DEPARTMENT OF HEALTH AND HUMAN SERVICES
OFFICE OF PUBLIC HEALTH AND SCIENCE
ADVISORY COMMITTEE ON BLOOD SAFETY AND AVAILABILITY

FIFTH MEETING

Volume II

Friday, August 28, 1998

8:13 a.m.

Hyatt Regency Capitol Hill

Ticonderoga Room

400 New Jersey Avenue, N.W.

Washington, D.C. 20001

P A R T I C I P A N T S

Arthur Caplan, Ph.D.

Stephen D. Nightingale, M.D., Executive Secretary

Janice K. Albrecht, Ph.D.

Larry Allen

James P. AuBuchon, M.D.

Michael P. Busch, M.D., Ph.D.

Ronald Gilcher, M.D.

Edward D. Gomperts, M.D.

Fernando Guerra, M.D.

Paul F. Haas, Ph.D.

William Hoots, M.D.

Carolyn D. Jones, J.D., M.P.H.

Dana Kuhn, Ph.D.

Tricia O'Connor

John Penner, M.D.

Jane A. Piliavin, Ph.D.

Eugene R. Schiff, M.D.

Marian Gray Secundy, Ph.D.

John Walsh

Richard J. Davey, M.D.

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

Mary E. Chamberland, M.D.

David Feigal, M.D.

Paul R. McCurdy, M.D.

CAPT Bruce Rutherford, MSC, USN

CAPT David Snyder, R.Ph., D.D.S.

Dr. Jay Epstein, FDA

Dr. Eric Goosby, DHHS

CDR Lawrence McMurtry, Deputy Executive Secretary

A G E N D A

AUGUST 28, 1998PAGE

Remaining Public Comment from August 27, 1998 Session

Alain Delongchamp 8

Centeon

Philadelphia, PA

Report on the Status of Prior

Committee Recommendations24

Committee Discussion [Old Business]--

Public Comment--

New Business--

Adjourn 225

P R O C E E D I N G S

CHAIRMAN CAPLAN: Good morning. What I would like to do is get underway with a little bit of housekeeping.

In one second, I am going to ask Dr. Nightingale to remind us all about dates that we should be holding for upcoming meetings. We try to schedule dates and keep them on for the committee. The odd thing is that we don't have to use all of the dates, but we have them if we want them. In part, as we go along today later in the day to look at upcoming issues, things that you think we ought to be looking at, it'll determine our schedule, to some extent.

I should also mention that there are some people who will be going off the committee because they had two-year appointments and I think, incredible as it may seem, this committee has actually existed for almost two years as of, what, October?

DR. NIGHTINGALE: October 9th.

CHAIRMAN CAPLAN: October the 9th, yeah. Time flies when we are having so much fun, but there it is, two years. So some folks will be going off. I don't have the list in my hand, but Steve may be able to at least say who is due to rotate off the committee. That's why the surgeon general yesterday was thanking some of you for your service. You didn't realize this, he was saying goodbye to you.

[Laughter.]

CHAIRMAN CAPLAN: The other housekeeping item is this: Just to review today's agenda. I gave you a homework assignment last night that some of you, I know, did, which was to think about some recommendation language. I am going to have Mack go up and run the overhead in a minute and try and write down some recommendations that you all would like to make about recombinant product as our focus.

I know that some of you did take that seriously. I have looked at a few things that people are ready to present, so I think we'll have some things to talk about.

What I am hopeful of is that we can get at that, roughly allotting two hours, to talk through what we might want to say at this point about that subject, take a break, come back for the final two hours to talk about future subjects, really freewheeling, talk about things, whether it's supply issues or safety issues that you might want to see us look at, at future meetings. We haven't really solicited.

We've been responding to requests for advice from the secretary and the assistant secretary of Health, but we could put some topics forward and say these are things we think need examination at this point in time, and they would obviously start to fill up our agenda down the road.

I am hopeful we can get done pretty much on schedule 12:00/12:30. I joked to Steve that the real lure for finishing up at that time is you can't eat your lunch until we finish. So it's sort of like the old Bulgarian Communist Party model, keep talking, no eating until we are done.

I think that it's appropriate at this point also to say we had someone who wanted to make a public comment yesterday, but didn't get on in time, Alain Delongchamp from Centeon, and I think it's important that we have that perspective heard, so I am going to let him offer a few remarks in just a second. In fact, if you would, you could head up that way.

Steve, why don't you review the dates, and if you've got the list of names, why don't we look at it, just so you all know.

DR. NIGHTINGALE: The dates to keep on your calendar, hopefully on a permanent basis, will be the last Thursday and Friday of January, April, and August. These have been selected partially on the basis of precedent and partially so that they minimally overlap the Blood Products Advisory Committee meetings, which meets quarterly.

I would also like to mention that everybody within the Humphrey Building and everybody on the committee, and I am sure in the room, joins my expression of gratitude to the doctors whose two-year terms expire. They are Dr. Albrecht, Dr. Gilcher, Ms. Jones, Ms. O'Connor, Dr. Schiff, and Dr. Hoots. Thank you very, very much.

CHAIRMAN CAPLAN: Some of you may thinking will we never see some of these people again? Not so clear, they have to go through the process of reappointments. New names will be put up. That takes place within the Humphrey Building, actually, is how that goes.

But even if nothing else is said, we really do appreciate the service, and the effort, and the work put in here. Steve and I have said to each other a number of times that we are very impressed with what the committee has done. We hear constantly from industry, patient groups, provider organizations that the committee has provided a very useful forum, and people think we try hard to listen carefully to what people say and try to bring some of what Cory Dubin yesterday was talking about as coordination, cross-communication to a lot of the blood issues, and that wouldn't happen if the committee hadn't taken its task as seriously as it has and taken its mandate so seriously. So I think we have been very productive here.

Alain, why don't we put you on.

MR. DELONGCHAMP: Thank you, Mr. Chairman. My name is Alain Delongchamp. I am the general manager for the North American Division of Centeon, and I am located at our Philadelphia offices.

I would like to spend the next few minutes to address some of the issues and questions that were raised by the committee yesterday afternoon.

Firstly, let me start by saying that Centeon is committed to the objective of manufacturing and distributing safe plasma therapies. We have always been and we continue to remain committed to that objective.

We also continue to remain strongly committed to the objective of supporting the patient communities who benefit from these products, and I would also add that we remain committed to the distribution of the two recombinant Factor VIII products that we have--Bioclate and Helixate.

As you probably know, these products are manufactured, in the case of Bioclate, by Baxter, and in the case of Helixate, by Bayer. So far in 1998 we have been allocated, as a distributor of those two manufacturers, a lesser amount of those two products than we had originally anticipated, for the reasons that were discussed yesterday; namely, the very high general demand for the recombinant Factor VIII product in the marketplace.

But in the second part of the afternoon yesterday, I picked up a few questions and left the room at five to 5:00 to call my staff in Philadelphia and ask them to put together some information concerning our sales of those recombinant Factor VIII products in the U.S. and overseas, and I would like to share that information with the committee.

During the period from January to July of 1998, inclusively, therefore, a seven-month period of time, Centeon sold the majority of its available recombinant Factor VIII product to U.S. patients. In fact, close to 60 percent of the available recombinant Factor VIII product we had was sold to patients in the United States.

In our estimation, the Centeon supply of recombinant products represented about 30 percent of the total recombinant Factor VIII product available to the U.S. patients during those seven months. Our plan is to continue to allocate at least the same proportion of our recombinant Factor VIII products to the U.S. patients.

Nevertheless, we recognize that the recombinant Factor VIII supply situation is inadequate and that the supply is insufficient. As a result of this, last month our medical director sent a letter to every hemophilia treatment center in the country and also to the National Hemophilia Foundation asking for consideration to be given to several alternatives to the continued use of recombinant Factor VIII products. This suggestion included the use of our ultra-high pure monoclonal Factor VIII product, Monoclate-P, where it was acceptable.

We are very confident in the safety record of Monoclate-P, and we view it as an acceptable alternative to the recombinant Factor VIII products. I have also asked my staff last evening to send me some information concerning the sales of Monoclate-P, U.S. and overseas, for the same period of seven months, and I would like to share that again with the committee.

Between January and July of 1998, inclusively, Centeon supplied 60 percent of our available supply of Monoclate-P to U.S. patients. In our estimation, this supply of Monoclate-P represents about 25 percent of the total ultra-high purity monoclonal Factor VIII product available in the U.S. during those same seven months. However, I must admit that the near-term supply of Monoclate-P cannot be predicted at this time.

As all of you know, Centeon has been operating under a consent decree since January of 1997. As part of the requirements of this consent decree, Centeon recently underwent an inspection by FDA of its manufacturing facility in Kankakee, Illinois.

As a result of that inspection, serious observations were noted, and Centeon is currently working on an action plan to address these observations as quickly and as effectively as possible, and we are discussing these plans with the agency.

I believe that the most important implication from our manufacturing situation for this committee regards the supply of available products, and towards that end, I'll try to make some comments and some observations for the committee.

Firstly, let me say that Centeon has inventories of Monoclate-P and Mono-9 available at its manufacturing facility in Kankakee, Illinois. However, FDA has instructed Centeon that we need to augment the review of our manufacturing documentation for these inventories before they are released in the market. We are pursuing options to accomplish this objective in an as efficient and timely manner as possible, and we are discussing these plans with the agency.

As a result of all of this, the level of Monoclate-P and Mono-9 product releases will be affected. At this time, however, we cannot predict accurately the availability of these two products for the next few months. I would certainly propose to keep the secretary of the committee informed on a regular basis of any progress that we would be having in this situation.

I also would like to say that I believe it is in the interest of the committee that we talk about the inventories that Centeon has of its IGIV, named Gamma RPIV. We also have inventories of that product available at the manufacturing facility, but the same release procedures and comments I have made for Monoclate-P and Mono-9 apply as well to Gamma RPIV. Therefore, it is probably premature at this point in time to really discuss the supply of this product as well in the near-term.

I also know that it is of interest to the committee to hear about our alpha-1-antitrypsin development program, API. And I would like to say that Centeon is strongly committed to this program. We are currently finalizing the protocol for the registration trial of our API product in light of the comments that were made by the BPAC committee members at their last meeting, and we are discussing this protocol with the agency. We are also discussing with the agency plans to manufacture and release API for clinical trials.

We are hopeful that these plans, once accepted by the FDA, will, in fact, not lead to any significant delay in our development of API. We will work with the alpha-1 patient community and this committee to keep everyone apprised of any additional development.

In closing, I would like to say that, certainly, Centeon remains strongly committed to the distribution of the two recombinant products, Factor VIII products that we have available. We also remain strongly committed to the manufacturing and the distribution of safe plasma therapies.

Centeon is currently responding to the observations that were noted at our manufacturing facility, and we will conduct a series of enhancements and modifications as required in order to meet those objectives.

As a result, as I have said, we expect some level of product supply in the next few months, but are unable to give any kind of quantification at this point in time of what that will look like.

In light of these comments, which most likely don't meet with the satisfaction of everyone in this room, I feel that it's imperative that the communication between our company, the patient communities, and also the treaters involved be strengthened.

I would like to reiterate a proposal that we formalize a communication mechanism with this committee and certainly commit to keep the committee apprised of any development on a monthly basis, even if it were to point out that there has not been any progress.

Thank you.

CHAIRMAN CAPLAN: Alain, do you want to take a question or two?

MR. DELONGCHAMP: Sure.

DR. HOOTS: I know you may not be able to answer this directly, but is there any potential that the inventory would not be released?

MR. DELONGCHAMP: Certainly.

DR. HOOTS: So it is possible that the inventory you have would be disallowed and never available for release?

MR. DELONGCHAMP: That's a possibility.

CHAIRMAN CAPLAN: David?

DR. FEIGAL: Could you comment on the export situation for the immune globulin?

MR. DELONGCHAMP: Certainly. Our IGIV Gamma RPIV, which is made in Chicago, is sold predominantly in the United States. In fact, I don't have the numbers with me, but I can tell you that it is more than 90 percent sold in the United States. We argue at times, is Puerto Rico considered to be part of the United States? We don't have responsibility for it, so we don't factor that in. I think if you throw in Puerto Rico, it's probably closer to 95 percent.

CHAIRMAN CAPLAN: John?

MR. WALSH: In lieu of the obvious impact of the recombinant factor product, if you are not able to distribute, what do you anticipate the effects will be on your ability to produce enough A1PI for a trial? If you can't produce for the trial, what would you project is the delay in being able to come to trial with product?

MR. DELONGCHAMP: I think that it's a bit premature to look at the projection of what the delay could be. Frankly speaking, we are very hopeful that the discussion we are having with the agency will not lead to any delay.

CHAIRMAN CAPLAN: Larry?

MR. ALLEN: Sir, you mentioned 60 percent of available product stayed in the U.S. and 30 percent of this--what was available to U.S. markets. Do you have numbers on what the actual demand is in this country, any projections whatsoever?

MR. DELONGCHAMP: Yes. We certainly have numbers of demand. I think that we deal with a very imperfect situation. Patrick Robert talked about it yesterday. The demand is not as easy to estimate in this market as it is in others. We do our best, and I have actually picked up on, I guess, some implied suggestions yesterday from some of the distributors who seem to be certainly willing to partner and sit down with us and talk more openly about what that demand could be. I think that that is something we would like to follow up as a company. Hopefully, it will help a great deal in managing the tight inventory that exists.

MR. ALLEN: Has your company attempted to make any adjustments based on the shortages in this country in terms of what you export?

MR. DELONGCHAMP: We have actually reduced the amount that we export for one of the two recombinant products, where that was possible. There were alternatives. As you probably know, in some countries the acceptance of plasma-derived Factor VIII is higher than it is in the U.S., and where that is possible, we are making some adjustments.

CHAIRMAN CAPLAN: Mike?

DR. BUSCH: What are the relative shelf lives of recombinant versus plasma-derived Factor VIII, for example?

MR. DELONGCHAMP: They are a few years for both of these products.

CHAIRMAN CAPLAN: Jay?

DR. EPSTEIN: I just wondered if you could help give the committee insight. Why, in your opinion, have the shortage situations for the plasma-derivatives and recombinant analogs not been shared abroad? Why have the shortages happened here and not affected European and other foreign customers?

MR. DELONGCHAMP: Well, I think that when you look at the situation in the U.K. you would see that there is a very critical situation as well there experienced. Again, there was a significant movement out for the BPL products that have resulted in quite a crisis situation, as we have in the U.S.

So I think that in some countries of the world you see a very similar situation. I know that, for ourselves, we have numerous problems in the number of Southern European countries as well.

I can't comment about Asia, since we don't sell any of those products in Asia.

CHAIRMAN CAPLAN: I have maybe the last question for you. I have a feeling that one suggestion/recommendation that is going to come up very soon is something about trying to form an oversight or sentinel function on the supply side; that, to some extent, events, whether they are FDA-driven, market-driven, over-prescription physician habits, whatever, patients self-medication, alter supply in ways that create problems that no single entity can pick up on and leave those reliant on blood products basically in the lurch with short-term shortages.

Do you have any comment about--I won't hold you to this. We'll put this in the speculative category--but do you have any ideas--I heard what you said about keeping the committee apprised. I think that's very useful, and I made a note. We'll definitely follow up with you about that, and maybe we can come up with a model that all of the providers can do--but if you were trying to think of what would be possible to prevent shortage, spot shortage, interim shortage, when events kind of take place that are in no one's domain or authority, but lead to difficulties, do you have any suggestion about what mechanism or what sort of oversight might help to prevent that from happening?

MR. DELONGCHAMP: I think that understanding much better the demand for these products, not at a macroeconomic level, but very much at a micro level would be extremely useful. What I mean by this is that all of us know that the market is, let's say, 775 million units, for the sake of argument.

What is really much more important is to understand how many 250-unit potency does one need to have? 500, 1,000 and 1,500, and that's information that really exists, but is extremely fragmented throughout the United States. I think if we could have a much better understanding of this, it would result in a much more manageable situation. Companies would be in a position to actually provide the requested potency at the time that it is requested and, therefore, you wouldn't have a stampede on the different potency in order to meet the prior need, which has that cascading effect of simply ruining any kind of projection you are making for manufacturing.

So if there was one area where we could all work together, that would be the one that I would point to.

CHAIRMAN CAPLAN: All right. Well, thank you.

MR. DELONGCHAMP: Thank you.

CHAIRMAN CAPLAN: Oh, Alain, can I ask you one other question? Steve just made a remark to me that I should get you on the record to say this.

Do existing antitrust laws make it difficult to do that, what you just outlined, in terms of trying to forecast supply?

MR. DELONGCHAMP: Yes. Yes.

CHAIRMAN CAPLAN: We are just putting you on the record.

All right. I appreciate those remarks. As I said, when an opportunity is made for an offer for the committee to get information, we'll find some way to follow up. I'll go on the record myself and say to Steve and Eric, on this one we want to make sure to go back to Centeon and see what we can do about collecting information, and maybe other manufacturers will be happy to get in line so that the committee can get some sort of monthly update on where things stand in terms of production supply issues, and we obviously can correlate that, to some extent, with FDA.

What I would like to do at this point is ask Mack to then come up to the overhead with his marker. I am going to toss the floor open for some recommendations.

One reason I was pretty sure that something would come up about having a sentinel or surveillance on the supply issue is that I was going to make them my particular issue, but I will wait and see what else other people might want to put on the table first. I am sure we are going to have some discussion about standard of care with respect to recombinant.

I am sure there are other topics. I know there are other topics that people would like to have the committee consider on this matter, so I'll hold off on my short proposal and let Keith start the discussion.

DR. HOOTS: Well, actually, I just wanted to pick up on your proposal. I think the time may have come to at least consider an oversight committee that has some broad reach, but perhaps a narrow representation to include government and nongovernment, but that it would open the possibility to get information about supply, cost, exportation, et cetera, that is otherwise considered proprietary, but would be constituted in such a way as to keep that information private, and with the acquiescence or the acceptance of the Federal Trade Commission, the U.S. Department of Commerce, et cetera, could actually entertain inquiries that might share information that otherwise would be considered antitrust, so that they could look at things.

There are a couple of things I think that there are precedents in the U.S. government for this; the Federal Reserve is certainly one for banking, and perhaps the Securities and Exchange Commission, and this is a precious resource, just like money is, for our society and, therefore, I think it might reach the level of significance to warrant that.

I think Alain just alluded to some things that this committee could perhaps or this group could perhaps receive data about and perhaps develop models, mathematical and otherwise, to help predict supply issues.

Just as an aside of that, one of the things that I was thinking might be possible, we are working very diligently, as everyone knows, on trying to track end users for possible safety reasons for recall, withdrawal, et cetera. Since manufacturers certainly know the release date on a product, if they were to follow release date and then use the system that's being implemented for another purpose to look at end-user receipt date or use, then you can use that as a surrogate for actual usage over time for each of the products. And as that period gets shorter, the eminence of a shortage would be on the horizon.

If one actually develops a shortage like we have now and that period of time were to start lengthening and the shortage not improving, then that would be indications of hording or stockpiling.

So those are kinds of things that could fall under the province of such an organization committee or group, and they would have, since it might be proprietary, but at least they would have access to it, and they would have the possibility, unlike this committee, of maintaining confidentiality of proprietary issues.

CHAIRMAN CAPLAN: John?

MR. WALSH: Mr. Chairman, I--

CHAIRMAN CAPLAN: Oh, different John. Two Johns.

DR. PENNER: Since we're into the supply-demand, we are in a unique situation, I think, with our group of patients here with respect to the fact that we have centers that handle at least 60 percent of the patient population that are involved.

Our centers are able, I think, to estimate roughly the amount of factor that is going to be used per year within I would say 10 percent because surgery and other things come up. We've had enough experience with our patients to be able to come up with that kind of data. So we should be able to estimate, I think, reasonably well what kind of demand there is going to be for a coming year if we want to get at that information from the centers.

The manufacturers, I think, should be able to tell us what kind of supplies they might be able to provide us for the year. And with that kind of information, then if we run into shortfalls, we should be able then to triage where we can get the supply and for whom instead of having this rather erratic thing that we talked about. And the same issue that we dealt with IV gamma globulin is calling five different areas hoping to get it off the spot market. So and so has managed to scavenge a couple hundred thousand units and things of this sort.

