Just looking at downers doesn\'t tell us about the ones
that don\'t get that far.

And it\'s not just for our food, because it impacts the blood industry.
It impacts the pharmaceutical industry. There is a lot of cost to all of
this. And are we going to have a stage where we say that people living
in the United States from 2000 to 2003 can\'t donate blood, because we
don\'t know what the risk is, but there probably was a risk then?

So we really need to know this and we need to know where it is, where
it\'s located. We have to know some sense of whether we can contain it
and whether we could stop it, and we don\'t even know the origin of the
risk, because we don\'t have any data. It\'s possible that with some
data over the next couple years, we could stop the whole thing.

CHAIR PRIOLA: Dr. Wolfe?

DR. WOLFE: I would just like to go back briefly to what I was saying
before, is that in the absence of any human case of blood transfusion,
in the absence, at that time, of even any animal transfusion, the
intracerebral injections were the main known animal transfusion, but
back three, four years ago, there weren\'t any animal-to-animal, you
know, cheap and whatever transfusions.

The Committee made a very wise decision, a very cautious one, saying if
you have been in that country or those countries during that period of
time, it doesn\'t make sense to allow you to be a blood donor. And
similarly, a lot of the decisions made in Europe were made in countries
after they had or when they started having or slightly before they
started having human cases.

And, you know, there is obviously something to be said for the idea that
a repository of infectious prions at some threshold is necessary before
you get a human case. We don\'t have any human cases in this country, so
we have no data on human cases, and we have no data. I mean, at this
point, technically, there has never been a cow in the United States,
indigenous U.S. cow, that has been infected, but it is largely, as
Pierluigi had said several times and Steve has agreed, we haven\'t
looked ever at anything other than those kinds of cows.

So I think that the charge that we are given, namely to advise FDA on
blood products, and this we can say, thus far, you seem to be moving in
the right direction to tighten up and reduce the chance via a whole
bunch of different ways and some new ones that we heard about today.
Given that we have no idea, for example, I mean, let\'s assume that in
New Zealand and Australia where they have done some testing, they have
never found a cow. In the United States and Canada, we have, you know,
three cows now, one came here, two were still up there.

I just don\'t know, and I\'m just reflecting in a slightly different way
what other people have said, how we can be asked based on no
information, there is no human risk data, there is no animal risk data,
how we can go terribly beyond what we have and look at these processes
and say yes, that looks like it will make this product slightly safer or
that much safer.

I mean, in my optimism, even though I am accused of being a pessimist,
we do have from the data from the U.K. and elsewhere, this is a bolus of
infected material that seems to be moving out of the world. How quickly
it moves out of the world, we don\'t know. And certainly, there will be
more human cases. Whether there will ever be a human case in this
country, we don\'t know.

So just to summarize all of that, I just think that in the absence of
any information about human risk or animal risk in this country, and
we\'re talking about sourcing that is more from this country than
elsewhere, we have already dealt with some of these sourcing problems
for gel, for instance, from Germany and other countries that actually
have BSE, I just think we can \-- and I suppose that\'s why we were
wisely not asked to vote on anything, because I don\'t think we could
vote on anything. All we can say is keep moving in a better direction.

And again, to reemphasize what other people have, pay a lot of attention
to the tracing and the feed ban related to that or downwind from that or
down the line from that, the testing. Think about doing some testing of
normal cows. I think that\'s the main advice we can give. I just can\'t
imagine it isn\'t to discriminate between blood and blood products and
vaccines and biologics or, I mean, the only one that\'s relatively easy
is the food one. I just think that isn\'t even worth discussing at all.

So, I mean, that\'s my views and I don\'t know. I would like to know
what other people think about that.

CHAIR PRIOLA: Dr. Nemo?

DR. NEMO: You know, I think the question has been framed. I think we
want to know what the magnitude of the problem is. What\'s the magnitude
of the problem? Now, I don\'t think that it is necessary to test the
entire country, but it is going to require some testing and some serious
testing. And you go to the source. You look for the BSE. And I think we
have units in place to look at human cases. Dr. Gambetti and Stanley
Prusiner is getting every brain he can get his hands on, and he looks at
it. So we have \--

DR. WOLFE: Steve is getting the brains.

DR. NEMO: Okay. Okay. Steve, excuse me. Excuse me, Steve gets them. And
so I think the question is how much do we test? I mean, that\'s what we
want to do and why are you doing it? The USDA asks, because we want to
know how big of a problem this is.

CHAIR PRIOLA: Dr. DeArmond?

DR. DEARMOND: Just to follow-up on your cite. I am not a pessimist,
either, although every time I come to this Committee, I seem to be. You
sound better when you say it though. I feel that the positive side is we
can\'t do anything until we know. It\'s like building a rocket ship. You
have to have all the data. You have to know what the extent of the
problem is and we don\'t know that and so we can\'t even start to solve
the problem at this stage. And maybe there is no problem.

CHAIR PRIOLA: Dr. Bailar?

DR. BAILAR: Just as a reminder, I would like to put on the record that
if FDA does go to an expanded sampling plan, as I think most or all of
us hope they will \--

DR. WOLFE: USDA.

