Blood Safety Transcripts

DEPARTMENT OF HEALTH AND HUMAN SERVICES
FOOD AND DRUG ADMINISTRATION
ADVISORY COMMITTEE ON BLOOD SAFETY AND AVAILABILITY

WHAT HAS CAUSED THE CURRENT SHORTAGES
OF PLASMA DERIVATIVES
AND WHAT CAN BE DONE TO CORRECT THIS SITUATION?

Tuesday, April 28, 1998
8:24 a.m.
Holiday Inn Georgetown
2101 Wisconsin Avenue, N.W.
Washington, D.C. 

PARTICIPANTS
Arthur Caplan, Ph.D., Chairman
Stephen D. Nightingale, M.D., Executive Secretary

MEMBERS

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.
Keith Hoots, M.D.
Carolyn D. Jones, J.D., M.P.H.
Dana Kuhn, Ph.D.
John Penner, M.D.
Eugene R. Schiff, M.D.
Marian Gray Secundy, Ph.D.
John Walsh


EX OFFICIO REPRESENTATIVES
Mary E. Chamberland, M.D.
Richard J. Davey, M.D.
Jay Epstein, M.D.
David Feigal, M.D.
Paul R. McCurdy, M.D.
Jane A. Piliavin, Ph.D.

C O N T E N T S

Page No. Introductory Remarks Dr. Arthur Caplan 4
America's Blood Centers Perspective James MacPherson 12
American Red Cross Perspective Christopher Lamb 32
Food and Drug Administration Perspective Dr. Mark Weinstein 65
Public Comment Period Tom Moran 92
Cory Dubin 98
Sandra Brandley 101
Patrick Robert 102
Donald Tankersly 110
Committee Discussion 116

R O C E E D I N G S

DR. CAPLAN: Let me ask everybody if they would take their seats.

What we are going to do is we have got two speakers who kindly agreed to be put over until this morning, James MacPherson from America's Blood Centers and Christopher Lamb from the Plasma Operations, the American Red Cross. We also have Mark Weinstein on this morning, and then we have two people in the public comment period who we will hear from.

At that point, we are going to move into discussion of some of the things that this committee would like to see happen as a result of the testimony that we have heard. I want to begin thinking a little bit about some of the directions we could go in.

I am just going to put some issues on the table, not for final form. They are really just things to be thinking about based on what we have heard so far that I think we may want to say something about, and there may be other things that we want to say things about, but this is just in the service of getting us moving today when we get to our discussion period.

One thing seems clear to me from listening to yesterday's testimony. To some extent, some of the shortage that has come up with IVIG arises because people in the manufacturing side are not watching one another's production plans, and so there is a shortage of data and a shortage of someone having access to that data to allow or trigger concern if it looks like production is not going to keep up with demand.

So, one thing we may want to think about is giving authority to some agency minimally to have access to the requisite information to make sure that this vital supply of blood products is not subject to market failure, inadvertent market failure if you want to describe it as such, because one company doesn't realize that another company is going off-line or isn't making enough product or inventory is slipping and no one is watching it in toto, and it does seem to me there is a problem here about having an outside party -- I am not sure who that might be, maybe the FDA, maybe some other agency -- with the authority to at least get the numbers.

We made a good start yesterday towards seeing some numbers for the first time about IVIG supply. I was pleased personally to see that this is going to happen on a three-month basis from now on, but I am still concerned, the whole area, because so many Americans rely on it, that we get timely information about what is going on, so that if there is a problem emerging, it can be flagged without violating various business laws and practices, and so forth, that companies have to operate under.

A second issue that came up for the long run that I noticed was this issue of off-label and growing use for various purposes of IVIG. It does seem to me that there is an issue here about what medicine and clinical positions and pharmacists need to be told about what to do both in circumstances of general use and under circumstances where there is a shortage.

We heard that people were battling one another for the right to access the supply, and at the same time some people came to us yesterday and had some very clear explanations, and I thought amazingly for some of them, even without access to an ethicist, had made up some very good principles about how to distribute the supply according to prioritization, about need, and so forth, and I think those are great, and I was very impressed with those, I hope you were, too.

There were some remarkable attempts to struggle with scarcity, but we want to make sure that if this scarcity is being driven in part by let's call it less than vital use of blood products, such as IVIG, that messages go out, from the NIH, from all federal agencies, that if we are in scarcity, and tomorrow morning, let me remind you, we will be in scarcity, that when we leave here we are still going to have an inadequate supply of that substance, it is not going to get fixed tomorrow morning, that we may want to issue some recommendations about what to do now with respect to off-label and non-approved uses, or areas where there isn't data to show efficacy.

That may also come in the form, I was even thinking potentially of a note from this committee to medical journals about what to do in the time right now shortage, so maybe workshops or information to practitioners and pharmacists letting them know that there is this shortage and what they should be doing and then continued efforts to make sure that the demand for particularly IVIG, or whatever the blood product is, is consistent with what is known about efficacy and appropriate use.

So, that is a second area. If demand is driving things, we may want to say some things about what to do about that in the short run, in the long run.

A third issue that came up yesterday, which I wasn't so happy about getting light shed on it completely, but if there is shortage, we heard some talk about the blood supply being something that Americans have to take seriously as a responsibility to try and manage as a community, and the rhetoric pricks up my ears of donor and donation as all through the collection process.

People donate if they think that the supply is short, there is an issue about where is that supply going, is it going overseas, is it going elsewhere before it is used in the United States, if we are the source of all the plasma for the world, if there are markets distributing, is the burden of shortage being handled equitably around the world.

It seems to me I am not quite sure yet how that burden is being distributed, but it is something the committee may want to say something about in terms of again response to scarcity.

The last point I will make, just to get you thinking again, is that we did hear some about products that might be emerging, that might be risk-free. This interest in recombinant factors is very interesting as one way to solve some exposure problems.

We want to push hard there and say that if some nations are moving very fast, Canada and the UK, toward the use of recombinant, we might want to make sure that obstacles to access here are removed and that we push hard.

Paul McCurdy said yesterday the NIH was going to do a consensus conference --

DR. McCURDY: We are thinking about it.

DR. CAPLAN: -- think about it, well, maybe they should think harder about it. We should tell them to think harder about it and sooner about it. That was well said - there is 30 years of experience, we are thinking about it.

[Laughter.]

DR. CAPLAN: But we may want to urge steps to both see this area developed aggressively with requisite research and discussion about when it is ready to go on line, and then to make sure that whatever obstacles, financial or supply, might be out there, are minimized and make sure that Secretary Shalala understands that there is an attractive option, other nations are pursuing it, and I would hate to see us come up with a supply of recombinant and then be selling it overseas, but not having our own citizens have access to it.

So, there may be ways to relieve some of the burden of disease and help the safety issue if we can move more to synthetic manufacture of some of the crucial blood products that are out there.

Again, those four points are merely to get you thinking when we move toward the area of discussion about things that we might talk about or recommend. I am sure that you all will have others.

As I think about the overall picture -- oh, I forgot one other thing, I was looking down at Marian there, she reminded me -- if we do have an emergency reserve, who is that has a handle on the accountability of the distribution of that emergency reserve.

It may be all right to leave that in the private sector, but it may need some oversight, particularly with patient and user input into how the emergency reserve is distributed. If anybody can call up as a physician and order the entire emergency supply from a private entity, that may not be the best use of the emergency reserve, and so I think we may want to say something there about what kind of accountability or oversight or who should be handling that. If we are going to have that, that may be an area.

I know FDA and others have mentioned to me that they have encountered problems with shortage in some other places, and they may have things to say about systems that they have used in the manufacture of drug that sometimes become short for handling that, but I am a little nervous about the accountability there as a fifth point with respect to what we are doing with this emerging notion of keeping a reserve on hand and who is controlling it, who has access to it, what's the equitability of that, and is that being used in any way in the spot market that we have heard about which seems to be driving up prices when scarcity does exist, when people take advantage of that.

We have heard that they do. Many people have come to us saying that they can get supply, but they have to pay two, three, or four times, where they have to agree to take on other product - where is that coming from, what is that all about, and what can we do to make sure that we are not auctioning this scarce supply to the highest bidder as the mode of distribution, or if we are happy with that, at least we should say so, I suppose.

So, those five points are ones that I thought of. As I said, you may have others that you want to put on the table, or you may want to modify or think about these, but I am hoping we can maybe get at some of those points, and you can divide it this way.

We have some issues to deal with because of current scarcity that will not end tomorrow morning. We have some issues, then, to deal with about what to do about scarcity to make sure we don't get in that situation down the road. Both of those I think deserve the committee's reflection.

Any other comments, any the panel would like to make before we get underway? Dr. Guerra.

DR. GUERRA: If this is an opportunity to add to your list, I would like to consider adding to that the use of the IG, the immune globulin for intramuscular use, which I think comes out or can come out as part of the manufacturing process.

Perhaps a shortage in that arena, which is primarily the public health shortage, is an even greater one in terms of the thousands of people that at times need to benefit from that in terms of post-exposure for a variety of conditions, whether it is after a bite incident or whether it relates to hepatitis or other conditions.

I wonder if it would be something to add to our list for consideration.

DR. CAPLAN: A little personal anecdote here. About a couple of weeks ago I went to Costa Rica just for a camping trip. Before I left, the doctor said would you like a shot of IVIG, and I thought, gee, I thought we were short in the world of this, how come I can get all I want if I promise to go to Costa Rica, but maybe I can't get what I want if I sit here.

So, that may be an area where the two supply streams intersect, and that is certainly something we ought to be thinking about.

Other comments before we turn to our first presenter?

All right. I want to say we have our work cut out for us, but we have things to do, I suspect we will get back to that, but also there are other issues we have to complete hearing about.

Jim MacPherson is here from the America's Blood Centers. Jim, if you would.

MR. MacPHERSON: Thank you.

DR. CAPLAN: Thank you, by the way, for agreeing to let us hold you over.

MR. MacPHERSON: Not a problem. I preserve fairly well.

I am not sure I am going to shed a whole lot of light on your difficult task, but at least I will color in a little bit of the piece of the puzzle.

I am Jim MacPherson. I am the Executive Director of America's Blood Centers. I want to thank the committee for this opportunity to explain where the independent community blood centers within this important issue of the availability of plasma pharmaceuticals.

ABC represents the independent, not-for-profit community blood centers that provide nearly half the nation's blood supply. Our members also provide nearly one million liters of plasma, which FDA classifies as "Recovered Plasma," for manufacture into pharmaceuticals.

Starting in the 1970s when plasma derivatives, like antihemophilic factor and albumin, began to replace plasma components that were provided by blood centers, the independents attempted to have their plasma fractionated into volunteer donor pharmaceuticals to be furnished to the hospitals they served.

Unfortunately, the costs were high, and the market at that time placed on premium on volunteer donor plasma pharmaceuticals. Because of their not-for-profit status, the community blood centers did not have the financial resources to withstand the price and availability market cycles, as well as recalls.

Subsequently, the independents began to sell their excess plasma outright to willing pharmaceutical companies. This practice continues to this day, but changes in recall procedures and market preferences have had a profound effect on where and how our plasma is used.

In the early 1990s, the independents began to see an increased demand for their plasma. There are two reasons for this. First, the Europeans place a high quality premium on volunteer donor plasma pharmaceuticals, so that both U.S. and European manufacturers began fractionating plasma into volunteer donor products for European consumption.

Second, nearly all recovered plasma comes from donors who give three or fewer donations per year. Consequently, this plasma has a higher concentration of plasma proteins than from paid donors, who often donate as much as twice a week. So, it is viewed as a richer raw starting material.

In the mid-1990s, plasma began to be recalled due to the potential infection with CJD, as you all know about, and like the Red Cross, pharmaceuticals made from ABC member plasma became especially susceptible to recalls from donors who subsequently came down with CJD. The main reason is because many of our donors are over the age of 60, about 25 percent actually are over the age of 50.

In addition, community blood centers have very close ties to the hospitals they serve, so when cases of CJD occurs, the hospitals kindly let us know, so that we can check to see if the patient was a donor, and occasionally, that has occurred.

Nearly all the CJD recalls have involved volunteer donor plasma, which I am sure you are aware of. Because volunteer donor plasma became a business liability, all the U.S. commercial manufacturers, namely, Alpha, Baxter, Bayer, and Centeon, stopped using it. As a consequence, nearly all one million liters of our members' plasma goes to Europe, most of it to the ZLB -- which is part of the Swiss Red Cross -- Central Laboratory in Switzerland and Immuno for manufacture into plasma derivatives.

Much of the plasma derivatives made in Europe do not come back to the U.S. except for immune globulin, and I should probably clarify that. We were told by the Swiss that about 90 percent of the paste made into immunoglobulin does come back to the U.S. as finished product, so although most of the albumin and Factor VIII and other things do not come back, the immune globulin does.

It has been proposed that the Central Laboratory in Switzerland fractionate plasma only from donors younger than 55, however, both they and us have resisted age restrictions for plasma donors because of ethical concerns. On the other hand, reality is forcing us to review those options.

Plasma derivative shortages may worsen, at least in the short term. The recent ramp-up for production of solvent/detergent-treated plasma has tied up perhaps 100,000 liters or more of volunteer donor plasma. The Red Cross can address that more directly since it is their plasma being made into S/D, and worse, the S/D process has a plasma loss of somewhere between 30 to 35 percent. So, the process itself will potentially consume hundreds of thousands of liters of plasma each year. That presumes that S/D plasma replaces fresh frozen plasma.

In addition, the independent blood centers are in the process of quarantining about 100,000 additional liters of volunteer donor plasma to be released as Fresh Frozen Plasma Donor Retested for transfusion use when the donor returns and is requalified as a donor.

The net effect of these occurrences is that temporarily, many hundreds of thousands of liters of volunteer donor plasma will not be available for manufacture into derivatives, neither here nor in Europe. The situation will ease, but will not disappear, when the ramp-up for these two new products are complete.

Finally, it must be said that the independents have been discouraged that our plasma cannot remain in the U.S. If we had the financial flexibility -- and we are not whining here, we are just stating the fact -- if we had the financial flexibility to invest in manufacturing plasma products in the 1970s, we may have earned hundreds of thousands of millions in profits over the last 20 years, but because we are not-for-profit blood centers, our mission is to serve the patient first, and protecting our bottom line has been, up until now, a distant second. I said up until now.

We also recognize the risk of such an endeavor. So, like the Red Cross, we would have been subjected to hundreds of millions in direct product losses due to the recent CJD recalls. We cannot afford to take such risks at the expense of the American public.

While we are pleased and honored to have the Europeans as our partners, we find it disappointing that U.S. citizens cannot benefit more from the fine plasma donated by nearly half of its citizens. We continue to evaluate our options for the future and recognize much, although not all, of the fate of the plasma rests within our own hands.

I thank the committee for allowing me to share this perspective. I also offer ABC's sympathy to the tens and thousands of those whose lives depend upon plasma products. We are community-based service organizations whose bottom line is our neighbor. We share their confusion and anxiety and frustration, and do what we can to help them obtain the safest product they need and deserve.

Thank you.

DR. CAPLAN: All right. Why don't we go right to questions. Jim, if you can just stay up for a second, I will open the floor to the panel.

Keith.

DR. HOOTS: Does any of your source plasma go to manufacturing in the U.S. or does all -- I guess we heard yesterday their capacity is pretty well filled with their own paid donors -- so all of the ABC goes to Switzerland as far as for processing?

MR. MacPHERSON: Yes.

DR. GOMPERTS: I wonder, Mr. MacPherson, if you could, for the committee, perhaps give a list, just run down the actual manufacturers in Europe that might purchase your plasma.

MR. MacPHERSON: The two primary ones are the ZLB Laboratory of the Swiss Red Cross and Immuno. There are a lot of smaller Italian and Austrian manufacturers, but they are pretty much less than 10 percent. So, the vast majority goes to those two.

DR. GOMPERTS: So, there is no plasma that would go to the Swedish Corby facility or the two British facilities?

MR. MacPHERSON: The British, thus far, no. I don't know if any goes to Sweden at this point.

DR. GOMPERTS: The French, Dutch, Belgium?

MR. MacPHERSON: Not to my knowledge.

DR. GOMPERTS: Okay.

DR. CAPLAN: John.

MR. WALSH: Is it your impression, Mr. MacPherson, that there is a market need for your plasma here in the U.S.?

MR. MacPHERSON: Well, as I said, before CJD, there was a premium placed on it, partly because it had that white hat of volunteer donor, but also, as I mentioned, because our donors only come back two or three times a year, it is a richer starting material, so it was very rich in both the components that are replaced normally, but also especially in the immune globulins.

So, we think that there would be a big demand here even in the U.S., and we have talked to the fractionaters who said, sure, we would buy your stuff if it wasn't for CJD.

DR. CAPLAN: Dr. Guerra.

DR. GUERRA: Suppose that ABC were willing to take a big leap and make a major capital investment in establishing a manufacturing plant, have you done some modeling to see what that would cost and what the benefits of that might be?

MR. MacPHERSON: Yes, we are just starting to look at that, and we have been having some preliminary discussions with the Canadian Government, because the Canadians are interested in building their own fractionation plant, but they have so very little plasma actually to maintain it.

So, there are possibilities, but it is too preliminary to really give you those figures, but, yes, we are looking at it, because we recognize that for the last 15 years, we have just sort of given it away, and it's a potentially rich resource that we could utilize better.

DR. CAPLAN: I think I understand this, but could you just go through again why the CJD liability issue is leading to this supply going overseas completely?

MR. MacPHERSON: Because of the recalls. I mean if they --

DR. CAPLAN: Is this something that would be handled by labeling, as our committee has talked about sometimes?

MR. MacPHERSON: Potentially, sure, but again, if you take a unit of plasma and you pool it with 50,000 or 100,000 other donors, suddenly, that becomes the subject of the recall. You have seen the recalls over the years. I mean they astronomical. So, I just think that as a business decision, the manufacturers in the U.S. have just said they don't want to.

DR. CAPLAN: The other reason I am headed in this direction is you remember yesterday, we heard that the first batch of emergency stock was from a recalled unit that was negotiated out to be allowed to be put there.

MR. MacPHERSON: Right.

DR. CAPLAN: And I am wondering, you know, the difference between what your practice is and what seems to have emerged in another area we found a use.

MR. MacPHERSON: I guess maybe to state it this way, we sort of go with the flow here at this point. We are not in control of how the products are used or where they are used. All we know is that the only market for this product has been overseas, and the Swiss, up until this past year, had not had a lot of recalls, just serendipitously, I guess, and now they have had a lot of recalls and they are having to reevaluate what they want to do, as well, because they are finally suffering the hundreds of -- or at least tens of millions of dollars in recall and product loss.

DR. GOMPERTS: When the Swiss withdraw in the United States, do they also withdraw in Europe?

MR. MacPHERSON: Yes. They follow the regulations of the highest regulatory authority over the product that they make, so if the FDA says you recall that product, then, they recall it everywhere. That is pretty standard practice at least in the European countries.

DR. CHAMBERLAND: Actually, that was similar to my question. Do you or does anybody else know if European countries themselves have any regulations or requirements for withdrawal when donors' diagnosis of CJD is subsequently identified?

MR. MacPHERSON: I am not an expert on this, but there are guidelines that are published by -- and I am blanking on the name of the organization -- the CM Medicinal something. They do have guidelines for CJD, but there is no -- it is up to individual countries. I don't believe that there is any, but maybe somebody else can answer that question better than I can.

DR. DAVEY: I believe the British experience, it is a bit ironic. They do withdraw for -- and correct me if I am wrong -- the new variant, but actually they do not withdraw for classic CJD, as we do here. I am not sure of the other countries.

MR. MacPHERSON: The French do not, to my understanding. The Swiss do primarily because they are following FDA regulations or guidelines.

DR. BUSCH: Just to follow up on that, that is my understanding, as well, is that for the most part, they do not recall, similar to the U.S., and so if a donor, let's say, in the U.S., a volunteer donor whose plasma was exported to the Swiss, subsequently was diagnosed with CJD, do you know what happens, is that notification passed on?

MR. MacPHERSON: They are recall, because they are FDA-licensed products.

