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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.]

AFTERNOONSESSION

[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.]