DR. BAILAR: Or USDA, that it must be on the basis of a sound sampling
plan. Sampling randomly is not the same as haphazard and there has to be
a proper randomization, some kind of a randomizing mechanism to make
sure that you get a really representative collection of animals for
testing.

CHAIR PRIOLA: I want to make a quick response to something that Dr.
DeArmond just said, and that was that you can\'t do anything until you
know. And, in fact, this Committee has done that in the past with the
blood and currently the FDA has done it and we have advised them to do
it in terms of these risk materials entering into the human food chain
or the medical product chains, so we can do that based on theoretical
risk. And it is theoretical because we don\'t know.

One thing that I\'m sitting here wondering is, let\'s say, from the
USDA\'s point of view, which is not our purview here, obviously, but
from the USDA point of view, they do decide okay, we\'re going to test
every animal. Does it change the way I\'m thinking? If there is one
positive BSE cow in the U.S., we\'re going to try to take steps to
protect the food chain, the medical product chain, the manufacturing
chain.

If there is 100, we\'re still going to take the same steps. I don\'t
know how we can change the basic steps we\'re going to take. Does it
change my basic thinking in what we should do? I don\'t think it does.
But it is important scientific data to have, but I\'m not sure that it
is essential for absolutely everything we\'re discussing.

DR. WOLFE: You were first.

CHAIR PRIOLA: Yes.

DR. DEARMOND: Well, I think though if you know that there is 100 and you
know that there is a common source of them, you can stop the source. If
you know there is 100 and there is a feed problem, you can stop the feed
problem. We don\'t know where this is coming from or whether there is
something festering in the United States, at this stage. So the numbers
do tell us something and their location and which herds and what they
have been eating. There are a lot of reasons, a lot of things to be
learned by getting numbers. And again, maybe there is only one and we
don\'t have to worry at all, but we don\'t even know that answer.

CHAIR PRIOLA: Well, but we are worried about just the one.

DR. WOLFE: Sure.

CHAIR PRIOLA: Yes. Dr. Wolfe?

DR. WOLFE: Well, it would matter greatly as to sourcing, for example.
Now, right now, we are assuming that it is okay to source in the United
States, because this cow was a Canadian cow. And it may turn out after
some testing, whatever it is, what random percent of over 30 month cows
is tested that it turns out there are no cows found. It may turn out
that there are 5 or 10.

But all I\'m saying is if really any of them turn out and in a way it
doesn\'t make a difference whether it is 2 or 5 or 100, we will no
longer be a BSE-free country. And the fear of becoming that is not a
justification for not doing testing. It works both ways. I mean, this
may seem like a digression, but it isn\'t. I was asked by the College of
American Pathologists to give a talk at a meeting that they had about
eight years ago on autopsy. And one of the arguments that had been made
for the decrease, and this was alluded to yesterday, the autopsy rate
was 45 percent in this country after the second World War. It is about 7
percent now.

One of the arguments that was made was that hospitals were afraid of
being sued because if they did autopsies, they might find something that
went against them, and it was someone from a medical malpractice
insurance company, St. Paul\'s who is no longer doing this, said, you
know, if you look, it goes both ways. In as many cases, the findings
will exonerate the hospital or the doctor from any kind of blame as they
will to point the finger in that direction.

So I think that testing, which I think is analogous to doing an autopsy
in a way, literally it is at some level, it can go both ways. I mean,
for those countries that have stopped buying American beef, if they are
assured based on testing that we actually don\'t have cows, that\'s a
plus. If, on the other hand, we find some, then we can\'t keep
pretending that we are a BSE-free country. So at that level, it does
make a difference whether we find any or not, because right now it\'s
none, literally. I mean, the Canadian cow is a Canadian cow.

CHAIR PRIOLA: Dr. Khabbaz?

DR. KHABBAZ: Yes. You know, I think as a Committee we probably can and
have pride in serving, in the back, in terms of actions already
recommended and taken to mitigate a theoretical risk. And I think we
need to commend the FDA and the USDA in terms of their response to the
one cow that we found and actions taken. I think what we have on the
table now with regard to all of these products and how much more should
we do or do we need to do? And really to answer that is critically
linked and I\'m disagreeing with you, Suzette, to surveillance.

I mean, we have discussed for the past two days surveillance. And what
are the goals of surveillance? Well, surveillance estimates the
prevalence of a condition and allows you to monitor the success of
prevention and control programs. And where this surveillance that
wasn\'t existent, because, you know, it allowed recognition of the test
and one can argue how, you know, what the estimates, the confidence
estimates around it are, we found a cow.

But now the question is what is the magnitude of the problem? And I
think what I\'ve heard us say and, you know, what has been said outside
of here is that, you know, do we have enough of a confidence, you know,
in the surveillance as is or as was to determine with certainty the
magnitude of the problem, and I\'m hearing us say is that probably not.
It probably needs to be improved. Now, not to the extent of testing
every cow, but targeting populations at risk and groups at risk and I
think there is a number of ways that that can be done.

But to find the magnitude of the problem is essential to address the
question of how much more do we do and how much more should we do. And I
want to get back as well to something that came up yesterday, which is
the feed bans. And I think the bans with regard to the human side are
great. But we do have the potential of mix up and lots of other things
really are to the animal feeds. And I think there are other ways,
perhaps, to address that. But that is what needs to be at the table in
terms of things that we can do to, you know, strengthen the basis of our
level of confidence in terms of everything that we\'re discussing today.