DR. BUSCH: Does the recall strictly apply to the IVIG that is exported to the U.S., or will that recall also apply to the other derivatives?

MR. MacPHERSON: Again, I am not the best person to answer. My understanding is if they make a product, and it's a licensed FDA product, they will recall it. Otherwise, they will follow whatever the requirements are for the individual countries.

DR. CAPLAN: Larry.

MR. ALLEN: Excuse me, sir. Are you saying that none of the manufacturers in this country will buy your plasma, is that what you are saying?

MR. MacPHERSON: Correct.

MR. ALLEN: And the specific reason is what again?

MR. MacPHERSON: CJD recalls.

MR. ALLEN: Because you have had so many in the past?

MR. MacPHERSON: Because there have been so many, well, because of the high association of recalls with volunteer donor plasma, that is correct.

DR. DAVEY: I think that as Jim pointed out, it is interesting, I think roughly 80 percent of the U.S. plasma market is in the commercial side, 20 percent volunteer, but the recalls are almost entirely reversed, 80 percent of the recalls are volunteer, 20 percent are from the source plasma side approximately.

I think, as Jim indicated, some of the thinking is that in the volunteer sector, where there is a close relationship with the donors, their families, and the hospitals, that the post-donation information comes back much more vigorously in the volunteer side.

We hear much more about whether a relative or a former donor or a son who might have gotten growth hormone or some shot 30 years ago, that information comes in the volunteer side, we feel, although I don't have data to back this up, much more frequently.

So, the recalls come much more heavily in that side of the market.

DR. CAPLAN: Let's go to Jane and then we will go to John.

DR. PILIAVIN: I just want to draw out what I think is the obvious conclusion from what is being said here. We know that at least historically, there have been more markers for a variety of disease entities in the paid plasma sector than in the volunteer sector notwithstanding the fact that this seems to be getting a lot better in the paid plasma sector.

If you are thinking about emerging diseases, it seems that we should expect to find it more in the plasma sector than in the volunteer sector, and we are saying that one of the reasons for our vigilance is not specifically because of CJD, but because of possible other kinds of emerging factors.

It seems, therefore, totally ironic that most of these recalls are happening in the area where we have more confidence in the blood supply in other ways. I think this just underscores what a number of people have said in previous meetings regarding the CJD issue.

This is that doing these recalls provides a false sense of security with regard to the entities that are probably there in the plasma. In other words, if the reason why we are having the recalls in the voluntary sector is because of better communication with the hospitals, and, of course, because we have got people who are older in the volunteer sector, those two things together, it is very, very likely that these entities are present at least as much in the paid plasma sector. We just don't know it.

I think that is like the ostrich with its head in the sand, you know, that because we don't have the information, we say, well, this stuff is fine, and the volunteer plasma is not fine.

Well, probably along the lines of all of the other things that might be in there, that we just don't know about yet, the opposite is true. I really think we have to seriously consider changing our attitudes towards the CJD issue, possibly by doing this kind of labeling, but the labeling still carries some sort of stigma.

I think part of the problem here -- I know I am rambling -- has to do with people's lack of understanding of probability theory, and that the simple likelihood of somebody undetected having CJD being in any pool of plasma is pretty close to 1. Nobody quite understands what that means, I think, and it is sort of if you can't see it, then, it's not there approach.

All of these recalls for CJD are there for, you know, just as we have said before, the tip of the iceberg, but the iceberg is there and it's in everything, and the only way to get rid of it is to just not use the plasma. Obviously, that is not a choice.

I don't know what the bottom line here is. It's just that I wanted to make sure that the conclusion came out in terms of what is being said here about the relative proportions of recalls.

DR. CAPLAN: I think Jane was rambling a bit until she got up to the call that we understand probability better, and then she lurched to optimism.

John.

MR. WALSH: I will try to be brief, but maybe I lost something yesterday. We are all concerned about safety, and we had a hearing on the CJD issue, and we made a recommendation to the Secretary with regards to that, which seems to address some of the perception or reality that you are experiencing with the manufacturers.

I am not certain that I heard yesterday -- and maybe I missed anything -- any of the manufacturers saying to us that they have a limited supply or a shortage of raw product to produce plasma derivative products.

MR. MacPHERSON: That's right.

MR. WALSH: So, if we are looking at a shortage, you know, availability of plasma derivatives, you know, for life-threatening diseases, and if the plasma is so plentiful, all of your plasma is going overseas, production seems to be the issue.

Does anybody on the committee hear anything different than that?

DR. CAPLAN: Jim, do you want to get in on it?

DR. AuBUCHON: That is what I heard yesterday, as well, John, however, if the manufacturers are producing as much IVIG as they can, if they are running as many liters through their plant as they possibly can, by shifting away from volunteer plasma and slightly higher immunoglobulin levels, they may reduce their final yield somewhat.

Now, that is probably only a couple percentage points, my guess, but it seems like all of the things that have affected the supply have only been a couple percentage points, and, in aggregate, they have created a large shortage.

DR. GOMPERTS: Can I just correct a misconception here? The handling of the donor, whether it's volunteer or paid donor, from the point of view of questioning, evaluating is essentially identical as I understand it.

The major issue in this particular circumstance, Dr. Davey, is a number one. In other words, when a volunteer donor contributes a unit of plasma, the amount of plasma collected is about 200 milliliters. With a source plasma situation, it's 800, so you get four donors to one donor from the point of view of going onto a phoresis machine.

Secondly, the individual volunteer donor goes into the blood bank once or twice a year. The source plasma donor is there, can be as frequently as twice a week. So, when you work this all out, the chances of an individual donor coming in and having a predisposing condition that might suggest a possibility of CJD, a slightly higher risk, it's a numbers game.

Now, the actual yield of immunoglobulin and albumin from a volunteer, a recovered plasma situation, is higher, so there is an advantage in using the recovered plasma, but the disadvantage is the frequency of recalls, not from the point of view of safety, the issues of concern out there for patients receiving albumin, immunoglobulin factor, whatever, this is a major issue.

DR. CAPLAN: Let me take one more question, but I wanted you to have a chance to comment.

MR. MacPHERSON: No, I would agree with what has been said, and just to reemphasize the fact that it is true that we are probably not talking about a shortage of plasma in this country, because as our plasma has been going to Europe, the paid sector has been increasing their output to make up for the loss of plasma.

DR. CHAMBERLAND: Just to follow up on something you stated earlier, you indicated that the Europeans, the Swiss Red Cross had experienced more recalls this past year. Are you hearing any sense from your Swiss Red Cross clients, they are potentially rethinking about buying recovered plasma from the United States because of the liabilities and the recall issue, hearing that they have to withdraw a product from both the U.S. and European markets, and that would further chip away, as we heard yesterday, the Swiss Red Cross, through Sandoglobulin, does come back to the United States, are you hearing any indication that they are rethinking buying U.S. recovered plasma?

MR. MacPHERSON: No, not really, because actually they just built a second factory, and it was to accommodate the huge increase in flow in the U.S. I suppose if the economics worked against it, they would probably do it, but at this point, we are their biggest client.

DR. CAPLAN: Thank you.

MR. MacPHERSON: Thank you.

DR. CAPLAN: Sorry, Paul, one quick one.

DR. McCURDY: Ed made a comment that I would like to follow up on a little bit, because I think there is an absence of data where it might be useful perhaps to have data. The screening program for the volunteer and paid donors is essentially the same.

We do know, however, there are data that indicate somewhere in the neighborhood of 5 percent of volunteer donors, at least in some of the centers where this study has been done, have deferrable risks that they own up to on anonymous questionnaires administered after the donation, but do not on the face-to-face interview.

There are no such data for the paid -- at least I am unaware of any such data -- in the paid sector. Nobody I think has -- I mean there have been a lot of assumptions made, but it is not clear why the marker rate, as Jane said, seems to be higher among paid donors than it is among volunteer donors, although they are coming closer together.

But I think there is an absence of data here rather than data on which to base firm conclusions.

DR. GOMPERTS: I can talk anecdotally around that, but one set of data is pretty clear. The source donor group tend to be younger, there is no doubt about that. Obviously, we have debated the issue of age cutoff certainly from the point of view of CJD. I think that is a major one, but also, the potential for exposure to growth hormone in the seventies, sixties, is, of course, higher in the older individual, as well.

DR. CAPLAN: One happy note for those of you exchanging anecdotes about this particular subject is that we will get back to the issue of donors probably in the next meeting. That is what we had, if you recall that far back, looking forward backwards, that is where we are going to take a look, so we may actually get back into this data issue there.

I was going to ask Paul, do you think that for CJD, this issue of donor deferral registry's post-deferral is going to make a difference relative to where that is likely to be a risk factor? I understood what you were saying about markers for other diseases and the paid versus unpaid donor pool, but just looking at this particular risk, if it's an older group and they are tracked more closely on the volunteer side than on the paid side, there is not going to be much deferral on the interviews that way for this particular risk factor.

DR. McCURDY: The at-risk behavior that I was talking about was at risk for either HIV or hepatitis. There is about to be released another questionnaire which will ask some questions about possibly at-risk activities for CJD, that is, eating central nervous system food, and so forth, but we don't know about that, and actually, we don't know how much of a risk factor that really is.

DR. CAPLAN: I am going to ask Christopher Lamb if he would come forward.

MR. LAMB: Good morning, Mr. Chairman. My name is Christopher Lamb. I am the Vice President of Plasma Operations for the American Red Cross. I am pleased to be here with you today to give the Red Cross perspective on the IGIV shortage.

The first overhead relates to the role of the American Red Cross in providing IGIV to the American public. Overall, our goal is to optimize the use of volunteer plasma recovered from whole blood collections. The American Red Cross collects about 6 million volunteer donations, whole blood donations each year, and that translates into about 1 million liters of plasma that is sent for further manufacturing into plasma derivative products.

Let me just make one comment, a follow-up on Dr. Gomperts' remark. The average volume per donation for the American Red Cross is 283 mL per donation, which contrasts to 800 mL for a source-phoresed donor, and regardless of the issue of CJD, this has enormous impacts on pool size, which I will get to in a second, in terms of the ability to reduce batches from donor pools less than 60,000 is much more difficult for the recovered side than it is for the commercial source side.

The American Red Cross is unique in the sense of what we do is we take our recovered plasma and rather than sell it outright to commercial companies, we have our own plasma program whereby we have entered into what is referred to as "contract fractionation" agreements, where the plasma is sent for further manufacturing to commercial facilities, and then those plasma products in general are returned back to us.

Our primary agreement is with Baxter. Eighty percent of our plasma goes to the Baxter Highland facility. All of those plasma products are returned to us for distribution in the United States. Twenty percent of our plasma goes to the Swiss Red Cross, again, under a contract fractionation agreement.

Historically, through 1997, all of the albumin was returned to the American Red Cross. The IGIV, as you heard yesterday, because of a long-standing agreement between the ZLB, the Central Laboratory of the Swiss Red Cross, and Sandos, now Novartis, the IGIV was distributed under the trade name Sandoglobulin by Novartis.

We have reached an agreement with the Swiss Red Cross whereby the IGIV will start coming back directly to the American Red Cross for distribution in the United States. We expect the first deliveries of that product to begin in late June.

In total, approximately 3 million grams of product are produced from the American Red Cross, either from the Baxter facility or the Swiss Red Cross, which is approximately 15 to 20 percent of the U.S. need.

[Slide.]

In terms of the IGIV shortage, our perspective on this, firstoff, is as we have heard a lot of comments in terms of increased usage, we have seen about a 10 percent annual increase in the volume of this product -- and I will get to this in a second -- and I want to walk through with you the impact of CJD withdrawals and what they have done to the supply of our product.

There have been a couple of other impacts on our supply which I will go to in detail in a second.

[Slide.]

From market research that we have in our possession, and I don't want -- the market research isn't -- I don't want to be too specific. This is a general overview of our forecast of what we see in the marketplace and what it has grown over the years. We extrapolated, in 1997 based on prior increases, and assumed a 10 percent growth. Yesterday, people were saying that there may be 8 or 9 percent growth, but it is clear, over the last 10 years, there have been a substantial increase in the usage of this product.

Interesting enough, if we look at this forecast as reasonably accurate, I would guess the total U.S. demand is between 17 and 18 million grams. If you take a look at the data that was presented yesterday in terms of industry and what they are supplying the U.S. market, of maybe 10 to 11 million grams plus the Red Cross, 3 million grams, and other product that is coming back from the ZLB from non-Red Cross sources, you probably have a supply of around 17 million grams, which gives you a estimated shortfall of probably around 1 million grams.

If this increase continues at a rate of somewhere between 5 and 10 percent, you can begin to see how probably the shortfall is not going to be abated over the next 18 months.

[Slide.]

I want to specifically look at how the Red Cross supply of IGIV has been affected, primarily looking over the last nine-month period of time when we have seen the shortage. So, I can go, if the committee would like, and take a look at 1996 and the full year of 1997 and what we project for 1998, but looking just at this particular nine-month period of time from July 1, 1997 through March 31st, 1998, we had a theoretical total supply of our product of about 1 1/2 million grams of product.

Approximately 10 percent of that volume was impacted by finished product that was in process and ready to be released, but was withheld from the market because of a donor theoretically at risk for CJD.

We had another 6 percent of product that was either in our finished goods warehouse at the time of a withdrawal or was returned as a result of a withdrawal. I did not have the time to break this information out, but this is product that had been released to the marketplace and either was in our possession or had been returned, so about 6 percent of the product was quarantined or returned, and approximately another 6 percent is other intermediates, which would be fraction, the fraction paste, whether it is fraction 1 plus 2 plus 3, or fraction 2, and whatever stage of intermediates was not able to released to the marketplace.

Historically, the Red Cross, if we were not able to fractionate all of the intermediates at the Highland facility, we would send that to the Swiss Red Cross to ensure optimal supply of the product, so in one form or the other, this material is not available to the marketplace.

So, approximately 22 percent of our total supply has been impacted over this nine-month period of time due to the CJD issues.

The second issue relates to the 60,000 donor limit. In late 1996, basically, seeing the recommendation that was likely to come out of the Blood Products Advisory Committee of a desire by consumer groups to limit batches from donors of 60,000 or less, we started to implement this, and we basically saw a decrease in output of about 3.8 percent.

I want to touch on this briefly. This was raised earlier. The issue of pool size and batch size is a very complicated one. Facilities have been designed and optimized traditionally to maximize output. Interesting enough, when we first started marketing this product, we actually promoted the fact that our batches were from a minimum of 60,000 or more donors to give a broad spectrum of antibody protection, but facilities, you can't change facilities overnight.

The tank size, the columns used to purify the material, the lyophilizers are all very fixed in terms of the way the production setup goes, and they cannot be changed overnight, and any changes to them automatically, in our case will result in a decrease in supply.

The notion of going down to 15,000 donors per batch would essentially wipe out our supply, would wipe out any supply from the Swiss Red Cross, and would probably decrease the available amount of product by close to 5 million grams.

I think the committee ought to seriously consider this. There was a full day discussion before an expert panel headed up by Dr. Koop. It's a very complicated subject, and I think if the committee would like a fuller briefing on this, we certainly could come back and discuss it further, but it's a three- to five-year process which would in essence mean building a new facility to make smaller batches. It's not a trivial exercise, and one I have looked at in depth and had engineering studies to look at this, but just the immediate impact from us, our standpoint, was about a 3.8 percent decrease in supply.

The third factor has been other manufacturing problems or issues, for example, which is traditionally during the course of a year, you have a batch that is rejected for particulation, a batch that is rejected for high IGA content, and this impacted about 6 percent of our supply.

So, during this nine-month period, we saw about a 32 percent decrease in supply or about 500,000 grams of product.

[Slide.]

The fourth factor impacting our supply relates to CGD investigations. When we receive a post-donation callback of a donor, who potentially is theoretically at risk for CJD, in other words, a donor comes in and donates and says they received human growth hormone or they may have received a dura mater transplant.

That product immediately, any product in our possession immediately goes into quarantine, and we don't release that material until we resolve the investigation. Let me give you a couple of examples of how that impacts our supply.

In late October, early November, we received a report from a young woman who had donated a few months earlier. She came back a second time and indicated that she had received human growth hormone. What happened was she had come for the first time and donated, she went back, talked to her mother, and her mother said -- she asked her mother about the questioning, the questions she had been asked, and her mother said, you know, you did receive growth hormone.

So, she comes back a second time. We received this information. The material immediately gets quarantined at the manufacturing site. We start an investigation. The woman allegedly was treated at Georgetown Hospital. We went to Georgetown Hospital, and determined that it was, in fact, recombinant growth hormone. However, there was something in the record that the donor had been treated at Children's Hospital.

We went to Children's Hospital, searched the records, and it turned out that the donor had been treated yet by another physician. We had to track down the physician, and finally we determined, in this particular case, that the donor had not received human growth hormone, but had, in fact, received recombinant growth hormone.

We were able to exonerate the case, and so the product was, in fact, release in January, but during the November and December time frame, we did not have this product.

The same is true with dura mater cases. We recently, in the last month, had a case where a donor came back and said that they thought they had received a dura mater transplant, and, in fact we went back. It was a very reputable institution, and the dura mater transplant was 30 years ago, 1968, we have a healthy donor, who 30 years ago, in fact, has received a dura mater transplant.

What we have been able to determine is that, from the head of the Department of Neurology, is that the dura mater transplant certainly was a single source, certainly was from a U.S. source, but we are not sure whether or not there was an autopsy done on the donor of the dura mater, which these are the three conditions for releasing material, and in 1968, autopsies were not common for donors of dura mater, and so this is an issue that is still under investigation, but in the interim, the product is in quarantine.

So, these kind of CJD investigations either lead to product which is ultimately withheld from the marketplace or it's delayed in terms of reaching the marketplace.

I would mention that over 80 percent of our withdrawals relate to the issue of human growth hormone or dura mater. We have had very few withdrawals from donors who have died of CJD or donors who have had two or more relatives with CJD. The major issue relates to growth hormone and dura mater, and I would urge this committee to take a look at those two issues alone would substantially reduce the number of withdrawals in the marketplace.

I would also add that typically, when we are actually able to get the medical record, it turns out that in over 80 to 90 percent of the cases, in fact, the blood donor did not receive growth hormone, they received testosterone or they received something else, but oftentimes we can't get to the medical records because we are talking about 20, 30, 40 years ago, the physician's records are not available, and we are relying on a lot of anecdotal data, and that is the situation that we are faced with in terms of the CJD.

[Slide.]

Let me go to the next overhead, which is the American Red Cross response to the IVIG shortage. We have tried to focus every effort on rapid release and distribution of IVIG. The FDA has done an excellent job in reducing the amount of time that they take to approve a lot. It went from several weeks to less than a week, and if any case, a situation comes up where a lot is held up, I always can easily make a call to the FDA, Alice Kirkarkijimski, and she is able to resolve it within a day.

We process probably on a daily basis about 10 to 15 emergency requests. Most emergency orders are filled. What we do right now, we have two contractual commitments, guaranteed contract commitments with groups of hospitals. One is University Hospital Consortium, the other is Premier, and we guarantee the supply of that, and if we don't fill that supply, we have got to go out on the open market and purchase it.

So, we what we try to do -- and that represents about 70 percent of our supply -- so what we have tried to do is meet those two guaranteed obligations and reserve the rest for emergency use.

It is very difficult to target for particular indications. We were working with IDF. They talked about, during the December and January time frame, where they were screening requests. We would get a request and we would say to a hospital this is for a primary immune-deficient patient, and they would say, yes, we would have one of those, yes, we use it for this patient, but when they were shifting from one group of patients to another, it is very difficult to know, so it is very difficult from our perspective to really say that we can target this particular product for this group of patients with this indication.

But clearly, while we do focus on trying to fill emergency orders, currently, we have, for example, 126,000 grams of IGIV on back order as of last Friday, and again back orders are prioritized based on emergency or guaranteed contract commitments.

[Slide.]

Again, the issue of is there hoarding of product, I took a look at the last 11 batches that have been released into our possession, and if you take -- the average time of batches in our possession is 14 days -- if you take out one batch, which is Lot No. 6 here, which is actually a 2 1/2-gram-per-vial, which is not a very desirable use, it takes a lot of reconstitution time, we have offered it to hospitals. It definitely is not a preferred size, if you take that out, 10 or our 11 batches are in and out of our inventory in nine days, and in some cases, it is one day.

