Blood Safety: Transcripts - January 1998

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES
ADVISORY COMMITTEE ON BLOOD SAFETY AND AVAILABILITY

Third Meeting

"The Influence of Transmissible Spongiform Encephalopathies

on Blood Safety and Availability"

Volume II

Friday, January 30, 1998

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

Arthur Caplan, Ph.D.

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.

Kristine Moore, M.D., M.P.H.

Tricia O'Connor

John Penner, M.D.

Jane A. Piliavin, Ph.D.

Eugene R. Schiff, M.D.

John Walsh

Paul R. McCurdy, M.D.

Stephen D. Nightingale, M.D.

Mary E. Chamberland, M.D.

David Snyder, Rph, D.D.S.

C O N T E N T S

AGENDA ITEM

Committee Discussion

Lunch

Discussion of Supply Issues

Old Business

New Business

Adjournment

P R O C E E D I N G S

DR. CAPLAN: Accordingly, I asked Ed if he would tell us a bit about albumin and the problems that come up in the manufacture of that product, which he has kindly agreed to do. I was shocked to see that no matter where he went, he travels with a couple of slides and is instantly prepared to talk at a moment's notice.

I'm going to ask him to get us back on track. Then what I'm going to do is open the floor for reconsideration of those themes that I talked about yesterday for you to consider that we might move through. Just to remind you--I'm sure you slept on them and have many other ideas about other topics or themes that we might use to organize our morning deliberations.

One was prevention and upstream issues with respect to safety of the blood supply. What can we do to make sure that CJD and TSE are minimally problematic for the blood supply now and in the future? What do we want to say about that given what we've heard?

The second theme I had was surveillance, testing, and monitoring to see what is in the blood supply, making sure that we know what's out there, and who do we tell about it and how and when.

Third was managing known or probable risks in the supply of blood and blood products. That takes us to how do we distribute lots that are believed to be in jeopardy. How do we reach the point where our policies that are in place through the federal agencies are contributing to shortage in ways that don't make sense relative to public health and the overall need for blood and blood products.

And the last theme I had was protecting vulnerable groups. We heard some yesterday from certain groups who couldn't get products. That may in part be due to withdrawal of tainted units or units that people are worried about in terms of product. That's why I wanted Ed to tell us a little bit more about this area as well today. But also other groups, hemophiliacs, who are constantly exposed to the blood supply and are very much worried about the risks that they bear if efforts aren't made to minimize the risk of TSE and CJD in the life-saving substances that they have to be exposed to on almost a continuing basis. Children are involved. High users of blood are involved, people with particular medical problems. What are we doing to weigh their interests relative to the overall interests of society, who also obviously use a great deal of blood and blood products, but not necessarily on a systematic basis.

So prevention, surveillance, managing known risk, protecting vulnerable groups--those are the themes I thought we could use to organize a lot of this morning, but we can add to them or change them. We might even decide that we're going to look at three of them but not four, or two of them but not four, and that we have things to say about two of them but maybe not about the other two.

I think even if we have points to consider rather than consensus, that would be very helpful to the Secretary, to Dr. Eisenberg, to the agency heads. I think they want to hear not only from us about what we agree about, but they may want to hear points that we may not agree about but that are important to weigh, so that if we could even begin to list considerations as a public body that they need to bear in mind as they make decisions, say at the TSE committee level or in other places where agencies have to wrestle with problems, that would be of help to them, I am sure.

Before we move to Ed, let me ask Mac if he--oh, there you are. He had a couple of housekeeping announcements. Mac, are you back there? He's ducking this duty. Are you ready to give us the housekeeping?

Some of you left your room messy this morning--no, no, it's not that.

[Laughter.]

DR. CAPLAN: Not quite that bad a housekeeping job. Some of you want to get reimbursed, some of you believe you should be paid more, and this is the man who can solve all your problems.

DR. McMURTRY: I want to talk about essentially the reimbursement issues and travel in particular. If any of you took a taxi in--you want a microphone?

DR. CAPLAN: Yes, we want this on the record.

DR. McMURTRY: On the record. Okay. Anyway, I need you to know about receipts and things like that. Essentially, I don't need receipts. If you spent more than $75 on a taxi or limo, I do need that receipt. But anything under $75 I don't need. I don't need receipts for your meals. I don't need receipts for your hotels. What I do need, however, is I need to know the time that you left your home--I mean, when you walked out the front door Wednesday, and I need to know what time you walk in the front door tonight. So when you send your stuff in for reimbursement, please write that down on just a piece of yellow paper and send it to me, a sticky, I don't care. Just make sure I know those times.

The other critical thing is I sent everybody a conflict-of-interest form. I have gotten some of these back, and some of them I haven't gotten back. I have to have conflict-of-interest forms, or we're going to be illegal. So if you would, get these in to me just as quickly as you can. If you need to see last year's, let me know. I can fix you up with a copy of last year's. But I have to have these conflict-of-interest forms.

Also, regarding reimbursement, I sent you a green form for direct deposit. If you haven't, fill that out and send it back to me. We'll be happy to reimburse you, but it has got to be direct deposit. The Federal Government doesn't cut checks anymore. So if you will be sure that I have your conflict-of-interest and your direct deposit.

Yes, ma'am?

DR. PILIAVIN: I didn't get that.

DR. McMURTRY: Okay. I'll get you one.

DR. PILIAVIN: Or I lost it. Probably the latter.

DR. McMURTRY: If you know that you sent me one before and you have been reimbursed before, that one will still count. But if you're not sure, then send me another one.

DR. PILIAVIN: Can you get me another one?

DR. McMURTRY: You bet. Actually, I've got a stack downstairs. I'll bring them up.

DR. CAPLAN: They're all filled out to my account.

[Laughter.]

DR. McMURTRY: Okay. That's it. If you all have any questions, don't hesitate to call me, and I'll, you know, fix it.

DR. CAPLAN: All right. At this point, I'm going to turn the floor over to Ed.

DR. GOMPERTS: Okay. Steve and Art asked me to give the group a perspective of the manufacturing processes that are currently being used within the biopharmaceutical industry, and specifically, because of the debate at the recent TSE Advisory Committee, in relationship to the utilization of albumin. And albumin is a fairly well characterized protein solution that is used pretty broadly to stabilize various proteins and peptides from vaccines to complicated proteins. And my own particular narrow expertise is related to the recombinant factor VIII process, although I'm certainly not part of the manufacturing group that are involved in this.

But I thought I would give some--I was asked to give some perspective as to this process, and I'm trying to deal with it as generically as possible, and also to keep it as simple as possible.

Let's have that first overhead, please.

I thought we'd have a process check that advisory committees and focus groups sometimes can get the wrong end of the circle or the square, and moving on to the topic--you can tear them off or whatever. That's it. Okay.

Now, in the recombinant protein biotechnology manufacturing, the key to this whole process is the recombinant cell bank, which is an engineered cell line--and I'll get back to this--where you have the host cell together with a gene construct. And this cell bank is made up of a long-term storage system where the master cell bank is stored, and from there a working cell bank, multiple vials of these cells are taken and used over a period of time. And these cells are then put into a manufacturing culture system, which is called the bioreactor, and the target protein is then harvested and has to be purified because these cells are doing all sorts of things--and I'll come back to that--and the harvest then results in a process because this harvest is usually a complicated process. And this process has to have specific specifications so that we can make sure that the end result, the end therapeutic protein, does and is what it's supposed to be.

Next one.

Now, the actual factory is the cell line, and the cell line can be mammalian cells, for example, Chinese hamster ovary, baby hamster kidney, vero (?) cells which are derived from monkey kidney cells. So there are a number of different potential cell lines, but the bottom line is these cells are--they grow ad infinitum. They continue to grow provided you take care of them, and it's this particular target cell line that is then modified.

But, also, biotechnology has also focused on the potential for yeast to be engineered to produce peptides or proteins or even bacteria. And, of course, these cell lines are then--a target gene is included, and, of course, this target gene provides the blueprint for the protein. And it can be a protein, but it may also be a polypeptide, a short polypeptide, a long polypeptide, but it is the gene that we'll code for the ultimate desired targeted protein.

If you could move that up just a little bit.

So the recombinant process is taking this target gene and getting it into the cell. But to get it into the cell, you need something to carry it, which is called a vector, which is a bit of a bacterial DNA. And this carries this target gene, usually with enhancers, so that a little bit of DNA to make sure that the cell focuses on making the target protein rather than making just lots and lots of, for example, CHO cell proteins. And this is put into the host cell, and this is actually the genetic engineering process the gene jockeys perfected�some years ago.

Now, when you put the cells into--and start getting them growing, whether it's in a large bioreactor--and I'll show you a couple of photographs, slides, shortly--or into small vials, as we start to expand the cells from the working cell bank, these cells require an environment that is conducive to growth, because we have to keep these cells happy and comfortable, because it's only happy and comfortable cells that are going to do the job that we want them to do efficiently.

So we have to focus on the correct neutral pH. They have to get oxygen. They've got to breathe. And when they breathe, there is metabolism going on and carbon dioxide is produced, which has to be removed. They have to be kept warm and comfortable. There have to be salts and water, and there have to be nutrients, calories so that they can make their proteins, amino acids, the basis bricks and structure of the proteins, and, of course, trace substances, whether they are trace vitamins or even metals.

And there is the potential in this culture system to damage the cells, and we can damage them obviously by not enough oxygen or incorrect pH, but also there can be physical damage, such as these cells need to be moved around a little bit so the stirrer can't move too fast, or the oxygen bubbling through can cause damage to the cells. And, also, osmotic pressure, because if there is too much water or altered salts, there is an osmotic pressure gradient set up, and, in fact, albumin is a very important protein that maintains the osmotic pressure in our blood stream as you and I sit here, but also it is used within the bioreactor to help support the cells and also carry trace substances around, as they do in the blood.

In addition, these cells are living cells, and they make other proteins, including enzymes that break down the target proteins. So proteolysis has to be thought about and has to be focused on, especially with complicated proteins such as recombinant factor VIII. And then there are substances to encourage growth, such as insulin, transferrin, and including a soup that is obtained called fetal calf serum, which is really a number of different growth factors. So these are, in fact, proteins that are added to the whole solution to assist these cells in growing. So you've got the albumin, the insulin, transferrin, and these are just some of them. And they're not all added to the recombinant factor VIII system, but they are added depending upon the manufacturing process, depending upon the cell line that is established. So there is a lot of variation around this, and I'm just giving you a very brief overview.

Next one.

Now, the key technical events clearly is the establishment of the master cell bank, but it's also important to recognize that in a complicated protein such as recombinant factor VIII, the purification process has to be a very powerful one. And the process requires the monoclonal antibody system, which is bound to a fixed particle, a sepherous(?) bead, and this is used to bind the factor VIII and purify it.

So in actual fact, in the recombinant factor VIII process, we're really looking at two master cell banks: one for the CHO cell line, with the factor VIII, but also a cell line that makes the monoclonal antibody, which then is utilized in the purification process. So all those, the pH and the oxygen and the stirrer problems and pH, et cetera, all this will also focus in on the monoclonal antibody cell line, and the transferrin issue that was mentioned yesterday was really focused on the monoclonal antibody cell line in that situation.

Other key technical events are obviously the cell culture and protein production, purification, and using the monoclonal antibody here, final product stability and formulation, and, finally, quality assurance. Now, this is not a minor issue because each one of these steps--and these are a very brief summary of a very complicated process. Quality assurance goes all the way through because we have to be quite sure that the master cell bank is going to function right across those many, many vials exactly as the first one, that the thousandth vial is going to be the same as the first vial in all its characteristics, including the gene for the recombinant factor VII. And monoclonal antibody cell line, all the way through, quality assurance is a major target.

As I've mentioned, the master cell bank media components, the characteristics of the sugar, the water, the albumin, et cetera, all these have to be focused on from a quality point of view, cell line, manufacturing processes, purification, all the way through. And in actual fact, in the process for the recombinant factor VIII, there is well over 500 separate assays from start to finish that is used in routine regular manufacturing.

Now, the other view of this quality assurance testing program is focused on the drug substance, which is the crude product prior to moving it into the final vial. And, again, there is focus on the working cell bank, the inoculum, condition medium, the bioreactor condition medium. Inoculum is when you take the cell line out of the deep freeze and start to expand that cell line, which is somewhat different from that of the bioreactor. The post-production cell line testing, the chromatography systems, and finally, the bulk drug release testing and the environmental and utility testing programs, because the facility, the environment, the bioreactors, et cetera, have to be tested and assured that there is sterility and appropriateness in that environment.

Finally, the actual drug product which goes into the vial, we have to--when we get the bulk substance, it has to be tested. Does it meet all quality specifications that have been set up, sterility, endotoxin testing, and, finally, the release testing, and, finally, the lot release?

The working cell bank, which is used to expand into the bioreactor, is evaluated from the point of tumorigenicity, karyology. There is the potential, for example, of the CHO cell to have different chromosomes, abnormalities in the DNA that are manifested much larger than just a single gene. So karyology, iso-enzyme analysis, in other words, the cell line is examined in a number of ways to ensure that it is what it's supposed to be.

The cell line is evaluated from the point of view of growth rate and the doubling times, the amount of protein that we're targeting, how much is being produced, and this is a very important target, an important indicator of how well the cell line is doing, because if the cell lines are not growing properly, then clearly there is something wrong with the environment to that cell line. And if the amount of protein that is being produced is insufficient, that cell line is not doing what it's supposed to do, and there is something wrong, and that needs to be understood and corrected.

Also, the actual target gene insert, this has to be mapped on each event because we have to be assured that the target gene is going to make the protein that we want, not an altered protein, a different insert. This can change, and this has to be assured that it doesn't. And, similarly, the DNA sequence of the factor VIII.

Finally, purity of cell line from potential microbial and viral contaminants, and this is not a trivial issue.

Now, the purity testing of the cells prior to and after cultivation, we focus on the potential for microbial contaminants, such as mycoplasma, sterility for bacteria and fungi, and also the potential for adventitious viral contaminants. Is it possible for viruses from the external environment, is it possible for those viruses to have affected and infected that particular cell line as it's growing and making that particular protein that we have in the bottles, in the vials? And this is focused on regularly using multiple different cell lines to see if these cell lines have the potential for becoming infected by and, therefore, an indicator that there has been something that went wrong.

Also, the potential for retroviral contaminants is examined and evaluated in a number of different ways.

The separation process of the targeted protein from the crude media that is harvested from these cells goes through a number of different processes in this particular process for recombinant factor VIII. There's a filtration which is physical to remove the cells then from the actual solution. It's then passed across the monoclonal antibody chromatograph, and this binds the particular part of that recombinant factor VIII protein that the antibody is targeted at, binds the epitope. But, also, two separate steps, ion exchange chromatography, binding positively charges molecules and negatively charged molecules, these are designed to remove extraneous proteins that could come from the cell line, the CHO cells, that could contaminate the ultimate therapeutic product.

Next slide.

And just put in a somewhat different way, you have the conditioned media filtration and then the multiple steps ultimately resulting in the bulk, that bulk substance, the recombinant factor VIII, which is then characterized, tested, and tested again after it's put into the final vials.

Now, the potential for contamination with viruses, this could occur from the CHO cell line; it could occur from the monoclonal antibody cell line; it could be from adventitious viruses. And the process for the production and purification of the targeted protein is then validated with a number of targeted viruses, a number of RNA viruses enveloped and unenveloped, and the DNA virus as well, from the point of view of exclusion of these viruses from the actual process to give a fair amount of assurance that the ultimate product is not contaminated, in addition to evaluating the cell lines on each occasion.

Next slide.

Okay. Moving on to the slides, I thought just a few pictures to reinforce my words here. I have a cartoon of the CHO cell, and this is the vector that carries the factor VIII into the Chinese hamster ovary cell.

Next one.

A slide of the storage facility for the vials going into the lyophilizer here, the issue of sterility being important.

Next one.

We have the cells from the working cell bank that are being expanded. There is some stirring going on here, and, of course, these cells are suspended in various--water, solution, glucose, salts, and, of course, albumin there as well.

And the cell line needs various substances to allow a balanced growth situation such as amino acids, growth factors, minerals, oxygen, carbon dioxide, and there are waste products that have to be dealt with as well.

Next slide.

A bioreactor itself, and there are three of them in each particular suite, and, again, the sterility situation.

Okay.

And the characterization of the protein, this is three separate lots of the protein undergoing peptide mapping, and it has to be identical on each occasion. If there is a little bump that doesn't fit in, there's something going wrong here.

Next one.

And, also, the genome mapping that goes on here.

Good. Any questions?

DR. MOORE: What proportion of factor VIII that's used in the United States is recombinant?

DR. GOMPERTS: I cannot give you a definite answer on that, but it's probably 60, 70 percent.

Dr. McCurdy?

DR. McCURDY: The attempts or what was done to take care of potential viral contamination in the recombinant was fairly impressive. Could you contrast or compare what's done with the plasma-derived material to ensure that that's as unlikely to be contaminated as possible? I mean, you're using fetal calf serum. I presume that might have a very, very, very remote risk, but nevertheless a potential risk of BSE or something like that. And you've obviously looked at a lot of potential sources of contamination. Could you, as I said, compare or contrast what's done to plasma?

DR. GOMPERTS: I think, first of all, it's important to recognize that the biopharmaceutical processes that are used are not static, and that the systems are focused on from the point of view of improvement. And the processes--and I indicated here that albumin and insulin and fetal calf serum are used, but modern technology is focused on processes that will not--where it will not be needed, where albumin will not be needed, where insulin, for example, could be replaced with recombinant insulin and so on. So the whole process of the biopharmaceutical industry, like everything else, is evolving. I think that was not mentioned in my presentation.

Now, when one extrapolates to the human plasma-derived protein, first of all, the source of the protein in the biopharmaceutical recombinant process, of course, there's a lot of focus on the CHO cell. And in the plasma protein, the human plasma protein situation, of course, there is a lot of focus on the donor. And that has the donor focus and how the donor is characterized has also evolved to the point where today we're in a very much better situation characterizing those donors and understanding what is going on there, including asking them about whether they've had a hole in the head, in the dura mater.

Then, of course, the actual handling of the plasma and its fractionation. The actual processes in the fractionation purification are subject to viral validation steps. There are viral inactivation steps. Some of them are pretty efficient, but primarily targeted against the enveloped viruses. And the focus obviously on endotoxin and sterility and bacterial contamination are pretty extensive.

So the concepts, the issues, the problems that the plasma protein fractionation process has been focusing on, manufacturers have been focusing for some while, obviously impacted a fair amount of thought from the point of view of the recombinant process as well. So there is some analogy and homology as well.

DR. CAPLAN: I had two questions for you. One is--this is slightly off base, but I'm just curious. There was a discussion not far from here last week about xenografting and the use of animal organs and transplant, a lot of concern about piggybacking viruses using whole organs and obviously not subjecting them to these kinds of processes. But is there a concern that while we test for what we know, we might be carrying along some other viruses or retroviruses that we don't understand? Is that something that is in the background of all this? Or are people pretty convinced that the level of handling is such that it's going to be able to handle anything that hasn't got a test to detect it?

DR. GOMPERTS: Art, you know, as usual, you're on the ball. The process has to be robust, and we have to be assured that it can take care of, theoretically, anything that comes along. But the potential for contamination must always be considered. And, hence, the TSE issue, of course.

DR. CAPLAN: And the second question I had for you is: Can you comment at all about cost? How does cost drive recombinant production versus donor generated? I mean, are we talking significant savings when we can get volunteers and start that way as the culture medium? Or how does that work?

DR. GOMPERTS: Well, the major cost in a biopharmaceutical process is the plant and the expansion of the plant. Clearly, there is a cost in maintaining a production process, the quality assurance that is ongoing.

The major cost as far as plasma is concerned is if the plasma has to be purchased. If it's volunteered, then you don't pay for it. But, also, there is a cost in plant. So, again, there are some similarities within that underlies the basic investment and potential return on that investment.

Other questions? Yes, Dr. Guerra?

DR. GUERRA: That seems to be a very complex and involved process. I wonder, how long does it take from start to finish to have a product that you can then take to a hospital or clinic?

DR. GOMPERTS: We described a process from cracking that master cell--that working cell bank vial to finishing up and closing down the process when all the product has been made the cell line has the potential to become less stable. We call that a campaign, and a campaign lasts six months.

DR. CAPLAN: Okay. Thank you.

Well, at this point, what I'd like to do is open the floor for comments from the committee about whether the identification of the themes that I put on the table, matters of prevention and looking upstream to try and protect the blood supply from risks, surveillance, and testing, and monitoring, how we manage risk when it's in the supply or suspected to be in the available supply, what policies are doing to the way in which the supply is handled, and then looking out for the interests of groups especially vulnerable due to their reliance on blood and blood products, and due to perhaps in the case of children their inability to look out for their own interests.

Are there other issues that we should put on the table? Yesterday I said that I thought we could handle liability matters under the probable risk, what are we doing with the supply of blood. That's certainly an important sub-theme. But does anyone want to put any other major questions on the table?

If not, then what we can do, I think, is maybe turn to the first issue for a little discussion. That was the prevention and upstream issues, and here I can say a few words about a couple of things that I heard yesterday that I'd just be interested in having us discuss.

One was the whole question of how TSE and CJD might enter into the blood supply coming up through the food chain. And when I was talking about--or listening to this yesterday, a few people came up to me, at least one person, a congressional staffer, and said: Well, you know, we've been very attentive to that; we have tried to put a complete ban on the use of animal feeds for human food, that that is something that the FDA is alert to and they understand that in the food chain rendering and feeding animal foods to other--I guess it's actually a mammal ban, not just an ungulate ban, that these aren't supposed to be in the food chain any longer.

One of the things that occurs to me is that saying it's so doesn't necessarily make it so. Another thing that occurred to me is that it might still be important for us to comment on the importance of this practice, having watched what happened with this--what is it?--alternative CJD or new variant CJD, watching the BSE experience across the pond there, that this is very important for us to be stressing. It may be that FDA and the food industry understands it, but as an upstream threat to the blood supply, that makes it part of our concern.

We did hear a bit, also, as you recall, about the ways in which certain TSE organisms might be in the natural population. That was the discussion of the elk and the deer. I think we heard a 6 percent figure for some deer populations carrying possible TSE agents and whether we were doing what we should to monitor that and seeing how that might be entering into the human food chain through hunting practices or eating deer and that sort of thing. So that may be an area we want to say something about.

I heard yesterday, too, to put this in a different light, that we should do more in terms of having a stable supply of blood and blood products to try and encourage donors. If you remember, some of the testimony circled around the idea that if we have a lot of donors who are very healthy and not in risk groups, then that would help supply more plasma and other important blood substances to the overall pool. So when I'm thinking of prevention and upstream issues, do we want to say anything or do we want to flag something as important about how to expand the available pool of high-quality blood and blood products?

And the other area that I can think of where prevention, upstream questions come is: Are we doing what we need to do to identify, monitor, test for CJD? And this was the discussion we had yesterday about: Are we tracking epidemiologically this disease and TSE diseases in terms of death certificates? Can we get better epidemiology to see what's going on out there? Are doctors trained adequately to diagnose and discuss the possibility of this disease being present? Are we sure that the records are as good as they could be so that we know what's going on as a matter of preventative epidemiology?

I don't mean for that to be an exhaustive list, but I think those kinds of things fall under what I'm trying to capture when I say we need to prevent or think about improving the quality of the blood supply. So why don't we start the discussion off with that issue and maybe think about some of those problems?

DR. GILCHER: I think there are some basic ways that we can look at this, because in a sense we need a grid or a plan. For example, agents which are currently in the population--let's take the Creutzfeldt-Jakob agent, whatever that really is. Does it really pose a threat? And what we can look at is: Is that agent increasing in the food chain or the blood supply or the general population? And has there been any risk associated with it in terms of the transfusion of blood or blood products before we took out those particular individuals who we consider to be at risk versus an emerging agent?

For example, the new variant Creutzfeldt-Jakob agent may be truly be a different agent, and that would be a greater concern to me because that's an agent we want to keep out.

So what I'm saying is that we really need to be looking at what is already there and what may be either a mutation or a new variant or an emerging infectious agent that could get into the blood supply.

DR. MOORE: After the end of the day yesterday, I was thinking last night about this first issue, some of the prevention implications of looking at TSE agents. And I actually tried to outline the major modes of transmission, which are food-borne--we know through Kuru--and then there's this theoretical concern of animal to human food-borne transmission. And then a second area is iatrogenic, for which we have, you know, quite a bit of data as to the occurrence of that in the United States. And then the third area is transfusion-associated, which, again, is theoretical and not yet documented, but there's certainly reason to be concerned about that.

