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:
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:
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 PAGE
INTRODUCTIONS:
William Freas................................... 3
CURRENT CBER SAFEGUARDS FOR BLOOD PRODUCTS:
Dorothy Scott................................... 5
QUESTIONS/COMMENTS:............................ 19
CURRENT BLOOD DONOR DEFERRALS & THEIR IMPACT:
Alan Williams.................................. 21
QUESTIONS/COMMENTS:............................ 33
MINIMIZING RISK OF TSE IN AGENTS IN HUMAN TISSUE:
Melissa Greenwald.............................. 44
QUESTIONS/COMMENTS:............................ 50
USE OF BOVINE-DERIVED PRODUCTS IN THE MANUFACTURE
OF VACCINES & ALLERGENIC PRODUCTS:
William Egan................................... 54
QUESTIONS/COMMENTS:............................ 66
MINIMIZING RISK OF TSE AGENTS IN DRUGS:
Gerald Feldman................................. 79
QUESTIONS/COMMENTS:............................ 90
MINIMIZING RISK OF TSE AGENTS IN MEDICAL DEVICES:
Martha O'Lone.................................. 95
QUESTIONS/COMMENTS:........................... 105
FOOD AND COSMETIC SAFETY:
Morris Potter................................. 107
QUESTIONS/COMMENTS:........................... 111
OPEN PUBLIC HEARING DISCUSSANTS:
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:.................................... 133
COMMITTEE DISCUSSION:......................... 138
ADJOURN:
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 27th 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 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 26th 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 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 108 in one organ and 101 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 23rd ? 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 106 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 109 going 106
and you're right there at the level.
You've removed 1,000 fold or greater of the cells and you only started
with 103 infectious units or 5 times 103 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.)