So we see rapid turnaround, and at the end of any month, looking at January through March, at the end of any month we had basically zero inventory on hand, so each month we clear out our inventory and rely on releases for the subsequent month.

So, under no circumstances I think is any product being hoarded or held back from the marketplace by the American Red Cross.

[Slide.]

In terms of preventive measures, again, I mentioned we have a new agreement with the Swiss Red Cross whereby IGIV from our plasma will be returned to us for distribution solely in the United States. We do have yield improvement projects with Baxter, our primary fractionater.

I would tell you that yield is a constant preoccupation. It has been a constant preoccupation with the American Red Cross for the past 10 years that we have had this product. We review this on a quarterly basis. We look at any opportunities there are to improve yields. We have made tremendous improvements over the years, and we continue to make improvements.

I believe Baxter mentioned yesterday next month we plan to submit an amendment to the PLA, the Product License, for a new resin which we hope will we hope will further improve yields. Hopefully, this will be approved by the FDA in the next six months, and again this will offer some incremental increase in the supply of product.

We do plan to increase our collections. It was mentioned earlier that hundreds of thousands of liters are being tied up with the solvent/detergent-treated plasma product. This is not the case.

The amount of plasma we fractionate is the same in 1996 as it was in 1997, and is planned to be in 1998, and in 1999, we are hoping that through increased collections and also with some alliances that we have with other blood centers, we hope to increase the plasma that we throughput through our existing contractual arrangements, and I would offer the ABC, we would be happy to purchase their plasma to fold into our fractionation program at anytime to ensure that the products come back to the United States.

Finally, let me just comment on the issue of CJD research. I would guess that the Red Cross is probably the most active organization in this area. We have done a variety of studies.

This committee heard at the last meeting about work done by Bob Rohrer, Dr. Rohrer at the VA Hospital in Baltimore, and Dr. Brown, at NIH. One of the experiments that you heard was a fractionation experiment. This was done again in collaboration with the American Red Cross, and where we took 300 mice who had the mouse-adopted CJD strain.

They were sacrificed when they were just about coming down with the disease. We fractionated that plasma, and we took a look at is, under these extreme situations, if TSE or CJD is in blood, is it in plasma, and if it is in plasma, what fractions are there.

The committee asked that the experiment be redone, not only redone, but done at an independent laboratory. We have since worked with Dr. Brown where we redesigned the study. We went into the FDA. They had some very good comments.

One change to the experiment was in the original experiment, we looked at cryoprecipitate, 1 plus 2 plus 3, fraction 4, fraction 5. What we are doing in the next experiment is dropping out the fraction 2, which is the starting material for IGIV, to see if there is infectivity there, and if it's not, then perhaps we can exonerate the fraction 2, fraction 4, and fraction 5.

In addition, we have a similar experiment with Dr. Rohrer. His animal model is hamsters. Scrapie is the agent. Scrapie is 98 percent homologous with CJD, and that experiment is about to begin.

So, we are trying to work with the FDA, with the public organizations, to get more data to better understand whether or not this is, in fact, a risk and to give more a fact base to the policy and whether or not we should continue with the policy or change it.

So, these are experiments. Unfortunately, we are working with IC inoculation, intracranial inoculation as the infectivity, so the time to complete the experiment is generally a year or more. You have to wait until all the animals die, so it is not something that we can expect a quick turnaround.

In addition, we are doing other validation experiments to determine if CJD is in various fractions, like, for example, cryoprecipitate, would it be removed during the processing, and we have other experiments also looking at whether or not we can inactivate it with various techniques.

So, we have an extremely active program in this regard, and we hope over the next year or two we are able to bring more data to the table to address policy issues.

Let me just answer an earlier question that came up in terms of what is happening in Europe. There is the CPMP, the Committee on Proprietary Medicinal Products. Their policy has been not to do -- this is a European-wide group -- not to do withdrawals for donors who die of CJD, what we call the common variety of CJD, or for other at-risk issues like growth hormone or dura mater.

However, the way that is implemented is on a country-by-country basis. For example, the Swiss Red Cross, in fact, had a donor who died of CJD, and they did not do a -- this was a Swiss donor -- they did not do a withdrawal in Switzerland. In the UK, they do not do withdrawals, they only do withdrawal with a new variant CJD. In France, they do do withdrawals. So, you really need to look at it on a country-by-country basis, while the overall centralized group has taken a position, it is implemented differently on a country-by-country basis.

Thank you, Mr. Chairman.

DR. CAPLAN: Thank you. We will open the floor up for questions from the panel. Keith.

DR. HOOTS: In terms of the cost during the shortage, since you guy on the spot market, have you noticed, what has been the purchase price when you do in order to fulfill your commitments to Premier and UHC, what has happened over the last year and a half to the price of a gram of IVIG?

MR. LAMB: Well, because we have those commitments, we have used our supply to meet those commitments. We have not actually had to go out and purchase the product. Seventy percent of our available volume has been used.

DR. HOOTS: Have you looked at what the impact would have been had you had to do that, have you gone out to check?

MR. LAMB: Well, you certainly have heard extreme examples of product of well over $100 a gram. My guess, it has probably been between 45 and $55, in some cases, $65, so probably between 45 and $65 a gram would have been the cost had we had to go out to the marketplace and purchase the product.

DR. HOOTS: Secondly, you raise an interesting question about the fact that even in the face of shortages, you have longer shelf time for the pediatric size, which then raises the question, if there is spot shifts and market demand still very much at work here, and people are still having preferences, that pediatric size vials might be the ideal emergency supply to have, so that there would be less demand for that, and it also would be adaptable to every source of need or every targeted person.

I mean as a person who treats populations where convenience is exceedingly important, I don't like to see that happen, but if there is an incentive for people to get product, that might be something to keep in mind.

MR. LAMB: I think it is a good point, however, I would say that because with the smaller batch size, I mean with the pediatric, the 2 1/2 gram, that batch actually turns out to be much larger in terms of vials, and so when we make a batch of that product, actually, the volume is smaller, so in terms of optimizing output, we are much better off making a 10-gram size bottle than a 2 1/2-gram, so actually, we have shifted our production to optimize output.

DR. HOOTS: Right, and I didn't mean to shift to production, I meant in terms of what to hold in reserve.

DR. CAPLAN: Let me address two issues to you that came up in your comments. One is about this matter of pool size and the conversion of the physical plant, and so forth, to handle the smaller pool.

When I listen to people talk about this, I think the major message that I take away is that people would like to see a smaller pool in part to purchase or acquire safety and the ability to recall more easily without damage to the overall supply, and at the same time, there is a concern that output is going to be adversely affected, so you are weighing a balance there, but as far as I can tell, what I think most people are looking for is they want to see the safety side pushed up, but they would like to have a target, a firm target, for the conversion.

So, has the Red Cross in your own area been able to say, well, by the year 2002, we will have done the redesign or by the year 2004, we will have done the redesign? I mean what does the long-term strategy look like for getting us past this continued pool discussion?

MR. LAMB: I think that, firstoff, it is not clear that there would be any increase in safety going from the 60,000 to a 15. Clearly, there is an article, the Lynch, et al., article, which has modeled this out, so the benefits of going from 60 to 15 are really unclear, and in fact, some might argue that with those small batches, maybe you have, let's say, the example yesterday where you have 1 in 100,000, and so you would have one batch that is implicated and four batches that are not.

It is not clear in terms of infectivity about whether or not the viral load in that smaller batch now makes it more infectious. So, on both sides of the table, people have said smaller batch size is good, perhaps increase the risk, and some people argue it could decrease the risk, so there is really no consensus that there is any improvement in safety.

My position would be we have both within the Red Cross and with our manufacturing partners, very active programs in viral inactivations and other strategies to improve the safety of the blood supply, and rather than put $100 million into building a new plant, which is what a new plant would cost, we are much better off focusing on getting additional technologies into our products that would inactivate non-envelope viruses and potentially other emerging agents.

I think from a strategy standpoint, I think that is a much better way to go.

DR. CAPLAN: I think that is very helpful in one sense because what it tells me is that there still is a debate about how best to achieve safety, and the issue of infrastructure changeover is a little bit of a red herring.

If the industry, Red Cross, or anybody else believed that you would get the safety that I think some of the patient groups think you will get from a smaller pool size, the conversion would be being pursued, and so what we need to do is come clean, I think, about this and say with respect to pool size and how many units are used, and where we are going to pool, and so forth, that the debate is over whether we can stay at the same pool size to maintain output for whatever economic reasons, and at the same time make a commitment to get infectious agents out of those pools, or are we going to go to smaller pools in the name of safety and all concede that that is the strategy to pursue.

It seems to me what I have heard since I have chaired this committee about pool size issues, has been a blurring. If we are convinced that the pool size is the solution, by going smaller, then, the conversion date should be set.

If we are convinced that we can handle bigger pool sizes and make them safer, then, we should, in fact, say we are not going to do the conversion, but I think what happens is, to be frank with you, that we are driving a lot of people crazy about why aren't we, in fact converting.

We go year after year in this debate about pool size, and no one sees any effort made by Red Cross or anybody else to go to the smaller pool size. At the same time, I think it's partly because people on the provisions don't believe in the smaller pool size.

So, if we could at least be frank about what is going on, then, I think the public policy debate would move, we could engage what is the best safety strategy. That is a little personal angst expressed there.

MR. LAMB: I agree with that.

DR. CAPLAN: The second question. You commented to us that you were in situations sometimes with these dural matter look-backs or growth hormone look-backs where the records are fuzzy and it's not clear what we are chasing or whether we are going to know exactly what went on, and personal anecdotal reports, people may not be sure what, in fact, they ever did have happen to them. They are trying to recollect events from many years ago, and doctors and records are also not so good from many years ago.

This committee did take a vote about CJD and look-back, and tried to argue that there should be an attempt to work with FDA and others about look-backs, and these scenarios that you are presenting -- I am just speaking personally now -- do seem to me to be instances where some accommodation might be possible about recall of the supply.

It is one thing to say we have a unit from a known donor and we are going to try and keep it out there because we need IVIG. It seems to me -- I am just speaking personally now, not for the committee -- but I want to flag it for your attention as you talk to regulatory agencies, if you have got the look-back, and we are not sure whether it was really growth hormone or we are holding a unit because of the dural matter, but we don't know if there was an autopsy done, that is precisely one area where some facing the shortage we do right now, there ought to be some room for some accommodation.

MR. LAMB: I would agree, and we are working with the FDA on these issues.

DR. CAPLAN: Paul.

DR. HAAS: It is somewhat along the same line. Did I hear you correct to say that very few of the recalls were because of actual deaths relating to CJD?

MR. LAMB: That's correct.

DR. HAAS: The source of data that led to that conclusion, were they birth certificates or --

MR. LAMB: In those cases where -- I am sorry -- what --

DR. HAAS: I am just wondering if birth certificates were part of the source of making decisions that people didn't die because of CJD.

MR. LAMB: You mean death certificates?

DR. HAAS: Yes, death -- did I say birth certificates -- it is wrong. It was a bad day yesterday, I guess. Death certificates, they are notoriously bad. I guess I just want that cleared up.

MR. LAMB: We have probably done -- I don't have the exact number -- we have done more than 25 withdrawals due to donors at risk for CJD. Only a couple of those have been for donors who have died of CJD.

In those cases where someone has died of CJD, actually, the clinical diagnosis is fairly straightforward. You pretty much can go -- there is usually a neurologist whose opinion has been sought. In many cases, a second opinion has been sought.

The clinical course is fairly clear, and in some cases we have autopsies which have pretty much confirmed the diagnosis, but in 80 or more percent of the withdrawals that we do, are not because donors die of CJD, but because a donor allegedly has taken a human growth hormone or has received a dura mater transplant.

So, if a policy on those two issues alone were addressed, this would substantially reduce the number of withdrawals.

DR. CAPLAN: Ron.

DR. GILCHER: I think Mr. Lamb has made an important point about pool size, and the point that I want to make is really one of clarification, and that is, are we really talking donors per pool or are we talking donations. What I really hear is talking right now is donations per pool.

In fact, it would worsen our scenario on the volunteer sector side if we talked donors per pool because clearly, I think the number of donors per pool on the commercial size would be less by virtue of the volume of the donation and the frequency of the repeat donor by virtue of being paid.

But I think this is really an important point of clarification, and to me, what is really important is the number of donors per pool, and I think that is the real issue here, because if you are carrying it today, you are carrying it tomorrow, and you are carrying it essentially forever, so to speak.

But I think we are getting lost in the shuffle here when we start talking pool size, because the volunteer sector plasma is always going to have a much larger number of donors per pool. There is no way around that. I think we really have to come to some sort of understanding and clarification. Perhaps FDA could help us. I would be interested in the comments from Jay and others.

DR. CAPLAN: Ed.

DR. GOMPERTS: If one focuses on the pool size issue, but from the efficacy point of view, the efficacy of the product, and in this situation, IVIG is unique. In order to document a particular pool size in relationship to efficacy, clinical research studies would need to be constructed in all the different indications, Kawasaki, ITP, primary immune deficiency, and those studies would need to be done with whatever pool size one is targeting, let's say 100 donors, 1,000 donors, 5,000 donors.

A product needs to be made from that, and patients need to be treated and then evaluated, so the time and effort that will be required to determine a particular efficacious pool size, and almost certainly that will differ from the primary immune deficiency situation, the acquired immune deficiency, and the immune modulation situation, which in itself is heterogeneous.

So, the issue of efficacy, as far as IVIG, one can hypothesize and talk around it, but to get the data is not going to be that easy.

MR. ALLEN: A couple of quick questions. You mentioned that your donations are also volunteer.

MR. LAMB: That is correct.

MR. ALLEN: What is the difference between your plasma and ABC centers' plasma in terms of getting it manufactured in this country? Is it because you have contracts with manufacturers in this country?

MR. LAMB: Yes. We organized the plasma program so that the plasma is sent to a manufacturing site and the products are returned, unlike in the ABC situation, they are selling their plasma outright to a manufacturer, and they have no control over the distribution of the finished product.

MR. ALLEN: But they are saying that they can't get a manufacturer to buy their product here in the States.

MR. LAMB: Well, that's correct. By and large, the U.S. manufacturers, because of the issues relating to CJD, had made a decision not to fractionate recovered volunteer plasma, however, because we are in contract manufacturing, we in essence buy capacity, and so we have thrown away $120 million worth of product, the American Red Cross, of finished product since the policy was implemented in the August 8th, 1995 memorandum, we take that risk on ourselves, so we are not passing that risk to a manufacturer.

So, we bear the risk, we bear the potential benefits, so that is a much different situation.

MR. ALLEN: Also, in terms of autopsies, maybe you know something about this, maybe someone from the CDC can answer this, but I was told that at this point, there is about four to six medical centers around the country or maybe around the world that actually do autopsies on known CJD patients. Do you know anything about that?

MR. LAMB: There are a few select laboratories who specialize in doing autopsies of patients who are diagnosed with CJD. In the cases, the donors who, in our case, have died of CJD, we think have died of CJD, we arrange to have the autopsy done by the specialized laboratories.

MR. ALLEN: There are only a few, is that correct?

MR. LAMB: There are a few who specialize in it, I know that. We work with those few. I don't know if there are -- there may be more, but we certainly try to work with those who have the greatest degree of specialization, like Prusner's laboratory is one that does many.

MR. ALLEN: You mentioned projections. How did you project your needs, the needs of this country in terms of IVIG? You mentioned that earlier in your statement. Did you go by last year's numbers or do you guys do a projection --

MR. LAMB: In terms of forecasting the overall market?

MR. ALLEN: Yes.

MR. LAMB: We basically, for marketing research, we got some data, and then given that in the past, demand has been increasing by a rate of about 10 percent, we just took the last year and increased that by 10 percent.

MR. ALLEN: Okay. And of the 126,000 grams that is back-ordered, how many are emergency versus guaranteed contracts?

MR. LAMB: I don't have a specific breakdown. I would say very few emergency, because we do fill most emergency orders, probably the majority of those would be contract.

MR. ALLEN: Thank you.

DR. HOOTS: Just to put you really on the spot, and not to ask for an answer, but just in terms of the response the chairman was talking about, the recommendation that this committee made in January about recalls, part of that recommendation was that for the next year, in view of the shortage, what is implicit in that is that come January 1999, we should be looking at it again or somebody should be, FDA should be looking at it again.

In all the things we have heard in the last day and a half so far, that confirms what we all knew --

DR. CAPLAN: Keith, move your mike a little closer.

DR. HOOTS: I am sorry. It confirms what we have all known, which is not only are we very effective at providing for ourselves except in these extraordinary shortage circumstances, but we are providing a lot of products to the world.

We don't have, at least we can't recognize whether we have new variant yet in the United States. The possibility is certainly there. You alluded to the studies which we heard and which have been updated, and I think that is clearly where the answers have to lie.

Over the last six to eight months, one of things I think that we would want from people like your scientists, and we have already, the context of how to break out the exceedingly low risk of sporadic CJD which can be pretty closely defined -- and we spend a lot of time doing that -- from the totally unknown risk of new variant if it were transmissible as your experiments have implied, at least to cryo and fresh frozen.

So, just more as a comment rather than a question, I know you have thought a lot about this, and you might want to comment right now, do you think, say, by January, that we will have more information that will allow us to make that distinction? The British have made it because they do have new variant and they can look specifically. We don't know if it is going to be here, but we have responsibility to everyone including the whole world, since we are providing so much of that, to do that.

So, I want to kind of put that out there, because I think that is one of the leftovers we have from the recommendation that was made last time.

MR. LAMB: We would like to look at new variant CJD. We are working with Dr. Brown in this regard. The issue of bringing in the new variant CJD into the United States for experimental studies needs to be worked through, but in an ideal situation, we would like to repeat the fractionation experiments with the new variant version, but there are some logistical issues that need to be worked out.

DR. GOMPERTS: Chris, if I could follow up on a topic that you covered a little earlier on, when I read the New York Times article, it seemed to me that it identified essentially three causes for the shortage in the United States. The one was the increased utilization, secondly, the CJD withdrawals situation, and thirdly, the compliance issues.

Now, if we look at the situation in Europe, and while I do hear of perhaps shortages in Spain, but other countries there isn't, and ask you the question why is it that there aren't shortages in Europe. One, obviously, they are increasing the demand for the product, the patients are getting it. Certainly, I think in the case of some unusual diseases, there is a fair amount of utilization there.

The other one that you pointed towards is the withdrawal issue. As far as the situation of manufacturing in Europe, could you comment to the committee on that?

MR. LAMB: I can only comment on the CJD issue, as I mentioned, which is, at least on a country-by-country, could be less stringent than in the United States. I really can't comment on overall demand in Europe and overall capacity and how that is matching up. I don't know.

DR. CAPLAN: Let's do Carolyn and then I will let Mark Weinstein come forward.

MS. JONES: Just one question. Yesterday, the plasma, the Baxter and Bayer, and all of those, indicated that there is an effort to put a hold on the products until the donor returns. Has the Red Cross considered doing that with regard to the recovered plasma, holding it for a period? I know that would present a problem up-front, but maybe later on, with respect to withdrawals, it may ease some of that.

MR. LAMB: We have considered it. The issue is a little bit different with recovered plasma versus source plasma. With the source plasma, where you can come in as much as twice a week or multiple times, holding a plasma for 60 days so that you might catch a unit that may have seroconverted during that 60-day period, there is some efficacy in that approach.

However, on the volunteer side, donors are only coming back at most once every 56 days, so having a 60-day donor hold to catch the seroconversion doesn't give you that kind of a yield, so I think it is the difference in the type of collections that doesn't really make it effective on the recovered side.

MS. JONES: Well, if it's 56 days, why not a longer hold than what the source plasma hold would be? I just want to know what the difficulty for Red Cross would be with respect to that.

MR. LAMB: On the average, a donor comes back about -- a donor donates about twice a year, so for us we would be talking about a hold of maybe six months, and at that point, it really would take out a tremendous amount of volume out of the system in terms of products for what I think would be very little return in terms of safety, none probably.