Then if you'd look at sort of those three areas of transmission, and then started thinking about, well, you know, how do we approach this from a public health perspective, I mean, what are the surveillance needs in each of those three areas, and then what are the policy needs in those areas? For example, some of those policy issues I think we can look at today around transfusion, and some of them are actually outlined in a handout that Mark produced yesterday on policy change. And I would really like to see this group talk specifically to some of those issues because I think we can have some good input there.

Then I think there's also some policy needs in the area, for example, of infection control that have not been addressed and in issues around regulation of organ donors, for example. Some of those pieces are in place, but I still think that we have some gaps in terms of policy or regulatory issues in that area.

Then we can get into sort of policy issues with the transfusion area. Again, I think we can talk some about those. But I think that when we look at this whole issue, I think it--it started getting very complicated in terms of what I think some of the needs are. I think that, you know, we can look at surveillance issues; we can look at what are some of the critical research needs. And in doing this last night, I kind of started developing this grid of, you know, how do we approach these different problems. And it occurred to me that I think most of these issues start to get beyond the scope of this group, and I think that we could spend the whole time sort of trying to flush out, you know, what are the sort of public health prevention issues here.

And it occurred to me that one of the ways to approach this is for this group to make a recommendation that is a little bit more generic and that basically calls for the Public Health Service to bring together a group--this is sort of a method that's used very commonly in the Public Health Service, particularly by CDC--to develop some prevention and control recommendations. And the process way that this often works is to bring together a group of people with various expertise, and in this area you might need some USDA-type people. You'd certainly need FDA-type people. You'd need state health people. You need people involved in infection control, people involved in transfusion medicine, sort of an ad hoc group of a variety of different players to start looking at developing some guidelines for prevention and control of CJD, and this has been done, you know, with a variety of other communicable disease agents in the U.S.

That kind of a document can then be used to identify what are the policy needs, what are our infection control recommendations, what is needed in the area of regulation, what are the surveillance needs, and then what are the research needs, the gaps that we don't have filled in, and sort of start using that as a framework to develop a Public Health Service plan to address some of these issues.

So I guess what I would like to see this group do is really ask for that kind of a process to be conducted as opposed to us trying to flush out what are all of those issues, because I think it is a very critical and important area that needs careful consideration and really a process that could take up to a couple of years, I mean, to do that kind of thing and really draft guidelines and start looking at that, at least a minimum of a year-long process, if not more.

I guess that's my comment. I'd like to see us maybe--that our recommendation be that that process be started.

DR. CAPLAN: Ed?

DR. GOMPERTS: When I look at the issue of TSE and blood transmission, I'm sort of torn in a number of directions. First of all, I tend to be a little perhaps emotional about it because I personally and professionally have gone through the HIV epidemic, and I don't want to go through another one. And I sort of smell, sense that something could happen. So, you know, my response tends to be perhaps a little knee-jerk or emotional. I don't know. But then I try to separate myself from that and look at the science and what do we actually know and what don't we know.

Looking at what's happening and what has happened, we do know that this infectious agent, whatever it is--and that's one of the unknowns--this infectious agent can be transmitted and has reliably been transmitted through the food chain. And this we have seen among the New Guinean natives, the people. We've seen it with BSE. There was in our own country some years ago an outbreak in the mink encephalopathy episode which definitely was food-transmitted. So we know that major outbreaks have occurred that way, and that is going on right now, of course, in Britain.

They have been iatrogenic, and the blood transmission has the potential to be a iatrogenic situation, which we're looking at pretty carefully.

So if we look at where we stand from the point of view of CJD and blood transmission and CJD epidemic within our country, we're looking at it, as I see it, as an emerging disease, whereas in the United Kingdom and in Europe, it actually has emerged. So what worries me is this, I think, very really concept of silent subclinical amplification. And if we were to prevent this episode within our country, I think we have to focus on what's going on in Europe and what have the British people and government, how have they dealt with it. And it's obviously been devastating to the country, to their beef industry, dairy industry, et cetera, as well as the unfortunate people who have been impacted by this disease.

So when I look at what we're doing here, I'm not happy that the--we could do more. We have introduced a ruminant feed ban, and I don't know to what extent that is enforceable, but it has been introduced. But what I don't see is the second major step that the British introduced, and that is the prevention of utilization of animal brain material in the human food situation.

So while we're not feeding (?) cows, rendering them and feeding them to cats and dogs and zoo animals and cattle, healthy animals going into the abattoirs, filet steaks are being eaten, but so is the potential for bovine as well as porcine as well as sheep brain.

DR. CAPLAN: Hold on one minute, Ed. I just had an announcement. Are there some doctors here from Portugal? They need to call their office right away.

DR. GOMPERTS: So, you know, the Brits, I think in '89, introduced the ruminant feed ban and in '92 introduced the prevention of utilization of animal brain into foodstuffs. And that second part we need to do here, and the sooner, the better.

DR. CAPLAN: John?

DR. PENNER: I agree with Ed, and I think the protection and prevention level, we need to focus a little bit more attention.

One suggestion, we still have the problem with screening donors, and I'd like--I'm not aware that we have any kind of donor brochure--maybe I can be corrected on that--which while the donor is waiting to give blood could at least amplify his information a bit as to what they're getting at with respect to CJD and TSE. And then the questions, I suspect, are pretty varied around the country depending on the blood banking community that is asking the questions of the individual donors. And perhaps that needs to be a bit more specific and consistent so that we can exclude the individuals who come in who have had their brain surgery or have had the human growth hormone and perhaps we could reduce that incidence, at least, and that would be one way.

The next aspect I think is on the surveillance end, and I think what we could do very specifically is get the groups that have the heavy blood users to commit themselves to autopsies. In other words, to get their people--recognizing the difficulties in obtaining autopsies, that they'd commit themselves to having an autopsy when one of their members dies, so that we are at least able to look at this a bit more consistently over time and with enough of a population so we can say yes or no, there has been some evidence of this disease infecting them.

So those are kind of minutiae things, but they might shore up some of the problems that we're facing.

DR. CAPLAN: Dr. Hoots?

DR. HOOTS: To kind of add a little bit to what both Ed and Kristine said, I think one of the things that--and you led into it when you were talking about the elk and deer population. If we look at the likely agents to cause problems for our blood supply and for the population, certainly because the surveillance is adapted to things that we could easily first examine, like bacteria and fungus and all the way down to viruses, it's becoming--it seems that this is a paradigm for the potential for either a partial or complete zoonosis sort of infection, and I think one of the things that has traditionally happened up to now because of resources and everything else is that some association has been backtracked to an animal source for an infection, be it HIV or be it CJD or whatever. And if a more concerted, directed sort of effort on behalf of the Public Health Service, kind of like Kristine was talking about, could be directed towards--and, again, I'm a little naive in terms of what actually does exist, but just in terms of my own knowledge of how things have been tracked, it's always been retroactive and retrospective.

If we could use CJD as a paradigm, almost, for a strategy to look for zoonotic disease, disease where agents spread across species, I think in a way we could get a lot of bang for the buck, and using this as a starting point, because this is where we are now and this is where the big fear is now. But it might not only be beneficial for the purposes of CJD, but down the road it may be very purposeful and very important for other new agents, as you alluded to at the beginning--and you asked Ed about new agents coming into the blood supply or into the human food chain, either one.

So I think some sort of, at least, examination of what is there from the CDC and others worldwide, world health surveillance, and then how could we augment this using CJD as the reason and the rationale for putting resources into that sort of early look, and perhaps using, again, the short-term paradigm of the wild animal population in the United States that is a source of at least a TSE, maybe not a TSE that we get as humans, but we don't know that yet. And I think that's something that we might at least ask to be explored, because we don't obviously know how to do it, but we could at least learn more about how--if it's feasible, and if that's something, a direction, a bidirectional look instead of a unidirectional, retroactive, retrospective look.

DR. McCURDY: During the discussion yesterday, there were a couple of things that occurred to me that might be helpful in this area that are already going on in the Heart, Lung, and Blood Institute. We have several studies that have been looking at hepatitis, non-A, non-B, hepatitis C, hepatitis B and so forth. Some of the cases of hepatitis that are being reviewed through the years through death certificates and others were people who had their episode during World War II. So this is a very long follow-up.

We now have just started a follow-up, natural history type of follow-up on hepatitis C and other similar disorders in a pediatric, neonatal intensive care unit population. And it is our plan now--Dr. Niemo(?) and I discussed this briefly yesterday. It is our plan now at least to look into unusual neurologic syndromes that might have occurred in these people, and perhaps some of them died at a time when autopsies were more common, and if there is brain tissue, we may be able to get it, get blocks, and have it reviewed.

The neonatal intensive care units, of course, have very heavy, fairly heavy donor exposure, perhaps a transfusion from a different donor every day or two. At least until recently, current practice, I think, is to dedicate a donor to a neonate. But before, every day it was a new donor. So there's fairly heavy exposure there, and we should be able to get some information, probably negative, but we'll have to see.

DR. CAPLAN: One thing that I noticed yesterday, just following up the NIH story, was that there were a couple of comments from some of the people who presented to us that they found more could be done to sponsor basic research. I remember a little bit of complaint about having to shape the tighter experiments due to the shortage of rats, which I took wasn't a matter of volunteering but cost. And then I did see, too, that people said there is a need to maybe even centralize a facility that takes on TSE, and we may not have to resolve that particular issue, and what's the best way to organize and structure research in this area both on detecting new agents and studying existing known ones. But we could say, if we want to, something about the importance of making this more of a priority.

It's a little bit apple pie, but I don't think it would hurt since we did hear requests about that saying that some of the efforts are scattered and maybe not centralized or organized in quite the way they ought to be to study TSE.

But one thing that occurs to me, as I can sort of recap a little bit on this theme, because I will bet--I'm going to make a bet here--that we may have some areas of consensus. I like Ron's suggestion about thinking about this a little bit as emerging agents versus existing agents issue with prevention, and I heard Kristine's suggestion also that we could make a recommendation, which she actually quickly wrote down on a piece of paper, and I think it's a pretty good statement about what we could ask CDC to do and agencies to launch in terms of taking on some of these questions. But just to recap, it seems to me one set of things that people have now mentioned is whether we need some sort of standardization of what people are told about what they eat.

Should we be simply saying to people and urging a campaign that says you shouldn't be eating the central nervous system? Whenever you eat anything, don't eat that. Do we need standardization on what we tell donors in terms of what they need to be thinking about as things that may have happened to them to put them at risk? Do we need standardization of screening more than we've got, looking for potential donors to be able to be identified that might have encountered things that put them at risk of transmission here? Can we encourage in some serious way the commitment to autopsy? We're not going to order anybody, but we certainly can flag it and say that it would be very important to mount a campaign here, because if we're going to understand this and really get an understanding of what the theoretical risk is, this is a key route, and we could certainly do that without waiting for the CDC committee or some other agency to do something.

It seems to me that we may even want to say something about the importance in the national debate of talking about--with the FDA and the state agencies that are responsible for hunting, to let them know that this food chain issue is a real one and it's going to be stressed again and that this committee wants that watched carefully.

One might say, well, of course, we're going to watch it carefully. The nation's agricultural industry will collapse if we don't take this problem seriously. But I am worried about, personally, others ways in which things enter the food chain. And I think that's just got to be taken into account.

Again, while we could wait for specifics of how to carry that through from the committee, I don't personally mind us trying to say something like that now today and charging any committee or all of the agencies to keep a handle on it.

So those are some of the things I heard, and in this area, it may be that it wouldn't be too difficult for us to kind of get consensus on a lot of those points and maybe say something along the lines that I just tried to articulate.

Yes, Ron?

DR. GILCHER: Part of the reason I was dividing it into emerging and existing agents is--and I didn't say it at the time--it relates to outcome. And one of the concerns that we heard yesterday that's so important is that we could actually make our health care less safe if we remove products that need to be available for selected patients. And I think there's a greater risk--I don't know that I'm correct, but I believe that there is a greater risk in an emerging agent as opposed to an existing agent, so that if we're taking out with a withdrawal or even a recall a group of plasma derivatives, I would want to have us focus on the emerging agents versus the existing agents in terms of that, because right now we're having withdrawals that are related to the existing agents that, in fact, may be hindering health care.

DR. CAPLAN: Jane?

DR. PILIAVIN: I just want to very strongly second what you just said. I've been sitting here listening to this discussion as if--and the way we're talking about expending resources on this issue, it sounds as though we are actually faced with a threat, a known new threat. And what we're actually faced with is a set of epidemiological data in the United States that suggest to me very strongly that old-style CJD is not a threat to the blood supply. And I think it's absolutely critical that we sit and think about the expenditure of resources as well as the issue of withdrawal of product which with only an infinitesimal probability is dangerous, whereas not having the product has already probably killed people and, if the thing continues, will kill more people. And nobody, as far as we know, has ever been killed by CJD in the blood supply.

I think it's really, really important. I was glad to have Lola Lopes, who's an old friend of mine, here talking about risk, although she didn't, I think, focus as much as I would have liked her to focus on deciding between different kinds of risk. And I think, at least in my four years on the BPAC, we weren't allowed to talk about those risks. We were only allowed to talk about safety. This committee is supposed to focus on safety and availability and to try to do this very, very difficult decisionmaking about different kinds of risk. And so far today I've mainly heard people talking about the risk of what could be in the blood supply.

Now, I quite agree that if I were in Great Britain, I would be thinking very hard about the new agent. But I think there is as yet no evidence that that new agent is here. This discussion of monitoring the food chain I think is absolutely really important, but in terms of a whole lot of other issues, I just think we have to think about where best to put our money and our time and our effort.

DR. CAPLAN: Jim?

DR. AuBUCHON: You mentioned having information available to the general public and donors regarding what they should eat and what they should not eat. It's had limited success in other areas of consumption. But I think Ed was suggesting something really one step further, and that is a ban of central nervous system materials getting into the human food chain.

I don't always know what is meant when I read the labels on different foodstuffs in terms of what's in there, and possibly there's something there that we might not want there. I think that is worthy of further pursuit. We don't have any nutritionists or agricultural people around the table here. Possibly that's something that could be handled through the suggestion of a CDC-led group.

The other item I'd like to comment on was Dr. Penner's comment about standardization of questions. I think that is an important question. I think that for the most part, most blood-collecting agencies are asking the same question. Obviously about half the blood supply does go through the exact same sort of questions with the American Red Cross. The American Association of Blood Banks does have a standard questionnaire, which many institutions, although possibly not all, do use.

One consideration might be for an FDA-generated questionnaire. Many of the recently added questions having to do with newer types of HIV risk and now CJD risk have essentially been given to us by the FDA, and we ask them in the way that they are requested that we ask them.

So something to consider, although it's not necessarily the focus of just CJD at present.

DR. CAPLAN: Larry?

MR. ALLEN: Regarding the food chain, in this area, this region of the country, already we've been talking about some of the results of animal waste getting into the bays and things like this. One of the things that we're hearing now that the farmers are using now, are pooling some of this animal waste in the reservoirs, and then using it as fertilizer for certain food products. And I'm just curious as to is the FDA or anyone else monitoring the use of these types of new ideas. And, you know, there's a concern with pooling in--you know, keeping this waste in these reservoirs for a certain amount of time and the bacteria and fungi and whatever might develop during that time then being used agriculturally. So is anyone, to our knowledge, here monitoring this or studying what's happening with this?

DR. CAPLAN: I personally don't know, but if we flag this issue, we'll get a sort of--that may be the place for this. Kristine's group would, in fact, go specifically to--

DR. MOORE: I just want to also make just a quick comment that addresses a couple of the issues that people have raised, and one is that, you know, when you look at efforts of CDC and FDA and other agencies, USDA, there's a very large food safety initiative right now that's been put forward. So, again, I don't think that we really necessarily need to get into that a lot. The CDC is putting a lot of effort, and FDA and USDA, on it.

Then another big area at CDC right now is emerging infections, and there's a lot of surveillance projects and a lot of research projects. So just to keep it in perspective, there are a lot of other efforts going on that I think touch on many of the concerns, and very legitimate concerns, that people have raised in this brief discussion. Just so that you know that.

Again, I would like to see us really focus on what are the methods, particularly specific to blood safety, that we can comment on here today, looking at donor deferral issues, looking at product withdrawal issues, looking at the possibility of exempting certain products, the issue of labeling products, then this whole issue of leukocyte filtration and leukocyte-depleted blood.

I think that those are some specific issues that we can talk about as well as the need for research that's specifically would improve the safety of the blood supply. And I think one of the most important issues there is the development of a screening test. I strongly urge this group to make that a very high recommendation because we can't really learn a lot more about the epidemiology of this disease until we can identify the denominator and start looking at who the carriers are. I think we're hampered severely in our efforts to develop appropriate recommendations until we have some of those pieces in place.

DR. KUHN: I think to kind of go along with that is some of our focus of attention I think needs to--according to, I think, your four points that you have made here today or for us to discuss today, is to kind of take a proactive course of safety by recommending, perhaps recommending pool sizes according to what various users of product would perceive as reasonably safe. I know that was a discussion yesterday. I know for alpha-1 and the hemophilia population, they may feel comfortable with a different size pool, and as for people who were using IVIG, I think the primary immune-deficient people and I know sickle cell sometimes uses that. They might need a higher pool because they need high-titered plasma and it's derived. And I don't know how big their pool has to be in order to derive that high-titered plasma.

But I also think that this would--by limiting the pool size, it would also help to limit the economic impact on withdrawals. So I think we should kind of seriously look at that and hopefully make some recommendations towards that end.

DR. CAPLAN: Paul?

DR. HAAS: A quick comment back on the risk issue. Our discussion yesterday or the discussion we were given obviously used an economic type of example, a payout-loss type of thing. And I don't think that that was done just because it's an easy way to run an experiment. If you look at economic behavior, typically we're driven by cost. And one thing I guess I want us as a committee to be concerned about--I like what Jane was saying. That might make a whole lot of sense for us around this table, but I guess I'm a little concerned that once we get away from this table that, if the costs associated with blood products somehow comes down because the concern for the current CJD is less evident, that then the societal concern about this lessens, the government concern lessens, and then the focus on the new CJD doesn't happen.

I don't want my words to be misconstrued. I don't want us to create a false shortage out there, by any means. But if there is--if we get less of a shortage, there will be less of a concern. Economic behavior is very strong in that direction.

DR. CAPLAN: Paul?

DR. McCURDY: Another brief comment about something that is in progress. The National Institutes of Allergy and Infectious Diseases, in collaboration with Heart, Lung, and Blood, is looking into the question of pool size with regard to the various different needs of the immune-deficiency people, et cetera, et cetera. This is in its early stages, but probably should move forward more rapidly in the next several months to see how this goes.

The original pool size, I understand, was governed by the size of the centrifuge in Dr. Cohn's laboratory. Later it was arbitrarily chosen and then increased because the primary goal of immunoglobulin was to prevent measles. And it was tested for a number of times after that in measles epidemics.

That's not so much the problem anymore, and I think it does merit looking into and trying to develop some science behind it.

DR. CAPLAN: Let's do a comment from Mary, then Dr. Guerra, and John, too. Then what I'd like to do is take those three comments. Then I'm going to put some proposals in shaky language on the floor just on this area, and I'll tell you why. It relates to what Paul was just talking about. I think we should start off with both prevention and surveillance. I'm a little loath to just say leave it to the agencies to go figure it out. I want to tell them more than that, but at the same time, it seems to me if we listened to that risk discussion yesterday, one way to secure the trust and support of people who are in the vulnerable groups is to say we will commit to prevention, we are going to survey and monitor, we will research what's going on here. We're not going to turn you into the canaries. There's a lot of canary metaphors that came in yesterday saying, well, you'll know there's a risk when we start to die. And I think if the risk discussion I heard was correct, what we should say is, no, we will monitor, we will survey, we will prevent.

And so that is why we are willing to then look at some other questions about supply and pool size and so forth. But if we don't, then I think there is a fear, partly grounded in the history of the '80s with HIV, that the testing then becomes the human recipients, and that's not an adequate way to protect their interests since they're vulnerable.

I did have a mild plot here in starting with prevention and surveillance, but it is built on this risk idea that you've got to front-load in order to secure trust at the distribution of the system, roughly on equity grounds.

Anyway, so let's do those three, and then we'll maybe concretely look at and decide whether we want to endorse a couple of ideas.

Mary?

DR. CHAMBERLAND: Just a few comments on a whole range of topics that have been brought to the table. Maybe just to pick up where you just left off, maybe suggest a slight modification of the structure that you've outlined in terms of how the recommendations from this group might be put forward, and they sort of actually follow along the rubric that CDC has developed in organizing its emerging infections plan, and that would be to couple surveillance, what we call surveillance and response, research, both--and I've heard here today and yesterday both basic and what we at CDC more often do is applied research, prevention and control, okay, because I think you need to go through the first two that lead you to the prevention and control, and something that's sort of related is either the infrastructure that's in place currently within our public health service agencies, state and local health departments, et cetera, to carry out those activities. So that's just a slight modification of what you've been putting forward, which I think is a good approach to kind of construct some recommendations around.

Regarding surveillance, I just wanted to amplify that there are currently within the Public Health Service, and specifically within CDC, surveillance systems that generally organize themselves around pathogen-specific surveillance systems, surveillance systems that deal with donors, and then recipients. In the latter, clearly CDC's most evolved and extensive surveillance efforts relate around the hemophilia population and, you know, I think there are some gaps that could be further addressed. So we look forward to hearing recommendations from the committee.

I think the second major point I wanted to make, and to re-echo what I've heard also, is that which Jane and Kris have been saying, that we may be of better service to the department that has charged the group if we try and really focus most of what we want to recommend specifically on the transfusion-related issues. I've heard a lot of issues about food safety and animal disease and surveillance. And while those are clearly issues that impact on this, I think for our group to delve into them in a very detailed way would probably get us sidetracked to what we've been principally charged. I think we can--there are other groups in place, the TSE committee and others. And so I think if we put forward our concerns but try not ourselves to cope with it in a lot of detail, we'd be more helpful.

Then the last sort of comment was about--it's come up several times about recommendations about pool size, and I know that this is a topic that this summer generated a congressional hearing, et cetera. And I think I've heard John mention an interest in having that topic brought before the committee. And I think that is an important issue, but I don't think that we have had nearly the amount of information or structured discussion about that. So I guess I would just put forward a recommendation that before the committee would want to articulate anything very specific about reduction, you know, even recommending actual numbers, if that be the case, that we would probably want to evaluate that with more detailed information that could be brought to the committee.

MR. WALSH: I would reaffirm that, that we ask--I think Dr. McCurdy already said, the NHLBI is already looking at the pooling size issue. But I think it's also totally appropriate and important for this committee to request the FDA and industry to explain the reasons for shortages, what's impacted the shortages in certain blood products, and why. And I think to the extent that CJD withdrawals have impacted factor VIII and IVIG and alpha-1 protease inhibitor products, to some extent we didn't make Dr. Weinstein's hit list with the alpha-1, but we got over 16 lots withdrawn.

So I think it's very important that this committee ask for a specific report regarding what is affecting the supply and then address those issues more specifically.

DR. CAPLAN: Just so I don't forget, even though that's a matter that's going to come up, I suspect, under what I was calling managing known or probable risks, in the spirit of consensus, things that I suspect we can do, is anybody going to dissent from the idea that we request a report on why shortage exists and that we encourage industry to also supply this committee with a statement or report promptly about their views about why shortage exists?

Okay. So that's one we can hold for later, maybe.

Dr. Guerra?

DR. GUERRA: I certainly support the notion of trying to better define the scope of the shortage, but along with that it would be very helpful to see, you know, the trends in supply and demand. The demand side has certainly been increasing very significantly.

But I think a part of the discussion of some considerations for the future, there's no question that the public health side of it is very compelling, and we need to better define the scope of it. I think that we would fall short if, in fact, we focused all of our attention just on the domestic side of it and how that impacts the populations here, given the fact that we're so much of a global community today and that there are parts of the world where I think the food chain issue is a very significant one and where people that left their home countries years ago, probably having been perhaps exposed to those parts of the food chain, that because of culture and tradition or need and whatever, availability of their food sources, have for many years, I'm sure, ingested any number of products that were closely tied to the central nervous system.

I think we would have a wonderful opportunity to make some very long term observations of individuals that have come from those parts of the world. But I think part of it--this reminds one somewhat of the early days of the AIDS epidemic. I think that the clinicians and certainly in the instance of postmortem exams that were being done, the pathologists were not so experienced and knowledgeable about really making the kind of assessments or interpretations of the material that they were studying and being able to attribute that to a common pathway of the HIV-AIDS virus. And I think we were seeing--as I looked at some of the death certificates of individuals that were dying within certain age groups, very unusual conditions that were being signed out and coded on the death certificates but, in retrospect, really were manifestations of AIDS, the full sequence of events, et cetera.