CHAIR PRIOLA: Dr. Bailar?

DR. BAILAR: I would just like to emphasize that the need for an expanded
testing program is very closely linked to the need for identification of
individual animals, sort of a lifetime history of ownership and place
of, what you would call, residence. The ideas that when you find a
problem in the testing, then you should be able to trace it back to the
place of origin to see what might have gone wrong and whether it is
fixable.

So that the tested animal is, in a sense, representing not just a random
sample from the U.S. herd as a whole, but representing a particular
collection, small collection of animals somewhere that might have
additional problems. I think this is done in a way already, but I would
like to see it made more formal, including this link between animal
identification and testing.

CHAIR PRIOLA: Dr. Johnson?

DR. JOHNSON: Yes, I would like to. I think everybody here seems to agree
that we have to do more testing. But on a different subject and one that
I haven\'t really heard before today, and I thought it is worth
discussing, and that is with the idea of biologics and vaccines and
bovine serum and so forth. It seems to me the idea of sort of moving to
Australia is not the solution, because I happen to be one of the people
who believes that this occurs spontaneously in cows like it does in
humans, and that Australia will have a case eventually just like we\'ll
have more cases.

So that maybe what we really ought to do, which seems to be more
reasonable, would be to look into these negligible risk herds, which I
never really heard or thought about before, and I\'m sure there aren\'t
enough of them, like everybody agrees, but we don\'t know how many there
are. We don\'t know how many of them are pure like the ones that Bob
told us about or how many of them are sort of a mixed bag like the ones
that are run by, what\'s the grocery store chain?

DR. WOLFE: Whole Foods.

DR. JOHNSON: Whatever they are. The place where Sid shops.

DR. WOLFE: That\'s very personal.

DR. JOHNSON: And that proves he is a pessimist.

DR. WOLFE: They have very good stuff there.

DR. JOHNSON: Yes, I buy my beef at Giant. Anyway, I think that it would
be \-- what we could do is if we can have some idea of how many of these
sort of herds there are and how much there is and how difficult that
would be to expand, and then which products are really at greatest risk,
whether it is the serum and vaccine or whatever it is and then you could
sort of have a list of the agents and a list of these. You could really
see how this might \-- how you might pattern, what more you need to do.
What you would have to do.

It seems to me it would be good to start on this now to get ahead of the
game, because this may be a direction we have to. This may be a
direction we\'re forced to go in the future and it would be hard to
start from a total \-- get started from a total stop position, I think.
So I think the FDA should start looking at that as a potential option
and backup at the present time, starting now.

CHAIR PRIOLA: Dr. DeArmond?

DR. DEARMOND: Well, after Dick\'s lucid production there, I don\'t know
what I have to say. But I just wanted to follow-up again on some of our
\-- one of the reasons we are, at least I am, a little less confident is
that over the last 10 years, what is it, about almost 20 million head of
cattle have come into the United States from Canada, and I don\'t know
how many tons of feed have come from other places.

And a lot of the \-- and then I understand all the downers are ground up
or at least the dead ones are ground up and then they can go into feeds
for chickens. Is that right? But then the chicken feed, farmers being
very frugal, will buy that and give it to their cows. So it is getting
very confusing and there is a lot of opportunities in there to generate
BSE in the United States. And, again, that\'s why the need for more
data. But we also need to stop some of these things. If we can really
identify how prevalent chicken feed to cows is, that would be
interesting to know also.

CHAIR PRIOLA: Okay. I feel that I should clarify that I was not against
surveillance, continued surveillance for BSE and variant CJD in the U.S.
I guess I was just trying to look at it from the opposite point of view,
which is that surveillance is absolutely essential for sourcing issues,
as everyone has rightfully pointed out. Are the stop gaps after that? So
the prohibitions on the high-risk materials being incorporated into
products that can be injectable or ingestible into humans, the blood
supply deferrals, are those a sufficient stop gap in the presence of one
cow or 100 or 1,000 BSE cows?

Are they still a sufficient stop gap no matter how many animals you
detect by surveillance? I guess that\'s my point. Because there is
another potential, they are designed to protect the public at a later
stage than the source and material, their recommendations for TSE
clearance and manufacturing are specifically targeted towards that. So
that\'s what I was just trying to get at to see what other people had,
the opinions of the other members of the Committee. Dr. DeArmond?

DR. DEARMOND: Yes.

CHAIR PRIOLA: Thank you. That was good. That was the shortest answer
today. Dr. Nemo?

DR. NEMO: Yes, I think we\'re pretty much at our limit what we could do
with the blood supply based on what we heard today from Dr. Williams
that we are really pushing the envelope as far as availability is
concerned, and I don\'t see any added benefit of adding a new regulation
or restriction or broaden the deferral, at this point.

CHAIR PRIOLA: Mr. Bias?

MR. BIAS: I would again suggest, a suggestion that I made yesterday,
that there be a more formalized relationship between the agencies
regulating who have jurisdiction. We do that for the blood supply and it
has worked very effectively to have the heads of those agencies meet and
discuss this as an ongoing issue, and I would suggest that here. If you
have got four different agencies working at a problem, even if they are
cooperative and they like each other, you have a greater chance that
something is going to be missed. I would just suggest that they
formalize that relationship, that that group be given a charge and then
move forward from there.