DR. CAPLAN: Thank you.

MR. LAMB: Thank you.

DR. CAPLAN: Next, we are going to hear from Mark Weinstein of the FDA. After that, we will have a brief public comment period, then, we will take a break. Then, we will resume our deliberations about what, if any, recommendations we want to make.

Welcome back.

DR. WEINSTEIN: Thank you.

Good morning. I am Mark Weinstein, Director, Division of Hematology at CBER.

Today, I will give you a brief summary about FDA's perspective on IGIV shortage, evidence of the shortage, our assessment of the main reasons for it, some of the actions that FDA has taken to alleviate the shortage, the current situation, and finally, some of our considerations for the future.

First of all, how do we at the FDA know that a shortage is real? FDA does not have a branch that monitors the supply of blood products on a routine basis. The number of lots available for distribution theoretically can be obtained from lot release data.

However, manufacturers may decide not to distribute certain lots found acceptable by the FDA for their own reasons. Thus, the number of FDA-released lots may overestimate the number of lots actually available for distribution. Also, lot release data do not include the amount of product in the lot.

Our primary means of identifying whether a shortage actually exists is to monitor the number and persistence of complaints from consumers, manufacturers, and distributors.

Throughout much of 1997, the FDA received sporadic reports about shortage of clotting factors, immune globulins, and albumin. Occasional calls about shortages are not unusual and may reflect a local transient market fluctuation. The effect on public health of a transient shortage may be mitigated by the production of a comparable product by another company. One manufacturer's shortage may be another manufacturer's opportunity to sell product.

There may also be a certain degree of skepticism about reports of apparent shortages because it has been argued that rumors of a shortage can be used by some to leverage the release of product that otherwise would not be released.

During most of 1997, the FDA addressed requests for information about product availability primarily by surveying manufacturers as to how much material they had in inventory, and informing the requester about potential sources of the product.

In cases involving the theoretical risk of CJD-contaminate material, there a number of case-by-case assessments of risk that led to the release of product if the evaluation concluded that there was no measurable additional increase in CJD risk.

By November of 1997, however, it became clear that the IGIV was truly in short supply. FDA received hundreds of phone calls from many different sources including from distributors, from major treatment centers, such as Walter Reed, Johns Hopkins, and Duke University, and from consumer groups, such as Immune Deficiency Foundation.

Calls from consumers were persistent and came from all parts of the country. FDA contacted manufacturers, large distributors, and group purchasing organizations. They reported that there was little product in inventory or available on the market nationwide.

Now, we will give you an assessment of the reasons for the IGIV shortage. The shortage seems to be the result of many factors including, but not limited to, increased demand for product, decreased production, and increased withdrawals and recalls because of compliance and CJD issues.

Regarding demand, it has been increasing by about 10 percent per year according to the Market Research Bureau, a private marketing research company specializing in surveillance of the plasma derivative industry.

The number of approved indications have increased over the last five years, so that each manufacturer has increased the approved indications for its particular IGIV. Among the approved uses, as we have heard yesterday, are for treatment of primary immune deficiency, immune-mediated thrombocytopenia, Kawasaki disease, bone marrow transplantation, and pediatric HIV infection.

There has also been an increase in the off-label use of IGIV that includes treatment of a large number of neurological disorders, autoimmune diseases, and hematological disorders.

Some of these off-label uses are considered as standard of care at many major medical centers, whereas, others are not, and are based on limited studies or anecdotal reports.

Although hard data are not available, off-label use is estimated by the Immune Deficiency Foundation and physicians at major centers to represent about 50 to 70 percent of IGIV use. Alternative therapies are available for many of these diseases.

Concern about CJD is another contributing factor to the shortage. Multiple IGIV lots have been withdrawn because of donors who, after donation, were identified as being at risk of, or having developed, CJD. Many of these lots were distributed and largely consumed before withdrawals came into effect. However, substantial amounts of intermediate materials not yet processed into finished products were also affected by the withdrawals.

We believe that the failure to process CJD-implicated intermediates has been the primary effect of CJD on product availability. Distribution of IGIV in the United States decreased during 1997 by about 10 percent compared to 1996. We estimate this from data supplied to the FDA by manufacturers as part of their reporting requirement described in 21 CFR 600.81.

Manufacturers are required to report data about product distribution in the United States every six months. This regulation was instituted in October of 1994, and thus gives FDA access to data acquired after that time. While these data do not give us real time information, they do provide accurate information about the amount of product actually distributed in the market.

Recently, FDA has attempted to make a more quantitative estimate of the relative magnitude of the possible causes of product shortage by using this distribution data. This was done by first estimating what the shortfall was in 1997 compared to 1996. The estimated 10 percent yearly increase in demand plus the decrease in distribution in 1997 compared to 1996 gives an estimate total shortfall of about 20 percent compared to actual distribution in 1997. This is similar to the calculation that Dr. Penner was making yesterday.

The next chart shows what individual manufacturers distributed in 1995, 1996, and 1997. You can see that some manufacturers produced less in 1997 than in 1996. In one case, this was primarily because of compliance issues. In other cases, the shortfall could be attributed primarily to withdrawn CJD-implicated in-process intermediates.

The lack of product from the manufacturer who produced little product in 1997 because of compliance issues accounted for about 60 percent of the 20 percent shortfall. Again, this is a model system, a rough estimate, but it gives you some sense of the magnitude of these withdrawals and these activities.

The shortfall of product from other manufacturers because of CJD issues amounted to about 20 percent of the 20 percent total shortfall. While other manufacturers reached or surpassed their 1996 distribution levels in 1997, we assume that they could have produced more had they not been affected by compliance or CJD issues. These factors account for part of the remaining 20 percent shortfall in distribution.

Other factors that may have contributed to the remaining 20 percent shortfall in distribution include decisions to retain product for later distribution to cover periods of planned plant shutdown and potentially not packaging IGIV for the most efficient use of product.

Regarding the last factor, if IGIV distribution is considered on the basis of number of vials rather than kilograms, actual distribution of product was reduced by 19 percent from 1996 to 1997 rather than by 10 percent. On average, there was 7.7 grams per vial in 1996 versus 8.4 grams per vials in 1997.

The reason for a larger amount of product per vial is presumably a marketing decision based on assessment of demand, but might not necessarily lead to the most efficient use of the product. This is an area that needs further investigation about product usage and information from physicians, patients, and manufacturers.

Export of IGIV is another factor that affects the amount of material available for domestic distribution. FDA does not monitor or control exports. When we have asked, manufacturers have told the FDA that exports are not a major factor responsible for the shortage. Exports account for zero to roughly 25 percent of distributed product depending on the manufacturer according to anecdotal information received by the FDA.

The FDA does not have quantitative information about the fate of product once it is outside of the direct control of manufacturers, thus, the amount of product that might have been released to the market, but was held up in the distribution chain is not captured by this analysis.

Next, I would like to turn to the actions that FDA has taken to help alleviate the shortage.

During the third week in December of 1997, Lead Deputy Commissioner Friedman, Deputy Commissioner Pendergast, and Dr. Feigal, Deputy Director for Medical Affairs in CBER, spoke to the CEOs of the leading plasma derivative manufacturers to convey our concerns, to learn more about the reasons for the shortage, to stimulate consideration of bringing in European-approved product for emergency use in the U.S. under IND, and to set up hot line numbers and product supplies for emergency use.

The FDA has been working with manufacturers to facilitate increased production and distribution without compromising the quality of the products. Obviously, this involves discussions of industry plans to come into compliance without disrupting production.

FDA has expedited review of licensed supplements related to IGIV. The FDA's lot release process has been shortened from two to three weeks to two to three days.

Two companies have agreed to consider bringing in European-approved product under IND for emergency use in the U.S. Also, to address the problem of off-label use, FDA sent a Dear Doctor letter to physicians on January 28, 1998, to alert them to the shortage and to provide guidance for prioritizing the use of IGIV. The letter also listed 1-800 numbers which are now in operation to obtain product for emergency use.

FDA has increased its efforts to monitor supply. FDA has repeatedly called manufacturers to assess how much IGIV is in shippable inventory. In some cases, these surveys have helped to identify situations where FDA could help to expedite regulatory review of lots pending release. On at least one occasion, there was no shippable inventory available from the major plasma fractionaters. FDA was able to help relieve the acute shortage by expediting the release of a few lots of IGIV that were pending.

With regard to CJD concerns, FDA allowed the release of IGIV made with albumin potentially contaminated from an at-risk donor for emergency use with appropriate labeling. FDA is considering further relaxation of the CJD recommendations of December 1996 in accordance with the advice of this committee and other advisory committees.

The current situation. Phone calls regarding IGIV have decreased from November 1997 levels of 10 to 20 a day to 5 to 6 per week. About 40 percent more lots of IGIV have been released per month since November 1997 than were released in 1997 prior to November.

However, this increase is partly due to the short-term effects of expedited lot release and availability of material that was under internal review by manufacturers. The shortage continues and probably will for some time because many of the causative issues have not been fully resolved.

In particular, a number of manufacturers are in the process of coming into compliance with Good Manufacturing Practices, and are not functioning at full capability. 800 numbers are in place for emergency purchase, but in some cases, manufacturers are using them only for consumers who enter into contractual obligations. For a period during March, product was not available even when calling the numbers.

Regarding our future directions. FDA is considering updating the January 28th, Dear Doctor letter with more recent information including new hot line telephone numbers and central distribution points for IGIV products that are to be used for emergencies.

FDA is considering increasing surveillance of product distribution to assess the long-range potential of a product shortage before it actually occurs. This would involve receiving product distribution reports more frequently and trending the data.

Modification of current CJD recommendations will help to alleviate the shortage to some extent. Labeling products according to CJD risk may be one way of modifying the current recommendation. Thus, products at minimal potential risk may warrant a generic label, while those at higher potential risk may have a lot-specific warning label.

Further modifications in our CJD recommendations will come about as we learn more about the disease through research and surveillance.

FDA continues to meet with plasma fractionaters on an ongoing basis to investigate ways to further improve product availability. One item of discussion may be potential violations of the Sherman Antitrust Act involving vertical ties and exclusionary distribution contracts.

FDA may further investigate why the 800 telephone numbers are not being used as intended by the FDA. In the long term, the shortage problem will be reduced most substantially as manufacturers come into compliance with GMP and production is increased.

FDA stands ready to assist manufacturers in meeting all GMP requirements.

Thank you.

DR. CAPLAN: Thanks, Mark.

We are going to again open the floor up for questions. John.

MR. WALSH: I would just caution the FDA -- and I know we have talked about this off-line -- to use the number of phone calls into the agency as a gauge for judging whether or not, how severe a shortage is.

DR. WEINSTEIN: Right. This is, in fact, I should say one of the most difficult areas that we have to contend with, be able to assess where we are at any one time during this shortage crisis, to obtain some sort of trending information to know when we are actually getting out of the crisis or shortage situation.

I think that this is an area that does need to be explored more fully. We realize that the phone calls that are coming in to the FDA might be a minority because now they are being directed out toward some of these 1-800 numbers and directly to manufacturers.

Getting a handle on where we are during the shortage period is something that is difficult for us.

MR. WALSH: A lot of blood consumers like myself, blood plasma derivative consumers like myself, you know, would not necessarily bother the FDA once, twice, three, four times. We would focus attention elsewhere.

From the alpha-1 community perspective, you understand there is a shortage and there is going to continue to be a shortage until there is another manufacturer being able to produce product. So, no more phone calls are necessary from our community, we don't want to bother you with that, but we want that understood and focused on.

The other thing is you mentioned increasing monitoring of product shortage. With the distribution side, the FDA has no regulatory authority over the distributors of products, that is correct?

DR. WEINSTEIN: That is correct.

MR. WALSH: Is there any way that you could suggest that this committee would inquire or investigate or pursue some direct oversight or attempt to understand more thoroughly some of the inequities in distribution that we have heard over the last couple days?

DR. WEINSTEIN: I think that this has to do with the state health boards, I believe who are more involved in the regulation of distribution of product here. I, frankly, am not certain where the Federal Government would enter into this process. Potentially, the Federal Trade Commission may have a role in this, but it is not clear to me where this authority would lie.

MR. WALSH: If I may, just one more. With respect to emergency supplies or emergency inventories, does the FDA have regulatory authorities as to how the different manufacturers would use external sources, private or internal sources, with respect to treatment algorithms or triage formulations?

DR. WEINSTEIN: We have asked the manufacturers, as you have heard, to set up the emergency of supply, but we have not gone further into developing a program specifically about how each manufacturer would handle the emergency.

DR. CAPLAN: Marian.

DR. SECUNDY: Is it within your purview, can you do that even if it were just points to consider or guidelines?

DR. WEINSTEIN: I think that is something we would have to explore.

DR. SECUNDY: I am speaking about the actual regulatory authority of FDA, because that is a very deep concern that I have. You referred to the product availability and contractual obligations. I imagine that you were talking about the emergency supply that has been set aside with your request as one piece of that, and then there is apparently clearly an absence of guidelines and standardization or procedures relative to that emergency lot.

As Art said earlier, that would be of great concern relative to equity and access issues. So, I would hope that you would look into the question of what the authority of the FDA might be in this matter, and we, of course, will I hope talk about that.

You made a reference, following up on Mr. Walsh's comment a few minutes earlier, to an antitrust possibility. Would you expand upon that? I am sure, based upon what you responded to him, you are not seeing that as an FDA function, but could you say some more about that?

DR. CAPLAN: Why don't you comment on the antitrust, second part of that question, and then I see Dr. Feigal wants to say something about the first part of that question.

DR. WEINSTEIN: Well, it has just come to our attention that in some cases, as we heard actually yesterday, that there is product, that if you buy this product, then, you have to buy this other product at a higher price or something of that nature, and these are issues that --

DR. SECUNDY: What would be the procedure for you to refer that to FTC or is that something that the committee ought to do?

DR. WEINSTEIN: FTC is aware of some of these situations now, and I don't know where they are in their investigatory process here. I do know that there have been reports to them about these situations.

DR. CAPLAN: I have to insert before I go to Dr. Feigal, that I think the American public might be disappointed to know that it was underwriting 800 numbers for the private sector to make special deals.

DR. FEIGAL: I think the one example actually was probably somebody in the middle, a middleman rather than one of the manufacturers.

I just wanted to comment on what our authority is for the shortages. None. We have no authority whatsoever. These are done at our request, and we ask the companies to voluntarily set up systems to do that. We also tried to provide some guidance in terms of prioritization with the Dear Doctor letter where we pointed out the kinds of conditions that we thought the use of the product was most effective and the need was the most compelling.

The whole issue of FDA involvement with product shortages is a difficult one for us, not just with blood, but in many other types of areas, because we do not have very direct access to the kinds of information we need, and it was not a mandate that was given to us by Congress.

Nonetheless, there are some responsibilities that we do have, and we try and do these with voluntary cooperation with industry, and, in general, industry I think makes very good-faith efforts to do this. I think there are some areas where we have concerns and areas where there is improvements needed.

DR. CAPLAN: Let me just ask quickly since I am curious, Mary, do you know from the CDC point of view if there is any authority here relative to the protection of the public health about the matters we are pursuing?

DR. CHAMBERLAND: CDC, as an agency, has no regulatory authority in this area at all.

DR. CAPLAN: Carolyn.

MS. JONES: From the HHS perspective, I think HCFA has some responsibility here on the reimbursement end, that some of their regulatory arm could be put to bear on some of this.

DR. CAPLAN: John.

DR. PENNER: The issues of allowing some of the important pieces of this to be put together for information, the hospital pharmacies are really the ones that are controlling the situation. I presume that these individuals in the hospital pharmacies are being at least alerted to the problem and will have the most interaction with you.

I am still getting at least the idea that all of our pharmacists are ending up calling around to each of the different manufacturers, and are not calling the 800 number. Can't they just call the 800 number and from there they don't have to call the individual manufacturers, is that the way the hot line is supposed to work?

DR. WEINSTEIN: There are a number of 800 numbers that manufacturers have set up. There has also been a proposal by at least some distribution firms, I think that we heard yesterday, about FFF is being one of the firms that have volunteered to take on this effort.

DR. PENNER: But I am not so sure it is entirely voluntary. I suspect there is a profit motive maybe involved, but at any rate --

DR. WEINSTEIN: This is one of the difficult areas obviously in this situation.

DR. PENNER: But no attempt to coordinate this into, say, one phone call at least can get all of the information at this point.

DR. WEINSTEIN: No, there is not just one phone call.

DR. CAPLAN: Dana.

DR. KUHN: First of all, I would like to compliment the FDA on its deliberations in getting some of the questionable product labeled and released. I think that that was a very good move until some kind of surety is established regarding all the questions involved with CJD.

Second of all, Mark, I wanted to ask you, can you comment upon some of the compliance issues specifically and how these have slowed production, because I noticed your chart had a large percentage that had to do with compliance issues?

DR. WEINSTEIN: I think that we saw that very well illustrated yesterday. A number of manufacturers came forward there and showed, let's say, the volume of review now that is undergone for each lot of material. There is a great deal more of a review of the batch records. There is greater assurance of product quality that is going on here.

We heard about the numbers of people that were being recruited to look, to assure quality, and we heard about training that was going on to prepare these people do a proper review. All those elements there have taken a considerable amount of effort on the part of industry to achieve, and the effort, the process is time-consuming, it is difficult, but in the end, we will have a better product.

DR. KUHN: Do you see that being soon resolved?

DR. WEINSTEIN: I think again we heard estimates from the industry yesterday about their planned scheduling of improvement here, and that at least one of the manufacturers felt that they would be in full production by the end of this year.

There are other manufacturers there who are also dealing with these same issues, and hopefully, they will also be able to achieve their compliance duties.

DR. CAPLAN: Let me just follow up on that. We have talked here about CJD and tried to understand how to deal with the risks that it poses relative to recall or trying to understand the probability involved of is this an endemic problem or is it really a problem at all with respect to blood transfusion, and so forth.

I don't want a detailed answer here, but just on the Good Manufacturing Practice, there is always some judgment involved there, too, about compliance, and so forth. We have seen reports that there are hundreds of violations or things that have been tagged in different manufacturing places.

If the industry is being pushed to produce because of shortage, and at the same time is being held to the absolute letter of GMP, is there room for discretion there?

DR. WEINSTEIN: Yes. I think that practically each one of these situations, there is a case-by-case analysis if there is thought to be a further analysis that is needed that will get a result here, you know, there are questionable situations about whether a person actually received growth hormone or not. We allow time for an investigation to occur, as Chris Lamb mentioned.

There is another element I think that we would like to explore with industry further, that we have mentioned a number of times here, and this is the idea of properly labeling according to risk here, that product could be on the market as it was for the CJD-implicated albumin and the IGIV with proper labeling here.

We feel that that is one situation that properly, on a risk assessment basis, could be used to get more product out there. This involves the cooperation of industry with this stratification.

DR. CAPLAN: I am going to go to Rick and then come back over here a second, but before I do, one other question. Would you comment on whether you think that the FDA was not as vigorous as it should have been in monitoring Good Manufacturing Practices over the years, in other words, what we are seeing is a build-up of problems, because we weren't watching manufacturing carefully, which is now taking a long time to clear because it is sort of a logjam situation?

DR. WEINSTEIN: I think that we have a better system now than we have ever had before. We have better training, we have instituted this program whereby inspectors receive additional training at the center here, and are able to view things with a more focused view on GMP issues than ever before.

DR. DAVEY: Mark, I am also encouraged about your comments about labeling. I would like to follow up on that a bit. I think, as the committee heard at the last meeting, I think as Jane pointed out earlier, the CJD withdrawals are really quite arbitrary and given an illusion of safety for the non-withdrawn lots and an illusion of non-safety for the withdrawn lots, while really perhaps all lots have some implicated donor in the pool.

Given that analysis, would the FDA look favorably on a generic label for all derivative products, saying there is a theoretical risk of CJD transmission in all derivative products, and with a label such as that, would you be able to really aggressively relax guidelines about perhaps dura mater and growth hormone?

DR. WEINSTEIN: This is an issue that is under discussion certainly, but I think that there is a certain degree of stratification that would still be prudent on the basis of scientific evidence, the idea, for example, if a donor did succumb to CJD, who had recently donated to the blood supply here, we understand that there may be a higher titre potentially in that donor than in somebody who may be at risk, and is not identified as having CJD.