I think that it is incumbent on this committee's work and the recommendations that we initiate an educational process so that the pathologists that are doing the neuropathological evaluation of tissues that are submitted, and at the same time perhaps encourage the greater use of postmortem examinations in those instances where individuals perhaps could fit the spectrum of disease that maybe could be attributed to new variant CJD or some within that spectrum so that they really come up to speed with really what that consists of.

I suspect that there would be a wide scatter as they look at tissue specimens in trying to reach that diagnosis. But I think if we could give them some of the information and the tools to better reach at least that diagnosis on a list of others, it could be very helpful in at least help us to come closer to understanding what some of the numbers might be.

Then I think that we need to also carry the public health message around the country, from local health officers, the state level, where a lot of information is assembled, to see if we can begin to determine--and also this relates, I think, to the whole issue of zoonotic transmission of disease or emerging diseases in nature, et cetera, where we are observing some very interesting trends, you know, whether it's clusters of animals that are dying in certain parts of a region, a state, or whether it is other clustering of conditions that require hospitalization, very unusual conditions that I think collectively could really inform this discussion from a public health standpoint.

DR. CAPLAN: All right. We'll let agony dominate there.

Larry?

MR. ALLEN: Two things. Regarding product shortages, along with whatever recommendation we make in that regard, we need to find out about projections, what these manufacturers feel is needed based on whether or not there's going to be recalls or not. I know they're not just arbitrarily making certain lots of product without having some projections. We need to know what they feel these projections are, first of all.

Secondly, regarding the donor pool size, irregardless of if there are studies being made now on what's the proper size for different products, there's a matter of trust here that I don't think has been dealt with. Some of the speakers yesterday spoke of being told that they--they were told that the lot sizes were 30,000 to 60,000, only to find out that they were much higher numbers. I would like to know--maybe someone like Dana or someone else here could say--I would like to know who--where did they get these initial numbers from, you know, and why did these things happen? This is very important to the public trust in general. And we need to know why these things happen in the first place so we can make sure they're not repeated again.

DR. CAPLAN: I have a sense that the issue we're going to talk about after we examine a couple of statements about prevention, public health upstream issues, is going right to what was number 3 for me, which was managing known probable risk and the supply issue. People are chomping to get there. That's fine. We can go right to that after we do this.

There's a reward if you will all simply asset to what I'm about to say. You can have a break.

It seems to me we want to flag a concern, and I'm going to say that I'll ask Dr. Nightingale to write very fast here, but we'll try and hone the language, so to speak. This is just for the spirit of it. But it does seem that we could agree that we are concerned about both the problem of identifying and assessing the level of risk that known agents currently pose to the blood supply, and we're very worried and concerned about this issue of emerging agents, and that we need to make sure that we have a prevention and public health approach that responds to both. So that would be the first thing I'd sort of put out there as a preface, that we're trying to wrestle with both. We know we've got theoretical issues, but as Jane said, I guess we still don't know that anybody ever died of CJD. So--

DR. PILIAVIN: From blood.

DR. CAPLAN: I mean from blood, but we have this problem also of the emerging agents that threaten the blood supply, and that both need to be attended to in all agency and federal approaches to protection of the blood supply.

Are we comfortable with that kind of spirit approach there?

It seems to me then the next thing we might want to say is that, while much is being done to protect the food supply, it is of concern to this committee that these efforts be carefully monitored, that they be pursued zealously, that consideration be given to making sure that CNS substances do not enter into the human food chain in any way, either through current agriculture or hunting or just what's going on at restaurants, and that this has global implications in terms of trying to understand, too, what happens with some Americans or residents here, what they may have been exposed to.

But what I'm getting at is it seems to me that part of the need to protect the food supply is that we stress its importance, that we want to make sure that we are not just talking about animal feeds, but what we're talking about ultimately is what goes into human beings, and we would like to see policies and steps taken to ensure that more or less we have a zero tolerance here. Is that something we could move towards?

Actually, when you were talking before about changing food habits, one of the things I was going to say on that score is this might be a restaurant approach as opposed to a food approach. I know what I can order in restaurants and I could get brains at a number of places if I wanted them just for lunch. So it may not just be a matter of telling people what's good for them to eat, but we may be talking here about something that the committee is trying to set out and say, look, there's a real risk here for new agents as well as existing agents, and we're trying to discourage this.

So I'm looking to see do you want to push in that direction. It has ramifications for how people outside this room are going to hear this. That's not a small statement you just made.

T2A DR. MOORE: I actually don't think we ought to get into specifics there. I think our message should be that we are concerned about multiple modes of transmission and that they need to be addressed--including food-borne transmission, and that these issues need to be addressed.

I think for us to really get into specific issues like, well, should people be allowed to eat brains or should there be regulations around central nervous system issues, I guess I'm a little uncomfortable with that as a public health person. I really think those may be very important issues, but I think that it needs the right people at the table to look at those issues. And I think that I would rather call for a process that allows for that, that we--our focus is blood, but we are concerned about prevention and control, broader prevention and control issues, and would like to see processes that address those issues.

DR. CAPLAN: Let me read one other thing here, since I'm doing a little tactical maneuvering. Kristine actually wrote up a statement, and I'm just going to read it to you. It says: Disease prevention and control concerning TSE infection--that's the topic--and the recommendation she suggested we think about is that we recommend that the Centers for Disease Control and Prevention--and I added "and other federal agencies as appropriate"--rapidly develop a document that addresses issues around disease prevention and control of TSE infection in the United States. Specifically, the document should address issues around possible food-borne transmission, iatrogenic transmission, and transmission from blood and blood products. Surveillance, education, research, and prevention strategies should be addressed as part of this report.

So that's a recommendation that's on the table, which I can read back, if you need to hear it. But the reason I'm doing something a little tactical is: If we don't say this committee announces to the United States that no one should eat anything from the central nervous system as one of our conclusions, thereby having pickets with white big chef hats standing outside the doors, we can certainly say we want a group to answer this, and fast. And that is one of our concerns.

So what I'm trying to do is make sure that we don't just say, well, the committee will look at this and seven years later we'll find out. I think it is of interest to us to get an answer fast, rapidly. We'd like to have a recommendation on this matter of should there be any CNS allowed into the human food chain, period, by any means, and what's going to be done to stop that.

I am willing to make that as a recommendation to a group such as this to answer it on scientific expertise grounds. Are we comfortable that way? Okay. I see a lot of head nods that way.

DR. SCHIFF: Do you need a motion here?

DR. CAPLAN: I'm moving toward that.

DR. SCHIFF: So moved.

DR. CAPLAN: Okay. Second?

DR. MOORE: What's the motion on the table?

DR. CAPLAN: That your proposal go with the recommendation that one of the first injunctions we have is an answer to the question of should CNS be banned from the human food chain, the ingestion of CNS? We want an answer to that question from this group.

DR. MOORE: That's a recommendation--

DR. CAPLAN: No. We are charging the group as something to look at. The question on the floor is: Should we create this group the way I read it? All right. We'll do it in bits and pieces.

Let's put this proposal forward, motioned, and then we'll discuss it, and I'll repeat it again. We recommend the Centers for Disease Control and Prevention and other federal agencies rapidly develop a document--there's no time there, but rapidly--that addresses issues around disease prevention and control of TSE infection in the United States. Specifically, this document should address issues around possible food-borne transmission, iatrogenic transmission, and transmission from blood and blood products; surveillance, education, research, and prevention strategies should be addressed as part of this report.

So that is--the motion is that we endorse that. We can have some discussion of that.

DR. JONES: I am comfortable with that, but with the exception of the need to have to be a little bit more specific and not say "other federal agencies," but say who we mean. I'm not comfortable with CDC having the charge alone. So we are talking about HHS and FDA specifically, I imagine, and I don't know what other regulatory agencies might be--

DR. CAPLAN: Probably USDA.

DR. JONES: Yes. So somebody--you know, I think we need to specify that.

DR. CAPLAN: We can add those. That's fine. We can add specifically USDA, HHS--

DR. JONES: And then state a time specific for a return response.

DR. HOOTS: I think we need to sort out those two issues about the CNS versus everything else, because I think that the proposal for the report is very global. It is going to take a lot of time if it is going to be done well.

The other issue, at least as it is being discussed, is much more exigent, and I think they should be separated out.

DR. CAPLAN: Dr. Guerra?

DR. GUERRA: If not separated out, perhaps rearranged in a sequence, because to go directly to the food chain really calls a lot of attention to it, and we may not quite be ready in terms of the information.

The other question I have is how we're using iatrogenic in this recommendation. Kristine, do you want to respond to that? I'm not sure that it's so different than we use it in regard to blood products--

DR. MOORE: Yes, I was thinking of the issues like--there was list, I think Larry actually showed a slide yesterday. I can't remember what the title of your slide was, but had known iatrogenic--

DR. SCHONBERGER: Pituitary-derived growth hormone, gonadotropin--

DR. MOORE: Dura mater transplant.

DR. SCHONBERGER: Dura mater, neurosurgical procedures.

DR. MOORE: Right, there was sort of a list of procedures that had been associated with--it was really basically that list, was what I was thinking about.

DR. GUERRA: I think it's a very specific list so that one could probably--rather than just using iatrogenic--

DR. SCHONBERGER: Corneal transplant.

DR. MOORE: Yes, corneal transplant. Maybe we could give some examples in there.

DR. GUERRA: Otherwise it's a bit open.

DR. MOORE: Maybe in the food one, we can give examples of brain tissue.

DR. SCHONBERGER: The organizations that have been involved have been NIH, Department of Agriculture, the Food and Drug Administration, the CDC particularly, and then, of course, the entire academic and private institutions and so on. But those are the main governmental institutions.

DR. GUERRA: Has the World Health Organization been involved at all?

DR. SCHONBERGER: Yes, of course.

DR. GUERRA: Because I guess that should be on the list as well.

DR. CAPLAN: What we're going to do here a little bit is, even though we've got some expertise that is sitting over that way, I want to keep the dialogue going over this way.

Ron?

DR. GILCHER: Much of what I wanted to say has been said, but in summary, the concern that I have is the introduction of central nervous system material into the food chain. There are those people who want to eat it knowingly, but there are those of us who do not want to. And it gets introduced into processed foods, for example, and we unknowingly are eating this.

I think it is very important to have both the educational component from the standpoint of educating the public, but there needs to be the public health perspective of making sure that it's not introduced into foods unknowingly, and, therefore, the public is ingesting this without ever knowing they have done so.

DR. CHAMBERLAND: Just a suggestion from a procedural point of view. I know that you and probably most of the people sitting around the table are chomping at the bit to go to a break; however, thinking back to the last time the committee had to deal with voting on specific recommendations, I would propose, so that we are all very clear about the recommendation that is currently on the table, that it either be put on a transparency or written out so that we could actually see it individually. As you recall, we had to go through a post-meeting exercise of, you know, passing around various drafts of the recommendation.

So I think to make sure that there is real clarity about the recommendation and how people might want to modify it, I would suggest that maybe that happen during the break.

DR. CAPLAN: We are prepared. We have an overhead ready to go. So we will do that once we get toned down here a little bit. We'll put it up on the overhead and look at it when we come back.

I fear that we may not be able to avoid the post-prandial, further ruminant recycling of the recommendation to you in the mail, but, Paul?

DR. HAAS: Very along the same way of Mary's comment, and it has already been made, is that given the broad nature of the recommendation as it now stands, I am afraid it gets out of these hands and then disappears.

I would like the recommendation to be very--maybe targeted, use bullets, and along the lines of what someone else said, after the bullets, maybe specific times or whatever--be very direct about this.

DR. CAPLAN: My inclination also is to say that this group, its first order of business should be to answer specifically by date Y what they want to tell us about this food chain issue. This is just me speaking personally now, not as Chair, but I am very worried. People keep telling me that we're on top of the food thing and we've got the food ban in, and I'm not convinced that that is the whole answer to this question, partly because of what comes in here from other places, partly because of who comes in here from other places, partly because of what is processed, and partly because of other ways that we just allow things to be put on restaurant tables and so on.

So I would like--that to me is an area we should be pushing, and even though others are saying, ah, we're on top of that, I'd like to see this group charged, if we agree to create it--which is the motion--with that kind of task. There are a couple of other tasks that we might assign them, but it seems to me that is one that we would like to get an answer to right away, and we may not have the expertise to do it in this room, but we certainly can express a concern that that be a first order of business.

The reason I go through that is, as we move on voting on this, we can say that we want this group and that we can tell it some things that we think it ought to be doing by a certain time as you think about this.

DR. GOMPERTS: As I understand it, the proposal is to have government write a report, an educational report, different departments within our government to write that report. That report would be focused on TSEs, food, et cetera. It's a rational proposal. However, the proposal should be that we ask government not only to give the current status, but an evaluation of what is taking place within our country in relationship to what is going on in other countries, in other major--parts of the world where there are major epidemiological issues, United Kingdom, Europe specifically, in addition where issues and problems are perceived and what is to be done about those issues and problems. So it's more than just a status end.

I think the time line issue is absolutely critical. We don't want to wait 18 months for this. I think a six-month time line is--I shouldn't go longer than that.

DR. CAPLAN: Is that a suggestion to modify the proposal to six months?

DR. GOMPERTS: Yes. Six months, and ensure that, A, there is an analysis of epidemiological issues in other parts of the world as will impact our country, and, in addition, a statement of where the issues, where the problems, where the holes are, and how they're going to be met.

DR. SNYDER: I just want to bring one thing up. I may be a little naive on this, but it seems to me from what we heard yesterday that we know that units are being withdrawn. It's not totally clear to me all the reasons, but it seems pretty apparent that in some cases, because units are drawn, they enter the manufacturing at some stage, and then subsequently they find out that one of the things that we know or known iatrogenics are, you know, discovered, in my opinion, way too late.

If we know, for example, when the first dura mater transplant was performed, if we know that human growth hormones are definite risk factors, then those units should be banned--banned or placed on hold until somebody with the proper credentials can either say that, no, this person never had growth hormone or, you know, the dura maters won't even be being transplanted at that point in time.

To me, that is something that we can do right now that will affect the withdrawals. And, Dr. Penner, I agree completely with you. That is something that can have a pretty immediate effect. If it's even any question, don't let it enter the blood supply. Hold it until you can resolve that issue, and just make that a standard.

DR. CAPLAN: Again, leaking toward the supply question. Let me put the suggestion back on the table to rephrase it, and then I want to do a couple of other things that people suggested we recommend. But keep in mind that if we say that appropriate federal agencies, which we will spell out--I won't pick on the CDCP anymore, but appropriate federal agencies be convened to develop a report, within six months has now been suggested, which will thrill everybody at the agencies, that addresses issues around disease prevention and control of TSE infections in the United States, existing and emerging. Specifically, the report should address issues around possible food-borne transmission, iatrogenic transmission, and transmission from blood and blood products. Surveillance, education, research, and prevention strategies should be addressed as part of the report.

I think Keith had an emendation that he wanted, that the report also reflect what is going on in other countries faced with TSE agents, and--I'm not phrasing that right, but something about capturing our response relative to what other countries are attempting to do. And then it seems to me if we vote on that and say yes, we'd like to get that, we can then tell them some things we want to do next, like please address the issue of food supply first in your report or feature that or get to that first.

So does anyone want to move a vote, or would you like more discussion on that little paragraph?

DR. PILIAVIN: I think we want the transparency.

DR. CHAMBERLAND: We want to see it.

DR. CAPLAN: Oh, excuse me. You want to see it on the transparency. I won't even hold you to what you vote on, but are we ready to say that that goes to a transparency? Let me put it that way.

DR. PILIAVIN: I don't think we need to vote on that.

DR. CAPLAN: Okay. We'll try and write that up.

Here is what I'd also like to see, maybe if Steve can really write fast, just some other simple things, maybe on transparency. When we come back, we can look at them. One was that we encourage appropriate patient groups and professional societies to stress the importance of autopsy, and training of persons to interpret findings and educational efforts to understand how to interpret the results of autopsies with respect to TSE, some phrasing like that. If we got that, I think we'll be able to get some place with it, that we request that the NIH tell us about the needs they have to take on the challenge of TSE now in emerging agents, and whether they have suggestions about the organization infrastructure that they think would meet the challenge.

I keep thinking, by the way, that we've listened to $100 million withdrawals on the supply end, and if I was not mistaken, it was $7 million on the budget end. Am I right about that? So what I'm asking here is for the NIH to do something they'll hate to do, which is tell us why they need more money and what ideal structure they would use to take on this emergent area, as well as the existing one. That could include veterinary, animal monitoring as well as people. So we need a specific set of recommendations that we can consider and then endorse about budget infrastructure and how their research is set up.

We saw those slides, and Paul has told us a number of things that are going on at the different institutes. But maybe if we got a sort of overall picture, at our next meeting we could then say, well, we think this is a plan and this is a challenge and we recommend that Congress move on this and that this happen. So some phrasing about the infrastructure budget requirements to take on both existing an emerging challenges. I think we could get that up and request that that come back to us maybe for endorsement.

The other one that I thought was--and I'm opening the floor for others--that we ask for standardization and screening of donor brochures and materials with respect to TSE. It's a pretty simple thing. I'm not sure whether it ought to be FDA-generated or whether it should come from AABB or who ought to do it, but that standardization is important and that knowledge about TSE be reflected in donor screening and recruitment and that that just ought to be happening. That just seems to be important.

So those are some other ones I think we can probably get up and onto a slide and maybe it won't generate too much discussion. Any others that anyone on the committee thinks we need to--would like to see done as well on the public health prevention side of this? I know we'll talk supply as soon as we get done. I could see that gleam in your eye.

I know we'll have a convivial, fun time enjoining the agencies to get reports to us within five minutes. Why don't we take a 15-minute break? And we'll see you back here.

[Recess.]

DR. CAPLAN: All right. You may take a minute to read that. While you're looking at it, we can open the floor up for some comment and discussion. Kristine?

DR. MOORE: This is just a small issue, but I am wondering, we may want to say expert working group or groups, because Mary and I were talking that the people that may deal with iatrogenic issues in hospital infection control issues, you know, may sort of have their own little group, and the people who do food safety and food-borne transmission, USDA, that's a different set of players. And I'm not quite sure how this might best be structured within the Public Health Service, and I'd like to give them a little bit of flexibility. So I suggest it say group or groups.

DR. CAPLAN: Okay.

DR. MOORE: And I also think that six months, as I mentioned to you during the break, I think six months--you know, I'm really--having served on some of these kinds of groups, my experience is that it's been a one-year to two-year process to bring people together, draft--

DR. CAPLAN: Actually, hold up on that.

DR. MOORE: Okay.

DR. CAPLAN: I'm about to say something nasty, so I'm catching myself here. But it was something on the spirit of let's see if we can agree what we want them to do, and then we can fight about how fast they can do it.

DR. MOORE: Okay.

DR. CAPLAN: Yes?

DR. JONES: Who changed CDC and the other agencies to the Public Health Service? I thought we said we were going to be specific.

DR. CAPLAN: Yes. What we can do there--I don't know how that got changed. That was probably Jim's fault.

DR. AuBUCHON: It's not my fault, but I was watching over your shoulder.

[Laughter.]

DR. AuBUCHON: Steve suggested that the Public Health Service was the appropriate agency to put up there in order that the recommendation or the final output came back to this committee. And he pointed out that there are a number of Public Health Service interagency guidelines that are produced, and that was just his thought, that that was the most appropriate way through government circles to get this taken care of.

DR. CAPLAN: Let me say to the group--

DR. AuBUCHON: That's his information. I know nothing about it.

DR. CAPLAN: Let me say to the group on this one, we will get it as specific as need be, but we probably don't have to worry about that particular substantive issue right now. We can give an "e.g." or an "i.e." or an example and just list them there so that it's clear. We want them to get the right groups. They'll want to get the right groups. We may not be able to figure out exactly who should be there, but we can give some for instances or examples and flesh that out. So what we might say up there at the Public Health Service thing is say, "e.g., USDA, FDA," et cetera, something like that.

DR. CHAMBERLAND: The other thing is I would say the wording "establish an expert working group" is very--let me put it this way: There are already established groups, advisory committees that exist that actually would be available to address some of these issues. And so I think we're--I don't want us to make a recommendation that is so--that locks us into such tight language in the sense that we're not--I think we need to have the department come back and tell us what currently exists in terms of formed working groups, advisory committees, et cetera.

For example, I know within CDC there is an advisory committee on hospital infection control issues. CDC's advisory committees actually operate differently than some of the other committees in that they produce products. The infection control guidelines that are issues now are the recommendations of an advisory committee, and it's one of CDC's thick MMWR reports.

So if we wanted, for example, iatrogenic transmission to be addressed, that's a logical group. It already exists. They could write a report.

DR. CAPLAN: You know what? That reminds me, we might want to amend that.

DR. CHAMBERLAND: Then there's this whole--the FDA and Department of Agriculture may have groups or mechanisms.

DR. CAPLAN: Yes, we can say establish--

DR. CHAMBERLAND: We may not want to reinvent the wheel.

DR. CAPLAN: We can say establish as necessary an expert working group or groups. Again, the point of the--what the committee is asking for is answers to make the agencies generate them up from the information they have. I personally will go on record and say if there is a 400-page report on iatrogenic illness, I don't want it sent to me. I want to see something that is usable, that responds to the concerns that the committee has. So it may require some kind of abstracting or summary. But I do understand that we don't want to call for reinvention. This is not an attempt to say please set up more and more bureaucracy. But the way to phrase that, Mac, again, might be--

DR. PENNER: Establish or utilize.

DR. CAPLAN: Establish or utilize an expert working group or groups. Then I think in the spirit of what's--Trish?

MS. O'CONNOR: Since we are the Blood Safety and Availability Committee, would it be a good idea to start out explaining why--since we start out talking about food-borne transmission--and, of course, that does affect the blood. But do we need to sort of say--there is so much that's unknown about this disease and it's possible that it's transmitted through the blood, and this group, that this is why--

DR. CAPLAN: Yes. And, in fact--

MS. O'CONNOR: --you're recommending this?

DR. CAPLAN: I think that's a good idea. Somewhere back in Steve Nightingale's notes--remember I had that little preface that said because we are concerned about the safety of the blood supply and the issue both of existing possible risks and emerging risks.

MS. O'CONNOR: Right.

DR. CAPLAN: So that should be the preamble to this recommendation, or something like that.

MS. O'CONNOR: Right.

DR. CAPLAN: And I know that Steve had something come up. There's an emergency down where he is. But he's got these notes. When he comes back, we'll tell him to transform them. That's what I hope to get to you in the mail, and I was joking in saying there's no way we're going to be able to escape a little bit of post-meeting, check this through the mail, and it's that preface. But I think you're right. We do need to explain why are we worrying about food. People are going to want to know that. And the answer is because we're concerned, from what we've heard in the past couple of days, about not only existing but emerging, and this is one way to sort of push our concerns.

As I said to you before, just to hog the mike slightly on this matter, I know that people are doing things. I heard that clearly, and I know there are agencies out there outside the ambit of health agencies that deal with human beings over at the USDA level. But I don't think that should stop us, my personal view, from saying what you want to say about coping with existing and emerging risks. So it seems to me that's very important.

I'm not persuaded that our piling on on this matter is going to be a deficit or a problem, that we're sort of saying we're concerned about this, too, and we want this to happen.

DR. HAAS: Could you say something about how you see the role of this expert group, whoever it is, in making recommendations about blood components, plasma derivatives, and policy, how that differs from this group? Do you see this group making a recommendation back to the department on blood not involving you? Are you asking for a group to make recommendations to you?

DR. CAPLAN: To us.

DR. HAAS: To us.

DR. CAPLAN: To this group.

DR. HAAS: So you'd like another expert panel to be called on to make policy recommendations on blood and transfusion before you consider them?

DR. CAPLAN: I think the sentiment is that some of the issues up there require scientific expertise not currently present in this room. But before we say do X, Y, or Z, we better get in usable form that information back in front of the committee. Do I have that sentiment correct? So it's really back to us, and, again, that's why I'm stressing, I don't know that it requires setting up five new groups. There may be five groups already doing it, but it's getting that information out of each agency, coordinated, usable, back to us on those questions, is the way I would see that.

DR. JONES: Then why not, rather than say establish an expert working group, why aren't we recommending to the Public Health Service that they coordinate the development of a report to this group that does what you listed there?

DR. CAPLAN: That's better language.