CHAIR PRIOLA: Dr. Johnson?

DR. JOHNSON: I have a question, because I think we all agree that it
would be nice to take brain out of material where it is not listed as
being brain or not obvious that it is brain you are buying and eating.
And I was just wondering if because of the Congressional Bill which
unleashed the nutritional supplements, is FDA going to have to prove
deaths from eating brain before brain can be taken out of nutritional
supplements? Because that was what would happen with the ephedra. You
had to show 100 deaths or something.

CHAIR PRIOLA: Dr. Wolfe?

DR. JOHNSON: Sid would know that.

CHAIR PRIOLA: Yes. Dr. Asher probably has some comments.

DR. WOLFE: The law, the Dietary Supplement Health and Education Act of
1994, gives FDA the authority to ban something if two conditions are
met: (A) It poses an unreasonable risk of harm; and (B) If it is used as
recommended. So initially for several years, the FDA claimed that that
authority didn\'t enable them to ban ephedra, which we asked them to ban
two and a half years ago, and they finally agreed that it could be
banned using that standard.

I would suppose that given the virtual impossibility of finding out the
source of brain that one could easily say that ingesting a dose of brain
that is arguably much larger than that needed to cause an infection
could post to \-- you know, be viewed as posing an unreasonable risk of
harm. So, you know, we have certainly pursued that since that little
lower right hand corner of Dr. Potter\'s diagram is sort of
inflammatory.

CHAIR PRIOLA: Dr. Asher, do you have a comment?

DR. ASHER: In response to Val Bias\' suggestion, I just wanted to point
out that there is a coordinating committee at the level of the
Department of Agriculture and the Department of Health and Human
Services represented by upper management from the FDA, and I believe the
NIH. Lisa may have attended that. I mean, I cannot comment on how
effectively it works, but the need for such a coordinating body has been
recognized by both USDA and FDA and Secretary Thompson\'s Office.

DR. JOHNSON: I don\'t think they would deal with this kind of an issue
though. I mean, if we\'re talking about the issue of banning raw brain
in nutrient supplements, as an irrational thing to do, which is
potentially dangerous, the interagency committee is not going to deal
with that.

DR. FERGUSON: Can I jump in and just say yes, it has, because, I mean,
we have had longstanding interagency committees, both at the policy
level, at the technical level, at whatever level you choose. They have
existed and they have worked very well, you know, in response to the
Canadian case in May. There were many discussions amongst the agencies,
because of the impact, and none of us can do anything in a vacuum.

We can\'t make our own decisions on our own. We well recognize that that
whatever decision we make at APHIS impacts what FSIS does and it impacts
what FDA does. I mean, at least, within USDA, we have APHIS and FSIS
under the same department. But, you know, that\'s exactly the type of
things that those policy groups, at all the levels, have dealt with. You
know, we get together at all levels to say, hey, these are the regs that
we\'re going to propose. Do you guys agree? Do you disagree? How is it
going to impact you? You know, here is your draft. Where do we go from
here?

DR. JOHNSON: That doesn\'t happen on the one I sit on with for NIH.

CHAIR PRIOLA: Other comments from the Committee? Any comments as to the
potential BSE variant CJD contamination of vaccine related products,
which was a subject brought up by Dr. Egan? Dr. Wolfe?

DR. WOLFE: Well, just that the elegant study from your lab and the
conclusions of this study, namely that it will flourish in fibroblasts
begs, as someone said this morning, that you got to look at the other
cell lines that are used for making vaccines and check out whether they
are susceptible as well and make decisions as to what is done in the
future about vaccines, and that\'s an obvious research follow-up to this
study that you all did.

CHAIR PRIOLA: Thank you, first of all, for the compliment. Any other
comments? I want to make sure that the Committee has aired all of its
views and concerns, that the FDA has heard most of what it needs to
hear. I mean, it\'s apparent that there is a great reluctance to give
any sort of definite, I don\'t want to say recommendations, but discuss
any definite changes to what is currently in place because of the
testing issue that everyone is very concerned with the surveillance
issue.

DR. WOLFE: Just two seconds. I mean, I think there is a great
reluctance. On the other side, FDA did not ask us any specific
questions, which is, I think, the first meeting we have had and I think
that it goes both ways. I think there is some appreciation for why no
questions were asked and why we can\'t answer them.

CHAIR PRIOLA: And I think that\'s true. The FDA, yes, acknowledges that
it is an ongoing situation that requires more data. And, yes, that\'s
why the lack of questions. They are very interested in the discussion,
though, which is why I\'m, you know, making sure everyone has commented
themself. Dr. Bailar?

DR. BAILAR: I have a question that would help me in my own quantitating
thinking. What is the price elasticity of beef? If the price goes up 1
percent, what happens to purchases? Does anybody know? Does it go down
by 1 percent or .25 of a percent of 5 percent?

CHAIR PRIOLA: Any of the USDA people want to tackle that one?

DR. FERGUSON: We let our economists deal with that.

DR. WOLFE: Any beef industry people in the audience quietly sitting
there?

DR. BAILAR: It seems to me this will be one critical input to decisions
about any new steps that are reasonably costly, like a major expansion
of testing.