So that at least we'd be able to apply ourselves in an effective manner if we had some, at least, central area of knowledge as to Centeon has some, Baxter has some. You can get it from here and at least go through the same situation as I think we did several meetings ago on the gamma globulin.

CHAIRMAN CAPLAN: The other John?

MR. WALSH: I think staying on the demand and shortage issues, not only the projected demand and related supply problems, but also understanding what the FDA has gone through recently. It's unfair to burden them with the responsibility for establishing the severity of a shortage. Right now they handle that in the Office of Compliance, and they gauge it by call-ins.

But the patient communities, as presented at the FDAMA hearing two weeks ago, have all experienced situations where leadership has been asked to discourage calls into FDA because there's nothing the FDA can do about a shortage, which is reality, and it's not fair to put that burden on their staff.

Unfortunately, there's been a couple of occasions that the FDA has been asked to present data on the number of call-ins, which demonstrate severity of the shortage, which are inaccurate because we could flood the FDA with calls and what good is that going to do? And it looks like we don't have an IGIV shortage or an alpha-1 shortage and now recombinant shortage, but, in fact, we do.

So I think in the context of setting up a sentinel responsibility, it needs to include some way to measure the level of a shortage, and whether that's working directly with patient advocacy organizations or distributors or providers or maybe a combination thereof, it needs to be addressed.

CHAIRMAN CAPLAN: Dana?

DR. KUHN: Bill, I think the idea of the sentinel function I heard you talk about, Art, and John, and then Keith talking about a committee, whether this would be a committee or a person, I think this builds upon our last recommendation, No. 1, of the short terms that we had in April, and that would probably take that short-term recommendation into a long-term.

But, again, I am not sure how much information we have been able to receive since we made that recommendation. This would be a sure way of being able to obtain that information on a regular basis. So I think it's a great recommendation to head in that direction.

CHAIRMAN CAPLAN: John?

DR. PENNER: We still have the gammaglobulin situation, where we're paying four and five times pricing off the spot market, and we know that some distributors have selectively held back and have it available and others don't. The manufacturers should know this, and I think the manufacturers ought to be involved in some sort of a procedural arrangement whereby they can be asked directly for where the product is, how much is available. Whether the public should be involved, it would perhaps be very nice if they could be on such a committee, but this would be one way of handling it and keeping the government out of it.

CHAIRMAN CAPLAN: I mean, I guess just to say what I really feel about this. When we hear about runs on dose sizes creating shortage or we hear about speculators gouging on prices and to yo-yo the community that depends upon a steady supply of lifesaving product, particularly children, it seems that we can't leave them just to the vagaries of the market.

I don't hear industry saying or the FDA saying or anybody saying that they would be offended if someone somewhere could collect information that would help us diminish these crises of spot shortage. It just seems inherently unfair to leave these problems, these sort of hording behavior, gouging behavior, off-and-on availability of product uncertainty about what's going to be there, that's just not adequate.

And I think we've got, to me, a classic case of market failure. It's not being driven by any particular bad motive. It's just that if you have a bunch of private competing concerns and a lot of users who vary the demand, you are going to get in trouble if you don't have someone with some ability to pull information and anticipate and manage that a little bit.

I think we should stay out of the issue. I am going to suggest, if there turns out to be sentiment for a recommendation of this sort about creating some sort of sentinel approach to monitoring supply, whether it's a person or a committee or who it is or what it is, I think we can make a recommendation pretty assertively that says we need to have information collected that stabilizes our understanding of supply, that allows the industry, consumers, providers to have the assurance that they are not going to get caught up short, and they are not going to wind up getting gouged. And we want to see proposals about that.

It's a tricky area because you are talking about commerce, and federal trade, and antitrust. They're going to have to talk to a whole bunch of people about how to do this, and companies are going to want secrecy of this information if they are asked to give supply projections and all of that sort of thing. I understand all of that, and I don't think we will get it solved here.

I would urge us to think, if we go in this direction, of a general recommendation that says we want to see the secretary pull together whatever team of people it takes to figure out how to have a sentinel or monitoring or surveillance system in place on supply that can attend to the problems we are talking about, price gouging, spot shortage. The goal is to prevent this kind of behavior and work with the appropriate players to get it done, export, the whole thing.

I was a little bit, as I have come to these meetings, I have been a little disheartened thinking we'll never get a handle on export. But maybe the way to do it isn't to try and create a czar of rationing, it's to try and have just somebody or a group looking ahead and then trying to manage the thing, so you don't have to worry about the export problem.

So, again, the bottom line of those remarks is to say I think this is a good place to go, but I don't think we have to micro-manage it here. We just have to say here is what the goals are. We want to prevent these problems, and we understand it's going to take a real push to put together Justice, Commerce, FDA, the appropriate players, FTC, to make it happen, but we want you to do it. We should push that. So just put that out on the table for thinking about this recommendation.

Fernando?

DR. GUERRA: I'm just wondering whether the manufacturers would be willing to commit to having a central area to contact when there is shortfall and centers need it, need the product, that they should tell them. I know each individual manufacturer is willing to have some sort of set-up for this, but usually they shift you around, and you have no idea where you are at, and I don't think there's been a commitment here, and would they be willing to at least fund something of that sort of centralization.

It seems to me, in trying to develop a sentinel system of some sort, that we have to better understand what the components of that would be, and I am not sure, at least in my own mind, that that is clear. We have some estimates of the size of the population that is most affected and that would need this, but we also know that that population is growing in some instances, but do we know by what percentage it grows every year? I don't know. I know that in our own community we probably will see maybe five to seven children affected with hemophilia that are in each annual birth cohort. I am sure that there is some from immigration and other circumstances that will add to the total number.

I am not sure that we always have a clear idea of how precise the estimates are for estimating what the dosage in terms of units is for maintenance therapy of a population and then to handle the emergencies. But I suspect that based on prior historical information from the hemophilia treatment centers that one could probably arrive at some fairly good estimates in terms of what that might be.

I don't know what, and perhaps Keith or some of those that actually are hands-on practitioners in those centers, what are some of the other variables that would enter into that, so that we could have a better estimate of what that is?

And then I think that we have to somehow attach this to the other side, and that's how many deaths are occurring every year within that population, so that we take that into account as well.

I think, again, going back to some of the public health models, there needs to be a connection in terms of the sentinel system information, the tracking of population. That could be very helpful.

CHAIRMAN CAPLAN: Dave?

DR. FEIGAL: A couple of comments.

I guess I was struck yesterday by the marketing data that showed that actually the production of these products has been steadily increasing over the long term. So this isn't an industry that's backing away from these products. In fact, more and more of them have been made every year.

But I guess it's also striking at how precarious the balance is between supply and demand because we are seeing relatively smallish disruptions in terms of the big picture, a 20 percent shortfall, sometimes a 50 percent shortfall, but often smaller than that, creating a problem for a supply which is still larger than it would have been a decade ago. So there are some interesting issues about managing this.

The other things that we heard is that some of the things that industry can do to respond; namely, increasing capacity, have a long lead time. It takes about five years of planning to bring a new factory on-line from a hole in the ground to something with licensed product.

We are also dealing with time frames where we have disruptions in supply that are more typically months to sometimes a year in order, and some of those are due to compliance actions by the agency, others are part of the business process of companies; as they retire old facilities, old lines, and have to go through switchovers or need product for clinical trials. There's a variety of those kinds of disruptions.

I think the usefulness of having real-time data at the agency level would allow us, when we are notified of disruptions or when we anticipate them because of our own actions, that we can try and balance what's happening elsewhere.

The other, I think, general theme is something that is harder for either the agency or the companies to control, and that is the very complicated way that medical products are distributed. The manufacturer knows the first person they sell the product to, and that may be it. That product then may go through a number of other hands, and finding exactly where it is, is something that is very difficult.

There is a fairly elaborate system of market tracking on the drug side that somehow has gotten around all of the antitrust issues that allows pharmaceutical manufacturers to know sales down to the pharmacist level, but that's a very expensive system. It took a long time to put together. It's a proprietary system. Even the agency has to pay to get information out of that system. We actually have not found that system very helpful to us in terms of managing pharmaceutical drug shortages.

I think the one thing that I think, just is my own personal opinion, that we haven't optimized has been our way of dealing with emergency supplies once we identify that there are disruptions for whatever reason. And I think that's really a challenge to industry to take a look at how they've done with their emergency response in the last year, particularly with immune globulin, and see if they can do it better with clotting factors, with other things, on a voluntary basis, on a more cooperative basis. Because otherwise I think it invites proposals for some other kind of more central kind of system.

And I agree with the comment yesterday that the government doesn't have a very good track record on managing shortages and doing rationing of products. I think industry has generally been a little more nimble in meeting those kinds of needs. But I think our current systems aren't adequate to meet the needs.

If I had to pick an area to prioritize, aside from the things that FDA can do behind the scenes with better data, it would be to challenge industry to bring us a proposal for a better emergency system.

CHAIRMAN CAPLAN: I was just thinking that the total number of people in the United States, it seems to me, ballpark number, who regularly rely on blood products for lifesaving maintenance is probably 50,000. There's sort of roughly 20,000 hemophiliacs, immune deficiency, alphas. There can't be much more than that. That sounds like a pretty good number. Now that I've said it, it will be quoted forever. But if that's roughly true, we should be able to know exactly where they got their supply. That's not an impossible--we should be able to find out the person who administered got it, and we should be able to find out where they think they got it.

So if we had some standardized system imposed by this sentinel function for collecting information, not just from the production end, but on the recipient end, how many people do get supply by scrambling to the spot market, et cetera, et cetera, we should be able to keep--this is not an undoable task. It's a finite number of people. It's not trying to watch prescriptions for 250 million people, which would be quite a job.

So, it seems to me, again, part of the problem of the difficulty with the market is that some information may be out there, we don't collect it, and we can't use it, and then coordinate around it, leaving other market phenomena to take place. So you might be thinking, if we said as a recommendation we want to see a sentinel system created that collects adequate information on production and use that would avoid or limit problems of shortage, price gouging, hording, that's what I think we want. I don't much care how it gets done. I leave it to greater minds to do it.

But it seems to me, from what David is saying, some of what we could use is the standardized information that would then let some coordination take place. It doesn't have to be micro-managed. In other words, it doesn't have to be run by a government rationing board or something. The information should be moving and everybody should be able to come to the table--the FDA, the industry, providers--and say, "Look, here's the situation. We are facing this shortage. It looks like inventory is dipping. We are seeing a burst of people buying off the spot market. Something is off here."

So I would suggest that we might think about a recommendation like the one I just said, which is just to ask for an oversight sentinel on supply, some mechanism, and its goal should be to reduce shortage, hording, speculation, price gouging. That's what we want. So you might think of that as a more narrow type of recommendation.

Let's see, I was filibustering there for a while. A new voice, Ed?

DR. GOMPERTS: I would like to point out to the group that in the agenda for this particular meeting there has really been very little representation from industry in regard to the supply of the clotting factors, recombinant and plasma, unlike the situation with immunoglobulin at our last meeting.

I think, if we are going to continue on this issue, and especially move towards a major recommendation, that we do hear from industry and the industry group so that--at least what is being planned? Has anything been planned? How is it working with the immunoglobulin?

Looking across the product line, each particular biotherapeutic, whether it's immunoglobulin, recombinant Factor VIII, alpha-1-antitrypsin, et cetera, has its own unique issues, and we should, in fact, broaden our perspective

to the supply of red cells. Is there anything that might impact that? Because our view should be short-term, and certainly the recombinant Factor VIII issues hopefully are just short-term, medium-term, but long-term as well.

There are many factors that are brought to bear on a particular supply situation of a particular biotherapeutic. In the situation of recombinant Factor VIII, to some extent the shortage, which we are seeing right now, is perhaps being pushed a little by this committee. I'm just focusing on--there are many issues--but in regards to the recombinant Factor VIII, there is only one factor.

So I really think that we need to--it's an important issue. It is what this committee is being asked to do. We have to look at supply, and make recommendations as to how the supply issues, problems, et cetera, can be dealt with. In regard to, again, just to repeat, in regards to the Factor VIII/Factor IX situation, we should hear from industry. Thanks.

CHAIRMAN CAPLAN: Yes, Jim?

DR. AuBUCHON: The concept of a registry of patients and their utilization of different biotherapeutics--I like that term--has some merit I think. And it would be interesting to consider expanding that to encompass another idea that has been discussed before, and that is a national registry system that would allow for rapid patient information and product withdrawal or recall, should that become necessary.

As we have discussed before, recall or withdrawal can become very complicated because of the numerous links in the chain between the manufacturer and the ultimate consumer of product that may be stored in any one of a number of different places. I raise that issue with some reluctance, knowing that, as you have talked about, Dr. Caplan, when we start discussing some type of national patient data base, people run for the hills. But it is something I think at least worthy of consideration.

MR. WALSH: Mr. Chairman?

CHAIRMAN CAPLAN: John?

MR. WALSH: In conjunction with what Jim just said, the industry, Congress, the FDA, and the Plasma Users Coalition has taken a step towards that direction. The IPPI, Novartis, and Red Cross have contracted with a third-party contractor called the National Notification Center, Inc., to develop a voice processing platform with DT&F technology for notification of withdrawals and recalls of plasma-derivative products.

The objective there would be to have information, just like Jim suggested, immediately available and have it a flexible system, so that if somebody wants to get a Fed Ex response or a telephone notification or just wants to call in and put their lot number in, they have that capability. That system is currently being defined--specifications are being defined, and an advisory panel has been convened I believe for the 16th of September. I would suggest that this committee ask for a report on the progress of that at our next meeting.

Additionally, I think this platform would be an excellent vehicle for us to look towards to expand to the next level, would be to expand and actually include a registry of sorts, where all consumers would log in what product they are on, who the manufacturer is, and who the provider is. It's contracted by an independent, confidential database group. It's not industry controlled, but it's industry funded. And we are going to be soliciting participation from all of the consumer groups to participate in the national--for notification of withdrawals and recalls anyway.

So a natural extension of that might be the most cost-effective approach to get a registry, if you will, or a database of all plasma users and what types of products.

DR. GUERRA: I think that, in that regard, there are a number of prototype models that have been in existence for some time and that are operational that handle data sets that are even much larger than that--certainly, with the immunization registries that have been in place in some local communities and states.

The difficulty has come with trying to take that to the national level primarily because of the whole imposition on the rights of people and what have you. There has certainly been a growing constituency that has limited that effort to take it to the much broader scale.

But I think that the model exists that would serve this purpose very well. Immunizations, where we are currently tracking 15 different antigens for children over the course of their early developmental years all of the way through college entrance, that has built into it automated reminder recall and adverse events that are picked up, and when you have to do recalls of particular lots numbers, et cetera. So I think the model is there.

The Department of Defense has an even bigger model that is applicable worldwide for many of its troops. They are currently using it to begin to implement the use of anthrax vaccine to a worldwide community. So I think that if, in fact, this would be a good way to do a sentinel for this population, I would suggest that we look at some of those models because it would allow this effort to take place very quickly.

CHAIRMAN CAPLAN: Just to specify--I am trying to think about some language we might move toward--we could ask for the spirit of what Dr. Guerra is talking about, what Ed mentioned earlier, a little bit of what Jim had to say too. We don't have to say, "We recommend the creation of a sentinel system." We could ask for we would like to have proposals put to us or some options presented at the next meeting by the secretary and appropriate staff about how this might go, keeping in mind the prototypes you are talking about, the information that John just presented about the registry, that end.

We could then bring, again, comment. We could have more industry presentation or more whoever presentation. So we don't have to--what we are trying to get here is pushing in a direction to try and think about how to do some sort of sentinel function.

If you want to go stronger and say we want to have a single proposal on the table by then for our consideration, fine. I just note that it doesn't have to be we want this finished. We could ask for some options or points to consider that a serious effort be made to put together some options, as much as we saw presented for the IVIG.

Remember, the difference was it sort of got resolved before, but far be it for me to ever argue against action, but it sort of got done, but we could ask for that kind of thing. It doesn't have to be--

Jay?

DR. EPSTEIN: I just want to make a few comments about the four issues that I think are on the table.

First, let me state what those issues are; whether we should make a recommendation that recombinant factor should become standard of care, and I think there are some pros and cons; second, recommendations regarding alleviating or removing cost barriers to use of recombinants; third, the issue of monitoring of supplies; and, fourth, strategies to address current shortage. I think those are the four topics that we are really on.

First, regarding whether recombinant factor should be standard of care. I think that we've heard a great deal of support for the use of recombinant factors based on their excellent safety record since they were first introduced in clinical trials in the late eighties, and a lot of theoretical endorsement based on what is thought to be the increased margin of safety.

I think we shouldn't lose sight, however, of the fact that we have been told that, for the foreseeable future, plasma-derived factors are going to remain necessary on the market, that we do not want to disparage the use of those products, which particularly the monoclonal affinity purified products, which appear to have an excellent safety profile, albeit with theoretical risks. I think we have also been told that, at least in the short-term, there are differences in recovery, particularly for the Factor IX, that relate also to issues of availability cost caps and the like.

So I think that we need to tread very carefully in that area; that it would make sense to me for us to endorse policies that would foster the increased use of recombinant factors without, in any way, disparaging the use of apparently safe plasma-derived factor. So that is comment one.

With respect to removing cost barriers, we spent a lot of time talking about and listening to statements about the insurability of the use of some of the more recently developed factors, and I think we should make a statement about lifetime caps, and I think we should make a statement about third-party reimbursement despite cost differentials.

I think we could also make a statement encouraging more states to adopt safety net programs. I think we heard an example of a model in Georgia that had obvious benefits to the patient population.

I think we also need to think in terms of the interplay of the Orphan Drug Act on products in this area. One thinks typically of the Orphan Drug Act as having been created to deal not just with products that are used in low numbers, but where there is no profitability. I would call into question the issue of applicability of the Orphan Drug Act for products which are, in fact, profitable, despite the fact that the numbers are low. I wonder whether that mechanism that was created to generate incentives, in fact, has become a disincentive in that it's a barrier to new entrants.

I am not making these statements on behalf of the FDA. These are personal observations because we do implement the orphan drug approvals. So those are personal statements. But I think that we should at least call for a re-examination, whether the current legal framework does or doesn't create the incentives that we seek.

Then the third issue is the monitoring issue. I concur with what's been said earlier about the need to be able to model the system. We've said a lot about modeling supply, but I think we have to monitor the two arms of that, which are the production side and the demand side. I think that we've heard a lot less about how one would go about modeling demand, and it has various dimensions. We are dealing with the overseas demand. We are also dealing with the dynamics of domestic demand.

And I just want to support Dr. Guerra's statement that we need to understand it more explicitly at the micro level; you know, who needs what, how are those populations changing, what is the forecast.

So, to me, the central issue in that is that we have to go beyond gathering data, where I think we have spent most of our discussion, into the idea of modeling that system. I would place my support in calling for resources to develop, not just the systems that would gather the data pertinent to supply and demand, but also to get the mathematicians involved to see if we can't model the system in a useful way as a flow dynamic, more or less the way people figure out how much oil you need.

Then on the last issue of addressing current shortages, I think that issue needs to be separated from the other three issues. We have tended to lump it. But I think that the shortage situation is, if you will, a current event. Although it has to impact our thinking in the other areas, they have their own life anyway.

So I think we need to talk about strategies to address the current shortage, and I think that, as was the case with the consideration of IGIV shortage, we have to be thinking in terms of short-term remedies and long-term remedies because the issues have both a short-term and a long-term dynamic.

I think that in the short-term issues, it's hard to get away from the notions of practice guidelines and efforts at allocation because what else are you going to do? I mean, you either have to reduce the effect of demand or you have to take control of what products there are and get them to the people most needy. So I think that the recommendations fall naturally into those two bins.

In the area of long-term, I am not sure that I heard anything new compared to IGIV. I heard that we need to figure out how to raise production, and I heard that we are still stuck on the issue of whether it is thinkable to have some kind of export controls. The thought that troubles me is that I think we've heard that our country still has enough production capacity to supply the needs of our population and, yet, we are not delivering that product to our population.

Now I think that the arguments are quite different in the area of plasma-derived than in recombinant. In the area of plasma-derived, you can argue that you have used U.S. plasma, but that's a national resource and, therefore, there's some kind of moral or civic duty to make that resource available nationally.

In the case of recombinant, I think it's harder to make that argument. I'm not sure what argument we can put there, unless we simply decide that it's a national strategic issue, that it's something that we have to do to protect our population more or less along the lines like national defense or national emergency. But I think that that will take an effort to convince the public and that it probably has to be done through legislation.