DR. CHAMBERLAND: A clarification for me, because I'm a bit confused. Is this report supposed to just summarize existing information about what is known about food-borne, iatrogenic, or blood-borne transmission? Or is this report supposed to make specific recommendations? Because what I heard Kris initially articulate was a report that addressed surveillance, research, prevention, and control.

And I agree with the point that was just being made that--I understood the charge to this committee was to make specific recommendations about transfusion-transmitted infections or related issues, and I--

DR. CAPLAN: Not what is known. I think--

DR. CHAMBERLAND: Are we comfortable with sort of passing on to another group the responsibility for making recommendations? Because, quite honestly, within the PHS right now, FDA has laid out for us their existing--their current policy, their current guidance, their current regs that relate to the CJD issue. And Mark Weinstein's talk yesterday outlined some additional areas that are under discussion. And I got the sense that the FDA is seeking some input from this committee or comment from this committee on what they currently have in place and where they might be going. Is that correct?

DR. CAPLAN: Yes. Actually, you've led all the way back around to the need to then charge this group with answering a couple specific questions. If we are meeting in six months and they say we told you what we already know, I'm not going to be happy. But I would very much like to see us, if we then approve the creation of this coordination of a report, which I think is a good idea, to say we would like a specific answer to the question: Should there be a ban on CNS in the food supply? That is something I would like to have a recommendation back on, since I think it is of concern to this committee that we have the expertise necessary--if you push me today, I'll say yes. I think the agencies don't want to hear that quite today. They probably want to say something about the pros and cons of that, but I think the group is ready to say something about that, if we can get something back specifically on that matter in six months. What do the agencies think about putting a ban on CNS in the food chain? Where are we with this?

That is clearly part of the way to respond to the emergent issue, and if we approve this creation of this coordinated group, I'm going to offer to the group a couple of other opportunities to say other questions they might like specifically addressed in that report. One would be, to me, should we try to ban CNS animal substances in the food chain across the board, and what could we do to do that? Is that reasonable?

I think the American people are going to want to know: Should we be serving it at dinner? What about the elk? Where are the hunters? What are you doing to coordinate the state health department interventions, et cetera, et cetera? It should be a fun report.

Yes?

DR. MOORE: Just one point of clarification from my perspective. I was also think of this as sort of a broader audience than this group, you know, really more of an MMWR that is used more widely by state health departments, not just a report for this group. I see several documents that could come out of this, and maybe one of them is a report to this group. But I also see it as a broader--you know, trying to address some of the issues that you've raised by sort of a different group of people that have the appropriate expertise in those things.

DR. SNYDER: Just one quickie. Technically, it should be the Department of Health and Human Services.

DR. CAPLAN: That gets the charge?

DR. SNYDER: Yes, because organizationally, although it still exists in law, the Public Health Service, as far as the current organization, with operating divisions, it doesn't really exist within the hierarchy that's currently in--but as I said, in law, it still does exist. But I would do it that way, since we are the Secretary's advisory committee.

DR. CAPLAN: You can make that note, too.

DR. HAAS: I'd just like to comment. I guess that--and this is sort of a daunting task, in part because you're asking the Department of Health and Human Services to make recommendations on a product that it does not have any jurisdiction or any authority over. So, at best, what the department could do would be to advise the--make a recommendation to the Department of Agriculture. So that is a little bit tough.

The other problem with the six-month time frame is that there is a good deal of potential to use existing committees, but because of the law that generates public advisory committees, they have to be chartered, they have to be listed in the--well, if you want to--unless you want the report to be written by government officials only and not have public hearings, not have comments. You're essentially asking for a group to make a recommendation without the input of industry, without the input of people that would be affected, without--essentially, when you take the short time frames, you essentially have real limitations in terms of how you put together outside input because of the Federal Advisory Committee Act.

There are some real challenges in doing something as broad as recommending taking an entire group of products off the market that aren't even in the jurisdiction of this department.

DR. CAPLAN: Well, you know, my response to that--and I'll let others get into this if they want to--is to say I don't know that we want a recommendation. I think what we want to know is a report that gives us information about a concrete question like should we take all CNS out of the food chain. What facts can be coordinated by the department from whatever resources they have to do to get it that bear on this question?

I think we're ready to offer some advice about that. My hunch is if we advised on it today it might lead to an interesting set of headlines tomorrow. But I do think that it would be appropriate to ask the agencies to move on this and pull together the relevant information.

It's not that we need a recommendation, but I think in this area, for prevention, trying to anticipate whether we've got the--here's a second issue. Do we have an infrastructure comparable to what other nations are doing to anticipate challenges from new risky TSE agents? That will be my second proposal that I would like to get some facts about.

Then we can recommend, I think at the next meeting, whether we think we're up to it or not up to it. But while I hear the problems, personally, about what it's going to take to make the agencies move, I also heard a lot of concern here today that emerging agents may not be getting the response they want. So I think the committee--my personal inclination is to just put our foot down collectively and say, yes, but we need facts that bear on these issues.

If you want us to vote in lieu of being able to pull together that information, I think we'd vote on the side of caution. That might be something to ponder, for those who want to be motivated to collect information.

DR. JONES: I think that I'm concurring, Arthur, but I think perhaps in response to some of the governmental officials that we need to be very explicit relative to the fact that we're talking about a progress report and that we're talking about utilization of existing information, existing organizational mechanisms, and not the creation of a new set of advisory groups or entities, to bring forth information that perhaps then do address more specifically the questions that you were raising earlier. We might need to delineate under each category specific questions: if they have the information, this is what it is; if they don't have it, they should say so; if they can't get it because of lack of jurisdiction, they should say so.

And I suppose, going back to my concern about who put the Public Health Service up there, was the notion that we had talked about the Department of Agriculture as inclusive in this, and it was not just HHS. So, again, we need to make that clear that we're talking about a coordinated response from governmental agencies that are affected, but not one that is going to use the traditional bureaucratic delaying tactics for making decisions. We wan information.

DR. GOMPERTS: Clearly, it's a complex issue, and what I see this particular committee with this type of statement doing is, first of all, focusing government on this issue. I think there are so many officials who should know about this issue who do not, whether it's federal or state or whatever. I think this is a very important means of focusing our government as well as outside government on this issue that there are unknowns and we need to know where we stand today. That's the first thing.

I think from a time line point of view it's probably doable. There needs to be--one way to do it would be to have a formal workshop where government officials and perhaps knowledgeable scientists are asked to talk around this issue and actually work to develop a document, a report, as to where things are today. I think it's doable. And that time line is doable. The question is, of course, resources to do that, and I don't think the resources are all that considerable to bring... That's one way to shut me up.

[Laughter.]

DR. CAPLAN: While Ed restores his microphone, let me say that what I'm hearing, just so you'll understand what you're going to be asked to vote on in a second, if I can move us to close discussion on this, is we recommend that the Department of Health and Human Services coordinate a working group or groups--maybe that sound still like we want to invent something--coordinate an effort to develop a report may be enough, without getting into the creation of groups, to address these issues. The task is to report to us an audience, not to anybody else, on these themes, and with that change, are people ready to countenance a vote on the creation of that? Or do you want to discuss further?

Can I get a motion then?

DR. CHAMBERLAND: Jay wants to comment.

DR. EPSTEIN: I sense some lack of clarity here. What I'm hearing is the sense of the committee that there are some topics that you want to talk about on which you feel you were not brought the relevant data. I don't actually hear you asking for an action plan or asking--I'm sorry.

I would just like to comment that my sense of what's being said here is that the committee is putting forth a sense of the committee that there are topics you think you should address on which you have not been given information. Now, partly that's because they weren't seen as within the scope of the agenda for the meeting, but, you know, we've evolved to this point. And I'm not sure it's really at the level of a recommendation at all. You're simply saying here are some topics we think are important for this committee to address, and we want the data brought to us.

I'm just having trouble trying to distinguish that framework of looking at what's being said from what exactly is the recommendation. Because all the discussion around this recommendation has focused on what information ought to be brought to this committee, and that's what we do as a matter of course. You establish topics, you change the agenda, we bring you information you may need. And that's all I'm really hearing here.

Maybe I'm missing something.

DR. CAPLAN: John?

DR. PENNER: Jay, I don't see anything wrong with the way this is being asked. I think we are asking for that information, but we can't sit through maybe about 12 or 15 hours of five different groups getting together to try to consolidate this information. We could have them do it themselves without us being present so at least we can get an idea where we're at at this point. Who is overseeing what's going on in USDA? Are we having products that are being scrutinized? Do we know whether the elk are being taken care of or whatever? For all we know, we may be talking about things that have no meaning; they've already been done.

So we need that consolidated, and I think rather than spend two or three days here, it would be better to have the agencies put it together. That's what I think Art's after.

DR. MOORE: I guess my original thought was a bit different. I think that Art started out the morning by saying, you know, what are some of the upstream issues that need to be addressed, and I was trying to look at a mechanism that would allow some of those issues to be addressed separate from this group. Because I did not envision information coming back to us so we could make decisions about whether or not it's appropriate to have certain materials in the food supply. I was just trying to figure out what's the mechanism within the Public Health Service or within the Department of Health and Human Services to facilitate some of the concerns and questions that Art raised initially which were, you know, what do we know about this or what do we know about that.

Jay, my sense was to get this into a different form, not for this group, but just to make a recommendation that there is a need for developing guidelines. And I don't see that at all as part of this group. But when you get outside of our areas, I don't think this group has an infection control expertise. I don't think this group has food technology expertise. We don't have the surveillance expertise.

You know, I think that there's just a whole lot of issues that are very pertinent to the question about how prevalent TSE agents are in the population that may ultimately lead to issues around blood safety. But I don't think that those are issues that belong to this group.

DR. CAPLAN: Now, what the Chair is going to do is something extraordinary? I'm going to actually restrict discussion at this point to people who vote on this group. Agency people and other people who are ex officio I think I don't want to hear from for a minute because I want to find out what the group wants.

I'm interested in what you all, the voting members of the Blood Safety and Advisory Committee, want. On the table is a proposal that you get a report back from HHS that is coordinated about information on those questions, that this be brought back to you as the audience, not other federal agencies, not the world, not the MMWR--you--and that what you are then going to do is probably ask two specific questions beyond that, which is: One, what, in fact, should be done about the food chain? Two, do we have an infrastructure to anticipate emerging diseases that is comparable to or at least as good as what other nations have done? The two things I've got concretely on the table.

If you're a voting member, not an agency person, does that capture what you would like to see?

DR. JONES: Can I put that in the form of a motion, Arthur?

DR. CAPLAN: Okay.

DR. JONES: I so move.

VOICE: Second.

DR. CAPLAN: Discussion?

DR. PILIAVIN: I think I would like to find out a little bit more about the TSE committee in FDA, because it's conceivable that that committee has already done most of what we want here. I begin to feel like I'm the Scrooge here, but I am concerned about spending time and effort and money on things if it isn't necessary to spend time and effort and money on things. And maybe Jay, whom you didn't want to hear from, could tell us whether the TSE committee--

DR. CAPLAN: Remarkably enough, I still don't.

Again, what do you as a committee want to hear from these agencies? I think that's the issue on the floor for discussion.

MR. WALSH: I think in following on with what Jane said, I think we're asking for information. If the information's available, I would expect that the agencies would present it in a form that we could digest it and come back with a recommendation, which is what our charter is. So if the TSE committee, task force, has already got this information, I would expect it be made available to us and it would be a time saver and a money saver. I don't think it's inappropriate for us to ask for information to be able to make a recommendation.

DR. CAPLAN: Right. And I think again, just to be clear, the way this is phrased, it may not require anything more than providing and coordinating as opposed to creating a special group. We can sort of drop that kind of phraseology as far as that goes.

DR. SCHIFF: Yes, I agree. I think what we're concerned about, as has been stated many times, is not the well-established CJD. We've heard many times that really isn't changing; they're taking measures. We can argue about if those measures are too stringent. What we're worried about is this variant. And if the screening of donors is going to be did you have dura mater, did you get pituitary, it may have no bearing whatsoever on this. And you are getting at where the mode of transmission may be. It may be in what they're eating, as occurred in England. And if that's the case and we're concerned about the blood supply, then we have to be looking at something completely different in screening donors.

So I think this information, even though it may be getting away from safety of blood, that it does relate to it, and it would be helpful to this committee, if we're really trying to make the blood safe for what may be an emerging variant.

DR. AuBUCHON: I support the recommendation. However, my attempt to be Scrooge would just be to offer my comment that I think we have heard, between this meeting and our prior meeting on CJD, presentations by the world's experts who are performing experimental studies on this subject. And we will not see any additional research information come to us. We may learn something more about what other agencies are doing, and that may be important to us.

DR. BUSCH: Yes, I agree. I think we've seen most of the data that exist. We've heard the limited resources, the focus on this is very recent; and I think what we are asking for here, at least what I would like to see us asking for, is really a strategy, a consensus statement of what we know but more of an alert to the public and a strategy for building a research agenda toward these issues.

DR. CAPLAN: I think that's something we could--the spirit of allowing us to be able to--the information should come to us in a way--and I'm looking for something that we'll probably be doing in the mail here--that we would be able to communicate and alert the public about these matters and the challenge of emerging threats to the blood supply. That's part of the way we want the information crafted, is what we're calling for on what has now become modified enough that even though we'll vote on it in a second, we'll probably have to send it out to you and let you read it again carefully. But we can at least approve as a first go. I think I'm going to ask for a vote on this.

What you're voting on is--Steve, can you read that? We'll recommend--I do want to change that first line--that the Department of Health and Human Services coordinate an effort to develop a report within six months--we're changing that, so we're not talking about groups and new outfits.

DR. NIGHTINGALE: The formality is it will be within the aegis of the Public Health Service--my understanding in my short time in this job is that if it is under the aegis of the Public Health Service, it will in some way simplify the task of accomplishing what you wish accomplished.

DR. CAPLAN: Give us the metaphysics of whether it exists or not.

DR. SNYDER: No, no, no. Not the metaphysics. Just the idea that, you know, when you're looking at some of the food issues and the food chain issues, the Department of Agriculture is going to have to be in there. But that means that the Secretary needs to talk to that Secretary. So in coordination with--

DR. CAPLAN: Yes, yes.

DR. SNYDER: --the U.S. Department of Agriculture.

DR. NIGHTINGALE: Would the phrase "coordinate an effort to develop" convey the sense that you wish?

DR. CAPLAN: Yes.

DR. NIGHTINGALE: So the first sentence now reads: We recommend that the Public Health Service coordinate an effort to develop a report.

DR. CAPLAN: And remember, too, this will come with a preamble that says because of the threat of emerging agents, as well as the existence of current risks, we want this. That's what the backdrop is, so that it's not up there as part of the recommendation, but that will be the preface to it. That's why we're moving on this.

All in favor of that modification, with the provision--

DR. NIGHTINGALE: A point of order.

DR. CAPLAN: Yes?

DR. NIGHTINGALE: On behalf of the Public Health Service--a point of order. Does the motion that we're voting on including a preamble to be written, or is it the text as modified on the screen?

DR. CAPLAN: With the preamble, which is buried, actually, in your notes, believe it or not, somewhere. Preambled that way, can we move this forward and make it subject to fine-tuning and revision by mail? All in favor?

[A show of hands.]

DR. CAPLAN: Opposed? That was easy. Okay.

Now, Steve, was it possible for you, given the problems that came on downstairs, to capture any of those other quick recommendations we had about training and so on?

DR. NIGHTINGALE: The first of the ancillary issues was a question about the NIH budget, and it was a recommendation regarding priorities of the NIH budget. I believe implicit in that from the discussion yesterday by Dr. Gibbs and others was a discussion about the priority of developing a screening test.

DR. CAPLAN: Let me ask--we didn't get that on slides, though, overheads. Not yet? Okay.

Then I want to ask the group just an administrative issue. You will recall before the break, many hours ago, that I listed a set of possible recommendations about autopsy, training, the NIH budget in terms of making sure that the agency let us know what they think it would take to anticipate new risks and to test for current risks in the blood supply, the development of the screening test. We can, I think, if it's easier rather than trying to do this in our heads, send these out. Would that be--do you want to try and work through those quickly, or would that be all right if we just tried to construct them and mail them out to you for approval? Mail them?

DR. PILIAVIN: Talk about them.

DR. CAPLAN: You want to talk about them some more.

DR. McCURDY: Just a point of clarity. I think one of the crying issues or the very definite need is a test that facilitates research in the study of the TSEs. A test that would facilitate research is probably--not necessarily but probably different from a screening test. And it may be that one evolves from the other, but I think it might be worthwhile to talk about a test rather than use the adjective screening.

DR. CAPLAN: Okay. I understand.

DR. PILIAVIN: Perhaps it's my training as a social psychologist, but I really do believe in the efficacy of group discussion in terms of the clarification of issues.

DR. CHAMBERLAND: I was just going to say--

DR. CAPLAN: Oh, by the way, we can open the floor back up to the entire huge swatch of humanity now.

DR. CHAMBERLAND: I think I'm following up on what you just said, Jane. I would have difficulty if I was a voting member of this committee to kind of know what I was voting on in some instances. I'm sorry, Art, but I didn't really quite grasp everything that you just said that you suggested be put in the mail to the committee members.

Are you outlining a series of recommendations that would be made about this committee is in favor of resources?

DR. CAPLAN: Yes.

DR. CHAMBERLAND: I really think it would be helpful to have a draft of those done over lunchtime to see where we're going.

DR. CAPLAN: We can try that, okay.

DR. CHAMBERLAND: And some discussion.

DR. CAPLAN: We can try that.

DR. CHAMBERLAND: Because we had a lot of--it made it hard doing it by the mail.

DR. CAPLAN: Just to remind you again, Steve, what we're talking about here before we try to get these down, then maybe on the slide side and also then shuffled toward the non-controversial matter of supply issues, one was a recommendation that we try to have patient groups and professional societies encourage--highlight and encourage the importance of autopsy, in training of persons to interpret the findings, educational programs to help professionals understand the diagnosis of TSE.

We had a recommendation about the need to standardize screening of donors, that brochures and other information be sensitive to the challenge posed by TSE. During the break I had some discussion with people from the Red Cross who said we're doing a lot of that, and we want to make sure that that, of course, goes on across the board, but that would be a second recommendation that came up from the discussion this morning.

The third is that we ask the NIH to specify what their research needs and infrastructure would be to deal with the challenge of TSE now and in the future, including the development of a--I should use Paul's language here--test. Not a screen, test for these agents, that this be a priority. I think those are the ones I had.

So we can look at those probably pretty fast right after lunch and kind of review those, unless there are others that I forgot here.

DR. MOORE: This may be a little bit tangential, but yesterday there was some discussion about better diagnosis not just in human populations but in animal populations as well.

DR. CAPLAN: Part of that NIH--yes.

DR. MOORE: So the veterinary community may also be included in that training effort.

DR. CAPLAN: I forgot that, but that was part of that NIH issue of what are we doing to monitor animals as well as people.

DR. HOOTS: Yes, and just to extend that one more step, not only testing as a determinant for TSE but discrimination of TSE agents or between agents.

DR. CAPLAN: Those aren't so bad. There's only three or four of them there, so we can do those right after lunch.

John?

DR. PENNER: Could we then perhaps provide some thought for the lunch break about the supply area?

DR. CAPLAN: I think we're ready to head that way unless anyone wants to comment further on other things that came up about--remember, we're still talking prevention and upstream issues. That's what these recommendations are meant to capture. If we've got that on the table, then let's shift at this point to a discussion of a place where--never wish for something, you might get it, which is, well, is the committee ever going to say anything about various things that it has been asked concerning issues of risk, management of supply, withdrawal of product and so on. That hour has come. We'll talk about this now until approximately noon, I suspect.

What I was going to do is basically open the floor to see what specific sub-issues people might want to talk about under the general rubric of supply. Unlike the prevention and upstream issues, I don't have a proposal to make, but John does.

DR. PENNER: Jane brought this up, and all of us have talked about it, and yesterday we heard from a number of the blood user groups as to their feelings about whether products should be released or not released. And there's a good deal of divergence of opinion here, depending on the group, and what their resources are for getting alternative products. Some, as you already heard, such as the alpha-1 antitrypsin, don't have other resources, other availability. So that one has to then weigh risks, and I don't think that a governmental agency is in a position to be able to weigh those risks without the population being involved that are receiving the products.

So with that in mind, I would propose that we would at least develop a committee, which would be public users, an advisory committee, that would be able then to review the product use for individual groups or users. That would include individuals from each of the user groups. It also would include individuals say from the manufacturers.

It would be the purpose of this group to recommend product retention or exclusion based on the risk for individual users. They would be able to review any of the recall cases that have questionable decisions and identify, therefore, restriction of use of those products.

I think that is the general tenor that I'd like to get across, and I think Jane could add more, and others. But--

DR. CAPLAN: Are you thinking about this--not to put more load on here, is this with the TSE group that exists?

DR. PENNER: With the TSE group, whatever--because I think we need some group that is able at least to look at it on the basis of need and decide that perhaps it's more important that this product be available than restrict it, because the individuals who are using this product will suffer significantly without it, recognizing that there is a potential or theoretical problem that develops if you use the product, as opposed to a real honest to goodness life-threatening situation without it.

The public can be involved in that, and I think we've got a number of things that we can add to a preamble to that, such things as given the fact that there's no evidence of blood transmission for the infection, given the fact that there is only a theoretical or possible infection in certain individuals, given the fact there is no assay for the agent, and given the fact that the product preparation may even reduce or eliminate any infectivity, depending on which product we're talking about and what procedures it goes through, and then given the fact that different populations have different risk factors or needs for product, some of which are life-threatening.

DR. NIGHTINGALE: Dr. Penner is undoubtedly aware of the regulatory complexities his proposal raises. Would Dr. Penner wish to specify any potential resolutions to those complexities at this time?

DR. PENNER: It would be a matter of establishing a group or committee that would be advisory to FDA on this subject.

DR. NIGHTINGALE: That advisory committee would be distinct from the Blood Products Advisory Committee; is that correct or incorrect?

DR. PENNER: That's correct.

DR. CAPLAN: Well, why not? Okay. Let's go this way, and--

DR. HAAS: I'd just like to point out some of the challenges of doing that. In fact, you know, we do consult with patient and consumer groups when we do this. But we're available 24 hours a day for emergencies and for supply problems. We have complete access to confidential trade information and other types of information which companies are not willing to make public or discuss publicly. The law--and it's something we didn't invent; this is Congress--requires that all public meetings be announced in the Federal Register six weeks before the meeting.

There are some products where, in fact, you do have a couple of months before you have to make a decision, and it could come to such a committee meeting. But I think there are other areas where this would largely be an after-the-fact review of decisions that we would already have to make, because I don't think you want to put us in the position of not being able to release product that we currently have the authority to release until it has been publicly discussed and vetted by a larger group, and discussed by a group that may not have the full--the access to the same kind of information that we have.

So I think that we are all very sympathetic to the notion that everybody has to participate in this decision and that the people who use the product perhaps have the most important opinions about some of these decisions. But this would be the fourth advisory committee on blood products that would require meeting, staffing, Federal Register notices, and how its jurisdiction would differ from our other advisory committees and what you would like them to do that you at your committee on availability would not consider, I guess my question would be: Is this a function that this committee would be willing to serve, knowing that you would probably need to meet at least probably monthly?

DR. CAPLAN: There's a threat.

[Laughter.]

DR. AuBUCHON: I like Dr. Penner's idea; however, I've lived in the Washington area twice, and I don't really care to do it again.

I wonder if we might be able to accomplish the sense of Dr. Penner's approach in a slightly different way, and that is, to recommend or encourage the FDA to continue to consider or increase its consideration of the supply issues and the burden that the lack of particular derivative availability may have on certain groups of patients. There are certainly mechanisms available, I believe, for the FDA to contact various patient groups and get their input in an informal manner to consider as part of the decisionmaking process.

I am not aware of this as fact, but it is my feeling and understanding, however, that that won't entirely solve the problem. Because even if the FDA tells a manufacturer, okay, we will let you release this particular lot, that authorization comes with the requirement that it be labeled in a particular way, and that potential users be advised that there is possibly an increased risk of transmission of CJD through that component. As a result, even with that special authorization, many manufacturers are probably not willing to release the derivative because of the fear of future lawsuits. They're unlikely to be sued because something isn't available: It's just not available, sorry, that's the way it is. However, if they release it, even in a compassionate mode, they may get sued because it's thought to transmit something in the future.

Without the type of liability backstop protection that vaccine manufacturers have, they can--in this situation, my guess is that many manufacturers just aren't going to push it.

