Blood Safety Transcripts
U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES
ADVISORY COMMITTEE MEETING ON BLOOD SAFETY AND AVAILABILITY
Third Meeting
"The Influence of Transmissible Spongiform Encephalopathies
on Blood Safety and Availability"
Volume I
Thursday, January 29, 1998
8:05 a.m.
Hubert H. Humphrey Building
Room 800
200 Independence Avenue, S.W.
Washington, D.C. 20201
P A R T I C I P A N T S
Committee Members:
Arthur Caplan, Ph.D., Chairman
Larry Allen
James P. AuBuchon, M.D.
Michael P. Busch, M.D., Ph.D.
Ronald Gilcher, M.D., F.A.A.P.
Edward D. Gomperts, M.D.
Fernando Guerra, M.D.
Paul F. Haas, Ph.D.
William Hoots, M.D.
Carolyn D. Jones, J.D., M.P.H.
Dana Kuhn, Ph.D.
Tricia O'Connor
John Penner, M.D.
Jane A. Piliavin, Ph.D.
Eugene R. Schiff, M.D.
Marian Gray Secundy, Ph.D.
John Walsh
Stephen D. Nightengale, M.D., Executive Secretary
Consultant:
Kristine A. Moore, M.D., M.P.H.
Ex Officio Representatives:
Eric Goosby, M.D.
National Institutes of Health:
Paul R. McCurdy, M.D.
Food and Drug Administration:
David W. Feigal, Jr., M.D.
Centers for Disease Control and Prevention:
Mary E. Chamberland, M.D.
Health Resource and Services Administration:
David Snyder, Rph, DDS
C O N T E N T S
Call to Order
Stephen Nightengale, M.D.
Executive Secretary, Advisory Committee 5
Welcome and Remarks
John M. Eisenberg, M.D.
Acting Assistant Secretary for Health
Department of Health and Human Services 7
Recent Advances in the Study of Transmissible
Spongiform Encephalopathies
Animal Models
Dr. Robert Rohwer
University of Maryland, Baltimore 10
Epidemiology
Dr. Lawrence Schonberger
Centers for Disease Control and Prevention
Atlanta 41
New Variant Creutzfeldt-Jakob Disease
Dr. Robert Will
National Creutzfeldt-Jakob Disease
Surveillance Unit, Edinburgh 75
Further Expectations for CJD Research
Dr. Clarence Gibbs
National Institutes of Health, Bethesda 104
Risk Perception and the Perceived Public
Lola L. Lopes, Ph.D., Dean
College of Business Administration
University of Iowa, Iowa City 120
Food and Drug Administration Regulation of
Transmissible Spongiform Encephalopathy
Implicated Blood Products
Dr. Mark Weinstein
Food and Drug Administration, Rockville 152
Open Public Comment 175
Committee of Ten Thousand
David Cavenaugh 176
Hemophilia Federation
Jan Hamilton 182
Immune Deficiency Foundation
Jerry Winkelstein, M.D. 185
National Hemophilia Foundation
Donald Colburn 199
American Society of Clinical Pathologists
Roslyn Yomtovian, M.D. 203
American Red Cross
Richard Davey, M.D. 206
Pall Corporation
Barry Wenz 226
Margaret A. Somerville, Consultant to Pall, Inc. 230
Premier, Inc.
Paul Just 235
IPPIA [International Plasma Producers
Industrial Assoc.]
Jason Bablak 240
P R O C E E D I N G S
DR. NIGHTENGALE: Good morning. My name is Stephen Nightengale. I am the
Executive Secretary of the Advisory Committee on Blood Safety and Availability and this is
the third meeting of the committee. Let me proceed immediately to the conflict of interest
statement. If the mike is rolling, then I will begin to read. The mike is rolling? The
mike is rolling? Okay.
The following announcement is made as part of the public record to
preclude even the appearance of a conflict of interest at this meeting of the Advisory
Committee on Blood Safety and Availability. General applicability has been approved for
all participants. Since no particular matters will be addressed by this committee on
issues dealing with specific products or firms, it has been determined that all interests
reported by the committee members present no potential conflict of interest at this
meeting when evaluated against the agenda.
In the event the discussions involve specific product or specific firms
for which the members or other participants have a financial interest, the participants
are aware of the need to exclude themselves from such involvement and their exclusion will
be noted for the public records.
A copy of the waivers are available on written request under Freedom of
Information Act. With respect to all other meeting participants, we ask in the interest of
fairness that they address any current or previous financial involvement with any firm or
products upon which they wish to comment. At that point, the members of the advisory
committee who are present--I think I'll ask the committee members to identify themselves
for the record beginning with Dr. Gilcher.
DR. GILCHER: Dr. Ron Gilcher.
DR. AuBUCHON: Jim AuBuchon.
DR. HAAS: Paul Haas.
MS. O'CONNOR: Tricia O'Connor.
DR. GOMPERTS: Ed Gomperts.
DR. HOOTS: Keith Hoots.
MR. ALLEN: Larry Allen.
DR. GUERRA: Fernando Guerra.
DR. KUHN: Dana Kuhn.
DR. PENNER: John Penner.
MR. WALSH: John Walsh.
DR. CHAMBERLAND: Mary Chamberland.
DR. MOORE: Kris Moore.
DR. BUSCH: Michael Busch.
DR. PILIAVIN: Jane Piliavin.
DR. SNYDER: Dave Snyder.
DR. NIGHTENGALE: Okay. At this point, I will turn the gavel over to Dr.
John Penner, who is the deputy chair, until Dr. Caplan is able to get here, and he can
introduce Dr. Eisenberg.
DR. PENNER: We'll begin with Dr. Eisenberg, who is the Acting Assistant
Secretary for Health, Department of Health and Human Services. Dr. Eisenberg.
DR. EISENBERG: First, let me just introduce myself. I'm John Eisenberg.
I'm serving as the Acting Assistant Secretary for Health. My daytime job is as the
Administrator for the Agency for Health Care Policy and Research. And it's been my
pleasure to serve in this role, in the Acting Assistant Secretary role, since the summer.
Let me just say that when I came into this job in the summer, I became aware quickly of
the complexity of the issues that this committee, this advisory committee, deals with, and
in particular the issue that you dealt with with regard to hepatitis C and the exposure,
the inadvertent exposure to hepatitis C through blood transfusions.
We have a Blood Safety Committee in the department. We have reviewed the
recommendations of this advisory committee. We've discussed them inside the department.
We've discussed them with the Secretary, and we have prepared a letter which the Secretary
has approved which I want to read today, and which we can make available to you, and then
I'll make a comment after I've read this letter. So let me read the letter to you. It's
addressed to Arthur Caplan as chair of the Advisory Committee on Blood Safety and
Availability. And it reads:
Dear Dr. Caplan: Thank you for your thoughtful recommendations for persons
inadvertently exposed to hepatitis C through blood transfusion. Your recommendations have
greatly assisted the department's extensive review of this matter.
I support your recommendation for the use of direct notification efforts
to reach those individuals who received a transfusion from a donor who later tested
positive for hepatitis C by a confirmed second generation screening test. I also support
your recommendation for a public and provider education effort directed at those who
received blood before this second generation screening test was available. This education
effort will also benefit others at risk for hepatitis C, regardless of the source of their
risk.
In addition, the letter from Dr. Shalala goes on, I intend to go beyond
your recommendations. I consider these steps to be only the first phase of a comprehensive
plan to address this significant public health problem. It is my intention to effectively
reach as many people at risk as we can. Today's decision will allow us to move immediately
to address concerns among transfusion recipients at greatest risk. At the same time, we
will educate the public at large, evaluate our efforts and take even more steps to address
unmet needs as identify them.
I am directing the Public Health Service Blood Safety Committee, chaired
by the Blood Safety Director, which let me say as an aside is the Assistant Secretary for
Health, to meet regularly to review progress in these efforts and to make appropriate
recommendations for further action. We'll keep you informed of our progress.
Sincerely, Donna E. Shalala.
So, in essence, what this says is that the Secretary has both thanked you
and accepted the recommendation that this committee, this advisory committee, has made,
and also said that we would like to go beyond that level to identify individuals at risk
of having been inadvertently exposed to hepatitis C through blood transfusions and to
determine effective ways of identifying those individuals. She has asked a number of us
within the department to quickly work on a plan. That will include a number of different
agencies, and I will hard to get that plan put together as quickly as we can.
So let me on behalf of the Secretary thank you for your tough
deliberations, difficult deliberations, on a very complex issue and recommendations which
have guided us in making what I think is a very important public policy decision to
identify those individuals who have been exposed inadvertently to hepatitis C through
blood transfusions. And let me just say as an aside having become very familiar over the
past few weeks with the complex epidemiology and clinical issues and operational issues,
and the large amount of uncertainty that continues to exist about this issue, I want to
thank you for the very clear and very helpful advice that you've given to the department
and to say that we will use that as our starting point for a comprehensive effort to deal
with this problem. So thank you very much.
DR. PENNER: Thank you, Dr. Eisenberg. We'll proceed. Dr. Lopes will not be
available this morning, who had been the next speaker, and will be able to speak, I think,
tomorrow. So we'll proceed on to Dr. Rohwer, University of Maryland, Baltimore, on animal
models. Dr. Rohwer. Is Dr. Rohwer here?
DR. ROHWER: I just want to mention that my principal affiliation is with
the VA Medical Center in Baltimore. I think we're going to have to have some of the lights
down here. I can speak to these slides until we get to the data slides anyway. I'm going
to only briefly mention the prior published work on the issue of the infectivity of blood
in the TSE agents and spend most of our time discussing some experiments that have been
done over the last couple of years both in my lab and in collaboration with Paul Brown's
laboratory at the NIH. And I'll finish by giving you my own personal perspective on these
diseases and their significance for the blood supply.
I'm not going to spend much time on this. But the next overhead will
summarize very briefly what we know from preexisting work in this area. The two
experiments that aren't on this slide are the most important ones, which are several
attempts at the NIH to inoculate, to transmit the disease via blood inoculated either
intracerebrally or by transfusion into various primates from the source of blood being
CJD-affected humans.
In no case have any of those transmissions been successful. There have, on
the other hand, been several accounts, four accounts in particular, claiming to have
transmitted the disease from human, infected humans, to rodents. For various reasons,
these results are questioned, I think, by most of us in the field. And they certainly
would need to be repeated before we grant them much significance.
There has been a lot of work using experimental rodent models with these
diseases and attempting to establish whether or not the blood is infected, and in general
the results have been variable, but people have seen low titers of infectivity in the
blood. There seems to be white cell involvement as a carrier of that infectivity, and this
is by inference. People in an attempt to increase the efficiency of these transmissions
concentrated white cells and inoculated white cells to try to find the infectivity in
blood. And it seems to be several investigators have seen it at preclinical stages of the
infection.
It's been seen in several hosts and strain agent combinations, but there
are other investigators that have seen nothing. And so the question is are these
methodological differences? Are there true differences between animal models or is the
appearance of infectivity in the blood a sporadic occurrence? And so these are all
questions that still need to be established, though the experiments that I'm going to show
you today show two clear cases in which infectivity was present in the blood of two
different rodent models.
Finally, with all of the experimental work to date, there is one possible,
very important artifact which I see now most of you can't see, unless we can shrink that
down a bit, and that's represented on the next overhead. And what I'm talking about here
is that--I can see we're going to have a problem with this, Steve, especially when we get
to the data unless we get it--and what I'm talking about here is the fact that without
exception, the experimental work that's been done in this area has been of the following
nature:
Very large amounts of infectivity have been inoculated into the donor
animal, the animal that is to be made sick, from which blood is going to be obtained to
test for whether or not the blood contains infectivity. And then subsequently blood is
taken from a recipient animal, and when infectivity is found, it's found at very, very low
levels. Because of the nature of these agents, their very robust nature and their tendency
to resist inactivation and removal, it's possible that what's being inoculated, even
several months out in an infection, could be residual infectivity, residual inoculum being
reisolated in the blood of these animals because you're only obtaining parts per 10,000 or
parts per 100,000 in some cases in the recipient animal.
So one of the questions that we wanted to look at, though we hadn't looked
at it very thoroughly yet, is whether or not this accounts for the infectivity that has
been seen in the experimental models, and I'll mention some of that later. So just keep
this slide in mind. Next.
Now, there are two types of experiments that we had done, and in general
the outstanding questions that we're trying to get at and most of this work should be
considered as prototype preliminary work, trying to establish whether or not we have
reasonable animal models to work with and what those animal models might be, and then
there are a number of important questions. Does the appearance of infectivity in the blood
of these animal models depend on the route of inoculation; the dose of inoculation, and
there I'm referring to the artifact I just mentioned, that the time after inoculation at
which the blood is collected; is there infectivity present during the preclinical period
of these diseases, which is very extended, and in humans we know it can last as long as 40
years? What is the actual titer of the infectivity in blood? There has not been an actual
measurement of that to date, but I'll show you our measurement today.
What is the distribution of that infectivity in blood components and
fractions? And finally, is the infectivity that's associated with blood if it's in blood,
is it transmissible? There are good arguments you can make to suggest that even if it's
there, it may not be capable of transmitting an infection. It may be there by virtue of
the fact that it's being cleared from the body by some lymphocytic process or something
like that. So merely moving it, say by a transfusion from one animal to another, might not
cause an infection.
The first group of experiments I'm going to talk about do deal directly
with the transfusion issue and the titer of infectivity in the blood. And for these
experiments, there are several of them here, but they're all done the same way. An animal
is inoculated with a hamster adapted scrapie agent. Scrapie is the TSE disease that occurs
in sheep, and it's the disease that's most frequently used as an animal model because
particularly in the hamster it goes relatively quickly. We can get disease in this animal
in a couple of months.
The animal is inoculated. When the animal becomes sick or in some cases
during preclinical disease, it is put under deep anesthesia and its bled by cardiac
puncture to obtain as much blood as possible, and in this group of experiments, the first
priority was to take the first 2 mls that were recovered and transfuse them into a naive
recipient.
When sufficient blood was present, another 2 mls were taken and buffy
coat, the white blood cell fraction, was obtained from that and inoculated intracerebrally
into a donor animal. The point of this experiment is simply to ask is there infectivity in
the blood at all? For example, if we get a negative transmission after this whole blood
transfusion and we don't know whether there's infectivity in the blood in the first place,
we really haven't said anything.
The reason we went to buffy coat is this is a very efficient way to look
for infectivity in blood. If the infectivity is truly concentrated in buffy coat, then we
can concentrate it into a single inoculum, about 50 microliters, inoculate it by the most
efficient route by which this disease takes in an animal, the intracerebral route,
directly into the brain, and then if this animal gets sick, we have a plus or minus
situation. Yeah, the blood contained infectivity. It didn't. But it doesn't tell us how
much infectivity might have been there.
This was a guess. No one had actually before we did this actually taken
whole blood and just inoculated it without any manipulation or anything into the brains of
animals. There's a technical problem here, and that is to inoculate by the most efficient
route, you can only inoculate 50 microliters, a very tiny amount. So to inoculate any
significant amount of blood, you have to inoculate a lot of animals. What we did is we
took one ml of blood, inoculated it, 50 microliters at a time, into 20 animals and if
there is any infectivity in that blood, we would presume some of these animals would get
sick.
There were several parameters that we varied. And those are given here. We
looked at a high dose inoculum. This is what people used. We use it because we can get
disease in 80 days. If we use a very low dose, one to ten infectious doses per animal, it
takes a lot longer. It takes about half a year to get the disease in the first place, and
that's just the starting point for these experiments. And this is just to show you we went
through this whole repertoire with each one of these.
There was also data in the literature that said the IP route was for
sure--the intraperitoneal route--was for sure a method by which you could find infectivity
in the blood using high dose. We used that more or less as a control and we did some
animals at high dose. It takes longer by the IP route to get clinical disease, and we also
bled some of these animals in the preclinical stage of the disease. Next.
Now I'm going to show you two charts getting you the results of these
experiments. And they're organized in the same way. Each line on this chart represents
what happened to the blood of a single animal donor. So, for example, this is the only
transmission that we got by the transfusion route so we'll start with it. We took the
blood from an animal that was clinically ill with scrapie after receiving a high dose
inoculation and bleeding the animal during its clinical disease. We transfused two mls of
that --this column is for transfusion--we transfused two mls of that into a recipient
animal and 261 days later, this animal developed scrapie itself.
We took the blood from that animal and 50 microliters at a time inoculated
it into 20 other, actually only 19, one of these died of the inoculation, so we had 19
recipients, and out of those 10 recipients, 12 of them developed scrapie.
So we can say that the blood was for sure infected and the blood when
transfused caused an infection as well. On the other hand, this animal, we didn't have
enough blood to do this experiment or enough animals, this animal was transfused in a
similar way. So was this one. So were all of these, and none of those animals came down.
In all we had 22 animals in this group which were transfused, and this is the only
transfusion transmission that we obtained. However, in every instance, when we inoculated
whole blood we did get infected animals. So our feeling is--you'll see on the next slide
that we have a bunch more of these whole blood inoculations--my feeling is that probably
all of these bloods contained infectivity, but only one out of 22 tested actually gave a
transmission by the transfusion route.
This blood is particularly important because the donor received a very low
dose intracerebral inoculation. This donor could not possibly, the blood of this donor
could not possibly have been contaminated with infectivity by the inoculum itself, the
inoculum that was used to infect the donor. This infectivity had to have come from the
infection itself. There is less of it, but we don't have any statistic here, and this is
within the range of infectivities we saw for the other samples. Let's look at the other
samples.
Skip that diagram and we'll just go to the next colored chart. Here are
the results of the IP inoculated donors. These were purposefully inoculated for this
purpose and we'd gotten better by then. We got enough blood that we could do buffy coats
as well on a number of these. So here, again, for example, let's look at this animal.
Here's an animal that was, the donor blood was transfused and the animal lived for 559
days--that's an extraordinary amount of time for a hamster--and we saw no transmission. I
will say that all these negatives had been reinoculated into other animals, the brains of
these animals, to see if there was anything incubating there. They're still negative.
These are true negatives. There isn't anything there.
And here we inoculated the buffy coat from that blood, a two ml equivalent
of whole blood, and got nothing, even after 627 days. However, the whole blood when
inoculated killed five out of the 18 animals that were inoculated. Here's one where we
only had enough blood to inoculate eight. One was killed. And here is the only buffy coat
that we have seen to date that came down with scrapie. This was a big surprise to us. We
expected all of these to be positive.
And, again, what we see, these were done, bled during the clinical period
of disease. These were bled preclinical period of disease, and these were bled during the
clinical period of disease, and as you can see, there was infectivity in both periods. You
know this is mixed up. This is supposed to be clinical. This is supposed to be
preclinical. And in every case when we did whole blood, we did see infectivity in the
blood, and those infectivities seemed to range here--if this had been 20--you know
somewhere between two and three infectious units per ml here in this. So we're ranging
between two and 12 to 13 infectious doses per ml in blood.
Next. So what can we say about these things? There is infectivity in whole
blood, subject to the--well, not subject to the caveat--it's present when the donor
received even a small dose of infectivity. It was present after either IC or IP
inoculation of the donor, though the comparison there is with the high dose inoculum. It
was present during the preclinical period of the disease as well as the clinical period,
and the titer was two to 12 infectious units per ml. Very surprising and
contraintuitively, the infectivity did not seem to be concentrated in the white cells. We
weren't expecting that, and we're now exploring that in more detail.
Finally, the transmission can occur by transfusion. Now let's say a little
more about the transfusion transmissions. This is one transfusion that has proven positive
to date. We have another 15 or so that are almost a year old and none of those have been
positive. This makes me a little nervous. We have one transmission out of 22 so far
completed, but we don't know what the denominator is. Is this one out of 22 or one out of
22 million? Another way to look at this is this was one transmission in 44 mls of blood
transfused total.
We haven't looked at anything like the blood volume that is associated
with a typical human transfusion, and it's a little remarkable to me that if the
infectivity is at the level of ten infectious diseases per ml, in a 500 ml transfusion,
for example, you'd expect 5,000 infectious doses. That's quite a bit. And either there is
something different about the way in which the infectivity is presented in a transfusion,
which our data actually suggests, or it's less in humans.
The donor had received a high titer inoculum so there is a potential
artifact that still has to be looked at here. We're putting on--these are much harder
experiments to do, but we're using low titer inoculum donors for doing another whole
cohort of these transfusions, and we don't know--but because of this we don't know that
the transmission was because of spillover from the infection derived infectivity or from
endogenous infectivity. Both could be present in those bloods. And there is no way to sort
it out in this type of experiment. The most important datum to remember, however, is that
the epidemiology suggests that if this type of thing occurs, it must occur very rarely,
and, of course, Larry Schonberger will say a lot more about that in a few minutes.
Okay. Another question, of course, is the vast majority of blood is not
used as whole blood. Rather components and fractions of blood are what are used, and so
it's important to know where the infectivity is in blood and how it partitions during
plasma fractionation. And I'm going to talk about two types of experiments. In one, we
used whole blood from a CJD. This is actually, this strain is actually from a GSS patient,
which is a variant of CJD, infected mouse and hamster scrapie that was spiked, high titer
scrapie from brain that was spiked into human blood as a spiking type of experiment.
We'll talk about the endogenous blood experiment first. This is a tricky
question to investigate because you don't know exactly how to go about it. The problem
with using whole blood is we know we have low titers, the incubation times are going to be
long, the sensitivity will be low, but at least we know that the infectivity will be in
the appropriate context. It will be the way infectivity in blood. In the spike, we have
the advantages of high titer and short incubation, high sensitivity, but is it relevant?
We don't know. Okay. And I'm not saying.
The CJD mouse experiment was done as follows: A cohort of mice were
inoculated to form a donor pool. They were bled by cardiac puncture. The blood was pooled.
It was separated into components, red blood cells, plasma, and buffy coat, and the plasma
was separated into cryo I plus II plus III, IV and V. Each one of those fractions was then
inoculated into a large number of mice because we expected there to be very low titers.
Next.
And an experiment would like this would benefit from even larger numbers
of mice. This is--okay--these are the results and I'm going to walk you through this. This
was a specimen in each case. This was whole blood, red blood cells, white blood cells from
the buffy coat. We also spun the pellet, the plasma, I mean, again, and got a tiny pellet
from that and inoculated that. The platelet free plasma, a portion of that plasma was then
half of it was taken and fractionated through the cone fractionation to obtain these
fractions. These were the specimen volumes. There are weights over here, and in every case
we had to dilute this stuff because it was toxic to the mice. So we had to go through a
dilution before we could put it into the mice so that the actual volume inoculated was
less than we had hoped for, and the actual fraction of this total volume that was
inoculated is given right here.
This is probably the most important column to look at when interpreting
this data here. So, for example, in the case of whole blood, we inoculated 11 animals, but
we only inoculated .15 percent of this 45 mls of whole blood. We saw no infections. That's
not surprising. We didn't inoculate enough to see infections even at ten--
DR. PENNER: These were all intracerebral, were they, Bob?
DR. ROHWER: These are all intracerebral inoculations. All we're doing here
is we're asking is it there or isn't it so we're using the most efficient route of
inoculation. Red blood cells, we didn't think it would be there, so we didn't expend many
animals on that. That's probably unfortunate because it probably bears looking at. White
blood cells, we did expect it to be there. We inoculated more of this, and we got two
animals dead out of 12 inoculated. We were optimistic. We thought there might even be
enough to kill a dilution but there wasn't.
From this plasma pellet, we got another four down out of 23. Plasma, out
of 132 animals inoculated, eight got sick. Down here, cryo, 11 inoculated, five got sick.
I plus II plus III, 43 inoculated, six. But here in fraction IV, 86 inoculated, fraction V
94 inoculated, no infections. Now you can use the fraction inoculated and the proportion
of animals positive to calculate how many would have been positive if the whole fraction
had been inoculated. That's given here. And this gives you -- this is what the recoveries
would have been if we could have inoculated everything. We should have seen 135 dead here,
ten here, 264 here.
The surprising things here are that the infectivity associated with plasma
is greater than that associated with the white blood cells. We were not predicting that.
We didn't expect that, and it still remains a surprising finding to us.
When this plasma was fractionated, we recovered about ten percent of this
infectivity in the cryoprecipitate and fraction I plus II plus III. Saw nothing down here
at this level. Now, the problem is that we have only inoculated, in terms of talking about
whether fraction V, which is, of course, a very timely question, whether fraction V bears
infectivity or not, we've only inoculated 30 percent of 1.22 grams. We haven't inoculated
much. And we didn't see any infections, but in terms of talking about what the load might
be, you can't say a whole lot from this type of experiment. I mean it's reassuring, but it
doesn't quite get you where you want to go, and the only way to get there is do a spiking
experiment with all the caveats associated with that, and we'll get on to that next.
So fractionation of spiked human blood same type. I mean in this case we
took human blood, and at this point we thought that infectivity was with a cellular
fraction, so we took a dispersed brain cell fraction from a clinically affected hamster,
washed them, and then dunked them into unit of human blot. Took an aliquot of that and
fractionated the same way we fractionated the mouse blood. Only this time we know that we
put in a huge amount of infectivity. So we're going to do serial dilutions and do an
endpoint dilution titration for each one of these fractions to see how much infectivity we
recovered.
We do eight serial dilutions, inoculate four hamsters at each dilution,
and we look at which dilutions kill, which don't. Some of these will kill. Some won't. At
some point you'll get a breakpoint, and that gives you some idea of what the titer was in
that fraction. I'm going to give you this data in the form of graphs because I think it's
easier to see. No, this is going to be hard to see. I guess if you leave it like this,
Steve, I'll point out what the columns are here.
This is a log scale over here. We put in about ten logs. This is the spike
itself. This is whole blood after it's been spiked. The sensitivity of the assay is about
a half log. So there are together here. And you can see we didn't get much separation
between white blood cells, red blood cells and plasma. Probably this spiking experiment is
not worthwhile for these types of separations. So what I'm going to talk about now is
the--and these are total recoveries. Let's go to the next one where we'll talk about
fractional recoveries.
Now I've just normalized everything to whole blood, and you can see that
this may or may not be meaningful, this drop in titer between whole blood and white blood
cells here, plasma here. My suspicion is it isn't. That what we're looking at is the
assay. But here we look at a comparison between plasma and cryo, and we're seeing some
significant depletions in infectivity. Since I feel that this is the most significant
thing to look at, let's just look at this and normalize everything to plasma in the next
curve.
So what do we have here? This is the log fractional recovery relative to
plasma. If plasma is one, then we've got two logs removal in cryo, two logs removal in I
plus II plus III. So we're recovering about one percent of the infectivity in cryo and I
plus II plus III, about ten to the minus four, or .01 percent in fraction IV, and you
can't see it here, but it's five logs down here for fraction V. Okay.
There's another way to look at this, which I think is probably what
everybody wants to know, and so I've summarized it in this graph right here. If we take
these two experiments, the mouse fractionation and the hamster fractionation, and just ask
what would be the distribution of infectivity in a single unit of blood, presuming that
blood has the titer that we've seen in both the mouse and the hamster experiment, and I
forgot to mention that the mouse experiment also if you divide the amount of plasma that
was there or blood that was there by the volume, by the titer, we got about ten infectious
units per ml again. So we have two. One rather indirect measurement, one direct
measurement giving this value.
If we presume that the titer is that, then what could we expect on the
basis of these experiments from 500 mls of whole blood? We could expect 5,000 infectious
units in this. Plasma accounts for about half of that. So we have 2,500 in plasma. If the
infectivity fractionated the way it did in the mouse experiment, which is the better
experiment, we would have seen 280 infectious units in cryo I plus II plus III, 210. And
in fraction IV, we can't do this because we didn't see anything. So we have to go to our
hamster spike for this data. What I did here was I went to the hamster spike and the
clearance between the plasma and cryo in the hamster spike was 100-fold and in the mouse
experiment was tenfold. So I multiplied these values by ten as a worst possible case
figuring that maybe this hamster data is off by a factor of ten.
If you do that, we would see two infectious units in IV and a tenth of a
unit in fraction V from a single donation. In a worst case scenario, you might see two or
three donations in a pool of blood. That would be a really extreme situation in a pool of
blood of maybe 60,000 donors. So this is what you could expect your level of contamination
to be for an entire pool. Another important thing to remember is these are the crude
fractions. This is not Factor VIII. This is cryo. This goes through a lot of refinement
between here and Factor VIII. In fact, that's true for every single one of the commercial
products that are made from this material. There is a lot more opportunity for clearance
between here and there, but it does mean there is something to clear. I mean it's
important to look at it. Yes.
Now, Steve, do I have time to say a few things about perspective?
DR. NIGHTENGALE: Take all the time you want.
DR. ROHWER: Okay. Now how do we put this data in perspective? I think a
lot of the concern about Creutzfeldt-Jakob Disease comes from our experience with AIDS
beginning in the '80s, but this is a very different disease. And just to contrast them,
AIDS was a newly emergent disease in the '80s. It hadn't been seen before in the human
population. We have every reason to believe that Creutzfeldt-Jakob Disease has been with
us since time immemorial and we know it's been here at least 100 years. This disease
produces very high titers in the blood, and it's a blood-borne disease. That's the route
of infection or a route of infection.
Here we have very low titers. The disease is basically a central nervous
system disease like rabies. It's quite a different story. On the other hand, we now have
effective screening methods of AIDS, and we have no preclinical tests for this disease,
and we don't have any prospects for one in the immediate future.
What is our exposure to CJD infection? The incidence of clinical CJD in
our population, in the population worldwide, is about one case per million persons per
year. That means that in the United States we should expect about 250 cases in our
population of 240 million people. This, however, isn't the whole story because CJD has a
long incubation period that can range from a minimum of two years in iatrogenic
transmissions where it's inoculated directly by accident, by medical accident, into the
brain of a person, to we know from one of the human growth hormone transmissions and also
from Kuru, which is a long story, that the infection can take up to 40 years or more.
So the true prevalence in our population must be this incidence times the
incubation time, whatever it is. We don't know that. Okay. But if it was 40 years, we
could have up to 10,000 carriers in our population. If ten percent of our population
donates blood, we have 24 million donors, and these are ballpark numbers here. Don't take
them too literally. We should see about 25 clinical CJD cases a year. We're only seeing
about five, which means we're missing the big bulk of them. I mean these are clinically
associated donors. We could have as many as a thousand CJD carriers donating to the pool a
year.
If we had a 40 year incubation period, then we would have one carrier per
24,000 donors. If we had a 20 year incubation period, it would be one carrier per 48,000
donors. Ten year incubation period, one per 96,000 donors. We don't know what this number
really is, but we're in the ball park of having a donor for practically every pool of
60,000 donors. Well, knowing this, does it make sense to withdraw product on the basis of
the few Creutzfeldt-Jakob Disease cases that we have identified?
We can't differentiate, I don't feel we can differentiate pools on the
basis of these occasionally identified cases. The great bulk of the exposure is from the
undiagnosed cases, the carriers that are out there in the population. And as a
consequence, virtually all pools must be exposed to this stuff. And just picking on a pool
because we happen to know that a CJD donor contributed to it really gives us a false sense
of security. It's misleading. And really the best security comes from the epidemiology. As
far as we know, we don't have a problem.
Next. So what do we do about this disease? The experiments we're doing
right now suggests that there is infectivity associated with blood. I don't think we
should drop it. But the majority of the exposure is coming from preclinical cases. We
can't detect these cases. So the exposure is ubiquitous. Therefore, the proper goal
without a preclinical test for this disease is separation, removal and inactivation of
these agents during processing of products from plasma, blood fractions and blood
components.
Now, if there is a danger associated with blood and blood products, I
think it comes from a completely different quarter, and that is the intraspecies recycling
of the infectivity that could be present in this carrier population. In those instances in
which we've had epidemics of TSE disease, they were always caused by this phenomenon. We
had this vaccine back in the '40s which killed thousands of sheep. Kuru was--the eating
of--endocanibalism [ph] in Papua New Guinea--was transmitting the disease. And most
dramatically the bovine spongiform encephalopathy or mad cow epidemic in Europe where it's
clearly a case of cow meat and bone product being fed in feed supplements back to cows and
the disease was being recycled in that way, and in these cases, the danger was and
continues to be silent subclinical amplification over many cycles of passages through the
host before you see it and become aware of what's going on.
And as a consequence, how this applies to transfusion is as follows: If
CJD blood contains infectivity, if CJD can be transmitted by transfusion, the disease
could be amplified through transfusion from previous transfusion recipients or blood
product recipients. It could take many incubation times to materialize. We're talking
about decades, maybe even centuries, but it's a practice that I think should be reviewed
and considered now, and we need a lot more data to see if this is a real threat or not,
but if there is a threat from these products, I think it comes from this.
And then the last slide is or possibly from this source. This is a plot of
the BSE epidemic in cows in Great Britain. And over here on the left displaced by a decade
is the beginnings, we hope is not the beginnings but is the identification of these first
cases of New Variant Creutzfeldt-Jakob Disease. The big question in everybody's mind, the
big fear, is that this will follow the same course that cattle took after 1985 and turn
into something like this. If we have a big subclinically affected population of New
Variant Creutzfeldt-Jakob Disease, one, the number of people, the level of exposure may be
far greater to these diseases than we are currently considering, and also there is
something different about this disease.
I am not at all confident about extrapolating the work that we have done
using classical Creutzfeldt-Jakob Disease and sheep scrapie to this particular disease.
This disease has jumped species barriers fairly readily, where the other TSE diseases
we've known in the past have never done that. And we need to study this disease directly
to find out whether infectivity is also present in blood and whether it has the same level
of virulence or not as the models we have studied to date. And I'll stop there.