So, short of that, I think you are dealing with trying to find incentives for increased production, and I am not sure what they are if they are not market forces. And I don't think that I know enough about how the economic incentives work to make this happen, but I think that's where the effort should focus because we are not talking about nationalizing these industries. So, therefore, we have to be talking about whether it is profitable for the industry to invest in facilities and distribution networks and the like. So we really ought to be focused on the economic incentives issue there.

I don't think I've changed any of the issues, but those are my comments on what I think are the four issues.

CHAIRMAN CAPLAN: Larry?

MR. ALLEN: Along the line of Jay's third point and some of the other comments that have been made here, I think one of the issues is a formula for determining demand. If we were able to put together a group of government, consumer, and industry and have them review past demands and other variables that have an impact on demand for each product, including lot size and potency size, and come up with a reasonable projection with the goal of industry meeting just, say, maybe 110 percent of the U.S. demand, then some sort of procedure to accurately chart these goals could be put in place, and industry would have a guide to use regarding import and export.

So I think the main thing that I am concerned with now is getting a formula to properly project what the demands are, what the demands have been over the last five or ten years, and what they should be for the next five or ten years, and then trying to meet those demands, along with coming up with some vari--including the variables that have some impact on demand and shortages.

DR. GUERRA: I agree that we need to develop that kind of methodology to allow us to, perhaps, have better estimates than we presently have, but I'm not sure that that will allow us to compensate for those unknowns and the unpredictable, at times, increase in demand.

I wonder, and I would ask Jay if there is some federal policy that allows for stockpiling of those important biological, therapeutic agents that are in the best interests of a country. We do it in anticipation of pandemics, and there is a stockpile of flu vaccine, for example, and it's prepared in anticipation of some bad things happening. I suspect other things, with the threat of bio-terrorism, we have stockpiles of certain things.

It seems to me that there are enough people at risk for many of these conditions that do require ready access to these agents in the instance that they need them, and that industry cannot keep up with the immediate demand that sometimes exceeds what the projections are.

Is it possible to do that in terms of the federal policies that allow manufacturing so many doses? And, obviously, shelf life issues come into play in a lot of things. I just raise that as a question.

DR. EPSTEIN: Well, I know of no authority under which we can simply mandate that the industry contribute to a stockpile. On the other hand, there are examples where this has been done voluntarily. Now, there are some examples where it's in the law, and vaccine inventories for childhood immunization are under the Childhood Vaccine Act. But for the products that we are talking about, I know of no authority to simply mandate.

In the area of immune globulin, for the intramuscular immune globulins, the producers, the U.S. licensees, voluntarily make their inventories available for distribution through a common distributor, where the allocations are then determined by the Centers for Disease Control based on requests from the states.

Now that's a much simpler system because most of the need is for addressing hepatitis A outbreaks. You have defined need, and we also have a well-modeled system, where we know the approximate monthly use, and we are able to, therefore, manage an inventory against an expected need.

Given the diverse indications for some of the derivatives, that's less feasible, but other derivatives, potentially, it could work--perhaps looking at requests from HTCs as opposed to requests from states. But I would emphasize that that's being done voluntarily.

Short of a voluntary system, I think the only mechanism by which the government could achieve reserves or stockpiles would be to buy product and then hold it in reserve and then distribute it. That puts the government in the business of being a distributor or broker. I think there are reasons that the government tends not to do that. One is just we become liable and, two, is maybe we're not good at that. We're not in the business of business.

So I think that it would take probably new congressional mandates for us to really pursue this, and they could go down either of two paths--the path of setting up funded, nationalized systems that operate as businesses, or the path of creating mandates so that industry had to comply with some kind of contribution to a repository, which is then managed at some central level by some entity.

Now I may not be the most knowledgeable thinker on this subject because I have come to the issue, of course, very indirectly because of these particular blood product shortages, and I don't know what precedence there are in other parts of the economy and other branches of government. But that's the limit of what I know that we could do.

CHAIRMAN CAPLAN: Eric?

DR. GOOSBY: Could I just comment? I think that Jay has outlined it accurately. There is the possibility, though, of, through the Public Health Service Act, the secretary can declare a status of emergency, and that's a very ill-defined concept. There's a lot of room for interpretation of it.

Where she could mandate usually in a time-limited fashion, and that's what we would have to get some guidance on from general counsel, to create perhaps a dynamic inventory where shelf life was taken into consideration, and they were brought back into circulation before shelf life came out. But a certain percent was always readily available. And I think Jay's consideration around who does that would be still of issue there.

There are examples of that for, as you were saying, for antiterrorist activity that is well worked out and does come under the Public Health Service Act as well as under the military authority.

DR. EPSTEIN: Jus tone point that I didn't mention. We do actually have the authority in the Public Health Service to become a manufacturer. The PHS Act does provide that the government can manufacture products. There's been very little incentive to pursue that option within the government, just because we are not equipped to do it. But we have the authority.

CHAIRMAN CAPLAN: David?

DR. FEIGAL: I just wanted to remind us all that, when we were talking about the intramuscular immune globulin shortage one of the concerns was that the stockpiles that the military had created was exacerbating the shortage. They, in fact, had switched over to the vaccine to deal with their hepatitis A problems.

But I think we would have to look very carefully to make sure that any kind of stockpile, in fact, didn't exacerbate a shortage.

DR. EPSTEIN: Could I comment? I certainly agree, but the problem comes with trying to create the stockpile while you are in the middle of the shortage. You can't do it. You can't do it. Fundamentally, you have to get production ahead of demand for at least a while, and then you don't create a static reserve because the problem is the products have short dating, and they all expire. What you have is a dynamic reserve, where you are always putting things in and taking things out.

But I agree with Dr. Feigal. You really can't do this while you are in the midst of the shortage situation. You have to plan for this and develop it over time, and you have to get ahead first.

CHAIRMAN CAPLAN: Let me see if I can jump in at this point. I like Jay's outline of some of the key issues that we may want to make recommendations about. Just to remind you, again, what about standard of care with respect to recombinant factor, what about alleviating cost barriers to access, monitoring supply, dealing with shortage. Those are the four that he went through.

What I would like to ask is are there any other major issues at that level that anybody else would like to put on the table for us to think about? If we don't have that, then I'm going to suggest, having had the opportunity to discuss, that we do spend a minute now actually with the first one, the recombinant standard of care issue. I think that will get us into the more do we have consensus to say something or don't we have consensus to say something. But are there any other major themes that anybody would like to bring forward?

Jim?

DR. AuBUCHON: I want to discuss the--

CHAIRMAN CAPLAN: The recombinant thing? Okay.

DR. GUERRA: A couple of them. One is I think we discussed yesterday there seems to be a gap of communication and information that somehow we need to build into however we handle this because that gap is widening. I think the issues are getting more and more complex, and certainly those that can most benefit from a lot of these newer therapeutic interventions do not always have access to the state of the art information.

The other one has to do with I think surveillance, not just on the side of monitoring the supply and that sentinel, but also, as was discussed yesterday, and I think when Dr. Satcher was here, the importance of recommending the support that is necessary to track those conditions that are so closely tied to blood and blood products, the emerging new infectious illnesses, and that the capacity does not always exist, but the level of the front lines, where we have to deal with reportable diseases, where we have to recognize emerging trends, changes in some of the conditions that are affecting populations. But we need to have the capacity to recognize, and to diagnose in the lab capacity, and collection of specimens and all of that, and that support has not always been there.

CHAIRMAN CAPLAN: Dana?

DR. KUHN: I'm not sure, Art, if this would come under the sentinel function that we have been discussing or not, but I think we are still concerned about exporting of our source plasma and our finished products. So would it be a possibility to also add to one of our concerns or one of our recommendations, wherever it would fall under, that when necessary in times of shortage, that the federal government--I am not sure if they can do it--but if they could regulate the export of source plasma finished products in order to ensure the safe and adequate supply of plasma derivatives, recombinant products for the American user communities.

DR. PENNER: To get back to your first request on the business of using recombinant.

CHAIRMAN CAPLAN: No other big thematic issues?

[No response.]

CHAIRMAN CAPLAN: Okay. Let's talk recombinant.

DR. PENNER: If you are ready for that.

CHAIRMAN CAPLAN: Yes, you can talk, and then we'll put Jim back on.

DR. PENNER: I believe the National Hemophilia Foundation has recommended that we proceed with the use of recombinant as much as possible, at least urging that the transformation be made. I don't, as a treater who handles mostly adults and almost all of my patients are on plasma-derived product, I have no concern about placing those same patients on the recombinant factor, so long as it's not a cost factor.

All of my patients, as they are coming along, who have been on recombinant are staying on recombinant. So I don't think that's a really big issue with respect to what recommendations should be made if we are just talking about which product to use. I think, at this point, most of us would agree to using the recombinant.

CHAIRMAN CAPLAN: Let me note, since I know something about--grudgingly so--the world of managed care. Should this committee say, what hinges on this, that recombinant is the standard of care or that we recognize it as the standard of care, and we should move as quickly as possible to make it available to all who might benefit or something like that, we will be sending a message of sorts to third-party payers. That's part of what hinges on when you do this sort of thing.

DR. AuBUCHON: I fully support the right and ability of any patient, particularly hemophiliac, to choose the most appropriate therapy for themselves in consultation with their physician. I would be opposed to a body such as this one promulgating a medical standard of care, particularly after not fully appreciating all of the issues, not having a thorough discussion of all of the issues.

Mr. Dubin, yesterday, briefly mentioned one of the rationales for considering recombinant Factor VIII as a standard of care, and it has certainly some merit. But I don't think that this body is the appropriate one to establish a medical standard of care.

DR. DAVEY: Art, I would just second what Jim has said, and I believe also the thrust of what Jay said earlier. Standard of care is a phrase we have to be a little careful of because it implies that other material is not the standard of care. I think there is evidence that, indeed, highly purified monoclonal human material has a safety record that is at least equal to that of recombinant.

So I think we have to be careful with that phrase standard of care. I would suggest, again, something along the lines of, perhaps what Jay said, that we endorse the movement toward recombinant material or something along those lines, and avoid the phrase "standard of care."

MR. WAlSH: Having listened to those, Dana Kuhn and I had polled some of the Plasma User Coalition Group last evening, and we apologize for not including Larry and Trish in that process, and we certainly--I don't have any objection, if Dana doesn't, to looking at that term "standard of care" and certainly understand and appreciate the concerns related to that.

But there are a couple of things that we have identified that Mack has put up on the slide is, first of all, to come up with an expression from this committee that we support the surgeon general's recommendations in his testimony yesterday. I haven't seen a hard copy of the testimony, but three of the issues would be: Recombinant as a blank-blank for persons with hemophilia where appropriate; support for research for new technologies; and the maintenance and expansion of surveillance. But highlight what the SG said yesterday in a kind of a preface to our statement here with respect to recombinant.

And then in discussion of recombinant, it's to support that recombinant should become a blank-blank for all persons with clotting disorders; that all financial barriers should be removed--and, again, this is for discussion, obviously--should be removed to ensure access; that Medicaid should establish a reasonable national reimbursement standard for recombinant clotting factors--

CHAIRMAN CAPLAN: Let me jump in there because what will happen is we'll start making lists, and we won't remember them. Back up. Let's try--pull that slide off, Mack--let's see if we can go with a reading, if you will, of what the surgeon general--didn't you have that surgeon general statement, Eric?

Do you want to read that, Steve, just to remind folks what we are talking about there.

DR. NIGHTINGALE: The surgeon general said that, No. 1, we should encourage the current transition from plasma-derivatives to their recombinant analogs where the technology is available.

No. 2, support basic research to develop this technology for diseases such as the immuno deficiencies and alpha-1-antitrypsin deficiency, where the technology has not yet matured.

And, No. 3, maintain and, as necessary, expand or intensify surveillance of blood donors and recipients for emerging and re-emerging infectious diseases.

CHAIRMAN CAPLAN: If there is sentiment to talk about whether we should endorse those, since John has got that on the table, if you will, as a proposal, does the committee want to endorse those? I can read them one by one again so you can talk about them a little bit.

DR. NIGHTINGALE: The first one reads encourage the current transition from plasma derivatives to their recombinant analogs where the technology is available.

DR. HOOTS: Does that satisfy--I'm sorry.

CHAIRMAN CAPLAN: Fernando, no, yes?

DR. GUERRA: That seems like that's a little bit too soft to encourage. It's a little passive.

DR. NIGHTINGALE: Would you like to say promote rather than encourage?

CHAIRMAN CAPLAN: Endorse?

DR. NIGHTINGALE: Richard likes endorse.

CHAIRMAN CAPLAN: How would that read? Can you do that fast?

DR. NIGHTINGALE: We would endorse the current transition from plasma derivatives to their recombinant analogs where the technology is available--endorse, promote, encourage.

DR. AuBUCHON: All three.

DR. GUERRA: Right, transition.

DR. NIGHTINGALE: Endorse the current transition from plasma derivatives to their recombinant analogs where the technology is available.

CHAIRMAN CAPLAN: Let's just talk about that for a second. I want to look for some phrasing about recombinant.

DR. SNYDER: I'm just going to say why can't we just endorse the surgeon general's recommendations and then go on further to say that the committee feels that the financial barriers by managed care or Medicaid be removed.

CHAIRMAN CAPLAN: Actually, just so you know, I was going to look at or suggest we look at what do we want to say about recombinant and move right to financial barriers, move to the surveillance monitoring functions, and then try and examine something about shortage and what we want to do about it.

So if you want to just endorse this straight up, that's fine. If you want to tighten the language, that's okay too. We can endorse it, modifying it to say, instead of encourage, we promote, demand, insist, whatever. So that's the sequence of--that's exactly what we are going to do.

Keith?

DR. HOOTS: I think, for managed care and for otherwise and, specifically, since the issue we've had before us has been related to recombinant products for hemophilia, and we specifically talk about developing for alpha-1, I think that language should stay in.

In other words, just say for hemophilia and where technology is available.

CHAIRMAN CAPLAN: The transition for plasma--

DR. HOOTS: And the next part, which is to develop for alpha-1 and other diseases because I think that clearly is one of the things on the table, and I think I am concerned that if we make it too broad that it's too easy an escape for managed care to say, well, yeah, it's available, but the other is available too, and blah, blah, blah. I think specificity is helpful here rather than threat.

CHAIRMAN CAPLAN: Instead of saying where the technology is available, you might say support the transition from plasma to recombinant analogs for hemophilia?

DR. HOOTS: Yes, and then you can add--

CHAIRMAN CAPLAN: Actually, that's in the next sentence, though.

DR. NIGHTINGALE: Where the technology is available, such as clotting factors.

DR. HOOTS: Or specifically, okay.

CHAIRMAN CAPLAN: If you want to be specific, you can do it that way.

Jim?

DR. AuBUCHON: Not wanting to put in any wiggle room more than we need to, and possibly we could even remove the phrase "where the technology is available" because, obviously, if the technology is not available, you can't transition.

I would like to ask the opinion of the two hemophilia treaters on the panel, Dr. Hoots and Dr. Penner, whether we should also add, where medically appropriate. Again, I am not trying to put in wiggle room, but we've had a little bit of discussion, for example, about the different half lives of the Factor IX recombinant.

Are there some circumstances where you might not want to transition a patient to a recombinant analog and would not feel constrained to do so on the basis of seeing this in print as a federal recommendation?

DR. PENNER: We might have an inhibitor situation occurring, which would fit into this. Individuals who have been on one product of plasma-derived for many years and now you switch them to a recombinant, would you be more apt to develop an inhibitor and an antibody to that new product, and you might prefer not to. So I like the idea of having a little flexibility.

While I have the microphone, one downside on all of this, and that is, as you remove some plasma-derived products, you tend to increase the cost of other products that are derived from that plasma.

CHAIRMAN CAPLAN: I'm going to suggest, Mack, that we just take out "where the technology is available." Just erase that if you can or cross it out. We may have some other qualifier along the lines that Jim is talking about now in terms of where--there may be a phrase of "where deemed appropriate" or something.

Dana?

DR. KUHN: Could we insert "where medically appropriate"? That way we don't--

CHAIRMAN CAPLAN: Yes, we can put that "where medically appropriate."

DR. KUHN: --where we wouldn't disparage anybody who has to use a monoclonal product or--

CHAIRMAN CAPLAN: Just to go on record, Dana and I talked about this, and Jay mentioned it too. It's very appropriate and important that our recommendation not frighten anybody into thinking that if they are not being transitioned tomorrow morning they have unsafe product to worry about. We heard about the monoclonal antibodies. The record was very impressive. So they ought to do that. We want to urge a move, but not frighten anybody.

DR. PENNER: They can always sue, you know.

[Laughter.]

CHAIRMAN CAPLAN: That's true. Get in line.

Mary?

DR. CHAMBERLAND: I just wanted to have the committee members clarify for me, or maybe it's all clear to you, that the language that we are crafting right now is this being viewed as a statement that the committee is making as opposed to a specific recommendation to the secretary of the PHS?

I understand that there may be recommendations that follow, but I think we should be clear that some things that comes out of this committee are simply their own personal statements or endorsements or views and that other things are recommendations.

CHAIRMAN CAPLAN: This one is in the latter category.

DR. CHAMBERLAND: This is a recommendation.

CHAIRMAN CAPLAN: Uh-huh.

DR. CHAMBERLAND: Oh. Then I don't think that's clear to everybody.

CHAIRMAN CAPLAN: We are definitely--just so we are clear--we have entered into recommendation phase. That's what we are talking about here.

DR. CHAMBERLAND: So endorse, this is a recommendation for the secretary to endorse?

CHAIRMAN CAPLAN: Uh-huh. I mean, it's coming from--we are playing off the surgeon general's recommendation that this be endorsed, and we are saying we endorse that with a little language finesse here.

DR. CHAMBERLAND: We are endorsing the surgeon general's statement or recommendation.

CHAIRMAN CAPLAN: Right. And we're telling the secretary we endorse that too.

DR. CHAMBERLAND: Okay.

DR. HOOTS: I think that's an important point, and one of the reasons I think it is very important to be specific here is because the next part of the language, which has to do with reimbursement, is very specific. If you don't have a strong statement about the medical and scientific justification, then it's too easy to say, Well, okay, there's wiggle room at the top. Therefore, we can have wiggle room at the bottom in terms of reimbursement, and maybe we can just not be quite as assertive about reimbursing this product, which may be at a higher cost.

MR. WALSH: Mr. Chairman, the draft originally submitted to engage this dialogue was based on a preface, the statement in support of the SG, and then specific recommendations that could be argued.

DR. EPSTEIN: I think it would be a stronger recommendation if we recommended to the surgeon general, the Department, that steps be taken to accelerate the transition. I don't have a problem with the logic if members prefer, first, to state the endorsement. But I think that to put it into a recommendation format, you need to tell someone to do something. I think that the thing that we are reaching for is that we want to tell the government to tell--

CHAIRMAN CAPLAN: I like that. That's very good.

DR. EPSTEIN: --the government to take steps to accelerate this process.

CHAIRMAN CAPLAN: Why don't we try steps be taken to accelerate the--

DR. EPSTEIN: Right. So you could either do it in the original statement. Instead of saying endorse, you could say "The committee recommends that steps be taken to accelerate the transition from plasma derivates to recombinant analogs where medically appropriate."

As I say, alternatively, you could have an endorsement statement followed by recommendations. But this statement, as written, is not a recommendation.

CHAIRMAN CAPLAN: Steps be taken to accelerate.

DR. CHAMBERLAND: Right.

CHAIRMAN CAPLAN: Steps be taken to accelerate.

DR. CHAMBERLAND: And I believe that Dr. Satcher, after stating these three, whatever, his recommendations, what he said afterwards is he looked forward to receiving specific recommendations from the committee. So I think that would follow very well from what Jay is saying and what Dr. Satcher intended.

CHAIRMAN CAPLAN: We can endorse it and then urge that steps be taken. That's a little bit of an odd sentence there, but I think that's where we're going to go.

I like the acceleration because it also gets to what Keith is concerned about, that we not just leave too much room to make loopholes.

Can I get a motion to move that language along?

DR. AuBUCHON: So moved.

CHAIRMAN CAPLAN: Second?

DR. GUERRA: Second.

CHAIRMAN CAPLAN: Discussion about the language?