DR. CAPLAN: So to just have two issues up on the table, maybe we can focus in for the time being on Dr. Penner's proposal and ways in which the committee might want to see consumer involvement either added to existing structures or something new put on the table that the FDA would have to do to incorporate more consumer perspectives. And then there is a second question, which I would like to hold discussion on for a minute, about what might we say about liability and compensation issues for harm in terms of trying to encourage increases in the supply of blood that's out there. But let's put that one on hold for a second and just look at the Penner suggestion about consumer input.

The proposal is to create a new body that would advise on issues when they come up about withdrawal and withholding, and I suspect is not yet clear, I guess, to the TSE group. Is that what you were thinking? Let's talk that way for the time being.

DR. MOORE: This is a point of clarification. Yesterday, Mark, when you presented the transferrin case and talked a little bit about that, it sounds like what I'm hearing, it relates to what you're saying because that was kind of there were some decisions made on a case-by-case basis and consumers were involved in that decision. What's the process? Who was invited to be involved in that process? And could that model, which is a much less formal--I am also very concerned about creating another formal group that doesn't have the flexibility that I think you may be actually hoping for. Is there a less formal way, and can we use that kind of a process to achieve what you're suggesting?

DR. WEINSTEIN: There has been an initiative, in fact, in that transferrin situation there, a decisionmaking process, an analysis, risk analysis was performed by the FDA with the involvement of the CDC and the NIH, a decisionmaking process, how this occurred, how--you know, each step of the way, the analysis was given to the hemophilia community. We asked for their input about the--what they thought of this decision. There was communication at all levels here as this progressed.

DR. MOORE: Yes, I think there are a couple of issues here. One, some of the issues that I think you're suggesting could actually be addressed by this advisory group, but I'm wondering if we could maybe modify your proposal to say something like that a protocol or a process be developed for case-by-case issues of product release, with a risk/benefit analysis and involvement of consumer groups, maybe modifying your language.

DR. PENNER: Formal protocol.

DR. MOORE: Formal protocol. Would that be able to be achieved in a way that might be useful, particularly when you're dealing with sort of these case-by-case situations? I think basically it would be this group basically condoning that process.

DR. WEINSTEIN: I think you proposed that. There are confidentiality issues here that come into play here, you know, whether the individuals we are consulting with have the access to confidential information, that can occur if they are to help in the decisionmaking process here, if they are learning of our decision, somewhat there can be a difference in--

DR. MOORE: Maybe seeking input, like come up--using the model that you basically used. I think confidentiality is certainly a very important issue, and I don't know if--I think you can't really breach confidentiality there, but somehow involving consumers in the decisions, which is what you did before.

DR. WEINSTEIN: Well, as I say, this is what--our usual procedure is to involve the members of the affected communities in telling them about situations that are developing and their thoughts come into play about our final decisions.

DR. CAPLAN: Let me just ask a question to the committee, some of whom have members from these communities that are affected. If we were to say as a preface to John's proposal, just as a preamble or preface, that the committee had a sense that consumer involvement and groups at risk is not adequately reflected in the current processes used in making decisions about supply and withdrawal, if we were to make that as a preamble, is that something that members of this committee, particularly those who are in some of these groups, feel is true? Or is it the case that as the agency tries to reach out to the public and affected groups that people do feel engaged and involved as appropriate?

What I'm trying to get at here is, for the committee members, are we trying to fix something where we have a sense that more consumer involvement is important, more accountability is important? Or is it the case that some of what is going on isn't well understood and that has to be systematized? And I'm just asking if you have experience with one of the affected groups, if you could comment on that.

MR. WALSH: We haven't had any experience with being consulted about having product released, you know, with the acknowledgment of potential issues on a withdrawal basis. But I think based upon the model that Mark presented yesterday, if we as a committee made it known that we--you know, not necessarily applaud the FDA, but that this seems like a good process, but we would encourage the FDA to have members of this committee or have this committee help facilitate interaction with a consumer group on a particular supply issue or withdrawal issue, then that would be appropriate. And I think that needs to be formalized. I think that's part of our charter, obviously, the reason why we have consumers sitting on the committee, is to express a consumer's input. And I think we ought to probably formalize that in some way, short of what Dr. Penner had proposed.

DR. CAPLAN: Dana?

DR. KUHN: I think we have gotten consumer input with the testimonies yesterday and hearing what their concerns were and even giving direction in the ways that we should be going. I think as far as the shortage of supplies that are going, you definitely need to continue to have consumer input. Because how do we know--you know, I've heard stories about IDF patients dying because they did not get their product. And I think that we need to continue to have that consumer input.

But, you know, is the issue here--are we talking about developing another committee to look into--that has consumer representation?

DR. CAPLAN: That's the Penner proposal.

DR. KUHN: I think we already have it here, and I think we need to just utilize it and continue to get that information coming to us to make these decisions.

DR. CAPLAN: Let me note, by the way, it was said--and I think it's true--there is a set--that must be on my mind now, but there is a set of questions about needing to act fast and make a decision within the constraints of proprietary requirements and so forth that regulatory agencies face. There is also an opportunity for this group, if we want to in certain instances, to review what was done. That is possible, and we could say the way the process worked didn't reach out far enough, we want that formalized, we'd like to have some discussion of how that goes, and then critique it or comment upon it and so forth.

So in one sense, what is put on the table is whatever we propose to get standardized or formalized, consumer involvement in decisionmaking, has to be responsive to the fact that decisions have to go quickly sometimes, and then at the same time, can this group here offer more input, or should it, to the procedures and policies that are followed to make sure that the voice of consumers is heard.

So there really are kind of two. One is, Is the consumer input into the withdrawal decisions as they arise adequate? Another is, What could we do to be more involved in commenting on how that goes?

DR. FIGAL: Well, I would just respectfully ask that before you pass a resolution that starts by declaring that it has been inadequate, that you give us an opportunity to systematically present how we do have outreach to the communities, how we do involve them with different decisions, where it's easy, where it's hard. And we haven't really done that. I think you've heard some of that as a byproduct. If you'd like to do that in a future meeting, we'd be happy to do that because it can always be improved. But it's a very important issue to us, and we work very hard at it.

DR. HOOTS: In another way I think we may be in a good position to help on the prospective side of this. One of the things that we really haven't had direct information about, except vicariously from the testimony yesterday, is the things that are specifically impacting supply at any point in time. There are clearly issues that haven't been discussed that we probably need to not necessarily be aware of on a confidential basis in terms of Company X being off-line for X period of time, or those sorts of thing. But, clearly, those issues probably are having a substantial, and maybe even substantial even beyond some of the things we've already talked about, impact on supply.

I think that we are in a position by our charter to have a reporting mechanism give us information each time we meet, or even between times we meet, if it's not frequent enough, about what things are impacting the nation's blood supply in terms of availability. You know, has one company run into a problem? Not specifying what, just say that there is a problem, and that we anticipate the impact of this problem to be eight months down the road the number of units of grams of IVIG or units of factor VIII or factor IX may be cut by this percentage, and, therefore, that we would anticipate there is going to be an issue.

I think by having--I know the FDA does this on a routine basis. I think we, in terms of trying to look at it globally as well, and also to maximize the amount of--to help the FDA get the maximum consumer input, could utilize this information, because I think those--a lot of times we hear or we have heard, at least in this meeting, issues that clearly will impact the supply, like recalls from CJD. But we don't know how to frame that into the total context of the supply, and until we have that information, we may overreact in our recommendations or underreact in our recommendations.

So I'd like to see us get more of those supply issue-related data into this committee.

DR. GOMPERTS: Listening to the discussion on the supply issue, I think first of all, I don't think this committee has heard enough about it yet. The supply issue is complex. There are many factors, starting off from donors and different types of donors, all the way through to specific products. And I believe this committee needs to spend some time on this, and my recommendation is our next committee meeting should spend a fair amount of time on this issue.

We have heard from Dr. Weinstein, as far as the immunoglobulin issue, that it's a multifactorial issue and that, indeed, the FDA is looking at a number of ways to alleviate that particular problem.

What this committee should be looking at is some ways, as well, where possible avenues could be sought from alleviation, whether it's the CJD issue or others, but at least we should start thinking along those lines.

From the point of view of consumer representation, we heard really clearly yesterday--and we've heard in the past as well--that the hemophilia community are very concerned about transmission of infectious agents, and that is the top priority, and that will and should continue to be the top priority.

However, at this point in time, supply of factor VIII and factor IX to that community is not massively constrained. But once it is, then it will--certainly the issue of supply to that community will very much become a top--because the management of a bleeding disorder, a bleeding situation, has to be a priority.

However, a different group of consumers, or consumer groups we are not hearing from and won't hear from, are those with, for example, immunoglobulin is used in the management of Kawasaki disease or Guillain-Barre, or for that matter users of albumin in a shock situation.

So we have to look as broadly as possible from that point of view, but as far as Dr. Penner's point is concerned, I think the Blood Products Advisory Committee of the FDA should be asked to look at this, the supply issue, that there is broad consumer representation on that committee. And that certainly is one way to do it as well.

DR. PILIAVIN: I'm not exactly sure how to say this. Obviously safety is the most critical issue. However, I want to return to the data we saw yesterday which suggests that there is no safety issue with regard to CJD, the normal old-fashioned kind which has been around for over a hundred years, and there's no evidence that anyone has ever gotten it through the blood supply.

Certainly there has been concern among consumer groups, particularly the most strongly organized of them, about safety, and they have indeed been very badly burned in the past, and this is all very understandable. At this point, I think we really need to focus on the safety issue around availability, and I'm putting it that way on purpose because I really see this as, at this point, a more critical safety issue. And, again, it seems to be affecting groups that don't have a voice, and here my sociologist hat goes on, and I am really very concerned about the way a system works that listens only to those who have, for one reason or another, political power and doesn't listen to the concerns of those who, for whatever reason, historical, economic, have no such power.

I would like to at least talk about the possibility of changing the current set of regulations regarding recalls based on what we think we really know about the data. I don't think that at the present time traditional CJD is a danger to the blood supply. And what is a danger to the blood supply is all of these recalls that, number one, prevent there being product for people who need it, and, two, drive up the cost of this product so much that even if it is available, many people are not able to afford it.

DR. MOORE: I actually agree with Jane, and I would like to--I think one of the issues that this group was asked to look at is: Should we even have these product withdrawals? And I really would like to see some discussion of that.

Along with what Jane has said, I would just like to add the point that many people who are either at risk for CJD or who subsequently develop CJD and have previously donated blood products are never identified. And I think that--that's one issue. So there probably is a greater level of contamination--I mean, we're kind of--I don't know if you guys heard the story of the person who looks for his keys under the lights because that's where the light is. You know, and I think that that's an important consideration here, that it may be that contamination is fairly ubiquitous and that we're being able to address this, a small piece of the issue, and it's unrealistic to try to capture every possible infectious unit that may end up in a blood product.

The other thing--and I think it was mentioned yesterday--that I think is an important point to consider is that when you actually look at the product withdrawals, my understanding--and, Mark, correct me on this--is that most of the product--by the time there is a withdrawal, most of the product has already been distributed and used, anyway. Is that correct? And what was your figure again yesterday of the percentage of product that is still available?

DR. WEINSTEIN: Actually, I have a little mini-presentation here about the relationship to withdrawals and product supply and all that sort of thing. I don't know if we want to give it now or--

DR. CAPLAN: Can you do it in two minutes?

DR. WEINSTEIN: It will take ten minutes.

DR. CAPLAN: Maybe we'll do that after lunch.

We have basically three issues on the table. One is: Does the committee wish to say something about consumer perspectives and involvement? There's a Penner proposal that appears to me to be at least comatose right now but could be revivified. There is, nonetheless, an issue about what to do about consumers, and John may want to rethink based on the discussion he heard how he might want to revise or revamp that proposal to present to us.

Secondly, we have the compensation question, which I disconnected from this but which is not irrelevant to issues of withdrawal policy. If we think about ways in which we might try to approach compensation for harm or proven harm or move toward the kind of thing that has been done with the vaccines, we could say something about that and say we urge the exploration of ways to enhance compensation and reduce liability for this situation so that we don't find legal liability getting in the way of supply. That is something for Jim to think about over lunch.

Then this third issue has now come up. Does the committee--are we prepared to say anything about withdrawal policy given what we have heard about risk posed by standard existing CJD in the blood supply relative to what that is doing to the availability? And we don't have to necessarily have Jane make a proposal; she sort of made one for us that we recommend that CJD be treated differently than it currently is under policy with respect to withdrawals. And we can discuss that certainly when we come back, too.

If we do those three questions, plus a review of the other recommendations on prevention, plus a little bit of old business, that is going to pretty much make up the rest of today's meeting, because there is an opportunity there to go back. You saw the letter from the Secretary. Anybody remember hepatitis? It was a thing we talked about a long time ago. But we have a response, and we can comment on that response if you so are inclined as old business.

So those are the things that I think are going to make up the agenda after lunch. If we are going to do this and get out of here by 3:30-ish or 3:15-ish, then we've got to be back here at 1:00 on the button. Okay? Okay. And somewhere there is a 10-minute presentation on what we are doing already on the supply. We will see how that evolves.

But, in any event, Jim, if you want to think a little bit about compensation, John, if you want to think about how to reshape that proposal about consumer involvement, then we can go to those things. We will start with the recommendations, the other ones on prevention and upstream kinds of things.

Okay. See you in one hour.

[Luncheon recess.]

[1:07 p.m.]

DR. CAPLAN: I'm going to ask Dr. Nightingale to put the three recommendations about prevention and public health up on the overhead.

While you are pondering these three bits of advice that we are delivering, let me remind you again about order of business here. This morning we were trying very hard to say that we needed information supplied to us by existing agencies or whatever it takes to make sure that we are confident that the infrastructure exists for handling emergent threats to the blood supply. That is what that request or recommendation, depending on how you would like to phrase it, is all about.

These three other recommendations are in the spirit also of trying to anticipate future threats to the safety of the blood supply and its availability, asking for these things to be done.

Then I think we have in front of us the amicable and interesting review of Dr. Penner's idea about the participation of the laity in the deliberations of FDA with respect to withdrawal. We have the issue of compensation and whether we would like to ask or advise that agencies or PHS take a look at what they have in the vaccine area and whether that might be extended this way. And most particularly then, we are going to go into a discussion of what we know now about CJD, what do we want to say about its impact on the blood supply.

I think in particular the agencies are looking to us to see whether we want to say something about that, advise about whether there should be a change in that, and so that's pretty much what I want to do. I know I promised 10 minutes on the subject of what FDA already knows about CJD-related post-donation. In fact, in the interest of time, I'm going to ask that those get distributed, and we will, in fact, ask questions as needed instead of having a presentation on this, because I want to make sure I let--during the break, people were chewing my ear off about the CJD thing. So they may have inhaled about as much information as they want, and they may want to exhale a bit of what their views are about that.

So I am hoping we can actually go quickly through these. Remember, the recommendations that are up there--can you read them? A little focus on that. Now, don't be picky and ask to read these.

The first one is meant to emphasize the importance of postmortem examination for the protection of public health, training physicians. I think we are missing one thing here that I recognize we didn't get up there. But we have a training recommendation. We have a recommendation about standardization of procedures for screening donors ta risk.

By the way, if that is already being done by many groups, that is fine. We are just urging that it be done. It doesn't matter whether people say we are already doing it. It's just that we want to make sure that it's done.

We are recommending that the NIH tell us what it needs in the way of infrastructure and research to promote research on TSE, both animal and human, trying to look forward to the challenges that we heard about yesterday. And what is missing up there, the other recommendation, Steve, was that we try to encourage autopsies with respect to--oh, it's on the tail end here, recognize--essentially, dealing with autopsy tissues. Well, let's see.

What I'm looking for here, too, is that we encourage people--and the affected groups, right. The importance of postmortem examination. Does that capture that all right? Okay. It's just my verbiage there.

Discussion? And use the microphone, please.

DR. AuBUCHON: With respect to the second recommendation up there, I think indeed you are correct that the standardization is pretty much already in place because the FDA has been very clear about the questions that we are to ask perspective donors about their CJD risk.

However, I would like to offer for the committee's consideration the expansion of that and recommend standardization of donor information and donor questions, donor medical history questions, for all subjects. In other words, have the FDA prescribe precisely what we are to ask all donors, as a minimum.

DR. CAPLAN: Comment?

DR. PILIAVIN: I would like to go back to the issue that was raised, just as a suggestion for what we ought to ask, as to--we were talking about this at the break. Wouldn't it make sense to have people ask if they have ever had brain surgery, have them temporarily deferred until they can come back with you and tell you yes or no whether they had a dura mater transplant. That way we would certainly avoid almost all of these potential recall problems.

Similarly, with the hormones, have you ever had a shot that a doctor told you was a hormone? And then if they say yes, go and find out what it was.

DR. CAPLAN: One of the things that I've heard about that particular issue is that sometimes it takes a little while for the wheels to turn, that they donate and then they go home, they think about it, they ask, so they may not have an answer right on the spot.

DR. PILIAVIN: I can't imagine not knowing you'd had brain surgery. I mean, the specifics of the brain surgery.

DR. CAPLAN: That may be, although I guess some of this was when you were a child or when you were small or you have to ask your mom, did I ever fall down? But I get the point. We can certainly encourage that as part of Jim's comment.

DR. AuBUCHON: Yes, well, this could be potentially problematic, because although brain surgery is pretty dramatic and one knows that one's head was opened up, there are other types of surgeries where dura mater grafts may have been used that are not brain surgery, including spinal surgery. And if we say brain or spinal surgery, then we'll have a number of people reporting to us that they had lumbar disk surgery, and they will call that spine surgery, when that probably did not involve dura grafts. So it gets complicated.

DR. CAPLAN: Let me make a suggestion here and try and incorporate these two into that second recommendation. We could modify this and say that we want--we urge standardization of donor information, and that the committee feels that it is very important that this information try to reflect risk factors so that these donors can be more effectively isolated. And then let the specific questions be handled. Would that be--I mean, they know where we're going, and they can work on the phrasing. Is that all right? Did you get that, Steve? I know you weren't paying attention. It's on the tape, though.

I don't even know if I can repeat what I just said, but what we're trying for is that we want standardization of donor information and donor deferral, with special attempts, a special effort being made to try and discourage--to identify and discourage people who might be at risk so that they are not put into the supply. They can work out the details in the questions that might do that, whether it's brain surgery or did you ever have a dural transplant or have you ever had growth hormone and so forth. But the question should be, as part of standardization of donor information, aimed at trying to isolate people who might pose risks. And so that's what the committee would like to see done, standardized pushed.

Are we all right with that modification on No. 2?

I heard him. What modifications are you proposing? he said. That we would modify the standardization, recommendation No. 2., to include standardization of donor information and more questions aimed at identifying and isolating people who might be at risk of TSE in the blood supply. That's where we got into this--and Jane is actually scratching away here. But I'm willing to say for discussion purposes we could probably--we've got the spirit of it in terms of what's being sought there, standardization of donor information, questions that would identify persons who pose risk being standardized, so that they could be used to isolate.

DR. SNYDER: I'm just wondering, since for growth hormone small children--that's usually when they receive it, there's a possibility they could not know. But what would be the value of having a registry of some type where any time there is a dura mater transplant, that that person's name is entered into that registry, or if there is growth hormone administered, that's kept on record.

DR. CAPLAN: A donor deferral registry?

DR. SNYDER: Basically, yes.

DR. CAPLAN: There are donor deferral registries now, and when we talk about standardization, that is part of what would happen. You'd enter this information into the donor deferral registry.

DR. PILIAVIN: He's talking about something when the procedure was done, not depending on the donor itself. None of that sort of thing goes on with donor deferral registries.

DR. CAPLAN: But if we ask for standardization, it could, easily. So if you write this correctly and we take it on faith that we get the language here, what we're looking for is an attempt to get those questions standardized, get that information, and then kept in the donor deferral registry, so that anybody who did once have a pediatric growth hormone injection would pop up on the registry as deferred.

DR. SNYDER: I'm front-end on that. I'm back to what Jane said, back to when the original--

DR. CAPLAN: Oh, okay. Zing down here. Kristine?

DR. MOORE: I would like to offer a comment on mentioning registries. That's a very--that's a major issue that gets into confidentiality. We've been dealing with this immunization registries issues, and it requires legislative action. It is a very big, big thing, and I'm not sure we really want to wade into that.

DR. CHAMBERLAND: Yes, I think along those same lines, the development of a registry that would presumably be hospital- or provider-based that would record identifying information about people that received dura mater- or pituitary-derived hormone therapy, and then how that would then be cross-referenced against a donor registry, and there is no national donor registry, you know, et cetera, I think are very complex issues and the confidentiality issue. So I'm not sure that that is something that can be really addressed.

DR. HOOTS: The other thing, I wasn't clear if he was talking retrospective or prospective, but obviously prospective is going to be low yield because it's recombinant growth hormone now and because they're doing brain autopsies before they--I mean, you're looking for CJD before they clear the dura mater, anyway. So it would only work retroactively and retrospectively, and then you get into all the problems of finding data that we talked about with hep C.

DR. CAPLAN: Ron?

DR. GILCHER: I agree with Mary. I think trying to create these donor deferral registries is a real can of worms. I think there is actually an easier way to do this, and I wasn't going to say this, but since we've gotten into it, if we handled it at the blood center level, for example, it would be very easy in our system to specifically, when the donor comes through who has the history of back or cranial surgery, not allow that plasma to go into the pool. The red cell can be used as an individual donor, but we could simply limit that plasma from getting into the pool so that we wouldn't--the cost of taking it out up front is a few dollars, as opposed to a couple million dollars or more if it gets into the pool and taking the pool out.

So, again, I think we could make those kinds of recommendations and working with FDA could do it at the blood center level and totally avoid the whole issue of registries.

DR. CAPLAN: Okay. I know Jane is busily writing here to see--a minute.

If I could, could we get a motion to move on the first recommendation?

VOICE: So moved.

DR. CAPLAN: And discussion--I guess I need a second, technically. Second?

VOICE: Second?

DR. CAPLAN: Discussion?

[No response.]

DR. CAPLAN: Vote. All in favor?

[A show of hands.]

DR. CAPLAN: Ah, we like that one.

How about No. 3?

DR. CHAMBERLAND: I just have a comment about No. 3. Perhaps, Art, you're planning to address this in a subsequent part of the discussion this afternoon, but I think that I heard comments raised in the last couple of days about the identification of gaps, particularly with respect to the development--you know, basic research, development of screening tests, et cetera. But I also think that there are other gaps within the PHS, the issues related to surveillance of these diseases, and I'm sure there are gaps, you now, in terms of with the FDA.

So I'm wondering if No. 3--while I don't deny that there's a real need, I don't know whether it should perhaps be made more comprehensive to broaden maybe the different agencies within the PHS that have varying roles and responsibilities that relate to the issue of TSE.

DR. CAPLAN: Further discussion? We can add one, but I think if we've got that one sitting up there and folks seem comfortable with it--

DR. BUSCH: One word perhaps in terms of tests, it should be which can diagnosis and discriminate among these conditions.

DR. CAPLAN: I have a feeling if we get that, some of the things about surveillance will fall out--into place, I mean.

DR. CHAMBERLAND: As I read the recommendation as it stands now, it's to promote research--it recommends to one agency within the PHS, NIH, promote research on the TSEs. And so that's rather restrictive, and I guess I'm just--yes, I think that there are other agencies within the department that clearly--

DR. CAPLAN: I mean, should we just add FDA to that one?

DR. CHAMBERLAND: Well, maybe within the PHS.

DR. NIGHTINGALE: Would the committee feel that changing National Institutes of Health to Public Health Service would meet Dr. Chamberland's suggestion?

DR. SCHIFF: I think you're talking basic research here. You need a test. They don't have a test, and I'd focus it, and I'd leave it at the NIH. I don't think anybody will do it better. You need some basic scientists on this, and rather than spreading the money all over the place, give them--you know, money doesn't necessarily solve this problem. They tried that with cancer for years. But at least give it a crack, focus it, and say put this money toward developing a test.

DR. CAPLAN: Ed?

DR. GOMPERTS: I'd take that one step further. I think we need to know what the etiologic agent is. It's basic research. And I don't think there's been enough.

DR. CAPLAN: Kristine?

DR. MOORE: I totally agree with the need for basic research, particularly the etiologic agent and testing. But you also have infrastructure support there, and I think that there is a big public health component to this that also affects what we're trying to do here. So I would go back to not limiting this to just NIH. I mean, I think CDC certainly has a role here. I think FDA has a role. And so back to what Steve had said about the Public Health Service, I just really hate to exclude these other agencies from being part of that.