DR. PENNER: Bob, if you could hold for a minute up there. Dr. Schonberger
is going to be talking about the epidemiology so if there are questions about the
experimental aspects of the program that Dr. Rohwer has presented, why don't we handle
them now. Are there any questions? I guess I have one question. First of all, how do you
prepare the plasma? Are there any cellular elements still persisting? Is it centrifugation
or can you be sure that there aren't some lymphocytes that are present?
DR. ROHWER: There undoubtedly are cellular components still present.
Basically what was followed was a standard, the same centrifugation conditions that are in
the bag separation method that's used by the ARC. And this stuff is not absolutely clean.
However, if you look at that data, you can't account for that residual infectivity in the
plasma unless you've got a cell contamination of the plasma equal to or greater than the
cells you recovered in the buffy coat and plasma pellet.
DR. PENNER: Do you presume that the lymphocyte population buffy coat would
be higher than even what would be present in the plasma then?
DR. ROHWER: Yes.
DR. PENNER: Or have you looked at it?
DR. ROHWER: Oh, yes, I would. Yes. But to answer your question directly,
it was not measured and we strongly regret that. You know we don't have a datum for that.
Okay. It's being looked at again.
DR. PENNER: Any other questions from the panel? Yes, Ed, Dr. Gomperts.
DR. GOMPERTS: Bob, I enjoyed your presentation. Thank you. The mouse
spiking experiments, are these your observations or are these--because I've heard similar
data from Paul Brown and his group?
DR. ROHWER: This was a collaborative experiment with Paul and myself.
Yeah.
DR. GOMPERTS: Thank you.
DR. BUSCH: The inoculation to this animal, with the hamster experiment,
for example, that was then the source of the blood for the transfusion, was that
intracerebral in the first instance?
DR. ROHWER: There were two groups of inoculations there. Are you talking
about the first group of experiments?
DR. BUSCH: Right.
DR. ROHWER: Yeah. That first group of experiments, that first panel, those
were all intracerebral inoculations. The second panel were all intraperitoneal
inoculations, yeah. And that, of course, is if I get the drift of your question, I think
it is very important to look at possibly more natural routes of exposure to these
diseases. There is, however, substantive technical problem, and that is we are undertaking
to infect the animals by the oral route, which is probably one of the more likely ways in
which you acquire these disease. However, to infect an animal by the oral route, you have
to give it a whopping dose to get predictable infections.
It's more likely in the natural situation that people get very small
doses, but in a very large population, we get a few cases of Creutzfeldt-Jakob Disease
from that low dose exposure. To do this in the animal models would be unthinkable. I mean
we have to inoculate thousands in order to see a few sick, and we'd never be able to look
at preclinical stage of disease. So there is always going to be a flaw in that type of
paradigm.
DR. PENNER: Okay. Dr. Kuhn.
DR. KUHN: Just two questions. Number one is where was this published, and
can we get a copy of this publication?
DR. ROHWER: This work has been in progress. All of these experiments have
now been brought to completion or at least they're at a point where we feel we can publish
them and they're being prepared for publication now.
DR. KUHN: Okay And the second question is this. Unless I misunderstood,
you said that the infection, the infective agent inoculum, you know, was toxic to mice
unless diluted, and in that slide if I were to understand the statistics correctly that in
cryo then there would probably be anywhere from a 25 to 45 percent infectivity rate and in
fractions I, II and III, a 14 percent infectivity rate.
DR. ROHWER: You're in the ball park, but I wouldn't try to attach that
type of specificity to those numbers.
DR. PENNER: Yes. Kristine.
DR. MOORE: The first thing I want to say is I think you gave an excellent
presentation. Again, I really appreciate the data that you shared. You showed one slide
that had the number of infectious units in whole blood and on down the line down to the .1
in five. Can you comment and maybe I missed this in your presentation on how transmissible
and how many infectious units, what's your sense, might lead to actual transmission? You
know you were using very high inoculums in your experiments, but what's your sense of what
that means?
DR. ROHWER: Yeah, excellent question. The transmissibility of these
diseases depends on the route of inoculation very, very strongly. And unfortunately the IV
route is only--the most efficient route is the IC route, and everything has a consequence.
Since we don't actually have our handle on what the agent is, everything is spoken about
in terms of IC inoculations, but compared to the IC route, unfortunately the IV route is
the most efficient, and it's only about tenfold less efficient.
However, IM, or subcontaneous routes, or very, very inefficient, at least
with the diseases we've studied to date, and orders of magnitude, thousand-fold,
10,000-fold less efficient by those routes. And so that is a consideration, that is a
parameter, and that is something that is taken into consideration when everyone does a
risk assessment concerning these agents, is how would a person be exposed to it in the
end.
DR. PENNER: Any other questions from the panel? One, maybe last one, is
susceptibility that you've not covered. You're dealing with a population of animals that
are bred, but we're dealing with the population of humans who have variable immune
capabilities. Some have been reduced by chemotherapy and a number of other things. Do you
think this would play a role in the infectivity of this process?
DR. ROHWER: We know that there are, very rarely there occur people with
mutations in the prion gene which puts them at much higher risk to these agents. One camp
claims that these mutations cause their disease. Another way of looking at it is that
these mutations increase their susceptibility to something that's in their environment.
I'm in the latter camp, but neither approach has been proven. And these are the Familial
Creutzfeldt-Jakob Disease cases, GSS cases, Fatal Familial Insomnia, et cetera. Whether or
not immune status affects these diseases or not, it probably does, but it has not been
addressed in a way that's exactly comparable to the immune compromised populations that we
have in our human population. Yeah.
DR. PENNER: One other question? Yeah. Keith.
DR. HOOTS: You raised a very interesting question at the very end about
the looping vaccine and Kuru.
DR. ROHWER: Yeah.
DR. HOOTS: Suggesting and certainly some of the other data suggests that
multiple passages increases virulence relatively speaking.
DR. ROHWER: That's not my point.
DR. HOOTS: That's not your point?
DR. ROHWER: No, no. My point is that because of the long incubation time
of these diseases, you can harbor a subclinical infection for your life and die of a heart
attack and no one will ever know it. In the meantime, you could have been a blood donor
and if your blood is then given to somebody else, you could have transmitted the disease
to someone else who has a similarly long incubation period and we never see the disease.
But if that goes on long enough, you build up the baseline of carriers in
your population to a point where it becomes, you do start seeing cases, and that's exactly
what happened in the feeding history or at least that's my interpretation of what's
happened in the feeding history of BSE in cattle in Britain.
DR. HOOTS: So you would not infer that anything with New Variant has to do
with the fact that adaptability occurs not only crossing species, but in fact that there
is a potential that adaptability in the New Variant towards virulence occurs with multiple
passage?
DR. ROHWER: In the case of New Variant, that's one comforting thing about
it. The animal models probably have more relevance than anywhere else because the BSE New
Variant CJD strain seems to be very invariant compared to what our experience has been
with Creutzfeldt-Jakob Disease and scrapie. That is one of the peculiarities about this
disease, but I think it would give one a lot more confidence in the animal models used to
study New Variant as a consequence of that. It probably isn't undergoing a lot of
adaptation. It doesn't need to.
DR. PENNER: Okay. Thank you, Dr. Rohwer. We'll start with Dr. Schonberger,
if we could, for the epidemiology. Dr. Schonberger is from the Centers for Disease Control
and Prevention in Atlanta. Dr. Schonberger, thanks.
DR. SCHONBERGER: Steve, you can move the front a little bit to make it
bigger, if you want to turn it. All right. Well, good morning. I'm a physician
epidemiologist with the Centers for Disease Control and Prevention, CDC. And I coordinate
CDC surveillance activities on Creutzfeldt-Jakob Disease, CJD, in the United States. As
one who also provides consultations to patients and physicians directly affected by the
current interim U.S. Public Health Service policy on CJD and blood safety, I am pleased
that this interim policy is being reviewed by this committee.
As requested by Dr. Nightengale, I will rediscuss CJD and blood safety as
I had done with this committee last April, focusing primarily in relevant published and
ongoing epidemiologic studies. As we heard so impressively this morning from Dr. Robert
Rohwer, there are important laboratory experimental studies that support concern about the
possible risk of CJD transmission by human blood.
A key unanswered question about the results from the studies in the rodent
models of CJD, however, particularly the infectivity of blood throughout most of the
incubation period, is whether these results apply to CJD infections in humans and indicate
a risk in transfusion medicine?
Next slide. In addition to the laboratory experimental studies, other
causes for the existing concern about the possible risk of CJD transmission by blood
include several characteristics of the disease itself. CJD is invariably fatal. It is
caused by an unconventional agent. Disinfection is unusually difficult. Incubation periods
are long and variable. And there is no practical screening test to identify those who are
incubating the disease. In addition, since the 1970s, iatrogenic cases of CJD have been
increasingly recognized.
Next slide. This next slide summarizes the iatrogenic cases of CJD by mode
of infection and incubation period and illustrates on the right the variability of the
mean and range of these incubation periods. The mean incubation periods vary between 1.5
years for those who had direct brain exposure to contaminated stereotactic EEG equipment
and 18 years for U.S. recipients of contaminated human growth hormone. The incubation
periods shown on this slide for the hormone recipients are calculated from the midpoint of
the therapy to the onset of CJD. The longest incubation period illustrated on this slide
is 30 years and this number may increase with ongoing surveillance, based on experience
with Kuru.
Note that at least one iatrogenic case first appeared after each central
nervous system mode of infection within 1.3 years. And after each intramuscular mode of
infection, within five to 12 years. None of the reasons I have mentioned for concern about
transmission of CJD by blood products including the laboratory experimental data has yet
to establish the magnitude or even the existence of the possible risk of such transmission
to humans.
Next slide. For this assessment, epidemiologic data are useful, including
case reports, case control studies, routine surveillance data and special studies of
persons with unusually high exposures to blood. Based on the existing epidemiological
data, CDC has concluded that the risk, if any, of transmission of CJD by blood products in
humans is small and remains theoretical. The term "theoretical" continues to be
used to describe this risk because we are aware of no compelling evidence that has been
reported for any instance of CJD transmission to a human recipient by a blood product.
Next slide. The continued absence of convincing reports of blood
transmission of CJD provides increasing reassurance about the size of the risk. Although
spontaneous or passive reporting of disease by physicians is almost never complete, it is
noteworthy that strong evidence for an etiologic association of CJD and receipt of a
Lyodura graft was initially obtained through a follow-up investigation of a single
spontaneously reported case of CJD to CDC in 1987. Astute physicians were the first to
suspect and report the relationship. It was also an astute physician who in 1985 first
reported the probable etiologic association of CJD and receipt of pituitary derived human
growth hormone.
Shortly thereafter, the National Institutes of Health and CDC began
conducting both retrospective and prospective investigations of recipients of this hormone
distributed by the National Hormone Pituitary Program since 1963. One finding of this
investigation has been that the passive reporting by the astute physician in 1985 had
detected one of the earliest cases in this CJD outbreak in the United States.
Some reassurance about CJD and blood safety is also gained when reports of
possible problems are received by not corroborated on follow-up investigations. Earlier
this year in the United States, for example, concern about a possible CJD illness in a
12-year old deceased hemophilia patient was alleviated by negative follow-up brain tissue
studies. A pathologist had raised the question about CJD in this patient. Similarly, Dr.
Maura Ricketts of the Laboratory Center for Disease Control in Ontario, Canada, recently
confirmed to me that a follow-up investigation ruled out a suspected cluster of CJD
reported among recipients of a single lot of a plasma derivative derived in part from a
known CJD donor, that is a donor who subsequently developed CJD.
Had the CJD diagnosis for the young hemophilia patient in the United
States or the suspected cluster of CJD cases in Canada been confirmed, either confirmation
could have provided strong evidence for CJD transmission by a blood product.
Next slide. In addition to the absence of convincing case reports of CJD
transmission by blood, case control studies also provide epidemiologic data relevant to an
assessment of the risk of such transmission. The results of five such CJD case control
studies including one large study in Europe that is not yet published support CDC's
conclusion that the risk if any of CJD transmission by blood must be low. As shown in this
slide, an article published by Dr. Wientjens, et al. in Neurology 1996, reported that a
history of transfusion was not a risk factor for CJD. This finding was based on a
reanalysis of a combination of three case control studies in Japan, the United States, and
the United Kingdom. Only 9.8 percent of 174 patients with CJD compared to 13.7 percent of
328 control subjects had a history of a blood transfusion. The adjusted odds ratio was 0.6
with a 95 percent confidence limit between 0.4 and 1.2. Control subjects included spouses,
neighborhood controls and various hospital controls, and in none of the three studies
analyzed separately was the proportion of CJD patients with a history of blood transfusion
higher than that for their controls. The CJD cases in the three studies were diagnosed
between 1970 and 1984.
Next slide, please. A fourth case control study published by Drs. Esmond
and coworkers, January 1993, in the Lancet, included 63 cases of CJD identified between
1990 and 1992 in the United Kingdom. These 63 cases were not included in the pool data
published by Dr. Wientjens, et al. in 1996. These additional 63 cases of CJD were
identified in the United Kingdom through prospective national surveillance begun primarily
because of public concerns about the possible spread to humans of Bovine Spongiform
Encephalopathy.
As in the other case control studies, a history of receiving blood was not
a risk factor for CJD. Only six, ten percent, of the 63 CJD cases compared to 14 percent
of the 63 age, sex matched hospital control subjects had a history of receiving blood. It
is noteworthy that in this latter study, the authors specifically remark that they tried
to correct for a possible bias towards an increased prevalence of transfusions in their
hospital control group by excluding from the analysis all past medical and surgical events
related to their current hospital admission.
Next slide, please. In an analysis of all 155 CJD cases from the United
Kingdom, Dr. Esmond and coworkers documented that a similar proportion of CJD patients, 15
percent, and controls, 13 percent, had a history of donating blood as well as of receiving
blood. In brief then, the published case control studies indicate that a similar
proportion of CJD patients and controls donate blood but that having a blood transfusion
is not a risk factor for the disease.
With regard to this latter point, the next speaker today, Dr. Robert Will,
of the National CJD Surveillance Unit in Edinburgh, Scotland, kindly shared with me that
the current case control study, the data from the European Collaborative Study of CJD Risk
Factors, that they're further corroborating these earlier published case control studies.
Dr. Cornelia Van Dwine [ph] of the Netherlands is the principal author of this European
study, which with its over 340 enrolled cases is the largest CJD case control study to
date. And he may have more to say about that later.
Next slide. In addition to case control studies, the risk of transmission
of CJD by blood can be assessed through long-term follow-up data on recipients of blood
products derived from an identified CJD donor. In 1995, a letter from Germany in the
Lancet journal was the only such published data available. This letter indicated no
evidence of transmission of CJD to either 27 patients who definitely or eight who probably
received a blood unit from a CJD donor who died in 1991. None of the recipients in either
group died of CJD. The transfusions were received between 1971 and 1991. At least 13
patients in the two groups including at least seven who definitely received a blood unit
from the CJD donor survived ten years or longer after the transfusion, and eight patients
in the two groups lived for more than 15 years afterwards.
Next slide. In 1995 at the request of the Food an Drug Administration, CDC
and the American Red Cross initiated a long-term follow-up study of recipients of
transfusable blood components derived from CJD donors who are reported either to the
American Red Cross or to any one other blood center that might wish to participate. The
initial collaborators are listed on this slide. Although Ms. Marian Sullivan recently left
the American Red Cross to become executive director of the National Blood Data Resource
Center, an affiliate of the American Association of Blood Banks, she continues to serve as
this long-term study's project leader and principal investigator.
Next slide. In brief, using primarily the National Death Index, this study
has gathered information on the vital status, and if deceased, whether CJD was the cause
of death in 196 recipients of transfusable blood components from 15 donors who
subsequently developed CJD. At last report, none of these recipients had died of CJD.
Based on the evidence collected to date in this study, 42 of these recipients lived five
or more years after their transfusion. These transfusions were received a median of five
and a half years before the onset of illness in the CJD donor.
12 of these 42 recipients survived at least ten years after their
transfusion including five who lived between 16 and 25 years afterwards. The numbers of
CJD donors and investigated recipients and the duration of follow-ups after transfusion
will continue to increase in this ongoing study.
The next slide, please. Additional epidemiologic evidence on the possible
risk of transmission of CJD by blood products is available from other ongoing
collaborative CJD surveillance projects at CDC. For national surveillance of CJD 1979
through 1995, for example, we extracted information on the deaths of U.S. residents for
whom CJD was coded as one of the causes of death on routinely reported national multiple
cause of death data. These data are based on information reported on death certificates.
During this 17 year period, a total of 3,904 cases of CJD were reported to CDC through
this national mortality system.
This slide shows the total age adjusted as well as the age specific annual
death rates per million population in the United States for the years 1979 through 1995.
Note particularly that the total age adjusted annual death rates illustrated by the red
line have been relatively stable at about one CJD death per million population. These
relatively stable annual CJD death rates and the previously described evidence that
persons with CJD do not differ from control subjects in their history of receiving or
donating blood support the conclusion that despite regular blood donations by donors who
subsequently develop CJD, blood transfusions do not appear now to be amplifying CJD
infections in the population.
My best projected estimate for the comparable CJD death rate for 1996
based on available partial data for that year, which thus far consists of 218 additional
reported cases is that this death rate will be similar and probably slightly lower than
the previous year.
The next slide. This next slide shows by age group the number of CJD
deaths and the number of these deaths reported with Hemophilia A or B, Thalassemia or
sickle cell disease, diseases with increased exposure to blood or blood products. Note by
the zeros in the third column of the slide that none of the 3,904 cases of CJD identified
in the multiple cause of death data, 1979 to 1995, were reported also to have had
Hemophilia, Thalassemia, or sickle cell disease. Because many of the patients with these
diseases as well as other patients are exposed to blood products at a very early age, and
because the incubation periods observed for iatrogenic CJD cases related to intramuscular
injection of hormones have been as short as five to 12 years, it is also noteworthy as
indicated on the bottom of the slide with the asterisk that no CJD cases were reported in
persons five to 19 years of age in the United States during the 17 year period.
The additional 218 cases reported to date for 1996 continues to be
consistent with the data for the previous 17 year period shown on this slide. According to
Dr. Bruce Evitt, Chief, Hematologic Diseases Branch, CDC, the clotting factor concentrates
used by hemophilia patients to control bleeding are made from plasma pools derived from an
estimated average number of between 20,000 and 30,000 donors. Although as many as several
hundred thousand donors may have contributed to plasma pools associated with some lots of
factor concentrates in the past, manufacturers appear now to be reducing this maximum
number of donors associated with an individual lot to 60,000.
Since regular recipients of such concentrates can be expected by chance
alone to have had exposure to CJD donors through these treatments, hemophilia patients
constitute an important sentinel group for assessing the possible infectivity of a blood
product from such donors. In addition, recent animal models that we've heard today
indicate that cryoprecipitate prepared from the blood of CJD infected rodents is more
infectious than other derivatives. Since the mid-1960s, an estimated several thousand
hemophilia patients have received cryoprecipitate, particularly patients treated before
clotting factor concentrates became widely used in the early 1970s. Thus, in addition to
general CJD surveillance through the multiple cause of death data, which indicates the
absence of CJD in any hemophilia patient in the United States between 1979 and 1995, CDC
has actively sought cases of CJD specifically among persons with hemophilia.
The next slide. About 12,000 of the estimated 17,000 hemophilia population
in the United States are cared for in hemophilia treatment centers. Despite increased
publicity about CJD in this hemophilia community since late 1994, no case of CJD in a
hemophilia patient has been confirmed to date. In addition to alerting over 120 U.S.
hemophilia treatment centers in September 1995 about CJD surveillance, CDC has continued
to make follow-up inquiries quarterly to the largest of these centers where the majority
of the active hemophilia patients are enrolled.
In addition, Ms. Anna Kurinsik [ph] and Ms. Elizabeth Barnhardt from Dr.
Evitt's Hematologic Diseases Branch report that as of the end of 1997 CDC had obtained
histopathologic slides of brain tissue or the brain tissue itself on 29 deceased
hemophilia patients to search for a possible unrecognized CJD infection. On
neuropathologic review, none of these brain tissues were found to have evidence of CJD.
The mean age of these patients at death was 40 years. Eight died at over age 50 years. 21
of the patients were known to have severe hemophilia disease with a baseline factor
activity of less than one percent. The major causes of death included AIDS, post-hepatitis
cirrhosis, liver failure or lymphoma.
Next slide. At the suggestion of Dr. Paul McCurdy and to assist in a
further assessment of the absence of CJD among hemophilia patients who specifically
received cryoprecipitate, Dr. Arthur Thompson submitted to CDC a follow-up report in April
1997 on a cohort of cryoprecipitate recipients currently under surveillance in Seattle.
Earlier this month, I spoke with Dr. Thompson and he updated his report through 1997. This
cohort has included 101 patients with a blood clotting disorder who had received at least
100 units of cryoprecipitate between 1979 and 1985. 90 of these patients had Hemophilia A.
Altogether during the seven year period beginning 1979, this cohort was known to have
received just over 238,000 units of cryoprecipitate.
Since members of this cohort received additional cryoprecipitate before
and/or after this seven year period, this measured exposure represents only an estimated
one-half to two-thirds of their overall exposure. Each unit of cryoprecipitate came,
however, from an individual donor. Recent follow-up date on this cohort revealed that 76
were alive, a minimum of between 12 and 18 years after their receipt of cryoprecipitate
and 25 were deceased. None had developed CJD.
The follow-up information specifically indicates that at least three of
the surviving hemophilia patients had received cryoprecipitate from a known CJD donor. One
of these hemophilia patients received cryoprecipitate in 1985 from a donor who developed
CJD about ten and a half years later, and two of these hemophilia patients had been
exposed to donations in 1986 from another donor who died of CJD about four years later.
Next slide. In ending this discussion of CJD and blood safety, I emphasize
that despite some laboratory experimental evidence suggesting a potential for blood-borne
transmission of CJD, the accumulating epidemiologic data from both published and ongoing
studies of the classical forms of CJD prevalent in the United States have strengthened
CDC's conclusion about this risk. The conclusion is that the risk, if any, for
transmission of CJD by blood products is small and at present appropriately regarded as
theoretical.
Next slide. The most important controversial aspect of the present interim
policy in the United States i that it calls for the retrieval and quarantining of plasma
derivatives derived in part from a person who either subsequently develops one of the
classical forms of CJD prevalent in the United States or who is at increased risk of such
CJD. This aspect of the current policy appears to help reassure many concerned people
about the safety of the blood safety, but this policy also leads to the frightening of
increasing numbers of persons who learn that they have received a withdrawn product.
There are legitimate concerns about the appropriateness and efficacy of
this aspect of the current policy because, as Bob had mentioned, the vast majority of
blood products derived from CJD donors are not withdrawn. Often they are used before the
CJD illness in the donor becomes clinically apparent. Our current interim CJD blood safety
policy is potentially very costly. Withdrawals and quarantines of blood products from CJD
donors and donors at increased risk of CJD were estimated by a member of the American Red
Cross earlier this year to have affected over $100 million worth of blood products.
In addition, our interim policy risks creating or aggravating product
shortages, particularly since to my knowledge there is no agreed upon warning label or
mechanism in place to use quarantine product to prevent or reduce shortages that might be
created. If, for example, during the next few months, an unused lot of end date human
intravenous immunoglobulin should need to be withdrawn from the market because of the
current interim policy on CJD, this withdrawal would aggravate an already existing
scarcity of a product that is known to be potentially life saving. Finally, based on
currently available epidemiologic data, the current interim policy does not have a clear
benefit in terms of preventing CJD.
Next slide. As final observations, the issue of CJD and blood safety
illustrates that even a relatively rare transmissible disease can sometimes create an
important evolving complex public health problem. The associated risks deserve ongoing
evaluations. Surveillance and other epidemiologic data can be very important for
continuing to assess these risks and to help guide our public health policy. Thank you.
DR. PENNER: Dr. Schonberger's presentation is open for discussion. Dr.
Caplan.
DR. CAPLAN: I was just wondering in the reporting from death certificates,
are you satisfied that clinically these CJD cases would be recognized by people filling
out their certificates, and then related to that, what plans are afoot from the
epidemiological point of view to do more routine requests for autopsy and tissue samples
from hemophiliacs? Is there any plan afoot to go and sample, try and request and organize
a program so that a larger number is there than the 28 you had?
DR. SCHONBERGER: My understanding from Bruce Evitt who has gotten
increased funding to do this, and he has, in fact, initiated such efforts, and he tells me
that reports even, for example, for last year are expected to increase, and so I think you
will see more of this type of looking for the silent unrecognized cases. With regard to
death certificates, death certificates are notoriously incomplete. We recognize that. We
did a study right after the announcement from the UK about the problem of the New Variant
and had our Emerging Infectious Disease groups do a very active surveillance in a
population of about 63 million in the United States, and we found an amazingly good
correlation between what they were able to find through active surveillance and calling
all the neurologists and what we had in the death certificates. It came out to something
on the order of 87 percent. There's also been studies in the distant past about death
certificates. We put in the MMWR that we thought it was at least 80 percent based on the
study that had been done earlier, and that study may well not have used what they call the
multiple cause of death data. That study may have used even the underlying cause, and what
we have found is that frequently the doctors will put CJD on the death certificate but not
have it as the underlying cause, and we've learned to increase the sensitivity of our
surveillance by looking at every diagnosis on the death certificate.
The other issue is that one would have to assume that the cases that are
somehow being missed, that few percent that's being missed, is somehow different from the
cases that we are finding with regard to their exposure say in these case control studies
to their exposure to blood, and we don't really suspect that that's the issue.
The other issue is that the cases that are young tend to stand out and
that the real problem is to try to get physicians sensitive to the concept that maybe CJD
could occur in that population. And as I say, since there was this very extensive donor, I
think he was in the ten gallon club or something in 1994, we've been very heavily
announcing to the hemophilia physicians and the hemophilia centers to look at this issue
and not ignore any hemophilia patient that might have symptoms of CJD and it's an
education process. I would say that Bruce talks about needing to change behavior of people
so that they will be willing to have their full brains donated for this kind of study.
It's happening slowly, and the numbers should increase.
DR. CAPLAN: Just to follow up on that, are you persuaded that the effort
to teach doctors who treat hemophiliacs or other high blood users to recognize this as a
possible underlying cause of death is adequate where it's at or is there more to be done
there?
DR. SCHONBERGER: Well, I understand that Bruce is continuing to work on
this issue. I'm sorry--is Bruce, did he come? You know my own judgment is you always need
to improve that, and what we're worried about is that people who developed AIDS and had
some dementia from AIDS might be missed, and, in fact, most of the 29 deaths that we've
looked at, in fact, died of AIDS and that one case where I mentioned in that 12 year old,
one of the pathologists saw some evidence of spongiosis, but apparently that is also seen
in AIDS dementia, and we had the specimen go to Dr. Dirmand [ph] for a look, special
staining for prior, and it was quite clearly negative. There's always room for improvement
in this type of surveillance.
DR. PENNER: Dr. Kuhn.
DR. KUHN: Yeah. If you would just indulge me just a couple minutes here.
It seems my perception that the reason that there was no CJD evidence of cause of deaths
in hemophilia between 1979 and 1995 in your slides is more than likely they were AIDS
deaths, and so that number might be a little bit skewed with statistics there. Also, I
think there probably hadn't been autopsies or clinical autopsies done on those AIDS death.
I know you've done 29, but I understand from Bruce Evitt that there is approximately 1500
AIDS dementia deaths in hemophilia. Now, I know they haven't had clinical
autopsies either. I know you're starting studies on that.
So I think that, I mean I feel like it's kind of inclusive, you know,
whether or not those were CJD deaths at that point, and then one other question I wanted
to ask you is you said that there was one person received blood from a donor in 1985 and
two in 1986. What was the end result of their lives? Are they still living?
DR. SCHONBERGER: Yes. The ones that received a blood from a CJ donor are
still alive, and they're being watched. Thompson is aware of these people.
DR. KUHN: Right. Okay. Thank you.
DR. SCHONBERGER: Yeah. Let me just respond a little. The age of the
patients that I mentioned, I'd say eight of them were 50 years old or older. There was
even one in the 60s. Okay. So even though AIDS did devastate the population, there's no
question--it's a terrible tragedy--there are still many of them that are older. The main
issue in terms of policy decision is not so much whether we've ruled out every possibility
that there's a risk because epidemiology isn't going to be able to do that if that's what
you're asking for us to do. We're trying to give you a picture of what we do have, and you
make your best sort of judgment from that.
But I think the point that Bob Rohwer was making, withdrawing product that
is regularly coming from 60,000 different donors and people who have received that, just
statistically an epidemiologist will tell you that these people are exposed. Okay. And
that the effort of withdrawing and putting all this effort to withdraw an occasional one
that you happen to catch--okay--and then informing that person so that person has the
sense that, oh, my God, what did I get--all right--when we know statistically and
epidemiologically that that one particular lot doesn't make a whole lot of difference in
the overall population risk or in that individual's risk.
For example, if you're a mild case of hemophilia, and you should get
notified, I have these people, they call me, they get scared, oh, my gosh, you know,
they've withdrawn the product, it's almost unfair to that person in my view--okay--to have
scared that person when I know that all his friends who are the severe cases were not
informed are actually exposed to more CJD donors than this individual that happened by
chance to be informed. So there's a problem here with that aspect of the policy.
And the other issue is, and I've heard different stories and maybe you can
look into this, is the IVIG shortage. You know a letter went out yesterday to doctors
talking about an IVIG shortage. I understand that that's not directly related to the CJD
policy, but the truth is that in October and in November of this year, we had, and you'll
read it in the Hemophilia Foundation newsletters, many lots of IVIG withdrawn. It turns
out that most of that product was already used. So that's why I say it probably didn't
contribute too much to the current shortage. But if, and I said in my talk, in the next
couple of months you get another CJD case, and it happens to affect a IVIG lot that is
still available, that's been unused, and that has to be withdrawn, then what this
committee has to balance is what's the consequence of keeping a life saving product from
other people, and as I was walking here, several people were claiming that they knew of a
splenectomy that had been done because IVIG was not available, and I know Kawasaki
Disease, you get increased risk of heart disease and so on. So there are consequences to
this withdrawal policy from a health to health. And that's what this committee has to try
to weigh, but you're right, I can't say definitely that it couldn't cause an occasional
case. The epidemiology isn't that sensitive to be able to tell you that.
DR. PENNER: The splenectomy should have been done anyway, but Dr.
MacDonald?
DR. MOORE: The first point I want to make is I agree with the comments
that you've just made and certainly support that perspective, but I do have a couple
little questions on the data that you've presented.
DR. SCHONBERGER: Sure.
DR. MOORE: First of all, on the case control data, were there power
calculations done on those studies or are you aware of any?
DR. SCHONBERGER: Well, the power that I showed you for the one where it
was given in terms of the 1.2 maximum relative risk, I think what you find when you look
at each aspect of the epidemiology, each one itself doesn't have that great a power.
DR. MOORE: Right.
DR. SCHONBERGER: And that what you sort of have to do is kind of pull back
and look at the whole gestalt of all the studies together.
DR. MOORE: Right. Which I do agree with, but I did want to ask that
question. And the next one, getting back to a point that Art had made, in looking at the
follow-up on the hemophilia patients and the death certificates, when you pull death
certificates, did you cast a wider net looking for neurologic disease, you know, because
it may not have been listed as CJD on the death certificate, but there may have been
unspecified neurologic something?
DR. SCHONBERGER: No.
DR. MOORE: Okay.
DR. SCHONBERGER: No, they would have to have had a specific code for CJD
on the death certificate for that aspect of it. But that's why rather than just depending
on that and because of the importance to the hemophilia, and it's the one group that you
can pretty well rely has been exposed, you know, to as I mentioned a part of the fraction
of the plasma that Dr. Rohwer has indicated is just where the material might go in the
plasma, and consider most of that population exposed, and that's why we've been doing this
special effort of surveillance independent of the mortality data on the hemophilia
population, and Art Thompson assures me. He says I have a good handle on my patients. It's
like family. I mean I'm not as familiar with it, but Thompson apparently is very--his
nurses and so on are very tied to many of these patients.
DR. MOORE: And I think that certainly is very true in many hemophilia
centers. And my last question was just related to laboratory diagnosis. I'm not aware of
what kind of work is being done trying to look at laboratory diagnostic tests for CJD. I
mean some of the new molecular epidemiologic tools or molecular tools that are available.
Can you just comment on any type of look at some of that?
DR. SCHONBERGER: Well, I think that Dr. Joe Gibbs is one of the leading
world's authorities in this area, and maybe he's going to be talking--I don't know if Dr.
Gibbs, you want to discuss some of the laboratory developments in this area for a
diagnosis?
DR. GIBBS: Well, I will present that during the course of my presentation.
DR. MOORE: Okay.
DR. CHAMBERLAND: Larry, I know you touched on it, but I didn't catch all
of it, and maybe you can amplify on it, in the follow-up study of recipients who have
received blood from donors who were subsequently diagnosed of CJD, what are the
distribution or mean range of times from the receipt of that transfusion and the donor's I
guess diagnosis of CJD and the date that he donated?
DR. SCHONBERGER: Right. It's a median of about five and a half years with
a range from there's one that got it right away like, in fact, there's a question about
whether the patient had already had onset of some symptoms--
DR. CHAMBERLAND: Donor you mean?
DR. SCHONBERGER: Yeah, donor. All the way to 21 years, but most of them
are right around that five year period. Of course, we don't know what the--I saw Bob took
a 40 year range for prevalence so that's one of the issues. The animal models tell us that
they're positive throughout the incubation period, but that's one of my concerns is that
data really applicable to people?