DR. WOLFE: The flip side of that is that there has already been a
measurable mass of loss of money to this industry, and I have to say
it\'s probably because we haven\'t tested at all and we therefore can\'t
assure them of anything at all. So that is already a factor that has
gone into affect without having even made sort of the downside of not
having tested as opposed to the benefits.

CHAIR PRIOLA: Dr. DeArmond?

DR. DEARMOND: I was going to say the same thing, but then in simple
calculations of the cost per pound of beef, Stan Prusiner says .2 cents
a pound increase. And if you look at a saleable amount of beef for food
products now is around 500 pounds out of a cow.

DR. NELSON: Is this testing every cow? Is that what you are saying?

DR. DEARMOND: Yes. Say for a cow that is tested, you get 500 pounds.

DR. WOLFE: Using his test or using which one?

DR. DEARMOND: No, all of the tests are running about the same. And he
says he could come in under that.

DR. WOLFE: This is the \"under that\" price.

DR. DEARMOND: Yes. So say it is 500 pounds and it is \$30 a test, well,
say \$20, that\'s how much, how many cents? It comes out at about .4
cents or less. So it\'s not a huge amount.

DR. GAMBETTI: It\'s that already, because I read .3 cents.

DR. WOLFE: There you go.

CHAIR PRIOLA: Dr. Nelson, do you have a comment or Dr. Bracey?

DR. BRACEY: Yes. There was one topic that you brought up that we
haven\'t covered. And earlier yesterday, my thinking was that perhaps
leukocyte reduction would offer a reasonable benefit. But, in fact, I
think that after really considering the data, there still would be
enough transmission that it would be more a matter of perception than
actual significant risk reduction. So I think as a Committee, we should
make some sort of a statement in terms of whether or not we would want
to recommend mandating a universal leukocyte reduction. And based upon
what I heard yesterday, I\'m not sure I would be at that point.

DR. NELSON: I think BPAC has already discussed this issue and has
recommended it, but not based on the CJD risk. Based on HLA
sensitization and post-operative fever and other things, we specifically
weren\'t supposed to discuss the CJD risk, but it looks like, you know,
it ain\'t perfect, but it looks like it may help a little bit. And given
that the risk may not be high, we\'ve found one case so far, then maybe
a 50 percent reduction would be significant. It\'s hard to know.

CHAIR PRIOLA: Yes, and I think it gets back to the issue of threshold
level of infectivity that Dr. Brown brought up that the 50 percent may
very well be a big chunk of that or all of it. Any other comments?

DR. ROHWER: This is Dr. Rohwer.

CHAIR PRIOLA: Oh, I\'m sorry.

DR. WOLFE: He doesn\'t like to speak.

CHAIR PRIOLA: Dr. Rohwer?

DR. ROHWER: Yes, no. Just to clarify, I think that in any measure that
is taken to remove the infectivity from blood, you\'re going to have to
start with leukocyte reduction. There is two quite different physical
states of the infectivity in blood. One is cell-associated and one
isn\'t. You\'re going to have to get rid of those cells first before you
can tackle the problem of removing the non-cell-associated infectivity.
So it is a \-- I think the way I put it was I see it as a necessary, but
not sufficient step in the process of solving this problem.

CHAIR PRIOLA: Bob, before you sit down, can I ask you a question? I
thought of this yesterday while you were talking. It gets to the soluble
PrPsc or infectivity that you see in the blood versus the
cell-associated. What is that based on? You said, you know, the nature
of the agent.

DR. ROHWER: You mean the solubility?

CHAIR PRIOLA: Yes, it might be different in blood.

DR. ROHWER: Well, I guess, it\'s more accurately called
plasma-associated and it remains stably in the plasma in the absence of
cells with which it could be associated. So it\'s non-cell-associated.

CHAIR PRIOLA: Thank you.

DR. NELSON: I\'ve heard incidentally that there will be a substantial
cost to a unit of blood by filtration, but it was felt to be justified.

DR. BRACEY: Yes, well, I think that considering again the fact that, I
guess, at this point, probably the majority of the country is using
leukocyte reduced blood. Well, at least 50 percent of it.

DR. NELSON: I think all of the Red Cross blood is leukocyte reduced.

DR. BRACEY: Yes. Yes, they are. The figures I have heard are anywhere
from 50 to 55 percent. I think that hearing the information then perhaps
we should take a stand or make a recommendation for a universal
leukoreduction.

CHAIR PRIOLA: Dr. Linden?

DR. LINDEN: Well, two comments. In that regard, I don\'t know if Dr.
Page can comment on that. I\'m not sure that is true for platelet
concentrates necessarily.

DR. PAGE: Peter Page, Red Cross National Headquarters. The Red Cross
currently will provide red cells that are leukoreduced or not leukocyte
reduced, based upon what the hospital customer requests. After that
policy was made, we now provide over 90 percent leukoreduced. In the
non-leukoreduced, which is less than 10 percent, that includes
autologous units. So our customers have chosen, basically, to stay with
leukoreduced red cells.

All platelet phoresis products, I believe, in the country are
leukoreduced. As far as platelet concentrates provided from whole blood,
as Dr. Linden asked, Red Cross currently is leukoreducing them all.
That\'s not a requirement, however, of FDA or AABB, so I believe that
there are some non-leukoreduced platelet concentrates that are available
in the United States.