So, the idea of generic labeling is part of the story of many products that may help us relax our policy at a certain level depending on the product and depending on the risk factor here. For other products, as we heard advice from the TSE Committee, the idea of products perhaps used for recombinant products or for vaccines, that we might have a different level of concern regarding those.

But I think that this notion is being considered at the FDA of having some risk stratification.

DR. CAPLAN: Just to come back over here, I see Jay wanted to get into the recent question.

DR. EPSTEIN: Yes, Art, I just wanted to give my own reply from FDA's point of view about the issue of flexibility on compliance issues. I just wanted to point out that although FDA became aware of serious problems involving manufacturing practices, our response was not to suspend licenses or revoke licenses.

We certainly took strong measures to ensure that these deviations would be corrected, however, we did not obligate cessations of production, and, in fact, there has been a lot of latitude offered by the FDA to work through these issues and achieve the necessary endpoints, whether it be validation or improved quality assurance oversight.

DR. CAPLAN: Did you want to say anything about whether, in fact, there was a build-up of problems because of the failure to keep an eye on Good Manufacturing Practices over time?

DR. EPSTEIN: Well, I think the way we see it is that we became aware at a certain point in time that there was a global problem in the fractionation industry in that it had failed to modernize GMP practices over a period of time.

So, you know, there might have been isolated observations over time, but there was not this comprehensive assessment that came into play about two years ago, and there is no question that once we came to that view, we took aggressive action across the face of the entire industry.

But as I say, the actions that FDA took were not directly to cause stoppage of production. Some of that action was voluntary, indeed, most, if not all, of that action was voluntary. It represented industry's, if you will, best effort to address the problems, but there was latitude to deal with it in different ways.

DR. CAPLAN: Ed.

DR. GOMPERTS: As we look ahead through 1998 and probably into 1999, the shortage will continue. You mentioned there are efforts at FDA to look at licensing European manufactured the U.S. plasma source product.

To what extend do you foresee that bridging this gap?

DR. WEINSTEIN: It will be a contributing factor to it, it won't solve it. It will be one element in the picture. Again, the percentages are very hard to calculate here, but it will be a significant factor, but as we said, when companies come into compliance and the production rates are sustained here to their full capability, that will be more leading to a reduction in the shortage situation.

DR. CAPLAN: Larry and then one more question after that, and then we will go the break and do the public comment when we come back.

MR. ALLEN: You mentioned earlier that there were decreased production with some plants. This was beyond the CJD and the GMP problems, these were just decreased production?

DR. WEINSTEIN: No, this was directly related to compliance issues.

MR. ALLEN: Have you worked with the manufacturers recently in terms of your forecasts? You seem to be one or the only agencies at this point that has actual forecasts for 1997 and 1998?

DR. WEINSTEIN: I think that what we heard from industry was their forecasts here. We hope that those --

MR. ALLEN: Do you have a forecast, does the FDA have a forecast based on product need?

DR. WEINSTEIN: No, the FDA would not forecast product need. It would make some modeling assumptions here, as you saw, as I did for this, but we don't truly know what is going to be. We are encouraging and working with companies to get them up to full capability.

MR. ALLEN: Has the FDA at anytime during this shortage considered stopping the CJD recalls at all, have you considered just saying everything can go through, have you ever considered doing that?

DR. WEINSTEIN: I think that we would not do that without good scientific evidence that this was a prudent measure to take here. I think that we have done what we consider to be in the best public health --

MR. ALLEN: So, your stand is still the same basically? You are saying the conservative approach is still --

DR. WEINSTEIN: We are still working our recommendations of December, but obviously, on a case-by-case analysis here, and there is a degree of flexibility in that depending on risk assessment.

MR. ALLEN: And the last thing was I understand the statements you and Jay have made about the manufacturing plants, but are the reports true that some of these plants have not been inspected as far as compliance for years and years?

DR. WEINSTEIN: No, every plant has been inspected, and there is a yearly inspection going on now for fractionation plants. They have been inspected for years.

DR. CHAMBERLAND: I just wanted to follow up on some of the possible labeling strategies that have been proposed. Mark indicated the FDA is considering possible schemas where products would be labeled, perhaps different labels. Rick Davey also brought up the issue of just generically labeling all plasma products as potentially carrying donations from donors who may have CJD.

Even if FDA were to, let's say, move forward for some labeling strategy, would not manufacturers then be -- it would have to be voluntarily undertaken by manufacturers. You could not in any way require them to do this, is that correct?

DR. WEINSTEIN: Not under our present authority.

DR. CHAMBERLAND: So, the schemas that FDA is considering, whatever they might end up being, would be something that industry would have to voluntarily elect to do? We have heard repeatedly that when labeling strategies have been proposed or at least discussed, that industry has been reluctant to do so because of liability concerns. Am I understanding you correctly?

DR. WEINSTEIN: I think that Dr. Feigal has --

DR. FEIGAL: Well, I think the issue has come up that some companies would rather -- when we have talked about labeling specific lots -- companies have said that they would rather not even market that lot than put a lot out that suggests it is a second-class product.

That has come up with the issue of labeling some lots, but not all. The issue of our ability to have class labeling, we do have authority to do that. It works best when there is agreement between the manufacturers and the agency on what that class labeling should have. If we feel that it really is a strong safety issue, then, we have the authority to require it.

I think in this area where the products that have been affected have been voluntarily withdrawn, we are in that kind of gray area of sort of how strongly do we feel about this, but I think that these are all options that we can look at, and I think would address some of the concerns that we are not finding the silent cases, that there is some inherent risk to certain products, and there may be some base statement about CJD that is appropriate for all products, and that, as Mark suggests, there are other products which would have a greater exposure and you would have a different decision process about their appropriateness, maybe a stronger labeling, maybe excluding them from certain products that you want to keep particularly clean, such as vaccines, for example.

DR. CAPLAN: All right. Thank you, Mark. We will take our break now. Let's shoot for 15 minutes and then we will come back and have the public comment.

[Recess.]

DR. CAPLAN: We are going to go into our public comment period at this point. I think we have Tom Moran up first, and then I have got probably four or five others. Then, what we will do is discuss some of the issues we have been listening about for the past day and a half, try to aim for, I think, hopefully, somewhere around a 12:25, 12:30 break, and then we come back and go at it. Jim AuBuchon told me he has got to leave a little bit early, unfortunately, but I have his proxy to vote everything.

Let's go to Tom Moran.

MR. MORAN: Tom Moran. I am President of the Immune Deficiency Foundation, and the comments I am making this morning are in behalf of the primary immunodeficiency consumers of IVIG.

Our basic takeaway from this meeting is the fact that it seems as though the shortage will continue into the foreseeable future in light of a scenario where demand increases at 8 to 10 percent per year, and that the supply appears to be flat at least into the foreseeable future. So, this causes concerns among our community.

IPPIA's offer to share production, release, inventory, and emergency supply data correlate will assist treaters, consumer organizations like IDF and others to manage the shortage. We would encourage IPPIA to work with both Novartis and American Red Cross to combine data, so that we can obtain a single comprehensive picture with respect to production and release, and issues like that.

It has been acknowledged that there are medically necessary uses for IVIG both on-label and off-label. It is also acknowledged that there are some uses for which the benefits of IVIG therapy is unclear, unproven, and for which equivalently efficacious therapies exist.

IDF will encourage national medical societies, national clinical services, for example, pharmacies, and national home care companies, and others, and individual medical centers to review this issue and, where appropriate, to recommend the adoption of rational and compassionate protocols for IVIG prioritization and rationing.

We will include industry in these discussions, particularly with respect to their emergency supply programs. I think we are all on a learning curve. Speaking on behalf of IDF, I know that we are.

Let me digress for just one moment and tell you our experience with respect to providing emergency supplies to individual patients. As we mentioned yesterday, Miriam O'Day mentioned in her comments yesterday, IDF arranged for over 2,100 patients between December 15th and February 15th to receive IVIG primarily directly through manufacturers.

How that came about was fundamentally, we got hit with a tidal wave of phone calls beginning around December 15th from individual patients, physicians, and pharmacists seeking IVIG for primary immunodeficient patients.

Acting in a good samaritan role, we then began to contact. The first question we asked is, are you primary immunodeficient, we are here to help you, and secondly, what product or brand are you on, and we will contact that company and try to help you get it.

This grew -- well, it never grew -- it really just hit us immediately. We did this reflexively between December 15th and February 15th. Because of the persisting, probably in the hope that this was something that would last a week or two weeks or three weeks, at the time we didn't have the data that we saw yesterday to understand that this was not a very short-term scenario.

Toward the end of January we sought and obtained advice from legal counsel who suggested that IDF abandon this program because of the fact that we were in effect beginning to act in a gatekeeper type of role with respect to this product.

We were referring patients who did not have our diagnosis, primary immunodeficiency disease to the 800 hot lines at the manufacturers' companies. In effect, we were creating a priority for our patient population, and the concern was that someone might bring an action suggesting that IDF was denying access to the drug, and we did not want to be in the role of providing access to a drug or denying access to a drug, or, for that matter, making these kinds of decisions.

So, we moved from a reflexive, good samaritan, let's try to help folks in our community get this product to the sobering legal realities behind this, and the board of trustees, very reluctantly, had to abandon this role, and so as a result, we would then receive calls after February 15th and the best we could manage was to refer people to the 800 numbers at the manufacturers.

We are now considering as a result of yesterday's testimony, other methods internally within our organization to see if we can't find means in light of the fact that the results from the physician and patient survey that we showed yesterday morning, in light of the fact that 50 percent of our patients are reporting adverse health effects from this shortage, we have got to do something.

So, we are in about the second or third iteration, if you will, and on the learning curve, with respect to how our organization is trying to manage or deal with this shortage and help our patients.

We have -- and I won't because of the limits of time, won't go through it -- but we are intimately familiar with the different strategies used by different companies in this industry. I have to say that I believe that they are also on learning curves and also in probably their second and third, and probably as a result of this meeting, in their fourth iteration of how they are going to be handling emergency supplies.

My point is that the Immune Deficiency Foundation will approach all of the companies and have these discussions with them, so that we can come up with the most equitable and fairest way to handle this issue.

What we don't want to see is creating a hierarchy of misery or competition among and between patient groups, all of whom may need this for medically necessary purposes. We think this is the wrong tone and it's not something that the IDF is going to go and say us first. In fact, one other quick digression.

Our Medical Advisory Committee had a meeting on this subject in January. We invited members to FDA to participate in that meeting. The conclusion of the IDF Medical Advisory Committee was that the highest priority for immune globulins should be patients presenting with Kawasaki's disease.

I think it is very important that all of us act with the broadest possible perspective. I am finishing the comments now.

IDF is grateful for this committee for tackling this critical issue. Because of the co-joined issues of the IVIG and alpha-1 shortages, they cut across scientific, technical, safety, and economic factors, and as you polled around the different agencies around the table, it seems as though as this committee is the appropriate forum to bring all of those issues, particularly issues related to the economic and business side of the equation, so to speak, for which there seems to be some confused regulatory or administrative responsibility.

So, what you are doing here is extremely important. It is a unique forum from that perspective. We would like you to keep this, the IVIG and alpha-1 shortages on the top of your agenda. We would like you to return to this issue in the future until it is resolved.

Thank you very much. I would be happy to take questions if there are any.

DR. CAPLAN: In the interests of time, I am going to say we will take one or two questions for each person who presents.

Thanks, Tom.

Next, I have Cory Dubin.

MR. DUBIN: I just couldn't bring myself to spend two days in the dark. Everybody was so surprised, I thought I had better go back to being who I am.

Let me jump right in and just march through some points straightforward.

Chris, we love you, but it seems to be a red herring for Red Cross to be talking about manufacturing when you are not doing the fractionation, so we are a little concerned about that issue since your product goes to two of the others to be fractionated.

I think we don't want to be safety'd to death on pool size. I think there is some clear basic safety margin increases that we do get going below 60,000, and I think what we, on the Committee of Ten Thousand, are concerned about is that we protect the immunodeficient communities' need to have efficacious pools.

That is the one thing that we are certainly concerned about and willing to listen to, but I think we were clear yesterday, it is time to move on this, and want to do that.

Some quick comments about FDA, and, Jay, you have a very unique way of saying yes, I might add. We think that FDA has stepped up GMP. We agree with Dr. Caplan that there has been a period where this backed up.

I think as patient communities, we can't very call on FDA to get on the stick and be vigilant, and then turn around and be upset with them if there is a shortage. I think we need to be real careful about that, because we have been asking the FDA to step up their vigilance for four years, and I think we want to be careful to make our requests clear, and then not turn around beat people up if they are trying to do exactly what we have been asking of them.

So, I think that is something we, on the patient community, have to take some responsibility for, because a heightened regulatory climate today has much to do with us, and we need to be responsible that we made those demands, and if they are going to be carried out, we don't want to turn around and beat people up about it.

Now, a couple of questions. Antitrust came up. Don't people think it is unique that this is an industry that has kept the price one and two cents with each other over 20 years? Does anybody want to look at that? I mean we think there is antitrust issues that have been going on for a long time in this industry, and we have made no bones about it, and we have been public in our statements.

This is a particularly ugly situation, though, when we hear about an individual distributor or two stockpiling this product and driving up the price, particularly ugly when an 800 line is established with everyone agreeing that this is a public service situation, and somebody is using it to sign up customers. Unacceptable.

I think again that circles back to what we were trying to say yesterday. This is a unique industry. This is a publicly supported industry in the sense of the costs are shifted to societal costs, whether it is private insurers or government programs, the costs don't come out of our individual pockets for factor immune globulin. That rarely happens.

So, I think it is important to look at it in that context. In terms of flexibility, the Committee of Ten Thousand agreed with a proposal recently that if you had a single donor dura mater situation, where you had an autopsy on file, we agreed those units were relatively free to be released from our perspective, that we thought that was a place we could build in some flexibility.

Although we do agree with what Mark Weinstein said about someone who has subsequently progressed and died of this disease, there are titre issues that may be relevant, that may be important, more important than a single donor dura mater question, and we want to keep those distinctions intact, but we do think there is some flexibility here, and a way to get some more units out the door, especially of immunoglobulins, which is part of the reason we are all here.

I think in closing, what I want to say is, I want to turn it back to pool size. It is time. I think we have demonstrated that there is a building momentum to make this change. The benefit you will all gain from the user communities and building of trust, but even more important for your perspective, in a heightened regulatory climate, I think you are going to find the economy -- I think you already know this, I am just speaking to the choir -- in a heightened regulatory climate with more recalls, smaller pools are most cost effective for the industry.

Thanks for the time, gentlemen.

DR. CAPLAN: I have got Sandra Brandley next.

MS. BRANDLEY: I represent the alpha-1 community, and as we are a community with a single provider from a sole manufacturer, we would like to ask that FDA look at any regulations which may limit or restrict other manufacturers of plasma products who are not engaged in an A-1 PI product to move that paste to the manufacturer who is involved in that if that would be at all helpful.

We heard yesterday that additional paste might make a difference. We know that we are in a very tight situation and will be for the foreseeable future, at least for the next two to three years, but if that is a possibility, we really encourage the FDA to look at that, and hopefully look at that very aggressively.

Thank you.

DR. CAPLAN: Thank you.

I have got Mr. Robert, Patrick Robert.

MR. ROBERT: Mr. Chairman, thank you for the opportunity of addressing the committee. I am Patrick Robert, President of Marketing Research Bureau, a market research firm dedicated to monitoring the plasma industry for the past 25 years.

I just wanted to complement some of the information which has been provided in the past two days by sharing with you some data which we collected in 1996 on the U.S. IGIV market. As you can see, a total market in dollars was approximately 413 million U.S. dollars, and you have the market shares on the righthand side, on the right column, with Bayer leading the market, 29 percent market share, followed by Alpha and then Baxter and Centeon.

The prices are given per gram and per unit, 2.5 grams, averaging approximately $26. These are prices to all of the U.S. customers, that is, hospitals, group purchase organizations, home care companies, and distributors.

I don't have a very good breakdown of those, but my personal estimation would be that approximately 70 to 75 percent goes to hospitals, 20 percent goes to home care companies, and the rest goes to distributors.

The 1997 figures are not compiled yet, but obviously, there will be some changes in terms of production as we have seen yesterday. The IGIV has become the driving force on the marketplace since plasma-derived Factor VIII is increasingly replaced by recombinant Factor VIII.

I would like also to perhaps respond to one of the questions on why there is no shortage in Europe and other places. My personal impression and observation is that IGIV is used to a much larger extent in this country than it is in practically every other country.

We have just completed a study on plasma products in Europe, and found that the usage of IGIV per gram was the highest or one of the highest in the United States, whereas, it was rather low in Spain, France, and other places, so I would say that IGIV is much more mature as a drug, as product in the U.S. than it is in Europe, and this is part of the reasons. Some people may disagree, but I think this is one of the reasons why perhaps there is no shortage in Europe.

I could go on, but thank you for the opportunity of addressing the meeting.

DR. CAPLAN: Thank you.

Questions? Larry.

MR. ALLEN: You mentioned about the shortage over in Europe. Do you know if there is an inventory, what the inventory is like over in Europe in terms of emergency?

MR. ROBERT: I don't believe there is a shortage whatsoever in any case, so as far as I can see, there is no need to build an inventory.

MR. ALLEN: Is there a surplus over in Europe is what I am saying, is there a product over there that is just --

MR. ROBERT: I don't know if there is a surplus. What I can tell you is that supply meets the demands, supply has increased in the past few years. Supply manufactured by European companies, such as the European plant of Centeon and Octapharma and Immuno, and so on, and so forth, and these companies have been able to export their products to Latin America and Asia, and so on, and so forth, increasingly.

So, it seems to me that there is enough supply to not only meet the European demand as of 1997, but even to export. Maybe if I may just add something which I have said to CBS sometime ago, about the price per gram in different countries. I don't know if you are interested to hear that, but in Japan, actually, in Asia, Japan representing 90 percent of market, the price per gram in 1996 was found to be $64. In Europe, it was approximately $30 per gram, North America was $25.50, and Latin America was $12.

Now, bear in mind that these are prices in countries within the region, and supplied by the local, by the domestic fractionaters, so it is not necessarily what the U.S companies obtain when they export, which is very small, as we have seen.

MR. ALLEN: In your opinion, could the European manufacturers handle the demand for the European countries without any aid from the U.S. manufacturers?

MR. ROBERT: I would say to a large extent, yes, because the market share of the U.S. companies in Europe is not very much. I just check this, this morning, and found that it is in the order of 5 to 10 percent, so depending on the country obviously.

MR. ALLEN: Thank you.

DR. CAPLAN: John, quick, and then we will move on.

DR. PENNER: Just a quick one. I would like to compliment Mr. Robert for the clearest piece of information we have had for the past two days.

DR. EPSTEIN: Could you clarify, Mr. Robert, what percent of the European supply is made for the U.S. plasma?

MR. ROBERT: Honestly, I know, but I don't know. I would have to make some calculations, but what I can tell you is from U.S. Government sources, in 1996, 3.5 million liters of plasma were exported from this country to other countries all over the world, including Japan, Austria, and so on, and so forth.

So, not all of it, of course, is turned into IGIV, but a good portion of it, of course, is manufactured into IGIV use within Europe.

DR. CAPLAN: All right. A special pleading here just in the interests of time.

DR. SCHIFF: I am a little concerned about the percentage of distribution to these distributors. You mentioned 10 percent. We are now talking about an emergency supply of the order of 450 kilograms, and we heard that some of this, maybe all of it, was really being distributed by a middleman type of outfit called FFF, who might be very legitimate, but what percent of our supply is that, the 450 kilograms? I am talking now at the present time, and if this is in the hands of this distributor where there is no regulation. That is of concern to me particularly in the face of a shortage.

Can you give me an estimate of what percent of the supply right now is in the hands of distributors right now, and keep in mind this emergency supply that we were told about?

MR. ROBERT: To be honest with you, I don't have the figure. This 10 percent was my personal estimate based on a number of conversations and discussions. I would have to go back and do a survey or study on this.