DR. PENNER: Another question? Yes.
DR. GUERRA: Has there been any observation made of possible vertical
transmission say from a mother to an infant during pregnancy?
DR. SCHONBERGER: The only data I know about that is from the Kuru
experience, and, Joe, do you want to comment at all on that?
DR. GIBBS: Yeah. There was the incidence of the transmission of
Creutzfeldt-Jakob Disease through the use of contaminated silver electrodes, electrodes
that had been in depth in a patient with Creutzfeldt-Jakob Disease and didn't sterilize,
then used on two young people, and one of the young people gave birth to a son, and that
was now more than, I suspect, now more than 15 years, and the son is doing well.
Experimentally, we've attempted to show vertical transmission with the human diseases
since the very beginning of the studies of human diseases. There's been no evidence of
vertical transmission.
DR. PENNER: Did that answer your question, Dr. Guerra?
DR. GUERRA: Yes.
DR. PENNER: Yes, Dr. Gomperts.
DR. GOMPERTS: Larry, a couple points. The first one is clearly there is
surveillance going on in the hemophilia centers among hemophiliac individuals who have
died with neurologic disease. What about other populations where there is a need for
chronic transfusion, sickle cell, Thalassemia, primary immune deficient individuals? Is
there an attempt to do such epidemiologic evaluation?
DR. SCHONBERGER: The only evaluation is through the routine mortality,
whereas I said we've not seen a single death record that codes both CJD and sickle cell
disease or Thalassemia on it, but there is no, we haven't done what we did with the
hemophilia population of going out and doing the more active type of surveillance in these
other populations. I must say that we did in the process of doing the intensive work in
the hemophilia population come up with a von Willebrand's Disease recipient because they
happen to have gone to the same hemophilia treatment center, and that patient was not
included among my 29. If you want to add that, that would be a 30th case that we have
submitted for special autopsy finding. That case was an older person who had received
cryoprecipitate and had had many blood transfusions and exposure to blood before he had
started to receive the cryoprecipitate so he had lots of exposure to blood, died of AIDS.
Older gentleman, I think he was 66 years old, and there was no evidence of CJD in the
brain.
Now one of the questions is do you expect to find if somebody does not
have neurologic symptoms, you know, evidence of CJD in the brain, and I can tell you that
a study of the human growth hormone patients did identify such a case. There is one case
in the U.S. of a person who was a human growth hormone recipient whose autopsy was
relooked at as a result of the special surveillance that we had going, and the patient had
not died with neurologic symptoms, had died of a respiratory problem, and we found
evidence in the brain of that individual of CJD, and it's really largely based on that one
case that we've really decided to look at hemophilia patients who may not have a diagnosis
of CJD. In a sense, there are two reasons. One is could the doctor have misinterpreted the
signs, but the other is could we even find evidence of CJD that was inapparent?
DR. GOMPERTS: Larry, one other point. Bob Rohwer raised the important
issue of silent subclinical amplification, and I'm sure your epidemiologic surveillance
would pick that up once that became apparent and it wasn't subclinical.
DR. SCHONBERGER: Well, it depends how explosive it's going to be. If I
show you the data and then you can probably take from that data and try to speculate how
it could still be missed, and I could come up with a potential way that we could still be
seeing what we're seeing, and if you're talking about a very long period and, you know,
have it slowly build up. But, you know, we do have the reassurance, because as we've
learned, this CJD that we have in the United States has been around for a long time, and
blood transfusions have been going on for a long time. But this disease can, you know,
have a very long incubation period. So you put that into that context. What is more of
concern is what you'll hear about from Rob Will, which is the New Variant CJD, and the
reason that that's of more concern is that in part is not only what we do see from it
shows that it seems to be behaving differently, and we don't have as much experience. And
the data that I'm presenting is really relevant to that part of our policy that deals with
the recall and retrieval of blood that is derived from CJD that is the classical CJD that
we have prevalent in the United States, and I think--Bob will clarify this--but I think if
they in the UK go out and check and find out that the CJD case that gave blood--and Bob,
correct me if I'm wrong--and you find out that it's the classical form, you say, ah, okay,
no problem, and you don't start withdrawing the blood. But if it's the New Variant, then
you have more concern. At least that's been the policy in the past. I don't know if that's
now going to be changed.
DR. GOMPERTS: I think that's the point. As I see it, blood is one aspect
of the potential iatrogenic transmission, as we've talked about. There are other
possibilities that we may not know about. The other way of transmission is through the
oral route. So the question on the tow in my mind is is it possible at some point or
another where a dose effect becomes important, which we won't know about, and then it will
become apparent through transfusion or other iatrogenic type situations?
DR. SCHONBERGER: All we can say now from the data is that we don't see
evidence of that now, but you can speculate that, as was done, that maybe something like
that could happen.
DR. PENNER: Dr. Gilcher.
DR. GILCHER: Two questions. One may be more appropriate for Dr. Rohwer and
the other for you. But the first one, in animal models, have there been any protective
mechanisms that have been identified that prevent transmission of any of the spongiform
encephalopathies? The second question, which is in a sense related, in humans is there any
other disease associations or specifically non-associations with CJD or other
transmissible spongiform encephalopathies?
DR. SCHONBERGER: With regard to the first one, maybe Bob--what I'm aware
of would be the Codon 129 story. I mean one of the issues right now with whether the human
population is susceptible to New Variant CJD is related to these transgenic mice
experiments, and up to this point, all the New Variant cases have had a methionine genetic
picture at the Codon 129, and the mouse that they've been using has a valine-valine at
that position, and it appears to greatly --there's a lot of research in the literature
that would suggest that that tends to provide the human with some resistance. If you take
a group of sporadic CJD and look at that allele, you'll find that it's much more enriched
for methionine than you would in the general population. So in the general population,
let's say you might get 40 percent or something of methionine and methionine. In the
regular sporadic cases, it's probably over 70 percent. Okay. So there is at least that
component, and Bob, are you aware of any other mechanisms of susceptibility and resistance
in animals that you're aware of?
DR. ROHWER: Well, there are comparable genetic effects in animals, and
there are polymorphisms in the prion gene which affect the incubation time in mice, for
example, in a very dramatic way. It's doubled the time, as a matter of fact. But I think
one of the really important things there to be careful about is that even in the case of
meth-meth and valine-valine and the heterozygous and zygotes in humans, John Collins has
some very compelling data that you're not preventing the infection in those animals,
you're just delaying the onset of clinical disease. The course takes much, much longer to
reach clinical effect in certain background, genetic backgrounds, than in others.
And that's definitely the case in say the scrapie model or scrapie mouse
models that we know about with the incubation time polymorphous. They all get it. It's
just a matter of when they get it.
DR. SCHONBERGER: Maybe let me get Bob Will on this, too. Dr. Will is a
coauthor, as I recall, on some of these case control studies that have been published, and
the question is, and I know sort of what you wrote and you're also knowledgeable about the
European study. He's asking about whether there are any other identified risk factors in
epidemiologic studies of CJD?
DR. WILL: I think the answer to that is that overall there's no consistent
additional medical risk factors that have been identified in any of these studies. Some of
them, individual things like a previous trauma in one study, some sort of head and neck
surgery in Japanese study, but if you look at the data and together as a group there is no
consistent finding. One problem with that is that the numbers are so small that you don't
know you're not missing something in following these studies, but certainly even in the
larger study, European study which we're sure to publish, there is no striking medical
risk factor.
DR. SCHONBERGER: Thank you, Bob.
DR. PENNER: Any other questions from the panel? If not, we will be taking
our break. Before doing so, our esteemed chairman and TV celebrity is here, Dr. Caplan,
who will take over, Art. And I think we're adjourned and we'll return in about 20 minutes.
[Recess.]
DR. CAPLAN: Before we get underway to continue with the next two speakers
in our program, I think Dr. Nightengale has an announcement that he needs to make about
the public session this afternoon.
DR. NIGHTENGALE: Yes. So that everybody can see me, I'm Steve Nightengale,
and if all those who wish to speak this afternoon at the open session could meet me right
after this session, we could arrange a mutually agreeable order of presentations. I'd
appreciate that. Thank you.
DR. CAPLAN: We have an open public comment period you'll see in the agenda
this afternoon, and one of the things that I want to be sure of is that we leave time for
the panel to talk about a number of the issues that have already been raised in the
presentations. I flagged certainly three issues that have come up already. Is surveillance
adequate with respect to CJD? Obviously the issue of policies about how to quarantine or
withdraw or handle supply that might be at risk is an issue. And they're even questions
about whether we need to do more to try and report possible cases and whether there could
be educational efforts that would lead to improved death certificate monitoring,
encouragement of autopsy and so on?
So I've flagged a couple of issues myself that I would like to hear some
discussion by the panel about later and you may begin thinking, I hope, about issues that
jump out in your mind, and what I'm going to be pretty tough about, just so we know when
the public comment period comes, is five minute presentations. While it's important that
we get as much input as possible, we need some time too to talk about what we're hearing.
So I'm going to ask all the speakers this afternoon to keep it to five minutes. If they
want to submit written statements, that's obviously welcome by the panel. I have a feeling
we will be talking about this again tomorrow so there will be time for some more
interaction with the audience in terms of issues, but it is essential that we leave here
today we have some chance to discuss some of the things we've heard and maybe even pick
out some priorities of issues we think important.
Let me ask, if I can, are there any other issues that any of the panel
want to get to before we go to the next session? I know that we'll have an opportunity
tomorrow, too, just so the panel knows. We've got some old business and new business
sessions in there both to look forward to future issues and to look back particularly with
the hepatitis C and the letter that we got from Dr. Eisenberg and Secretary Shalala and so
on. So some of those issues we definitely have time to discuss a little bit, if any of you
want to do that.
Our next speaker in a series of what has already been very illuminating
talks is Dr. Robert Will, and he's going to tell us about new variants that have come up
with CJD.
DR. WILL: Well, first of all, I better just explain what happens in the
United Kingdom in relation to surveillance of CJD, and that is since 1990, we've been
trying to identify every suspect case in the United Kingdom, and this has involved direct
referral largely from neurologists of all suspect cases, and in the great majority each
individual is visited by a research registrar, who examines the patient and obtains
various information on risk factors from a relative, and we try to obtain pathological
confirmation in cases actively, and the current postmortem rate is about 70 percent.
In this way, we believe we get fairly accurate case ascertainment. We also
get fairly accurate information on risk factors in CJD. In the United Kingdom, previous
surveillance has taken place using identical methodology between 1980 and '84 in England
and Wales, and we also have some retrospective data going back to 1970s. We have a lot of
data on classical CJD on which to judge any change. Could I have the first slide, please?
Now, what I was going to do was to explain a little about what Dr.
Schonberger has already said just to reinforce some of the implications of the
surveillance of CJD and case control studies. In the England and Wales study, '80 to '84,
CJD, 15 percent of all cases had previously acted as blood donors. Currently, in the
European study, it's something of the order of ten percent of all cases of classical CJD
have previously acted as blood donors. The policy within Europe is not to advise
obligatory withdrawal of blood product, and one of my colleagues, Professor Pockuri [ph],
has calculated that if we started to withdraw all product from these identified donors
through active surveillance, we would end up with severe shortages of potentially life
saving treatments.
And I think it is the case that if you could carry out active surveillance
for CJD, you will identify a significant proportion of cases who have previously acted as
donors in the past.
Next slide, please. As far as lookback studies are concerned, Larry
Schonberger has already described this one case from Germany which was looked at
retrospectively with no good evidence of transmission of CJD, but this is one case with
limited follow-up data. We have initiated a similar lookback study in the United Kingdom
which has potential advantages because what we have data on were blood donors from 1980 to
'84, and if we were able to identify the recipients around that time, we would have a long
potential follow-up period in relation to the development of subsequent CJD should that
indeed occur. And the reason I put this up is just to remind me to say that we're having
enormous difficulties with this study, and the reason for that is that the data really
isn't there.
The actual data from the past linking donors to recipients is missing or
is difficult to find, and I find that very disappointing because I think in looking at the
reality of whether nor there is a risk in relation to blood donation in CJD, this type of
study is likely to give the best information, and I don't think we're going to be able to
get information from this study.
DR. GOMPERTS: Dr. Will, could you identify if in a particular donor if
it's New Variant or classical?
DR. WILL: I'm simply talking about classical CJD at the moment.
DR. GOMPERTS: Thank you.
DR. WILL: And the reason I wanted to mention this is to inform you of the
policy currently is we do not do withdrawals with classical CJD in the United Kingdom, but
we have recently adopted a policy or the government has of suggesting that they should be
withdrawals of product from all individuals with New Variant CJD who have acted as blood
donors, and so far we have found four out of 23 cases who have previously been blood
donors with New Variant CJD and active withdrawal of product has taken place.
And I think one important question is why is the decision different
between the two types of CJD, and I thought perhaps I would just discuss the evidence in
relation to New Variant CJD as to why we think it's different. Could I have the next--
DR. PENNER: Any autopsies on the patients, the 21 who are dead?
DR. WILL: Sorry? This is a case, this is the German study published from
Hess, and I just put it up to remind me to talk about the lookback. Next please.
As I said, we've obtained a lot of information on Creutzfeldt-Jakob
Disease, and here age specific incidence rates for age of death for the classical form of
CJD, which shows the usual pattern with a rise up to middle age, late middle age, 69/70
sort of age, there's the maximum, and a decline in the elderly. And this has been
replicated in country after country with systematic surveillance.
In late 1995, early 1996, we began to identify young patients with suspect
CJD, and these are these individuals who are crosshatched here showing a completely
different and unexpected age distribution from previous experience of CJD. And this age
factor was the first clue that something odd was happening in the United Kingdom in
relation to CJD.
Could I have the next slide, please? So far this is an old slide that
keeps on being outdated. There are 23 cases of New Variant CJD in the United Kingdom, 22
of them are pathologically confirmed, and one has been classified as probable, and there
is only one case of pathologically confirmed New Variant CJD in France.
Next slide, please. These New Variant cases are very different from
classical CJD as a group. In sporadic CJD, as I've said, the age range is 50 to 75. In New
Variant CJD, it's 18 to 50 at death. The mean age at death is about 29 in relation to
about 65 with classical CJD. The duration of illness in sporadic CJD is usually less than
a year. The means about four and a half months from onset to death. Currently, New Variant
CJD, the mean duration of illness is about 14 months, which is quite different.
The presenting symptoms, which I will not go on about, they're interesting
neurologically, I think, rather than anything else, are predominantly psychiatric or
sensory, and the great majority of all these patients have been seen initially by a
psychiatrist rather than a neurologist. The investigations are different. In sporadic CJD,
about two-thirds of patients have what's called atypical EEG, which is very important in
diagnosis. This appearance has not been seen in any of the New Variant cases of CJD. And
critically, the neuropathology in the two types are quite different.
Can I have the next slide, please? This is the neuropathology in New
Variant CJD. The cerebellum shows extensive deposition of PrP protein, the disease
associated protein, and quantitative analyses have suggested that the level of protein
deposition is about twice that in conventional forms of CJD. What's also striking is that
the neuropathology appearances in all the cases with pathological confirmation have been
almost identical. The slides are almost interchangeable between cases. It looks like a
consistent new clinical and pathological phenotype of CJD.
The next slide, please. One of the possibilities was that these cases
might be genetic in origin because genetic forms of CJD familial cases often are younger
than the sporadic cases and kind of unusual clinical and pathological features, and the
situation currently is we now have 23 cases in the UK, and none of these cases have a
mutation of the prion protein gene following full sequencing of the open reading frame. As
I think has previously been mentioned, all the cases of methionine in homozygotes is a
Codon 129 of the PrP gene in comparison to 80 percent of sporadic cases of CJD and about
30 percent of the general population. It could be regarded as a susceptibility factor, but
I'm concerned that, in fact, may what happen is that we may see other genotypes at a later
date.
What's happened with the French cohort of growth hormone recipients is
that they initially started seeing methionine cases, then they saw valines. And most
recently they've got four heterozygotes with the longest incubation periods, and it may be
that this is not a true susceptibility factor but might influence the incubation period in
relation to an external infecting agent.
The other point about it is that some of these patients have a rather weak
family history of dementia, not New Variant CJD, I must stress, and we cannot exclude
currently the possibility that there may be other genetic factors outside the PrP gene
that might be important to susceptibility in these cases.
Next slide, please. Now, I'm only going to briefly mention risk factor
analysis. One of the questions is is there some common linking factor between these
patients that might explain the development of this unusual disease. None of them been
treated with human growth hormone. None of them have had a neurosurgical procedure, and in
relation to age and sex match control patients, the frequency of surgery in the past of
any sort is just the same, and indeed none of the risk factor analyses have shown any
specific factor that is unique to these patients.
Next, please. Here is the distribution of cases by onset of illness. This
is important because sometimes these patients move when they become ill. In fact, two of
these individuals died in countries other than the United Kingdom. This shows a general
distribution of cases. You are able to see very clearly there is very few here, there is
one here, and there is a general distribution throughout the United Kingdom. So it seems
that if this is a new disease, the risk factor seems to be relatively widely spread.
Next slide, please. And just to show the epidemiological problem of these
cases, this is from the original publication, and if we look at the age distribution, age
less than 30, we've got 25 years of experience of CJD in the UK with only one case under
the age of 30 in 25 years. Under the age of 30, I think the figure now is 16 patients
since 1995 in this particular age group, and you don't need to be a statistician to work
out that this requires explanation.
Next please. So is there a causal link between these cases and BSE? And
this is important because it may have implications for what is done about blood derived
from these patients. And one is the timing. Did it happen at the right time of its BSE?
Did it happen in the right place and do we have a common linking factor between the
patients?
Next slide, please. Well, this has been mentioned before. Incubation
period in human TSEs, the only information that's available comes from iatrogenic CJD.
What I'm interested in here is looking at the minimum incubation period if we assume that
these cases represent the early cases perhaps of an external exposure, a novel exposure,
and the mean with peripheral inoculation, which is probably what's relevant, for example,
reached a maturity almost about four and a half years minimum incubation period, one case
in France. And in Kuru, the minimum, I think Dr. Gibbs would agree, is around about four
and a half years in one child.
So how does that relate to the potential exposure to the BSE agent in the
UK? Could I have the next slide, please? This takes a bit of explaining. This graph here
is not a graph of the BSE epidemic because that may not be an accurate reflection of
exposure to the BSE agent. This comes from Professor Anderson's mathematical model of the
number of infected cattle that were required to produce the subsequent epidemic. This
starts about 1983, peaks about 1989, then according to the model would decline like this,
but in relation to human exposure, some legislative measures were introduced in 1989 which
would have reduced exposure to brain and spinal cord and other tissues significantly
perhaps by much more than this, but any human exposure declined suddenly at that time. And
now we have the onsets of disease of New Variant CJD 1994, '95, '96, leaving a minimum
incubation period from the peak of about six years and from the start of potential
exposure of about 12 years.
I think it's reasonable to argue that this type of minimum incubation
period is what you might expect, particularly when you're crossing a species barrier. This
is not human to human transmission. This is a BSE agent crossing to a new species and that
is likely to lengthen any minimum incubation period, particularly by the oral route. So I
think it happened at the right time of its BSE.
Could I have the next slide, please? Did it happen in the right place?
Well, here's an old slide from last autumn of the number of cases of BSE by country, and
as you can see in the UK that there were about 170,000 cases of clinical BSE by that time
in relation to smaller numbers in other countries, 256 in Switzerland; 224 in the Republic
of Ireland; et cetera, with small number of cases in imported cattle, I just stress. For
example, in Canada. These figures have changed a little since then but not markedly, and
the question is if BSE is the cause of New Variant CJD, it should be happening mainly in
the United Kingdom and not in other countries and, of course, that's exactly what's
happened, 23; one in France.
It's possible to ask, well, how do you know? How do you know there aren't
cases in other countries? Since 1993 in France, Germany, the Netherlands, Italy, Spain,
and now other countries within Europe, systematic surveillance has been going on using
similar methodologies to the United Kingdom. We believe that the information from these
countries is not only comparable, it's crucial to the hypothesis that New Variant CJD is
occurring mainly in the United Kingdom. So we think it's happening in the right place if
it's BSE.
Next slide, please. But we have not been able to find any common linking
factor. All of the patients have eaten meat at some time in the past, beef or beef
products, but not at a different rate from age and sex matched controls. And I think it's
easy to overinterpret this problem with identifying a common linking factor, and there is
a number of reasons. We have to use a surrogate witness for dietary history, often a
parent, who may not give a fully accurate account of dietary history. Often because of the
prolonged incubation periods, we're interested in exposures that took place ten or 15
years ago, and it's notoriously unreliable even asking directly from a witness about past
dietary exposures. There's respondent bias--we already know that from classical CJD
studies. But I think this is the most important issue.
If BSE did enter the human food chain in the United Kingdom, as I think it
almost certainly did, probably brain and spinal cord tissue, I think most likely spinal
cord tissue in mechanically recovered meat, then this product would not necessarily have
been uniformly contaminated with time. It may have been used in different products at
different times, and individual batches of individual products might have contained
different levels of infectivity. So identifying a common exposure 15 years later may be
impossible using case control methodology.
Next slide, please. So is this a new infectious agent? And that's the
critical question. That's the epidemiological evidence in which the original hypothesis
was based, and there has been more evidence subsequently. Here's a slide of the
appearances on H and E in New Variant CJD showing a Kuru plaque with a halo of spongiform
changes, a florid plaque appearance.
And the next slide shows a similar appearance which you can see here is a
plaque of halo spongiform change, and this is a particular model of scrapie. This is
Icelandic scrapie in mice. This is a slide from Dr. Bruce, and the reason I'm showing this
is that the pathology in mouse models can be defined by the agent strain. So the
implication is is it possible that the new pathology in New Variant CJD reflects a new
strain of infectious agent?
Next slide, please. And I don't know if I have time to explain this in
much detail, but I'll start at the beginning. These are transmission studies by Moyer
Bruce and colleagues, which were published fairly recently in Nature, and at the
top--along the bottom here are incubation periods measured in hundreds of days. These
symbols represent different types of inbred strain of mouse with different genotypes
influencing incubation period.
And the top of the findings that you have had in some strains of scrapie
over the years at the Neuropathogenesis Unit in Edinburgh, and what you see is a wide
variation in incubation periods using intracerebral inoculation in these different types
of mice. There is no consistent pattern. In similar experiments done with BSE agent is the
R-3 mice that seem to consistently go down at an earlier incubation period than anything
seen previously in scrapie, about 310 days. And then the different types of mice, C-57
blacks, come next, then next, then next. And this information on BSE is taken from
different animals at different stages of the epidemic and indicates in this experimental
model one strain of infectious agent in this bioassay system consistent in all cases of
BSE so far examined, and this is different from any strain of scrapie so far examined.
Surprisingly, Feline Spongiform Encephalopathy in the domestic cat is
thought to be due to oral exposure to the BSE agent, and in the experiments done with FSE,
the pattern was exactly the same within minor limitations as BSE, and similar experiments
have also been done with Niola [ph], Kudu [ph], and various other experimental species,
and the BSE agent always looks like this in these experiments even going through a
different species. So the hypothesis was if New Variant CJD is caused by BSE, if we
inoculate the same mice and if they get the same incubation period, that would be strong
evidence this was the BSE agent. And that, of course, is what's been done with three cases
of New Variant CJD. The initial results with the R-3 mice were published. We now have the
C-57 black mice who are also going down at exactly the right time if this was the BSE
agent.
Next, please. The other way of looking at this is to look at lesion
profiles within the brain and using our standardized system for scoring pathology in nine
brain areas and drawing diagrams according to the severity in brain regions. And in
scrapie you've got no consistent pattern. In BSE you get a consistent pattern with very
little variation in the transmission experiments so far carried out. If you look at Feline
Spongiform Encephalopathy and BSE in cats, kudu and Niola, you get the same pattern as BSE
neuropathologically in the mice. New Variant CJD looks exactly the same as both BSE and
BSE in other species. And classical CJD, sporadic CJD, is different in these experiments.
The critical information we require in this experiment is to compare the
BSE, the New Variant CJD transmission, with other forms of sporadic CJD. Next slide,
please. And here we have again the same type of slide with incubation period leading to
death, and we studied some studies some years ago because of the discovery of CJD in two
dairy farmers who had BSE in their herd, and these experiments were initiated to see
whether there was evidence from laboratory studies that it was BSE in these individuals.
We didn't think so from the pathology and clinical features. So here we have sporadic CJD
contemporary and from the past, and what happens is the mice gradually die of intercurrent
illness. This is what happens in these experiments if there is not transmission.
Here are two farmers. Again, same pattern of sporadic CJD. The New Variant
CJD cases die off all around 310 days, just the same as BSE and FSE, and we believe that
this evidence is really very strong that the agent causing New Variant CJD is the same
agent that causes BSE.
Next slide, please. One of the questions that we have to address is what's
likely to happen if that is the case? This is the BSE epidemic showing start in 1985-86,
reaching a peak and then declining. A great number of measures were taken to protect
public health mainly about 1989, and prior to that date, there is no doubt there may have
been human exposure to the BSE agent, and although we have no direct evidence as yet, we
think probably there may have been fairly extensive exposure to high titers of
infectivity.
Of course that doesn't tell us what will happen. There may be major
species barrier between cow and man. You may need a very large dose to effect
transmission, and we just cannot say what is going to happen.
Next slide, please. We have drawn graphs showing each case by onset,
death, with confirmation and referral delays, et cetera, and as you can see, as far as
onsets are concerned, these disease is occurring at a more or less constant rate, and some
modeling was done in the first 14 cases to give some idea of what might happen, knowing
that this modeling was highly inaccurate and can only give you ball park figures at best.
Next slide, please. And this is the sort of data that came up. You could
have a small variable--a number of variables you can alter including critically the
incubation period and incubation period spread, which affects these numbers enormously,
and of course we cannot know what the incubation period mean would be if BSE is spread to
the human population. And you can get figures of only 100 or so cases, which is what we
hope will happen, but you can get very much larger numbers depending upon the incubation
period, up to 80,000 patients in a very long incubation period, and higher figures if you
extend that.
The current situation in the United Kingdom therefore is that there are
unknown number of individuals who may be incubating New Variant CJD. We hope that it's a
small number. Some of these individuals may be donating blood and may have infectivity in
the blood, which can be present well before the onset of clinical disease. So we are in a
new situation in which we have a new infectious agent affecting the human population.
I personally don't think that the relatively reassuring evidence from
classical CJD in relation to blood can be used as an argument in this instance because
it's a new type of infectious disease in a way. Any observational data about what happens
with recipients of the donations from the New Variant cases will take years to accumulate,
and so the question is what to do in the UK, and this whole issue's anxiety has been
heightened by some other findings.
Could I have the next slide, please? Sorry. This is just an estimate of
what's happening, and it shows no overall change. Next slide please. Yeah. This is a slide
from James Ironside, which is a section of tonsil, as I'm sure you all recognized
immediately, and this is from a patient who died of New Variant CJD, and what it shows is
PrP immuno-staining, probably in the follicular dendritic cells, and this is of some
concern because we've done two classical cases of CJD who do not show this pattern. There
is no staining in the tonsil. And 12 Japanese cases have been published, again with
classical CJD with no staining in the tonsil. And we also are told that there are a small
number of cases with positive tonsilar biopsy in New Variant CJD, a handful.
Next slide, please. This is Dr. Ironside again, and this is spleen from
New Variant CJD and it shows PrP immuno-staining indicating that the abnormal form of PrP
is accumulating in the spleen in New Variant CJD, and I think the current figures are
small. We only have a handful of cases like this, but previous investigation of classical
CJD has been carried out for other reasons in the past, and apparently this pattern of
staining has never been seen in a previous classical case, the implication being that the
lymphoreticular tissue in New Variant CJD might contain higher levels of prion protein
than in classical CJD, and therefore there may be a need to be worried that the levels of
infectivity in blood may be higher, too.
If so, the question is what to do, and currently the recommendation, as
I've said, is that we are notifying the Department of Health and the National Blood
Authority if we identify any case of confirmed New Variant CJD who has been a blood donor,
although, of course, as with classical CJD, when you try to look back to find out what's
happened to the product, all the labor product has been used years before the patient
developed the clinical illness and much of the derived product, plasma derived products,
have also been used. So the question is should anything else be done? And consideration is
being given to leucodepletion of all blood donations in the United Kingdom. Whether that
will be done or not is currently under discussion, and we are awaiting a risk analysis
being prepared by some mathematicians.
So I'm not sure what will happen, but all I wanted to make it clear--I
hope I have done--is that we believe that New Variant CJD is different from classical CJD.
We believe that the risks in relation to blood even though it's a theoretical risk are
different from classical CJD, and that therefore the measures that have been taken from
New Variant CJD have not yet altered any policy decisions in relation to the classical
type. Thank you.
DR. CAPLAN: And we can basically open the floor to the panel for
questions. I think I'll let Dr. Will field those. Just recognize the hands as they go up.
DR. GOMPERTS: Dr. Will, I have a couple questions for you. From the point
of view of studies among individuals who are multiply transfused in the United Kingdom and
potentially in Europe as well, are there formal studies to evaluate individuals with
hemophilia, for example, primary immune deficiency and so on?
DR. WILL: The general view in the United Kingdom in relation to the
surveillance of CJD has been to use the surveillance system itself to look for cohorts
that might be at greater risk, and that's particularly true with BSE, for example, where
there was a question that we should be very interested in abattoir work as you might be
injured while dealing with cows, and the current view is that if that were to happen, we
would identify these cases already through the surveillance system, and with all the
background information on occupation, we would detect a change.
However, with the hemophiliac issue, it has changed, and what has happened
is that a neuropathology study of people who die with hemophilia and HIV infection, which
also, of course, in the United Kingdom has been carried out, the preliminary findings, and
I'm not in a position to discuss them in detail, but the preliminary findings indicate
that no case of an individual who died with hemophilia and HIV encephalopathy has shown
PrP immuno-staining. These individuals look as though they die of the HIV itself and not
of CJD.
DR. GOMPERTS: Is there intention to follow individuals with sickle cell
anemia?
DR. WILL: No. Again, that is not something that we are doing at the
moment. The same argument would apply, and I think also within Europe, the hope is that if
we identify a high proportion of all individuals who develop CJD, that through that we may
identify unusual types of CJD or individuals as a group with unusual risk factors. But as
far as I'm aware, there is no current intention to actively follow up individuals with a
particular medical history.
DR. GOMPERTS: From an epidemiological point of view in order to protect
the population, and I might be reading into the information here, but my assessment is
that the key event was the specified offo ban [ph]?
DR. WILL: In relation to public health, I think that's a critical issue,
yes.
DR. GOMPERTS: Would you hazard a case as to what you might recommend in
the United States, North America generally, from the point of view of New Variant CJD and
specified offo ban?
DR. WILL: I don't think I would be presumptuous enough to do such a thing,
no. I think what is true is that the development of the BSE epidemic was largely hidden
for many years because of the recycling of infectivity within the cattle population,
almost certainly driven by high titer tissue being recycled to cattle, probably before the
disease was even recognized, and the difficulty with this is that if you feed animals to
animals, then there is a risk that you will recycle infectivity before there is any
evidence of that clinically in the form of a disease. And so I think one of the tragedies
of BSE is that the eventual epidemic, even though measures were introduced relatively
early, like in July 1988, there were still many thousands of cases because much of the
recycling of infectivity already happened.
That's not to say that the measures were introduced perfectly because they
were not. But I still it's quite clear from calculations that have been done is that if
the feed ban had not been introduced cattle to cattle in 1998, say a year later, there
would have been a much bigger catastrophe than there has already been. And I'm not sure if
I'm answering your question. I'm trying to do it indirectly.
DR. CAPLAN: John.
DR. PENNER: Comments on laboratory diagnostic procedures, spinal fluid, et
cetera?
DR. WILL: Yeah. It's a very important question for us in relation to
blood, for example, because we, of course, don't identify confirmed cases of New Variant
CJD, we are referred suspects who are in the early stages of an illness, and the evolution
of the illness is often what tells us what's wrong with the patient. The EEG is not a
useful test in New Variant CJDs. We have been interested in other diagnostic techniques.
In collaboration with Dr. Gibbs, we've been trying to evaluate the 14-3-3 immunoassay in
New Variant CJD and indeed published an article last year about that indicating that
although we believe that the 14-3-3 immunoassay may be helpful in classical CJD, we're not
at all so sure in New Variant CJD.
We've been trying to combine the European data in relation to this
investigation and of large number of cases, and we believe that the 14-3-3 immunoassay
will probably be introduced in the European surveillance system as part of the definition
of classical CJD. However, in New Variant CJD, we have, I think, five cases positive, six
cases negative. We're also concerned about one potential false positive. So it doesn't
look so good. We are very interested in other investigations that might be helpful, and
there is at least a suggestion that the MRI brain scan may be helpful in the diagnosis of
these cases. But we still have to compile more information on this, but it looks as though
the evidence of posterior thalamic high signal may be a relatively specific investigation.
DR. CAPLAN: Mary.
DR. CHAMBERLAND: In the instances in which New Variant cases that you've
identified today have had a history of donating blood, can you tell us what efforts are
underway to follow up the recipients of products from these donors?
AUDIENCE PARTICIPANT: Repeat the question, please.
DR. CAPLAN: What efforts are underway to track down recipients of products
from donors?
DR. CHAMBERLAND: New Variant donors.
DR. CAPLAN: New Variant CJD donors.