[No response.]

CHAIRMAN CAPLAN: All in favor of that particular first recommendation, raise your hand.

[Show of hands.]

CHAIRMAN CAPLAN: Opposed?

[No response.]

CHAIRMAN CAPLAN: So that is unanimous.

What was No. 2 on the surgeon general's list of things we are considering to endorse?

DR. NIGHTINGALE: No. 2 was support basic research--

CHAIRMAN CAPLAN: Mack, do you have enough overheads up there to do one per recommendation?

This is a very indulgent government expense here, unlimited overheads.

DR. NIGHTINGALE: To support basic research to develop this technology or diseases, such as the immuno deficiencies, and alpha-1-antitrypsin deficiency--

CHAIRMAN CAPLAN: You can just put alpha-1. We'll fill it in.

DR. NIGHTINGALE: --where the technology has not yet matured.

MR. WALSH: I just have a point of clarification. The technology has been developed by NIH in the eighties for alpha-1 protease inhibitor recombinant aerosol, and it's sitting there at the Office of Technology Transfer with five patent license applications waiting. So there's five companies that have identified an interest in developing a product. How do we get that beyond the stage of developing?

DR. NIGHTINGALE: This is a technology that, perhaps, is not yet matured if implementation is part of the maturation process. As Mr. Walsh and I discussed prior to this meeting, the issue was where to put this phrase in. The issue was to make sure that the phrase was in.

CHAIRMAN CAPLAN: Jim?

DR. AuBUCHON: I would suggest removing the term "basic," as some of the research is going to be clinical and applied.

CHAIRMAN CAPLAN: That also gets to what John is talking about, supporting clinical transition, not just lab.

Jay?

DR. EPSTEIN: I would like to add von Willebrand's disease to that list. It's feasible and moving very, very--

CHAIRMAN CAPLAN: Just a "vw," and we'll know what that means. There must be something conspiring about these diseases and their word length on our overheads.

Other comments?

[No response.]

CHAIRMAN CAPLAN: Can I get a motion on that one?

DR. GUERRA: So moved.

CHAIRMAN CAPLAN: Second?

DR. PENNER: Second.

CHAIRMAN CAPLAN: Further discussion?

MS. JONES: One question. Do we want to limit it? You said "this technology," so we are directing everything toward recombinants. Suppose something else comes down the pike. Should we be so specific as to this technology?

DR. NIGHTINGALE: These technologies?

CHAIRMAN CAPLAN: I know what you are asking. The thing is supposed to be referring to recombinant, basically. My answer is I don't think it's incompatible. We are advocating the support of approach to recombinant. If better things come along, it's not incompatible at all. We'll have to revisit the recommendations, so to speak. I know what you are saying. It's sort of like every egg in this basket.

DR. PILIAVIN: Could we just say nonplasma-based?

MR. WALSH: Because there's a problem with IGIV and recombinant.

CHAIRMAN CAPLAN: I see what you are saying, nonplasma based. Yes, how about that? To develop--to support research to develop nonplasma-based technology.

DR. EPSTEIN: Or to develop alternatives to plasma-based technology.

CHAIRMAN CAPLAN: Alternatives to plasma-based.

DR. GUERRA: Yes, Art. I would like for us to also consider those other diseases that are usually not thought about within this category, and that is some of the acquired and/or transient conditions that are associated with, for example, disseminated intravascular coagulopathies related to infection or overwhelming sepsis and things like that where we have to use some of this technology as well.

DR. PENNER: I have "such as," which this is just examples, so that it allows you to carry it on to infinity, if you wish.

DR. GUERRA: I realize that, and that's why I qualified my comment because I think that this directs us more in terms of those chronic illnesses that fit this pattern, but I think there are also some acquired very short-term conditions that probably occur in even greater numbers and that put a lot of people at risk.

CHAIRMAN CAPLAN: I understand what you are saying. I am going to urge us not to do that because it's going to being hard to spell that out. I think the "such as" carries--I am going to suggest the "such as" carries the weight. I know what you are saying about transient and short-term versus these others, but I think John is right. I think we will get it out of the "such as." If we try to phrase it the other way, we'll go crazy trying to list.

Other comments?

[No response.]

CHAIRMAN CAPLAN: Let's see if I can move this one. All in favor?

[Show of hands.]

CHAIRMAN CAPLAN: Opposed?

[No response.]

CHAIRMAN CAPLAN: That one goes unanimous. Now that third one, the financial barrier one?

DR. NIGHTINGALE: Not yet. The third one: Maintain and, as necessary, expand or intensify surveillance of blood donors and recipients for emerging and re-emerging infectious diseases.

CHAIRMAN CAPLAN: This is actually appearing on our list just because it was, in a sense, we are being asked to say what the surgeon general said on this one is good. It's a little off from the recombinant issue, per se. I don't mind saying it.

What we are doing here is revisiting some of our older concerns about making sure that we have adequate monitoring and surveillance for safety for TSE, other emerging challenges, and so on. You remember what this would cash out to be is everything from our talk earlier about who is looking at the dead oak up in the mountains of New Mexico all of the way through why do we still not have a ban on awful--I mean brain consumption and sweat breads and all of that kind of junk.

So, to me, that's what all of that is about. I don't see it as especially a controversial thing for us. I know it's out of place, but I don't mind us sort of saying this is a good idea just to reiterate it, that's what it is doing now.

Comment?

[No response.]

CHAIRMAN CAPLAN: And I wanted to get those other things down on the record, so that we'd cash them out.

MS. JONES: I don't think it should be Recommendation 3. If we put it towards the end, come back--

CHAIRMAN CAPLAN: I understand that. In fact, we'll relocate it outside of this recombinant set. Good point.

DR. EPSTEIN: Mack, I can't read what you've written.

[Laughter.]

CHAIRMAN CAPLAN: He degenerated.

DR. EPSTEIN: It's my eyesight.

DR. McMURTRY: Maintain or, as necessary, expand or intensify surveillance of blood donors and recipients for emerging and re-emerging--

DR. NIGHTINGALE: Infectious diseases.

CHAIRMAN CAPLAN: You know, I gave my little speech, but I'm looking at this language myself. I do want to make sure that we are repeating the importance of keeping an eye down the food chain. This doesn't quite get that because we are saying monitor the blood donors and the recipients. Expand or intensify surveillance especially or parti--

DR. PILIAVIN: How about the population?

CHAIRMAN CAPLAN: Surveillance of the population?

DR. NIGHTINGALE: Blood donor and recipient populations?

CHAIRMAN CAPLAN: I like that better.

MS. JONES: Should it be intensify--I have to read his writing--expand or intensify--

CHAIRMAN CAPLAN: Surveillance.

MS. JONES: Surveillance of emerging infectious diseases in blood donor and recipient populations.

DR. PILIAVIN: Why can't we just say "in the population."

CHAIRMAN CAPLAN: In the population and forget about blood donor recipients.

DR. PILIAVIN: Forget about donors and recipients.

CHAIRMAN CAPLAN: In the population. I see what you are saying. Surveillance in the population.

DR. NIGHTINGALE: The original intent, when this speech was being developed, was to ensure that populations that would remain at risk or become proportionately a greater fraction of the risk, such as the alpha-1-antitrypsin population, was not neglected in any surveillance effort.

CHAIRMAN CAPLAN: That's all right, though. Population will still get us there.

DR. GUERRA: Yes. I think that really gets to the heart of the surveillance in the population base, that if there is an emerging condition that one identifies, even in a nonblood donor or recipient, but that could potentially put that group at risk, one needs to know about it.

CHAIRMAN CAPLAN: You didn't say it, but in the spirit of what you've been talking about, it doesn't make us take a stance about local versus federal or something.

Jay?

DR. EPSTEIN: I actually preferred the original version, and I'll tell you why. If you put a box around surveillance and donors and recipients, it's a target for initiatives and funding. If you don't put a box around it, many other efforts can go in other directions, which I think aren't the main focus of this committee. So I prefer a statement that focuses on the donor and recipient because it's more likely to result in an outcome that concerns this--

CHAIRMAN CAPLAN: Do you want to do this then by, a suggestion might be two sentences: "Maintain and expand surveillance in the donor and recipient population" and, also, same language, "in the population"? Do you want to do it that way?

DR. EPSTEIN: No.

CHAIRMAN CAPLAN: Mary?

DR. CHAMBERLAND: I agree with Jay in that there already is underway at all of the PHS agencies plans for the monitoring, detection, research efforts towards emerging and re-emerging infections. I think my concern is that the response to such a recommendation, if it's less focused or more global, would be we have those programs in place or they are being put in place.

So I think, if the committee really--I think there would be a better likelihood that perhaps we could target down on recipients and blood donors if that language stayed there, and if you make it more dilute, we may lose what actually is at the heart of the matter.

MS. O'CONNOR: You could cover both by just putting "in the population, especially blood donors and recipients."

CHAIRMAN CAPLAN: Jim?

DR. AuBUCHON: I agree with Mary's and Jay's comments and would also suggest--I hate to get this specific--but changing the word "infectious" to transmissible. Make sure that we cover those things that might be transmissible, but not necessarily, per se, infectious.

DR. SNYDER: I concur with Jay also and also with what's been said; that for funding purposes, the narrower the focus, the more bang for your buck.

DR. PILIAVIN: I withdraw my suggestion.

[Laughter.]

CHAIRMAN CAPLAN: I liked it, but all right. I guess the elk will wander where they wander, or they'll be picked up anyway.

Mary?

DR. CHAMBERLAND: Art, I know that this has come up in an earlier meeting and this meeting as well, the concerns about the transmissible spongiform encephalopathies. I think, and perhaps Jay or Dave could speak to this a little bit more specifically, but there is another Advisory Committee in place, and I think there are also efforts in the other agencies, Department of Agriculture, et cetera.

So my concern has always been that, while this is related to this committee's work, it's something that I think--it's not something primarily is our focus, and I think we should perhaps track, and monitor, and learn what these other committees are doing, but I've always felt a little unsettled that we're kind of getting into an arena that is not our primary focus, and there are other groups and efforts underway. Again, I can't speak to what those are.

But the sense is, is that we are dropping the ball by not speaking directly to it when, in point of fact, there are other efforts underway to do that.

DR. FEIGAL: I think the word "maintain" helps acknowledge that there already are some existing efforts to plug into. So I think that's not as much of a problem.

The only other comments, a slightly different topic, is by just mentioning emerging, we don't emphasize the importance of dealing with the infections that aren't emerging, like hepatitis C. They've always been there and are still benevolous. CHAIRMAN CAPLAN: We could put existing, emerging, re-emerging, that's all right.

DR. FEIGAL: Yes, existing and emerging.

CHAIRMAN CAPLAN: I think I detect a consensus emerging here. Did I move this thing?

DR. NIGHTINGALE: Nobody moved it.

CHAIRMAN CAPLAN: Can I get a motion to move on this one?

DR. GOMPERTS: So moved.

CHAIRMAN CAPLAN: It's been moved. Second?

DR. AuBUCHON: Second.

CHAIRMAN CAPLAN: Last discussion?

[No response.]

CHAIRMAN CAPLAN: All in favor of that language, understanding that we are going to take this away in its presentation from the recombinant issue and have it someplace else, raise your hand to say aye.

[Show of hands.]

CHAIRMAN CAPLAN: Opposed?

[No response.]

CHAIRMAN CAPLAN: Good. We may be in a position then to take a look for a second at the issue of monitoring. This was the question of do we want to say something about the creation of a sentinel or monitoring function to keep an eye on production, demand, and utilization? I guess the language I would be looking for is something like, "The committee would like to hear proposals" or "specific proposals at its next meeting about monitoring and sentinel functions for the blood supply." Maybe I'll stop there. That might be a way to start.

I am ready to admit that we might need to hear some options or ideas about how to do this and have some more input into it before we finalize. But I would like to get the ball rolling here so that we do it later.

DR. NIGHTINGALE: Do we need a formal motion or recommendation for that to happen or can staff do that just after hearing our discussion?

DR. HOOTS: Either way. Your choice.

CHAIRMAN CAPLAN: God, it never occurred to me we wouldn't have to recommend. You mean, we just tell them and they do it?

[Laughter.]

DR. HOOTS: I think some language about confidential information and how to deal--the fact that this sentinel could receive, process, and react to confidential information from manufacturers or other sources because that's the one thing that is difficult for this committee to do or any other committee that now exists.

CHAIRMAN CAPLAN: Let me propose this. Again, I don't care if it's a recommendation or in this one we are just issuing something that the committee wants staff to do and ask Steve to talk with Eric and to move Satcher to do it and the secretary, as necessary, to get involved with. I don't really care how we do it.

Would you allow us to craft a little language outside of here that would say something like, "In light of problems of supply shortage, hording, price gouging, it is very important that efforts be made to create a sentinel system that has access to confidential information in order to reduce these sorts of problems"?

In other words, we can write the preface language about why we are trying to set this up on our own. I mean, we'll show it to you later. Then we want to hear some options about this for our next meeting. Recognizing that we know we're in the zone of confidential information. That's part of what we are trying to figure out some way to allow a body or a person to function that way.

We'll understand that there may be a little preface to this, so that it's clear what we are trying to get at, what the problem is.

All right. Let's bite the bullet. Do you want to make a recommendation or in this one do you want to direct Steve and Eric to do this? I don't really care.

DR. NIGHTINGALE: Nor do I.

CHAIRMAN CAPLAN: They don't care. No one cares.

All right, well, let's take the easy route. Instead of a recommendation, why don't we then direct staff to move within the Humphrey Building to come up with options about the creation of a sentinel system to monitor production, demand, utilization, and to create modeling projections in response to these problems of shortage, and speculation, and price gouging, and so on, which you have talked about, which we will get that down.

DR. NIGHTINGALE: Do I need the buzz words?

CHAIRMAN CAPLAN: If it motivates you.

DR. NIGHTINGALE: I'm motivated already.

CHAIRMAN CAPLAN: Just so you know what's bothering us.

DR. KUHN: Art, would it also be the function of this sentinel perspective to also address the source plasma and finished products being exported?

CHAIRMAN CAPLAN: Yes. That's absolutely part of that.

DR. KUHN: I want to make sure it's in there.

DR. GUERRA: And, I guess, to also be sure that this effort includes review of what is already in development or has been developed and has been tried, in terms of registry and tracking of populations.

CHAIRMAN CAPLAN: Right. And we did hear about the system that John mentioned about the warning system that is starting up at the other end. That's important to take cognizance of, find out about. I'd like to get a report about that as appropriate.

Carol?

MS. JONES: I think that we should really stress the idea that the committee wants to be presented with options and not limit itself to necessarily a sentinel system to do it. Because I think creating a bureaucracy of a system like that, when the government is under such resource constraints, FDA has a lot of resource issues, that I think we need to look at the options that allow possibilities to monitor production and demand domestically and internationally for these products. Don't just focus on the idea that there needs to be a sentinel system.

DR. NIGHTINGALE: I assume the committee understands that the logical way of implementing this would be a suggestion or a recommendation to the surgeon general in his capacity as the blood safety director to take these actions.

CHAIRMAN CAPLAN: The chair would say that any proposals from anyone within earshot, voluntary or otherwise, about how to do this would certainly be something that Steve would be more than grateful to hear about.

So if someone wants to come in with some ideas, submit them, we heard Centeon say something about some ideas they had about information exchange and so on. So those ought to be encouraged, and I'll make sure to say on the record that Steve should be looking for soliciting input about ideas from all sources.

DR. FEIGAL: We may be able to do the old proverbial I can't remember if it was 7 or 11 blind men and the elephant way of painting the picture. I think that different players have different access to parts of the picture.

FDA has certain information and industry has certain information. I think the patient demand is one that maybe the CDC could even comment whether or not their state system and sentinel system might have some opportunity for doing some of the things on the patient end of that. We may not be able to put together a single system, but we may be able to tap a number of sources by slightly modifying some resources that are already available.

CHAIRMAN CAPLAN: Remember, the committee did hear last time too there were some studies done, the Immune Deficiency Foundation gave us some information on IVIG and what was short. So there is stuff out there is sort of pulling it together from many different sources, so that it can be used to help to respond to supply issues.

DR. HOOTS: I was just going to say, in response to David's comment, we have heard data about the UDC at the CDC which will be helpful. The other part is the PHS pricing program, the data that Pat McGuckin presented, putting those two together, which is already kind of in the pipeline as well gives us a much better handle than we've ever had before about the utilization and demand side of the equation.

DR. GOMPERTS: Art, I strongly endorse this committee hearing issues that pertain to the complexity of supply and demand of these biotherapeutics. I think, from where I sat here, the issue of hording and price gouging I think there is the potential for that. However, if it is going on, it doesn't seem to be a major factor at this point in time. However, it is an issue, and we do need to hear about it, and mechanisms to prevent this potential manipulation.

CHAIRMAN CAPLAN: One other thing, just as long as you are getting the sentiment here, as part of this, we would also like to hear something about the possibility of standardizing information so that demand could be better charted than it might be.

I can't come back to my own brilliant insight about the fact that there is only roughly 50,000 people, so maybe we could have more standardized reporting and have some sort of a data pool that would give us who is being gouged, is it a big problem. We'll know because we can just ask people and say, "Where did you get it? Did you buy it on the spot market? What did it cost?" that kind of thing, without violating anybody's confidentiality, but we'd have some concrete basis rather than just speculative sort of talk.

I don't think we have to vote on anything, but I think we've given a sentiment to staff about that one, and that clearly will become a big part of our next meeting, listening to that.

DR. NIGHTINGALE: Actually, I would actually prefer that there be some statement on the record by the committee, the equivalent of a tail wind, if you will, for us, such as that the Advisory Committee directs its staff to develop options to be presented to the Blood Safety director for the creation of a sentinel system to monitor production, demand, and utilization of blood products and to create modeling projections for future demand.

DR. AuBUCHON: So moved.

DR. EPSTEIN: Second.

CHAIRMAN CAPLAN: Sounds good. All in favor?

[Show of hands.]

DR. EPSTEIN: Do we have that in writing?

CHAIRMAN CAPLAN: Opposed?

[No response.]

CHAIRMAN CAPLAN: You will see these, by the way, for finalization.

DR. NIGHTINGALE: Who seconded it?

CHAIRMAN CAPLAN: Jay.

My list of issues to talk a little bit next is the dealing with the current shortage of products specifically for hemophilia, people with hemophilia who rely on clotting factor. The current shortage that we heard, I don't know if we want to say anything or nothing about that.

DR. SNYDER: Before we do that, could we return to the financial barriers? We never really addressed that.

CHAIRMAN CAPLAN: Excuse me. I jumped them. Good point. I had that next on my list, and I just jumped over that.

After recombinant, we were going to talk about alleviation of financial barriers, and that is what we should talk about next.

One issue that was before us is whether we want to say something about caps, specifically. We could certainly urge that financial barriers be removed or that steps be taken to remove them, but here we are probably going to need a little bit more specific talk about some for instances.

DR. SNYDER: To go maybe one step further back, I was looking at what the surgeon general's statement said specifically about Medicare and about reimbursement. Wasn't that the third item?

DR. NIGHTINGALE: No. The third item of the surgeon general was to maintain and, as necessary, expand or intensify surveillance was the third item.

CHAIRMAN CAPLAN: He had a Medicare--

DR. SNYDER: Or was that on your sheet?

MR. WALSH: That was on our sheet.

CHAIRMAN CAPLAN: That was on the sheet that Dana had in front of us, which we could put back up there. We might as well have that in front of us. Some language is up there, "All financial barriers should be removed to ensure access." That probably is a call for national health insurance, I think, and "Medicaid should establish reasonable national reimbursement standard for common clotting factors." But there is some language there.

We are talking about state program safety nets, caps, that sort of stuff. So I am open to language about--some proposal about financial barriers.

DR. HOOTS: I think specific languages about lifetime caps related, in this case, to hemophilia need to be made, but they can't be made alone because then deniability of insurability becomes the next issue. So either that is approached or else we make recommendations specifically that HCFA come up with a strategy after those have been removed, so that the private sector can't penalize people for going for recombinant if they already have coverage. But if they deny them coverage, which, again, is maybe a bigger issue for the broader health community than just hemophilia, that HCFA have a broadened safety net to pick up individuals.