But on the subject of distributors, I would like to make a personal comment on this, if I may. I think not all of them are gouging and abusing. Most of them actually are individuals or companies, brokers who are conscious that they play a special role in the marketplace where a doctor or hospital can call and get the product within a few hours.

Now, of course, there is necessarily a mark-up for this particular situation and service, so I think one has to be careful when looking at this. I am sorry, I do not really have an answer to your question.

DR. CAPLAN: Before I let Dr. Guerra talk, Ron, why don't you tell me what you told me during the break just on that matter?

DR. GILCHER: I think this is actually important and fits in very well at this time. We had the need for IVIG for a patient in our system at the Oklahoma Blood Institute, and I just called in at the break to find out what we paid.

We purchased through an emergency release from one of the large companies, who is represented on your diagram, 100 grams for which we paid $39.50 per gram, so that apparently would be the 1998 going price compared to the 1996. Those were 10-gram vials, $395 each.

MR. ROBERT: I think, if I may, I would like to clarify the situation of pricing here. The prices that you see here, I do not think that they will be that different in 1997, even 1998, but these prices represent, well, 90 percent or 80 percent of the supply of IGIV to the marketplace.

Now, the spot price, which has been the object of all these press and television programs, the spot prices are those precisely used by these brokers and dealers, and so on, and so forth, and I have done a spotchecking of the spot prices over the past months, and found that they vary from $35 to $85, 85 being at the very end of the curve, most of the prices ranging between 45 and $65.

DR. CAPLAN: It would be fair to say, then, that as far as the speculation or spot marketing that goes on, it is probably close to double the price from the --

MR. ROBERT: Yes, probably, I think it is fair to say.

DR. PENNER: From the manufacturer in two years.

DR. CAPLAN: No, into the middleman. Ron is talking about a direct purchase.

DR. GILCHER: Mine was directly purchased from one of the manufacturers listed there.

DR. PENNER: So, the manufacturers are putting a higher price on things.

DR. CAPLAN: Dr. Guerra and then we will move on.

DR. GUERRA: Two questions. One, the volume in kilograms that each of the manufacturers has listed up there is not the total volume that they have accessed or produced indirectly through the producers of these different products?

MR. ROBERT: I expected this question. It is slightly different from what Mr. Bult presented yesterday for the simple reason that IPPIA did not take into account the Red Cross and Novartis figures, formerly Sandos. So this kept in mind, the figures tally pretty much.

This is product that has been sold, some of which may have been produced earlier in 1995, whenever.

DR. GUERRA: Do you have access to information about how much is wasted, wasted either because of some breakdown in shipment or lack of preservation?

MR. ROBERT: No, I do not have that.

MR. ALLEN: Sir, you mentioned you have been doing this for 25 years?

MR. ROBERT: Well, the company.

MR. ALLEN: In your estimation, would you say the amount of product that is being shipped over to Europe by the U.S. companies, would there be enough, if that product were staying in this country, would there be enough to deal with this shortage that we are experiencing right now? I understand there is an issue of guaranteed contracts for some of these manufacturers, but I am concerned in terms of if we kept the majority of that product that is being shipped over here, what would that do to the shortage at this time?

MR. ROBERT: I would just like to refer you back to Mr. Bult's overhead yesterday, where if I remember correctly, he indicated that 2.6 tons, I believe, I don't remember, had been exported, so one has just to see whether that would cover the shortage, which I believe it would, but this is a different discussion.

DR. CAPLAN: Thank you.

I am going to go to Donald Tankersly, the last person up for public comment.

MR. TANKERSLY: Thank you, Dr. Caplan, members of the Advisory Committee on Blood Safety and Availability. My name is Donald Tankersly. I am now a consultant to the plasma fractionation industry. I am speaking here on my own behalf, not as a representative of industry and, indeed, industry may not be in agreement with these opinions. In fact, I had not intended to speak at all until the subject of pool size or donor exposure number was introduced yesterday.

I have been closely associated with IGIV for 27 years, extending back about 10 years before the first product was licensed in the United States.

Let me also state in response to a comment that I heard yesterday from Dr. Penner, that I have personally prepared IgG on a laboratory scale from plasma, including my own plasma, by Cohn method 6, Onkley method 9, and have done so, not just once, but many, many times.

As you may have surmised, I want to address the donor number exposure issue or, its used more common, if possibly somewhat misleading terminology, the pool size issue.

Some may find it hard to believe, but I don't enjoy taking an unpopular stance on controversial matters, however, I seem to have a knack for doing just that. Let me give you a historical perspective, if I may.

In 1989 and 1990, there was considerable controversy and debate over the advisability of applying a test for anti-HCV to plasma intended for fractionation. Now, for the vast majority of people, this question was a no-brainer. It was intuitive that such testing might prevent some infectious units from entering fractionation pools, so testing had to be good.

Only a very diehards at the FDA were concerned that the depletion of antibodies to HCV and fractionation pools could have adverse consequences. These diehards, including myself, succeeded in delaying anti-HCV screening for a few years, but ultimately, this screening was adopted and there is now substantial evidence that the transmission of HCV by gamma globulin in '93 and '94 were direct consequences of this screening.

Now, intuitive feelings are often extremely difficult to question, in part because by their very nature, there may be little direct scientific evidence to support an intuitive opinion. After all, if there were evidence, then, one would not need to resort to intuition.

I can understand why some people believe that pool size is an important aspect of product safety, and while I share this view, my opinions are diametrically opposed to those expressed yesterday. I believe that product safety may be compromised by a substantial reduction in pool size.

Let me attempt to illustrate this view. For any infectious agent that might be present in the blood supply, be it a well-characterized virus, a newly emerging virus, or a prion, the average concentration of the infectious agent in plasma pools is equal to the average concentration in a viremic unit or a prionemic unit, if there is such a word, times the prevalence of the infectious agent in the donor population, period. There is no "n" in the equation.

The mean viral concentration in a plasma pool is independent of pool size. Now, having said that, let me go on to assure you that the variance in the viral concentration certainly does depend upon pool size. The smaller the pool, the greater the variance, and I have tried to illustrate this with an example.

Here, I have considered the case of an agent with a prevalence in the donor population of 1 in 5,000, and this might be considered typical for Parvo B19. The probability is about 0.81 that a pool of 1,000 donations will not contain a viremic unit.

The viral concentration in such an instance will, of course, be zero. There is about an 18 percent probability, however, that a pool of 1,000 donations will contain one viremic unit, and the concentration of virus will then be 5 times the value for a very large pool.

There is a further probability of about 1.8 percent that a pool of 1,000 donations will contain two viremic units, in which case the viral concentration will be 10 times that of the mean of a large pool, and there is, in fact, even a further small possibility, about 1 in 1,000, that there will be 3 units in a 1,000-donor pool.

Thus, although the 1,000-donor pool has an 81 percent chance of containing no virus, it may also contain levels that are considerably more than the mean.

At the other extreme, consider a 50,000-donor pool, shown in black. The probability that such a pool will contain no viremic unit is very small and essentially zero. The probability that a 50,000-donor pool will contain 25 or more viremic units is also equally low and essentially zero, and even in this highly improbable case which occurs less than 1 in 10,000 pools, the viral concentration in the pool is only 2 1/2 times the mean, which is one-half that of the 18 percent of 1,000-donor pools that contain only 1 viremic unit.

Notice that the range or variance of viral concentration in the 50,000-donor pool is rather small, and most of the pools having a viral concentration very close to the mean value of 1.

I want to close with other point. Last week, I had the opportunity to visit with representatives from the Dublin blood bank. As some of you are aware, an Rh-immune globulin made at this facility transmitted hepatitis to more than 1,000 Rh-negative women to whom it was administered around 1977.

Each lot of this product was prepared from about 1.6 liters of plasma obtained from 10 donors, certainly a small donor exposure number by anyone's standards.

This can be contrasted with U.S. experience that Rh-immune globulin has never been implicated in HCV transmissions despite the large donor exposure numbers for lots produced between about 1975 and 1985, and despite the fact that a large percentage of these lots contained HCV RNA.

Now, it is certainly true the Irish product was not made by the tried and true Cohn method 6, Onkley method 9, and it is possible, and perhaps even probable, that the process actually used had little ability to remove HCV.

Nonetheless, can we be confident that the transmission of HCV by this product was not the result, at least in part, of the small size resulting in high viral loads with little or not antibody diversity in the preparation to neutralize any virus that might have found its way into the final product?

In conclusion, I hope I have demonstrated that decreasing pool size is not a panacea. I believe, at best, it is ineffective, and at worst, it could lead to increased dangers. The mean viral concentration is independent of pool size. On the other hand, the variance can increase dramatically in small pools.

Other considerations in regard to the specific nature of immunoglobulins suggest that both utility and safety of IGIV is intimately linked to the pool size from which the product is derived.

Because of time constraints, I certainly won't discuss them at this meeting, but they have been presented at other pool size meetings in the past, and probably in the future.

Thank you for your attention. I will be happy to answer any questions.

DR. CAPLAN: All right. If there are no questions, let me thank you for that presentation.

What I would like to do at this point is move us toward a consideration, preliminary but nonetheless, let's start down that road of thinking about things that we would like to consider in the way of recommendations, areas of concern, matters that we believe that Secretary Shalala should be apprised of.

We may have things to say about intermediate agencies or it is certainly appropriate, since we have FDA, CDC, PHS, and NIH also listening attentively, to what this panel wants to tell them to direct recommendations in that area, as well.

To refresh your memory, if I can find it when I was clicking along at a high rate of speed here, I had put out on the table some areas that I thought we might want to talk about, maybe come up with some recommendations on.

One was in the area of data and data access for agencies to keep an eye, not only on distribution and sort of material that we just got, but also about inventory and about real time information about what is going on with respect to this important product.

FDA has said that they don't have real time data, but they are getting some reports. Perhaps we could recommend that we want to see more data available and available for monitoring, so we don't have unanticipated shortage burst upon us. The clinical use issue off-label, and approved both in times of scarcity and more generally.

Development of comment about how to oversight and deal with shortage in the here and now, and also with the emergency supply. The issue of overseas use. The issue of recall and whether we are satisfied that our message on that matter has been attentively heard.

Those are some of the issues that are up on the table, and one way to begin is maybe to amend or add to that list as people think appropriate.

Paul.

DR. HAAS: One thing I would like us to try and do in thinking through your list and anything else that might come up, is try to get our discussion focused on short-term responses and then longer term responses.

DR. CAPLAN: I like dividing that discussion myself that way, and with the concurrence of the panel, what we might do is say let's focus first on shortage and how we are dealing with that, and then we might talk subsequently about shortage and how to prevent it, how to try and alleviate that. If that is a division you are comfortable with, we can certainly go that way.

MR. WALSH: With respect to the production quotas and statistics relevant to availability, the supply side, I also think that somehow the FDA should be given a vehicle, the wherewithal, if you will, to project what the demand side is. If, in fact, there is a lot of off-label use for IGIV, for example, what are those uses and what are the projected patient populations, so that you can compare demand to supply, and then have that data available to you.

DR. CAPLAN: Let me make a suggestion here. We will soon focus our discussion first on dealing with the shortage in the here and now, but just because some people may have some ideas they want to get out on the table, we can come back and sort them out, so let me just collect a little bit here, things that people may want to say, and then we will go back and focus first on this what do we do with the shortage in the here and now, and what recommendations, if any, we want to make about that. So, a little open-ended interlude here for just ideas to come out.

Keith.

DR. HOOTS: I would like for us to discuss a little bit more the tracking of cost and particularly cost inequities or price gouging, and what sort of federal and/or state resources might be applied to at least scrutinize the situation to try to minimize the potential that individuals or companies are taking advantage of the situation.

DR. CAPLAN: What we will try to do here also, I see I have got Steve penciling away, before the lunch break we may be able to just list out these areas and maybe sort them into short term and long term, too, so we don't lose what you are saying.

Other areas? One that I forgot myself, but that I brought up, was trying to lower obstacles to access to recombinant product, making sure that if that is one of the safety issues that influences supply, that we think about that.

DR. HOOTS: That was one of the ones I wanted to add to the list, as well. I want to make one comment now in that regard, just because it is relevant to what Mr. Tankersly just said.

In regards to the pool size issue, and since it clearly has -- and Mr. Dubin graciously was talking about the importance of the IVIG component in terms of helping to determine what the optimal pool size is, and then Mr. Tankersly just made some very cogent arguments about the difficulties of determining exactly where you draw that line, I think one of the things that ought on the table in the context of what you just alluded to, is maximizing the potential for recombinant use for populations for which it is available, so that we essentially can narrow the discussion of pool size in terms of rationality to those populations or that population that is most dependent on plasma-derived sources, and that, at least in our discussion, clearly are the users of IVIG, since the prospect of ever having a trillion recombinant molecules to replace all the different variable regions are virtually infinitesimal.

DR. AuBUCHON: I would like to raise for the committee's consideration the issue of the ethics of export of a biologic product in short supply in this country. We have many goods in this country that are in short supply in other parts of the world, however, the domestic market is usually adequately supplied before export occurs.

In this case, it appears that export may be exacerbating a shortage problem that currently exists domestically.

DR. CAPLAN: One of the reasons I am particularly concerned about that matter is not to get into issues of not being concerned about the needs that people elsewhere around the United States may have for products that are just as life-saving in Europe as they would be in North America or the United States, but the premise for some of the collection of the supply of raw materials is that it will be done to help the community, and so unlike some other things that we make or use, this is an area where I think we have got some obligation to honor with some of the public things they are doing when they make the raw materials available.

DR. PENNER: I think we ought to be addressing the public or government's role in meeting the needs of patients in the presence of a product shortage.

DR. McCURDY: Art, you raised the issue of community, and I think when one does that, one needs probably to define what one needs. There are some people in the blood banking area that have defined community very narrowly as this city or this hospital. There are others that define it more broadly, and there may be even a few who might define community as the world.

So, I think when you talk about community and helping the community, you need to consider what your contract says. There a number of blood centers, for example, who are net exporters of blood to other major cities or other sections of the country, and there are some of us who think that is a good thing.

DR. CAPLAN: Jane.

DR. PILIAVIN: The whole issue of who, if anyone, has the responsibility for monitoring, I think is important. It looks as though this is something that no one has got any responsibility for, but it is really important.

DR. KUHN: I am not sure how I want to put this, Art, but it's a concern that I have, that I am hearing that alpha-1's are not going to have product for two years. I guess it is called production or how are we going to encourage production for this availability of this product which they urgently need.

DR. CAPLAN: We did hear FDA at one point tell us that they have worked -- I think it was Mark in his slide -- to say to encourage production. I would actually be curious about what that boils down to.

MR. WALSH: If I can address that for a minute, I would consider that on the immediate term. It's the availability of paste, as Sandy Brandley said in her open remarks, to help the one manufacturer, sole manufacturer produce more product or maximize their production capability.

A follow-up to that is, in the longer term, it is to have the FDA look seriously at some of the dosing issues on what is most efficacious, 60, 90, 120 milligrams per kilogram, for example, using product in exacerbation, period of exacerbations, and also some delivery mechanisms, i.e., aerosolized delivery, as Dr. Brantly talked about yesterday.

DR. CAPLAN: That actually reminds me, John, that when we talk about trying to manage scarcity in terms of recommendations for label and off-label use for IVIG, that really splits into two issues. One is taking areas where something is known about efficacy, and trying to call upon people to use it.

A second is to call for the development of further information about how to use scarce supplies of valuable blood products effectively, efficaciously, so there is really two issues out there.

DR. GUERRA: To follow up on John's point, I would put it in the context of I think we need the evidence base for efficacy in terms dosage per kilogram of body weight for a lot of these products, because I think many arbitrary decisions are made in the therapeutic environment, and it seems that we need to somehow begin to assemble the numbers now and look at them, and to look at some outcome measures.

I wanted to also see if it might be possible to develop a model for reporting that would include the FDA role together with the CDC role for surveillance, because many of the conditions for which these products, especially IVIG, are being used are reportable conditions - Kawasaki's, Guillian-Barre, and a number of others, and I think that would cover some of perhaps the off-label uses.

I think that there is certainly an infrastructure in place for surveillance that begins at the local public health level, the state level, to certainly the national level, and then with the CDC role that has the capacity for doing a lot of that kind of surveillance through the EIS network. I think it could be a very helpful way to do that.

The other suggestion, which I made earlier this morning, has to do with the continued increased demand for IMIG or what has often the public health use or greater use for this particular product, and listing those condition, and the documentation of the shortage that exists, not just here, but around the world with millions of people at perhaps greater risk for that.

I am unclear as to what the secondary markets are there. Some reference was made to secondary markets yesterday. I wonder if there would be some elucidation of that, and also what we mean by biological distributors of these products, is that another layer that is imposed in this, and I think we need some clarification on that, as well as a listing of the different distribution sites.

They mentioned doctors, hospitals, home health, wholesale, biological distributors. I think there is also a large one that is missing from that list, and I again raised the question yesterday, but we call attention to the federal contracts, because certainly the Department of Defense needs to have access to this perhaps with even greater priority.

MR. ALLEN: Along the lines of what Jim was talking about earlier, and we heard about the demand over in Europe versus the manufacturers over in Europe, can we maybe ask the FDA to work with the U.S. manufacturers to determine what percentage of the products that are going over to Europe are guaranteed and what percentage we may be able to keep in this country to deal with this immediate shortage? That seems like -- it is short term obviously -- but it is immediate in a sense, and that might be something that could be done very soon.

DR. PENNER: Richard mentioned something about a generic label for risk exposure that might be useful here. Considering the fact that it doesn't seem to prevent people from smoking, we might just have the Surgeon General put something on these.

DR. CAPLAN: Other ideas, other thoughts? Looking at antitrust relief for exemption -- let me just say here I like lecturing people from the blood industry and people who come from consumer groups about this history quite a bit, since you all know more about it than I do, but this area has received has received special treatment by law, the blood act that gave certain immunities and treated this, not as product, historically opens the door to the question if it is seen as a special product with special status in federal law, then perhaps it has --

DR. SECUNDY: Special obligations.

DR. CAPLAN: -- special obligations with respect to competition, and so forth, by monitoring it. It's a wedge, I am not a lawyer, thank God, but it would perhaps open the door to what I think some of us are starting to think about in terms of data and monitoring, so that we don't have market failure.

Some of what we have heard about is market failure with no one kind of sitting in the catbird seat to say, well, inventories are being depleted and we have got GMP obstacles, so we are going to get a shortage here, but if the companies can't talk to one another, no one is anticipating something that is definitely anticipateable.

DR. SECUNDY: And the other thing is, I guess really in response sort of to Dr. McCurdy, we do have models for scarcity issues and for definitions of community in times of scarcity that have been used historically within our environment, so we might want to revisit those and look at them in relation to this situation.

DR. CAPLAN: One comment, too, to keep in mind as we wrestle with this question of domestic and foreign and export, and attending to our needs, Paul is correct to note that community often means taking care of national needs and even though we may talk a lot about local needs in order to generate that, there is this long history in blood of trying to use product around the country.

I want to flag one other that Marian will know is near and dear to my heart. We had a product in this country some years ago about organ transplant and people coming from overseas to get transplanted here. Congress did act to put a restriction on what centers could do to transplant foreigners.

We have a law that makes it illegal to use more than 10 percent of the supply at any institution for transplant to non-Americans. So, people have attempted to grapple with scarcity in one regard by saying, well, we are going to give some special status to national needs in time of shortage or when supply is short.

Again, I don't know how exactly we want to make a recommendation. We maybe just want to ask that that be attended to, and that the sense of community that is important in this panel is the national community, but there is that precedent. It is there. There has been an attempt to deal with that issue, at least in the transplant area that I have watched over the years.

Paul.

DR. HAAS: A question and then depending on the answer I guess a comment. Is it true that there are independent units, I suppose hospitals that do their own collection of blood and fractionations, making IVIG, et cetera? Is that at all happening?

DR. CAPLAN: No.

DR. HAAS: So, everything that we have heard is pretty much under the total supply.

DR. CAPLAN: I don't think this is a comb industry too much.

DR. HAAS: I was hoping not, but I just wanted to make sure.