DR. WILL: Yeah. I mean it's a very important question for us, and I think
what has happened is that in some of these cases, of course, I don't want to go into
details about individual patients, but donations may have taken place many years before,
and for example, not for years, and so any product has been used. That is not true of all
the cases. However, what has happened is that the blood authorities are trying to trace
recipients and keep a record of all recipients who have received anything derived from the
New Variant donors, and the current situation is that whenever we find a patient with
strongly suspect New Variant CJD, the details will be forwarded on to the national blood
authorities who will cross-check with the previously existing lists and see if there is
any correlation. That's the way we've decided at the moment to do this.
I should also make it clear that when we originally obtained information
and did a lookback study with classical CJD, this went through an ethics committee, and I
think that was going to be your next question--I'm guessing--and the view of the ethics
committee was that because CJD was untreatable, because there was no diagnostic test,
because the risk to the patients were theoretical and probably very small indeed that we
should not inform recipients who were identified, and that was the decision of the ethics
committee with the caveat that if anything should happen in relation to treatment or
investigation or diagnostic test of infectivity, that that would all change.
The current situation in the United Kingdom, I believe, is that individual
recipients of New Variant CJD products are not being informed at present. And can I just
--I'm sorry to go on, but I will just make one more comment about that. And I think it's
been discussed earlier, I think, by Dr. Schonberger, my own feeling about is that this is
a very difficult issue, and I think different people with different backgrounds will have
a different idea about what the best thing to do is, and I'm very reluctant to say too
much about this, but I do think that you shouldn't underestimate the public health
implications of informing individuals of a risk when there may be negligible risk and
major concern about the implications, and this is particularly true of us in the United
Kingdom where New Variant CJD is a matter of high public profile and is a very distressing
disease indeed, and causing anxieties to individuals perhaps unnecessarily may have major
implications, and it is said that there have been direct public health implications to
some individuals in Australia who were informed about the risk through growth hormone.
DR. CAPLAN: Let's go Keith and then we'll go over here.
DR. HOOTS: What's the epidemiology of the French case, and is there a
direct UK link?
DR. WILL: No. That was investigated in detail, and the situation is that
individual in France had lived in a particular area of France throughout their life and
never visited the United Kingdom. It's, of course, very difficult to be sure about dietary
habits, but France was the biggest net importer of beef products from the United Kingdom
in the 1980s. It also imported potentially infected cattle and meat and bonemeal, and so
as far as that case is concerned, although we can't say for certain it's linked to the
United Kingdom product at all, it's certainly a possibility. There has been some
speculation that the individual was a body builder and might have been exposed to some
form of iatrogenic transmission, perhaps using bovine growth hormone, for example, but I
think that's purely speculation.
DR. SCHONBERGER: The question had been raised about the public health
response to the New Variant in the United States and what might be appropriate. What you
should know is that even though we do not have any cases, we looked at the data that Bob
and others have produced from England and have been very impressed about the importance of
that ruminant to ruminant ban and how cases started to disappear as soon as they did that,
and you can analyze that through the births of the cows after the ban, and you see a very
sharp decline. Impressed with that, we, at least the CDC and FDA said should we institute
such a ban in the United States even though we don't have the problem? And although that
was quite controversial to some groups, I guess it affects primarily the renderers and so
on who have invested life savings to produce their plants and so on right next to where
the cattle is and so on to then feed it back to the cattle, the decision was to go ahead
with such a ban, and in June of 1997, such a ban from the regulation initiated by FDA has,
in fact, established that ban here in the United States. It had various dates of when it
became more and more effective. I think as of October 4, it was fully effective, involving
even material that was in the pipeline.
DR. CAPLAN: Why don't we do one more maybe from Mike and then I'm going to
ask Dr. Gibbs to make his way up this way.
DR. BUSCH: I was just wondering if transmission studies by transfusion
similar to what Dr. Rohwer described have been conducted either with BSE or with these
animal transmissions which seem to have rapid incubation?
DR. WILL: Yeah. I mean I think as far as the BSE situation is concerned, a
whole range of tissues have been inoculated into mice to determine whether there's
infectivity and all blood components have been negative so far, although there is a query
about bone marrow currently which is uncertain, not yet been confirmed.
One of the difficulties with this is that it may not be entirely analogous
to Dr. Rohwer's experiment because I think some of his models have a very high titer of
infectivity before you start, and it's always difficult to know whether such models are
truly applicable to other situations. However, indeed, we are thinking, have actively been
pursuing investigation using transmission studies using blood components from New Variant
CJD cases inoculated into other species, and indeed it's likely that that will happen
shortly. And one of the surprising results and implications of Dr. Bruce's experiment is
that R-3 mice seem to be susceptible to New Variant CJD, which is quite surprising,
because rodents aren't usually susceptible even by intracerebral inoculation. So similar
experiments using R-3 mice and blood components from New Variant CJD cases will also go
ahead.
DR. CAPLAN: I wonder if I could get you to respond quickly to just one
other naive question? Why are you referring to this in the UK as New Variant CJD as
opposed to old variant BSE?
DR. WILL: Well, it's the family grouping, and there is a very active
family grouping of the New Variant families would agree with you entirely. And they want
us to use a different name. I think it is a variant of CJD. It's a human prion disease.
It's a spongiform encephalopathy. It's got prion deposition, et cetera, so I think that's
true. The question is to find a different name that's acceptable, and the families now
refer to this condition as human BSE, which I think from their point of view is perhaps
quite accurate, but I think it's not a very good scientific term.
And certainly in the United Kingdom, the fact that CJD has been used to
refer to this condition, has led to enormous confusion in the general public between CJD
in the classical form and New Variant CJD as to which is caused by beef, et cetera. So I
think a new name would be a good idea, and if anyone has any good ideas of a
scientifically valid name, then we'd be very happy to use it.
DR. CAPLAN: We'll assign that to the nosology committee here. All right.
I'm going to ask Dr. Gibbs to come up. He's following right on in this hearing of trying
to understand New Variant and explain to us some of the underlying biology here.
DR. GIBBS: No, no, no.
DR. CAPLAN: Just kidding. You don't have to do all that.
DR. GIBBS: I want to thank you all for having me here, giving me an
opportunity to talk. I would like to open it up by going back to the definition of CJD
amongst the people in the United Kingdom, whether it should be called New Variant or not.
I prefer to call it atypical form of Creutzfeldt-Jakob Disease, which to my way of
thinking is more descriptive. I don't know a single human disease that doesn't vary in
clinical presentation and pathological response to that infection. I'm open to being
educated, but I don't know one, and so I always tell my students learn to diagnose the
atypical and you'll never miss a typical.
I put this overhead up just to remind you that there are other diseases
other than Creutzfeldt-Jakob Disease of the group of the spongiform encephalopathies. And
here we have terminology that has been used from time to time: unconventional viruses,
transmissible cerebral amyloidosis, prion diseases, virions or viroids.
Next please. Now the most important thing in response to the topic I was
given by Dr. Nightengale is to recall to you that we have four diseases, I think, five,
one, two, three, four, five, six diseases in human and about the same in animals that form
the group that we have named the transmissible spongiform encephalopathies. Kuru, which is
still occurring incidentally; Creutzfeldt-Jakob Disease; Sporadic Creutzfeldt-Jakob
Disease, which accounts for about 90 percent of all cases of Creutzfeldt-Jakob; Familial
Creutzfeldt-Jakob Disease which accounts for the ten percent; and somewhere in and around,
I don't know where, what the percentage would be, would be the New Variant
Creutzfeldt-Jakob Disease; and then finally the Gerstmann-Straussler-Scheinker Syndrome,
referred to as GSS; Fatal Familial Insomnia.
And in animals, the counterparts are Scrapie, Mink Encephalopathy, and the
importantly, and taking on more importance is Chronic Wasting Disease of deer and elk. And
I'll just pause for a moment to mention that this occurs in Colorado and Wyoming, and last
year, last year, the heads of all animals that were killed by hunters were required to be
turned in to the state hunting group and six percent of all of those deer and elk that
were killed last year had spongiform encephalopathy, and normally it would go to the
render--six percent. That's quite a bit. Then there's Feline Spongiform Encephalopathy
that Dr. Will just talked about, and, of course, the underlying big problem with Bovine
Spongiform Encephalopathy.
Now, the next slide, please. Now, since my title was to look to the
future, I just want to make a few comments, and since I am representing not my laboratory
but the NIH in toto, NIH is totally committed to supporting both the intramural and
extramural long-term research on the transmissible spongiform encephalopathies to the
resolution of this problem. I have been assured that that is the case.
The major intramural research is focused in two laboratories in the NIH
complex: our own laboratory of Central Nervous System Studies under the National Institute
of Neurologic Disorders and Stroke, on the Bethesda campus; and then the Laboratory of
Persistent Infections, National Institute of Allergy and Infectious Diseases, housed in
the Rocky Mountain Laboratory in Hamilton, Montana.
Of course, there are other intramural research supported by the National
Institute of Diabetes, Digestive and Kidney Diseases, National Institute of Heart, Lung
and Blood, National Institute of General Medical Sciences, and the National Institute of
Aging. And I should tell you that the bulk of the support as with the usual budget of NIH
goes to extramural research.
The Laboratory of Central Nervous System--next--studies on safety of blood
and blood products. This work is being done in collaboration with Dr. Rohwer, as you know,
and with the people in the National Institute of Heart, Lung and Blood. Determination of
infectivity in human blood by in vivo testing; identification of cell types carrying PrP
and leucophoresis/leucodepletion, experiments that are underway and will be intensified
using chimpanzees as the model because of their exquisite sensitivity to the agents that
we're dealing with.
We look at the pathogenic mechanisms of prion diseases and the mechanism
underlying the conversion of prion protein, the cellular form to the abnormal isoform
which is the term PrP res or resistant to a fair degree of exposure to protease K. And we
look at this both in vitro and in vivo. Now, there is a question in my mind and a question
in the minds of others: is prion the infectious agent or is it a product of the infection?
That has not been determined by any stretch of the imagination. I think it's wrong to
restrict our thinking to that kind of concept. I think we have to be more aggressively
looking for the underlying cause of the transformation of a normal cellular protein into
its abnormal isoform, which then recruits the normal cellular form and turns it over to
the abnormal form.
And then we're involved in the development of diagnostic tests. We did
develop a test, as Dr. Will talked about, what we call the detection of the 14-3-3 family
of proteins in cerebral spinal fluid, both animals and humans which spongiform
encephalopathy by one dimensional gel electrophoresis and western immuno blind.
Now, this year, well, since 1956, in 1996, 1997, 1998, we've had an
ever-increasing number of cases, spinal fluids being sent to us. In 1997, we had over 700
specimens being sent to us. We want them, we'll test them, we don't charge you to test
them, but what happens is it becomes clear that physicians are not familiar with the
clinical diagnosis of Creutzfeldt-Jakob Disease. There is a big need for training of
physicians as there is a need to train veterinarians in the recognition of the animal
spongiform encephalopathies and the product of a veterinarian, but I don't recall anybody
to my knowledge looking for Feline Spongiform Encephalopathy at the present time. We
simply don't know.
Then Bob Will talked about tonsils. Well, you know, tonsil biopsy is not
necessarily a safe procedure by any stretch of the imagination. I go back to a long time
ago aboard ship when we had a doctor that loved to take out tonsils and then go off on
liberty and have one or two people almost die from hemorrhaging from the surgical
procedure. So tonsilate biopsy is a touchy invasive procedure. How successful it is? Well,
Bob told you himself. That there is a the problem of sporadic cases not showing the same
results that they got in the New Variant cases. And we have tried to extract prion protein
from two cases of Creutzfeldt from the tonsils of two cases of Creutzfeldt, and we have
been unable to do so.
We now have developed and will soon be describing an even simpler test for
the detection of the 14-3-3 protein using an ELISA test which will make it much more
available to clinical diagnostic laboratories throughout the world.
Immunohistochemistry of other things--so far only thing the postmortem
tissue or biopsy tissue, and then you have to know what antibody you're going to use. It's
not so simple and straightforward that you might think. We're trying to develop other
diagnostic tests on blood, urine, and other tissues that can be more easily gotten than
spinal fluid. And then finally we're looking at the molecular biology and the molecular
genetics of the spongiform encephalopathies.
We tend to be somewhat more practical than basic. There is still the two
attitudes of basic science and applied science. And of course, there are those that say
there is only basic science which becomes applied.
The Laboratory of Persistent Infections in NIAID, the other major
laboratory within the NIH is in Rocky Mountain Laboratory. You can see on this overhead
their studies that they have undertaken and are pursuing. Cell free conversion of
protease-sensitive PrP to the protease-resistant form, which is exactly in one sense what
we're doing. While there may seem to be some overlap, it really isn't overlap or
duplication. It's rather supportive of one lab supporting another lab in knowledge and
trading information. I won't go into any details on this because I'm limited to time here,
but those are the programs that NIAID is pursuing in the Rocky Mountain Lab.
And next I'll just give you a quick run-through on some of the other
Institutes that are involved here. The National Institute of General Medical
Sciences--they're looking at Bakers yeast as a model for transmissible spongiform
encephalopathies, a very interesting problem, a very basic problem, one that mimics what
we know about the prion proteins. Here we have a conversion of a normal protein to a PSI
relying on a cellular protein, a heat shock factor involved. And investigators are trying
to determine how conversion occurs, which would then relate to how does this conversion
occur in the mammalian species for the normal cellular protein to the abnormal protein.
And it gives you some indication on the bottom of the amount of money--I
don't want to get into money because we don't have any--but there are institutes that do
have money. So you can see how the support, and the next one will show you ever more money
in another institute, the Institute of Diabetes, Digestive and Kidney Diseases, and the
figures you see there are the institute's expenditures on TSE and TSE-related problems.
And the next slide shows you the National Institute on Aging, and I
apologize that my secretary put the names of the investigators in here. I shouldn't do
that, but at any rate, it gives you an idea, if you look at the bottom of the amount of
funds that are being expended towards the TSE problem, and most of the problems that you
see up there are an approach to the basic understanding of the basic mechanisms of these
diseases.
And finally, to get back to the subject I'm supposed to speak about, on
the last slide, the future research. Well, I've given quite a bit of thought to this, and
it, and my synthesis of thought comes from the discussion with my colleagues but here and
abroad. Dr. Will, and myself and others will next month be at the World Health
Organization to talk about the criteria for the diagnosis, treatment and surveillance of
these diseases. I have proposed to the Director General of the World Health Organization
that there be yet a further consultation on diagnosis and infection control within the
ward, within the operating room, within the nursing home and within the home of the
family.
What we need are better diagnostic tests. There is no question about that.
We need something that would give us the earliest indication that we're dealing with a
patient with Creutzfeldt-Jakob Disease. Better it should be on other than spinal fluid or
brain, if possible. They should be simplified for clinical laboratories universally. And
they should be applicable to both humans and animals. We're looking at urine. We're
looking at blood, and the Swiss have recently described the development of a monoclonal
antibody that recognizes the abnormal isoform of the protein, does not recognize the
normal cellular form, and that offers a great potential should it be sensitive enough to
perhaps detect infectivity if, in fact, it is in human blood, and I'm not convinced of
that yet.
Is human blood infectious? If it is, at what stage is it infectious? What
cells are involved? These are critical questions even with the long incubation that you
see in humans we know about. Can you extrapolate mouse/hamster data to the human
population? And what evidence, what true, solid, reproducible evidence exists to show that
human blood is infectious? What contains the infectious agent? I don't have that data.
I transfused chimpanzees with donor units of blood from advanced clinical
cases of Creutzfeldt-Jakob Disease and those animals are still alive 27 years later. That
tells me something. I'm not so sure that the route isn't up the peripheral nerve into the
central nervous system, and therefore if you find it, are you sure you're free of nerve
endings in this product?
Transplantation surgery. I had a call from Geneva just yesterday wanting
to know does the United States have regulations on transplantation surgery on donors? And
I checked with Dr. Asher at the Food and Drug Administration, and there is limited
regulation on I think corneas and skin and heart valves and things of that sort, but on
heart organs, there is really no written regulation on that. I'm more worried about that
than I am about the blood. I have cases where the patient has had an automobile accident,
goes into a coma, never recovers from the coma, had already agreed to donate his organs
after death, organs were taken for transplantation and finally somebody looked at the
brain and found out that, in fact, he had Creutzfeldt-Jakob Disease. And that's going to
happen again and again and again unless we get a good diagnostic test that can--you know,
transplantation surgeons are sitting like those birds in the tree waiting for them to die
so they can grab the organ fast enough, and it even gets down to the nitty-gritty of the
ethics of when is life waning and who's going to make that decision. Is it brain dead? Is
it cessation of heart beat? Whatever it is, it's an ethical problem.
And we get another ethical problem. We have an ethical problem right now
where fertile embryos frozen away, and it turns out that they were grown in a medium that
contained albumin derived from a batch in which one of the donor's blood came from a
patient that died of Creutzfeldt-Jakob Disease. Now, the lady that donated these fertile
eggs wants to kill all of these fertile eggs, i.e., ethical problem.
So I think we have to look at this in the broader sense and as Dr. Will
pointed out, the policy in the United Kingdom to withdraw simply because of or not to
withdraw, I think, has to be examined amongst this group. I'm not one for pulling stuff
off the shelf when the risk to benefit is so small.
Financial support. Would you believe as best as I can do it I come up with
somewhere between seven and $10 million support by the National Institutes of Health to
both the intramural and extramural research program. Can you imagine how we could solve
problems if we had one-third or one-fourth or one-fifth the budget of AIDS? And let me
assure you in my opinion, if BSE should occur in this country, the economic disaster is
going to be so great that you will forget that you ever had AIDS in this country. It won't
make any difference. And I would further suggest that many of the problems that we're
faced with right now certainly need further support financially. There needs to be almost
like a Manhattan Project where the president put a bunch of good scientists under the
football stadium in Chicago and said, now, go to work.
And I tend to agree with Dr.--a friend of mine at Merck, Sharpe and Doan,
a retired gentleman, who said, you know, for AIDS, we should long ago have had a Manhattan
Project where you bring people together who know what they're doing, and not fragment the
studies that are being fragmented.
And finally, for the future, I've already mentioned the fact that we will
be in Geneva next month early to talk about improving diagnosis. I'm writing a paper now
for the New England Journal on the diagnosis of Creutzfeldt-Jakob Disease along with my
colleague Dr. Johnson at Johns Hopkins, but we need to train people to recognize
Creutzfeldt-Jakob Disease and the related spongiform encephalopathies. It's currently not
good. We need to know more and train more people in infection control on wards, operating
rooms, nursing homes. We need to have better training for the diagnosis of BSE in cattle
and other species. And finally we need a great deal more epidemiology. We need a facility,
a staff, and a location to carry this out. Thank you.
DR. CAPLAN: Thank you. Why don't we open the floor for questions from the
panel? Dr. Gomperts.
DR. GOMPERTS: Dr. Gibbs, thank you for your presentation. It was
excellent. Two comments. First of all, clearly the etiologic agent, whatever it is, needs
a lot more attention from my point of view than the way I see it's getting. Is there any
intention through the NIH to put RFAs, RFP type mechanisms to stimulate laboratories,
scientific thought, encourage basic research in this target?
DR. GIBBS: Yes, I think there will be announcements. I can't--of course,
I'm not in the position to say what institute will put this out or when it will come out
or how big an announcement it will be. As you know, NIH has had an increase of, I think,
7.5 percent in their budget this year, and like everything else, 90 percent of the NIH
budget goes to extramural program. I think it's been recommended, and I think it's a good
idea to perhaps bypass some of the big names in the field and give the junior
investigators more of an opportunity to get support.
DR. CAPLAN: Other questions or comments?
DR. MOORE: This is a little tangential, but I was sort of intrigued by the
Chronic Wasting Disease in deer and elk. What's thought to be the mechanism of
transmission there? Is this a new phenomenon or what--this was news to me. I hadn't heard
about this, and I'm just curious.
DR. WILL: Well, it's not a new phenomenon. We've known about it for a
number of years now. First, from the mule deer in Colorado and then suddenly we found out
it's in the ranging elk in Colorado. And then finally it jumps over into Wyoming from the
western part of Colorado into Wyoming where you have three species of deer and elk
involved in this. We don't know the origin of it. We don't know whether it's from grazing
with sheep that have had scrapie since a large area there is for sheep raising.
Let me put it this way. These are ungulates, by the way, and on the range
it's quite possible they were given feed supplements, for all I know. But I'll give you
the Gibbs' principle once again. And that is if we accept the rate of Creutzfeldt-Jakob
Disease sporadic is one to two deaths per million population per annum all over the world,
no matter where you go, you'll find it, and if we accept that the cause of the sporadic
Creutzfeldt-Jakob is the post-translational modification of a normal cellular protein into
its abnormal isoform which changes its configuration, shifting from an alpha-pleated to a
beta-pleated structure, and if we find that normal cellular protein in all mammalian
species thus far tested, ergo it follows that all mammalian species should have a rare
event of a spongiform encephalopathy occurring unless--unless we're all wrong and there is
an exogenous agent that triggers the transformation of the normal protein.
DR. SCHIFF: Without belaboring the deer phenomena, wolves eat elk, and I
would think they'd eat the brain, too. Have they seen this in the wolf population?
DR. GIBBS: I don't think they've looked. You know it's like the
question--Mission, Texas, where the Department of Agriculture had a scrapie study going on
for several years. The coyote down there would kill and consume the sheep. I asked did you
ever see this in coyote? Well, we never looked. So the answer is if you see a deer
stagger, you're going to presume that it's been wounded by some hunter and you're not
going to do anything about it. If you see a rabbit stagger, you figure something happened
to him that's bizarre, but you'd never think of spongiform encephalopathy. So nobody knows
because nobody looks.
DR. CAPLAN: Any other questions or comments? Thank you, Dr. Gibbs.
DR. GIBBS: Thank you, sir. Look into those ethical problems.
DR. CAPLAN: I will solved them by after lunch which is where we are going
next. What we're going to do is reconvene here at one o'clock, and we're going to have, I
think, a presentation first by our delayed in Cedar Rapids speaker so please reassemble
here at one o'clock. Thanks to the morning speakers for a great talk.
[Whereupon, at 11:50 a.m., the meeting was recessed to reconvene at 1:05
p.m., this same day.]
A F T E R N O O N
S E S S I O N
[1:05 p.m.]
DR. CAPLAN: Our speaker, Lola Lopes who was trapped in the fog and
volition, has made it here, and I've been looking forward to this talk because a lot of
the issues that we've been listening to this morning and, in fact, that this committee
tries to wrestle with more generally do require some understanding about risk and risk
perception and how the public sees risk, and so I think Lola will be able to shed a little
bit of light in this area.
DR. LOPES: I'm very glad to have made it here. I was excited to be invited
to this group because I don't know anything about the topic of today's primary discussion,
and I wanted very much to learn about it, so you can imagine that I wasn't real happy to
spend the day sitting in Cedar Rapids and miss the opportunity for learning. I'm a
psychologist by training, and I work in the area of risky decision making. I'm interested
in how regular people think about risks and the risks they choose. Much of the work I do
myself is laboratory work based on pretty abstract tests, but I think that there is
definite bearing on the issues of how people, citizens make choices among risks in the
real world.
Today I'm going to focus on three different issues. The first is just to
start out by talking a little bit about the idea of risk, the concept of risk, and
probability distributions. Then I'm going to talk about psychological factors that
underlie people's risk perceptions and their choices among different risky options, and
I'm going to wind up then taking a little look at some of the different ways in which
experts and the public look at risks.
You'll see in the next slide--you don't have to be able to read the text
here, just the headlines--this is an article that appeared in the New York Times by a very
good writer not long ago, and this is very typical of the view of public risky
decision-making that we see in the media, the notion that people have distorted ideas of
risk, that they do not understand risks very well, and are consequently making mistakes.
My stance on this is that that is not a very good characterization of what's going on when
experts and the public disagree.
So let me step first into the very abstract world of the kinds of tasks
and situations that I study myself, Stephen. What you're looking at are a set of
probability distributions. These are given to subjects and laboratory tasks portrayed as
lotteries or gambles. So much of my work and indeed a lot of the work in the experimental
study of risky choice involves monetary risks, but these particular distributions do show
the kinds of characteristics of distributions that are important in different views on
risks.
Let's just take one of them to begin with. Look at the one that's labeled
the "Peaked." These are just labels so we can talk about them easily. You'll see
a bunch of tally marks. Those represent lottery tickets, and there are 100 lottery tickets
all together. The numbers at the left of each row represent amounts that can be won or
prizes, and the notion here is that we might reach into that lottery and pull out a ticket
and the person would win whatever amount was attached to it. Now, in fact, the notion of a
risk and a distribution of risk begins with that very basic idea that there are a set of
possible consequences and attached to each of those possibilities is some probability or
some likelihood of it happening.
So in this particular distribution, you can see that the most likely thing
to happen is an outcome of around $100 give or take. There are very small probabilities of
very bad outcomes and very small probabilities of very good outcomes. Now, the other five
distributions are they also each have 100 tickets and they have exactly the same average
value. The mean of each of these distributions is $100, and the words that get attached to
this notion of the average outcome, you'll see it portrayed as the mean or the average or
very frequently the word "expectation" or "expected value."
Now that's sort of a misnomer as a term. If you look at a distribution
like say the long-shot, the mean of the long-shot down there at the bottom, it's got a
whole lot of zero tickets and a few really, really big tickets. The mean of that is $100.
We say that the average or expectation is 100, and yet the person who expected 100 would
be really off the mark because that is, in fact, a pretty uncommon outcome. There are
other measures of what we call the central tendency of a distribution. The mean is one,
the average outcome. It's particularly important where you have, for example, long runs,
and the mean can really come to represent a true average, but other measures are the mode.
This is the most likely outcome. So for the long shot, the mode is zero. The bimodal
distribution has two modes, one at zero and one at 200. The mode of the symmetrical
distribution is right around 100.
There is also the notion of a median. A median is the middle outcome. So
you can think of it as the outcome that's attached to the middle ticket as we move up from
the bottom to the top. The mode of the long-shot is about $49. The mode of the--oh, I'm
sorry, thank you, Jane. The median is about $49. The median of the peaked and the
rectangular and the bimodal is right where the mean is, at 100. So we have different ways
of talking about the central tendency, a single number characterizing a distribution. A
great deal of the data that is presented in public domain concerning risks are data about
means. And the numbers that get portrayed in newspaper articles like the one I just showed
you tend to be means and not any of the other measures of central tendency.
There is also the notion of the dispersion of the distributions. All of
these gambles have measurable dispersion. The typical way we measure it is a number called
the "variance." You can see it, for example, most easily if you look at the
peaked and the rectangular and the bimodal distribution. Those all have the same mean,
median and mode, $100, but the dispersion of the peaked distribution is very small. The
dispersion gets larger as we go to the rectangular and larger still for the bimodal,
meaning just the sort of average difference among outcomes.
Dispersion is exactly what finance experts are talking about when they
help you make decisions about your portfolio, when they talk about mean variance models,
or maximizing returns with some constrain on risk, they're talking about dispersion. But
dispersion tends not be mentioned in discussion of hazards or public health risks. It's as
though we all go through the same statistics courses, but only certain measures are the
ones that come to be useful in particular domains.
The final notion here that I think is important if you're thinking about
distributions is the idea of skewness. This is which way the distribution points. The
symmetrical distributions have zero skewness. They're evenly balanced from low to high. We
have things like the long-shot distribution which is positively skewed. It has a little
skinny tail with a very small probability of, in this case, a very good outcome happening,
and a very large probability in this case of bad things happening. If you take a look at
the two gambles called the riskless and the short shot, those have the same mean and the
same variance, but they have opposite skewness, and you can see that the riskless, this is
a gamble everybody likes, minimum outcome 70 bucks and it's gravy above that up to $200.
The short shot also is a well liked gamble. It has a very, very good chance of a pretty
good outcome, but it has some chances of bad outcomes and when we take these two head to
head people like situations where they have some sort of floor, some sort of secure base.
Now, you can put on the next slide. I'll just sum up what I've been
pointing out with these gambles. First of all, the notion that when we talk about risk,
we're talking about distributions in which possible outcomes are paired with
probabilities. Now, my distributions have well defined probabilities. I make them up. You
know I want them to be very clear for my subjects to understand, but the really
interesting difficult risky choices quite often involve situations where neither the
outcomes nor the probabilities are very clear, and that certainly is the kind of situation
that you are working with right here where we cannot say for sure exactly how large the
probability is that some particular form of transmission is going to present problems.
We also, again, have measures of central tendency, the mean or average or
the more technical term, the expectation, though that's the bad term, the one that's a
little misleading, the median, and the mode. We have dispersion or the variance of
outcomes. Where there is no variance, we say there's no risk. You have a sure outcome. You
have $100 for sure or you have $100 loss for sure, no variance. As we begin to get
dispersion, we begin to see risk as existing.
Finally, skewness. This is a psychologically central part of the way
people reason on distributions, but it is hardly ever mentioned by anyone. Okay. Let's
take a look at the kinds of things that ordinary human subjects think about when they are
making choices between risky distributions. These happen to be graduate students, most of
whom are married with families, most of whom in making decisions about monetary outcomes
have some idea of making decisions in these realms of money. These are two very, very
typical subjects. Subject No. 8 was asked which of these gambles would you prefer to draw
a ticket from and keep the amount for yourself if you were allowed to choose either for
free? Subject 8 chooses the peaked and says there are too many chances of getting a lower
prize in the rectangular lottery.
Subject No. 11 also chooses the peaked. I'll take the peaked. It looks
like there's a better chance of getting at least something. These are extremely typical
responses from subjects, and, in fact, of that set of slides of gambles I showed you
before, most people prefer them in the order that they were arrayed along the slide, the
riskless, the peaked, the short-shot, the peaked, with something like the long shot and
the bimodal being at the very bottom. Now, here it's easy to understand this set of
preferences.
That if we put up the next slide, for choices like this that are involving
gains or wins or good outcomes, people appear to be security minded, and I mean by that
that they focus on avoiding bad outcomes more than they do on achieving good outcomes, and
this leads them to choose the safer options. It's also the case that when we have people
expressing what they'd be satisfied with like that Subject No. 11, they tend to have
modest goals if they're dealing with good things. They want to get at least a little
something and that will satisfy them. What we tend to find with most people when we're
dealing with gains is that these are really easy choices, that it seems so simple to them
to pick the safe one because they're avoiding bad outcomes and they're doing as much as
they can to guarantee at least a little something.
Now things get more difficult when people are making choices among bad
outcomes, and, of course, that's the world that you folks are dealing with here today. So
let's take a look at these same two subjects when they are choosing between the same two
distributions except now the numbers are defined to be losses. Which of these two gambles
would you choose if you were forced to draw a ticket from one or the other and pay out
that amount of money out of your own pocket? Now, here Subject 8 says it's very hard to
select one or the other. I selected the rectangular because it gives you more chances of
paying zero or even under $50. I'm still unsure that I selected the right one. This person
would like not to pay very much, but there's a lot of unease expressed here.
Subject No. 11, who agreed with Subject 8 for gains, disagrees here for
losses and says I go back and forth on this. The gain on improving the chances of a low
loss increases the chance of a higher loss. I picked the peaked to try to reduce the
higher loss so that we have now Subject 11 is focused on avoiding the very bad outcomes in
the distributions. If we put up the next slide, we can sort of summarize what's different
here for losses. The first is that to the extent that people are security minded, their
focus on avoiding bad outcomes would lead them to a choice of safer options, ones with
small variance, ones where they're almost guaranteed to lose some, but where they're
avoiding the chance of losing a whole lot, of a real catastrophic loss.
On the other hand, most people have the aspiration of not losing. We don't
want to lose money and we don't want to lose lives, and where that is the case, the
aspiration level then pushes the person to the goal of achieving low losses which would
lead to a choice of a risky option. Now, what happens here is these two goals exist in the
same people. So this is not just a conflict between two different people each of which is
focusing solely on one goal and they happen to be in conflict, but the individual person
is capable of running both analyses, and seeing the pros and cons of each of the choices.
So individuals facing losses are facing conflict, even internal conflict.
And this is one of the things that when you begin to talk, try to get a
public discussion or even a group discussion going involving losses, there can often be
major disagreements, not because people don't understand the same set of facts, but
because they tip different ways on which of the goals they finally decide is the more
important.
Now, I want to at this point step back away from these abstractions and go
back to that New York Times article and just do a little bit of pulling apart the
relationship between what gets portrayed about the competence of the lay public to make
decisions and how that relates to the psychological literature that tends to be quoted in
these articles.
What I'm going to do here is pick just a few paragraphs out of that
article, which as I say, was a very fine article. It got the facts straight, but the
interpretations here are something that I believe that we can perhaps question somewhat.
Daniel Goleman, the author of the article, says the list of worrisome risks seems to
extend on and on like a litany of plagues. Too often psychologists say people's worries
about a given risk are out of proportion with the fear either far greater than the actual
danger or occasionally less.
Late last summer, many New York parents were distressed to hear that in
some public schools, asbestos was flaking and exposed. In response to their fears, the
opening of the school year was delayed even though health officials explained that the
risk of dying from exposure to asbestos was less than the likelihood of getting hit by
lightning, and that the children are probably at greater risk from playing in the streets
during the weeks schools were closed to fix the asbestos. Now, if I could magically
underline or highlight here, I'd point out people's worries about a given risk are out of
proportion. That is not just language. It may be language to Goleman, but it's not
language in the way that experts think about risks.
Most of the times you see comparisons about risk like the relationship
between asbestos and lightning. What's being talked about is the mean or average number of
deaths annually due to a particular cause, and there is the implicit and sometimes
explicit assumption that your fears should be proportional to those means; something that
causes twice as many deaths should make you twice as afraid.