UNIDENTIFIED SPEAKER: Is there a price difference?

DR. PAGE: There is a substantial increase in cost to leukoreduced red
cells and platelet concentrates, yes. And that has basically already
occurred through over 90 percent of the red cells that Red Cross
provides.

DR. LINDEN: I don\'t think that\'s necessarily true though of non-Red
Cross areas. It would not necessarily be as high. But my other question
really relates to the question of is a 50 percent reduction really that
significant and can experts in this really explain that to me, because
for other pathogens, we always talk about log reductions. And, you know,
we\'re expecting many, many logs when we look at, you know, viral
inactivation, for example.

So why is it that we think that a mere 50 percent reduction for prions
would be a significant contributing factor in infectivity? I mean, how
is it that this is different from other pathogens in accumulation or
risk? Can that be explained to me by an expert?

CHAIR PRIOLA: Dr. Rohwer, do you want to address that?

DR. ROHWER: Yes, I\'ll comment on that. Yes, I have the same problem. If
we\'re just looking at plasma and we go from 10 infectious doses per ml
to say 4, 3 or 4, but we are infusing 500 mls of that, we\'ve still got
1,500 units of infectivity or at a 10 percent efficiency of
transmission, maybe 150. By definition an infectious dose is the amount
that is required to initiate an infection, we\'re still going to have an
infection. And that\'s why I made that statement rather casually, I
guess, yesterday, but I did mean it.

It\'s not clear to me whether there is enough benefit in that to merit
leukoreduction on the basis of a 50 percent removal. That doesn\'t
negate what I just said a few minutes ago that I think to have an
effective removal strategy for blood and blood components, you\'re going
to have to have leukoreduction as part of that strategy. That will be
essential. But on its own and by itself, it is something that I think
has to be evaluated very carefully to know what kind of benefit you are
getting from that, and that evaluation depends on exactly how those
products are used and administered and I\'m not an authority on that.

I mean, I\'m working from the assumption that typically you give a full
unit of plasma, and we get the \-- and I\'m making my estimates on that
basis. There may be circumstances under which it is used in smaller
quantities or something like that where a twofold difference could make
an actual \-- could be important. I\'m not sure. But, indeed, what we
are usually looking at is log removals. And we are a long ways away from
that here.

DR. NELSON: Well, a leukoreduced unit still has 10^6^ PBMCs in it. So
it\'s not \-- it ain\'t free of cells.

DR. ROHWER: That\'s true. It\'s not free of cells, but it\'s probably
free of cell-associated infectivity or largely free cell-associated
infectivity, because you\'re starting with 10^9^ going 10^6^ and you\'re
right there at the level. You\'ve removed 1,000 fold or greater of the
cells and you only started with 10^3^ infectious units or 5 times 10^3^
infectious units to begin with, which means that that part that is
cell-associated is probably gone or negligible, at that point.

DR. LINDEN: Yes, wait, Dr. Rohwer, if I could just follow-up, though. Is
it your opinion, speculate your expert opinion that if a donor had, you
know, prionemia as it were, because of variant CJD, and donated a full
unit of blood that current leukoreduction technology would not be
protective of recipients of components. I mean, I hear you saying that
would be an important starting point from manipulation to perhaps plasma
derivatives or other technologies. But that the components would still
likely be infectious. Am I understanding you correctly?

DR. ROHWER: Yes.

DR. LINDEN: I mean, aside from like the Pall next generation filters and
stuff we\'re hearing about.

DR. ROHWER: Right. No, you are understanding me correctly. With this
proviso, I am talking about a simple component separation. Plasma, buffy
coat, red blood cells. Now, a red blood cell concentrate goes \-- you
were expressing some more plasma out of that fraction as being taken
back up and adenine and that kind of thing, and we haven\'t actually
had, though we have prepared those materials, a chance to test them. So
I don\'t know how much actually gets \-- as you move toward platelet
concentrate, platelet-poor plasma, those kinds of things, we haven\'t
made those specific measurements on that material that was fully
leukoreduced in this full scale experiment.

We have on a scale-down process, as part of that Cohn fractionation that
I showed you before, we have looked at some of those fractions, but they
are not \-- that\'s not done in the same rigorous way that this
leukoreduction experiment was done in the sense that it was scaled-down.
It was done in a Sorvall centrifuge. You know, on a smaller scale
instead of in a blood bag. And we have those materials. We would like to
look at them, but they are expensive to titrate, and that\'s the hitch
there.

CHAIR PRIOLA: Dr. Bracey?

DR. BRACEY: Yes, I\'m not sure that we will know the answer any time
soon, but it just strikes me that the BPAC has made the recommendation.
Although some of the initial indications, there have been some trials
that have come up to raise questions about that, there still are
positive studies. There are also other potential benefits such as
problems with alloimmunization for transplant patients, etcetera,
etcetera. There is a large market share that has already moved toward
this.

Great Britain is currently leukocyte reducing. We do know that there has
been transfusion transmission. I guess, you know, I see no real harm for
making a recommendation, aside from economic harm, for this universal
leukocyte reduction. Again, the data are incomplete, but if you look at
it from a risk-benefit assessment, there really is minimal risk, I
think.