Also, the biggest problem right now is eligibility for HCFA-related problems, and that varies state by state. That's why Medicaid, the language has to be directed from the HHS through HCFA and not directly to Medicaid because then you are going to go state by state. Medicare you can direct nationally, but Medicaid you cannot, unless there is specific language from HCFA that says Medicaid programs will do this.

So I think we need language that says that we would recommend that the secretary or the under secretary impose specific language to HCFA about reimbursement of recombinant factors for people with hemophilia, otherwise we're kind of paying lip service, and we actually could make a bad situation worse if we just remove caps and do nothing else.

CHAIRMAN CAPLAN: The fear, by the way, for those of you who didn't follow, is if you pull caps, there are many carriers who will then say we won't insure you. It's very simple. We've seen that happen many times. So pulling a cap is not necessarily doing anybody a favor at anything if that's all that happens.

Let's see, Mack. Let's go to a blank sheet here. Do you want to try--I'm trying to reconstruct your language here--"We are concerned to remove financial barriers and, thus, direct the secretary--to recommend to the secretary that language be--we condemn the secretary--"

[Laughter.]

DR. HOOTS: That rules--that HCFA rules be implemented.

CHAIRMAN CAPLAN: That HCFA rules be implemented.

DR. HOOTS: "--that ensure that individuals who, for financial reasons, are denied access to recombinant have access to expanded coverage to assure that this does not occur." I think it's the broadest language I could come up with.

CHAIRMAN CAPLAN: There must be a way to say that shorter.

DR. HOOTS: Yeah, there's a probably a better way to say it.

CHAIRMAN CAPLAN: "That HCFA rules be implemented to guarantee access"?

DR. NIGHTINGALE: That ensure patients have access to sufficient--

DR. HOOTS: Yeah, "--to recombinant factor replacement therapy." Because the good news about putting this kind of language in is that let's say it's in the time of a shortage and there is not enough recombinant, if they have access to recombinant because of the pricing structure, they will always have access to factor, which right now a number of people don't because of eligibility factors related to Medicaid and, also, in our part of the world for--

CHAIRMAN CAPLAN: All patients.

DR. HOOTS: Patients who don't meet eligibility for citizenship or other issues. But if the federal government says that recombinant, if you have hemophilia, and you are here, then you have access to recombinant, then it's up to them to come up with the rules changes that ensure that. If we try to micro-manage the rules changes, we'll get into all kinds of language.

CHAIRMAN CAPLAN: If a rule is being implemented that assure that all patients have access to--

DR. NIGHTINGALE: Recommend to the secretary that HCFA rules be implemented to ensure that all patients have access to recombinant clotting factors when medically necessary?

DR. HOOTS: To reimbursement of recombinant clotting factors. Period. I don't think "when necessary" is even necessary--is not necessary.

DR. PILIAVIN: Well, I, given what we said before about not wanting to legislate medical practice, I think we do need--the way this is worded now it sounds like we are saying everybody should have this stuff, even though some people presumably shouldn't, given what we said before.

DR. HOOTS: I agree with you, but I think the reality is because of the cost structure of recombinant, that if the government mandates that people have access to recombinant factor, then the reimbursement mechanism is in effect. So that if they are on other products, they will get reimbursed. If it's stated that people with hemophilia have access to the best--I mean, I'm afraid if we dilute it, then what's happened before with HCFA, and I actually should have brought you the numbers, but--

CHAIRMAN CAPLAN: But, Keith, let me just interrupt to say, if we say to ensure that all patients have access, we are not saying that they have to get it--I mean, that that has to be the treatment of choice. All we are saying is it has to be fiscally possible for them to get it, if that's what is deemed appropriate between them and the doctor. I think to have access is not meant to say you must take this treatment and you and your doctor can't choose anything else. It's more you should be able to get it.

I think the way this is written--I know what you are about to debate, but you don't have to. It's not telling anybody what they have to do for treatment in the doctor's office. It's just saying you should have access, and don't have that limited by fiscal barrier. Then you can negotiate what--some people may, for who knows what reason, not choose to use that product.

DR. HOOTS: Yes, I think the key issue, and maybe that is what Jane is approaching on the narrow issue is about which product. I am not so concerned about which product. I am concerned that there are so many people out there who have access to no product because of reimbursement.

But I think, in light of the fact that we've made a recommendation of an acceleration towards recombinant, if we tie the two together, it strengthens the cogency for the secretary to push this agenda. If we separate the two agendas, there is a possibility that the second part of the group who, for whatever reason, could be carved out is saying they don't get recombinant and, therefore, we don't have to cover them. I think that would be a real tragedy if that happened.

CHAIRMAN CAPLAN: Further comments? Jim?

DR. AuBUCHON: I fully support what has been displayed here, but I do feel compelled to note that although this therapy is very important for this group of patients, there are 37 million Americans with no health insurance coverage, and some that have insurance coverage, that cannot afford medications and other treatment that are at least if not more important for their well-being.

CHAIRMAN CAPLAN: I am reminded yesterday we spent some time talking about who gets reimbursed, and can you get the helmets and the pads and all that stuff. Do we want to say something like "have access to reasonably reimbursed"? "Reasonable reimbursement?"

DR. KUHN: Yes. I was going to say "reasonable reimbursement" because there are certain, like Medicaid could reimburse--

CHAIRMAN CAPLAN: Right. I mean, you could reimburse to say certain cents.

DR. HOOTS: Yes, certain cents over acquisition price.

CHAIRMAN CAPLAN: Yes.

DR. HOOTS: I would support that.

DR. NIGHTINGALE: "Reasonable" is a word that tends to die in the midst of a bureaucracy. It kind of sinks like molten lead in the sea. "Adequate" might be a less depth-charged word.

CHAIRMAN CAPLAN: I mean, all these words are open to somebody's interpretation of what is reasonable and adequate, but we are trying to--I think by adding it at least what we are trying to do is say it shouldn't be inadequate, which is a worse situation.

DR. McCURDY: One of the things--

DR. GOMPERTS: I think--excuse me?

CHAIRMAN CAPLAN: Yes, Ed, and then we will go to Paul.

DR. GOMPERTS: I think we may broaden it. "Recombinant protein biotherapeutics," in the event of the recombinant alpha 1 antitrypsin becoming available, or we could say "recombinant biotherapeutics including recombinant clotting factors."

CHAIRMAN CAPLAN: That would just mean inserting the--

DR. NIGHTINGALE: Instead of "clotting factors" just write "biotherapeutics."

CHAIRMAN CAPLAN: Oh, sorry, sorry. Paul first, and then--

DR. McCURDY: Are we creating, help me understand, are we creating a new entitlement here under HCFA? How does HCFA guarantee access and reimbursement without doing it themselves? Can they mandate that private insurers do this?

DR. NIGHTINGALE: Yes and no.

CHAIRMAN CAPLAN: Sort of. I mean, they can only do what they can do, but there are things that they can do, is the way I would put it. They can--where we were talking about the Medicaid directive and so on, that's how it happens. Other carriers then usually have to follow in line. I mean, they have some authority but they certainly cannot mandate the private sector carriers, but they become standard of reimbursement if they put it through what they do control.

DR. McCURDY: Eligibility for Medicaid is means-based, and one of the problems of various different patient groups, the ones we are talking about today and some that we are not, is that when they get old enough, they come off their parents' insurance, they have trouble getting their own insurance, to get on Medicaid they have to quit their job and sell off assets if they have any, et cetera. And all of these things produce some problems.

If you create a HCFA, a Medicare entitlement, that would solve that, but I don't know that this committee has the--I think that is a congressional action that needs to do that.

DR. HOOTS: I think to be candid here, yes, what we are talking about here is an entitlement, and I absolutely agree with what Jim said. I mean, I think in the best of all worlds we wouldn't be having this discussion at all because people would have coverage.

The reality of the situation is, substantial numbers don't, and clearly we have to start--I mean, we are--part of this equation is blood safety and availability, and that is the one thing that we can impact. And I know we are not here to create social legislation, but if we are talking about access and safety, it does seem to me it still comes within our purview to discuss and make strong recommendations in this regard, while at the same time acknowledging that we may not be able to solve other things we wish we could solve.

DR. SNYDER: I really think the committee needs to hear from HCFA for what options might be available. That, or we need to tone down what we are telling the Secretary--you know, asking--or ask the Secretary to investigate with the HCFA, you know, what mechanisms could be used to remove financial barriers, because that addresses Paul's concerns.

But I think that we are--you know, we don't have somebody from HCFA here, and I know enough about HCFA to get me in trouble and that's about it. So I think we are going into territory that, as Paul is saying, could present a problem.

CHAIRMAN CAPLAN: Is the problem by using the word "implemented"? Do we want to say HCFA rules be "developed" or something like that?

DR. SNYDER: I don't even know if they can develop a rule--

CHAIRMAN CAPLAN: I know, but then at least we are opening the door to--

MS. JONES: I think the first question is, we need to determine whether HCFA is not covering risk now. The question raised yesterday, you know, didn't revolve around HCFA reimbursement, it revolved around private payer reimbursements. And what you're trying to do is to use HCFA as the bulldozer to push private payers to reimburse for that, and we need to find out whether HCFA currently does not reimburse for recombinant products.

DR. NIGHTINGALE: In anticipation of this meeting I did contact both the Medicare and the Medicaid officers in HCFA who are responsible for these programs, for clotting factor reimbursement, and they both indicated to me that at present certainly the Medicare reimburses for recombinant factors, and the Medicaid program accepts reimbursement to the extent of its current authority.

In the case of Medicaid, it is not a mandated coverage in every State. So the issue I think would be, from the perspective of the HCFA employee, would be a directive to HCFA to consider making such coverage mandatory would be an action that at least the--that HCFA could pursue.

CHAIRMAN CAPLAN: Fernando?

DR. GUERRA: A few years ago when cost was a very significant barrier to accessing immunizations for children, the Congress passed the Vaccines for Children Act that assures that children that are uninsured, that are on Medicaid, that are Native American populations, could always access immunizations in that network of providers in the public and private sector.

It has worked very well. It has raised immunization coverage levels very significantly. And the way it is set up is that the vaccines are provided to the providers as long as they use them only for those designated populations where the Public Service or the CDC, and I suspect HCFA, ultimately on a contract basis acquire the vaccines.

It seems that if in fact within this population that needs to access many of these products there are those that are on Medicaid and those that are uninsured, that there would be a supply that would be essentially acquired by--I guess through the Public Health Service contract price that already is available to the Hemophilia Treatment Centers, and that could then, you know, be made available for this population without having to deal with caps and all of that.

And I think that it also puts the burden on the private sector that generally there is a limit in what they can--if they access any of these products, the only thing they can charge for really is the administration cost.

CHAIRMAN CAPLAN: Shifts in the language, editing, in light of that comment, anyone have any refinement of language? Instead of "rules be implemented," which is now striking me as two narrow, but we want something that would allow the exploration of what Dr. Guerra just talked about; I mean, there is clearly something here that lets you go and look, and say lets HCFA explore options to ensure?

I mean, everything from the equivalent of the vaccine program all the way out to Medicaid being--having a policy in place. I don't want to come up with weasel language, you know, that is too weak, but I'm trying to let them look and come back and tell us, "Well, here's what we do, here's what we don't do, here's what we could do," across the board.

DR. HOOTS: I think Fernando's suggestion is a good one, and I think one of the things, a way we may be able to handle the softer language is the way we did earlier, which is to report to this committee progress towards implementing, or whatever, a strategy that will accomplish this.

Because otherwise I think it kind of allows them a lot of latitude to say, "Well, we're working on it," whereas if they are somewhat time framed and somewhat at least directed towards actually developing something, rather than, "Oh, yes, we saw your language, we're behind it, but."

CHAIRMAN CAPLAN: Do you want to read it?

DR. NIGHTINGALE: Would you agree to language that says that the committee recommends that the Secretary of Health and Human Services directs the Health Care Financing Administration to explore strategies to ensure that all patients have access to reimbursement for recombinant--

DR. HOOTS: And could we follow it up then to submit proposals therefor, or thereof, or whatever, to this committee in some sort of time-framed sort of way?

CHAIRMAN CAPLAN: To explore it, and then what is being asked is an addendum that says "and to report to the committee in a timely manner."

DR. HOOTS: Yes.

MR. WALSH: Mr. Chairman, can we say at the January meeting?

CHAIRMAN CAPLAN: We can probably say whatever we want. The question is what they will do.

[Laughter.]

CHAIRMAN CAPLAN: I like language that is timely, so that I--you know, if it happened at the March meeting--April meeting, excuse me--okay.

DR. NIGHTINGALE: It's more likely to happen at the April meeting. There's a lot going on at HCFA right now.

CHAIRMAN CAPLAN: In a timely fashion.

MS. JONES: Could we add, you know, because I'm still getting back to the fact that the issue is not necessarily with HCFA's reimbursement but with private payers, could we add language that the Secretary might encourage private payers to do the same, or something along that--

CHAIRMAN CAPLAN: See, the reason I'm not worried about that is, it's encouraging to ensure that all patients have access. That means they should be touching base with the private folks and having that discussion.

MS. JONES: But--yes.

CHAIRMAN CAPLAN: I mean, I don't mind encouraging the private--

MS. JONES: I think that's too light a touch.

CHAIRMAN CAPLAN: So what would you propose, then? If you want, I can have Steve read the real--if you can't sort of wander through that.

DR. NIGHTINGALE: The current version.

CHAIRMAN CAPLAN: Yes. Mac, why don't you see if you can copy this down, too, as he reads it. Just ditch that one. It got edited enough.

DR. KUHN: How about "all means of reimbursement"? Would that include carriers?

CHAIRMAN CAPLAN: All means?

DR. NIGHTINGALE: Let me try this one. Let me read it before Mac writes it and see if it passes current muster.

"The committee recommends that the Secretary of Health and Human Services direct HCFA to explore strategies to ensure that all patients have access to adequate reimbursement for recombinant biotherapies, and to report to this committee in a timely manner."

Do you want to write that? Worth writing down? Okay.

"...recommends that the Secretary of Health and Human Services direct HCFA to explore strategies to ensure that all patients have access to adequate reimbursement for recombinant biotherapies, and to report back to this committee in a timely manner."

DR. HOOTS: One other thing, just to deal with what Carolyn was talking about in terms of private sector. When I said I didn't think the cap issue would solve the problem, I think, though, I agree we can't let private sector off the hook.

And one of the ways to do that, and it's ironic because it actually happens with some insurers who have separate pharmacy programs where the factor doesn't count against their lifetime maximum, if we were to make a specific recommendation in that regard, that reimbursement for factor concentrate does not count against the lifetime maximum among private insurers, that way it does several things.

One is, it means there is a level playing ground between hemophilia and other people with chronic diseases, a relatively level playing ground. Secondly, it reduces the likelihood that they will dump the patients on--they can dump the patients onto the public sector for reimbursement and cost the taxpayers. And, third, it helps equilibrate across State lines, which is now a real, real issue, particularly as managed care has become more powerful.

DR. NIGHTINGALE: That would be one of the strategies.

CHAIRMAN CAPLAN: I mean, that's clearly a strategy to explore. Part of the reason, to be honest, I'm hesitating about even going there is, it is starting to mandate things into the private sector that it is hard--I mean, they have to--whatever happens, you have only got the Secretary and HHS and the relevant agencies to do it. It's hard for us to say, "Don't count X against the cap."

It's a reasonable strategy to explore. I don't think it's one that we can actually put forward as an--we don't have any leverage to make that happen. That's just an aspirational thing.

Yes, Jay?

DR. EPSTEIN: In looking at this statement, I'm a little bit troubled that we are focusing at all on HCFA. Why not simply direct the Secretary to do this exploration? After all, it might be useful to contact ACPR, CDC, HRSA, legislative initiative.

CHAIRMAN CAPLAN: Yes, true.

DR. EPSTEIN: I mean, we foresee that there is a role for HCFA.

CHAIRMAN CAPLAN: You can say "HCFA and other appropriate agencies." I don't have any problem with that.

DR. EPSTEIN: But I think that what we are confusing is that we see HCFA as part of the solution, but do we really want to focus the exploration of options on HCFA?

CHAIRMAN CAPLAN: Do you want to just say "HCFA and other appropriate agencies"?

DR. EPSTEIN: Well, I would omit it, but I can live with that, yes.

DR. NIGHTINGALE: HCFA is the agency that pays the bills.

DR. EPSTEIN: But paying the bills may not be the answer. In other words, it may not be that HCFA pays the bills. There are other possible outcomes. But again, I can live with that, "direct HCFA and other"--

DR. NIGHTINGALE: Okay, and other--

CHAIRMAN CAPLAN: Appropriate agencies. All right. I have a feeling we are stumbling toward something that we might entertain a motion on here. Do I hear one of those? Are we ready for that?

DR. GUERRA: So moved.

CHAIRMAN CAPLAN: Second?

MS. JONES: Second.

DR. NIGHTINGALE: Last shot?

CHAIRMAN CAPLAN: Comment, Mike? No? Just ready to vote?

Okay. All in favor?

[A show of hands.]

CHAIRMAN CAPLAN: Opposed?

[No response.]

CHAIRMAN CAPLAN: All right. Unanimous. Put that one through.

Shortage. I jumped ahead to that.

DR. BUSCH: Just one thought. I think the first motion or the first proposal to explore steps to accelerate the implementation of these factors is sort of the primary point, and these recent two issues, the one on the research and then this other one with respect to reimbursement, are sort of subsidiary. Those are good steps to pursue this.

I think there is one that perhaps hasn't been explicitly discussed, which is perhaps related to the modern production, but I really don't have a sense of what production capacity is forthcoming. And perhaps another step that could be pursued would be to compile the production plans with respect to recombinant product of the different companies so--

CHAIRMAN CAPLAN: You know, that really is part of that sentinel. When I was talking about production, I expect them to really do that, just to be clear about that on the options thing. It's really to get that in there, absolutely.

I have a feeling, by the way, that some of that information is scattered around. All we need to do is have somebody that can collect it without violating antitrust, anticompetitiveness, proprietariness, and so forth.

When Mr. Robert gives us his best guesses as he tries to project ahead what the market is, he could do better if he could peer into the calculations that each company is clearly doing. It's just that no one can give them to each other. They can't give them to him. They'll be violating

--but maybe we can come up with something that somebody could get them, so that then they could keep a handle on that. But absolutely, that is a key component of the sentinel thing.

Let me ask this: I think we have one other area that I'm alert to, which is in my head, which is do we want to say something about shortage. There is also this problem about bladder. So we could take a break and come back and say something about shortage. You may not want to say anything about shortage. But when we reassemble--I got feedback about the bladder thing pretty fast--so when we reassemble in 15 minutes, if you want to spend a little time, if you have something you think we should say about shortage, please write that down. And if you think there is some other issue that we have neglected, please try to craft some succinct language about that.

Okay, 15 minutes.

[Recess.]

CHAIRMAN CAPLAN: All right. Before the break I said that one issue that remained that I knew, a major issue, there may be others that the committee wants to put forward, but one I knew was there was the issue of shortage of clotting factor and whether we want to say anything about that.

I can tell you that three issues I have heard mentioned about current shortage are--we haven't got to language yet, Mac--but people asked about:

Do we want to say anything about how we feel the Secretary might suggest or examine allocation with respect to children or people who are immune compromised with the available supply of recombinant product?

Do we want to say anything about inventories and the desire to build those in the context of shortage, or is that not the place to do it?

Export is there, and I guess we could even say, are certain shortages being exacerbated now because of product being overused or lack of information about dose levels, and so on?

We may not want to get into any of this detail. I would just--this is more of a summary of things that I heard mentioned during the day yesterday about specific response to shortage.

So if anyone has some language they would like the committee to consider, let's open the floor for that. Dana?

DR. KUHN: Again, in regard to the--I have some language here that I would like to submit. I think we have talked about export for such a long time in regard to IG/IV, and now to recombinant, that perhaps we need to get on the record of having some kind of a language and some kind of a means by which we can check and balance the export of our products, especially when we heard from Dr. Gilcher that there is a--70 to 80 percent of our source plasma is going overseas. I think there needs to be a way to try to maintain that for our American people.

So this is just proposed language. I don't know if we are putting or making a policy here, or if we are causing perhaps the FDA or whomever to regulate, a new responsibility, but I do think there needs to be some kind of a policy here in which--and a recommendation which we can suggest strongly about keeping our product here in the United States to address shortage.

DR. McCURDY: It is my impression from various different sources that source plasma itself is rarely the limiting factor in the production of these plasma protein derivatives; that that is, within probably limits, expandable and contractible.