And this is something that we can see again and again. This is a very
frequently used kind of way of communicating information, and there is always the message
here that there is one risk we don't want you to worry about so what I'm going to do is
find some other risk that is numerically higher than that and say you're being silly for
carrying about this one instead of that one.
There is a tendency here also to assume that all these parents were
responding to was the probability of death, not to the fact that their schools were
crummy, and that they knew there were other schools that weren't crummy, and that they
were concerned about other factors than just probabilities. That tends to be hidden not in
the newspapers obviously. It's all over the newspapers in other stories, but when we're
talking about risk, it tends not be there.
Let's take one more statement from--he continues a little further. Now
studies are showing that these skews in perception follow hidden psychological rules that
can explain why one risk is exaggerated in people's minds while in another is played down.
Let's ask the question. Do we have instances here of exaggeration and playing down? Is
that real or is it only apparent in the data? Let's take a look at data from a classic
study that was published. This one actually is quite old. Many of the risks that we're
dealing with nowadays don't appear here like HIV or BSE, but the data are sound. This kind
of thing gets replicated again and again.
What you're seeing here are the rankings of a set of risks to health and
life. A group of 15 nationally prominent experts on risk assessment were asked to rank how
dangerous these different risks were, and a group of 40 women from the League of Women
Voters, intelligent informed lay citizens. Each of the columns shows what rank the members
of the League of Women Voters gave a risk and what the experts gave the risk. If you look,
this is not a complete list--I think there were about 30 on the complete list--if you
look, though, at this subset, you'll see that there actually is pretty good similarity
between these two lists of numbers, but when this particular data set gets looked at, two
comparisons get singled out.
The first is nuclear power. That the women rated it as number one risk.
And this was about 1976. And the experts ranked it 20 out of 30. In contrast, there's
X-rays down near the bottom of the second column that the League members rank that as
number 22, quite low in risk, while the experts ranked it as seven. There is a tendency to
focus on the disparity here without ever noting that actually the match is pretty good.
Now, the authors of this particular work were careful in what they did,
and they wanted to know really whether this was due to an overestimate or underestimate of
the dangerousness of these things, of the true number of fatalities, or if these two
groups defined risk differently. So they asked the same group of people to estimate the
average number of fatalities per year from each of these things, and I'll show you two
figures here. The first one simply plots the true frequency against the mean responses and
these are from the women.
If they were absolutely accurate, if they had memorized the data on these
hazards, the dots would fall on that straight line, and you can see that they don't fall
on the straight line. That very, very small risks, things like only about ten people a
year appear to be dying from smallpox vaccinations, tend to be estimated at about a
hundred, and very, very large numbers tend to be underestimated like the rate for all
cancer is estimated at a smaller value than the true value. But for the most part, there
is a regular relationship between the actual number of deaths and the true number of
deaths, and if you think about it, how on earth would a person who didn't work collecting
this kind of data know how many people died from smallpox.
What's important here is not so much these actual estimates, but the
ranking of them. So we can put up the data for the ranks here, and now things look very
different. Notice that at this point the members of the League of Women Voters actually
think that nuclear power claims the least number of deaths in this particular sample where
it actually if you look at the real data claims it would rank in at 20th. So they are more
sanguine about this than perhaps a technical expert would be. For X-rays, the League also
overestimates the number of deaths from X-rays.
This is a place where the message that we should get from this data set is
that when people are thinking about risk, and especially controversial risk, say like
nuclear power in your neighborhood, whatever, if you're in one of the areas where a plant
might be cited near you, one set of conclusions says people are just ignorant, they don't
understand, they distort, the exaggerate, they overestimate. But when we look very
carefully here, we see that they know the numbers and that basically there's a difference
here in the decision they make but not strongly in the data base that they use to make the
decision.
Okay. Let's take a look at a few more statements from Mr. Goleman's
article. The first: risks that are associated with catastrophes are especially frightening
to the public, and risks from exotic technologies create more dread than do those
involving familiar ones. Now, he's presenting these as oddities, as things that are part
of lay psychology, but things perhaps that knowledgeable experts do not and should not
relate to.
Let's ask the question is it a distortion to be concerned with
catastrophes and with new technologies? We have another slide. This one shows--think of
the screen as showing you the distance, psychological distance, among different risks in
people's minds. To the extent that two dots appear close together in this graph, it means
that people see some similarity among the riskiness of these hazards or events or accident
forms. To the extent they're far away from one another, people say those are just very
different kinds of risks. You can see down in the lower left corner, bicycles and boating
and motorcycles and home pools and fireworks are all pretty close together.
In the upper right corner, we have things like radioactive waste, nuclear
reactor accidents, nuclear weapons fallout, and so forth. If we drew a picture of the way
that risk data are often thought about, that is in terms only of the annual number of
fatalities, the dots relating their distance from one another would fall on a straight
line, and the only dimension would be that one end of that line would have the risks that
cause the most deaths, and the other end would have the risks that caused the least
deaths. That there is only one dimension, it's unidimensional, annual numbers of deaths is
all that we should mean by risk. Well, what we see here is that people's conception of
risks is bi-dimensional, two-dimensional. That we need a flat surface to represent the way
they think about risk. Actually there is a third maybe dimension here, but these are the
most two important dimensions.
And when psychologists see something like this that shows that people have
a two-dimensional notion of something, they try to study the layout of the risk and get
some idea really of what causes a particular risk to be on the right side or the left
side, to be on the top or on the bottom. So there is an attempt to name the dimensions,
and, in fact, the names that the authors of this study gave them, they called the first
the horizontal dimension dread risk, the extent to which we have just this icy feeling of
dread thinking about things like nerve gas accidents, and down at the left side, we don't
want our kid to be hurt in a skateboard accident but that doesn't cause that same
deep-seated sense of psychological dread.
The vertical dimension has to do with how much is known about the risk. So
down at the bottom, we have things like auto accidents and bicycle accidents and
commercial aviation. These are things for which insurance companies, for example, have
years and years and years and years of data, actuarial data. We understand these risks
very well. We can predict with pretty good accuracy how many people are going to succumb
to certain kinds of risks in a given year just based on the frequency base from the past.
At the top, though, are the things that at least at that time were
relatively new technologies and relatively unknown. There certainly were not databases. So
for things like--at least most of them were relatively unknown at the time--and there the
kind of data that were available came from entirely different estimation process of
engineers and experts trying to figure out the likelihood that there would be a big
accident say with a supersonic transport. And it's a different kind of base. So the things
that the people are responding to makes sense. They're interpretable.
Let's take this characterization of them just one more step and I'm going
to relate it back at this point then to my opening remarks on distributions. That
dimension that gets called dread--now dread is a psychological construct. You know it
refers to that icy feeling in the pit of your stomach. It makes it sound like it's pure
psychology, but that same dimension is really a dimension of variance, that the
distributions at the high end of the dread scale tend to be those long shot distributions
where there is a very, very, very small probability of some really, really, really
catastrophic terrible outcome, very high variance distributions.
And over at the left are low variance distributions, things that are
probably relatively normal in shape, peaked at a number that we understand very well. So
at the same time that we can be describing people as responding with dread, we can also
say that variance matters to them, not that they know how to compute it, but they're
sensitive to the aspect of distributions that a statistician thinks of in terms of
variance.
The vertical dimension has to do with the goodness of the outcome and the
probability estimates. The kinds of stimuli that I show my subjects, they would be so far
down at the bottom that they're off the bottom of the slide. I mean they are absolutely
clear both as outcome and as probability. Insurance companies approach that kind of
certainty. But the kinds of risks basically that tend to be at the focus of public
concerns are the ones that are so new and so iffy that we don't know what the outcomes
really are going to be, and certainly we can't assign probabilities to them.
Now, many risk experts believe that there is no difference between the
kind of frequency based probabilities that we have say at insurance companies and the kind
of estimate-based probabilities that we get from other sources. This gets very arcane into
the literature on basian versus frequentist definition of probabilities, but there is here
sort of an allegiance to a view of what probabilities are. People are apparently not
baseans. Ordinary people believe that there is a whole lot of probability that is well
known from experience and one that is an estimate. And so this is dimension again that at
least some statisticians would agree with, whereas others, the baseans, would not.
I'll end with just one last slide. These two ideas came from Goleman's
article. The first that risks that are imposed loom larger than those that are voluntary.
The word "loom" is another psychological word. It's a perceptual word. And it
has to do with sort of this overpowering perceptual almost illusory phenomenon that these
things appear to be bigger, that they are looming.
The second one, risks that people can take steps to control are more
acceptable than those that are beyond their control. Again, keep in mind this is presented
as one of those little distorting oddities in the article. Now I don't have any data or
studies to show you about this slide, but I'm going to just suggest here that one of the
things that really should be very important in any public discourse on risk is that you
cannot get away from people wanting to have control over their risks and not to have risks
imposed on them without their consent.
It may be a difficult thing to educate people about very, very complex and
unknown processes and diseases like the ones that we're dealing with here today, but these
I suspect should never be seen as oddities, mere psychology. This gets to the issue really
of consent. I feel real good about this meeting today. I was delighted when I heard from
Stephen, in fact, that for this particular situation, one that is in its infancy in terms
of public exposure that already the public have been invited to sit at the table to be
part of the learning process here, and that the special kinds of vigilance and concern for
process issues that the public has are going to be part of our coming understanding of
this particular disease. So thank you very much.
DR. CAPLAN: Thank you. Don't leave. Stay right up here. One of the risks
you take when you come up here is that people may want to ask you questions which you can
then decide if you can control.
DR. LOPES: Okay.
DR. CAPLAN: Comments, questions? Keith?
DR. HOOTS: One the questions that struck me about like the League of Women
Voters versus the experts, has anyone looked at the fact that these women, many of whom, I
presume, either were or have been mothers, I mean their children might be grown, but they
may have had a maternal experience, and therefore instead of looking at the risk in terms
of their own relative risk look at it as a shared risk or even unshared risk with their
offspring?
DR. LOPES: Future generations. To the best of my knowledge, no one has
looked at that particular issue. Now data like these have been replicated with other
groups of citizens, but I think that the issue you raise, and I'd be willing to bet that
you could find more concern with long-term risks, with risks to future generations, with
risks that would take the lives of young people. I think that so long as the focus is on
the differences being due to distortions, the questions are not likely to be asked that
say is this a legitimate way in which mothers might react?
DR. PENNER: What about awareness of risk? You have risks that people can
steps to control, and if you can't control them, what about would you prefer to know about
the risk or prefer not to know about the risk if you can't control it?
DR. LOPES: The data that I know about on this tend to be data from the,
for example, the genetic testing industry. What I know about this is that some people want
to know and others don't want to know, and I don't know that. I don't know of systematic
studies of what determines which way people think about it. That's another interesting
population for study. Most people who contribute to the literature that winds up in
articles like the one that I showed you work with normal subjects, with people who are not
facing say particular risks.
I think most of us in terms of public knowledge like the idea that there
are not people hiding things from us. But given perhaps the chance to know for sure
whether I carry some kind of a lethal gene, that becomes then something that doesn't have
to do with public consent or with my role in deciding how to balance things, but how I
feel about the rest of my life.
DR. PENNER: So the corollary to that is what you're saying is an
opportunity to know the risk if you want to?
DR. LOPES: Yeah.
DR. PENNER: Not necessarily as you say, some people would just as soon not
know. That's fine, but you have a choice?
DR. LOPES: The choice, the choice, yes. And I think that we're beginning
to see in psychology now a subfield, perhaps some of these people might come and talk to
you about political psychology, people who are actually studying what factors make people
accepting of particular kinds of risks. People accept all kinds of risks, but they don't
like the sense that they're being kept out of the loop on this.
DR. CAPLAN: Actually I just wanted to follow up with a question on that.
One of the things that comes up in looking at risk in the blood supply is that there some
sentiment by some that the risk is just so low that there is some notion of background
risk or risk that we all take, the playing in the street versus asbestos in the building
type thing. What's your comment about this idea of ordinary risk or background risk and
how that shapes decisions about what people expect to know or want to know? Is there some
threshold here or--
DR. LOPES: I think probably people are going through risk benefit
calculations. For example, most people accept the background risks of living a life, going
out on the street, driving a car, all of the things that with very large probability over
time lead us to trouble. We simply accept that. For something like the blood supply, I
think that to the extent that people begin to think that this is a very low risk but
perhaps one that I do not need to accept for a given surgery--I mean the number of people
who are banking their own blood, for example, before a surgery, they are apparently saying
that they don't see a reason to take even that very low risk.
Some people would say they surely must be overestimating the likelihood of
something bad happening, and perhaps none of the experts on the blood supply in this room
would make a similar choice. I don't know what the data are for physicians. But I think to
the extent there that people understand the risk, they're saying this is planned surgery,
I can bank the blood. That's quite a different decision from deciding, no, no transfusions
even though I might need one after an accident. So something can be in the background or
not with respect to a particular use or particular instance, I think.
DR. AuBUCHON: If I could ask for your comments on a confounding problem.
You've been talking about risk perception. The other that I think we often face in talking
with a group of people who are not familiar with the technology or with the specific risk
is risk comprehension, and the data that I have seen about the level of numeracy, as it's
been called, analogous to literacy, the numeracy of the general population is extremely
low. And unfortunate. People cannot manipulate numbers. They don't understand numbers, and
particularly at very small risk they misinterpret what the numbers really mean.
DR. LOPES: I think here that that classic study is very important. Quite
often the measure of a lay person's understanding of a risk is whether or not they agree
to the treatment that their physician or the risk expert wants them to have. So the
measure of whether those League of Women Voters really understood the risks of nuclear
technology would be whether or not they ranked that as low in risk on their list. Now when
we look further, we see that they understand that numbers, that what we might have
interpreted as a problem with numeracy is a different set of values.
It may well be that people do very stupid things because they don't
understand the numbers. They don't understand even the raw numbers, much less how to
manipulate them. But I think it's very important to beware of basing the judgment of
whether or not a person understands on whether or not they agree to a particular course of
action. Those are two separate things.
One of the things that just interests me from reading magazine stories and
newspapers is the degree to which parents who have very sick children sometimes come to
really understand and work hard at reading the literature from very technical sources.
When people are very, very motivated and take something personally, they can understand
things that should, I mean under ordinary circumstances, be well beyond what we might
suppose. People work very hard to understand, but quite often the result of that is that
they want to make their own decision, which is a different thing, and here I think is
sometimes where the arguments between the informed public and experts arise.
I mean there are a whole lot of people who don't read newspapers and don't
understand any of this thing, and I, you know, would rather model my comments on people
who do make an attempt to understand.
MR. ALLEN: Is there a variance or a study on people who are taking risks
for themselves or their offspring versus people who are in control of risk for other
people?
DR. LOPES: There have been some laboratory studies done that show that
people will make very different decisions when you frame the problem as one of them making
a choice for themselves, for example, as to wearing a seatbelt, if they're getting in the
car to go to the corner grocery store, or making a public policy decision concerning a law
for seatbelt usage. People put in the frame of thinking of this from a public policy
standpoint make the decision that it ought to be regulated, but they say for themselves,
no, I don't always do it.
Parents quite frequently do the same thing with their children, that they
ask their children to be more cautious or to take better care of themselves than they do
for themselves. Yes, there have been studies on these differences in framing, and here I
think again the notion of decisions that are being made that will affect an entire society
and very far downstream, which is one of the things that we have here, people are looking
at those as having a different kind of significance than ones that are just a casual piece
of behavior affecting only me.
DR. KUHN: Can you share a little bit of the perspective of clients who
participated in shared risk?
DR. LOPES: No, I cannot. You mean that people, for example, who jointly go
into situations where--
DR. KUHN: I guess what I'm trying to bring out is like in our situation,
you know, where we're having a product, there is a certain amount of risk in which maybe
industry would have to assume and there is a certain amount of risk in which consumers
would have to assume.
DR. LOPES: Ah, yeah.
DR. KUHN: And what has been the experience of when two parties assume
basically equal amounts of risk?
DR. LOPES: I'll tell you if there is in the psychological literature any
kind of an answer to that question, I have never seen it. But I was saying during the
lunch break, it interests me a lot that we have the notion of informed consent. We have
the notion that risks can be explained to people, and that they can choose to assume a
risk, even a risk that is one that perhaps their physician might not want them to have.
The problem is that if something goes wrong, that paper is worth nothing, that the
company, the physician is liable. I consider that to be a problem not of psychology but of
the law, of the notion that we are going to have no standard of informed consent so tight
that a person can be held to it. I believe that that is a very troublesome problem, and
it's one that is affected by greed as well as regret. People make the wrong decision.
They're looking for a place to put the blame. It's perhaps a very humanly understandable
situation, but one that I think the policy issues there really have to do with law, and I
have no idea whether or not that kind of thing can be changed.
DR. CAPLAN: Maybe one last question and I'll take if I don't see other
panelists with a question. One of the things that comes up, and we've talked about it a
little bit at the breaks informally, some different panel members, is trying to figure out
how people calculate risk when they're facing a short-term benefit versus a long-term
risk? And I think in the blood supply area when we get talking later on today about
withdrawing products like clotting factor or IVIG versus the risk of a dread disease, a
low risk but a bad outcome, strike you down, one of these CJD diseases and so on, do you
have any comments about sort of taking risk avoidance for long-term very bad outcomes
short of risk averseness to wanting to not have a terrible outcome versus a benefit that
might be in the short-run?
I suspect some people in this room, to come back to Jim's comment about
innumeracy might say, well, it doesn't make any sense to forego a lot of benefit at the
front end to avoid a long-term risk that's distant or something like that?
DR. LOPES: Thinking back to the distributions, one of the things that I
see with my subjects, again, in my abstract task is that people behave differently with
respect to risks if they feel that there is some kind of a cap on the risk, if there is
some sort of boundary that they can pretty sure that nothing worse than that is going to
happen. I think that with respect to health risks like this that kind of cap, that kind of
in a way a kind of sharing, a kind of saying that we're going to try to keep things at
least where the risk is in this range, might come from the sort of increased vigilance
that was mentioned in the talk right before lunch, that we don't just put aside these very
low probability catastrophic possibilities, but we actually find a way to allow these very
faint signals like, you know, are the wolves, in fact, dying, to allow those faint signals
to be heard amidst all of the clamor of the high probability, more commonplace risks.
It has been interesting, if you read about sort of the confrontations
between the public and with scientists, there have been many cases where the public have
been right about certain things happening. That there may have been toxins, for example,
in well water or in cattle feed, that kind of thing, and it has been very difficult for
ordinary citizens to be heard because our system really is not set to try to detect faint
signals, that it's a much easier to consider people to be cranks than to try to keep an
open mind, or at least a database somewhere where odd things can be collected and maybe
once in awhile a junior clerk can be assigned for a week in the data base to look for
patterns.
I think that kind of assurance that we don't know what's happening here,
we're going to do our best to get good answers for the long-term, would help people in
feeling better about accepting a short-term risk right now. You know I'm not speaking here
from laboratory base, I'm just speaking from listening to the kinds of things that
ordinary people say and relating it to the kinds of answers that I get in my own pretty
structured work. But I think that there needs to be sort of a level of trust developed
that these very low probability things are not just going to fall into the cracks
somewhere, and that tests will be considered, you know, will be developed and so forth.
DR. CAPLAN: Thank you.
DR. LOPES: Thank you.
DR. CAPLAN: Thank you, Professor Lopes. What I think we'll do at this
point is--Steve, if you can see--one of those mikes down there, I believe, is live, and if
we flip it back to the table behind you, we can move into the public comment period, and--
DR. NIGHTENGALE: We have Mark Weinstein first.
DR. CAPLAN: Oh, we have one more speaker to go before that. Sorry. Never
mind. Enough of that.
DR. CAPLAN: In the spirit of Professor Lopes' remarks, enough with the
experts. Actually, let me look at my program. We have Dr. Mark Weinstein here from the FDA
to talk about the regulation of TSE. Then what we'll do after we get to the end of that
session is I think we may take a brief break, and we'll have--do you have an order for the
public comment period? Is this known to anyone except you and me?
DR. NIGHTENGALE: It's known to the participants.
DR. CAPLAN: Okay. So the participants know, and after this presentation,
questions and answers, we'll then take a brief break, and then we'll go into the public,
first public comment period, and I'll ask the first two people to be up there and ready to
go after that. So Mark.
DR. WEINSTEIN: This is one of the most risky parts of the afternoon here
describing the Food and Drug Administration's regulation of transmissible spongiform
encephalopathies implicated blood products. We'll get our slides going here.
Okay. I'll briefly review the December 1996 recommendations that the FDA
issued regarding CJD. I will then give a presentation about the effect of these
recommendations on product withdrawals. Next I will talk about modifications to these
recommendations that have occurred since they were issued. These modifications occurred
because of an unanticipated situations and as new information became available. Situations
I will describe include the so-called Transferrin case which involved performed a risk
assessment for a product indirectly exposed to a CJD implicated substance.
I will also discuss a risk assessment that was performed on product
derived from donors who received dura mater transplants. Next I will summarize the
recommendations made by the TSE Advisory Committee in October of 1997, and finally I will
describe a situation that occurred involving the use of CJD implicated albumin as a
processing reagent in the manufacture of IVIG.
The next few slides summarize the December 1996 recommendations that the
FDA issued regarding the CJD issue. The criteria used to designate whether a donor is at
risk for CJD included the following. First, the donor is questioned about CJD to assess
potential risk. The donor is questioned about a family history, whether the donor is a
recipient of human pituitary derived growth hormone, or whether the donor received dura
mater transplant. Donors with relatives with iatrogenic CJD are not considered to be at
increased risk. The donor is considered to have a familial risk and is to be deferred if
the person was told of a family risk previously or if the person has two or more family
members with CJD.
The donor is considered to have a possible family risk if the person has
one affected family member. The donor with familial risk may resume donations if genetic
testing is negative for CJD risk.
With regard to the disposition of products, of CJD implicated products,
for products from donors who have been recognized to have CJD subsequent to their
donation, all products for injection are to be destroyed and consignees are to be notified
to retrieve and destroy product. For products from donors at risk for CJD, this includes
those who have received human growth hormone, familial CJD donors and dura mater
recipients, the recommendation is to quarantine or destroy plasma derivatives and blood
components in all cases of donors at increased risk unless the donor has one family
member, only one family member with CJD. Plasma derivatives may be used if made from
contributions from a donor with a history of only one known family member with CJD.
Plasma derivatives from at-risk donors may be used for further
manufacturing into non-injectable products if labeled with appropriate cautionary
statements such as biohazard or intended only for further manufacture into non-injectable
products.
With regard to notification of recipients of these products, consignee
notification is recommended unless the donor has only one family member with CJD. It was
recommended that recipient counseling decisions ought to be based upon a risk/benefit
decision by physicians or caretakers.
Now, the following two slides describe the effect of these recommendations
on withdrawal of product. The first shows the number of donors identified as having CJD
risks which led to market withdrawals of plasma derivatives and categorizes the type of
CJD problem. In 1994, for example, there were two individuals who were identified as
having overt CJD, and this identification led to the withdrawal of product.
In 1995, we can see that the number in that category was approximately
nine, while the number with a family history of CJD were three. You can see that in 1997,
that most of the withdrawals occurred because of identification of individuals with dura
mater transplants, the second highest category were those who had received human
derived--pituitary derived growth hormone, and actually the lowest number were those with
a family history of CJD.
The next slide shows the percent annual production subject to withdrawal
because of CJD. You can see that for anti-hemophilic factor, the blue, the range is
roughly from 15 to 25 percent of the annual production of plasma derived Factor VIII over
the period from 1995 to 1997. For IGIV, it ranges from roughly five to 15 percent. That's
the white bar, and for albumin, it's on the range of seven to 12 percent. Now, there are a
number of very important things to keep in mind when you examine this draft.
Number one, it only indicates the proportion of product subject to
withdrawal, not the actual amount removed from the market and returned to the
manufacturer. This is a point that Dr. Schonberger raised earlier. In fact, a large amount
of material may already be consumed before the withdrawal notice is actually made.
Secondly, it does not include material that has not been made into final
product. A manufacturer may have considerable amount of intermediate product that can
never be made into product because of the withdrawal, and this figure is extremely hard to
get a handle on of how much product would be affected in the future that's never going to
be made because these intermediates are being held by the manufacturing and have not been
produced further.
Thirdly it should be noted that this withdrawal has affected primarily
product that was made using large numbers of donors. This includes product made from
donations from non-paid donors and product made by manufacturers who have many donors
contributing to a pool of plasma.
I'll now turn to issues that emerged after the recommendations of December
1996. The first involved indirect exposure to implicated material. This is the so-called
Transferrin case that included in late 1996 and early '97. In this case, the protein
Transferrin, which is used as a growth factor in cell culture, was made from a pool of
plasma that contained one donation from a CJD donor. The Transferrin was used in cell
culture that produced monoclonal antibodies. The antibodies were then purified from the
cell culture medium and linked covalently to an affinity column. The affinity column was
then used to purify antihemophilic factor.
The FDA made a risk assessment with respect to the antihemophilic factor
with the cooperation of the CDC, the NIH. The decision was that the AHF exposure was very
indirect and that a shortage was likely to occur if the AHF was withdrawn. The product was
released for use with consumer organizations notified of the decision-making process. In
the future, similar cases will be handled accordingly. Now, it should be noted that the
TSE Advisory Committee in October of last year endorsed FDA's policy of risk analysis on a
case-by-case basis for products exposed during manufacturing.
The next situation involved in vitro exposure of tissue to CJD implicated
lots pertaining to reproductive tissues. The case arose out of the post-donation discovery
of two donors at risk for CJD who contributed to albumin. One donor possibly received
human derived/pituitary derived growth hormone 30 years ago, and the second was one that
had a dura mater transplant. The implicated albumin was used for the culturing or
injection of reproductive tissue. Products and processes affected by this material
included semen, in vitro fertilization, intra cytoplasmic sperm injection, and frozen
embryos for implantation.
The FDA recommendation was to dispose of easily replaced materials;
materials that are not easily replaced should be saved or used. Prospective recipient
notification was recommended, and retrospective notification was encouraged.
The next issue involved dura mater grafts. Should recipients of non-pooled
dura be allowed to donate? If so, how should products be labeled? The case arose when one
manufacturer discovered retrospectively that 19 or more donors had received dura mater
grafts. There was a prediction that plasma derivative shortages would occur based upon the
number of affected lots. In the risk analysis, the following facts were considered:
First, non-pooled dura has never been reported to have transmitted CJD.
The TSE advisory committee's advice in 1996 was to release derivatives if a donor received
non-pooled dura. In this case, FDA permitted release of products when it could be shown
that the dura was not pooled in processing and that the dura donor had negative brain
autopsy.
Now, with regard to the 1997 TSE advisory committee recommendations, these
recommendations are summarized in the following slide. With regard to excipients, the
exceptions to withdrawal recommendations of December 1996 should be considered only for
life or health sustaining products in short supply. However, albumin is to be exempted
from the withdrawal recommendation when used as an excipient unless it is being added to a
vaccine or non-plasma product.
With regard to manufacturing processing reagents, the safety of a product
manufactured by processes that use withdrawn plasma derivative as a reagent is to be
considered by FDA reviewers on a case-by-case basis, and one of the examples of a case is
the Transferrin situation.
Now, most recently we encountered a situation involving the use of CJD
implicated albumin as a manufacturing process reagent. In this case, albumin that was
derived from a donor who received human pituitary derived growth hormone in the United
States 13 years ago was used as a manufacturing reagent to make IGIV. Our risk assessment
included the following facts:
No U.S. recipient of human growth hormone extracted after 1977 has
contracted CJD. The donor is in good health. However, it is known that incubation period
for acquiring CJD from human pituitary derived growth hormone is on the order of four to
30 years, but could be longer. The manufacturer of albumin reduces potential CJD
infectivity as was described this morning. The implicated plasma unit was diluted in a
plasma pool by approximately 10,000 fold, and the residual albumin concentration in the
final IGIV product was 0.3 percent or less.
The resolution of this case was that the manufacturer released the IGIV
with appropriate labeling that described the CJD potential, but only released it upon
direct request of health care providers who are in urgent need of the product.
This last slide shows the policy changes that are under discussion at the
FDA. They include that blood products made from dura mater recipient donors be exempted
from the December '96 recommendation if the dura mater has not been pooled, the dura donor
brain was autopsied and found free of CJD, and the firm submits the protocol to the FDA
describing their procedures for investigating this situation.
Next, recipients of any pituitary derived hormones including human
pituitary derived gonadotrophins should be indefinitely deferred from donating. It is also
recommended that there be a quarantine or destruction of any blood products from
recipients of any pituitary derived hormones. This expands the scope of the pituitary
hormone recommendations from just covering the growth hormone. And finally, there is
consideration of exempting albumin from the withdrawal policy if it is used an excipient
in a blood product. Thank you.
DR. CAPLAN: Now we go to questions. Ed.
DR. GOMPERTS: Mark, thank you for your presentation. Clearly, the focus of
this committee, your advisory groups, your group, industry blood groups, et cetera, are
particularly focused on blood and blood transmission. When I look at the epidemiology, it
doesn't seem to be there, whereas clearly if one looks at the epidemiology, the food issue
comes up again and again, and blood donors do eat, and there is the potential for a
disease that is emerging to emerge, and this has already happened, unfortunately, in the
United Kingdom.
Could you perhaps help us as to how FDA is looking at the food issue from
the point of view of epidemiology and so on?
DR. WEINSTEIN: Unfortunately, I cannot help you in that direction here.
That's beyond the scope of my interest here. I think I would have to get someone here from
that particular segment of the FDA.
DR. MOORE: You showed some of your graphs that had a product that was
withdrawn and sort of the reasons it was withdrawn and included post-donation discovery of
dura mater or whatever. How are those histories--these people are questioned
prospectively, I assume, at the time of donation?
DR. WEINSTEIN: Right.
DR. MOORE: And then is there a way to try to improve the histories that
are obtained? I'm just wondering how those histories are obtained where people then later
come back and say, oh, yeah, I did have a dura mater transplant or--that's kind of
surprising to me, and I'm wondering if there is a way to improve the history taking?
DR. WEINSTEIN: Right. This is a factor, a known problem that we have in
question, in asking. There may be situations, they are unfortunately known situations
where people do not remember at the particular time of being asked, and then they go back
to their families and they inquire and they find out later on, yes, there was something
there. It's very--
DR. MOORE: Is there a way to improve the quality of ascertaining to help
deal with some of these issues? To reduce the risk of post-discovery--
DR. WEINSTEIN: Right. There is an undertaking in the FDA to try to examine
the questionnaire that is asked of donors.
DR. MOORE: Because the implications are often quite costly.
DR. HOOTS: Just a follow up to Kristine's question. Has thought been given
since so many, I think, at least some of the examples where this has occurred were because
a person was in an automobile accident and had head injury and actually underwent
neurosurgery, and then only when the question was raised and they had already donated,
then they go back saying, well, what did they do with my neurosurgery and then they found
out. Has thought been given to asking specifically on the donor referral have you had head
injury and were you operated on?
DR. MOORE: That's exactly the kind of thing I was wondering. Change your
criteria for exclusion to help eliminate this problem with more broad, you know, casting a
broader net.
DR. CAPLAN: Jim.
DR. AuBUCHON: I could maybe help answer a question and ask one. I think a
number of these pick-ups are also on donors who give the history that they did have a dura
mater transplant after the time that they donated in the past when they were not asked
that question because the question has only been around for a short time. So if their
prior donation was five years ago, they never would have been asked that and never would
have been deferred. So it's not necessarily a problem with the question asking.
DR. MOORE: What's the shelf life of these products? I mean how long will
that continue to be a problem, the retrospective, you know, do these products last years
and years and years?
DR. CAPLAN: Dura mater? Long time.
DR. MOORE: No, not the matter, but the pooled plasma?
DR. WEINSTEIN: Well, the derivatives are shelf life is on the order of
maybe three years. However, there are blood cells, frozen red cells here, that have a very
long, years long, shelf life. So those remain.
DR. AuBUCHON: My questions pertain to the FDA's consideration of changing
their approach to implicated albumin and allowing it to be used as an excipient in some
circumstances. Could you explain--I think I know, but I want to make sure--could you
explain why the FDA is considering its approval for use as an excipient but not as a lot
of albumin to be infused? Is it just the inoculum size that is of potential concern?
DR. WEINSTEIN: I think that the questions that were raised that were given
to the TSE advisory committee were very limited in their focus here, but if one extends
their recommendations, I think it's clear that one would have to consider albumin as a
product rather than simply having this rather narrow focus. That would be the logical
extension of the TSE advisory committee's recommendation.
DR. CAPLAN: Keith.
DR. HOOTS: In follow-up to that question, with regard to ultra-high purity
Factor VIII, I know some of the discussion that the TSE advisory committee had made a
differentiation between recombinant with albumin as a stabilizer versus monoclonal with
albumin as a stabilizer because the former has no [?] so it would be a pure excipient in
the former case but the latter case, the monoclonal technology itself has inherent risk
from plasma donation even though there may not be a recognized donor into the pool. What
was the final upshot or has there be an upshot in distinguishing those two components or
are they treated the same as far as the excipient?
DR. WEINSTEIN: Well, I think that the, as I understand the TSE advisory
committee's recommendation, it was that for recombinant products for which there is no
inherent risk in themselves here, to add the albumin, which may have a little bit of risk
here, you're raising something, the risk from something that has zero to something that
has something more, and so their advice in those cases was not to have those products
exempted from the withdrawal policy or recommendation, I should say.