DR. CAPLAN: Let's move this on a mini-vote. Do I hear a lot of sentiment to replace NIH with PHS on this proposed alteration, or do you want to leave it as it is? How many want to leave it as it is?

[A show of hands.]

DR. CAPLAN: How many want to modify it to include PHS?

[A show of hands.]

DR. CAPLAN: Okay. Can I get a vote or a motion to move on the third one?

VOICE: So moved.

VOICE: Second.

DR. CAPLAN: All in favor?

[A show of hands.]

DR. CAPLAN: Okay. Opposed? Abstaining? I've got to do this more democratically.

All right. Now, how about No. 2? Got any language that you're ready to try out?

DR. PILIAVIN: I'm ready to try. It's a little long.

We recommend that FDA develop new screening or processing procedures designed to better exclude individuals who might have iatrogenic risk factors for CJD as follows: one, temporarily deferring donors who report a history of brain or spinal surgery or injection of any hormone product until details can be obtained, or, two, develop an algorithm at the blood center level that use only red blood cell products from such individuals and discard the plasma until details of the treatment are known.

DR. CAPLAN: That's definitely overhead material.

DR. SCHIFF: I'm bothered by "any hormone product." You might have women taking estrogen.

DR. PILIAVIN: Injectable hormone.

DR. SCHIFF: Insulin is a good one. You know, I think it gets too broad.

DR. CAPLAN: Okay. Well, let me ask this: On the second proposal that we have up there, if we were to add something along the lines that Jim proposed, not quite get ourselves to the registry and deferral thing, we may be able to move this and come back to this one via mail and subsequent discussion.

Jim?

DR. AuBUCHON: What I would suggest is rather than Jane's proposal--nicely worded, but I'm afraid it will get us into more trouble than it's going to help us--I suggest that we take the proposal as on the screen, but put a period after the word "donors." We recommend nationwide standardization of procedures for screening donors, period. And then the FDA, with its usual means of getting expert advice on these types of subjects, can come up with a standard set of what they feel is the best way to screen out those donors who may be at risk for CJD, HIV, and all other concerns that we may have.

DR. CAPLAN: Too broad? I'm seeing--

DR. SCHIFF: Yes. I think we're trying to get at TSE. I'd stick with--I think we've got to stay focused here or it won't get done.

DR. CAPLAN: Comments?

DR. PILIAVIN: I'd rather go back to that.

DR. CAPLAN: Anybody want to move that second one, then, in that spirit?

VOICE: So moved.

VOICE: Second.

DR. CAPLAN: I should allow for a little more discussion, but let's try all in favor, see where that gets us. We've got sentiment out there on that one.

[A show of hands.]

DR. CAPLAN: Opposed? Abstaining?

[A show of hands.]

DR. CAPLAN: All right. One abstention I see--two. Two. I'll let that one fly up there. We'll try and wordsmith it a little bit.

DR. HOOTS: Are we voting on Jim's--

DR. CAPLAN: No, no. 2. We dropped Jim's. It's just like it is right up on the board.

DR. HOOTS: Oh, okay. Sorry. I didn't know what we were voting on.

DR. CAPLAN: Jim's amendment was gracefully rejected. Jane's proposal was thrown out the window. It's what's up there.

The focused proposal, your 4. Okay. Hoots changed his vote.

DR. NIGHTINGALE: I heard reference to wordsmithing with respect to the second of the three. Could you define what, if any, wordsmithing is anticipated by the committee?

DR. CAPLAN: You can think of this as what the NFL would have done. As we review the tapes, we'll see to make sure that we got the language that people were calling for. That's what I meant. Nothing that isn't on the record, of course. We wouldn't wordsmith them that way--at least if they catch us. Okay. So, we could actually pull those three things off the wall.

What I would like to do next is move us back, if we could, to a discussion of the supply issues, and I'd like to open up the discussion, even though this will, I suspect, be one we may not resolve, but we shall see. Everything we've done up until now has been with an eye toward handling issues as they may come up as threats to the blood supply of new TSE agents, with a little bit of attention to trying on the standardization side of dealing with CJD. But we have this question before us now, which we can talk about for a little while here.

Given what we know about CJD, as we talked about before lunch, is the committee ready to offer any advice to the agencies, PHS and the agencies, and its member agencies, about what this committee believes should be done with respect to withdrawals as a way to cope with the threat that CJD poses or theoretically poses to the blood supply?

I'm just going to put that question out there, and I'd like to have comment. Dana?

DR. KUHN: I guess after the testimony yesterday, it became overwhelmingly evident to me that the reason that we are here today is because of a past history of HIV. It was described and studied by the IOM, and that is history and that is reality. And we are also here because of the concerted and organized efforts of community groups rationally advocating for blood safety. And as far as CJD goes and changing the charge of this commission, I believe that there is not enough scientific evidence at this time to be able to change that policy--I'm not saying amend the policy--to help the shortage of supply. But when you have persons like Dr. Rohwer saying as far as we know we do not have a problem, and we have Dr. Schonberger saying CJD by blood transmission is small and theoretical, and then when these are not published yet but they are in the works of being published, I don't consider that good scientific evidence.

I believe that we need to really think about this before--and what is more, we are talking about relaxing the CJD policy at the same time the BPAC is recommending readmitting high-risk donors back into the plasma pool. There's something wrong with this picture at this time.

I think, thinking about the big picture and dealing with supply also, you know, we have blood collection sources, fractionaters, and we have the FDA. And it seems that they all have pertinent information, and it is all treated as propriety. And I understand that each one has propriety rights, when in actuality this information is germane to the public health issue and policies, and often this information is only obtained by congressional committees or consent decrees.

It would be an ideal to have this information regarding collection, pooling sizes, process, practices, and to be honestly shared for the ultimate achievement of making good policy for public health safety and ensuring trust issues, which we heard about and were given information about. Until this happens, I don't think we're going to have good enough information to make good policy.

I think also in regard to the policy that we have before us right now, this present FDA CJD policy brings equity to the shared risk, those of the manufacturers and those of the consumers. Consumers have had to shoulder all the risk, and I think it has to be shared risk. I think we have to look at this as a policy which levels the amount of acceptable risk each has to assume, one the loss of revenue--and I don't want to continue to see the loss of revenue. I think each one deserves, each industry person deserves to have revenue. But I don't think we need to have the loss of potential life and health, either. There is a balance that needs to come out here.

Then I think I would rather sit here four years from now and say we could have changed the policy than to sit here four years from now only to say we did the best we could based upon the scientific data, which is incomplete at this time, while thousands of people are dying.

I think that's where we need to start to focus attention here. Unless someone can prove to me that they have good scientific data that has been published and that we can confirm, saying that we can release this product in, and we're willing to accept the responsibility, I think--and especially, as I know, that industry has so many protections now, blood shield laws and product liability laws, there is no shared responsibility here. It's all being taken on one shoulder, and that is the consumer.

DR. BUSCH: I guess I'll be the con here. I feel the policy should be reversed, and I think it's worth quickly reviewing the history of the policy's implementation and then addressing the scientific rationale for the policy and the consequences of it.

In terms of history, the original review of this issue back in, I believe, late 1994 by the BPAC resulted in a virtually unanimous vote not to recall derivatives. The other vote was to actually withdraw cellular components when a donor did acknowledge a risk of CJD, and the rationale was it's not a big loss to the system. That was subsequently reversed by a special advisory committee convened specifically to address this issue, and with broad community representation. And we've lived with the policy for three or four years now.

During that time, I think the science is that the epidemiology does not support a transfusion-associated risk of this phenomenon. There is the laboratory data which does suggest it's potentially possible.

The other I think very important scientific analysis that Dr. Rohwer alluded to and I believe is impressed now is the analysis of the relative risk of a derivative that was made from a pool that had a recall versus one that did not. And the truth is, at least the evidence supports that there's a very long preclinical infectious phase. Given the incidence of CJD and the likely infectious prodromal phase, it's very likely that all derivatives are manufactured from product that could be contaminated if this is an infectious product and that the likelihood that the case that happened to be in the light and come to light and been pulling those products selectively as reducing risk is extremely small, and I think it's a false sense of security to the community that's being put out there that the products they're getting today are safe when, in fact, we know that many of these will likely be recalled with the subsequent disclosures, if the disclosures really work.

That really gets to the third issue, which is the consequences of this policy in terms of the blood collection arena. Not only is there hundreds of millions of dollars of lost revenue, which from the gateway.html sector I know is the marginal revenue that can go into research toward increased safety, as Dr. Davis said yesterday, but the consequences have in essence been because the whole blood sector gets this information back, it is my understanding that 80 percent of the recalls have been from the whole blood collection arena, whereas the whole blood collection arena is only responsible for about 20 percent of the derivative distribution. And, in fact, the source plasma arena has in truth managed to circumvent this policy by its exclusion of older donors, by their limited follow-up of donors over time, and most impressively, they used to buy recovered plasma, and now that recovered plasma is sold to Europe where it's fractionated and used, and the notifications that might evolve related to a U.S. donor are simply ignored in Europe, where they have addressed this decision and decided it's inappropriate to recall these derivatives.

So I think the consequences of this have been actually a gutting of the volunteer donor recovered plasma programs that essentially are going to be phased out unless this policy is changed, because the whole source plasma industry--the whole derivative manufacturing industry has gone to source plasm, commercial paid donors. And I don't think that's in the interest of the nation's blood supply.

DR. MOORE: I think another issue to consider that we haven't really talked about or seen data on from this group is in the processing of these products, what is the likelihood--or how effective are the current procedures in possibly eliminating the CJD agent? And are there data that we could see that might help with knowing whether or not the--you know, what's done with blood products may be actually eliminating these agents, too. That's another issue that we haven't really considered. And are there data from the blood banking folks or people here that could speak to that issue?

DR. PENNER: I think at this stage it's impossible for us to take a rigid stand because we just don't have enough data to be able to do so in saying to eliminate all the product or to allow all the product to go in, because in either event there are risks that we have to take, and we don't have the information to be able to determine.

It seems to me, then, the only option we have is some sort of a flexible program that would allow the products to be evaluated as to their need to be withdrawn or not to be withdrawn, depending on the needs of the groups that require the products.

Therefore--and this was what I intended to come up with on the original proposal was some way of having some more formalized consumer evaluation or involvement in the process for the withdrawal of the products.

Now, we had heard that there is a procedure or process, but we don't really know anything about it, and whether the involvement of the consumer is very formal or is it very informal, as it's carried out now. And perhaps that's the one thing that we could do as a group, is at least to require a formalized type of consumer involvement in the withdrawal decisions, and that might easily be--it may even be present, for all I know, but at least it could be identified and then we could say that as far as we're concerned as a committee, it could come to us to have to review and we could decide whether the consumer is being well represented in the decisions that might be a little bit more arbitrary than we think would be worthwhile.

DR. HOOTS: Well, at the risk of adding more--probably fog than anything else, I think there are times when we're lumpers and times where we're splitters, and I really am hearing so many arcane angles to this one issue of do we relax this for the sake of supply. I think we need to step back for a moment and very, very carefully decide what we're discussing.

Mike raised some very important issues related to private paid donors versus public sector voluntary donors. That's a very important issue in its own right.

We have heard issues related to historical safety concerns, and clearly that's our number one mandate, supply being our number two mandate. I think we have to be very, very careful and very sure that we don't feel extorted in any way about issue number one until we have explored all the opportunities to make sure we've maximized issue number two; that is, that we know enough about the supply issue to guarantee that we have interceded in every way that we can to maximize the supply, to forestall the shortages, before we make categorical decisions that might in some way or even theoretically reduce the safety.

My concern is that we haven't done that. I don't think--I mean, I've spent a lot of time over the last almost two decades trying to understand how the supply works, at least for one component, factor VIII, and I've learned a lot. But I also know that there are arcane nuances that are into the equation at every turn that I don't have a clue to.

I think we need to know at least some of those arcane influences before we decide that categorical decisions about making safety decisions are going to influence it positively enough to justify the risk.

I still think on the safety side as well, even though all the epidemiologic data so far weighs in heavily on the side that classical CJD does not confer a substantial risk to our population, there are enough issues related to ambiguities about that, about the relationship, even though we think we know that BSE caused new variant. But in terms of the TSE categories in terms of what allows things to jump species, et cetera, things that we don't know, that I think we have to be very cautious on the safety side first. But I think in the meantime we do have a responsibility to ascertain everything within our power about how to maximize, first and foremost, safety being considered a priori, how to get the supply maximized for each of the constituent groups that we now represent collectively, and, secondly, that we make sure in the process that we don't throw out babies with the bath water in terms of sacrificing the volunteer blood donor group for the commercial side or vice versa. Because we are in this together all the way, it seems to me, and I don't think we have the luxury of saying we're going to do it to the benefit of this side and to the detriment of this side. We have to balance all the issues, and I don't personally think I have anywhere near enough information to balance those issues at this time. I want to know more before I vote about making dramatic changes in the screening process.

DR. GILCHER: I'd like to support the prior three committee members, but especially what Dr. Busch said. At lunch there is always an educational forum at each table, and specifically what Dr. Busch discussed was the subject of our lunch educational forum. I'd like to be sure that all of our committee members understand that 80 percent of the world's supply of plasma is derived here in the U.S., either as raw product or as finished product, and it goes to Europe.

Theoretically, there should be no shortage of any of these products here in the U.S. There may be a shortage somewhere else in the world as a result of the fact that we would have it. But we generate the plasma in this country, but we don't see the benefits of it. And I think that we should really understand that as a committee better. The total committee should understand the sources of plasma in the world and that 80 percent of that is derived here in the U.S., but we don't have 80 percent of the product available, and then the excess goes somewhere else in the world. And, clearly, we have shortages as a result of the economics of that.

The second point that I'd like to make is that--and I agree with Dr. Busch, and maybe I have a slight modification in that I think the line in the sand needs to be redrawn. For example, I think the issues with withdrawal of finished product because of family history should probably be relooked at. On the other hand, where the donor has CJD and is in the pool, perhaps their erring on the side of safety and withdrawing the pool is a different issue. But I think we should relook at the specific issues and redraw the lines in the sand.

DR. HAAS: It does follow right from--because I was at this educational forum that Ron was talking about. The type of thing that's coming from Keith's comment and others, I think another aspect of that is that if we were all talking about private sector issues, we just let the market drive it, price and quantity be out there, if it was all public sector, we would be making the political decision. But it's a combination of the two. And one aspect of that combination that I don't think I've heard here in these two days is that, given that I'm hearing that an awful lot of our volunteer plasma is shipped out overseas, another way to deal with that is whether there's a regulatory way to lessen that move that could provide us some of the plasma that's not here.

Again, I'm certain there's a lot of complications associated with that, but that's another way of dealing with the type of issue that Keith was talking about as opposed to how we look at the safety issues.

DR. PILIAVIN: I would like to reiterate something I said this morning. I think it's misleading to talk about safety versus availability. There are a variety of aspects of safety. Only one of those aspects of safety has to do with transmissible diseases in the blood. Availability is a safety factor if what you mean by a safety factor is something that affects whether people get a product that makes them healthier or saves their lives. And my judgment at the moment, from what I've heard--and I certainly hope that we hear more about availability and what causes shortages and so on. But what I'm hearing right now is that our major safety problem with the blood supply and the blood product supply at the moment is availability for certain groups of people.

In the conversation I had yesterday--I was not in on that particular forum at lunch--I was talking to someone who says that it's a mystery to him why nobody is concerned about the fact that more people die from A/B/O mismatches and they're dead the next day than die from any of the other things that are currently a problem in the blood supply. And then if we're thinking about safety, one of the things we ought to be thinking about is how to reduce the human error that leads to these A/B/O mismatches, not be thinking about theoretical factors that nobody has yet died of.

DR. SCHIFF: I want a point of information here. The message I got from the presentation of the British experience was that they don't do these things in England. Now, if anybody is more concerned about this problem then they are, I would like to know who they are. So here you have scientists who are acutely aware of this emerging variant, the BSE, and yet in their blood system they are not putting in these measures.

I think they are looking very carefully for any way they can curtail what was like a small epidemic there. So I would take advantage of their experience and endorse what Jane is saying. I don't feel that we are relaxing safety at all here. I think, if anything, we're going to help people, and I'd pull out all these restrictions.

Now, from a psychologic standpoint--and that's what it really is; it's emotional. If you had somebody that had CJD, you hate to take their blood. But I think that's strictly emotion and it's a psychologic effect, not a scientific basis for doing it.

MR. ALLEN: I'm not going to sit here and pretend to be anybody's expert on the material that I'm hearing today or any of the past meetings. I'm curious as to the percentage of these products that are being withdrawn because of CJD versus other reasons, other contaminants, or whatever. I can't believe that we're--what Dr. Busch said to me, one thing he said kind of summed it all up. He said there's a scientific possibility. Science is all we have to go by here.

None of us here can claim to have enough information to know what is going on with this particular agent. Until we do, whether you consider some of our opinions emotion or not, that's the facts. We do not have enough scientific information.

It was also mentioned about a false sense of security. We've heard that before. There was also a mention of what's done with blood products may be eliminating this agent. "May be" are the key two words in that statement. We just do not know.

One of the things that made me want to be on this committee was to help re-establish the American public's trust in this government, and that's why I'm still here instead of walking out of this door. So what we need to realize here is that this goes beyond the group of people sitting at this table and our own personal opinions about this. There's a matter of trust here. I would rather look at someone and discuss why they lost a certain amount of money versus looking at someone and why they lost their brother, sister, mother, or whoever.

We need to learn from the mistakes that were made in the past and make sure, irregardless of the consequences financially, commercially, we don't repeat them. There's got to be some options where we can increase the production of these products, be it through smaller pooling sizes, which has been discussed by the FDA. One of the mentions by some of the members of the FDA has been their approach has been to take the most conservative route. I don't believe they need our approval in order to withdraw these products or release these products. I don't believe they really do.

So there's more reasoning here than we realize. So I think we just need to all step back for a minute before we start talking about releasing these products until we, one, know more about these agents scientifically, and, two, know more about what we can do to increase the production of these products while we're working on finding out about this agent.

T3B DR. CAPLAN: One of the issues that has come up a couple of times now is steps to increase the supply. There's also a question on the table, which I'd be interested if someone wants to address it, about the impact of CJD on overall blood product supply. I took it as--I have a number in my head that 10 percent of albumin was going back because of withdrawals over the past year. Did I make that up or did I hear that yesterday? If I can get corrected on this. Yes, CJD-related.

DR. PILIAVIN: Ten percent.

DR. CAPLAN: Yes, that's what I think I heard in the testimony there somewhere yesterday. And pushing on the supply side--I guess for this committee, this may be the one place in the world where this could happen--of course doesn't address the issue of cost, what it costs to pull it, what it costs to get it out of there, and what that does in terms of budget; or to put it another way, even if we expanded the supply side and pushed for that to happen by some means, there is this question out there still that some will want to know about, about what it costs to track and recall--I heard a number, too, of about $100 million being spent by blood collection agencies to do the withdrawal process, so it's not a trivial expense even if the supply side goes up.

Jim, did you have something to say on the point? No? Mike?

DR. BUSCH: I think on the supply side, you know, one should ask why is 80 percent of the plasma derivative in the world derived from U.S. source material, and the truth is because the U.S. is essentially the only country that still has a substantial commercial paid plasma donor program. The rest of the world, the European Union, have moved exclusively to non-remunerated donors. In the U.S., there is a large and I think safe plasma derivative industry now because of the knowledge we've gained, the inactivation procedures that have been implemented. And I don't doubt for a moment that that could be expanded dramatically. As indicated today, all derivatives that are manufactured and being distributed in the United States are now exclusively going to be derived from commercial paid donors. And that's the side that can be expanded. And if that's a decision that this committee would endorse and we should push in that direction, I think that should be explicitly recognized.

One other point I wanted to make is that this history of CJD, family history, it was mentioned yesterday that only 10 percent of CJD is familial. So 90 percent of the problem in terms of family member history of CJD is totally irrelevant. Ninety percent of CJD is spontaneous and is not even being detected by this history of CJD question.

DR. CAPLAN: Jim?

DR. AuBUCHON: I have difficulties with both sides of this question, and I'm getting a little bit sore sitting on the fence. But could I suggest to the committee another way to look at the current donor screening techniques and the current decisions about what we do with plasma when we find a risk factor in a donor--and I don't have the answer even how I would answer this question, but if today, with what we know today, imperfect as it is, if we had no donor screening, if we had no quarantine and withdrawal process, would we recommend that those be implemented? In other words, we are starting from scratch. Would we put in what we have today? Or would we put in something else?

DR. CAPLAN: Ron?

DR. GILCHER: I can't answer your question, Jim, but in responding to what Mike said about the plasma supply, I have a great concern--and I have to say this, Dr. Busch--that is, I do not want to see the paid source of plasma in this country increased because, very clearly, I'm sure in your system as in our system, and in others, they are trying to acquire that plasma by going to the volunteer sector and making donations to the church or to the fraternity. And I would see that impacting the other aspects of our blood supply.

I really believe that in this country the volunteer sector could significantly increase the source plasma from volunteer donors. So I think this is a very important issue. I want to get that on the table.

DR. HOOTS: Just to kind of add to what Jim said in terms of how to think about these issues, one of the ways, I guess harkening back to the days of pre-HIV when we knew there was something there but we didn't know what, you kind of learned to ask yourself, well, when we can screen for this disease, what decisions would we make? And then how can we anticipate any--or can we anticipate anything in the meantime that gets us there?

I think in this case as well we need to say when we are able to screen, first of all, for a TSE, and then secondarily for a TSE that we know is implicated in causing human disease, you know, how will that relate to what we're doing now? And will we look back and say, all right, we had the proper strategy to go from what we didn't know to know what we do know.

I mean, obviously, that is kind of what we've been all the way around the table here. We don't know exactly how to do that.

I think if we frame our thoughts in those terms, it sometimes--at least it helps me in saying, okay, how much caution do we err towards? And kind of a corollary to that is that any decision you make at this time, is it influenced by whether that definitive diagnosis could be done 12 months from now versus 12 years from now?

I think those are the kinds of things that make this a very complex issue, and while we're having so many people around the table who are maybe either sitting on the fence, switching from one side of the fence to the other, or else saying I just prefer to deal with this particular issue but not that particular issue.

DR. CAPLAN: Let me ask for clarification on a couple of things just in this discussion. One is, Does it make a difference, as we think about this, the kind of disease we're talking about, the fact that it is usually a late onset disease unlike AIDS? It could strike people down younger. I understand that. But overwhelmingly it's a problem that most people outlive. Does that make a difference to the decision about using withdrawal as the way to deal with the risk?

The second question I have is, What if we do get a test? What if this NIH mandate that we give them and throwing money at it gives us a diagnostic discriminating test and it turns out that this particular CJD virus is really out there incubating and we couldn't ever get pool sizes down to the level that we would eliminate it? What would we do, to get into the hypothetical mode? Would we--do what?

I mean, we would screen, but what if we couldn't sort of get it down to small enough sizes that anybody would find it economical to make life-saving blood products? I have a feeling that it may be out there, and that our hope to find the test may--again, don't wish for what you don't really want, because when you get it, you may find out that there's more of it out there and you're not quite sure how to deal with it.

The third question I have is, to go back to something that John put on the table and that's been kicking around a little bit: If in the short run the issue is right now, today, there's no IVIG, there isn't enough supply for people with alpha-1 antitrypsin, and we know there are harms befalling us, are we ready to say that we have--is it possible really to use a more flexible response in terms of withdrawal policy? Does that get us anywhere in the short run, while we talk about building the supply? I mean, we're sitting here and the FDA and some of our friends on the government side have said you can't ask us to write a report in six months. Well, I'll make the statement, you won't get an increase in the plasma supply for a year, no matter what we do today. I'll just tell you that.

So for the coming year, if people still can't get IVIG, then what? And it seems to me when I listen to the testimony, I'm trying to weigh the demands of people in the here and now to say we can't treat, we have problems getting things we need. I would like to hear some discussion about a policy option. Is there some way to be more flexible in the shorter run, while we can certainly revising expanding the paid donor pool, trying to hound the companies into telling us what the heck they're doing, putting America First labels on all plasma products, little flags?

I mean, I can imagine a bunch of things we could do. I will tell you, if I'm sure of anything, we're not going to do them so that they will budge the plasma supply for some period of time. I mean, we can call for them, but it will take a while to have them. Whereas, we might be able to have a response that is flexible--or are we just blowing smoke on this? Are we about as flexible as we can be now and that's not going to really do anything?

So on those issues, I'd like to have some more comment or discussion. Ed?

DR. GOMPERTS: You've raised a number of points, and the previous comments have also raised a number of issues, so if you can bear with me.