CHAIR PRIOLA: Dr. DeArmond?

DR. DEARMOND: It seems like the precautions that are already set in
place are protecting the public for the most part from any vCJD infected
blood getting in, I mean, for the most part. There is going to be
something that will slip through. And as for a 50 percent reduction, it
may work in some people and not in others. So like that\'s getting to
the point where a couple of animals in an animal assay would get sick
and there are lots of factors with humans.

Some humans would be exquisitely sensitive to even a small amount and
others would be resistant. And we don\'t know what the injury state of
the patient is that might get this stuff into the brain, for instance,
and set off the disease. So the human situation is very complicated. You
wouldn\'t be able to predict what even a small dose would do in a human.

CHAIR PRIOLA: Go ahead, Bob.

DR. ROHWER: If I could revisit Dr. Linden\'s question again. Another way
to look at this is that the only thing that we throw away in a component
separation is the buffy code. And unless you leukoreduce, you don\'t
throw that away either. But if you leukoreduce, you are removing that
component. The rest of that infectivity is redistributed among other
fractions, all of which get used and go into products which get used one
way or another. And so that infectivity, what I\'m not sure about is
what that redistribution is, but that infectivity is still there. Does
that help you at all?

DR. LINDEN: Well, it does. And, I guess, I mean, I hate to disagree with
Dr. Bracey, because I agree with him on almost everything else, but I\'m
just not hearing that we have scientific evidence that a universal
leukoreduction would really significantly provide benefits in this
regard. I mean, I fully agree there are other reasons to do
leukoreduction, but I have not heard that there are significant benefits
to merit recommending universal leukoreduction for purposes of
preventing variant CJD, at this meeting.

CHAIR PRIOLA: Dr. Nelson?

DR. NELSON: Well, it seems like the risk of transfusion transmitted
variant CJD is not high. And classical CJD is even lower. And it may be
that some decrease in the risk provided by a 50 percent decrease in the
number of transfused prions might affect whether or not there would be
cases or how many there would be, because of the fact that we are not at
a point in the curve where large numbers of people are at risk, despite
the fact that there have been a lot of transfusions. In classical, we
showed what was it 116, 300 and 116 have been over five years, I think
it was.

We have had one out of, you know, only in the teens now, but the
likelihood is that the risk isn\'t high, but that it is there.
Therefore, you know, if there is a feasible way to reduce the risk even
by 50 percent, you know, it may be prudent to do it.

CHAIR PRIOLA: Dr. Wolfe?

DR. WOLFE: It sounds from what Dr. Nelson said though that the decision
to leukoreduce is being made independent of this issue, so you can
almost say it doesn\'t matter whether we\'re going to get 50 percent
reduction or not as sort of a ride-on or add-on to a number of other
diseases where there clearly is going to be reduced risk to say nothing
of transfusion reactions and everything.

So it is not \-- we don\'t have to even visit this decision at all,
because it is being visited on a much larger scale for a whole bunch of
other reasons and this is sort of a tag-along. So it fits in with Bob\'s
sufficient, but not \-- \"necessary, but not sufficient\" towards some
larger scheme in terms of blood safety. It is already happening.

CHAIR PRIOLA: Let me have Dr. Epstein comment to see if he can clarify
some things.

DR. EPSTEIN: Well, I just want to try to clarify that evidence for
removal of 50 percent of infectious units from a blood component should
not be equated with 50 percent reduction of clinical risk. Those are two
different metrics. What I\'m hearing Dr. Linden say, with which I agree,
is that we don\'t know if there is any reduction of clinical risk if you
reduce 50 percent of infectious units in the transfusable component.

And I think that the important point that Dr. Rohwer has made is that if
there is an effective strategy to remove some number of logs, not just
half, but 10-fold or 100-fold reduction, that it is logical to remove 50
percent up front by removing one unneeded component and then using other
technologies to deal with residuals. But unless and until we hear that
there are validated technologies to remove the remaining infectivity
from red cell concentrates or plasmas, I think we have to be somewhat
skeptical about the clinical benefit.

Even at that point, I mean, even if we remove one log or two logs,
questions will remain, because we have been told that a typical unit may
start out, correct me if I\'m wrong, Bob, at about 5,000 units in the
whole blood. So, you know, there is a long way to go before we can talk
about a de minimis risk if there is an infectious donor.

The second point that I would like to make is that the potential benefit
is dependent on how much vCJD you think there is in the donor
population. We think we have a very different situation in the United
States than in the U.K. I mean, in the U.K. there is a credible estimate
that quite a number of donors may be incubating vCJD. I don\'t know that
number, but it may not be small. Whereas, in the U.S., the thinking is
that because we haven\'t had a massive BSE epidemic and because we have
had donor exclusions in place, that the donor pool is unlikely to have
very many infectious individuals.

So even if there were a proven benefit of techniques to remove
infectivity in blood components from infected donors, we would still
have to think about whether it makes sense to implement against the
background of how many infected donors might there be. And I don\'t know
the answer to those questions, but I\'m just trying to put the issue in
its proper context.

CHAIR PRIOLA: Dr. Linden, do you want to respond to that?