And I think that it may be legitimate to be concerned about finished product going overseas, but I would wonder whether we would want to lump the two together. Because they are different, and I think the source plasma shortage, if there be any, tends to be short-lived, while the market tends to increase or in the other end decrease the availability.

So I think the product, finished product, is all right. Source plasma, I don't know as much about and I don't think that is limiting.

CHAIRMAN CAPLAN: Dr. Davies isn't here, but we had some discussion around the IV/IG issue about source plasma, Red Cross sending things overseas and so on. But I don't remember hearing anything at all that there was a problem of shortage about export of source plasma, per se.

DR. McCURDY: Actually, I am--I have been trained by my FDA colleagues. Source plasma is plasma that is obtained by plasmapheresis, and recovered plasma is that that comes out of whole blood donations, so I have been making the distinction.

I think that recovered plasma at the present time, because of pool size issues and problems about the number of donors per unit volume and so forth, that recovered plasma is more of a drag on the market than source plasma.

CHAIRMAN CAPLAN: Are you comfortable just getting--

DR. McCURDY: Yes.

CHAIRMAN CAPLAN: Okay, so we don't have to argue about that point.

Other comments?

DR. BUSCH: Well, just on this specific issue, recovered plasma right now I think is a problem, and it is in part the crisis that goes on in Britain right now, and they are, the British are out trying to buy recovered plasma all around the country.

CHAIRMAN CAPLAN: I see.

DR. BUSCH: And people are now, you know, because the price is better, I think they are looking to sell it to Britain for that development, as opposed to where it is now going to I guess Switzerland for fractionation.

I am also hearing rumors that the Red Cross, with the conversion to SDFFP, has moved a lot of their plasma into production of SDFFP, and that there are some issues with respect to availability of plasma for manufacturing of derivatives within the Red Cross.

So I think there are issues with respect to plasma as well as the final product.

CHAIRMAN CAPLAN: Richard, when you were out of the room we put this first bit of language, and Dana had some proposal about what we might say specifically in response to existing shortage, and we were--what Mac is etching out so usefully there, but don't take it up quite yet, was the language about source plasma and finished products, that we make some recommendation about trying to ensure that this supply is adequate for American user communities.

And the issue came up about whether recovered or source plasma is something we need to pay attention to, as far as whether that is moving elsewhere before it can be used by American user communities or turned into products useful to them. So I don't know if you want to say anything about that. I would be interested if you have a comment about that.

DR. DAVEY: In terms of the Red Cross, I think we have been very committed to having our recovered plasma that has been manufactured into derivatives remain pretty much wholly in the United States, and I think that is still our commitment in the American Red Cross. I believe that some of our material now is going to Britain, however. I'm not sure how much. I think it is a very small amount, but I believe some of it is being shunted to the British market.

I think one side issue, Art, which may help some of the shortages, is with the lifting of the CJD withdrawals, the American Red Cross, as you may know, has had a policy in place that plasma from donors over 60 would not be used for further manufacture into derivatives. That restriction will now be lifted, so plasma, that extra source of plasma that has not been available for further manufacture will now be made available, and I think that will help.

Also, we have several million dollars worth of material on quarantine right now because of CJD-related issues that we anticipate will be able to be released, and we think that will be helpful.

DR. KUHN: I think the spirit of this still is in times of shortage, emergency issues, emergency times, not--you know, I want us to keep that in perspective.

CHAIRMAN CAPLAN: Further comments?

DR. FEIGAL: Maybe this is another one where we need to recommend that the Secretary provide us with some options, because we have had comments earlier about the need to hear from the Commerce Department, Federal Trade Commission, really find out kind of what our options are. Are there things that can be done in the context of existing laws? Are there things that would work under the Public Health Service Act? Or do we require new legislation in order to be able to do any of this? So this may be one where we need to have more information on some of the options brought back to this group.

CHAIRMAN CAPLAN: Just in the spirit of that comment, I will just say this, a personal statement: that whenever the issue of export comes up, everybody begins to shake their head and say, "Boy, that's just a hornet's nest. We can't get in there." But I don't mind, if we decide to do so, to try and keep the heat on to see if we can get an answer about whether anything can be done.

One way to do that might be to say that we recommend to the Secretary that it is very important that plasma and finished products, in times of shortage, be available to ensure safe and adequate--and we want to hear options toward that end. In other words, it is flipping--we want this done, and then we have to have some recommendations about how to make this happen.

I don't want to just get a list of--I don't want to get a report back saying it can't be done, because the goal here is to say, "Look, you've got to make sure you have a safe and adequate supply for American user communities. Now what are we going to do in times of shortage to do that?"

I don't want to hear what can't be done. I want to know what is going to happen to do this, is what I'm trying to get at here. I'm a little afraid I will get back a nothing, "Pass a law." And what I want to do is make sure we write this so that we want to know specifically what can be done to get to that goal.

DR. NIGHTINGALE: One thing that might facilitate discussion of this issue would be to substitute the word--add the word "North" before "American" in this discussion, because there is a very substantial interdependence between the plasma supplies of the United States and Canada.

DR. GUERRA: I think that brings up another point, and that is that--and I have absolutely no idea how large the population would be of foreign nationals that come into this country to receive these products. I know in some of the border States that does happen on a regular basis.

Keith, I don't know what your experience has been in Houston. Certainly in San Antonio I know that there are any number, especially Mexican nationals that are able to pay their own way, that can access the supplies quite readily. And so I think that, you know, that becomes certainly a humanitarian issue, and--

CHAIRMAN CAPLAN: Let me--every--I think I have said this now at three meetings, but it must amuse me to say it, so I will say it again: that in the transplant area where there is extreme shortage of vital organs, there was a large trade coming into this country from overseas of people who could afford to get on a waiting list and pay the freight for transplants.

And Congress did decide to restrict that by legislation, to say that no center could do more than 10 percent of its transplants in any given center for foreign nationals. There has been even sentiment now to tighten that up and say Americans have to go first on all waiting lists.

So there is a little bit of precedent about dealing with the non-U.S., even for what Steve was talking about with the American user community. I don't mind leaving it as "the American user community," as long as we understand that a strategy to make sure that we have a safe and adequate supply for Americans is intimately tied up with the Canadians. I understand what the reality is of that.

That being said, I don't mean to say that we aren't tied to certain nations in an intimate way about how we exchange plasma and final product. It is just--I think we can still go with that language--I think it is just a recognition that to some extent we may have issues on both borders that are going to drive what is going on for Americans. I get that.

So it is a friendly suggestion that we not put "North American," but that we are trying to get to Americans but we understand they have to deal with our neighbors, our immediate neighbors.

MR. ALLEN: This statement here, the only thing that bothers me is, it says "in times of shortage." I think we need to be a little bit more proactive, and whoever works, whatever agency takes care of this should be monitoring this situation prior to us saying there is an actual shortage, because at that point then it is too late, literally. I think, you know, this is part of the sentinel program that we are talking about.

CHAIRMAN CAPLAN: Right, right. This is actually specifically in response to shortage.

MR. ALLEN: To the current reality, though. The other is in the sentinel idea, that we not get to this.

CHAIRMAN CAPLAN: Right. Exactly.

DR. HOOTS: In light of what you just said, and in the light of what Jay said earlier about potential development of reserve in a non-critical or at a time when supply is adequate, do we want to say anything about that, to say we have learned from the times of shortage to consider, when supply becomes adequate, the development of a reserve?

CHAIRMAN CAPLAN: See, I think that is part of the sentinel discussion.

DR. HOOTS: Okay, fine. That's what I--okay, that's good.

DR. GOMPERTS: You know, again, the issue is complicated. This is a fairly simple answer to a complicated issue, but if introduced with teeth, has the potential to cause serious disruptions which, when those disruptions occur, there will be responses and reactions for the short, medium and long term.

I think the answer really is, there was--to some extent there are barriers in the importation of plasma and plasma-derived product from, for example, Europe. Plasma centers need to be FDA-approved.

There are almost certainly plasma centers in Europe that would be FDA-approved because of practices in those particular plasma centers. Similarly, there are fractionation facilities that are almost certainly functioning under reasonably good GMP.

So I really think that the answer is perhaps an easier movement of plasma, of products, internationally. Because in that situation, the supply and demand situation does--has the potential to move, and perhaps it is--rather than putting up barriers, the answer is to look at innovative ways, ensuring safety, to deal with the supply situation.

You can look at it from both sides. If there are serious barriers, for example, to the exportation of recombinant Factor VIII products, and there is significant demand elsewhere, then plants--certainly it's a five-year process--plants, a plant will be set up elsewhere. And so there are all sorts of reactions and consequences when barriers are set up.

CHAIRMAN CAPLAN: How about this? Let me propose a little language here, that we urge the Secretary to examine innovative responses, including restrictions on export, in order to ensure--of plasma and finished products--in order to ensure a safe and adequate supply?

In other words, I understand what you're saying. You might say, "Well, we're going to import certain things that we wouldn't," or whatever. I don't want to let the issue of export control disappear, but I would like to see--I don't mind if it is lumped in with creative thinking, so to speak, about how to make that happen.

So the language I was talking about, Mac, is just a new sentence, that we recommend the Secretary--have you got it there?

DR. NIGHTINGALE: Yes. "We recommend that the Secretary examine innovative responses, including regulation of export of source plasma"--

CHAIRMAN CAPLAN: Just back up. You're a little fast for me.

DR. NIGHTINGALE: Okay. "We urge the Secretary to examine innovative responses, including regulating the export of source plasma and"--

CHAIRMAN CAPLAN: We can keep source plasma in. I have heard enough discussion that it seems to me there is no reason not to. I am almost tempted to add recovered, now that I understand.

Comment on that?

DR. GOMPERTS: I would expand it to regulating import and export.

DR. GUERRA: Somehow it seems to me that we need to connect this to the other one related to surveillance, or at least make reference to it in some way, because that ultimately, it seems to me, is what allows one to make some of those important decisions for regulating.

CHAIRMAN CAPLAN: I understand what you are saying there, and we can do that in the final presentation. I mean, we will make a transition sentence that says, in response specifically to problems of shortage, we recommend this; in order to avoid problems of shortage, we recommend this, or something.

We will do that. I understand what you want. We can lay them out so that if there is a connection between what Larry was talking about and what Fernando was talking about--

MR. ALLEN: Just briefly, at the last meeting Mr. Roberts mentioned that the international manufacturers over in Europe were able to supply, take care of the demand over in Europe, and that was for the IG/IV. I am curious as to if we might be able, at the next meeting, get some information regarding recombinant as well.

Is it an issue over in Europe as well? I mean, are the companies over there able to take care of the demand there? Is there a need, and these issues happen over in this country, for us to still send product over?

We don't know any of those answers, and I think until we find that out, we are not sure what can be done here.

DR. NIGHTINGALE: Mr. Robert did, I believe, and I hope I am quoting him correctly, point out that there were several differences between the European market and the American market: that the penetration of recombinant factor was less; that certain usage patterns, for

example--

MR. ALLEN: He said 45 percent.

DR. NIGHTINGALE: Yes, 45 percent that they might not use; immune, the immune tolerization techniques that we use here; and that that might explain some of the differences in demand and the capacity of the European industry to meet European demand. Dr. Gomperts knows more about this than I do.

DR. GOMPERTS: Yes. We are lumping Europe as one geography, and that is not accurate. There are some countries where the penetration of recombinant Factor VIII products is very low, for example, Italy; and high, as for example Germany and Sweden. Up until a short while ago, in Britain there was not much recombinant Factor VIII that was being used. There is now. The gate is open, although I am not quite sure just how much actually is going into the U.K. So it is heterogeneous from the point of view of supply/demand, yes.

CHAIRMAN CAPLAN: Dana, are we importing plasma and finished product? I mean, that is a question on my--I mean, you can ask the FDA.

DR. EPSTEIN: Yes, in the sense that we have licensed manufacturers whose facilities are abroad. Those licensees fractionate U.S. plasma which, technically speaking, has been exported first; and then again, technically speaking, we are reimporting the final product.

And I think we want to be careful not to exclude such activities under control strategies, because they actually contribute significantly to our supply. Something on the order of probably 10 to 15 percent of IG/IV, for example, comes that way.

CHAIRMAN CAPLAN: David?

DR. FEIGAL: I think it would be useful to, when we look at how imports and exports change the incentives, to review the experience with pharmaceuticals, because there was a time when there were various import restrictions.

And only two or three years ago those were substantially lifted because the effect seemed to be that because restrictions were being placed on, for example, investigational drugs manufactured in this country that didn't exist in other countries, companies essentially were not making good business sense if they manufactured their products in this country because they couldn't get them out to test in other countries, to do worldwide development.

And so in fact many of those restrictions were lifted, but--and there's many factors that go into this--but by the time they were lifted, more than half of the Phase I trials in pharmaceuticals had left this country and had gone abroad.

And, you know, these are some multinational industries that we are dealing with, and I think we need to be careful that we don't create incentives to have new manufacturing capacities built in other parts of the world where those factories will soon be perceived as meeting home needs that are written in a different language than the regulations we are looking at.

CHAIRMAN CAPLAN: I understand, though, the last series of concerns about being careful about import and export policy. Let me just say again, I think this language is pretty good because it is prefaced by "under circumstances of shortage," which we have X'd out there but should have back in there. See that first sentence? "We recommend the Secretary innovate responses under circumstances of shortage," so to speak, including.

Then what we are saying is, this is a specific response to a specific set of circumstances. We would like to hear some innovative thinking about import and export. So this is not supposed to be a general bit of policy advice. It is responding to a specific problem which, if we set ourselves up correctly, we won't have in two years or three years, since we will be all so smart to never let it happen.

DR. McCURDY: We have been focusing on, almost exclusively, on the plasma side of the equation. And the comment or the query about imports, I believe there is still a reasonable amount, perhaps a sizeable amount of a number of red cell products that are imported into New York, and possibly other places.

And I think that the red cell supply in the United States is marginal much of the year at best, and it would be very difficult to replace those if that should dry up completely. The Europeans were at one time collecting whole blood and saving the plasma and discarding the red cells, in an attempt to be self-sufficient in their derivatives, which they never were.

CHAIRMAN CAPLAN: Let me jump in here and simply say I'm going to ask Dr. Nightingale to take a whack at a little reading of a proposed language that I might move.

But what some of you are now commenting on is that if you start to fool with import and export policy under circumstances of crisis, other places have interests and may exercise their muscle in response to what you do. And you don't want to set up a situation where you can't get X because you have restricted Y and you are sort of fighting this out internationally with all kinds of adverse consequences.

The Chair is very sensitive to that. That is why I think we need to have some innovative thinking about how this goes. If we simply say we are not sending X to country Y until we meet our home need, if country Y is sending us something else, whether it is food or red blood cells or something else, we can be involved in a very interesting situation.

So I think what we need is an explanation of how this goes. It may be that we are going to hear back that we can only have a restriction on export that might be a month long or two weeks. There are all kinds of ways to look at possible responses.

It's a big issue. I understand why it's thorny. That is why we got to the Trade Commission and the international affairs and the ambassador to someplace or other. But I would still like to hear more about this, other than having people throw their hands up and say, "Nothing to be done. Too hard. Too complicated. We can't look at this question." I want to hear more than that. That is what I would like to hear back.

And maybe we can't do anything, that it's too sensitive an international relations thing and we are not going to do it as a nation. But--so do you want to try a read on what we've got here?

DR. NIGHTINGALE: I think, let me begin with the original words:

"When necessary (in times of shortage) we recommend that the Secretary examine innovative responses, including regulating the import and export of plasma and finished products, in order to ensure a safe and adequate supply of plasma derivatives and recombinant products for American user communities."

DR. PILIAVIN: The syntax of that is rather peculiar.

[Laughter.]

DR. PILIAVIN: I mean, what we are saying is that when shortages occur, the Secretary should do this, which is not what we mean.

CHAIRMAN CAPLAN: All right.

DR. PILIAVIN: I'm willing to vote for it as long as you promise to fix the grammar.

CHAIRMAN CAPLAN: Every time shortages occur, the Secretary runs out and considers--

DR. NIGHTINGALE: Professor Piliavin's comments are noted and appreciated.

CHAIRMAN CAPLAN: Subsequent to the important grammatical emendation, can I get a motion to move that recommendation?

MR. ALLEN: So moved.

CHAIRMAN CAPLAN: Second?

MR. WALSH: Second.

CHAIRMAN CAPLAN: Discussion?

[No response.]

CHAIRMAN CAPLAN: All right. All in favor?

[A show of hands.]

CHAIRMAN CAPLAN: Opposed?

[No response.]

CHAIRMAN CAPLAN: All right. Pass that one through.

The last item of business I have for the committee today in terms of recommendations is whether you want to say anything else about shortage or about anything else, whether there would be another comment or some other issue that you want to see addressed. John?

MR. WALSH: Mr. Chairman, somebody articulated yesterday, and I think it was Chris Lamb's substitute, the difference between the European recognition they are dealing with safe blood supplies and ours. And I don't remember the specific language, but there were several bullets that he listed that made it very clear to me that the Europeans are ahead of us in achieving an objective towards a safe blood supply.

I think we should create some language that would propose that we would at least catch up with them, and perhaps move on with some leadership in that area.

DR. SNYDER: Wasn't one of the issues filtration?

MR. WALSH: Uh-huh.

DR. SNYDER: That's what I thought.

DR. AuBUCHON: Mr. Chairman, I think that this needs--that this point, among others, should appropriately come before the committee, but I would reject the notion that the Europeans are ahead of us in blood safety. There are some issues that could certainly be considered, but I don't think that that has adequately been discussed.

CHAIRMAN CAPLAN: One of the things for future discussion, I know people have been whispering--it's funny, it's kind of like going to the movie The Graduate and having people whispering "plastics"--people whisper "leukocyte depletion," "filtration." These are things we can put forward for future topics. It's not that I don't think they are important. I think they are.

You might think, John, about whether that is something you want to see us try to wrestle with now, when we haven't really heard much about the filtration--

MR. WALSH: Let's put that on our futures list.

CHAIRMAN CAPLAN: Okay.

DR. McCURDY: The committee has, I think quite properly, focused on recombinant factors of various different sorts here today. But I don't believe that they as a group wish to release or decrease the pressure to improve safety of products which are likely for some time to be plasma-derived. Immunoglobulins, of course, is the major one of these, and so forth.

And there are things probably that can continue to be done to increase the safety, although they now are quite safe. And I just want to be sure the committee doesn't ignore those in the face of pressure on the recombinants.

DR. CHAMBERLAND: I guess I just wanted to suggest that maybe we could go back and consider some of the other strategies that might be possible to look at, short and long term solutions to shortages.

In particular Jay mentioned a couple of these in his comments a while back, that included issues related to the development of practice guidelines, to try and develop some documents or guidance about how products should best be used. And then also I believe, Jay, another component or potential component was how in a time of shortage available product could be allocated to those most in need.

So perhaps if we could--if there was any sort of discussion about those, I think the export-import issue I see as more of a longer term. I mean, it's something that would be very complex and not going to happen quickly, but there might be some other things that we could entertain discussion about.

CHAIRMAN CAPLAN: I mean, one concrete thing there which we have talked about is do we want to say anything about, in the face of existing shortage, about efforts we would like to see made to set some priorities for particular user populations for product? I don't know that we do; I don't know that we don't. Maybe that is up to medical judgment, we can't get into that. I am specifically talking about kids or immune compromised people and so forth.

DR. PENNER: A couple of quick items, I think, in that relationship, and that is, I would like to see us have a statement to encourage treatment centers to educate--no, excuse me, I would like to have them--to encourage industry to provide a single triage center for products in short supply, and to develop a product reserve to be held for distribution during shortages.

Then I think we have another area that we have to go into that I had mentioned before, and that is to encourage treatment centers to educate their patients on appropriate dosing, and that we might need to develop a consensus on therapeutic use as part of that.

CHAIRMAN CAPLAN: There is certainly--

DR. PENNER: So three different areas.

CHAIRMAN CAPLAN: Let me hold off on the reserve. The reserve inventory issue I think will come up under what we keep calling the sentinel issue. I see that as fitting in there for options of that.

The other two, the single triage center or a strategy using some kind of single or central triage is certainly fair game here, and the development about guidelines for appropriate use by patients and their physicians, certainly something we could say something about if you want to.