I think first of all, from the point of view of the subclinical incubation issue, I don't think that is an issue here. We could probably, from our point of view, dispense with that.

The second thing, from the point of view of the test, you know, we can find a screening test and screen as much as we want. That won't be the answer. The answer is, once we've identified the etiologic agent, to exclude it from the products, whether it's whole blood or whatever. And that is the target with HIV, which has been very successful. Testing, sure, but also inactivation. And that I think is a two-step objective, really--or three steps: identify the agent, screen it, and get rid of it.

Now, the other thing is, from the point of view of a step-wise approach to these different products, I think the albumin one is a fairly straightforward one, because we've seen through Dr. Rohwer's presentations, although it's--I agree with the previous speaker that it's not yet in the public domain from the point of view of peer review. However, we can see that on spiking experiments, the agent, whatever it is, is being excluded from the albumin crude fraction. And in that situation, if we are able to confirm that observation by a separate set of experiments, I think most of us, if not all of us, will be pretty comfortable from the point of view of albumin and not withdrawing albumin under the current concerns with CJD donors, et cetera.

Similarly--

DR. CAPLAN: By the way, let me just jump on that one and note to the committee, we could say, at least in this regard, that the committee urges the rapid completion of those experiments and that we do so with the hope that policy about albumin might be modified. That's a flexible policy.

DR. GOMPERTS: I'd take it one step further. There are several validation experiments that are being carried out by a number of different manufacturers looking at their processes from the point of view of spiking experiments, looking at not only the crude fractionation procedures that were done in the spiking experiment, but taking it further through monoclonal affinity, ion exchange chromatography, et cetera, with different products, to determine the exclusion capability of these various steps. And once these are done, and right now there isn't enough laboratory space and there's not enough hamsters to do all the validation experiments, they will be done.

So that may well--

DR. CAPLAN: If we need hamsters, they're at my house.

[Laughter.]

DR. GOMPERTS: But they will be done, and I'm sure when the data is in we'll certainly hear about it.

I'd also want to provide some information. We've heard about plasma donors and volunteer donors and paid donors. First of all, there are volunteer donors who volunteer because they're getting something out of it, whether they're getting a glass of orange juice or having their cholesterol test taken or a T-shirt or because of peer pressure, the Bloodmobile is at work.

Similarly, in other countries, individuals are labeled as volunteer donors, but they actually are getting a day off from work, whatever. So the discrimination of volunteer versus paid is a gray area.

However, for every one liter of plasma, there is approximately one paid donor, anywhere between 700 and 900 milliliters of plasma. Whereas, in a volunteer donor, you're going to have three to four donors contributing to that. So when one talks about pool size, are you talking about pool size from the point of view of volume, or are we talking about pool size from the point of view of donors? And that is not a trivial issue.

Another major difference between volunteer donors and paid donors is that paid donors can donate their plasma twice a week, three times a week, and do so. Whereas, the blood donor, the volunteer donor is a lot less frequent. And one of the issues certainly from the point of view of plasma safety that has been introduced by industry is that a first-time paid donor unit of plasma is not used until the donor comes back. And if that individual doesn't come back, it's thrown out. Because the data indicates that there is a higher prevalence of blood-borne viruses within those first-time donors, which does impact, if we extrapolate that appropriately, to the volunteer sector. That is an issue, especially with a CJD questionnaire. Because if an individual comes in to donate and he's asked these questions, and many of these things happened 10, 20, 30, 40 years before, and he goes off and he comes back nine months later, then tweaks and says this is what happened to me, then we have to chase that unit of plasma that was done eight or nine months before; we have a withdrawal. So the issue of donor, volunteer or paid donor, et cetera, is complicated.

Finally, if one were to suddenly increase the numbers of paid donors so there's lots and lots of plasma, it still has to be fractionated, and the fractionation facilities that we have today have a finite capacity, which is constrained. And by cutting back the actual pool size, you're going to worsen the situation, not alleviate it, because the filter presses and the centrifuges and the processes will turn out to be major bottlenecks, as they are.

DR. CAPLAN: Just on that, do you think the industry operates close to capacity now?

DR. GOMPERTS: Absolutely.

MR. WALSH: Just to get Jim off the fence before he gets injured, maybe it would be worthwhile to consider the fact that we need the presentation of what is the present procedure process for managing blood and blood product withdrawals. Information like that is available. Mark could provide it, and we need to have it. That sort of information up front, and then to take a look at that and see if the procedure is formal enough, does provide the consumer involvement and can respond effectively to some of the needs of this community. And at that point, we might wish to address some of the exclusion items. But at this point, I think we're kind of talking around the circle.

DR. HAAS: I think somewhat along that same line, I'm a little disturbed, if I'm hearing this correctly, that we're hearing about withdrawals, I think $120 million, the number that has been thrown out, and we're taking that, I believe, as a trend line, that that somehow is continuing on infinitum into the future. I'm not so sure that's a very good basis for a trend line. Will the withdrawals continue at the same rate given that we have a certain particular practice that's been in place for a couple of years? Or will those withdrawals drop off significantly?

I honestly don't know that answer, but if they drop off, some of the supply question gets addressed. But I guess I want us to be thinking about being careful about projecting $120 million continuing on for a long period of time.

DR. MOORE: One issue--I think there are a couple of issues that we've talked about today that may impact positively on supply, and one of them is trying to do an improved donor screening, which may alleviate some of the withdrawals.

Another issue that was brought up in Mark's presentation yesterday was the issue of exempting dura mater recipient donors if the dura was not pooled and if the dura donor brain was autopsied and found to be CJD-free.

Mark, do you have any sense of what that might do--say we approve of that and the policy gets changed. In terms of supply, in the handout that you gave us, it looks like there were 123 plasma units--wait, maybe--the second graph doesn't really show it, but just to get--do you have any sense of how many lots might be spared from withdrawal if the--

DR. WEINSTEIN: Fall into that category?

DR. MOORE: Fall into that category.

DR. WEINSTEIN: Part of the problem here, as I understand it from the TSE committee and the representatives of the dura mater industry, they're describing how frequently autopsies are done. I believe the number was very low, so that at least as they have been done before this issue was raised, something on the order of maybe 5 percent was the number that I seem to recall of autopsies that were done on these patients.

This policy or this procedure may have changed within the dura mater production industry here, but I believe that that would be a relatively small effect.

DR. MOORE: What about the pooling, dura that has not been pooled? What would that impact on if you relaxed restrictions?

DR. WEINSTEIN: If that was the only criteria, plus say the notification aspect of it, that would be--for the U.S., we have had only non-pooled dura since, I believe, '87, I believe.

DR. MOORE: And the way the policy is right now is that if it--pooled or non-pooled, those products are withdrawn if you find that history subsequently. Is that correct?

DR. WEINSTEIN: Well, as I mentioned in the presentation, we had a situation in which we used this criteria, that is, use non-pooled criteria. We used the situation of autopsy and donor notification to allow the release of some material. So that was an action that we took. It is not a formalized policy at the moment.

DR. MOORE: Because one thing as a group we might do is try to see if that policy could be changed to exempt dura that was not pooled, given the fact that there's never been a case of CJD in a donor--in recipients of non-pooled dura; correct?

DR. WEINSTEIN: Well, again, I think we should reflect on the TSE committee recommendations and how--this was criteria that was brought to our attention by the TSE committee.

DR. SCHONBERGER: Just as a matter of information, there's something like 66--that ballpark--of dura mater-associated CJD cases, and of that group, I think there are two or so that are not part of the pooled dura association. There may be another one that's under investigation now that may simply be a chance association that we're actually in the middle of an investigation. The bulk of the problem with dura mater has been one particular brand called Lyadura, and that product was made by a company in Germany, and they distributed the product internationally. But it was never really approved to be distributed in the United States. So our problem with that particular brand should be minimal. Therefore, in the United States, this problem of the dura mater-associated CJD should be minimal.

DR. CAPLAN: Jay?

DR. EPSTEIN: Thank you, Art. If I could just add a few clarifications. No U.S.-approved product has ever had a pool processing for dura. The TSE Advisory Committee in July 1996 recommended that we could relax the exclusionary policy in the case of donors who received a dura product that was not pooled in processing. However, the FDA, faced with a situation of 19 reported donors with a history of dura mater which would have affected at a certain point 100 percent of the inventory of one of the major suppliers, made the decision to exempt the policy, provided that it was, A, non-pool processed, but concurrently evidence of negative autopsy. Not either-or. Both-and. And we were able to exempt on that basis about one-quarter of the affected lots. What Mark says is correct, that for the industry practice as a whole, there hasn't been more than 5 or 10 percent use of autopsy routinely. However, in the incident that we investigated, about a quarter were able to be exonerated.

The other point that was made a little bit earlier--I think it was by Dr. Haas--is that these reports should decrease over time, because you have donors with this past history who are gradually being purged out of the donor pool, and as we learn later and later, the likelihood that there is an in-date product from that donor does decrease. So some of the problem will decrease. The part of it that will not decrease is the sporadic CJD, because one doesn't know when it's going to happen. But certainly for histories of prior receipt of dura mater or prior receipt of human growth hormone, at least in theory, all persons could figure it out today and tell us if they ever donated, and we'd be done with all the retrospective cases. There could still be some prospective for people who don't realize it until they're actually asked as a donor. And that phenomenon is quite real.

DR. AuBUCHON: Could I suggest that the FDA possibly consider requiring autopsies on all dura donors? After all, the prosector has to be right there, anyway, in order to get the dura, and requiring histologic examination of the brain would seemingly not be a difficulty for the families.

DR. EPSTEIN: If I may, the FDA is developing additional regulations for communicable disease controls related to transplantable human tissues, as well as cell-derived products, and we do have under consideration to promulgate a requirement for negative brain autopsy to qualify dura donation. And that's consistent with the more recent recommendation of the TSE Advisory Committee from its October '97 meeting. So that's exactly what it's in the works.

DR. CAPLAN: Nonetheless, it still might be useful if we endorsed that idea.

DR. EPSTEIN: Sure. But it is prospective. In other words, it's not going to change--

DR. CAPLAN: Right. I understand.

DR. EPSTEIN: --the fact that there may have been past donors.

DR. CAPLAN: I understand. But this is a parade that has a little rain.

Keith?

DR. HOOTS: Well, as Dr. Gomperts just told me, the other advantage to this is that it creates an economic incentive for autopsies. So it gets to our other issue as well.

DR. CAPLAN: That's true. That's true.

Let me suggest a split to some extent in how we might think about this issue of CJD. One set of questions, it seems to me, that agencies might be benefited by is if we said something about in the short run we would like to see such and such happen. Another set of issues is in the long run we would like to see such and such happen.

It seems to me we have heard some discussion about the need to make sure that the supply is where it should be. A lot of factors impinge upon that. The committee keeps asking for more information about why we have shortage. I guess we can certainly request that every step be taken, including whatever it takes to let people see proprietary information or be sworn in or have their memories erased, or whatever it is, that we have some understanding of shortage, that we certainly want to come back and address issues of ways to increase the supply, maybe looking at the paid-unpaid and so forth.

But in the short run, I keep thinking about the people who came and talked to us yesterday. Do we want to try and say something about CJD and withdrawal for the next, let's say, year? Do we want to say something about urging the FDA to take a flexible or tolerant attitude as a sort of general orientation, that they should lean in the direction of supply more than they have? That's one way to do it and let them figure it out at the TSE level.

We could say withdrawal should cease for the year, and then we'll come back. That's another opportunity.

We could say put some more consumer groups on and formalize that, and then let them work it out case by case as it breaks.

There are three proposals I'm putting before you. One--well, one is a split. Let's look at supply and come back and do what we can to encourage and increase the supply. But in the short run, with CJD there in the hear and now and shortage in the here and now for some groups that came and asked us and sat there in front of you, a response to them is to say, no, we're satisfied with how these things go; no, we think we should be more willing to err on the side of supply than safety, and that's the general message we want for the next year, or limit it time-wise however you want. We want to see a process formalized with consumers more formally involved--not informally consulted but formalized at the TSE level to make the call. That's another way to do it.

Another is to just say in the next year stop the withdrawals, let the supply move, and we'll come back and look at it, but it's time limited.

Any sentiment, any enthusiasm or comment on taking any of those strategies? Keeping in mind this background problem of trust and what people have to say generally about making sure that what will happen after that year happens. I understand that issue, too. But we could split the thing and kind of do it that way if there's enthusiasm for that.

MR. ALLEN: I personally would really like to know at some point soon what percentage of these withdrawals is because of CJD, period. That's important.

DR. CAPLAN: Does anybody want to try and take a whack at that right now? Jay?

DR. EPSTEIN: Since '95, it's about 50 percent of all the derivative withdrawals.

DR. CAPLAN: Fifty percent.

DR. EPSTEIN: Right.

DR. CAPLAN: By the way, what would be other major reasons?

DR. EPSTEIN: Well probably the second leading reason has been concerns over actual or potential bacterial contamination.

DR. CAPLAN: Okay.

MR. WALSH: How many of that 50 percent CJD withdrawal were the result of a person actually identified as having been deceased, diagnosed with CJD, as opposed to family history?

DR. EPSTEIN: Yes, Mark brought those data, and they're in the handout that you received. I don't know the figure off the top of my head, but you have it in front of you?

DR. CAPLAN: Do you remember, Mark?

DR. WEINSTEIN: I think it was something on the order of 30 percent. That was the handout yesterday.

DR. CAPLAN: Thirty percent were identified as having--

DR. WEINSTEIN: Yes.

MR. WALSH: It's 30 percent of 50 percent or a total of 30 percent?

DR. WEINSTEIN: Of the total CJD for '97, I believe, something on the order of 30 percent. We can look at that slide, if we want. We may have more handouts here.

DR. CAPLAN: Yes, Keith?

DR. HOOTS: From what you just said, if you add that to the ones that were withdrawn for dura and the ones that were withdrawn for growth hormone, which I don't think anyone on the committee has spoken in favor of letting those through, then we're essentially up to 100 percent. So what are we--I mean, other than that small percentage of family donors, we're not going to impact supply significantly regardless of what we say, unless we go way to the part that nobody has even talked about in terms of freeing up the supply from CJD risk.

DR. SCHIFF: One of your options was--I would like to take the bull by the horns here and beg the issue; that is, to relax the restrictions on CJD as they are right now, relax them for one year, reassess. Obviously it's controversial, but I'd like to beg the issue. I would support that.

DR. KUHN: And so I'm going to do a little more compromising, and I would say I'd be more willing to do a flexible program which would follow along the lines of Dr. Penner, saying let's have a little more consumer involvement with the withdrawal of the product, working closely with FDA. I think there was a time in which the hemophilia population was asked one time, was asked by FDA about some product that was very badly needed, and we were faced with a decision to make whether or not we would like to have this released into the population and it was badly needed. And I think that came down to be some of our own decisions on whether or not we should have it in the community.

You know, we then assumed responsibility in many ways, and I think if it does go in, maybe perhaps it needs to be labeled specifically so, again, people have an option if they get this bottle or this bag of whatever they can choose whether or not they want to take it by the label that's on it.

DR. AuBUCHON: With all due respect to the concern that chronic users of derivatives have for the safety of the blood supply, my primary concern is the future safety of the blood supply because at the moment I really don't see that it's being threatened by classical CJD as it clearly is already present in the population and probably in our derivative supply.

My concern is for, if any theory, the theory of amplification through future passages of the agent through more human hosts. Therefore, the idea of temporarily relaxing the requirements on donors or manufacturers regarding CJD for a defined brief period of time makes sense to me, because it addresses the critical problem--potentially addresses some of the critical problem that we are facing right now in terms of supply, but yet it gives us plenty of time to interdict the multiple passages through more people that would ultimately result in the real disaster, if one could occur through this disease.

DR. CAPLAN: Motions? Comments?

MR. ALLEN: Is there a potential that the manufacturers will say they won't release these products for fear of liability? I heard that yesterday.

DR. CAPLAN: I can't imagine in these United States that would not be a consideration. Yes, I think that probably is an issue. It may not be one that we can fix, but that certainly could restrict what they're willing to do even if we advise and advocate for more liberal policy.

MR. ALLEN: Then once again, our recommendations per se don't mean anything to the FDA in terms of what they actually do or do not--

DR. CAPLAN: They're advisory.

MR. ALLEN: Is that correct?

DR. CAPLAN: They're advisory.

MR. ALLEN: So they do not need our recommendation in order to release these products?

DR. CAPLAN: Yes. I think that's a fair statement, too.

MR. ALLEN: So then the next statement to me would be: Why haven't they done this, knowing about this shortage, on their own?

DR. CAPLAN: I think they've tried to form a policy that is oriented towards safety. I think that wheN BPAC advises them, safety dominates the discussions. So that when we get formed and get asked the question about availability and safety and put cost and supply into the mix, they may be looking toward us for a broader perspective. That's probably the way that sorts ut.

DR. JONES: Could someone clarify again just how much time--what we're really going to buy with a year in terms of what you would be able to determine? I mean, it would seem to me that we're talking longitudinal issues. So what will a year tell us? And then who is going to be keeping the data and the information during that year?

DR. AuBUCHON: I don't think Dr. Schiff's proposal or my support of it had to do with any data gathering during that year period other than the ongoing research that is already going on right now. Certainly we would not expect to see any additional information from recipients of transfusion products or derivatives within the next year that's going to help us, and none of us would, I think, propose that year moratorium with the idea that we could maybe infect some people and then find them and then resolve the question. That's obviously not the intent.

The year moratorium might provide us some leeway in terms of increasing the supply and getting us over a difficult period right now and at the same time allow us some additional--accumulation of some additional information from researchers to help us understand more about this disease and how it might or might not be transmitted or amplified in the future.

As I said, I'm not concerned about the safety today as much as I am the potential for more transmission in the future. That future might be 50 years from now.

DR. CAPLAN: Why don't we do, in the interest of time, the bold, extraordinary idea of entertaining a motion, if someone wants to make it, on the one-year meeting, then we can discuss it around the motion?

VOICE: So moved.

VOICE: Second.

DR. CAPLAN: The motion is that there be a one-year moratorium on withdrawals in order to increase the supply, not for research purposes, the shortage, to address the shortage.

MR. ALLEN: This moratorium, would these products be released labeled, first of all?

VOICE: Not at this time.

MR. ALLEN: So the consumer would have no idea of the potential of these products.

DR. CAPLAN: That's the way the motion is now. Just out there.

MR. ALLEN: Couldn't we correct this?

DR. CAPLAN: Yes. You can amend the motion. I'm just giving you the motion the way it was made. It was to put a moratorium on withdrawals one year to meet the shortage, and when you do that, you aren't saying label or disclose or consent, you're just saying to go that way. Did I get that straight? Yes.

Discussion?

MR. WALSH: I disagree. I think to throw out or disregard everything that's gone on up until this time in trying to provide at least some option of protection, even though we're unsure of what we're protecting, is going to get us into a good deal of difficulty. We already have the problem, as Allen has discussed before, of having lost faith--or lost face with the public with respect to what we're doing to protect them from the blood program here. We're going to just arbitrarily eliminate any controls at all and just say, well, let's go at it for a year and see what happens, which doesn't sound to me like it's a very honest approach to it.

DR. CAPLAN: Okay. We'll go to Eugene, then Larry.

DR. SCHIFF: Well, I'd disagree with that. We're not, you know, flippantly saying let's retreat here. I think we've really looked at this as best we can. We've benefited from the experience in England. And I think we're doing an injustice to people by continuing it. I don't think--I think--to save face, I think that's why we're here. You're trying to get a spectrum of disciplines here to carefully examine the situation right now, and in many cases you have to say, listen, we made a mistake, let's get rid of that. You know, what is it they always say? Fifty percent of what we say today is going to be wrong in ten years. If we only knew which 50 percent.

So I think that to retract this doesn't mean we don't care. I think it means we do care, and we think that what we have in place now is destructive. At least, that's what I feel.

MR. ALLEN: If we're going to do this, being the Blood Safety Committee, we should retract this based on labeling these products so that the consumer is aware of the risk. That's the only way we should be discussing this.

DR. SNYDER: From a liability point of view--I'm not an attorney, but there's a thing called informed consent, and there's a thing also called informed refusal, which is more prevalent now. So if you don't have that, they're not even going to want to play in this ballpark, in my opinion.

DR. MOORE: I was just going to say that going with the product, I suggest that we label all products. Because really this agent is probably in all of the products. If they are at very low levels, it has likely inactivated by procedures in processing the material and I really think that we are not--again, a point that's been made a couple of times. I seriously doubt if this policy is having an impact to improve blood safety.

DR. CAPLAN: Paul?

DR. HAAS: Almost a question but a comment. I understand that there is one company out there right now that has some withdrawn product and has said that we will make it available to the public knowing that we have withdrawn it. I guess there are all types of signing going on.

I would be curious as to whether anyone has used that product. If they haven't used the product, why haven't they used it? Does that mean that there really isn't this shortage out there?

I mean there are some interesting questions that that company's experiment could provide us and that might help in some of these questions that are going on.

MR. ALLEN: And also, can't we consider releasing products that are actually, that we are actually short on instead of just releasing everything?

DR. CAPLAN: There's actually two friendly amendments I guess they are. One is to think about labeling, although that may not be our purview relative to what the law requires about all this, but we could certainly say that we think that people should know.

And we could also say--and this was the weaker version of the release thing--that we favor this but we want it done on the basis of what has got demonstrable need as opposed to just for any reason, we're just going on a moratorium. So, that we could weaken the Schiff resolution that way.

DR. EPSTEIN: I think it's important that the Committee know the current policy of the FDA which dates all the way back to the withdrawal policy put in place in August of 1995, which is that we have been willing to permit distribution or continuation on the market, as the case might be, of products involved with CJD risks provided that the lots contained associated information or a notice or a label.

And it has mainly been resistance on the part of the industry to operate in that mode that has prevented the continued use of these products with appropriate notice. We have also brought several times, at least three times that I can recall, the question of a generic label on all plasma derivatives that would say that there is theoretical risk of CJD.

And that, too, has been resisted by the industry on the basis that it's not a proven risk and that if they were to put it on their label they would create liability in relation to cases of spontaneous or atherogenic in CJD in product recipients and that that's a long-term risk. I mean people may incubate or have had the exposure history 30 years ago and the company would be liable.

So, what we're talking about are, in fact, the issues that have been the stick point. FDA doesn't need, in fact, to be advised to permit distribution with appropriate warning labels because that's, in fact, their policy.

And in the specific case that Dr. Weinstein explained about the Factor VIII products that have been exposed to "implicated transferon" we did allow it. The notification there was not lot-specific. However, there was extensive dialogue with the hemophilia community. They were fully aware of the decision based on risk analysis.

In the case of the immune-globin intravenous, again, the use community was fully aware--

DR. CAPLAN: Jay, I do want to ask you a question. In the short-run when we heard yesterday there were a shortage of IVIG and other products, even if the FDA policy has been to release with notification in certain instances, is it your view or the FDA view that the shortage that seems to be present now would be alleviated by our saying that we would like to see more tolerance or more attention to this need?

In other words, we all understand that releases have been done but people were in here yesterday saying they were facing shortage and there are health harms taking place now. Is the policy not liberal enough, is the question?

DR. EPSTEIN: There would be some mitigation of the shortage. I think that absent other changes the shortage will not go away. But certainly the CJD related withdrawals have an impact. It's not so much the withdrawals as the quarantine. It's the products that are in process when the discovery is made and the large lots that are not released.

The lots that have already been released I think you've heard, we estimate that no more than, perhaps at most, 5 percent of the product ever gets retrieved because these products are in short supply and they are very rapidly consumed once distributed.

So, it's' actually not as much the withdrawals, it's the fact that the withdrawal policy results in the quarantine of products that is never distributed. And, so, that impact would be felt ultimately in supply. But I can't tell you today to what extent that would relieve the shortage. I wish I knew. I think it would be beneficial but I don't know that it would solve the shortage problem.

DR. AuBUCHON: Question, Jay.

I understand you can only speculate on this, but if the FDA were to allow the release of implicated lots without a warning label, do you feel that the manufacturers would be more likely to then take your authorization for release and go ahead and actually release those lots?

DR. EPSTEIN: Yes, I do. I think that the issue of labeling or user warning has been fundamental in the debate. I do believe that there would be distribution of implicated products because we have many times been asked whether they could distribute.

I think there is another sort of legal technicality when we say, would FDA authorize release? Because in many cases there's no release approval action required of the FDA, for example, if the product has already been released.

And since, as Dr. Weinstein explained, we currently view these as withdrawals, not recalls, because we can't prove a health hazard. There's a legal question about whether we would actually be able to interdict it.