DR. LINDEN: Well, I was actually about to say exactly the same thing,
except Dr. Epstein is so much more eloquent. Yes, I agree completely
that a 50 percent reduction in load does not remotely mean a 50 percent
reduction in risk. I think that we do not know the infectious dose. I
mean, that\'s one of our problems here. I mean, when you look at
bacteria, there are some bacteria we need a pretty high dose to get
infection of others, like Shigella, where a very small number of
organisms will transmit infection.

I don\'t think we know that here, but I think it is certainly reasonable
to speculate. I don\'t know the animal experiments, you know, well
enough. I don\'t think we know in humans what the infectious dose is.
But, you know, basically, I agree with, you know, all of what Jay has
said. And until we know that, it doesn\'t sound like we have, you know,
sufficient evidence to say that this would be useful for components.

But certainly if you\'re then using another method for inactivation, it
sounds like a very good method. But certainly, I look forward to hearing
more from, you know, Pall and other manufacturers about other methods
that may be useful for inactivation or filtration of, you know, these
types of agents in the future. It sounds like a very exciting field.

CHAIR PRIOLA: Dr. Rohwer?

DR. ROHWER: An infectious dose is an operational definition in this
field since we\'re not absolutely sure what the infectivity is or even,
for those people who are sure, what the relationship of the infectivity
with protein is. And as a consequence, by definition it means that dose,
the minimum dose that\'s required to cause an infection.

So in that sense, we do know what an infectious dose is. The route is
also important and possibly the matrix is important. And the transfusion
experiments that I showed you yesterday shows, at least in the hamster
system, if you give intact blood by the IV route, the infectivity is a
lot lower than we would have expected by at least another order of
magnitude, and so there is an issue there as well.

What I really wanted to address was something that Jay brought up just a
moment ago, and that is where does the risk to the blood supply come
from in the United States? And it\'s not clear to me that our exposure
to a very low level of BSE cattle in the United States, a yet to be
measured and determined level of BSE cattle in the United States, would
be the major source of risk for variant CJD in the United States, as
opposed to the 90 percent target for deferral and removal of risk by
deferral.

In other words, my guess is that we\'re more likely to see variant \--
we may be more likely to see variant CJD cases in the United States from
people who have traveled to Europe and spent time in Europe or have
traveled in France or traveled in Italy even than we are from our
exposure to BSE cattle themselves presuming that that epidemic is under
control.

And again, unless we make the measurements and find out, I still want to
be persuaded of that as well. But nevertheless, I think, in terms of
thinking about where variant CJD cases would come from, we have to
consider both sources and the traveler risk just seems much higher to
me, because we have a lot of travel exposure.

CHAIR PRIOLA: Dr. DeArmond?

DR. DEARMOND: Yes. I agree with that, but getting back to the issue that
was raised. It\'s true that we know what the smallest infectious dose is
in an inbred mouse strain or hamsters, which are outbred, but we
understand that very precisely. In humans, it\'s very complicated. So
the idea of if 100 people got infected blood, how many would come down
with the disease, and it could be very small even if they had the
maximum dose that one would predict from a variant CJD patient.

Certainly, you would have to worry about the methionine-methionine
individuals, but the others may be resistant. And even among the
methionine-methionine, there is probably a lot of other factors. So
infectivity in a human is extremely difficult, because unfortunately or
fortunately, we\'re not inbred mouse strains.

DR. NELSON: Did you say fortunately or unfortunately?

DR. DEARMOND: There was a program, a British comedy about space, where
these people are traveling and God is a mouse.

CHAIR PRIOLA: Dr. Bracey?

DR. BRACEY: But again, with regard to the issue of the travelers and the
risk posed, again, I think we face the real risk if we further adjust
the number of donors that are eligible, that, in fact, the delays that
we see in terms of surgeries will, in essence, turn into really bad
outcomes and we will see people that will have terrible outcomes related
to inadequate blood supplies. So I think that, you know, we are on the
precipice right now of just having a totally inadequate blood supply.

CHAIR PRIOLA: Dr. Rohwer?

DR. ROHWER: I don\'t want my remarks being misunderstood as recommending
a tighter deferral. I don\'t think that\'s \-- that was not my intent,
and I don\'t think there would be \-- the cost effectiveness of that
would be \--

CHAIR PRIOLA: Dr. Hogan?

DR. HOGAN: Yes. I just wanted to echo that in terms of tightening the
deferrals. It can be even worse for tissue than as opposed to blood,
because there is fewer donors and it\'s harder when you are talking with
a dead donor to find out where they have traveled. It\'s all
circumstantial based on what the family knows about it.

UNIDENTIFIED SPEAKER: It\'s insurmountable.

DR. HOGAN: Well, okay.

CHAIR PRIOLA: Any other comments, questions from the Committee? Does FDA
have anything they want to add or make sure the Committee should address
before we adjourn?

DR. MIDTHUN: No, but I would like to thank everyone. It has been an
extremely helpful discussion and certainly, I think we all recognize
that more data would be very helpful to help us go forward, but
certainly, in the meantime, your input in helping us to assemble how
best to go forward is much appreciated. Thank you.

CHAIR PRIOLA: Okay. Thank you very much. Thank you again to the speakers
and the Committee members. Everybody have a safe trip home, and we\'re
adjourned.

(Whereupon, at 2:04 p.m. the meeting was concluded.)