For monoclonal derived or plasma derived material, you are, of course,
making the product from plasma, and so the addition of albumin, another plasma derived
material to that, was not considered to be an additional risk factor to that because you
already had a risk in the material made from plasma, plasma derived Factor VIII.
DR. HOOTS: And was any question raised that the albumin came from a
different lot or anything like that?
DR. WEINSTEIN: There is a notion, well, it's--
DR. HOOTS: I mean like the albumin itself is in that case from where there
is an implicated infected donor, but the other, the actual source of plasma for the--
DR. WEINSTEIN: Well, it's clear that you had a way of limiting the numbers
of donors that contributed to the total final product here, you would reduce the risk,
but, of course, that runs directly into conflict with the idea of volunteer, non-paid
donor situations there where you have inherently more people contributing to the pool
DR. CAPLAN: John.
DR. PENNER: Mark, is it sort of a standard now that for any of these
exceptions that pass through a public committee and then with notification of recipients
or recipient institutions?
DR. WEINSTEIN: The modifications that have occurred have often involved,
well, they always involved consultation of the FDA with experts in the field and CDC and,
you know, trying to get as much information as possible, and there is also a notification
to consumer groups about the decisions that come about.
DR. PENNER: So that's standard policy then for the exceptions?
DR. WEINSTEIN: That is what we have been doing.
DR. CAPLAN: Actually, I think I was going to follow that question with one
that was maybe slightly less friendly, but I'm interested to see if you can decode this.
Over time, maybe by the end of our service to the department, we will actually figure out
the entire regulatory net, but I'm starting to understand that BPAC gives advice to the
blood division within FDA and the TSE group is giving advice to a broader group of FDA
because it has some food and other interest that come before it besides blood, and then at
the top of the pyramid or at the bottom, as one might have it, is us, who gives advice to
anybody about everything.
[Laughter.]
DR. CAPLAN: To the entire range of federal agencies, and I'm curious
then--this is the hostile part coming--BPAC has some public or non-governmental members,
and we clearly do, but in the TSE level, it looks more like it is still bureaucrats or FDA
officials or in-house people who may seek outsiders so that has a broad public base, too?
DR. WEINSTEIN: Oh, yes, yes.
DR. CAPLAN: And that would meet on the record, and, of course, people
would be able to attend if they wanted to when these cases come up?
DR. WEINSTEIN: Yes.
DR. CAPLAN: So that in the spirit of openness--this is the non-hostile
part--in the spirit of open review and so forth, the consultation might come and a request
to take a look at an exemption or whatever the issue might be, I could write a letter to
Mary Pendergast or whoever I felt like and say would you think about exempting Lot C94 and
I want a meeting of the TSE group to talk about this? How would I--if I felt I wanted a
change, what would I do or where do they come from? How does the ball get rolling here?
DR. WEINSTEIN: The ball usually gets rolling because there is an incident,
a case that occurs that's brought to our attention. And oftentimes depending on the
immediate situation, whether or not there's shortage, whether there is some crisis here
that has to be handled quickly, we will assemble those people who are the experts in the
field and engage them in conversation. The TSE committee and these other committees meet
on a more regular basis and often there isn't time to ask their advice here. But clearly
we are looking for direction and asking for consultation in all these matters, and the
broadness of this committee here--the initial, at least, concept of the BPAC committee was
that it have a scientific viewpoint on these questions here, whereas this committee will
have a broader input here, and, you know, economic considerations, all those things that
the FDA doesn't deal with here, but are clearly important in this issue would be raised
here.
DR. CAPLAN: One of the things I think we may not get to today but it may
of be of interest to figure out how things trigger or move through because again I think
part of our concern as a committee--I'll just say my own personal point of view is that we
be sure that the public understand what the mechanisms are, how things are put up for
consideration, review, exemption, whatever they are. That's just going to be an important
part of communicating surveillance, keeping an eye on risk and the willingness to bend
rules in response to certain situations, which may not be as widely understood in terms of
what's going on as it should be.
Let me ask you one other quick question. What sort of recall exists when
we have a thing come up like albumin that has been sent out to the reproductive technology
domain?
DR. WEINSTEIN: Well, our current policy if this is a
withdrawal--right--not a recall?
DR. CAPLAN: Yes.
DR. WEINSTEIN: And the notification goes out to these various centers
there and they then have a very hard decision to make here about how far to notify people.
That was this idea of notifying people who, notification based on best medical judgment of
the health care giver.
DR. CAPLAN: So if I had stored embryos or sperm from a suspect lot, my
reproductive, the clinic that's got these in their care should be telling me there may be
an issue?
DR. WEINSTEIN: The recommendation is for them to use their medical
judgment about that, and the recommendation also is to dispose of things that are easily
disposed of and to consider using those things that are not so easily disposed of.
DR. LOPES: How have the users, the recipients, responded when you have
notified them? For example, with the hemophiliac factor, has it affected their willingness
to use the product?
DR. WEINSTEIN: Yes, in many cases. They will send back material that has
been withdrawn. In fact, part of the whole thrust of a particular element that I'm very
much involved with at the FDA is improving our notification and withdrawal procedures,
telling people about withdrawals and recalls and--
DR. LOPES: But this would be patients, too? People have made the decision
to try other routes rather than to use an available source of--
DR. WEINSTEIN: When they are notified of such a situation, they have the
facility of sending the product back and having exchanges of new product. It depends very
much about what their particular situation, what the relationship is to their facility,
but usually I believe that there is a exchange of product.
DR. PENNER: It's not mandatory to notify the individuals, any of the
individuals in this case, as I think Art is bringing out. It's kind of up to the industry
or whoever you notified and the next step, whether they want to go on and indicate to
individuals that there's a problem.
DR. WEINSTEIN: There's very much of a classification of our activities
with regard to recalls and withdrawals, a withdrawal situation, which the CJD issue is
one, that's not considered to be a situation in which the product itself is known to be
violative, that is it be adulterated. You can't test for the CJD agent. You don't know
that it's in there. In other situations, like a Class I recall, the highest level of
recall here, there is a very determined effort to get the word out as broadly as possible
through newspaper notification, through every means that we can to broadly broadcast this
information.
DR. PENNER: I know that works in the hemophilic population that there's
been an attempt to do that.
DR. WEINSTEIN: Right.
DR. PENNER: Because there's a lot of vested interest obviously. But I
didn't know whether it might be handled the same way in other situations.
DR. WEINSTEIN: I think it's very difficult to have the same kind of
response to say recipients of albumin or something of that nature. This is not handled in
quite the same way. As I say, this is an issue that is a very, that is being handled with
great interest at the FDA here in trying to improve this whole process of notification.
Many of the people in this room, in fact, are involved in that process of developing a
system of better notification.
DR. CAPLAN: All right. Thank you very much. Oh, one more. Sure, go ahead.
MR. WALSH: Are you confident that the industry is being responsive to the
patient notification issues, to the extent that you think they should be in development of
a plan?
DR. WEINSTEIN: Uh-huh. I think that clearly there has been great interest
on the part of industry here. There have been many positive developments, at least for the
plasma derivative products such as the hemophilic, the products used for the treatment of
hemophilia and for immunoglobulins and so forth. And I think this process is moving along
quite well, and it will continue to move along.
MR. ALLEN: To one of Dr. Caplan's questions you mentioned that it's the
FDA recommendation that these centers notify these recipients. Are there any safeguards?
Do you go back to make sure these notifications have been made or what's the status with
that?
DR. WEINSTEIN: There hasn't been audit. There is not an auditing procedure
for those particular situations. We're talking about the CJD issue here, again, because of
the ranking of being a withdrawal situation. We have not done that sort--
MR. ALLEN: Is that something that you're looking into to make this
mandatory, once you make that recommendation or where is that headed?
DR. WEINSTEIN: That is under consideration. It's a very hard topic.
Obviously we're talking about hundreds of thousands of situations here of distributors, of
getting contacts between the clinic or the pharmacy and the recipient of the product here.
Again, I think it will depend on the specific situation here. Are we talking about an
imminent health hazard like a valvular heart problem or something like for heart valves
and that sort of thing, there is a very tight connection here between tracing a product
from the manufacturer directly to the recipient and knowing who that is. In some of these
other situations, there is not the same degree of traceability. We are working on that
part of the story though.
DR. CAPLAN: Well, I almost had you out of here, but now I have one other
question to follow up on. For some areas where there are risks or low level risks, or
people might have disagreements about whether they care or want to be notified, has there
been any thought given to trying to at least have a centralized information, web page or
some other repository where if you wanted to know, whatever you wanted to know, you could
go and see?
DR. WEINSTEIN: All this--right--this exists now.
DR. CAPLAN: That does exist now?
DR. WEINSTEIN: Yes, yes. A special, there are many different ways of
accessing information about blood products now that the FDA has initiated here. There is a
fax on demand and there is a web page and there are things that are very specific to blood
products here. So by that route, there is a way of obtaining that information.
DR. CAPLAN: Do you think that some of the consumer organizations or larger
patient driven organizations use that mechanism?
DR. WEINSTEIN: Absolutely, we know that that's the case here. But there is
a whole another initiative here that perhaps people, representatives from the Red Cross
and a number of other plasma producers here, and others who would like to speak to the
voluntary initiatives that have been carried out to improve notification process.
DR. PENNER: Hopefully, this is better than finding out that your brakes
are falling apart and there's been a recall.
[Laughter.]
DR. CAPLAN: All right. If there are no more questions, we will let you
escape. Thank you. What we'll do now is I'd like to take a 15 minute break, and I'm going
to try and go with the following pattern when we come back. Groups of three for the five
minute comments at the table over there. Who are the first three we've got up, Steve,
after--
DR. NIGHTENGALE: Committee of Ten Thousand, Hemophilia Federation and
Immune Deficiency Foundation.
DR. CAPLAN: Okay. If those individuals could be at the table right there,
we'll see you in 15 minutes.
[Recess.]
DR. CAPLAN: What I'd like to do with our first panel is if you would
please identify yourself and could you also just spell your name because there is a
transcript being made and that will help them a whole lot. Are we missing one of the three
up there. Tell me who I've got. I got Committee on Ten Thousand, Hemophilia Federation and
the Immune Deficiency Foundation. Actually, I know who that is. I think she's back up
there. Okay.
What we're going to do is this. I think we'll have five minutes maximum
from each. That was a hortatory injunction. And then ask the panel if they would like to
address questions to any of the people as they come up in a group. You do not have to feel
obligated to ask anything. It's perfectly fine to listen to testimony. I also have been
advised that I can tell you a lie. People are trying to work on the air-conditioning. Big
lie. Big lie. All kinds of opportunities for humor there, but we'll pass those and move on
to the first panel.
Why don't we go with the Committee on--excuse me. Names first and then
we'll start with the Committee.
MR. CAVENAUGH: I'm David Cavenaugh with Committee of Ten Thousand.
Cavenaugh is spelled C-A-V-E-N-A-U-G-H.
MS. HAMILTON: I'm Jan Hamilton. I'm president of the Hemophilia
Federation. J-A-N H-A-M-I-L-T-O-N.
MR. WINKELSTEIN: And I'm Jerry Winkelstein. I'm the chairman of the
Medical Advisory Committee for the Immune Deficiency Foundation. My name is spelled--it is
really Jerry. J-E-R-R-Y. And W-I-N-K-E-L-S-T-E-I-N. Thanks.
MR. CAVENAUGH: Dr. Caplan, members of the council, I am the Government
Relations staff member of the Committee of Ten Thousand, which we refer to as COTT,
C-O-T-T. I will be presenting remarks today prepared by Corey Dubin, president of COTT.
The debate continues regarding the risks to blood safety posed by CJD. On this side of the
Atlantic we are hearing that the standards adopted by the 1996 FDA Special Advisory Panel
are too restrictive and need to be changed in order to lessen the impact on supply.
On the European side of the Atlantic, a very different message is being
communicated. In December, it was reported that the United Kingdom Hemophilia Center
Directors' Organization had decided to issue a warning to all persons with hemophilia
regarding the possible transmission of CJD through Factor VIII concentrates. This follows
the high degree of concern expressed earlier at the WHO meeting in Geneva.
We also learned that the government of Portugal has begun removal of white
cells through the process of leucodepletion in response to the concern that New Variant
CJD, nvCJD, is transmitted through white blood cells. We are also aware of a recent
article in Lancet which noted the possible risk of nvCJD transmission through plasma
derived blood clotting factors.
We are perplexed by the different approaches. Why are the Europeans
expressing a high degree of caution when here in Washington we are being asked to consider
a relaxation of the standards established by the FDA Special Advisory Panel on CJD? The
issues are being presented today as if the risk landscape is unchanged from that of July
of 1996. The blood product transmission of CJD is under much greater scrutiny today than
it was then.
Given the above, we do not find this opportunity or advisable at the
moment for modification of the current FDA policies regarding CJD and plasma derivative
products. The ongoing juxtaposition of safety and supply at opposite ends of the graph
only serves to constrict the range of options. When new deferral standards or policies are
recommended or implemented such as the 1996 CJD decision, the manufacturers inevitably
claim that these policies will lessen the donor pool, thereby negatively impacting the
supply of plasma derivative products.
We cannot count the times we have heard from industry that quote "the
adoption of broader screening standards and more restrictive deferral policies will result
in a significantly reduced supply of products you depend on." This is true only if we
accept the proposition that the potential donor pool in this country has already been
tapped to the maximum.
The potential donor pool has yet to be tapped. It is time that we as a
nation placed blood donations in the context of good citizenship and undertake a national
program that will underscore the need for all Americans to regularly donate blood to
ensure an adequate and safe national supply. We have yet to see a major public effort
including the Clinton administration, the Congress, and the American Red Cross, to place
regular blood donations on the national agenda. We must not always look to the quick fix
to solve the problem of inadequate blood supply, especially in a situation such as this
where we find significant risks associated with the proposed modification.
We in the hemophilia community see this in part as also a question of how
we as individual persons with hemophilia reduce our exposure to all viral pathogens.
Simply stated, we have had enough of being the nation's blood supply guinea pigs and test
rats. We have already done our part and have shouldered two devastating and deadly
epidemics, HIV and hepatitis C. We are tired of addressing these critical safety issues in
a vacuous and compartmentalized fashion that never places the questions in the much larger
context that they actually occur within.
It is time that the FDA demand the data and information necessary to
undertake an informed overview of these questions. Critical issues such as plasma pool
size are not addressed in this discussion. This is an issue that clearly and directly
impacts the discussion of CJD and any proposed policy change. The use of such large pools,
up to 300,000 donors or more per pool, certainly impacts the issue of both risks and the
impact of potential product holds or quarantines. Given that the incidence of CJD in the
population is roughly one case per million, significantly smaller pools would
substantially reduce the impact of subsequently discovering that a donor had been at risk
or had developed CJD.
Since the amount of individual product units would be significantly lower,
the hold would therefore have a much smaller impact on product availability. It would also
reduce the overall chances of a given pool containing the plasma of a donor who
subsequently develops CJD. The question of pool size has not at all been addressed in the
discussions surrounding modifications of current CJD policies. This is another example of
what we believe is the consistent addressing of critical safety issues in a very narrow
fashion.
If the user communities are going to continually be asked to shoulder the
risk, then why do we not consider providing some type of umbrella remedy so that when
people are injured by these products they are not left to fend for themselves in a very
hostile environment, one where they are both confronted by their injury as well as the
legal and political climate that is not conducive to the redress of that injury?
We will not accept what we believe is a dangerous and irresponsible
relaxation of donor deferral policies in the absence of any initiative to address the
imbalance in who shoulders the risk. It is time for the creation of a broad remedy similar
to the Vaccine Injury Act for the users of plasma derivative products such as AHF. This
would send a clear signal to the user communities that the manufacturers and the federal
government are prepared to step up to the plate and share responsibility for the
inevitable injuries that are going to occur to the users of blood products. It would also
alleviate the need for lengthy and contentious legal actions that consume significant time
and resources.
If we all share the goal of creating the safest blood supply possible,
then why do we continue to be plagued by the same problems and barriers to a clear
understanding of any given problem? For COTT, the question continues to be will the next
emergent threat devastate an entire community before we effectively respond or will we
have created the kind of cooperation and strong regulatory climate that will result in the
impact being relatively small and contained?
At this time, the jury remains in deliberation as to the answer to this
critical question. We as the recipients of the last regulatory failure are certainly
committed to the changes necessary to prevent a repeat performance of the 1980s. COTT's
leadership continues to call for the creation of a new climate of cooperation between
industry, government and the user community. It is our contention that this is the only
effective approach to maximizing the protection of the health and safety of millions of
yearly users of blood and blood products. Thank you.
DR. CAPLAN: Thank you. Let's go right on.
MS. HAMILTON: Dr. Caplan, Dr. Nightengale, and distinguished committee
members, as found in our mission statement, the Hemophilia Federation exists for the sole
purpose of serving our constituents as a patient advocate for but not limited to product
safety, treatment, insurance and quality of life issues in a positive and proactive
manner.
It is because of this mission that we appreciate the opportunity to
present our concerns regarding the perceived potential for additional harm to the
hemophilia community through infection by CJD or any other contaminant. Our organization
is thankful for the establishment of the Blood Safety Advisory Committee and come to you
to urge your profound vigilance in preventing yet another disaster in this much
beleaguered community as well as the general population of America. We understand that
Portugal has instituted the use of a 100 millimeter filter system in the administration of
blood products because of their fear that CJD may be hiding in white cells of the blood.
The British have warned their hemophilia constituents that CJD may be
lurking in the blood supply. Canada has issued a public warning to blood and blood
products recipients regarding the dangers of contamination from CJD. Other European
countries as well have given similar warnings, yet our governmental agencies, our
governmental agencies, have stated that there doesn't seem to be an imminent danger from
this contaminant.
Does anyone hear an echo? An echo which eerily reminds us of the early
1980s? Are we once again being led down a path which will attack and eradicate several
thousand more persons with hemophilia? We are constantly being put in the position of
having to take the risks and our community is woefully tired of being the canaries in the
coal mine even if the risks are perceived.
We appreciate the policy of the FDA as stated on December 11, 1996 in
restricting donors with a family history of CJD or having received human pituitary derived
growth hormone or dura mater. Is this enough? We have learned through our debacle with HIV
that pooled plasma enhances the risk of contamination as was vividly pointed out in the
hearing convened by Congressman Christopher Shays on Thursday, July 31, 1997.
We found that once again we had been led to believe our maximum pool size
was between 20 and 60,000 donors only to find that in reality it was more often more like
250,000 donors. Please no more deceptions. Please no more half-truths. Our community is
much too weary of being deceived. We can't bear any more of these disasters.
Each of us have watched hundreds of our loved ones suffer the horrendously
devastating effects of HIV/AIDS. We have watched the intense suffering of our community
from infection by multiple strands of hepatitis, most of which could have been prevented
by the use of an available heat treating process decades ago. This is not conjecture but
has been played out in the European markets where the process was put to use.
In 1982 the National Hemophilia Foundation and the Centers for Disease
Control conducted a study in surveillance looking for AIDS opportunistic infections due to
the use of factor concentrate. If it's true that there is no threat to our population from
CJD, do you find it merely a coincidence that the CDC is once again conducting a
surveillance which was started in six hemophilia treatment centers, but will now be
mandated in all federally funded HTCs? Is that echo back again?
In conclusion, if there really is no risk due to the infusion of factor
laced with CJD or other contaminants and if our blood and blood product supply is
inordinately safe, then help us to remove the blood shield laws and product liability
laws. Why should industry be protected when the patient who depends upon blood and blood
products for his life is left with no defense? Additionally, we see an urgent need for
separate product lines for manufacturing factor concentrates apart from those used for
high titered plasma processed for other populations. Our community cannot afford any
additional risk of cross-contamination.
And lastly, back during World War II, our nation was encouraged to assist
in the war effort by growing victory gardens, wrapping bandages and to give blood to be
available for our men serving in this war. We have men and children serving in a war
today, a war for survival, a war for their lives. Perhaps today the Public Health Service,
the FDA, this esteemed committee, and even our Congress could conduct a campaign to highly
encourage voluntary healthy blood donation. Maybe with a bit of government incentive? Just
a little food for thought. And we thank you for the opportunity for being here today.
DR. CAPLAN: Thank you.
DR. WINKELSTEIN: Good afternoon. My name is Jerry Winkelstein. I'm a
clinical immunologist at the Johns Hopkins University School of Medicine. And I'm also the
volunteer chairman of the Medical Advisory Committee of a patient organization called the
Immune Deficiency Foundation. I need to describe for you what these diseases are first.
The primary immune deficiency diseases are a group of over 50 disorders, which have in
common functional defects that are intrinsic to the cells and tissues of the immune
system.
Most of these diseases but certainly not all are genetically determined.
They affect thousands of infants, children and adults. These patients usually present with
recurrent and chronic infections, but unfortunately many times with potentially fatal
infections as well. Some of the more well known primary immune deficiency diseases are
X-linked Agammaglobulinemia, first one to be discovered; the so-called common variable
immune deficiency, the most common and a disorder that usually affects adults as well as
children; and severe combined immune deficiency disease, a disorder that most of you
remember because it was popularized as the quote "boy in the bubble disease."
Now many of these disorders, in fact most, affect B-lymphocyte function,
and by doing so affect those patients' abilities to produce immunoglobulins or gamma
globulins as well as functional antibodies. Intravenous gamma globulin has for over a
decade become the mainstay of therapy for most of these patients. It's not an
overstatement for me to state or say that gamma globulin replacement therapy is critical
to the health of these patients. On the one hand, it prevents the fatal disseminated
bacterial and viral infections such as sepsis and meningitis to which these patients are
unduly susceptible, but it also prevents the ongoing chronic lung disease which
accumulates over the years from chronic bronchitis and recurrent pneumonias.
Now, as you know, there has been a recent shortage of gamma globulin which
has directly impacted on the care of these patients. Many factors have contributed to this
shortage or may have contributed. On the supply side of the equation, product recalls, an
issue relevant to today's discussion, limited manufacturing facilities and limited
availability of plasma donors may have all contributed in some way. On the demand side of
that equation, the use of this material for off-label uses and for unapproved uses by
physicians as well as a growing number of patients with primary immunodeficiency diseases
probably also plays a role.
For whatever reason or reasons, the consequences of this real shortage are
very significant to the patients with primary immune deficiency diseases. Attempts at
lowering the dose or stretching the dose out to an unacceptable interval, skipping doses
altogether, all of these things, put patients at significant risk for life limiting or
life threatening infections. I should say that I personally have seen many patients who
for one reason or another have not received their gamma globulin and that then developed a
serious infection and died, the most recent of which had his first anniversary of his
death on January 16.
Between December 15, 1997 and today, about six weeks of elapsed time, the
foundation, the Immune Deficiency Foundation, has fielded emergency requests from
physicians, pharmacists and home care health care companies representing well over a
thousand primary immune deficient patients who were unable to obtain their IV gamma
globulin. The IDF is working with all the manufacturers on a daily basis to obtain product
for our patients, and based on our assessment, this situation was imminent. The IDF on
December 10 of 1997 wrote the FDA supporting the recommendation of its TSE advisory
committee recommending the release of IVIG or IV gamma globulin lots in which albumin was
used as an excipient and that the albumin was derived from lots in which a donor or donors
were identified at higher risk for CJD. The IDF further recommended that manufacturers
immediately stop the practice of mixing albumin from other production lots in the
manufacture of IV gamma globulin.
I'm here today so that you will be aware that the IDF reaffirms this
recommendation in light of the shortage confronting our patients and the medical
consequences of no treatment or under-treatment or delayed treatment in these patients.
In addition, the foundation on behalf of its patients and the physicians
who treat them would like to make the two following suggestions. One, like most other
people, we would like the NIH to move as aggressively as possible to identify the agent
that causes CJD. Until that agent is identified, we'll never have a clear path to follow.
Number two, we'd like the FDA and industry to identify the precise causes of the IVIG
shortage. These two bodies must quantify the production and release of IVIG to the
marketplace. Further reliable data must be obtained on the current consumption of IVIG.
Who is using it? And for what purposes? Facts related to these issues bear on policy
decisions regarding withdrawal, recall and quarantine.
At the end, I'd say that as physician treating primary immunodeficiency
patients, of course, I'd like to know that the material I'm prescribing and using meets
the strictest safety standards possible. However, at the same time, I also need that
adequate supply of the material available for the treatment of these patients. The issues
we're here to address today and the issue impacting directly on the health and survival of
my patients is how to balance the problems of safety and supply?
The NIH, the FDA, and other oversight bodies such as this committee and
industry must all ensure that all scientific avenues are being aggressively pursued and
that appropriate measures are being pursued to understand and to relieve the apparent
shortage of this critical therapy. Thank you all very much.
DR. CAPLAN: Thank you. I'm going to open the floor up for the panel to ask
a question, make a comment in response if they so desire?
DR. KUHN: I'm sorry. I forgot your name.
DR. WINKELSTEIN: Winkelstein, sir.
DR. KUHN: Dr. Winkelstein, you said that you had a request of asking the
FDA and industry to identify the shortages of IGIV. I guess that's a question--
DR. WINKELSTEIN: The causes, right.
DR. KUHN: I guess I'm asking the question here does anybody, can anybody
from FDA or industry answer that question, you know, if that's what you're looking for? I
mean I'm curious to know why is there a shortage? What's the cause of it?
DR. WEINBERG: In fact, that's a very difficult and complicated
multifactorial equation here that goes into why there is a shortage, and it's not well
understood. There are a number of different factors. There is this increased demand for
the use of the material for IGIV. There have been situations where through the increased
oversight of the FDA regarding GNP issues here that manufacturers are devoting their
attention to making certain their products are produced in a safe GNP approved way, and
therefore have diverted some of their attention to meeting those issues.
There was a period of time when one company was not releasing any IGIV,
immune globulin, for a period of time, a number of months. All these are factors that
influence the supply of material. Certainly the CJD issue is one of those factors, and as
I indicated here, there is this issue of withdrawal of product that's already been
consumed. There's also the issue of product that can't be produced because the
intermediate pools are lots of material that cannot be processed further.
The final point here is that we don't have right now really a very good
mechanism to tease apart all these various elements in the equation here to find out what
is the dominant reason for the shortage. We know that one does exist here, but the exact
cause--I don't think there is--there is not one cause here. There are multifactorial
forces here moving on the supply issue.
DR. KUHN: Mark, since we're discussing CJD here, how much has CJD had an
impact upon that shortage of the IGIV? Is there--
DR. WEINSTEIN: I think that's the point. I can't, we can't really say.
DR. KUHN: You don't know. Okay.
DR. WEINSTEIN: It's very difficult to give a number to that equation.
DR. GUERRA: Mark, are there foreign manufacturers of IG product that could
be imported to sort of meet the critical shortage that is--
DR. WEINSTEIN: That is one avenue that we are investigating. There are
actually, there are products that are used in Europe that we are investigating as a
possible, another measure that will help in relieving this shortage situation. There are a
number of different avenues that we are pursuing and manufacturers are pursuing.
DR. GUERRA: There is considerable urgency from a public health standpoint
to somehow accelerate that process. Many communities have been very significantly affected
by community-based outbreaks of a variety of viral illnesses, especially hepatitis A,
where it has been very difficult to control it just because of that shortage. And I can
certainly understand from the testimony that's been presented in terms of the population
affected with immune deficiency states that again those numbers have been increasing in
communities. They're at even greater risk today than they were before because a lot of
these emergent strains of infectious organisms where I think the only possible hope for
getting them over a crisis is having access to these products.
DR. CAPLAN: Let me see if I can allow any other questions that the panel
would like to address to the first three who have testified. Keith?
DR. HOOTS: It's kind of a comment to Dr. Winkelstein. And I really from
the compassionate point of view really go out to your community because I don't think it's
in retrospect surprising that you're in the most vulnerable of all positions. In the
hemophilia community when we've had some shortages, we've at least had the advantage of
having a fairly homogeneous group of providers who could make priority decisions to shift
away from less urgent to more urgent needs. You're unfortunately caught in the unenviable
vise of having so many, as you said, off-label indications that are growing almost
exponentially by the day from Guillain-Barre and certainly ITP uses. As a hematologist,
I'm well of.
And I think maybe as, you know, it's kind of little bit aside from the CJD
issue, but as health care providers, one of the things I think we really have to think
about in terms of these issues, when you're making difficult choices about supply, but the
other confounders are entering into the equation, is how can we bring the players to the
table so that at least in the short term, until the difficult issues about determining how
much CJD withdrawal or quarantine is really contributing, but we know these other things
are continuing to contribute to your shortage, how can we collectively play a role to
prioritize because clearly your population should be prioritized, in my opinion, to the
very top of the pecking order?
I know in our own institution, within the last two weeks, we ran smack dab
into the shortage, and essentially what we did was put all the players around the table
and essentially created our own priority list, but I think there ought to be some advocacy
on behalf of populations who may be small who are thereby particularly vulnerable when
there is a particular pool by so many even larger number of communities, and I don't have
all the answers. But I think that's one thing that I would like to maybe see this
committee to at least address at some point because I think this may not be limited to
your particular community, but clearly you're among the most vulnerable, and I really am
greatly concerned about it.
DR. WINKELSTEIN: If I could add a brief comment. Not only are we as a
society in the difficult position of balancing supply and demand, but you've pointed out
that the demand has prioritization. And when the Medical Advisory Committee met over the
phone two or three Mondays ago and discussed this for an hour or so with the president and
vice president of the foundation, we came to the unfortunate conclusion that actually
children with Kawasaki's Disease because they're at such high risk for developing coronary
aneurysms ten or 15 or 20 years down the road actually have more priority than our
patients because ours is not a daily need, it's a monthly need.
So here now you've got different physicians or providers or whatever
euphemism you want to use trying to discipline themselves when they have conflicting
interests and conflicting loyalties. What then did happen out of that is that the
foundation and the FDA asked the individual physicians on this Medical Advisory Committee
to send to the FDA the deliberations of committees like your own how is each institution
handling that, but, of course, that may not be adequate. Clearly it's a stopgap measure,
but I think you've articulated the patient's concerns and the physician's concerns from
our point of view.
DR. CAPLAN: John.
DR. PENNER: Very quickly, it would seem to me that you could approach the
manufacturers and have a set-aside for these individuals and that would ease the
situation.
DR. WINKELSTEIN: That's being done, sir.
DR. PENNER: Because if that were set aside for them, then each
manufacturer doesn't have to worry about satisfying their clients and getting into this
warfare situation such as I have to give so and so because they're our regular supply and
so on.
DR. WINKELSTEIN: That's perhaps easier said than done because the
manufacturers to some extent, I would expect, have to be a little bit more neutral. They
have to be more well balanced. It's not their decision to make as to whether a four year
old with Kawasaki's deserves IV gammaglobulin more than a 30 year old with common
variable. It gets a little dicey. Nevertheless, we've made an attempt to hook our patients
up as they call us, over a thousand in the last six weeks, with individual manufacturers
and hoping, and they have been responsive, that the manufacturers would respond to
individual case by case requirements. But that certainly doesn't solve the problem. This
kind of body is more appropriate.
DR. CAPLAN: One comment from FDA down there and then I'm going to do one
more question and we'll move on to the next panel.
DR. FEIGAL: I just wanted to add--let me introduce myself. I'm David
Feigal, and I'm Deputy Medical Director for the Center for Biologics and I'm replacing
Mary Pendergast on this committee who left the agency for new opportunities. I just wanted
to mention two things which we've done to add to Mark Weinstein's comment. One is that the
acting commissioner for the FDA in late December called the CEOs of each of the four large
manufacturers of these products and asked them to do two things. One was to address how to
increase their supply in general. Another was to provide 800 numbers and routes for
emergency supplies for patients in the greatest need, and each of them had a different
mechanism which they thought they would provide product, but it was like the suggestion to
have set-asides, and we asked each company to do that.
And then the final issue that we discussed with them was just the general
issue around what's going on in terms of demand. Since supply is only off ten to 15
percent, and we have had other time periods where we've had this same amount of supply, it
seems to me more likely that there is an increasing demand for this product. And there is
almost an unlimited European demand for this product. Since we're the only large source
for plasma through the paid plasma donors, essentially as much of this material as can be
made can be sold overseas, and so when we ask companies, often which are European
companies, to bring product back to the United States, it's often product that they're
selling in their own countries and they're looking at the shortages in those areas.
The final thing I'd like to just mention briefly is that there is a letter
that has gone out, a Dr. Doctor type FDA letter, and also information will be publicized
in other ways, that does prioritize the list and points out what are the uses of this
product that truly are life saving and immediate and also identifies uses where the
benefits have not been clearly identified and suggesting that the medical community
prioritize this. So we're very sympathetic to and hope that we can help with this problem.
DR. CAPLAN: If I could, I just want to ask Mr. Cavenaugh. I'm sure we'll
pursue this with subsequent panelists who are going to come up and offer us testimony. But
just quickly, I'd like your reaction to the issue which I'm sure you've talked about many,
many times, but I'd like to have it here, the tradeoff between the cost and the pool size
in terms of what it might cost to use smaller pools of donors and the safety obtained
relative to what it would cost in terms of product to use smaller pool size?
MR. CAVENAUGH: I think it's important to reduce that quantitative terms
much more than has been done. I think as you heard part of our concern is that the
relative risk is, of course, much smaller and the tracing is much easier, and that's hard
to quantify. The latter of those is hard to quantify. But that needs to be applied to the
equation. The entire discussion on risk this afternoon was very educational in terms of
factors that are involved that we may not be giving credit for.
One example that occurred to me was, you know, what about the League of
Women Voters' opinions of things where they've had serious accidents happen to them? That
might shift them materially from the experts' views. And I think the role of involved
individuals and the costing out of what's necessary in life hasn't really been done yet. I
think that the charge to the FDA that I mentioned earlier includes that as an economics.