DR. GUERRA: I would certainly support these last items, and would put that into the context of, again, communication. I think we have to communicate what this committee has done in addressing, over the last couple of years, some very important issues. The discussion has certainly been encompassing of science, research, policy issues, supply issues, economics, importation, exportation, all of those things that I think the general public really needs to be brought up to some level of understanding.

And then I think that on the provider side, the clinicians also need to know what this committee has thought about and what its current thinking is and what some of the forthcoming recommendations might be, because I think there is a tremendous information gap out there and a lack of understanding.

And when we really take the Hepatitis C look-back recommendations to full scale in the not too distant future, it is going to again raise those tremendous concerns about the safety of the blood supply. And I think that we have to put all of this into a context that is reassuring and that at the same time expresses the determination that we have to always give that assurance to the general public and to our communities.

DR. NIGHTINGALE: May I--staff, clarify-- is Dr. Guerra suggesting something along the lines of an editorial for a journal such as Transplantation that all of the members of committee might wish to sign off on?

DR. GUERRA: I think that would be certainly one venue, but I think that it has to go to the lay press as well, and to the media, and other professional journals.

CHAIRMAN CAPLAN: Just so you know, I should fess up to doing this. Dr. AuBuchon seduced me into a talk for the College of American Pathologists where we talked about some policy issues that had come up, and I did go, and I claimed to be speaking for all of you when I was there, and I'm sure you'll get a lot of letters.

No, I said, you know, I'm just--

DR. AuBUCHON: And you were very eloquent, very eloquent.

CHAIRMAN CAPLAN: Yes, but that kind of thing can go--I mean, trying to go out into the professional societies, getting in front of groups, we can certainly look for doing that. I think we do have a staff directive here, not a recommendation.

But I guess what we are saying is, if we are going to see a sort of roll-out of Hepatitis C, if we are going to see specific policy initiatives put into place with a sentinel system or other things, that we then try to develop a strategy for having either a press conference or a media briefing or presentations at appropriate professional society meetings to try and do some of that. And various members of the committee could get involved in that, or do it locally in their own areas. So that is something we might think about.

DR. NIGHTINGALE: Yes. As you think about it, though, you need to remember that you are an advisory committee to the Secretary of Health and Human Services, who does have certain prerogatives.

CHAIRMAN CAPLAN: What are you saying? I understand what you're saying.

DR. GUERRA: I think as representatives, though, for a number of different organizations, and ultimately I think the populations that many of us care for and are concerned about, we have that obligation as well.

CHAIRMAN CAPLAN: Well, you know what, maybe this is tipping toward a recommendation, although I am not sure it is. But we might say something like, "We would urge the Secretary to work with the committee to try and disseminate the findings, deliberations of this body as part of," you know what I mean. We could do that. I would be certainly happy to see them try to use us, indicate that we are available to do that kind of thing, whether they want to do it or not.

DR. NIGHTINGALE: One approach to this is to remember that the advisory committee is free to advise, and for that matter to speak in any way they wish as individuals. It is when the advisory committee becomes or is perceived to become an official representative of the government that problems begin to emerge exponentially.

DR. KUHN: Is the Chair entertaining also future topics for this committee?

CHAIRMAN CAPLAN: Not yet. If we can--we have two--let's see. One idea that is up on the table is to try and develop a proposal that says we want to encourage the development of information and guidelines for patients and physicians about appropriate therapeutic use of clotting factor products, and I don't know if people want to pursue that or not. I am waiting to see that. And John had a proposal up about trying to consolidate, to triage.

DR. HOOTS: Yes, I think that that is a good proposal, and I think it--but we need to make sure that we acknowledge the ongoing efforts that do exist, without itemizing, just perhaps the same kind of language we had before, to encourage and extend ongoing efforts, because there is the Medical and Scientific Advisory Council for NHF that is working on that; there is the MCHB Advisory Council that is working on practice guidelines; and the CDC is working on prevention strategies like appropriate dosing for prophylaxis. So those things are in some ways ongoing. There is always a need for extending them.

CHAIRMAN CAPLAN: I mean, is there a sentiment to push towards this? Let's just stick with this for a second.

DR. PENNER: I think it ought to be added in, because I think there is another part of our needs to handle shortage, and it fits in with--there are other agencies out there that are attempting to resolve that, to provide more appropriate--but I think it should be included in our purpose.

MR. WALSH: Mr. Chairman, I think that with respect to the dosing strategies, we probably ought to include IG/IV and alpha in that, make it more general, and clotting factor.

CHAIRMAN CAPLAN: So it's something, Steve, it seems to me what we are talking about is we want to, in light of shortage, we want to encourage further efforts to develop and communicate standards for the prophylactic and therapeutic use of clotting factors. Blood products, excuse me.

DR. PENNER: Blood derivatives.

CHAIRMAN CAPLAN: Blood derivatives.

DR. GOMPERTS: To deal with the changing understanding of disease, the availability of products and utilization of those products, from time to time meetings are called by NIH, often together with CDC, FDA, to develop a consensus conference in relationship to the dosing and utilization of product X in relationship to disease Y, and it is probably a good idea that our recommendations should be focused in that direction.

CHAIRMAN CAPLAN: That's what that "communicate" is meant to convey.

DR. GOMPERTS: And certainly these consensus conferences are published subsequently and carry a lot of weight from the point of view of guiding care as well as reimbursement.

CHAIRMAN CAPLAN: Uh-huh. Other comments?

I'm not ignoring what you're saying, and I think that the reason I specifically said "communicate" is, I have in mind consensus conference mechanisms, letters to docs, that sort of thing.

DR. CHAMBERLAND: I think to clarify, at least what I was thinking of is our previous meeting about shortages of IV/IG. I think that is an area where the balance between approved and off-label seems to be very much a concern, and we heard presentations from individual hospitals or groups who had tried to implement their own triaging.

But I think that is an area, as opposed to where there might be within the hemophilia community, for example, these ongoing medical boards and ways to put forward standards, I think of that in particular as an area where this is lacking or could be amplified or bolstered.

CHAIRMAN CAPLAN: Okay. I'm getting that sense again that it might be time to get a motion on this. I don't know why I get these feelings. They just occur to me.

DR. PENNER: Moved.

CHAIRMAN CAPLAN: Second?

MR. ALLEN: Second.

CHAIRMAN CAPLAN: Discussion?

Noting in the record there has been some talk about NIH consensus, these can back up the recommendations, what Mary just said, too.

All in favor?

[Show of hands.]

CHAIRMAN CAPLAN: Opposed?

[No response.]

CHAIRMAN CAPLAN: All right. Do I hear sentiment to try and explore what John put forward

--I have to go back to the proposal--about a single distributional entity model?

DR. PENNER: I spoke with one or two of our industry people, and I think there is some interest in developing something of this sort. We can't of course mandate anything of the sort.

CHAIRMAN CAPLAN: No.

DR. PENNER: But if we could throw our weight behind it, at least it becomes a situation--they have to respond and say why not.

CHAIRMAN CAPLAN: Could we try something like this? And again, I'm not--here I am really just suggesting something. If you don't want to go this way, that's fine. Could we urge the Secretary to convene a meeting of manufacturers to discuss strategies for distribution in light of shortage? I mean just try to get them in a room to sort of say, "So what do you want to do here?" I'm not saying they'll get in a room, anyway. Maybe it's redundant.

DR. GOMPERTS: Didn't we deal with this in the--in our--the first proposal? In other words, hopefully at a future meeting there will be presentations as to approaches as to managing shortage, and of course--

CHAIRMAN CAPLAN: It is, although what I'm really concerned about here is we've got an existing shortage, an existing allocation challenge over the next, say even before we meet again, over the next four months. So do we want to say--I'm asking--to the Secretary, right away, get these people in a room and let's talk a little bit about distribution strategy with the manufacturers? I mean, this is sort of two weeks from now, not January.

DR. PENNER: Yes, I think we need the feet to the fire now, because the problem is going to become more severe, I think, as we go on.

CHAIRMAN CAPLAN: What did I say? "We urge the Secretary to convene a meeting as soon as possible," maybe, "convene a meeting as quickly as possible to discuss allocation of blood products in response to existing shortages." And it's a meeting of manufacturers. And up there just above "convene a meeting" you can put "ASAP". We'll know what that means when we finalize the--

DR. PENNER: And that will take care of the reserve situation?

CHAIRMAN CAPLAN: Right.

DR. PENNER: Because they can decide.

CHAIRMAN CAPLAN: Discussion? And a motion?

DR. EPSTEIN: Do you want to say "blood products" or do you want to narrow it to plasma derivatives and recombinant analogues?

CHAIRMAN CAPLAN: The shortage that we're talking about is plasma derivatives and recombinant analogues, so they don't have to talk about everything. That's--we'll--we'll flesh that out so we know what--I think this one we should be focused on because this is the two-week response, not the forever response.

DR. GUERRA: I just wonder if maybe it would not also be helpful to include in this meeting some of the agencies as well. Is there some important policy implications? I'm just thinking in terms of the CDC, for example, that monitors the availability of IG products for--

CHAIRMAN CAPLAN: No restriction on that. The Secretary can do it. I understand what you're saying, but there's not--that judgment will go. They can get whoever they want to the meeting.

In olden times I think this, what we are calling for here is a little jawboning, that they used to say when there were labor problems. You want to kind of get everybody around the table who is appropriate and see if you can come up with some immediate short-term strategy. But the Secretary is absolutely free here to bring in CDC or whoever else would be conducive to that, so no problem with that.

Motion?

MR. ALLEN: So moved.

CHAIRMAN CAPLAN: Second?

DR. PENNER: Second.

CHAIRMAN CAPLAN: Good. All right. Last shot at discussion?

[No response.]

CHAIRMAN CAPLAN: All in favor?

[Show of hands.]

CHAIRMAN CAPLAN: Opposed?

[No response.]

CHAIRMAN CAPLAN: Somebody ought to oppose something here. Okay. Good. I think that will actually be a useful thing to do, and that recommendation, Steve, maybe we can even get up there faster. I mean sort of like, come on, we've got to stay on top of this. Roll that one forward a little quicker. Sometimes it takes us a long time to get them typed and moved over in terms of speed.

My sense is, we may have exhausted the things that were on our plate, but last sweeping requests for anything else? John?

MR. WALSH: Sorry. I know nobody wants to go here. We started out the meeting, you know, with this--with the policy announcement on CJD, and a number of us have discussed whether or not we want to specifically make a statement about wanting to understand what the current or elaborate on what the current NV CJD policy would be.

And I know there is one in place, but it's not clear to us that--I guess what I'm concerned about is, the Surgeon General makes a statement that we're changing policy and it's over, it's finished, it's solved, it's resolved. And it might not be, and we would like to have, you know, at least some surveillance or continued interest in the science or whatever.

DR. CHAMBERLAND: Oh, absolutely. Yes, absolutely. That was--and I--you know, that was very much a part of the recommendations that came out of that Blood Safety Committee meeting, that to change the policy to option one, but that went hand-in-hand with an ongoing commitment for research and surveillance into classical and new variant CJD, with the eye towards modifying that policy if, you know, the data suggested that it should be. So very much--

MR. WALSH: Was that in his--was that in his testimony?

DR. CHAMBERLAND: Absolutely.

CHAIRMAN CAPLAN: Let me say, too, I don't know if you remember this, but even this committee said with its CJD discussion that it planned to come back and look. It didn't say, "We changed this policy for all time and we're done." It said, as I remember our own language, "We think because of the existing problem we're making this recommendation. We're going to come back and revisit." So we absolutely have it. We have assigned ourselves a revisit to this CJD business.

All right, I think I have a--well, thank you all for these recommendations. I think they will be very useful. We will try to get them written up and to you in the usual transmittal process.

I think I have a way to transition us toward the final thing that I want to accomplish before we adjourn today, and that is looking forward. Let's see if Miriam is still here. Miriam, are you still around? Can you give me five minutes on the IV/IG?

There is some new information that the Immune Deficiency Foundation had about IV/IG, that they asked to have a chance to share with you just a little bit. And so while we're making the transition over toward the future, it might be useful to hear that.

MS. O'DAY: Thanks. Again, I'm Miriam O'Day, Vice President of the Immune Deficiency Foundation, and we had presented some physician survey results quantifying the shortage at the April meeting. We have resurveyed a group of these physicians, and we documented in April the depth of the IV/IG shortage and its human consequences.

The next overhead. We are halfway through an update survey that captures May through August of 1998, and we are reporting preliminary and incomplete results here. And as you can see from the 200 and--the physicians who treat over 25 patients, the 221 drawn sample, we now have 73 completed surveys from those individuals.

The May through August period--and we're ready for the next one--shows a modest improvement but still a significant and serious shortage. Are you having difficulty obtaining IV/IG? 93.4 percent said yes in April, and 87 percent said yes in August.

The physician strategies for coping with the IV/IG shortage, it's apparent that physicians are employing, again, multiple strategies. They have, again, postponed scheduled infusions, switched to different brands, switched to less preferred brands, and the interval between infusions has increased. There are still 50 percent of our doctors increasing the intervals, and 40 percent of them reducing their dosages.

MS. O'DAY: Thank you, Steve.

How much difficulty are you experiencing now in obtaining normal supplies of IVIG? I would point out normal. The trend is that they have shifted from 47 percent saying a lot of difficulty to 56 percent saying some difficulty. And what I would say here is that there are a number of conclusions.

One is that they've become desensitized to the shortage. It may also indicate that there is a greater supply. More likely, we would say that physicians have become more savvy in ways of obtaining IVIG and other sources, other suppliers, other distributors.

Has the shortage of IVIG had a negative effect on the health of any of your patients? Forty-two percent still report, yes.

And most interestingly, of the physicians that we had a write-in box this time which we did not include last time, about the kind of negative health effects and of those offering comments, 61.5 percent noted increased infections which, of course, were for immuno-deficient patients can be life-threatening.

Thank you very much.

What I would say to this committee from those preliminary data is that although it is incomplete, it is conclusive. There's still a significant shortage in the market place and substantial health consequences for our patients.

And given the fact that we are still in the midst of this shortage and we have reports that several of the manufacturers are at reduced levels of production and lot release it is imperative that this committee encourage FDA and industry to formulate projections for supply in the fourth quarter of 1998 and develop contingency plans in the event that the fourth quarter of 1998 is as bad or worse than the fourth quarter of 1997 was for this community.

And I would be happy to answer any questions that you have.

DR. PENNER: Has there been any triage yet of products that we had talked about at one time?

MS. O'DAY: Has there been emergency supply program put in place?

DR. PENNER: Right.

MS. O'DAY: Each of the individual manufacturers does have an emergency supply program. And I would ask them for an update on how successful that's been. Obviously our physicians are still having a tremendous amount of problem obtaining supply.

We are working and negotiating with the manufacturers to put together an emergency supply program through the IDF which would be a physician registry and the physicians would have access to product. If it was an emergency we would ask them to use it as their last source of supply.

CHAIRMAN CAPLAN: Larry?

MR. ALLEN: Miriam, have you worked with industry in terms of helping them figure out what the demand is? Has that been possible?

MS. O'DAY: I would say that that some of the survey data that we've collected on our patient population has revealed to industry that there are larger numbers of patients on IVIG for primary immuno-deficiencies than they had previously estimated.

MR. GUIHEEN: Just an observation. On the IM side of the immunoglobulin products there continues to be an unrelenting and worrisome shortage. I mean we're having to use right now tetanus immune-globulin for trying to contain outbreaks in populations of at-risk children because we've not been able to get the immuno-globulin product. I mean that's been going on for quite a few months now.

MS. O'DAY: And if I could make one more final comment. I would say that we are very grateful that you focused on this issue at your last meeting and that we've had access to this committee to present our perspective and to make you aware of what's going on within the patient population.

We would encourage you to revisit your short-and-long-term recommendations from the last meeting. And we anticipate that IPPIA and the FDA will be giving us the retrospective production data at the September 9th hearing before Congressman Shays, but we would also like to see them do some projections into the next quarter.

Thank you very much.

CHAIRMAN CAPLAN: Jim, you wanted to say something about look-back I think, too.

DR. AuBUCHON: I just wanted to update the committee, thank you, regarding the status of HCV look-back. When we met last the FDA had just released their draft guideline, outlining the implementation of HCV look-back and the particulars that were to be followed.

Following that dissemination of the guideline an inter-organizational task force was established between the American Red Cross, the American Association of Blood Banks and America's Blood Centers with very important liaisons from the CDC, the FDA and HCFA. And I would like to publicly thank the members of that task force from the government who have been very helpful in responding to our requests for assistance.

The task force held a meeting on Tuesday and Wednesday of this week in Chicago at which 13 governmental and private health care and professional agencies and the commercial sector outlined how they were responding to the call for HCV look-back and where they stood in that process.

Following the presentations, the task force met and established a list of those items which appeared to represent gaps or impediments to completion of the look-back according to the time line and intent as had been outlined by the Food and Drug Administration and this committee.

The focus of the task force in establishing this list of gaps were really three-fold. One, we want to do the very best job that's possible in this look-back. We understand that it's only going to happen once and we want to make sure that the information is conveyed in a manner that does the most good for the greatest number of patients.

We want to do no harm to those patients who are notified and make sure that they have the appropriate counseling and testing and other support mechanisms and we want to learn as much as possible from this effort in order to better guide future look-back efforts.

Key among the gaps that were identified was a continued lack of coordination among Federal agencies, particularly with respect to disseminating guidance and the time-lines of those guidance. Again, we appreciate the assistance of the individual staff members we've been working with. They have been tremendously helpful, but there is a--I hate to use the word--but bureaucratic difficulty in the coordination.

For example, the blood centers are, for the most part, identifying the implicated donors and the implicated units and the dissemination of that information to hospitals according to the original FDA guideline is to occur, begin occurring no later than September 20.

However, the CDC is still formulating the guidance that it will give to the medical community and physicians, in particular, about how to handle those individuals who are identified through the look-back process. So, there's a discordance there because it may well be that the look-back effort may well be under way prior to that information being available.

Also, indeed, there was mention at the meeting that HCFA has not yet decided whether or not it will pay for the evaluation and testing of individuals who are identified in the look-back. So, there's clearly still some lack of coordination.

There's also lack of availability of a supplemental test that matches the most commonly used screening test for Hepatitis C. And that will undoubtedly cause many physicians some problems in interpreting the information that is obtained on the patients referred to them.

At a more basic level, there is also just a lack of awareness of this program amongst some institutions despite the Food and Drug Administration's release of the draft document. Not all hospitals understand that this applies to them. Not all hospitals are aware of it. The blood banking organizations have certainly attempted to disseminate the information but not all hospital transfusion services are a member of one or more of the blood banking organizations.

There's also a great lack of physician awareness about Hepatitis C in general and how to counsel, test and treat those individuals who may be identified. This is one of the focuses of the CDC's effort which has not yet entirely begun.

The blood banking community anticipates great difficulty in locating patients, possibly whose last known address is now a decade or more old. We would appreciate having access to the various data bases of the Federal Government including those of the Social Security system and the Internal Revenue Service that might allow us to have all of the effort that goes in at the front-end of the look-back to actually reach the person that we're trying to find.

And underlying all of these critical gaps is clearly a need for adequate government funding of the governmental portions of this initiative. We understand that the CDC's portion alone has an estimated price tag of around $50 million but that no movement has yet taken place to identify or provide that funding. So, clearly, additional resources will need to be committed to this in order for the effort to be successful.

Much of the effort will occur in the private sector. We understand that that's the way it has to be but we would not want the Federal Government to believe that they had entirely solved the problem after issuing the guideline and then leaving it to others.

So, in summary, we would hope that the Federal agencies would be able to coordinate the various time-lines and programs and to ensure that they have the appropriate resources to conduct not only the education but also the research and evaluation that is necessary in this program.

Thank you.

CHAIRMAN CAPLAN: One thing that occurs to me as we look forward a bit is, you know, we have moved along on a number of fronts to make recommendations, make suggestions, and in one sense an advisory committee is in a difficult position to monitor the implementation of what it advises. That after you give your advice, it's picked up by agencies, you move into administrative and political processes to see whether people are going to do what you advised.

On the other hand, there's enough balls in the air now of things that we've been freely giving advice that it is clear that we need to have some monitoring of the reporting kind that we just heard from the Immune Deficiency Foundation from Jim on the Hepatitis C look-back.