DR. PILIAVIN: The sociologist in me is forced to make a comment about we have been hearing different things about availability as a function of people's essentially social class background. There were some organizations that spoke that said we don't take that into account, and there are some that said, well, essentially, if you are indigent, you don't get this stuff now that there is a shortage.

I would like to put that somewhere on the agenda.

DR. GUERRA: It would be helpful somewhere along the way to better understand what the cutting edge of science and technology might be in terms of bringing some definitive relief to some of the conditions that today are being treated expediently with a variety of interventions that provide some short-term or ongoing benefit, but in the instance of the reconstituting of perhaps the immune system in individuals that have congenitally acquired immunodeficiency states, that I think we need to know more about it, because that may offer some of the longer term hope and benefit for the use of stem cells or bone marrow transplants.

At some time in the past, it had been stated that probably over 60 percent of the immunodeficiency disorders could be treated with bone marrow transplants. Whether that still holds, I am not sure, but it would be helpful.

DR. CAPLAN: Related to that, that makes me think, too, that we may want to say something to encourage the NIH Consensus Conference model with respect to the use of recombinant products, and also we may want to applaud, we can applaud pursuit of gene therapy as a research area that looks promising.

I might add we could also applaud the fact that the industry did give us some data, and we want to encourage them to pursue that, and they promised it at three-month intervals. You might think about whether you would like to see it faster than that or forever as a kind of contract that they are willing to come to the public with, with respect to what is going on there, so that certainly we can reinforce behavior as part of what we are doing.

I was reminded, too, in looking at the discussions about trying to cope in the longer term with different problems and disorders. We still come back to the CJD risk issue and how is that handled, and it does make me nervous to continue to hear that the Red Cross and a few people are trying to do those experiments on CJD infectivity and understand it, and see what is going on, when we might need a bigger effort there.

I mean it is great that those experiments are going on. We asked for them last time, but given all the amount of time we are spending trying to pinpoint what is CJD's infectivity, if at all, through blood transmission, what kind of risks are we talking about there, we may urge that a few more rats die in the name of answering this question.

I was glad to hear that what we asked for last time is happening, but I am also nervous that we may not still see the push that we would like to have to get a faster answer to that question. That seems to me to bear on this comparative risk and how we trade this off matter.

Paul.

DR. McCURDY: I might add that NHLBI is supporting in one way or another some of these studies. I think we bought at least some, if not most, of Paul Brown's mice, for example, and also supported some of the laboratory work done by Bob Rohrer.

I think it is fair to say that we would welcome discussions and ultimately, proposals for somebody to really put together a very careful look on these, although I think that the combination of the Red Cross, the Neurology Institute, and Heart, Lung, and Blood has been doing fairly well.

The major problem I guess is that even mouse experiments take six to 12 months to get an answer, and that in itself is a very difficult logistic problem.

MR. WALSH: I have just got one more with respect to long term. We addressed the patient notification withdrawal program and IPPIA and Red Cross, and Baxter and Novartis are all working on kind of a common program with respect to that, and I would just like to reemphasize the importance that we, as blood derivative consumers feel about direct consumer allocation vis-a-vis extended use of a neutral third party platform that is confidential for allocation purposes, and that might even be able to provide some clinical resource to help a triage for the distribution of emergency inventories in the event of shortages like we are experiencing now.

But right now, for those that aren't aware, the current allocation is the customer of the manufacturer, and that customer is defined as anybody from a wholesaler from a wholesaler to a home health care company, to a physician, to a hospital, and not to the patient.

I come from a city, I was born in a city, Boston, where James Michael Curley is the dead votes, and I live in a city now, Miami, where we just got rid of a mayor because of dead votes, and there is a lot of dead alphas and dead IVIG people unfortunately, some of whom are dead because they didn't get product, and couldn't stay healthy, that have allocations that their distributors, if you will, their care providers still use to this day, and irresponsibly, put new people on service or people that don't need it as much as people that have been on product for many years.

So, I think to go back without getting any more long-winded, direct consumer allocation program, we need to look at it.

DR. GOMPERTS: When I look at the situation and some of the proposals, clearly, it is a situation that is changing. The issues are recognized, and whether it is industry, FDA, consumers, the issue is getting a lot of focus, so I think, first of all, it may be useful to get data on a monthly basis to the Immune Deficiency Foundation. I think that could be very useful.

Secondly, I would like to see this committee have an update, hopefully not for two days, but certainly a short, relatively, half an hour, maybe an hour at our next meeting, and probably meetings after, because it would seem that there are things that are happening that would tend to alleviate the shortage.

The compliance issues are beginning to be overcome. It may well be that the very high spot prices may well constrain utilization, and there are other factors that are coming to bear on the actual supply and the importation of product manufactured outside the country.

So, as I look at it, it is a changing scenario, however, I think the excellent document the FDA put out from the point of view information could be reinforced and perhaps could be redone through another venue, such as CDC's MMWR. It may well be that CDC could be brought into the information supply situation, and also part of the MMWR, I don't know.

We need to look at that pretty carefully from the point of view of antitrust issues, but it may well be that there are some ways through that or around that at this particular point in time, but I think right now information is important as we manage through the short term.

Long term, of course, I will have a lot more to say.

MR. ALLEN: I agree with Dr. Gomperts. I just wanted to ask two questions. Two things. One may be more personal in the sense that I still need some understanding in terms of this issue about paid donors versus volunteers, and what is done with the plasma. That is the first thing.

Secondly, I am curious about once we relieve this shortage or the shortage is relieved, what is going to happen to the price of these products, are they going to remain high, as they are now, which is, as we know, is classic of what happens during shortages, or are these prices going to get back down to what relatively they should be based on what they were the last couple of years.

DR. EPSTEIN: I think one element that we have really not brought up in the last day and a half is the role of public health organizations including at the state level. It is probably not known to most people here that for the intramuscular immune globulin, there is a voluntary system in place where the manufacturers identify releasable inventories that are then managed by the CDC in cooperation with the states.

Now, the reason for that the major use of that product is hepatitis A prophylaxis in outbreaks, but I think that it is also a possible model where one could think of creating an allocation system driven by state public authorities, which would then have a closer linkage to defined indications.

I am not necessarily advocating this, I am just saying that it is another available idea.

DR. CAPLAN: Before we break for lunch, I will make a couple of suggestions about ways we might proceed. I am going to ask, as I always do at this point, Mac and Dr. Nightingale to try and transfer some of these ideas into two categories, short term scarcity problems and what we might say, and longer term issues about dealing with scarcity and trying to make it is alleviated in the future.

We will look for those on overheads, so we can talk about them, but I want to say, just talking personally, we have made some recommendations in the past and fine-tuned our language down to make sure that everyone as onboard.

We might think today about two matters. One is some of the issues that we are going to face, say, in the antitrust area, I promise you we will not solve here by working on the language. What we can do is call for Congress or the appropriate Justice Department officials to go after this thing.

If we try to do it as a micromanaged thing, it is almost senseless because we are in a big arena. There are other factors that drive what the nation's business policies are besides blood, and they will have to be taken into account.

So, I would urge us there to keep in mind that what we may want to do is give Points to Consider, directions or goals that we want to get to, and then ask how well people have done in bringing that about. Congress is certainly listening to this committee and ready to take on some of the things we point out, so that might be something that shapes how we make a recommendation.

It is also possible for us, in this instance, I think to raise some Points to Consider for others, that we don't necessarily have to come up with a recommendation where the language is nuanced and everyone is ready to sign onboard if we thought about some of the issues as labeling, I am thinking of here, I don't know, that we will settle that one today and get agreement on what the label should read, but we might say if labeling is a road to trying to get supply out there in the short run as an answer, then, we want that explored fully, and we leave it again to the agencies to work with the industry and the appropriate liability attorneys, and so forth, to solve it.

We won't write the label here of what that is going to look like. I promise you that is not going to happen either, but as we think about this over lunch, if we can give people endpoints to get to, and Points to Consider for government, for the industry, for the agencies, even for the patient groups, doctors, and pharmacists, then, I think we will do some good in the face of the current shortage, as well as in the long run.

So, maybe you can think about your recommendations in that spirit.

Why don't we break for one solid hour, unheard of for this group. Come back at 1:15.

[Whereupon, at 12:17 p.m., the meeting was

recessed, to reconvene at 1:42 p.m.]AFTERNO

ON SESSION







[1:42 p.m.]











DR. CAPLAN: What we have done -- if we can get everybody back, panel members, and so forth, to take their seat -- we have tried over the lunch break to assemble. Dr. Nightingale has worked very hard to get us short-term recommendations and long-term.

Short-term is at first, if we get more overheads, we may even see long-term, but we have filled up the overheads we have with the short-terms. These again are recommendations that I would like you to consider. We have seven that he and I could come together on, there may be others you want to add.

As I said, we are trying to use phrasing that is specific, but not micromanaged. We are trying to give agencies and government and business and the health professions a chance to work out some of the fine points about how to get there.

So, in that spirit, why don't you read the first one.

DR. NIGHTINGALE: The first resolution reads: FDA, IPPIA, and other appropriate entities should continue within their respective mandates to collect production and distribution data on IVIG, clotting factors and alpha-1 antitrypsin products, and do so on a monthly basis. These surveys should include IPPIA members, American Red Cross, Novartis, and any intermediary.

DR. CAPLAN: We probably don't want to say Novartis, but say something like private industry there, but we can make that change as much as I love Novartis. The general idea here is trying to make sure that people have production, distribution data in a timely way and are looking at it as a response to the immediate short-term problem.

Comments?

MR. WALSH: Are we going to have a similar resolution that addresses the supply statistics as there was demand statistics? Somehow we need to start collecting or have the FDA, or whatever, the demands stats.

DR. NIGHTINGALE: I attempted to include that by saying production and distribution. Do you want to amend that?

MR. WALSH: Distribution is a factor or production. It doesn't address demand.

DR. NIGHTINGALE: Give me a word. Production and demand?

DR. CAPLAN: You can say production and demand distribution.

DR. NIGHTINGALE: Production and demand then.

DR. CAPLAN: I mean you can say production, demand, and distribution.

DR. NIGHTINGALE: You probably want to include distribution, so that will make certain that it's clear.

DR. CAPLAN: But after production, you can write production. One other thing we probably have to do just for the tape, although we want them to not only collect it, but actually want them to share it, and they may be collecting it in some quarters, but we have got to get to share and report.

DR. SECUNDY: Collect and report. Disseminate to whom, to the committee, to FDA, who are we going to have the disseminated to?

DR. NIGHTINGALE: I would assume it would be the public at large, Dr. Secundy.

DR. CAPLAN: I would like to see it disseminate to the FDA, and I would like to see them report the public, as well, but start with the FDA, and that should make it public, I would assume, the way this is written. Yes?

MR. WALSH: Art, another problem we might have here is that it should continue. I mean right now there is no attempt to collect any demand side information from anybody, is there?

DR. CAPLAN: No.

MR. WALSH: Is that possible do, Mary?

DR. CHAMBERLAND: Actually, I wanted a clarification, when you said "demand," that IPPIA should collect data about demand, what are you thinking, the flow of telephone calls?

MR. WALSH: For example, right now could industry tell us what the demand for IGIV is?

DR. CHAMBERLAND: How would they measure that?

MR. WALSH: The different uses including off-label.

DR. CAPLAN: That isn't what I had in mind. What I had in mind by "demand" is some attempt to say last month we had requests for X number of units, and that is what we take the demand to be.

DR. EPSTEIN: Back orders.

DR. CAPLAN: Back orders and stuff.

MR. WALSH: The only trouble with that is in alpha-1, for example, we are told we can only get 50 percent of allocation based on historic purchasing from last November and December time frame is what all the distributors are told.

You are not going to go in and order 100 percent, because you are not going to get that.

DR. CAPLAN: On the other hand, I mean to be realistic, they are not going to know the demand in real time on day T until they have something to look at, so my hunch is what you are talking about here is just getting -- again, I don't want to micromanage this -- what I want to say is we want the best available report on demand.

How that gets worked out, I don't much care. We want to see timely demand information. That is the sense that we are striving for here.

MS. JONES: But we do sort of have to be concerned about how it is collected, because if you are asking several companies to do this, you want some consistency among the companies on how they collect that information.

DR. CAPLAN: I guess what I would say here is I will trust the FDA if this can be implemented -- we shall see -- to make sure they have a standardized reporting mechanism.

DR. HAAS: Art, just quickly on that. The hemophilia experience of 10 years ago was that we tried to go back to the treatment centers. Although that wasn't picking up 100 percent of persons with hemophilia, it was getting the dominant requests going through the treatment centers, so we tried to avoid the problem that John is talking about, so if there are a critical mass of treaters for alpha-1 for immunodeficiency, where you can get a solid sample --

DR. CAPLAN: It would be a better say to do it.

DR. HAAS: -- outside of the producers' end. I think you have got to get it from another sector.

DR. CAPLAN: I understand what is being asked for, and again, the general goal here is to get timely, accurate, standardized information on demand, supply, and distribution. That is what we want. I know that that slide is going to become a mess, but I have got it in the tape here now, the phrasing.

We are seeking the collection of timely, accurate, standardized information on production, demand, and distribution, and we can leave it to FDA to figure out how to make that get done and what's out there to get, but I think in the short run emergency, that is what we want, is to have this information out there, so the communities affected know what is going on.

Are we onboard with that? Anybody want to give me a motion?

DR. SECUNDY: So moved.

DR. CAPLAN: Jay.

DR. EPSTEIN: I would suggest that we make the issue of monitoring demand a separate point, because I think we are in an earlier stage. We have some knowledge about who knows about production and distribution. I think we need to, as a separate point, recognize the need to develop systems to concurrently monitor demand.

DR. CAPLAN: All right.

DR. EPSTEIN: Because I don't know who we are asking this --

DR. CAPLAN: You don't have to try and write this down, Steve. Just for the tape, what we are going to try and recommend is that we collect and disseminate accurate, standardized information on distribution and on production, and that we develop the same for demand.

Now I will take a motion on that.

DR. NIGHTINGALE: Before you take a motion, it greatly facilitates subsequent processing of these motions if what is voted on is precisely what is written down here.

DR. CAPLAN: I will give you that if you will do one thing for me. You need an eraser. If you have a cloth or if you want to sacrifice your shirt to the common good --

DR. PENNER: Art, if we could get a consensus on this, then, couldn't we finalize the phrasing and distribute it, so that we don't have to worry about the small points, it is just getting the consensus down?

DR. CAPLAN: Do you want to go that route?

DR. SECUNDY: Yes, with you and Steve doing the language.

DR. PENNER: Otherwise, it is going to take forever.

DR. CAPLAN: That is what I am worried about, too, and I think we are real close on this one, so if we have language problems -- they are going past you on this one, Steve. Unfortunately, although you would like to reconstruct this, what they are saying is the sentiment of the committee, that the motion is out there, without writing it down, is that timely, accurate, standardized information be acquired and disseminated on production and distribution with all the following that is up there, and IVIG, and so forth, and all the blood products, and that the same be developed for demand, and that is really what we are going to. We will work the phrasing out on that one.

DR. KUHN: Can I ask you just a question? The IPPIA, that is each individual company, we are assuming that, right?

DR. CAPLAN: Yes, program.

DR. HAAS: I guess a continued clarification, when it says "other intermediaries," it says when it leaves the companies, gets into the home care or whatever --

DR. CAPLAN: That is what we are trying for.

DR. HAAS: That is what I thought. We want to make that clear.

DR. SECUNDY: So, you have a motion.

DR. CAPLAN: Motion, yes.

MR. WALSH: Second.

DR. CAPLAN: Discussion? All in favor of this request to get accurate and timely information on demand and distribution and production, in a two-part statement?

[Show of hands.]

DR. CAPLAN: Opposed?

It is starting to look like the Bulgarian Communist Party meeting.

I am sorry, did we unanimously go with that? You may, however, dissent by oral indication, as well. That will remind the chair.

DR. PENNER: I would have preferred one on the demand side.

DR. CAPLAN: Okay. Do you want to do it that way?

MR. WALSH: I wouldn't object to that.

DR. CAPLAN: That is fine. A little parliamentary procedure maneuver here.

Let's vote first on the collection of -- you don't have to worry about this -- vote first on the collection of timely, standardized and accurate information on production and distribution of these various blood products from all appropriate agencies. Vote on that.

[Chorus of ayes.]

DR. CAPLAN: Opposed?

[No response.]

DR. CAPLAN: Okay. The same language. Develop that information on demand.

DR. PENNER: I don't think it should be those same entities.

DR. CAPLAN: Okay. I understand what you are saying. With appropriate modification for assessing demand, some of those entities aren't appropriate for doing that, if I understand what you are saying.

DR. SECUNDY: We said develop systems.

DR. CAPLAN: Develop systems to have that information, standardized, accurate, timely, on demand. You don't have to specify who is there.

Two resolutions out of one. What is the next thing we have got here, do you want to read that one?

DR. NIGHTINGALE: The Department of Health and Human Services and its operating divisions should explore in collaboration with industry and appropriate consumer groups, methods to optimize allocation of available products including management of emergency supplies and programs which distribute product directly from manufacturer to consumer.

DR. SECUNDY: Can we say with attention to issues of equity? I guess I would be comfortable adding "equity" as standardized and equitable somewhere in the language.

DR. PILIAVIN: You are speaking to the sort of social class issues?

DR. SECUNDY: Yes.

DR. PILIAVIN: Yes, good.

DR. SECUNDY: Steve, just put equity and standardization, and then you can build that into the language later.

DR. PENNER: Are you planning to get more specific on this at this point or do you want to just leave it free?

DR. CAPLAN: I wasn't. There is going to be some discussion about what that means, but not here I suspect.

DR. SECUNDY: Standardization.

DR. PENNER: Because we don't really give them any guidance as to what direction they should be going as whether we think it should be a public domain or whether it should be industry oriented.

DR. CAPLAN: Oh, you mean the actual outcome?

DR. PENNER: Yes.

DR. CAPLAN: I am trusting that if those groups meet to talk about it, they will get the right balance there. That is my thought about that. I mean that is sort of saying, okay, get the parties to the table, figure out how you want to handle this.

DR. SECUNDY: There is one other thing that we talked about earlier, and that is the inclusion of the medical profession. I don't know whether that would be AMA or not. I mean we are leaving out the providers.

DR. HOOTS: Reframe that as medical expertise and not specify.

DR. SECUNDY: Or professional groups.

DR. NIGHTINGALE: Consumer and professional groups.

DR. CAPLAN: That will probably do it.

DR. PILIAVIN: Consumer and provider?

DR. SECUNDY: I am happy with that.

DR. BUSCH: This statement that distribute directly from manufacturer to consumer, I am not so sure that is what we heard. I mean what I heard was the desire to link the source, the supply to the patients, but not necessarily to basically phase out hospital, pharmacies, and home care as the mechanism for maintaining the larger inventories that are then distributed on to the consumers if they need the product. They could envision that distribution straight to consumers could be problematic in terms of worsening the problem, in terms of the product being out in consumers' refrigerators, or whatever, and not being used.

I think this may go a little far in terms of direct from the manufacturer to the consumer.

DR. PENNER: I don't think that rules out an intermediary. I think that they have to come up with the appropriate delivery system that will be equitable as mentioned.

DR. HOOTS: Just change it to result from -- result in direct -- take out the word "direct" -- result in distribution from the manufacturer to the end user. That allows every necessary step in between.

DR. CAPLAN: Okay. Do you see where that goes?

DR. HAAS: Yes, we are not suggesting that each manufacturer set up their own pharmacy and dispense to patients.

DR. SECUNDY: That is what I meant by standardize.

DR. CAPLAN: He is bringing you a tool to use.

DR. SECUNDY: That is not going to work.

DR. CAPLAN: Keith, tell him where you want that language.

DR. HOOTS: Right there where distribute is. Results in distribution of the product ultimately from the manufacturer to the end user, and I think the key word is "ultimately," rather than "directly."

DR. CAPLAN: Right up there. You got it.

DR. SECUNDY: End user, not consumer.

DR. CAPLAN: How about a motion there?

DR. PENNER: Move.

DR. HAAS: Second.

DR. CAPLAN: Any other discussion?