DR. CAPLAN: All right. Thank you. I have next the representatives from the
National Hemophilia Foundation, American Society for Clinical Pathology, and the American
Red Cross, if they'd come forward. I'm going to ask for the same rough routine, name and a
spelling.
DR. YOMTOVIAN: I'm Dr. Roslyn Yomtovian. I'll be representing the American
Society of Clinical Pathologists. The spelling is R-O-S-L-Y-N Y-O-M-T-O-V-I-A-N.
DR. CAPLAN: I knew there was a reason we were doing this.
MR. COLBURN: I'm Donald Colburn and I'll be representing the National
Hemophilia Foundation. My spelling is C-O-L-B-U-R-N.
DR. DAVEY: I'm Dr. Richard Davey, D-A-V-E-Y. I'll be speaking for the
American Red Cross.
DR. CAPLAN: And why don't we start with Roslyn.
DR. YOMTOVIAN: Point of protocol. I think that earlier when Dr.
Nightengale--is he here--set this up, he wanted to group the hemophilia groups,
immunodeficiency groups together so if you'll forgive me, if you don't mind.
DR. CAPLAN: Okay. We can start--sure, we can do it that way. Fine. Put him
on the spot.
MR. COLBURN: And I thought I had a few more extra moments. Thank you very
much. As I mentioned, my name is Don Colburn. I'm president and CEO of American Homecare
Federation. Additionally, I serve on the Blood Safety Working Group of the National
Hemophilia Foundation and I have hemophilia.
The questions before the committee today on the possibility of easing
restrictions on albumin and albumin as an excipient is a very complex one. One of the
complications in making a determination on this question is the lack of concrete knowledge
concerning the possible contamination of blood products which CJD. It was this fear that
led NHF to advocate that all blood products should be withdrawn from the market if the
product came from the plasma pool where the donor was considered at higher risk for CJD.
This very moment is an opportune time to be having this discussion since
there is currently a shortage of immune globulin as we've just heard and other plasma
derived products as well. An easing of CJD restrictions for albumin as an excipient would
invariably ease this shortage which would benefit the hemophilia community as well as
others. Obviously we would like to see more product on the market than currently exists,
but one has to ask is this the best way to do so?
The hemophilia community, as you've heard, has been devastated by the
spread of HIV through the use of regulated blood products in the 1980s. I have witnessed
first hand and I have personal experience in dealing with the consequences of that period.
As a result, we should be extremely cautious before easing any restrictions as they relate
to the safety of the blood supply. We need to rule out the potential threat of CJD as well
as variant CJD before we can be assured that the blood supply will not be contaminated by
an easing of such restrictions.
Currently, there are conflicting data from which to conclude whether or
not CJD is actually transmissible among blood products. While ongoing epidemiologic
studies in the hemophilia community have been encouraging, NHF is concerned with recent
studies showing that the transmissible agent of CJD partitions into the plasma fraction of
blood. Albumin may well prove to be the safest of products derived from plasma, but are we
as yet prepared to say this with scientific certainty? We know the infectious agent can be
transmitted by peripheral administration through our experiences with iatrogenic CJD. The
risk of New Variant CJD to the blood supply are unknown, but we should take serious note
of the fact that the UK Hemophilia Center Directors Organization has taken the position
that the possibility of transmission through plasma derived products was sufficient to
recommend that no British made factor concentrates be used.
At present, we do not have the ability to determine if any plasma pools
are contaminated with CJD. While some experts may make educated assumptions about the
transmissibility of CJD and related disorders, there is yet a body of scientific evidence
to condone a change in policy at this time.
Are we at NHF overreacting to the concerns of CJD and its comparison to
HIV? Maybe. Maybe not. Truthfully, I do not know. However, when a community has been a
scarred the way ours has, we feel caution is the best way to proceed. Therefore, NHF
advocates the continuance of existing policy until the scientific data is conclusive. When
more sufficient data is available, this discussion should once again take place.
I'd like to make a few personal comments about what I've had the
opportunity to watch today. And I think that where our concern as an organization from
folks that I talk with goes has to do with the fact that if restrictions on what is called
classical CJD are lessened, then the desire to follow up on things like New Variant CJD
will just be taken away. There will be no hook to make sure that people keep watching that
as it evolves. And I think that that's a fear that we all need to be aware of.
Another thing that has a concern to me that I'm very pleased to see a lot
of this discussion revolving finally around the use of the chronic blood recipient, but
there is also that I guess what one would call the casual blood recipient. What harm--if
some of us who use it all the time have developed some type of immunity to this, what
about the folks who don't get it all the time? Are we just creating a whole group of
people who in 30 years are going to have CJD?
The last thing I'd like to comment on is that I think with our domestic
shortage that somewhere along here a recommendation ought to come that if there is there
is a shortage in the United States of America, where 80 percent of the world's product is
made, the product should stay in America for Americans first. Thank you.
DR. CAPLAN: Thank you. Ros.
DR. YOMTOVIAN: Thank you. Mr. Chairman, Dr. Caplan, members of the
committee, my name is Roslyn Yomtovian, M.D. I'm director of the Blood Bank and
Transfusion Medicine Services at the University Hospitals of Cleveland and Associate
Professor in the Department of Pathology at Case Western Reserve University's School of
Medicine. I am here today representing the American Society of Clinical Pathologists,
ASCP, where I serve as a member of its Commission on Continuing Education Council on
Transfusion Medicine.
ASCP is a gateway.html medical specialty society organized for educational
and scientific purposes. Its 75,000 members include board certified pathologists, other
physicians, clinical scientists, and certified technologies and technicians. We are
pleased to hear that you are addressing issues related to the possible transmission of CJD
by blood and blood products and wanted to take this opportunity to express our concern
with potential related issues with solvent detergent plasma which is currently under
consideration for licensure by the FDA.
The solvent detergent treatment inactivates certain viruses including
human immunodeficiency virus, hepatitis B, hepatitis C and the human T-cell leukemia
viruses. It fails to inactivate non-lipid, enveloped viruses and likely has little
activity against the agent of CJD.
While there have been no documented blood transmissible cases of CJD,
blood banks and transfusion services have been asked to withdraw previous blood products
from donors who now have a diagnosis of CJD or a family history of CJD. Since solvent
detergent plasma is produced from a pool of approximately 2,000 units of plasma from
routinely screened and tested donors, a market withdrawal is likely to have a major impact
not only on the product supply but on the time and effort to trace recipient use.
When a donor is subsequently determined to be ineligible because of CJD
risk and if his or her plasma was manufactured into solvent detergent plasma, there will
be no one but approximately 2,000 finished units of plasma that may be involved in a CJD
recall. The potential effect on the public may be enormous.
In light of this, the ASCP suggests that guidance be given to the
transfusion medicine community that answers the following questions:
Number one, what are the requirements for lookback investigations of
solvent detergent plasma transfusion recipients?
Number two, should solvent detergent plasma be managed like a blood
component, for example red blood cells, or more like a blood derivative, for example
albumin, when recalls, withdrawals, and notifications are indicated? Currently, recipients
of albumin are typically not traced when a market withdrawal occurs. Albumin is generally
dispensed by the pharmacy which is not required to trace lot numbers on a recipient by
recipient basis. Should solvent detergent plasma be dispensed by the pharmacy or the blood
bank? Will recipient tracing not be required if the pharmacy is used?
Number three, will providers of solvent detergent plasma need to formally
recall already distributed finished lots of the product in response to new donor
information indicating theoretical CJD risk?
Number four, how would the lack of transmission of CJD be documented so
that a lookback investigation may be truncated?
Number five, how many people should be recipients of each lot?
Number six, is it appropriate to exclude solvent detergent plasma donors
if two of their family members have a history of CJD?
And number seven, what are the standards for determining if a donor or a
relatives of donors are diagnosed with CJD? Should specific diagnostic tests be required
to diagnose CJD? And is an autopsy needed to determine the CJD diagnosis?
While we appreciate the challenge of addressing these issues surrounding
solvent detergent plasma, we believe it is in the best interest of the public to do so.
Thank you for your consideration of our remarks. I would be pleased to answer any
questions you might have.
DR. CAPLAN: Thank you.
DR. DAVEY: Thank you, Dr. Caplan and Dr. Nightengale and members of the
committee. I'm Dr. Richard Davey. I'm the Chief Medical Officer of the American Red Cross.
I don't have any formal statement for the committee today, but I do have some remarks from
the Red Cross perspective that may be helpful in your deliberations.
Just by way of background, the American Red Cross is responsible for about
45 percent of the nation's blood supply and about 20 percent of plasma derivatives. All of
the derivatives, plasma derivatives made from Red Cross plasma, are by definition from
volunteer blood donors. We are committed to maintaining the highest standard of blood
safety. We have a responsibility to do that, and we take that responsibility very
seriously.
I'd like to comment a bit, though, on the impact of withdrawals for CJD on
blood supply and upon the American Red Cross. We have had over $120 million of material
withdrawn over the past few years with the majority of these withdrawals occurring within
the last two or three years. That's $120 million of manufactured material that has been
sent back to us and has not been distributed. Much of it is now outdated and destroyed.
We've had 11 withdrawals since last July, July of 1997, alone. Now this has an impact on
supply. The exact impact, I think, as Dr. Weinstein has said, is very hard to get your
hands on, but clearly the extent of these withdrawals has an impact on the supply of IVIG
and albumin and other derivatives. And we're concerned about that.
I must also say that withdrawals of this magnitude have a substantial
impact on the activities of the blood operations of the American Red Cross. $120 million
has not been available for the blood side of our organization to perhaps use for other
purposes that are related to blood safety. These withdrawals do not impact just for your
information on any operations and disaster relief, AIDS education of the Red Cross. The
entire impact of these withdrawals focuses on the blood side of our organization.
The blood side of the Red Cross is responsible for the R&D effort in
our organization. We have activities that are related very clearly to blood safety. Chavez
Disease, tick-borne disease studies, we're very aggressively implementing molecular
testing of the blood supply. Coincident with the major impact of these withdrawals, our
R&D budget has been cut approximately in half. The work that we were doing on
tick-borne disease has been terminated and some of the other activities that are directly
related to blood safety in my estimation are not moving as quickly as they might be with
more adequate resources.
Given all that, we are very interested in looking at what we can do to
minimize the impact of these plasma withdrawals and doing appropriate research and
supporting appropriate research to give the FDA, groups like this committee, and others
information that can help us determine how we're going to handle this very difficult
problem. The Red Cross has always been very open about pool size. Pool size has always
been limited to 60,000. We don't mix pools together, and we are very clear on that.
Our plasma, the way we handle plasma from our donors has been modified
somewhat because of these withdrawals. We use plasma from donors only under 60 years of
age for fractionation. Plasm donations from donors over 60 are used for transfusable
plasma FFP. We feel that because most of the donors that do come down with CJD are in the
older age groups, this will minimize the impact of withdrawals and we believe it has.
We've also taken steps to notify recipients. We have a 1-800 number that people can call
when withdrawals occur. We've been very active in working with our colleagues in the NHF,
other provider groups, hemophilia treatment groups, and we want to do as much as we can
and more to share information with our colleagues that require information when
withdrawals occur.
We've also committed over $1 million in the American Red Cross to CJD
research. To my knowledge, that's more than any other private organization. We have
supported Dr. Rohwer's research very extensively. We also work very closely with Dr. Paul
Brown, collaboratively and in our own Holland, Jerome Holland's Laboratory for Biomedical
Research, Dr. William Droen has a very active program in CJD research. You heard this
morning of the epidemiology studies, the lookback studies that Marian Sullivan initiated
with the Red Cross, and we're continuing to work with her on that very important lookback
study. Dr. Schonberger reviewed that with you.
We're also looking very closely with Dr. Rohwer again at transmissibility.
We're anxious to continue with validation studies. Can we remove the agent from plasma
derivatives? And again, Dr. Rohwer and Dr. Brown are looking at this. We're also pursuing
inactivation studies, looking at gamma radiation, iodine treatment, other measures to look
at possibly inactivating these agents in blood products and blood derivatives. We'll share
these data as they become available and we have shared the data with the FDA and others on
these and other studies.
I think in conclusion, as I said at the beginning of my remarks, we are
committed to promoting blood safety and being as aggressive as we can in the American Red
Cross at giving the American people a safe supply of blood and blood products. The
question is how best can we do that? Are these withdrawals the best way to promote blood
safety? That's a question the committee is deliberating and with that question, I'll
conclude my remarks. Thank you.
DR. CAPLAN: Thanks to the panelists. Let's open the floor for questions
from the committee. Keith.
DR. HOOTS: Dr. Yomtovian, in number two under your question concerning the
immediate origin before it goes to a recipient of the solvent detergent fresh frozen, does
your organization feel like that should have any role in determining whether there's a
different procedural lookback or different procedure for tracking recipients, whether the
product resides in the pharmacy versus the blood bank?
DR. YOMTOVIAN: I think the ASCP is just raising this as a point of
interest for the FDA and other organizations to consider. It seems like in a sense a
double standard that if a product is dispensed from the blood bank, we have one way of
doing things, and it's dispensed from the pharmacy they have a different culture set,
value set, and they do it quite differently. So there really aren't specific
recommendations. It's a point we brought up to be further discussed.
DR. HOOTS: Just as a comment, I know in terms of when Dr. Weinstein was
talking to us that the whole role of how to do surveillance to recipient in terms of
quarantine is being looked at, and clearly I think that's one of the issues that's going
to be looked at in terms of looking at pooled products and particularly pooled products
that don't have a natural constituency pre-set like hemophilia. For instance, solvent
detergent treated FFP, IVIG, particularly as it's being used on the adult community widely
and even more so albumin which is oftentimes people receive albumin in emergency settings
and don't even know they received it. And clearly, one of the issues that has to be
addressed in terms of tracking for both notification and tracking is that issue and how to
make sure that as we get a more expanded notification in this country that includes all
those products. At least that's my take on it.
DR. CAPLAN: I actually had two questions. One is for Richard. I was
wondering if you could give me an educated guess about pool size, lowest reasonable, you
said 60,000. We hear numbers up in the 100,000 range. What do you think or would you
venture an opinion about, and I understand this is relative to cost and ability to monitor
and so on, but at the low end, is there some sort of bottom that exists there to say,
well, we couldn't really do this below 30,000 or 20,000 or five or something? And while
you're pondering that, I wanted to put another issue on the table for Donald.
I think that I'd be interested, and I know this issue has come up before,
I don't mean to square it off as an either/or, but when we hear about CJD as a late onset
disease that takes many years to incubate and often is something that is in older people,
I'm just curious about the view that you have personally and your organization about that
tradeoff again between having a supply and foregoing a risk that may not be the same as
AIDS which affects people in their youth, but in this case has a delay or is something
that's going to come later, whether that shapes your thinking about how the public is best
served with respect to managing the CJD risk? So I wanted to let you think about those for
a minute. Richard.
DR. DAVEY: Dr. Caplan, those questions do get into manufacturing technical
issues that I'm afraid get a little out of my depth. My understanding is that the
manufacturing process as presently constructed, it's very difficult to reduce pool sizes
below 55,000. It would require a major retooling and rebuilding of the fractionation
facilities so that I think the major progress in this area, as I mentioned, has been to
make sure that pools are not mixed and that pool sizes are reduced within manufacturing
constraints as much as possible.
MR. COLBURN: I liked your question. It's a good question, and there
certainly has been some thought given to it, and I think part of the challenge that we
have today is that as we have progressed with even the more purified plasma derived
products what we are seeing is that younger people, younger and younger people, it's not
uncommon to have someone in their first year of life have a port put in and go on up to a
prophylactic basis. So the concern really is twofold.
Do you look at a group of 30/35 year old people with hemophilia who all of
a sudden start to get CJD? Those of us who have been around and been exposed to a variety
of fresh/frozen plasma, pooled cryo, to recombinant products, there's probably in some of
us a little bit less--you know, AIDS has been enough, hepatitis C has been enough. So, you
know, another 30 or 40 years sounds pretty good to some of us for a disease. That's a bad
sign. And I really think that, you know, it is that kind of double-sided issue because
I've been involved in actual client notification of people who have received lots of CJD
material and it's amazing. One person who comes to mind was--literally is on disability
due to AIDS and just so misinterpreted what he heard that he thought he was going to die
next week of another new thing.
And I think those are the kind of issues that come in. So that without
question there is a segment of our population that is terrified. If you talk to moms of
young kids today, they are just like horrified by any of this. And if you talk to I think
some of those of us who have been HIV infected, hepatitis C infected, you know, we don't
like it, but the prospect of, again I'll say the prospect of a condition that would take
30 odd years to set in, I could live with that. And that's a horrible thing.
DR. CAPLAN: Just to follow up that quickly and then I'll let any last
question come forward for this panel. You suggested that maybe American made products
should stay in America. We do actually have a precedent in another area for doing this.
We've actually limited the number of transplants of solid organs that can go to foreigners
who come here because a lot of organs were going outside of American bodies. I was curious
about your thoughts, if you had given any thought to a recommendation that lots that might
be at risk of CJD only go to older recipients?
MR. COLBURN: I would say that that's not a bad concept provided that the
recipient has the choice option, and I think that's where we get down to it. And I think
unfortunately because of the way our society is today that if a company is going to put
out a product that may contain something, my guess is that their lawyers are not going to
let them do that. I mean and that's unfortunate because there are people, and, you know,
when you deal in the home infusion world, some of the things that Dr. Winkelstein was
talking about, those are going on today. You know do you give the 29 year hemophilic with
ITP enough IVIG to stabilize him to do a splenectomy or do you give it to the kid with
the, you know, immune deficiency syndrome. And I tell you those are choices that should
not be being made.
DR. CAPLAN: Paul.
DR. HAAS: I just had a couple of comments that I wanted to offer to the
committee--if the panel would like to comment on it, that's fine--that I've been reminded
of on the basis of Dr. Winkelstein's comments and Dr. Davey's comments about unintended
outcomes, unexpected ramifications of the intention to make the blood supply safer with
respect to CJD and the consequent shortages. For example, with the shortage of IVIG, which
does have multiple factors, at our institution we have seen a shift of hematologists away
from giving IGIV for ITP, which isn't available, to giving Rh immune globulin, and that
has begun to press now our supply of Rh immune globulin which may ultimately mean that
some pregnant women will not receive Rh immune globulin when they should, and we may have
more cases of hematological disease of the newborn. So people who are not in any way
involved with IVIG or any related compound may suddenly be affected by this.
The Red Cross, as Dr. Davey noted, has decided not to send plasma for
fractionation from donors greater than 60 years of age. While that's understandable from
one perspective, that will tend to push more units from younger donors into fractionation,
and this group of donors is more likely to be positive for other infectious diseases which
we do not about which are a concern, and that ultimately may lead to some consequence
there that's unintended.
If there is a move toward making pool sizes smaller, it is true that each
pool or whatever derivative we're talking about will be less likely to contain a
contaminant because there will be fewer donors involved. However, any contaminant that is
in the pool, and we've heard that just about every pool would have one anyway, would be at
a greater concentration because it wouldn't be diluted out by the negative individuals as
much, and might that increase concentration in something like albumin or IVIG, then being
pushed above a certain threshold that will lead to infectivity when previously it wasn't
seen?
I don't have the answers to any of these questions, but if we're talking
about a theoretical risk, we need to consider the theoretical impacts of our safety
measures.
DR. BUSCH: I wanted to add one more consequence that I think is intriguing
in light of the discussion about exportation of product. One of the other consequences of
the CJD deferral and the substantially higher probability that CJD is reported back in the
volunteer whole blood sector than in the source plasma sector is that now other than the
Red Cross, which has had to withstand this enormous economic impact, and their whole blood
collection is from volunteer donors, all of the fractionation to my knowledge by the
commercial plasma fracturers in the United States is now exclusively done from source
plasma. Other than the Red Cross system, all volunteer donor recovered plasma is now
shipped to Europe for fractionation. And, in essence, now the vast majority of derivatives
manufactured in the states are now derived from commercial paid plasma donors, and we
heard the hemophilia community endorsing the concept of an expanded effort to encourage
volunteer donations when the true consequence of the deferral has been a complete shift
other than the Red Cross, which has had their major problems, a complete shift to source
plasma derived product in the U.S. and a complete shift to exportation of volunteer blood
plasma from the U.S. to Switzerland where it's being fractionated over there.
DR. GILCHER: To add further comments to the general panel and to the panel
of three, Dr. Davey remarked that the decision was made, you said, Mike, as well, to only
use donors over the age of 60 for the transfusable product. And the reality is that the
manufacturers of the paid donor plasma are doing exactly the same thing, and the truth is
that the real reason is to reduce or eliminate market withdrawal. Theoretically, then, a
single plasma transfusable product could have a higher infective dose because that would
be the individual that would be more likely if they were developing the disease to
eventually have it.
Now, I don't know that that's true or not true, but my question to both
Dr. Davey and Dr. Yomtovian is this: The SD plasma is a great concern from the standpoint
that it is a pooled product, and my question to you, Dr. Davey, is will the SD plasma, and
the sole source of this, we know, is now from the Red Cross plasma pool, from no one else,
it's only from the Red Cross, will that be from donors over the age of 60 or under the age
of 60 because theoretically if that is going to be considered as a transfusable plasma
product, you could actually increase the number of infectious units if this is possible
with CJD in the SD plasma? And this is a concern. Can you comment on that?
DR. DAVEY: My understanding, Ron, is that the material will be made from
donors under 60 and will, of course, be going through a SD process which will inactivate
known infectious viruses of concern to transfusion recipients. So I think the question may
revolve around a process that inactivates known viruses against the theoretical risk of
other viruses being transmitted through this particular product. And that's for, I think,
the American clinical community to decide.
DR. GILCHER: Is there anyone who could comment on the other statement
which I made which is is it possible that there would be more likely a higher infectious
dose of a transmissible spongiform encephalopathy agent in plasma derived from donors over
the age of 60 since that will become the transfusable product? It will become the FFP of
this country is in reality what will happen to this.
MR. COLBURN: Can I make just a comment? You might be interested in a
historical perspective on that. That was the argument utilized for not going back to cryo
with HIV. Now, I recognize the two are not the same, but that was the strong argument that
you would receive a higher infectious dose unit in 15 units of cryo if you had one person
versus 10,000, 15,000 different donors. So for what it's worth, that didn't work.
DR. GILCHER: Of course that's a slightly different kind of issue.
DR. ROHWER: In terms of the possible variation in titer with age of the
population that you're sampling, what we do know from animal work and only from animal
work is that the closer you get to the clinical disease, the higher the titer, and, in
fact, when animals are experimentally inoculated and the growth of the agent in the brains
of the animals is assayed, and that's only been done a couple of times, at least by
myself, the agent seems to grow at a constant exponential rate from the time of
inoculation until death, but with a very slow incubation time or doubling time.
On the other hand, in the case of humans, we don't know at what point in
their life they are actively infected to come down with the disease in their 60s, for
example, and whether they're incubating again for ten years or 40 years. We don't know
whether that's the same situation exists there where you've got a continuous expansion
during that entire period, whether that's all happening in the brain or it happens in the
periphery and then moves to the brain. None of those things are known and aren't going to
be known. But since the highest incidence level of clinical disease is in that age group,
in that cohort, you could expect to contact the highest titers of virus among that group
of individuals.
DR. EPSTEIN: I'm Jay Epstein with the Office of Blood at FDA. Just a
couple of comments about the issue of SD plasma as well as the issue of concentration.
First of all, Dr. Paul Brown from the NIH specifically commented on that issue at a
previous meeting of the TSE advisory committee and pointed out that if indeed the titer of
infectivity in the pooled plasma or blood is low, and it has been estimated, as you heard
again today, at between one to ten infectious units per ml, then the effect of dilution
even in a pool as low as 2,000 is to fully disperse those infectious units such that the
number of a doses of product containing an infectious unit remains constant. And that's
true at any significant dilution level compared to the total infectivity put into the
pool.
Now, in the case of 2,000 units, it's a somewhat simple calculation
because you end up with the same number of units out as the units in. If we think that a
unit is about 200 ml, if we think that there are at worst ten infectious units, that's
2,000 infectious units that then get dispersed back to the same number of units. What you
end up with is roughly a one per unit infectivity. We don't know how the animal infectious
units compare to infectivity in man, let alone by intravenous exposure.
But I think that Dr. Brown's comment is important, which is that if the
infectivity is, in fact, not removed or destroyed, then if it's fully dispersed, you end
up with the same number of infections or risks of infection regardless of any further
dilution.
The second point that I would make is that the question whether solvent
detergent plasma because it is a pooled product raises unacceptable risks and should not
be approved by FDA was brought to public discussion both at a scientific workshop and at a
scientific advisory committee. I'm afraid that I don't recall the exact dates, but it was
within the last two years, and all of these issues were brought forward. The tradeoff
between inactivation of known agents versus the potential to further distribute and
therefore amplify infections of either unconventional agents that we know about or unknown
agents, and I would have to say that in many ways, it's like the discussion that we were
having earlier about risk perception, you know, where do you put your fate? Preventing
known risks or trying to avoid unknown risks?
And that's a very hard choice, and it was very obvious that it was a hard
choice. But in the end, the advice that FDA received was that because there was a
definable benefit to inactivation of known agents that are very worrisome agents, like
HIV, hepatitis C, hepatitis B, that FDA should approve validated products, despite the
fact that they're pooled products. FDA did, however, move to limit the pool size and we
set an upper limit of 500 liters which from practical purposes sets an upper limit of
about 2,000 on the number of donors.
And I think that what's reemerging here is the same question, but it's not
a new question, and it is the FDA's policy position to approve a valid application.
However, I think that the concept that it is then the sole available product needs to be
brought into question because there is potentially the alternative of a single donor
product where the product has been quarantined pending retest of the donor. We call that
donor retested plasma, and we will be having a discussion of that product as an acceptable
alternative at an upcoming meeting of the Blood Products Advisory Committee.
And then my last comment directed to Dr. Yomtovian, you did point out that
there is a difference in how notification currently is operating for pharmacy products
versus blood components, and you are correct. However, those are not directly reflective
of a FDA policy on the issue. Our policy is directed toward retrieval of end date products
which have been potentially contaminated by CJD or at CJD risk and we have remained
neutral. As Dr. Weinstein said, we have left it to medical judgment whether to inform the
recipient and we do not have any lookback requirements including recipient notification.
Our quote-unquote "lookback" requirements as they affect CJD are for
interdiction of product.
Now, it is true that in response to the request of the hemophilia
community, we have been developing notification systems applicable to clotting factors and
we have also done the same with the alpha-1 proteinase inhibitor and with immune globulin
because of requests from the IDF and others. But it's still not the policy position of FDA
to require that notification. The lookback component which is recommended by FDA deals
with consignee notification and interdiction of end date product. That's not to say that
the issue of notification is not important or not evolving. I think Dr. Weinstein made
those points clear.
DR. CAPLAN: And I'll be personally looking forward to the follow-up
correspondence between the ASCP and the FDA on those matters, which I'm sure will happen.
Let me thank that panel for their presentations and thoughts. I'm going to ask the last
four people I have scheduled to speak which is Premier, Incorporated, Pall Corporation,
Margaret Somerville and the International Plasma Producer Industry Association to come up,
grab one more chair. We'll go down the line, same routine again. I'd ask you to identify
yourselves, spell your name, and if you could bring one more chair up there, or actually
we could do this as sort of--oh, there is one up there, great. And I should welcome Margo
myself who I know and recognize. Why don't you start and introduce yourselves, spell your
name, and let the other panelists do it, and do you want to first?
MS. SOMERVILLE: No. I'd rather go after Barry actually. Thank you.
MR. WENZ: Good afternoon. My name is Barry Wenz, B-A-R-R-Y W-E-N-Z. I'm a
medical director and a corporate vice president of the Pall Corporation.
MS. SOMERVILLE: I'm Margaret Somerville. I'm Professor of Law and
professor in the faculty of medicine at McGill University and the McGill Center for
Medicine, Ethics and Law. I also have been a consultant to Pall on the use of leucocyte
reduced blood on ethical and legal issues.
DR. JUST: Hi. My name is Dr. Paul Just, J-U-S-T, and I'm a board certified
pharmacotherapy specialist, who is the senior director for clinical pharmacy at Premier,
Incorporated.
MR. BABLAK: My name is Jason Bablak. I'm with the International Plasma
Products Industry Association, B-A-B-L-A-K.
DR. CAPLAN: And let's go right down the line that way then.
MR. WENZ: Dr. Caplan, Dr. Nightengale, members of the committee, I want to
thank you for this opportunity to present. Leucocyte reduced blood has proved to have a
number of clinical indications. It reduces the non-hemolytic febrile transfusion reaction
as well as alloimmunization to Class I HLA antigens and the resultant refractoriness to
platelet transfusions. It decreases transfusion associated CMV transmission and infection
in the group of patients that it has been trialed in. It provides fewer complications in
post-operative patients, particularly post-operative bacterial infection linked to
immuno-suppression, and finally recent studies show that it decreases the bio-burden in
spiked bacteriologically infected blood.
Recently, altered prion proteins have been suggested as the pathological
vectors associated with the transmissible spongiform encephalopathies such as scrapie and
the New Variant Creutzfeldt-Jakob Disease. The B-lymphocyte proves essential in
transmission of the scrapie prion from peripheral sites of inoculation such as the
peritoneum to the central nervous system of experimental animals in studies done by Gutzi
[ph] and associates, and based on these observations, expert panels such as SEAC, the
Spongiform Encephalopathy Advisory Committee to the British Health Care System, and other
experts within our own country such as Paul Brown, who I think is well known to the panel,
have suggested that blood and blood products be leucocyte reduced as a potential
prophylaxis against the possibility of transmitting the New Variant CJD by transfusion.
In support of this suggestion, we analyzed the efficiency of B-lymphocyte
reduction by filtration of whole blood and packed red cell products. Whole blood was drawn
into medsep collection sets containing either CPD or CP2D and fractionated packed red
cells were suspended in either CPD SAG M or in CPD absol additive solutions, and all 20
units of blood were studied in the data that I will present. The filters used in the study
were the Pall Leucotrap Whole Blood Filter, and for the packed red cells, they were either
filtered with the Pall Leucotrap RCM 1 filter or the BPF for sterile dockable filter. All
blood was processed and filtered within eight to 48 hours after collection.
Total white blood cell counts in the filtered products were quantified by
a previously published cytometric method and phenotypes for the residual mononuclear cells
were performed also by a method currently impressed by harvesting the low number
population of WBCs on a nikodin medium resuspending the pellet in a buffered albumin
containing solution and labeling the cells with fluorescenated monoclonal antibodies and
specifically in the case of B-lymphocytes a combination of CD3 and CD-19 flurofor directed
determinants. These methods are all published.
The acquisition gates for those of you who are interested in flow
cytometry were set for all of the mononuclear cells using three parameters and that is
both high and low angle light scatter, as well as fluorescence intensity, and, of course,
units were spiked with known cells of mononuclear description, both to detect the ability
of the technology itself to recover a percentage of the cells which turned out to be
consistently in excess of 94 percent and also to make sure that the acquisition gates were
properly set. In all, 30,000 events per sample were analyzed using a BD flow cytometer.
The mononuclear cell distribution ranged in all instances for the
mononuclear cells in the prefiltration units with a fairly tight CV and a mean ranging
between 2.7 and 5.6 times ten to the eighth for each of the various subclasses of the
mononuclear cells. The distribution of the major white blood cell population in the
filtered pack red blood cells was quite distinct, and as a matter of fact it rallied to a
1.1 times ten to the three concentration for T-8 cells, a six times ten to the three
concentration for 10-4 lymphocytes and the monocytes and the B-lymphocytes were below
limits of detection. The limits of detection for this system as related to filtered native
blood product and the 500-fold concentration that was used are on the order of 0.004 cells
per microliter of blood or the subpopulation would have to total two times ten to the
three to be detectible by the technique. So for the most part, both the monocytes and the
B-lymphocytes were below limits of detection representing a minimal six log reduction of
these two subpopulations.
Our conclusion is that these data confirm that the B-lymphocytes are
reduced to or below the detection limits in the blood products filtered, and the use of
this technology is consistent with the expert recommendations that have been previously
made by SEAC panel and other individual experts on the potential prophylactic additional
safety measure that might be added by leucocyte reducing the blood and blood components.
In closing, I think you will remember that several of the previous presenters have pointed
out that Portugal indeed has gone to the action of 100 percent leucocyte reduction of all
blood and blood components for this specific indication, and there is both a feasibility
committee and another expert committee on impact studying this same consideration in the
UK and in other European Community nations. Thank you very much.
DR. CAPLAN: Thank you. Margaret.
MS. SOMERVILLE: Thank you, Dr. Caplan and Dr. Nightengale, members of the
committee. This whole issue of the possible transmission of CJD through blood or blood
products really involves decision making in conditions of uncertainty. And one of the
things that we can use to try to help us in those conditions is ethical and legal
analysis. Now, I'm assuming that you have this paper that I prepared; is that correct? So
that all I want to do is point out the remarks or the points that I'm making that what we
have here is that if we accept the facts as Dr. Wenz has presented them that recent
scientific publications indicate that leucocyte reduction could reduce the likelihood of
transmission of CJD through blood transfusions, what are the ethical and legal obligations
of physicians, health care institutions, and you could actually add to that regulatory
agencies either to use leucocyte reduced blood, which is one set of obligations, or
alternatively, at least to inform those receiving blood or blood products of the possible
advantages of doing this?