You may want to think about whether one way to have this done would be to ask one of the committee members, our committee, to work with staff in a particular area to just keep an eye on what we recommended, what's happened, and then make sure that a communication goes out to appropriate persons of the committee but maybe others, that we would just make that happen more routinely.

I mean I can't help when I listen to Jim's report, I know that you are following the Hep C, look-back issue pretty closely. There may be someone else who has a particularly keen interest in the say, IVIG and how well we are doing there. And if staff was working with them or even a subcommittee of them, we might make sure that we don't have things falling through the cracks because particular people would be keeping an eye on those recommendations.

Again, I don't want to say that we are the regulatory body. We're not. We give advice. It implements. It falls out there. You know, all we can do is come back and say, we told you to do this, it's a great idea and we're going to tell you again. We can't kind of compel a whole lot of behavior. But at the same time one feeling I have is that we may want to set up a little more infrastructure to keep tabs on what we're advising and how those things are being fulfilled.

And one model might be to have a subcommittee or a person assigned to watch specific areas of recommendations, like today's recommendations, the IVIG recommendations, the Hep C recommendations. So, I don't know if that has got any appeal, that might be a place to start talking about one sort of future structure we could set up.

DR. PENNER: I am interested in that $50 million, that seems like an awful lot of money for what is being required. Do you have a consensus of how that is going to be distributed?

DR. CHAMBERLAND: Perhaps I could just give a very global comment on it. The bulk of that money--and, again, that's money that is proposed for the next several Fiscal Years--the bulk of that money would be directed towards the establishment or the expansion of current counseling and testing facilities for the public to access for Hepatitis C testing. That's a big concern that once the guidelines come out that Jim, CDC is working on the development of guidelines for the prevention and control of Hepatitis C. Once the look-back effort is underway the concern that has been voiced by this committee and others is that where do people who don't have private providers go to get tested?

DR. PENNER: So, this is not just related to the blood situation? This Hepatitis C, the global aspect?

DR. CHAMBERLAND: A large and more comprehensive look at that. But certainly some of the people that would be impacted would be people who are notified and need a place to be tested. So, that the bulk of those monies that CDC projected would be needed include efforts to establish counseling and testing facilities or sites.

I want to assure you that there was a meeting in July of which I think actually several people here attended and in which CDC released a draft document of its guidelines for the prevention and control of Hepatitis C. It was a very useful meeting and a lot of feedback was received. The document is under revision. It's anticipated that in the Fall there would be the release of a guidance on the prevention and control of Hepatitis C, counseling messages, et cetera.

DR. PENNER: Did it cost that much for the HIV?

DR. CHAMBERLAND: The HIV counseling and testing?

DR. PENNER: Yes.

DR. CHAMBERLAND: Hundreds of millions of dollars.

DR. PENNER: And we never received anybody--when we did the counseling, we didn't see any of that money, so, I'm just wondering how we can get access to it.

CHAIRMAN CAPLAN: He missed out the first time. He wants to get it.

DR. CHAMBERLAND: Perhaps Fernando would like to amplify but there are counseling--

DR. PENNER: All the blood centers did their own counseling and referral--

DR. CHAMBERLAND: No. This is the establishment of the anonymous HIV counseling and testing sites that exist in all States that anybody has access to. And that's many millions and millions of dollars.

DR. PENNER: Well, I will have to get my application out.

DR. GUERRA: I think we learned a lot from the HIV and AIDS experience that allowed us to in a very costly way build up some capacity and it's my understanding, Mary, that some of this will be to build on the capacity that is in place in some communities because of what was done for HIV-AIDS to develop this new level of expertise. But they may be the same staff because a lot of the same populations are certainly at risk.

And I think that, you know, from what Jim was saying that our experience has been that it's not just the individuals that may be directly affected with a transfusion but those that are fairly close to them that are worried and concerned and apprehensive where in many instances we have to do the counseling, the testing, and hopefully the reassurance. And the screening test is somewhat expensive. At least, we have costed it out for the target population in our own community. And, so, we're asking just to try to initiate that effort in San Antonio just as a starter for about $100,000 extra to build on that capacity.

CHAIRMAN CAPLAN: Jim?

DR. AuBUCHON: I just wanted to make sure the committee understood how blood bankers respond to something that comes out with the FDA letterhead on top and that is very carefully and make sure that we meet all the requirements. And there are definite time-lines in the guidance document and blood bankers are trying to meet those.

What we would not want to have happen is the bulk of the notifications to go out into a population that generally does not know about Hepatitis C, the importance of diagnosing and treating the disease. We need the notifications to occur in the environment where our letter, our notification is going to have the appropriate impact. And that's why we hoped for the coordination of the various time-lines.

DR. BUSCH: Another consequence of the delay in the CDC's document being issued is the lack of appreciation generally that the general component of the look-back program which we endorsed and we proposed a balanced, partial, you know, directed targeted look-back to accompany the general program was not appreciated.

And as a result, actually the recommendation of this committee that the look-back begin only with second generation screened blood and extend back to 1987 has eroded. And a number of organizations that are unaware of the general campaign and the balanced response of this committee are proceeding to trigger look-back with first gen, even though they don't have contributory testing and extending back to earlier dates.

DR. AuBUCHON: Good for them.

CHAIRMAN CAPLAN: You remember that one of the discussions we had about how to do look-back and I think I was pretty adamant about this is that the trick is to develop a paradigm that works well so that people aren't just notified but notified and empowered to do something and that that takes an infrastructure to do it.

And I was trying, I remember sometime ago, to mediate a dispute about how far to look back by saying if we can set up something that worked from where we had the best data and the best possibility of coordination that would be a good model. So, the issue of how far to go, I know the Department of Defense and others are looking way back. We may revisit that, too, but the trick is that I think it's going to be important that this coordination take place.

This pulling the information together and then not having support or just not knowing what the doctor is going to say when asked, I have this test now, what does that mean? A look-back has to have all those parts. And I think that's where that money is. I think that's what we're being told is to sort of set that infrastructure in to do that, to have the answers, have the education, have the test, have the clinic, that's what you're saying the $50 million is?

DR. CHAMBERLAND: What I was saying is that the bulk of the $50 million in CDC's proposed budget was for counseling, testing, education. Another important component that I think gets to what you're saying is monies directed towards the evaluation of the look-back effort both the targeted and the general which is something very much that CDC is moving forward with the collaboration of ACPR, FDA and others. There are plans being developed to develop protocols as to how to approach the evaluation of this.

DR. GUERRA: And also for referral networks, for following the populations that are found to be Hepatitis C positive, to protect them against Hepatitis B and Hepatitis A, getting them into sources of treatment.

I mean it has a lot of different components and, so, it is going to cost some dollars.

DR. DAVEY: Yes. Just along those lines, we, in the Red Cross, we feel we were going to have to trace about 200,000 different components, which is a huge task. What Jim has outlined and Mike, these issues are very complicated.

We feel it will probably cost the Red Cross about $10-to-$20 million to do this. And we're trying to find out how best we can support that effort. It's the right thing to do and we'll do it.

And there's the looming issue of litigation which is of great concern and how we are going to manage this both as the Red Cross and as a community because that is certainly going to be a wave of issues on the legal front that we're going to have to confront.

CHAIRMAN CAPLAN: Do people think--let me just return to the idea of trying to designate at least one person to keep tabs on specific areas of recommendation that come out of meetings. I mean if you will indulge me one second, I might say, clearly, Jim has got an interest in the look-back and it doesn't exclude any one of you from talking to staff but I would like to have one person on our committee, at least, acting as a person to liaison on the issues that came out of our look-back thing with staff, making sure that timely reports and updates take place about our recommendations.

I don't have someone to put forward. I mean I can nominate someone from the IVIG. I can nominate someone from today's discussion of recombinant and clotting factors but does that seem something that we think is a reasonable idea.

Okay. Would someone like to volunteer to be that liaison person on IVIG? I'm just taking one now and if you want to really be on the Hepatitis Look-Back Committee you can indicate to Steve subsequently that that's something you dream of sitting with Jim on and can't wait to tell Jim on conference calls day and night about. But I will settle for one before I settle for N-plus-one.

Anybody want to--

MR. WALSH: I hate to do it but I'm in regular touch with the IVIG community.

CHAIRMAN CAPLAN: Okay.

How about for today's sort of discussion of recombinant products, clotting factor?

DR. HOOTS: [Head nods up and down.]

CHAIRMAN CAPLAN: And what your task is, is to keep a tab--I want you to know the recommendations in those areas very well and then be asking staff for a report that you could share with us--it doesn't have to be at the meeting, it can be in writing prior to the meeting--about those issues. And we would then make that report available to anybody else who cared to see it. It's not secret. I just want to make sure it doesn't fall through the cracks as we begin to grow out a series of things we can keep some tabs on.

And, as I said, if others want to volunteer to join that effort, that's fine, just let Steve know.

Okay. New topics, things we ought to talk about down the road if we can spend just a little bit of time doing this, I promise that we will end by 1 at the latest.

Yes?

DR. BUSCH: Yes. I would like the committee to explore other countries' experience in the arena of what they're terming hemo-vigilance. There's sort of a global growth in this concept of monitoring blood safety and its broader ramifications and there's a number of recent publications from other countries and programs that have been implemented that are really much more comprehensive than I think what we have discussed here and what we understand to be blood safety research and surveillance. And I think it would be very useful for the committee to perhaps spend a day or even a meeting and invite representatives from Japan and France and Britain and some of the countries that I think are foremost in moving these programs forward.

I think the U.S. program can be couched as one that actually is very effective but it's very focused and research oriented rather than a global hemo-vigilance program.

CHAIRMAN CAPLAN: By the way, all we're doing here is making a laundry list so we'll keep these.

DR. HOOTS: I think one of the things that we've heard in passing that we really haven't explored is notification outside of look-back. Notification particularly of plasma product recipients and recombinant recipients.

I think there's some clearly good strategies that are being developed, IPPIA and others, but I think there are some gaps for groups of individuals who may not be represented around this table that ought to be looked at.

DR. PILIAVIN: I would like first to talk at some point about standards and creative approaches and innovations in the actual procedures for recruiting donors and collection. Specifically I know that when I was on the BPAC we had at least one presentation on computer screening of donors. People talking to a computer rather than to a person. Things of that sort. Issues having to do with the use of incentives and what that does to possible safety issues. Just a general look at what are people doing now, what might they be doing in terms of getting the actual substance that we spend our time on this committee talking about the uses of.

CHAIRMAN CAPLAN: One reason that's very important is that we've spent a lot of time at our meetings looking at issues about blood safety and availability of groups that are heavy users, chronic regular users but some of the issues of what's in the blood supply overall for the intermittent or one-time user, that's our purview, too. So, the overall blood supply is, who is in there, how recruitment goes, is something we need, I think, to pay some attention to. So, I'm pretty supportive of our taking a look in that direction at some meeting.

DR. DAVEY: Yes. I just want to second what Jane said. I was going to propose somewhat the similar issue. We know we have periodic shortages now in the United States with blood donors and that's getting more and more serious. We can predict them now with over the Christmas Holidays and the summers and we're getting to the point where we're going to have critical shortages during those periods.

So, to have Jane on the committee is very helpful on this since she's done so much work on donor motivation. But we do need to look at ways to increase the number and the quality of our blood donors and get some behavioral science on board looking at that particular issue. The what motivates issue, what motivates donors, what is the role of incentives like Jane says.

Also, I think maybe we ought to look along the lines of questioning of donors. Right now, our donors go through an inquisition, a long list of questions which really turns off a lot of repeat donors especially when they have to repeat the same questions over and over again of whether they had sex with a man since 1977 blah, blah, blah.

And I think it would be worth looking at whether our questions are really doing the job of identifying the donors at risk that we want to identify. There's some data that perhaps they are not. Can we streamline the questionnaire, can we be more targeted? Is that doing a good job?

DR. GUERRA: I would like for us to some time in the future have an update on the cutting edge of science in terms of the Human Genome Project and how that is progressing in terms of trying to really get to the reconstitution of individuals that are at risk for some of these inherited conditions that ultimately have some profound consequences on supply of many of these products.

And the other I guess from time to time one reads especially in the lay press about the advance of some of the synthetic products and whether or not that would be something that would be helpful to be informed about.

DR. KUHN: I think we should probably hopefully we can still continue to look into emerging new threats such as new-variant CJD, if that comes down the pike, which could in the near future. Developing guidance and I guess monitoring whatever regarding that. That's one and another issue I think that we've heard about that might be a good--this might be a good forum for discussing it--is the development of a blood products prospective injury act in which we right now found out that there is a sentiment, not only amongst consumers but legislators, industry, as well as government officials, that this might be a good time to look into developing that modeling that after the Childhood Vaccine Injury Act.

DR. EPSTEIN: I certainly concur with things I've been hearing. I think that it would be useful to the FDA to have this committee look at the issue of how we make decisions regarding the risk/benefit of interventions. And the problem that we typically face is that we have a safe blood supply and we're contemplating adding a costly intervention for the sake of a marginal benefit. And this has been a repeated problem and it's a very hard problem especially because the FDA mandate does not include looking at cost.

So, I think an examination of the paradigm of decision making related to making changes in the safety protections would be a useful exercise.

DR. NIGHTINGALE: Along those lines, I would like to ask Dr. Epstein if he would like to elaborate on another topic which is the purview of this committee and the purview of the blood products advisory committee and where he sees them complementing each other or possibly competing with each other. An example would be the issue of donors which I believe FDA is having a couple of workshops on in the Fall.

Jay, would you like to comment on your perceptions of where this committee effectively overlaps?

DR. EPSTEIN: Well, I mean I think that the scope of concerns has been defined in the respective charters. And pretty much what we've created is a system in which the blood products advisory committee is chartered to provide scientific advice to the agency on regulatory matters concerning blood safety and availability. Whereas this committee has been chartered to provide more global input in the areas of economic, legal, ethical, you know, prioritization, social choice considerations related to those same decisions.

Now, this system I have to say is difficult for us to work with because what happens is we have to carefully dissect which issues and which pieces of which issues go where. We have to integrate the feedback that we get from different committees which can be conflicting.

And I would express my personal opinion that the concept that integrating global issues including cost issues in public health decision making at the regulatory level is necessary and that, therefore, it's very hard to isolate those decisions from those concerns.

So, to a certain extent the separation that we do is artificial but we live with it. So, I think there's some complexity to that system. I guess what you're asking, Steve, is should this committee examine that decision making system? I suppose it could. But, you know, it sort of doesn't fall to me to redesign that system. I'm not sure who it falls to.

DR. AuBUCHON: I would just like to mention again a topic that John brought up a little while ago for consideration at future meetings. And that is the potential role of leukocyte reduction filtration for cellular blood components.

DR. EPSTEIN: Well, could I suggest that that in my mind is a perfect example of a technical scientific issue. I think before it would come to this committee I would want to see one of our technical scientific committees examine the merits. And, you know, should it emerge that it's mainly a cost issue or mainly a social choice issue, et cetera, then I think it comes to this committee.

So, for that issue, in particular, we have a plan to bring it to both the blood products advisory committee to look at the aggregate risks and benefit trade-offs for routine leuko-filtration of appropriate products, red cells, platelets. And then we plan to bring to the TSE advisory committee probably this Fall the question of whether there is scientific evidence for reduction of TSE of the theoretical TSE risk.

And I think only after we have looked at the issue in those terms would it be appropriate to come and ask this committee well, are the costs justified? Because we won't discuss the costs with the BPAC and the TSE committee and, yet, costs will be a major practical issue if we add filtration to all blood.

So, I think that that's a perfect example, Jim, of the dilemma that Steve was trying to point out.

DR. AuBUCHON: And your plan sounds marvelous.

DR. NIGHTINGALE: I agree with Jay.

CHAIRMAN CAPLAN: I mean the reason it sounds marvelous in part is that instead of trying to pull all the scientific information together, we would certainly be looking down the road at a leukocyte depletion and filtration issue ready to have a report maybe some things in writing as you got to it.

I can't imagine this issue, unless it turns out there's no efficacy, isn't going to be something that we ought to get to. It's just that we ought to track it after all the leg work is done on the science and efficacy side, is what I'm hearing about that.

But that's an issue we can do. We should just be in close touch about where they are relative to pulling that, the scientific base together.

Others?

DR. PENNER: As part of this, I think we're still talking about the ability to at least apply some of the directives that we're coming up with or some of the recommendations. And that comes back to the physician education on use of blood and blood products. And that probably is a piece that needs to be attended to sometime.

CHAIRMAN CAPLAN: I have a favorite thing that is enormously controversial, which makes it one of my favorites which is I keep reading about the battles that are ongoing between collection agencies and fights over turf and their role in making an adequate supply of blood available to all Americans and that is something that I feel we might want to take a look at, at some point. How the overall organizations are going cost-wise and otherwise. Certainly fair game to ask about donors and what we're going to do to get them.

But I also think the infrastructure question is one that we might take a look at whether we've got the right system to get as much blood as we need to get. And whether the agencies and groups and so forth are doing what they need to do.

I do get, I have to tell you because I'm the chair of this committee, the occasional E-mail from someone who is really ticked off about watching some organizations fight in a particular region and not cooperate.

So, it makes me think there's something happening here that we ought to be on top of as a social policy body if we're getting disputes that are causing people anguish.

I mean I'm talking about ordinary citizens. I'm not talking about people in the blood world. They're just angry that someone is fighting over their donor status.

We can't have run out of ideas. It's impossible.

When Mike Busch announced this wonderful term, hemo-vigilance, I like that. One thing we could do if the Europeans came to us or the international voices talked some about hemo-vigilance. Just two other things to think about.

One, I'm not sure I always understand what our vaunted security forces, armed forces, national defense is up to in terms of hemo-vigilance, and we might have a report at some point, maybe as part of that, about what they're doing.

I know that the blood supply is of keen interest to the armed forces and as I said earlier, they're going to do a look-back that looks different from what others might be doing. And it might be interesting to know why and what's going on there and so forth.

We haven't actually asked for a report of that nature but part of the comparison might be to include a little bit there--that's a sector we haven't heard as much from--just to see what their thoughts are about what they're doing and what they may have some innovative things going on in that sector.

The other thing that occurs to me which you may or may not want to take a look at but has crossed my radar screen is that there is some concern about can the committee make recommendations about diminishing the reliance on various blood and blood products? And it gets back to the synthetics and sort of future issues that you were talking about.

We don't want to necessarily get into the business of telling physicians and clinicians how to practice but it's part of the OE. Are we making sure that we're making full use of all approaches to blood and blood product use in this country, what John was talking about, about making sure that everybody is educated about how to use all products all the time.

The overall supply of blood issue has, as we've seen with IVIG and recombinant factor, sometimes questions about utilization, how people practice, are they over-using, do they use too much, following standards and that could be a part of an examination of are we making good use of the supply of blood that we've got?

Is that optimally used, do people follow minimal good standards and that is an important one to look at, too, because there are massive issues of cost there. It is very expensive.

It's one thing to be talking about what we're doing for our 50,000 people who are on blood products, but if you're not using the whole blood supply efficiently that is very, very expensive within the whole cost of health care.

Hmm?

DR. McCURDY: Art, and the idea of optimal use of blood and blood products, I would like to see whenever the committee plans to look at not be trapped by the concept that the only sin in blood banking is over-use.

Because I think there are occasionally, perhaps not as much as over-use, but there are sins of under-use and I think it's nobody looks for that. There's almost nothing in the published literature about it and virtually all audits look at over-use and abuse rather than under-use.

CHAIRMAN CAPLAN: I never even thought about that. Good point.

All right. If you have other ideas, based upon some of the things that we've talked about, send them to me or to Steve. What we'll do is as we report out on the meetings, we will have this list there.

I'll try to talk to Steve a little bit about what might make sense to go to at the next scheduled January meeting.

Please, remember, the September date that you were holding, don't hold that any more. We're now on for a January meeting date which I think we'll probably use. We've got enough on the plate just off this list that we could certainly move to that.

I'm very pleased that we're going to try and come up with a monitoring mechanism from the committee to the staff to make sure that things don't fall through the cracks.

And there can be staff turnover, people can move on our own committee. So, some continuity that way will be very useful to have in place.

I want to thank everybody who presented testimony to us today and thank the members of the committee for their hard work, yet again, on another subject.

Thanks, and we will adjourn.

[Whereupon, at 12:49 p.m., the above-entitled meeting was adjourned.]

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