But, nonetheless, the current situation has been that the manufacturers seek the FDA concurrence before re-releasing withdrawn material or releasing quarantined material and there is reluctance to take that step if FDA says we can only accept that with a specific label.

DR. CAPLAN: Let me break Robert's Rules of Order because there is a motion and a proposal up. But if Dr. Schiff would allow it, I was going to see if we could hold off on moving ahead with a vote about that proposal about withdrawals being suspended and put forward a slightly different one to see if that might get us somewhere before we have to go out of here. That is that the committee recommends or advises that quarantine and withdrawals for the next year as they affect supply should be relaxed in order to permit an increase in supply and let the FDA work with industry to take such steps as necessary to make that supply possible.

It may be a judgment, it could be company by company for all I know about what's on that label and what's not on that label. We can certainly add something about the importance of consumer information to it. But what I'm starting to think maybe we could get a consensus on is that in the short-run, right now, to the extent to which quarantined and withdrawal are impeding supply to people in the here and now who need it, the FDA might be instructed by us to try and solve that problem by relaxing their stance on those issues.

Is that something we could get a consensus on? Maybe I will make a motion in my own little proposal there.

MR. ALLEN: With consumer notification?

DR. SNYDER: Unless I'm misinterpreting my FDA colleague, the issue is the companies and liability. So, unless there was some type of congressional action which formed something similar to the vaccine injury compensation program they may not be willing to assume that liability? Is that what you're saying?

DR. CAPLAN: If we wait for congressional action to form that compensation program, we will be solving the shortage into the next millennium.

So, as a short-run option, the question is, we can still say with consumer notification and let the companies and the FDA bang it out. I'm not sure that it is a completely useless recommendation to say we want to see quarantine and withdrawal edge toward supply in the short-run, even with notification in some form that this is going on. The FDA has told us that they try to notify in a lot of areas anyway so that is their current policy.

I think what may be involved here is lot restrictions and so forth in the short run. Any sentiment for--in other words, that we try to do whatever the policy is that they are handling for disclosure that maintains and that we try to relax to increase supply to meet immediate demand with respect to quarantine and withdrawals.

That's my motion. Any second?

MR. WALSH: This is in concert with the users?

DR. CAPLAN: The standardization of users involved?

MR. WALSH: Yes. I know initially you had mentioned that.

DR. CAPLAN: Let me keep it separate for now though we can come right back to that if we can get some agreement on this.

DR. JONES: Would you repeat what you said?

DR. CAPLAN: That for one year, starting from whenever, soon, one year for now, for the next year that FDA be advised by us to relax quarantine and withdrawal policy in order to meet short-term gaps in supply; that they follow standard policy that they have now about consumer notification but that they understand the committee's concern that this supply issue be addressed.

MR. ALLEN: I still don't understand why the FDA has not done this on their own? Why do we need to be a part of this if they don't meet our recommendations in the first place?

DR. CAPLAN: They can but I think they want it. Maybe they're eager to have your support in a public way. I mean in the sense they've come and asked us. It's not that they won't but they have asked you.

MR. WALSH: I thought I heard Jay say earlier that that's their current policy and that their current policy isn't working now because the manufacturers don't accept it because of the liability issue.

DR. CAPLAN: They have and we may not be able to solve all the rules. All we can say is, liberalize where you are.

MR. WALSH: So, we're just regurgitating?

DR. CAPLAN: No. I suspect the quarantine of the lots may actually be able to flow a little easier if this goes.

DR. GOMPERTS: I think the label issue is probably--

DR. CAPLAN: They're not going to bend their notification issue. I hear what your concerns are. I will tell you that the proposal is to try to urge them to be more liberal on the supply consistent with what they already do in consumer notification. If you wait for label withdrawal now or notification, modification in policy you wont get any.

DR. GOMPERTS: I understand that. But let me go one step back to something a little bit more basic. We have heard not only at this meeting but at other meetings that the likely scenario is each lot of whatever product has an individual in there who is in the clinical, who has donated plasma in the pre-clinical phase of this disease. And, therefore, what we're looking at here is an artificial distortion of the issue. Okay?

So, therefore, if we're looking at safety, if there is an agent in there, then none of this stuff should be released. That is the one extreme.

DR. CAPLAN: Understood.

DR. GOMPERTS: The other extreme is that there should be information in each of these products, in each of these lots that indicates that A, there has been no transmission, there is no epidemiology to associate cause. However, it is possible that this might occur, every lot, and then this whole issue goes away.

Now, from the liability point of view, yes, there is an issue. However, from a public safety point of view the availability of product right now and in the short-medium term is very real. So, I think the key to it is the information issue.

And to get a moratorium and say, yes, these lots will be released and we can do that anyhow with a label.

DR. CAPLAN: I know they can do it, they haven't done it, let me point out.

DR. GOMPERTS: Because--

DR. CAPLAN: But if you tell them to do it, they may do it.

DR. GOMPERTS: You are saying one product is potentially unsafe and this product potentially isn't. And there's that distortion. It's a legal distortion, it's a real distortion. And, so, let's deal with it the way it really is. Treat all products the same and have the information in there.

DR. EPSTEIN: The FDA did bring to its blood products advisory committee the proposal that all plasma derivatives be labeled with the theoretical risk of CJD. That proposal was not endorsed and it has been consistently resisted by the industry. FDA would accept that proposal but I think that we also have to take into account that there have been consumer complaints about that resolution.

Consumer organizations have said, you know, we understand your arguments that one lot is not different than another lot but, you know, boy, if you know about a CJD or CJD-at-risk donor, we want to know about that lot. And this is what the issue has really been all about.

DR. MOORE: Getting back to the industry point about labeling. We talked a little bit earlier and several people have brought up the issue of something comparable to the vaccine compensation issue which is a piece of legislation that I don't fully understand. And Jay, maybe you could speak to that. Like if there is some kind of label and a big part of the concern is industry concern would something like a compensation package impact on that?

That doesn't address the consumer issue that you just raised but--

DR. EPSTEIN: Well, I'm beyond my expertise speaking to that issue and there may be other people here who can. My sense, however, is that that kind of strategy would be helpful but, you know, it's a congressional issue to enact such a thing.

DR. MOORE: We could make that recommendation.

MR. ALLEN: I would feel a little bit more at ease if the FDA could go back, talk to the manufacturer, get a consensus of what's going on and then ask us to make a recommendation. Not until they have a consensus because once we make a recommendation we may not like what they end of agreeing to. And, you know, there's just too much open ground there for something to happen.

DR. CAPLAN: Let's see if this phrasing might be something. We will call it the Caplan motion, since I'm the only one who is for it.

[Laughter.]

DR. CAPLAN: And we will look at it and while we are looking at that, let me ask, can we get agreement--I don't want to let this slide away. We heard something, I think, that if we could conduct experiments aggressively with respect to albumin, that this might help free up the supply there. Is that something that we're all in consensus on in terms of recommendation that we urge that these experiments proceed expeditiously? Can I get a motion there?

This was the follow-up on the studies that we heard about from Dr. Rauer and it's all about spiking and titers, that if we could finish those things up quickly, given the ways in which we are handling albumin, it might be possible to say that CJD is not--if I'm getting this correct--such a risk with respect to albumin.

But these experiments have to appear and we have got to urge that they get done expeditiously? Yes?

DR. PILIAVIN: Yes.

DR. CAPLAN: So moved, second? Good. Vote?

All right that one is on the table and we will drag that one back out.

Who can be against rapid research. All right.

DR. NIGHTINGALE: Dr. Caplan's proposal reads, we recommend that during the next year the FDA work with industry to relax current CJD guidelines on quarantine and withdrawal of blood products to the extent necessary to relieve product shortages. We recommend FDA follow standard policies regarding notification while considering committee concern over shortages.

DR. CAPLAN: The last sentence?

DR. PILIAVIN: I propose if we omitted that last sentence.

DR. CAPLAN: On standard policies on notification?

DR. PILIAVIN: Yes.

DR. CAPLAN: Well, basically what you'll do then is you will be trusting that is they work with industry and we could add in here as part of this consumer groups to formalize the standardization, consumer involvement that we will let those parties bang it out but what we're trying to do is indicate that the shortage in the short-run is real. We don't want CJD to stand in the way of it in the short-run. That's really what that's trying to do.

So, maybe--

MR. WALSH: Appropriate consumer groups.

DR. CAPLAN: And appropriate consumer groups up in the work with industry, just put and. Put parentheses around it, let's see how that goes for a while. Vulnerable but not excised yet.

MR. WALSH: Why are we striking the last sentence?

DR. PILIAVIN: Because they're already doing it.

MR. WALSH: Then it should stay in there.

DR. PILIAVIN: But Jay has already said that this is essentially what they are doing and this is what industry wont buy. So, we are not going to get anything if we don't get rid of that last sentence.

MR. ALLEN: There's an issue here. How can you talk to the consumers about products being released without notification?

DR. CAPLAN: Well, my comment is, we could get rid of the last sentence, not because it means the end of notification. It means that whatever FDA does, it has to do standardly across-the-board.

I'm not sure that we've told them to change their notification policy. I'm trying to pump the issue of how they negotiate it out with industry. They may decide to create a compensation thing.

They may say the sentiment was that your liability is less because this committee told us that we want shortage alleviated. So, when you go to court, remind them of that. I don't know what they'll do. But in the short-run, it seems to me--

What I'm saying is if we eliminate the sentence, you don't say that we're giving up on notification, what we say is negotiate it with those groups, formalized, get at the shortage issue in the short-run to the extent CJD is affecting it and we will work out an effective notification policy to make it happen or compensation, or whatever it takes.

I actually am kind of--I don't want to see notifications just go flying out the window but I don't want to hamstring them into saying, well, here you don't, there you do.

I'd rather, if they can get industry to calm down and say, the message was, go with shortage. Bring that to court, that is what your advisory committee said, maybe that will calm them down. I'm not optimistic but it might.

So, that's my hope that if we tell them to get at the shortage thing in the short run that may give impetus to getting at product. There are other ways to mount liability reduction besides saying you did notify, you didn't, to tell you the truth.

If this committee says, shortage in the short-run is important for the sense of the nation, the public, that's what you use. You go to court and say that's what they told us to do, that's what we tried to do, industry saying.

I will be available to testify any time.

[Laughter.]

DR. CAPLAN: But I mean we may not be giving up on anything on notification.

MR. WALSH: I agree. I think this is about the best that we could come up with that would move through the system and provide some immediate response.

DR. SCHIFF: Why don't we vote with and without that last statement. I'm trying to get this thing going. In other words, take it out, vote on it, and if that doesn't pass, vote on it with it in.

DR. CAPLAN: Is there a second for that idea?

DR. PILIAVIN: Second.

DR. CAPLAN: Oh, gosh, all right. We're voting on, just to be clear, everything up until the brackets.

DR. PILIAVIN: With consumer groups in there?

DR. CAPLAN: With consumer groups in there.

DR. NIGHTINGALE: You got it in there.

DR. CAPLAN: All right. All in favor, please, raise your hand?

[A show of hands.]

DR. CAPLAN: All opposed.

[A show of hands.]

DR. NIGHTINGALE: I've got eight in favor, I have five opposed. That motion passed?

DR. NIGHTINGALE: I have eight for those in favor and I have five votes against. And Dr. Bush was not in the room, that's 14. Are there any members who did not vote?

No.

DR. CAPLAN: Dr. Guerra had to leave early, he's not here. We voted on that recommendation without the paragraph at the end of it. My vote is in favor of that.

What I think is important to do at this point, having done that, is to reflect the fact that there is a lot of concern on the part of the committee that notification and consumer understanding be attended to. We do have the consumer representative in there.

It has to be taken very seriously but the general goal is to try and address shortage in the short run without doing anything that inhibits what people can expect and cement trust between those providing them their blood and those who receive it, for the record, says the chair.

The other thing I think we need to do, having gotten this far, is probably shut that thing off and then move back to a discussion of something else.

It's a shift of gears and I'm going to ride us right to it because I want you to have a chance to comment on it. We have a letter that responds to our Hepatitis C policy in front of us. It's in your folders, materials at the back.

It says, we heard your recommendations about look back, we're going to do certain things to implement those recommendations. That's what I would consider to be old business.

Is there anyone on the committee who wants to respond or comment upon this response that we've received?

We did get a fax from the American Liver Foundation but that's a group providing you with input of what they would like to see happen.

Dr. Schiff?

DR. SCHIFF: Yes. I like the letter with one exception. There is an absence of specifics here. In other words, there is a strong endorsement, we're going to do more than you ask. But there's no time-line here. What are you going to do more? I would like to see more substance to it. That's what bothers me, but I like the fact that it's a favorable response.

DR. HAAS: I'm not quite as kind as Dr. Schiff in the sense that I saw it as milquetoast. I don't think the letter said much at all unless we get those specifics that are out there. I think we ought to ask for time lines. We ought to ask what the promotional campaign is going to be like.

Right now, I don't think we know anything other than they said, gee, that was nice work.

DR. MOORE: Just to speak to that a little bit. I was at a meeting right before coming here in Atlanta where we did, where time line actually was presented. And I think that the folks at CDC, at least, are working really hard at trying to come up with some very specific goals over the next six months. And I don't know if there is some way that that could be brought to this group.

I think that the issue is that those are still in formulation. But that was very encouraging to me in the sense that I think that they have some very concrete plans about bringing together people to talk about alternative test sites and trying to implement some of those issues.

So, I know a lot of thinking has gone into that and, you know, maybe we could get somebody from the Hepatitis Branch to address that. But anyway the information I have is it was very positive.

DR. PENNER: I think that's good but can't we just ask and get that information as soon as possible?

Can we put a time line in? I, for one, would like to see a time line come in and six months would be reasonable because things are moving along, the individuals have to be notified.

DR. NIGHTINGALE: This is Steve Nightingale, I should speak on behalf of the Office of the Secretary that it is the intent of the Secretary and everyone in the Secretary's Office to proceed as quickly as possible with the Secretary's recommendations.

As far as while there is not a specific time line for publishing, for example, a guidance, this is certainly under consideration and I believe that it would be reasonable for the committee to expect further notification from the Office of the Secretary prior to its next meeting, whenever that is.

I think it would be fair to me to suggest, to the extent that I can, on behalf of the Secretary's Office that that would be considered a reasonable time line on the Secretary's behalf if something further is not available to you by that time.

DR. CAPLAN: Does anybody want to suggest that they would like to have a written report prior to the next meeting as part of their--

DR. PENNER: Yes, I'll propose that.

DR. PILIAVIN: I will second that.

DR. NIGHTINGALE: We try to consult with our members as much as we can but I think you could anticipate the last week in April and the last week in July as target dates for the next two meetings of the committee. If we need to have an extra meeting in the year, that would be before the end of the Fiscal Year which is September 30th.

DR. CAPLAN: One of the things I hope we can do then is move on this vote to say that by the time we meet next, be it April or whenever, that we would have a report to us before the meeting so that we would be able to discuss it when we got here about the implementation of this recommendation, that is sort of the motion, I think.

In favor?

[A show of hands.]

DR. CAPLAN: Opposed?

[A show of hands.]

DR. CAPLAN: So, we will look for that to come.

DR. HOOTS: Can you just add to that that we get the information before it is released to the press?

DR. CAPLAN: Yes. In other words, we read it, know what's going on, then we're ready to talk about it when we get here. What I'm a little nervous about, personally, is that we get here and we kind of have to deal with whatever it is and we can't come grumpy if they didn't do, get going. We will be ornier if we have read it before it got here.

If it comes to us, I can't tell you it won't go the press at the same time, but I mean someone may give it out or leak it, we would, of course, want to try to keep all our communications confidential and act in a professional manner about all this, but I think what the sense of the group is that we would like to get a report as part of our next agenda book, have a statement, see what's happened to implement.

DR. PENNER: In the same context, can we get a report on the recall situation as to what has transpired after our recommendations?

DR. CAPLAN: You mean this?

DR. PENNER: Yes, just what we had voted on.

DR. CAPLAN: I assume that would be a communication to us, we would recommended that to FDA, so, I assume that is coming backwards, coming from there.

DR. PENNER: Okay.

DR. CAPLAN: Any other old business?

[No response.]

DR. CAPLAN: All right, new business?

One thing I would like to hear about is if we have an April meeting and we have a June meeting, we go that route for schedule roughly. What, are there topics and themes that we need to examine?

I mean clearly one of the things we have got to come back to, it seems to me, just without any dispute is we have got to get to the general question of what are we doing about supply?

Overall, where is the question of supply? Why shortage? What are we going to do about this with respect to blood and blood products? Having talked some about short-run issues and CJD, what's going on with respect to supply overall?

It is obviously an obligation we have to take seriously and go back and see what we can do on that score. So that would be one I would put on the table.

DR. JONES: We've heard a lot today about the other committees and other groups who are working in related areas.

DR. CAPLAN: The TSE and the B-Pack?

DR. JONES: And I would like to hear either from them or to have a brief report summarizing their mandates, their activities, their charges, so that we, perhaps a flow chart that we could talk about in terms of who is supposed to be doing what and how we interface or don't interface. It would be very helpful.

DR. CAPLAN: One thing we could do is at one of those meetings upcoming we could have a session where we just talked informally with no particular--I mean we could ask them sort of what are you working on, what concerns you have, how could we be helpful and so on, almost as a little bit of informal dialogue.

I've talked about this with Steve and I don't know if the committee cares. Is there a sense that you would like to have an opportunity to talk about issues, just open-ended, without having to have an agenda pressed forward so that you could just say, you know, CJD is great and I'm fascinated by Hepatitis, but what really bothers me about blood safety availability is X, whatever it is, why does it cost so much or why don't they collect more blood? Or, I don't know what it is.

But would you like to have time set aside for open forum? I mean any issues that people want to put on get discussed? I think the people that chartered us will give us things to do and it's always a fascinating activity but I don't think it is unfair that we let some issues bubble up if there are issues that people want discussed. Hemochromatosis, and there are a bunch of things out there that we could talk about and I'm just curious, does that seem like a reasonable thing to schedule a part of the meeting on, to have an open discussion?

I see a lot of heads nodding around that. So, maybe we should do that as part of one of the upcoming meetings, too, a little bit of exploration to see what issues we might want to get to.

Jim and then Paul.

MR. AuBUCHON: I would like to suggest a subject for future consideration to see whether the committee members would be interested in delving into this. It relates to the supply side and specifically how we take care of our donors?

When donors are found to be reactive in an infectious disease screening test, usually the results are attempted to be confirmed in some type of more specific confirmatory tests.

And then that information is in some way shared back with them to assist in their own health care in the future, in addition to helping the blood collector decide what to do in terms of future deferral of that donor.

There are some situations, most notably testing for HTLV-I, where there is no licensed confirmatory test and also an anti-Hepatitis B core. And this causes great difficulties in counseling of these donors.

And in some cases an unlicensed confirmatory test is available but the blood center may not use the results of that information to counsel the donor.

And, therefore, the blood center is often in a quandary and the donor is left in the dark. I think that this committee might be interested in learning about these kinds of situations and provide some impetus to rectifying problems where they may be found.

DR. HAAS: Mine is an elaboration on the supply issue, too, and it's an issue that Mike and Ron and Ed, I think, all talked about and that is this looking at the commercial fractionators, the voluntary sector.

Let's look and see how those things are fitting together, what's going on? Is there a real problem in terms of maybe hurting the voluntary sector or vice versa? What difference does it make? We ought to look at that really pretty closely.

DR. HOOTS: One thing I would like to hear a little bit more discussion about it was raised is recipient notification and the system, implementation of that system.

DR. CAPLAN: Gene?

DR. SCHIFF: This is almost naive, but I heard raised that there were more deaths from mis-matches than any of these things. Well, is that within our purview? If it is, let's deal with it. How can we correct that problem?

DR. CAPLAN: It absolutely is.

We did talk, too, and we could put this as a possible topic for consideration, compensation, liability. And a lot of what we were trying to grapple with now is through the process of notification. I will tell you that notification and warnings usually fall apart. You sign informed consent forms, you say you've been told.

When people use those as a way to protect themselves, they don't go far. There may a need to think about insurance or schemes that give people compensation if they can be established to have been injured through blood transfused diseases and so forth.

But that general issue is there and so compensation/liability questions are things we might want to be talking about. The other one I think that I have to put on the table that always interests me is why does a unit of blood cost what it does?

I've always been concerned that we spend a lot of money on it and we have all kinds of issues that come up about price but just as we ask the question about the donor, voluntary versus paid, how does that work?

I still remain interested in cost. And what can we do to drive down the cost, if anything, because that will free up more resources to do other things.

So, one of my pet interests is trying to look at that but that may be too ungainly, unwieldy for us but it is something I put on the table.

DR. KUHN: I would also like to look into probably what you would call a blood component injury act. Explore that.

DR. CAPLAN: Yes, yes.

MR. WALSH: I would also like in the context of the supply issue to get the answer addressed that I brought up yesterday or get an answer or some information with respect to what actually causes the supply and why?

DR. CAPLAN: The shortage problem.

MR. WALSH: And that might encroach on whether problems the FDA sees and the way that manufacturers are responding to the inspections and some of the observations made.

DR. CAPLAN: Steve, I have to say I was asked a couple of times in the breaks, what could we do, is it possible to go into executive session if there are issues of proprietariness and so forth?

Can the committee ask questions or see information that would otherwise not have to be made public or that people wouldn't want to make public in that area?

DR. NIGHTINGALE: Yes. This committee is governed by the very same regulation that all other Federal advisory committees are and you can go into executive session. I think a committee of this stature, a Secretarial committee does have an interest in maintaining openness of its meetings to the greatest extent possible.

I might add, since I have the microphone right now, discussion about how the future agendas, in fact, are made. While the Advisory Committee Act actually has the agenda under the authority of the designated official for the meeting, which is me, in fact, the way that we're going to make the agendas for the committee are to elicit comments from you, certainly during the meeting, but I would encourage you to make suggestions after the meeting, as well, preferably through Dr. Caplan, if you could.

What we will be doing is taking your suggestions to the blood safety committee which you will recall is the committee of the agency, the PHS agency heads, and those recommendations will be submitted to the Assistant Secretary for Health.

Because the charter of the committee states that this is a committee that advises the Assistant Secretary for Health and in the long run it has its greatest impact if it addresses issues that are of concern to the Assistant Secretary.

So, I think your time will be best spent if we go through that process but I wanted you to understand that that process is intended to incorporate your ideas and suggestions to the greatest extent possible.

DR. CAPLAN: Someone else asked me during the break just as a procedural issue, if requests come to talk to reporters, to comment on things that the committee does, and people aren't sure what to do about that, what should they do?

DR. NIGHTINGALE: As one says in other contexts, I'm glad you asked that question. We do have a press officer available at all meetings.

The decision of the Department is that the Assistant Secretary of Health, currently Dr. Eisenberg, is the Acting Assistant Secretary for Health, will be the person who responds to the press on behalf of the Department.

You are free to say whatever you wish but the official response will be delivered by the Secretary's Press Office.

DR. CAPLAN: If there's no more new business, I'm actually going to drive us toward a conclusion here. I think that we will be sending out some calendars, trying to pinpoint dates. I doubt we will be back here. Probably somewhere in D.C. in a hotel.

I think I'm going to push us because I hear a lot of concern about this and I think we owe it, based upon what we were trying to do, to address short-run shortage today to get supply up there, to find out what we can about why there is shortage, to push that issue forward.

We can't sort of yell about shortage and how we want to make advice about trying to meet that problem unless we really go at the general question of what we can do to increase supply.

And I think that has just got to be something we have to move to next. It seems to me we just have to go there.

Paul?

DR. McCURDY: I think it's worthwhile being sure that you understand there are really two major components to the supply of blood and blood products.

One of them is the derivative supply which we've addressed primarily today and we have had presentations today and the other one is the whole blood supply. And they are relatively separate.

The only cross-over is in the recovery of plasma area. And we've heard a little bit about that. But the whole blood, Pack Cell, platelet issue.

DR. CAPLAN: When I'm talking about supply now, I mean for blood products, I don't mean for--we can get to the bigger--

DR. McCURDY: I think it is appropriate to be specific because they are quite different.

DR. CAPLAN: Yes, yes.

But for what I'm saying is having, trying to wrestle with this issue of shortage and the immediate demand and how the committee wants to think through that.

We do need to come back and address the question of why is there shortage of blood product and what could be done to enhance the availability of blood product.

But I think we should, too, look at the blood supply overall issue. But I would like to see us get back to that blood product thing as soon as we can.

Thank you.

[Whereupon, at 3:18 p.m., the above-entitled meeting was adjourned.]

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