Now, I preface these remarks with what is a truism in ethics, and that is
that good facts are essential for good ethics, and good ethics are actually essential for
good law, too, so you have to preface this on the grounds that I'm accepting these facts
as we best know them at the moment. But that is also true for you. None of us have got the
exact facts. That's precisely the problem. If we did, we'd know what to do. So with that
in mind, we can actually analyze two major sets of obligations.
One of them are the physicians' obligations, and that's actually what we
call a microlevel or individual ethical and legal level analysis. The other group of
obligations, as you'll see in this paper, is the macro--it's actually probably both meso
and macro level. It's the obligations of institutions such as hospitals, transfusion
centers, and above that, the macro level, for instance, obligations of regulatory agencies
to also act ethically and legally. Now there are different ethical considerations and
sometimes often reflecting that different legal considerations at those different levels
of analyses.
If you go through the physician's obligation, the physician has got a
primary obligation of personal care. There's been a shift to what we call earned trust. A
primary factor of earning trust is full disclosure to the person in what's called shared
decision-making. In my view, that would indicate that you have to disclose to people any
possibilities that are reasonable for them reducing the risks that they face. From a legal
point of view, you find the same thing reflected. A physician has to live up to the
standard of reasonably competent and careful practice. Increasingly, the courts are
adopting a fiduciary obligation for physicians. For instance, in the breast implant cases,
Hollis and Down Corning, it's quite interesting, it went to our Supreme Court of Canada.
One of the defenses was that the evidence was not strong enough to know at the point at
which this woman was injured that the breast implants were harmful.
Our court held that there was a continuing obligation to disclose research
information to patients undergoing procedures as that information became reasonably
available, and a major problem that you have to or the major decision that you have to
make here, and it's actually a decision that is common to all of the decisions that you
will make about what you do with regard to the blood system and CJD, is the choice of your
basic presumption. And this is often something that people don't even realize that they're
choosing, and when you've got decision-making and conditions of uncertainty, the choice of
your basic presumption usually determines the outcome of your decision. Therefore, it's an
extraordinarily important choice.
Your choices in this case are--I'm taking, for instance, here, leucocyte
reduction as the pertinent example--the two choices are no, leucocyte reduction need not
be used unless it's shown to be effective, or, yes, this must be used but there may be
justification for not doing so in some cases. If you use a no-unless, you won't use it. If
you use a yes, but, yes, we should do this because there's a chance it will help, and
there are very few if any down sides to doing it, then that means that you would use it.
If you then add on to that ethics, and here where you've got an infective agent for a
fatal dread disease such as CJD, and we heard about that from our psychologists, then the
presumption--I would suggest to you because you would err on the side of caution and use a
precautionary ethic--would be that you would do the thing that is most likely to be
helpful.
You also have to look at the down side of taking one or other of those
presumptions. If you're wrong that this wasn't needed, the most you've done is spent some
extra money. You haven't done any harm. If you're wrong that it was needed and you didn't
do it, you've got people with CJD who need not have had CJD. In fact, again, we've just
had a case, a big case in Canada, where our courts held our blood agency liable for
delaying the implementation of donor deferral criteria that were currently or at time were
being used in the U.S., and we took about seven months longer to put them into effect.
And the court held that in that situation of uncertainty, we should have
acted on the side of greater care and that that delay constituted negligence. I haven't
obviously got time to go into all of this. If you go to the institutional level,
institutions have obligations to run a non-negligent system. You have to ask what does
reasonable care require to establish a non-negligent system. One of the big factors is
cost. In public institutions, cost is an allowable ethical consideration, both allocation
of resources to certain things and then within those issues.
Finally, you've got the major issue of informed consent, that even if you
decide that you're not going to do this as part of the required practice, do you have
obligations under the requirements of informed consent to tell people that they are
receiving blood that may not be as safe as it is possible to make it? The test for
informed consent, the scope of disclosure, one of two, and it depends which state you're
in in the U.S. which one applies, but the least stringent one, although still pretty
stringent, is disclosure of the information that the reasonable physician in the same
circumstances would disclose; the more stringent one is disclosure of the information,
which is risks, harms, benefits and potential benefits that the reasonable patient in
those circumstances would find material. In my view, certainly under the second and I
think highly probably under the first, you would have to disclose all the options
available. Thank you.
DR. JUST: Hi. Again, my name is Dr. Paul Just. Mr. Chairman and members of
the committee, thank you for the opportunity to comment on this important issue. Premier
is an alliance of over 1,700 hospitals and health care systems throughout the United
States. We represent over 30 percent of all hospital beds in the U.S. Among many services,
Premier's Group Purchasing Area contracts for over $8 billion worth of pharmaceutical and
material purchases. My comments today are principally related to the impact on
fractionated blood and plasma product supply created by concerns of the risk of their
contamination by the etiologic agent responsible for transmitting Creutzfeldt-Jakob
Disease. The impact on supply is ultimately reflected by an impact on direct patient care.
Over the past six months, we've received hundreds of calls regarding
difficulty or inability to acquire fractionated plasma products, primarily albumin and
immune globulins through normal distribution channels. Although many report that albumin
shortages have eased over the last several months, recent reports indicate that even
specialty suppliers are running out of immune globulins. The shortage of immune globulin
appears to be at a critical level. This month several pharmacists have shared examples
documenting the inability of their facility to treat patients with immune globulin for
potentially life threatening disease because they were unable to acquire the product from
any supplier at any price.
Some of these facilities have turned patients away referring them to
another facility with available product when possible. Hundreds of facilities have
reported paying up to three times and sometimes four times the normal price to acquire the
increasingly limited supplies of immune globulin. Some manufacturers have begun setting
aside supplies of immune globulin for emergency allocation on a case-by-case basis when
they receive a direct call from a health care professional. In such cases, although the
cost is higher than during periods of normal supply, it appears to be under twice the
former cost.
The shortages of albumin and immune globulin over the last year seem
primarily related to voluntary recalls by manufacturers of a very large number of these
lots of products related to concern over donor pool members who were either confirmed to
have CJD or considered to have a history of risk for CJD. There is international precedent
for recalling products when a member of the donor pool has been confirmed to have CJD.
Additionally, there is precedent for recalling lots following confirmation that a donor
has been exposed to an established risk factor for transmission of CJD. The principal
accepted risk factors include dura mater transplant, administration of a human pituitary
extract and the presence of more than one family member with a confirmed diagnosis of CJD.
A confounding variable is that despite the excellent efforts to
characterize the risk of CJD in each contributor to a donor pool, not all blood donors at
higher than average risk for CJD report the presence of risk factors at the time of
donation. It is interesting that several 1997 albumin and immunoglobulin recalls appear to
have occurred on the basis of an unconfirmed or questionable exposure risk factor in a
member of the donor pool who was not diagnosed with CJD. The following are noted from '97:
November 25, albumin and immune globulin recall because quote "a
donor who might have received human pituitary derived growth hormone in 1969."
October 10, immune globulin because quote "the first donor had a brain tumor removed
30 years ago and is unsure if received a dura mater graft at that time." September
17, immunoglobulin, albumin and others because quote "the first donor gave the
history of taking human pituitary derived growth hormone for about one month in
1964." August 16, albumin and others because quote "the second donor had a brain
tumor removed 30 years ago and is unsure if received a dura mater graft at that
time." And July 22, immunoglobulin, albumin and others because quote "the first
donor claims to have been treated 36 years ago in 1960 with human pituitary derived growth
hormone."
If it were fact that administration of a fractionated blood product
derived from a donor pool that definitely contained the etiologic agent of CJD would
ultimate induce CJD in the recipient, then such recalls should not be questioned. This is
not the case. It is fact that administration of any blood or plasma derived product does
not have zero risk. However, this fact must be tempered with an understanding of the
evidence related to the likelihood of transmitting CJD from human to human with a blood or
plasma derived product.
The extremely low risk of human to human transmission of CJD by its
etiologic agent in blood or fractionated blood products has been well characterized by
experts both in the medical literature and in testimony before various advisory
committees, to the FDA, HHS, and Congress. It's not the purpose of my commentary to review
such evidence in detail. I defer rather to the excellent summary provided in testimony
given on July 31, 1997 by Dr. David Satcher, Director of the CDC, before the U.S. House of
Representatives subcommittee. He made five key points.
First, quote: "CDC is aware of no compelling evidence for any
instance of transmission of CJD to a human recipient by blood or blood products."
Second: the results of five case control studies have demonstrated that patients
documented to have CJD were not more likely than control subjects to have received a blood
transfusion, thus suggesting that blood transfusion is not a risk factor for CJD. Third:
CDC surveillance data for 1979 through 1995 found quote: "None of the 3,905 reported
cases of CJD was also reported to have hemophilia, Thalassemia or sickle cell disease,
diseases associated with increased exposure to blood or blood products."
Fourth: a neuropathological examination of autopsy tissue from 26, as of
this morning now 29, patients with hemophilia did not demonstrate evidence of CJD.
Finally, he reviews first and second-hand information that traced for up to 25 years 178
and 101 patients respectively who received blood components from donors who were
subsequently determined to have CJD. No recipient was ever found to have CJD.
Additionally, present epidemiological data, primarily from the hemophiliac population
provides no conclusive support for the theory that CJD can be transmitted among humans
through blood or by any blood product.
Sensitivity and reaction to the CJD issue may have resulted in
over-conservative positions based on the theoretical risk of CJD transmission by blood and
plasma derived products linked to donors with a suspected but not confirmed exposure to a
risk factor for CJD. Actions based on this position potentially compromise best health
care practice today for the sake of reducing a future theoretical risk that is unproved.
No conclusive evidence has to date been discovered to substantiate the hypothesis that a
blood or plasma derived product can transmit CJD between humans when it administered
intravenously. Although it is prudent to recall product when donors have been confirmed to
have CJD or multiple family members with CJD now be the time to consider working with
manufacturers to develop guidelines for releasing some product that might be considered
compromised as long as it is so labeled during periods of severe shortage as exists today.
Thank you.
DR. CAPLAN: Thanks.
MR. BABLAK: Good afternoon. My name is Jason Bablak, and I'm Director of
Regulatory Affairs for the International Plasma Products Industry Association, the
international trade association representing the commercial producers of plasma-based
therapies. IPPIA members produce approximately 80 percent of the market for the United
States and include the four largest commercial fractionaters, Alpha Therapeutic, Baxter
Healthcare, Bear Corporation, and Syntion.
Continual improvement in the margin of safety of plasma-based therapies is
a priority to our industry. As part of this constant examination, IPPIA developed a series
of voluntary initiatives to further improve the margin of safety for these products. These
initiatives include the exclusion of one-time only donors, an inventory hold for source
plasma, and the implementation of testing using genome amplification technology. For
example, polymerase chain reaction.
These initiatives further reduce the potential that so-called window units
could enter the manufacturing process. During processing, validated viral elimination
techniques contribute to the removal of viral particles that may have been sub-detectible.
The combination of these safeguards helps to give patients even greater assurance of the
safety of their therapies.
Unlike known pathogens, however, there are currently many unanswered
questions in the science and technology for studying Creutzfeldt-Jakob Disease or other
TSEs. Most notably, the potential to transmit the disease through blood and blood products
is currently uncertain. There are no well characterized reagents available to conduct
assays for the protein marker of the disease, no sensitive in vitro assays are presently
available, and no early detection markers are known for identification of infectious but
asymptomatic individuals.
The effectiveness of current purification clearance mechanisms in
eliminating the infectious agent is under investigation. However, these studies are
complex, subject to criticism and difficult to interpret. Industry's response to the CJD
issue, as it is with all safety and quality issues, is to continue to seek new techniques
and strategies for determining and reducing risk even if theoretical, enhancing the margin
of safety, and improving the quality of plasma-based therapies.
Each IPPIA member company manages a comprehensive scientific research
program. Individually or through collaboration with scientific laboratories throughout the
world, our members are searching for answers that include whether blood or plasma products
are vectors for CJD transmission, whether reliable analytical procedures to detect
potential CJD infectivity can be developed, and whether manufacturing and/or fractionation
processes could remove infectivity that might evade preprocess screening systems.
However, the answers to these questions are difficult to determine due to
the unusual nature of the agent and the complexity of tools and studies needed to conduct
these investigations. This research is critically important and we encourage the
government to increase funding to help us find these answers. In order to manage possible
risks before these answers are known, both industry and the FDA have taken a conservative
approach in this area. This policy is highlighted in the December 1996 memo from CBER to
all blood and plasma establishments that was discussed earlier today.
While it is not currently known whether CJD can be transmitted through
plasma, industry has voluntarily agreed to withdraw plasma-based therapies manufactured
from plasma, donated by individuals who develop or who are theoretically at increased risk
for CJD. However, it is important to note that using the same scientific evidence, the
Committee for Proprietary Medicinal Products has determined that it will not institute
this type of policy in the European Union for classical CJD.
The primary action of the U.S. industry has been the withdrawal of
therapeutic products manufactured from the plasma of donors who are theoretically at
increased risk for who have actually developed CJD. Additionally, end process material is
also destroyed upon the discovery of such a unit. The combination of withdrawals and end
process destruction of material has detrimentally impacted supply, at times leaving
hospitals and other providers with a limited or just in time inventory of several products
including albumin, IVIG, Factor VIII and alpha-1 proteinase inhibitor.
The following is an example of the possible impact of this policy for
patients who rely on these therapies for their health and their very lives. One of our
members recently withdrew several lots of plasma-based therapies because the donor was
considered to be an increased risk for CJD. Subsequent to donating, this individual
reported taking human pituitary derived growth hormone several years earlier. Based on
this information, the company initiated a lookback and determined that one donation from
this one donor had been used for further processing.
Several lots of IVIG, albumin and Factor IX had been manufactured from
plasma pools containing this theoretical at-risk unit and were withdrawn according to the
current policy. Counting only the amount of material actually returned to date and end
process bulk not used for further processing, we calculated the number of patient doses
unavailable for use due to this particular event. Using numbers provided by the Immune
Deficiency Foundation for the average primary immune deficient, the equivalent of more
than 15,000 doses of IVIG were either removed from the market or destroyed in process.
This is enough therapy to treat over 1,200 patients for one year. Further, more than
11,000 doses of albumin and over 100 doses of Factor IX were also destroyed due to this
particular event.
As you can see from this one example of a single theoretical at-risk
donation, the impact of this policy on the supply of plasma based therapies is very
significant. While we must remain vigilant regarding risks associated with the theoretical
possibility of CJD transmission, we believe that we must also consider the risks of
inadequate supply to patients who rely on these therapies. The information provided here
is just one example of the impact of this policy on supply.
Finally, we encourage the government to continue to make more funds
available for research in this area, and we encourage both the FDA and the NIH to develop
a forum for global harmonization of the current state of knowledge and regulatory
requirements regarding CJD. Our industry stands ready to lend support in this effort.
Thank you for the opportunity to address this committee on this particular issue. Our
industry is dedicated to continuous improvement in our efforts towards increasing the
margin of safety in plasma based therapies for both known and unknown risks so that the
people who depend upon them for their health and their very lives will know that these
therapies are as safe as possible, effective, and available. I'd be happy to answer any
questions on this or also on the patient notification system that was discussed earlier.
DR. CAPLAN: Thank you. John.
DR. PENNER: Well, a quick question to Dr. Rohwer. If I remember rightly,
I'm recalling there was some question about lymphocytes about harboring possibly some of
the infective agent, but your data would seem to suggest that plasma was really pretty
well loaded with it. Am I correct?
DR. ROHWER: Yes, it is. You are correct in what we saw in our experiments.
That was a big surprise to us as well as everybody else. And because it was such a big
surprise, we'd like to see it again before we jump to any conclusions about it. But
basically the only thing that is consistent there is we saw it in two different systems,
and both in the mouse, endogenous infectivity in the mouse, and in the hamster. The
measurement in the hamster was rather indirect. It was the fact that we did see
infectivity in whole blood and then we would have presumed to have seen the infectivity in
the white blood cells prepared from that same preparation of whole blood and then did not
reliably detect it.
DR. PENNER: Maybe back to our panelists. How hard is the data on the
lymphocyte?
MR. WENZ: I'd like to add a point of clarification. We have to look at the
various studies that have been done that concern classical CJD and New Variant CJD. And
I'm sure Dr. Rohwer is more qualified than I am here. However, to the best of my
knowledge, the only instances where the B-cell has been incriminated and certainly the
work of Gutzi are addressing New Variant CJD, the current BSE equivalent, if you will, in
man prevalent in the UK.
DR. BUSCH: That's correct. I think Aguzi's work is with classical CJD in a
transgenic skid mouse model. The tonsilar stuff where they're finding increased prion
proteins in B-cells and tonsils and follicular cells is New Variant. Just in follow-up,
one concern I have in terms of this concept of filtration is I mean the fact that in the
Aguzi work that B-lymphocytes and when they do transgenic mechanisms they put susceptible
B-lymphocytes into an animal that lacks the prion proteins and therefore can't passage it
through the body and they demonstrate that those animals, the B-lymphocytes play a role in
endogenous propagation of these TSEs, I think that's a whole different issue than the
issue of transmission by a blood component where the viability of B-lymphocytes that are
in transfused blood is within a few days essentially zero, and the fact that these cells
may play a role in in vivo pathogenesis to migration to lymphoid tissue and to active
mechanisms does not imply to me that transfused blood from an individual would necessarily
play a similar role. So I think the issue of leucodepletion is premature relative to the
scientific data.
DR. CAPLAN: Paul, did you want to say something?
DR. McCURDY: Mike said it. I thought that the lymphocyte issue was in the
recipient and not in the donor's product so whatever you did to the donor's product didn't
necessarily deal with Gutzi's work.
DR. KUHN: I have two questions. One for Dr. Just and one for Mr. Bablak.
Dr. Just, the problem you said with the acceptance of I think you said five donors who had
possible dura mater or history of CJD, the problem with those donors not being able to
donate, was that problem due to the FDA policy to those who were doing the screening and
the case history and the interviewing in obtaining that information, and if so is it
possible that we may have to go back to screening criteria and try to beef that up a
little bit so that we don't have--it sounds to me like some of these are falling through
the crack. We could possibly have other donors, and then out of those five donors, how
many was that out of total, those five donors?
DR. JUST: Okay. I don't have all the information that will properly answer
your question. Where my data is extracted from are the recalls themselves which state the
reason for the recall, and they were the quotes that I've incorporated in my comments,
which are that there was a possible history of or the donor reported this. In terms of
beyond that point, I can't answer your question.
DR. SNYDER: But that was subsequent to their actual donation? In other
words, that blood had started to be processed before they found out.
DR. JUST: I would leap to the conclusion that that might have been the
case, but I can't say that with any certainty because it's limited data when you're
working off of the recall notification itself and don't have the information available to
the manufacturer when they made the decision to recall the product.
DR. KUHN: And then the second question was to Jason Bablak. What is the
industry doing to notify consumers of the withdrawals of CJD to both educate them and also
not to create a panic? I know Dr. Schiff and I were talking about this earlier.
MR. BABLAK: Well, I can talk about what we're doing to notify consumers. I
don't know too much what we can do to alleviate any panic. I think that's really between
the health care provider and the patient. As you're aware, I'm sure, we have started the
design and implementation of a patient notification system that all of our members and
some of the other non-IPPI members including American Red Cross and NOVARDIS which will be
a direct patient notification system. So it will work not only for withdrawals for CJD but
any other kind of regulatory action that will be instituted by the FDA.
This will be a direct patient notification system for patients who
voluntarily register with the third party that we will contract with to provide this
information. We are going to develop an advisory panel of patients, industry and medical
representatives, to help us design and run this system. There will be one toll-free access
number for all of the information, and all costs will be born by the manufacturers so
there will be no cost whatsoever to the patients or other interested individuals to
receive this information.
DR. CAPLAN: I had Kristine, then John.
DR. MOORE: This question actually kind of stems off of some of the
discussion here, but it really applies more to the FDA folks who are here. I'm not really
clear on the data that were presented. You presented some numbers on how many donors you
had from the various risk groups, but what isn't clear to me is how that information
directly relates to the product withdrawals, and I'm just wondering if it would be
possible to get a little bit better breakdown, particularly based on some of the
information presented here in terms of how these really--you know, how much product has
been withdrawn because a person subsequently developed CJD? How much product has been
withdrawn because of these questionable kinds of issues? How much has been withdrawn
because of a dura mater transplant that wasn't recognized at the time of the initial
history? And I think that might be helpful--
DR. CAPLAN: Let me jump in and say don't answer that, but--
DR. MOORE: No. Don't answer it. Bring it tomorrow.
DR. CAPLAN: If we can get some information on that, that would be very
helpful.
DR. MOORE: Right. Exactly
DR. CAPLAN: Either from the--
DR. MOORE: Just in terms of look how to look at the policy decisions
around this. I don't have a clear sense of this, and it would be very useful.
DR. CAPLAN: And I'll ask Steve to follow through on that to see what we
can collect about that.
DR. SNYDER: Another question that would go along with that is when was the
first dura mater transplant?
DR. MOORE: Yes.
DR. SNYDER: I mean 30 years ago I find hard to believe.
DR. PILIAVIN: This 30 years ago stuff is impossible.
DR. MOORE: One other question I just had real quickly, too, do you have
any sense among donors how many have brain surgeries? For example, I mean what's some of
the denominators for some of these risks, too, just might be helpful in terms of looking
at a reasonable policy.
DR. SCHIFF: Yes. I'd like to ask industry to help us on where I'm getting
some mixed signals. We heard from the FDA, they didn't have a clear idea of why there was
a problem in keeping up with the supply, for example, IV gammaglobulin. Yet from your
standpoint, it sounded like this CJD business had a direct impact here and has put you way
behind so that there are people who need this who are absolutely not getting it. I'd like
to know can industry respond and come up with adequate supplies and at the same time put
in place these withdrawals of CJD? Does that mean it's going to cost a lot more money? Is
money the issue? Can industry make up this deficit and why are there mixed signals here?
MR. BABLAK: I don't know if there really are mixed signals. I think
there's just a lot of factors that go into determining whether or not--to the extent of
what the shortage is, I think, a lot of them have been hit on here today which is an
increasing use of this therapy. Certainly some of the numbers we presented here give a
good indication that there is some result of this policy on supply. There may be other
issues that we're unaware of.
As the FDA stated earlier, the manufacturers and FDA have been in
discussions to determine what this is and if there are methods that they can do to
alleviate the shortage and so I can't speak for individual manufacturers but I can tell
you that those negotiations are ongoing and certainly--
DR. SCHIFF: I understand what you're saying, but people are talking. I
want to know can industry deliver or not? Or is this going to be--I'm sure they've talked
about it and they're looking at strategies. Are we going to be able to deliver or not to
take care of the problem? It's a big problem.
MR. BABLAK: I can't answer that question because we don't know the extent
of the problem yet or all the reasons that may be causing it. So I can't give you a full
answer. I can tell you that we certainly are working very hard to eliminate the shortages.
DR. CAPLAN: John. Oh. Go ahead, sorry.
DR. JUST: May I respond a bit to that? Our organization had sent a letter
to the four major manufacturers of the fractionated blood products asking them to explain
to us why there's a shortage. To date, we've received a response from one of the
manufacturers who identified in their response that their impression of the major reason
behind the current situation is the recalls secondary to Creutzfeldt-Jakob Disease.
MR. WALSH: I just have two comments to make. Firstly, the initiation of
the Plasma Derivative Coalition of IDF, Alph-1 Foundation, Alph-1 Association, COTTS and
NHF appreciates the cooperation of IPPIA and certainly the counsel and support from the
FDA to get as far ahead as we can with respect to the notification plan, and we would
encourage you, and this committee is certainly very interested in the longer-term, and
encourage IPPIA to get a report back as soon as possible and be able to implement that
plan as soon as possible.
Secondly, I was going to wait until tomorrow to bring it up under new
discussion, under new business or under general discussion, but Dr. Winkelstein I think
very eloquently stated the position of IGIV shortage, and it's been expressed, some
concern about availability or supply as well as safety. I'm alph-1 anti-trypsin deficient.
We've just heard within the last seven days that we're under critical shortage, specific
allocations, probably a stop in production. We can't get a direct answer yet from a sole
manufacturer for a single product. So here is another augmentation therapy plasma
derivative that we depend on to sustain a quality of life that people waiting for
transplants need desperately to stay healthy enough to continue to qualify for
transplants.
We've consumed--probably a majority of our community have consumed CJD
withdrawn product--I myself have had over 400,000 milligrams of withdrawn CJD prolactin
product. And I think probably a majority of our community, it's probably a correct
statement to say that most people have experienced the same. We don't know what there is
about CJD and what to look forward to or not to look forward to. Like Don Colburn said, I
think, alpha-CJD breath is better than no breath at all in our context. You know if you
get another 30 or 40 years, that's fine. We don't argue with that. But that doesn't take
away from the importance and seriousness of the safety issues.
At the Oversight Subcommittee, HHS Oversight Subcommittee hearings, we
learned for the first time that our pool size wasn't 20,000 like we were told for the last
eight or nine years. It was in excess of 300,000 in more than one instance. So pool size
is an issue that I hope this committee addresses at some time in the future.
In closing, I would just like to again express that the committee is
looking on these availability and supply issues, and it has to become more of a priority,
Mr. Chairman, and on behalf of the alpha-1 community, I would appreciate, and I've had an
opportunity to talk with several colleagues on the committee and representatives of the
FDA, whatever assistance they can lend both to the IGIV community and the alph-1 community
with respect to the immediate critical shortages of both of our products?
DR. CAPLAN: Larry.
MR. ALLEN: Does the FDA or any of you have any numbers in terms of what
the needs are for any of these products? Do we know what we need to build to to keep a
substantial supply available for these things?
MR. BABLAK: Not that I'm aware of, and one of the problems is that the use
of this product is continuing to increase so as we increase our production, increased use
of the product continues to use it.
MR. ALLEN: Do you have any old numbers from the last years? Does anyone
have anything that we can--
MR. BABLAK: I don't have any with me--
MR. ALLEN: No?
MR. BABLAK: --right now. I'm sorry.
DR. JUST: Just to give you a small sample, we had some numbers on about
six to 700 of our facilities in terms of what level of commitment they were supposed to
have. This is committed allocation, not delivered allocation necessarily. For the IVIG it
exceeds 1.5 million grams of IVIG for those approximately 600 facilities. If we look at
that as a sample of perhaps ten percent of all facilities in the U.S., there's a quick
snapshot, but again it is not delivered units.
DR. CAPLAN: Last question. And I thank the panel for their input. I don't
mean to put you on the spot from the IPPIA, but I sort of do. You've heard that suggestion
floating around about meeting American needs first. Any comment on that?
MR. BABLAK: That's a very difficult question to answer. Certainly, we do
consider America's needs, but as you are aware we also have international in our name and
also companies that are international so it's important to take the health of the world
into consideration, not just Americans, I think.
DR. CAPLAN: Somehow I thought you might lean in that direction of an
answer. All right. I will thank this panel for their input and while they're moving back,
let me tell you what I propose to do at the end of this long day. We're going to stay
here--no. I wanted to talk a little bit about what I had in mind for work just for a few
more minutes today and then tomorrow at least in the morning.
I think we're being asked across the board for some input on current FDA
policy, if you will on all agency policies, with respect to CJD in particular, and
obviously it's hard to talk about this without getting to TSE more generally, and I would
like to see if we can build towards some suggestions and recommendations even at this
meeting, even though we've been collecting information that we have to process and mull
over. My proposal is that we attempt actually to respond with some discussion and maybe
offer some recommendations on the issues that we've heard about tomorrow morning and
actually go at it by perhaps trying to focus discussion along a couple of themes that I
have been listening to and I'm going to propose four thematic areas to you for your
consideration that we might use as a framework for tomorrow morning when we begin again.
The first issue that I heard about that I think this group needs to offer
some comment is whether we think that upstream protections for keeping CJD and TSE out of
the blood supply are adequate. Someone said to me at the break, well, this committee isn't
chartered, is it, to look at the hunting practices of people who carry guns in Colorado
and Wyoming and find elk, to which my response is sure it is. I mean one way to keep the
blood supply safe is to make sure that things don't get into it. If we're not convinced
that there's enough vigilance with respect to the monitoring of animal populations or with
respect to food supply or whatever it is, then my personal view now is that we should say
something about it.
But be that as it may, it seems to me one set of issues that we've heard
about move to upstream protections, both from CJD and TSE. I think food, I think issues
about pool size fall in here. I think there are some questions that come up, too, about
even proper screening which we heard about about asking donors if they had a head injury
or head surgery or dural transplants any time in their lives and this sort of thing. Are
we doing what we need to do to keep infectious agents out of the blood supply?
The second one I can bring forward for you to think about or see whether
you think this is adequate is what are we doing to maintain surveillance for CJD and TSE
and is it adequate? Here I might just remind you that we heard something about the NIH
effort to try and monitor what's going on. Is the research budget adequate? Do we have
adequate criteria for making a CJD diagnosis on the part of does it have to be autopsy
confirmed? What is this discussion we've been listening to about you're a risk factor? Do
people understand what that is? Are we going to say anything about the education of
physicians and doctors who monitor deaths and have them say more about whether or not they
believe that CJD or any TSE type agent might be involved in the death or the underlying
cause of death? Are we satisfied that we've got an adequate way to detect what the problem
is out there. So that's the second set of issues that I or the second category I guess
that I'd put before you to think about.
The third is what are we doing when we have CJD, either a risk or an
identified donor in the supply, and how are we managing this problem in terms of supply
and availability? So it is John's question. What does the committee think about the
tradeoffs currently made under existing policy including withdrawals to handle the supply?
Are we winding up by being risk averse with respect to CJD or other transmissible agents
leaving the availability of supply too low for people who need it? Do we want to say
anything about that, talk about ways in which we might address it?
We've heard all kinds of suggestions about how that might be handled. I
don't mean to leave out anybody but just something so that again you realize what the
areas that I'm talking about. We certainly have questions about is the exemption process
for releasing batches that we heard about through the advisory committee structure that
now is at the FDA, is that adequate? Does that move product out fast enough when there is
a real need? Do we want to get into questions about whether or not we could label lots
believed to be at risk and have them made available? Do we want to go towards some
recommendations about the supply staying in the United States first?
I suggested in some fantasy interlude that do we want to talk about maybe
restricting who might get lots believed to be at risk on the recipient end and so forth?
So what might we do to address the issue of how risk from the CJD and other agents
influences the supply and are we satisfied that the supply distribution that we see coming
from existing policy is where we want it to be, and do we want to say anything about that?
The last one I could think of was the protection of vulnerable groups, and
listening to the testimony, there are clearly many people who are at risk because they're
high users of blood and blood products. Some of them are children, some of them are
newborns and so forth, and they obviously cannot handle some of the risks they're exposed
by consent or making risk/benefit calculations, or some may have no choice. They're just
going to be in the blood supply. Even the issue that we heard about just in the last panel
about putting a filter by the bedside or telling someone they could filter for leucocytes
or whatever. These are questions about how well are we doing in protecting those who at
high risk or who are vulnerable due to inability to protect themselves due to lack of
competency in the case of children, due to high use, and how are policies doing in
protecting those interests?
It seems to me whether it's sickle cell or alpha anti-1 antitrypsin or
hemophilia, the immuno-deficiency disease and so on, we do have some obligation as a panel
to think about how policies are protecting people who are at special risk. I don't mean
for you to say fine, I accept all those four categories, but I'm laying them out there so
that you can see what I intend to do unless someone can pipe up now and put some other
themes forward or wants to do it at the start tomorrow morning. What my plan is is to have
us go through those four areas, upstream, monitoring and surveillance, supply, and then
vulnerable groups and see if we want to say anything about any of those, whether we can
get to any consensus about any of those.
We'd spend roughly, you could divide the time on the agenda, it's sort of
an hour per area. It doesn't mean we can't revisit it. It doesn't mean we can't say more
about it later. But it seems to me listening to what I've heard so far, we would be remiss
if we didn't try to wrestle a little bit with what has been presented to us. So I'd be
interested in your comments about that plan for tomorrow.
DR. SNYDER: Are you going to address screening and then those four areas?
DR. CAPLAN: Uh-huh. Uh-huh. Surveillance screening.
DR. SNYDER: Okay.
DR. CAPLAN: And if other people want to put some other theme or category
forward. I mean it doesn't have to be right now. I realize that many of you aren't moving
ahead at this fascinating speed of classification, but tomorrow morning you could
certainly bring some other issues forward and say I think this category has been missing
and I'd like to have that listed as well. That would be fine. But does that seem like a
reasonable way to go and see whether we can get someplace?
DR. GUERRA: Yeah. I think it's very reasonable. I would like to suggest
that maybe perhaps in one or a number of these we could also include the issue of
liability and the possible consideration of something that I think was mentioned earlier
but that is certainly been very effective with the vaccine dilemma that we faced a few
years ago, and that is something along the lines of the vaccine injury.
DR. CAPLAN: In the interest of comity and amity I actually didn't bring
liability and compensation issues out on the room, but I think they are very important
under that supply category and the withdrawal policies and so on. So if you want do them
as a separate area, fine. If you want to sort of get into how they shape supply and
willingness to take risk and what it means for patients and what it means for providers,
either way, certainly that's an important area of liability and compensation and so on.
All right. Then, well before anybody decides to think up reasons why we
shouldn't go that way, why don't we do the sort of politburo type mechanism and call it
adjourned with the unanimous agreement, but we will meet again beginning at eight o'clock
in here tomorrow morning. I will see you then. Thank you.
[Whereupon, at 5:20 p.m., the meeting adjourned, to reconvene at 8:00
a.m., Friday, January 30, 1998.]
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