All right. All in favor of this resolution, which I would ask you to read, we are basically calling here for the development of a mechanism to optimize equitably and in a standardized way the distribution of the products.

In favor?

[Show of hands.]

DR. CAPLAN: Opposed? Okay. That one is in there.

The next one we tried out. Steve, you can read that one.

DR. NIGHTINGALE: Industry, in collaboration with FDA, should explore the possibility of importing additional plasma derivatives including intramuscular, as well as intravenous immunoglobulins.

DR. CAPLAN: This is in response again to the immediate shortage. That is what we are talking now. Comments?

DR. PENNER: Do you want this specific to cover shortfall or to cover emergent use, something of that sort?

DR. CAPLAN: Absolutely. We are presuming --

DR. PENNER: This is going to, at the outset, say for this emergency situation?

DR. CAPLAN: Exactly so. This will be prefaced by facing immediate shortage, these are things we recommend. You don't to write it there, it will be up in the general -- you can do it, but it is going to be clear that these recommendations are targeted toward a response to existing current shortage.

DR. GOMPERTS: But it would also, in the situation of licensure of procedures, and licensure of products, would have a long-term impact, as well.

DR. CAPLAN: It could, although we can come back to that --

DR. GOMPERTS: No, not could, it would.

DR. CAPLAN: I mean it will. We can come back to how long we want them to do this in the second set.

DR. GOMPERTS: In the acute situation, there are a number of ways to do that. One of them is an IND, in other words, product is allowed in under investigation. Every recipient is monitored, adverse events, efficacy, whatever, each one. That is the acute situation, and that is starting to happen.

Also, short term, as well as long term, is the licensure of fractions for further purification and filling, and specific products. That is short term and long term.

DR. CAPLAN: Does that call for a change in the language there? I understand what you are saying. I am not sure --

DR. GOMPERTS: I would just remove "while shortages persist." Why limit it to that?

DR. CAPLAN: This set of recommendations is coming under the rubric of because of shortage we recommend this, that is why. I said we are going to divide our recommendations into A and B, so it's tactical.

DR. GOMPERTS: Okay.

DR. CAPLAN: Jay.

DR. EPSTEIN: I think the missing term here is whether the emphasis is on facilitating import or investigational products, those that are not licensed versus whether the emphasis on simply increasing U.S. supply by making more imported products available underlies this. I think that is the distinction Ed is trying to make, because in the one case you are dealing short term, and the other is long term.

So, I think to clarify this is a short-term measure, you want to add the word "investigational products." Maybe we want to make the other point, too.

DR. GOMPERTS: I think investigational agents is going to limit that. It is certainly individuals will receive the product, but it is distinctly limited.

DR. CAPLAN: Here, I am going to argue that we should keep the phrasing as it is. I think what we are trying to do is encourage the exploration of how to increase product in the short run. There may be some discussion about whether that is under IND investigational, changing long-term licensing practice, I don't know. I think actually the phrasing here will get the trigger going to try to increase the supply side.

That is what I was talking about is be careful that we don't overmanage this.

DR. HOOTS: So you are saying either/or and?

DR. CAPLAN: Yes. There are three strategies one could play with, and I think I would be interested in hearing about all of them at a future meeting, as what worked.

DR. SECUNDY: So moved.

DR. CAPLAN: Second?

DR. HOOTS: Second.

DR. CAPLAN: All in favor of this resolution, so signify with your hand.

[Show of hands.]

DR. CAPLAN: Opposed? Okay.

No. 4. There are seven on this list that we came up with.

DR. NIGHTINGALE: Industry and FDA should explore mechanisms to expedite reallocation of raw materials to increase production of alpha-1 antitrypsin and other plasma derivatives.

DR. CAPLAN: This is the paste motion.

MR. WALSH: I want to move that. So move.

DR. CAPLAN: He is cutting of discussion, I think. This is, in part, an attempt to capture this concern about paste and intermediate products, to have them moved along in the short run, in the context of scarcity.

I don't see a discussion emerging here.

You can move that one.

MR. WALSH: So moved.

DR. SECUNDY: Second.

DR. CAPLAN: All in favor?

[Show of hands.]

DR. CAPLAN: Opposed? No.

DR. NIGHTINGALE: No. 5. FDA and industry should explore labeling strategies which would increase product availability without compromising public safety or trust.

DR. CAPLAN: This is the idea, as you will recall, that came up during the past day and a half, that we might be able, in the short run, to have more supply out with changes in informed consent, labeling, to those who might use these products.

DR. SECUNDY: I would be comfortable, and I don't know, if you think it would be too specific, to indicate with special attention to informed consent.

DR. CAPLAN: To explore labeling strategies which could increase produce availability. To me, I love informed consent. That is what I live for day and night, but I am just trying to figure out where to put it there.

Labeling and consent strategies or labeling and disclosure strategies?

DR. SECUNDY: Yes, labeling and disclosure.

DR. PENNER: Consent would be a real difficult situation.

DR. CAPLAN: Disclosure probably gets what we are talking about.

DR. PENNER: You would have to get signoff on every bottle that you have got.

DR. CAPLAN: Disclosure is probably the spirit of that.

I will take a motion on that one.

DR. SCHIFF: So moved.

DR. SECUNDY: Second.

DR. CAPLAN: Any other discussion on that particular recommendation?

All in favor?

[Show of hands.]

DR. CAPLAN: Opposed? Okay. Great.

No. 6.

DR. NIGHTINGALE: Industry should discuss with FDA, Federal Trade Commission, and patient representatives strategies to triage specific products to specific patient groups to promote public accountability of this process.

DR. CAPLAN: What we are trying to do here is ensure, to come back to concern about the earlier resolution, you may say we don't need this one, but we were trying to make sure that we had public accountability about the distribution.

DR. PENNER: That would come right after the second resolution.

DR. CAPLAN: Yes, it would probably read along.

DR. SECUNDY: You are talking about promotion of accountability to the public.

DR. CAPLAN: Yes.

DR. SECUNDY: It doesn't say that.

DR. CAPLAN: He says promote public accountability, but he means --

DR. SECUNDY: Accountability to the public.

DR. CAPLAN: We can fix that. I know what you are saying. It's a clarification of the phrase. It's all right.

DR. SECUNDY: The public is not accountable, but industry is.

DR. CAPLAN: We would probably re-order this to go back up under the one we passed earlier, so that the two are set. The drive here is to just repeat if we are going to have emergency supplies and triage, we want to make sure that is publicly accountable.

We have not taken a stance on whether the existing mechanism is or isn't, I might point out. Remember, this came up -- this is the FFF, the hand-off, where is it going. We just want to make sure that patients and the public know that there is accountability to the public.

Discussion?

MR. WALSH: I would just like to ask for clarification. What products, what is before products, to triage what?

DR. CAPLAN: Specific.

MR. WALSH: Specific products.

DR. CAPLAN: He means prolastin. IGIV.

DR. PENNER: Motion.

DR. GOMPERTS: I perceive FTC issues that could arise out of one of our earlier recommendations, the reporting of product availability, product supply, demand, as well.

DR. CAPLAN: Yes.

DR. GOMPERTS: So, clearly, that is an issue, whether you want to link this one to that early one, that is point one, the monthly data.

DR. CAPLAN: That is what I meant when I said I think we will move this one up, so it sits next to the other one.

DR. GOMPERTS: Okay.

DR. CAPLAN: But that issue is there.

DR. GOMPERTS: It needs to be broadened.

DR. CAPLAN: Yes.

DR. GOMPERTS: Okay.

MS. JONES: We are just focusing on the government agencies and patient groups, right?

DR. CAPLAN: Yes.

MS. JONES: Shouldn't providers be there since you are talking about triaging, and they have the expertise with regard to the specific disease conditions, and the like? They are not represented.

DR. McCURDY: Here in this group, you have been fairly specific as regard to products, which are the ones that are troubling us today, but it is conceivable, perhaps quite likely, that there will be other products that will come up in the future, and perhaps this would be a model for approaching subsequent problems as they arose.

DR. CAPLAN: I actually hope so, but my own comment here is that if we can put this in and make it work, we may actually get a model, and I was alert -- we will note just for the record -- that the FDA has had some experience with other types of shortage, and has tried to wrestle with that distribution thing, so there may be a way to make that expertise come together both for blood products that become scarce, anything else that becomes scarce in the blood arena, and it may be for other things, but under the short-term rubric, I think we should keep the language the way we have got it.

DR. PENNER: Are we going to have a time frame on this? Since we are dealing with an immediate shortage and an immediate problem, we need to be sure that something is getting done very quickly.

DR. CAPLAN: You mean how can we ensure that these things happen?

DR. PENNER: Yes, and some issues really have to be dealt with as soon as possible.

DR. CAPLAN: Hold that question until we run through the rest of the short-term ones, and then we can talk about that a little bit.

We have a part motion out there, I think, on this one.

DR. PENNER: Second.

DR. CAPLAN: Any further discussion here?

All in favor?

[Show of hands.]

DR. CAPLAN: Opposed? Okay.

I think we had one more in the short terms. I was just trying to get us through this and then --

DR. NIGHTINGALE: We have a temporary shortage of transparencies here.

The last issue that was raised for inclusion for short-term solutions was to explore constraint against exports of products while the shortage lasts. We didn't have any specific language in that. Would anybody care to propose specific language along those lines?

DR. CAPLAN: I am even happy with we urge the exploration of the -- let me see if I can do this.

DR. SECUNDY: Temporary moratorium.

DR. CAPLAN: What we are trying to do is urge an exploration of the impact of exporting blood products and steps to limit the impact of exports on domestic supply.

DR. PENNER: It isn't coming out that way.

DR. HOOTS: I mean obviously, this is in the context of the shortage.

DR. CAPLAN: We all presuming shortage.

DR. HOOTS: We have to make sure we balance the overall, both domestic and global interests, because on the one hand, we are proposing greater importation, and we are here saying maybe we want to restrict exportation, so we have to really -- I think this is one where we really do have to be very careful with the language about how we are going to -- you know, that it is really in the context of a shortage only, and in the context that there is not perceived shortage or there is not an actual shortage in the rest of the world, because otherwise I think it could be seen as --

MR. WALSH: For example, prolastin has been distributed in Europe on a very limited basis, and, you know, there are alphas in Europe that are sick and dying right now, that nobody in Europe, to my knowledge, is getting product. I am not saying that I would rather have everything stay here, but I would almost have to extend some consideration to what Keith just said.

DR. CAPLAN: My only comment about that is to try and address this -- that is why I was trying to look for a word like exploration of the impact. We haven't said that we understand fully, for different products, where it may or may not be adverse, and I hate to say it, but it isn't even -- it is a matter of national policy in foreign relations how we deal with this, which isn't going to get settled here either, but I would like to see it explored, and quickly, with some analysis of what the impact is on if we decreased it, on supply.

It seems to me people who can't get supply tomorrow morning will want to know why it is going overseas. They may get an answer that says it has to go overseas or it should. I am willing to live with that, but I want to be able to tell somebody if you can't get it here, and it's going over there, the reasons why.

DR. SECUNDY: Then, we just ask the question, and then have the country answer it.

DR. CAPLAN: I am fishing here for a we urge exploration of the impact of a temporary decrease in exportation of plasma derivatives while they are in short supply. I am trying to get an exploration --

DR. SECUNDY: I think that is reasonable.

DR. NIGHTINGALE: Can you read my handwriting up there? I have we urge exploration.

DR. SECUNDY: Right.

DR. NIGHTINGALE: Should I read that?

DR. CAPLAN: No, we have got it.

DR. GOMPERTS: I think the terminology is excellent. I think, by and large, that is happening, it is already taking place.

DR. SECUNDY: Well, we would like to see a report on it.

DR. CAPLAN: Sure. Here, we are urging for the report, this is an urge to the Secretary to come to some -- John asked before about how we know this is happening. This recommendation will go to Shalala. Shalala will turn around and say somebody should tell us the answer to this question, so in that sense, she could be asking any federal agency or collaborative, Commerce Department, anybody she needs to get an answer from. Or Steve, for example.

Further discussion? Motions?

MS. JONES: Move.

DR. CAPLAN: Second?

DR. HAAS: Second.

DR. CAPLAN: All in favor of urging that exploration of that issue?

[Show of hands.]

DR. CAPLAN: Opposed? All right.

How did we make out in getting some more overheads for the longer term? Steve, why don't you spend a little time just writing down those points we were talking about. You don't have to do it on the overhead. While we are doing that, just a brief discussion about these resolutions we passed and their implementation.

What they are, the audience is, we write them up and send them to Secretary Shalala. In one sense, what we are saying is at that level of HHS, these are our recommendations. We have some language in there about things that we would like to see the FDA do and other agencies and parties, but it becomes her responsibility to see that our recommendations are attended to. They are recommendations.

She could say I listened to your recommendations, and I choose not to follow them. That is always possible. But that is the level of the implementation that we have.

We can certainly preface these recommendations in the letter that I would be sending in your names to her by saying we would like to have a very timely response in the face of shortage. I think they understand that we are trying to address this tomorrow morning, the problem of shortage, but that is what I can say about that.

DR. PENNER: I think that is very agreeable. I don't think we can do anything more than stimulate enough interest to want to proceed, and we have to do it right away.

DR. GOMPERTS: In regards to these recommendations, we will get feedback, I presume, not only to the ones today, but the recommendations that were made, that we heard about earlier at this meeting, the recommendations that we made at the previous meeting.

DR. CAPLAN: You meet on the HCV look-back, and so on?

DR. GOMPERTS: Yes, the NIH funding.

DR. CAPLAN: I will say this. I think that we have had a partial response when Eric was here yesterday telling us about the HCV look-back. He was telling you an update, and there is a plan rattling around, which I don't think has been released yet. I believe it's CDC's, but I may be making this up, about how to do a look-back.

DR. CHAMBERLAND: I think the committee members got copies of a plan for the prevention and control of hepatitis C. That was directly in response to committee recommendations, and was developed within CDC and sent to the Secretary.

DR. CAPLAN: If you didn't get that, it will be coming right away in the mail right after this meeting, so occasionally, responses are going to be coming to the agency or the division saying here is what we are doing, we heard your recommendation.

Personally speaking, I didn't know what the status was on follow-up of that encouragement to NIH research that Paul had told us about, that we had heard about with the Red Cross working with them, and I think that one fell between the cracks a little bit. I will try to make it a point, when I send this letter, with these recommendations about short-term scarcity, to Secretary Shalala to ask that she respond to each one as to what steps will be taken or whether she agrees with the recommendation, and then I will just send that back out to you, so we will try to do it as here is ours, what do you think back.

DR. GOMPERTS: I think also the response to the recommendations, by and large, is not going to happen. Some of these may well happen pretty short term, but some of the others are going to take place, not over three months, but over nine months, et cetera. Therefore, it is probably a good idea to keep track of these.

DR. CAPLAN: There are two other truths that we need to understand. One is we are making these recommendations in public. I will send you this letter. It will clear out of the agencies with language, and so on, probably in a couple of weeks. We will try to expedite it as fast as we can, but I presume some information about our recommendations might be on the Secretary's desk as early as tonight, maybe in the media.

So, there are transmission processes going on here. We have to write them up and sort of send them along and transmit them. That is how that works.

At the same time, I will make it a point, too, and I should tell the committee this, to make sure that, for example, Congressman Shays knows what these recommendations are. I know he is planning a hearing -- I think it is scheduled for May 7 -- on some of the matters that we are looking at. I am going to try and get these recommendations over there, so that he has them and knows what our thinking was. That is another appropriate audience, I suspect, for us to be in communication with, that a congressman has made his interest known to me in what we are doing, so if it's all right with the group, I will send it that way, too.

DR. NIGHTINGALE: Dr. Caplan, this is Steve Nightingale. I was writing during some of that last conversation, but the part of it that I heard, I would like to clarify that the recommendations of the committee regarding TSE's have been presented to the Blood Safety Committee, and this was actually contained in the text of the speech from Dr. Satcher that was read by Dr. Goosby, that each of those has been addressed.

We refer specifically to the recommendation by the NIH. It was very clearly understood, this by some of jocularity, was perhaps inappropriately placed in the text of Dr. Satcher's statement, that the NIH takes the committee's interest in developing tests for transmissible spongiform encephalopathies very serious, and in particular, that will be a high priority of the new director of the National Institute of Neurologic Diseases and Stroke, that the identity of that person has not yet been announced, but when it will be, that will permit the Department to give the committee a more explicit response to its recommendations than was possible at the time that the Blood Safety Committee considered its recommendations.

DR. CAPLAN: They will see the statement from Dr. Goosby.

DR. NIGHTINGALE: Yes, yes. That statement, to clarify, was rapidly transposed when it became clear that Dr. Satcher was going to have to be at the White House all day on Monday rather than here. I would reiterate Dr. Satcher's regrets that he could not be in two places at once. Everybody is very proud of the job he is doing, but that is beyond his job description to be in two places at once.

DR. CAPLAN: So, in answer to feedback issues, we will try to make sure we will get the text to you of that. That is what Eric was reading, the sort of point by points in response.

Two other issues which I can get to while giving Steve a little more time, long-term comments and recommendations we might want to make. One is it looks like having -- is Mac around here -- I think the date we came up with was July the 23rd. There he is. Mac, come back here.

July 23rd, 24th, was that what we were thinking about?

MR. McMURTRY: Yes.

DR. CAPLAN: As the date that seemed to emerge for all kinds of reason it is likely for us to be meeting next here in Washington someplace, and we are talking about a one-day August and September or September retreat, and all that means is a more open-ended, not focused on answering a question discussion, but that obviously would give us some time if we thought that some of the recommendations that we had made from a very busy committee, about hepatitis, about research, about test development, about shortage on blood products were not being followed up. We could spend a little time composing some communications to appropriate people to let them know about that.

We don't have an August or September date yet, because we have got to look to hotel availability and location, and so forth, but for scheduling reasons, it looks like the July 23-24 date is about the best we are going to be able to do. I know that some of you may have had something else on the calendar, so I am hoping you can scramble a little bit with this advance notice to try and be here either for all or part of that.

We planned on doing it a little bit later, but we started to run afoul of various blood meetings, so we had to back up. But that will give us a chance to kind of take stock. Again, while Steve is busy transposing, on these areas, we have been wrestling with some pretty tough topics, a look-back and now today, trying to cope with the scarcity issue.

I want to commend the committee for working very hard in dealing with them. The reason I am proposing the more retreat format for us for that day, there may be other issues you want to have come forward.

We thinking, at the next meeting, the topic would most likely be donation and supply overall. We would finally get to hear from those of you who have been thinking about that overarching issue, we will have a chance to go at that.

It has been hinted at in our discussions obviously today about donor and paid supply, and what is going on back and forth here, but then we could stop, maybe take our breath a little bit from the work we have been doing, see if there are other topics that need to be addressed that we haven't got to yet at the retreat, and also look back a bit and say, okay, so, we made recommendations, we think we are doing some good here, we are spinning our wheels, so that is sort of the sequence I have in mind about that.

I would be open to any -- if people don't like that structure.

DR. DAVEY: I have one question. Perhaps I am jumping the gun. Is the committee going to consider a long-term recommendation on clinical use of IVIG? Is that coming up?

DR. CAPLAN: Yes.

Steve, is that first recommendation up there, we could sort of go to that?

DR. NIGHTINGALE: Yes.

DR. CAPLAN: Maybe I can just read that one. You have to change your time frame here and think about long-term efforts to avert or ensure or minimize scarcity. We are outside the box now of what to do with the short-term crisis. Think of the short-term crisis when I do. I think about it for the next year to 18 months.

That was mentioned a lot as a likely period in which some supplies will be short. What I am thinking about here is not meant to make us wait for 18 months before something happens, but it's the first set of recommendations were targeted to the reality of scarcity in the here and now.

These are steps we think we might be able to take to try and diminish scarcity and also to make sure that we don't find ourselves confronting it with other products.

MR. WALSH: I would like to suggest we try to address, in the immediate term, some requesting that the NIH look at some alternative treatment strategies for both the IGIV community and the alpha-1 community.

DR. CAPLAN: Do you want that a recommendation? I mean I don't mind that as a longer term.

MR. WALSH: It is going to be a longer term, but it is something that needs to start. Are we suggesting that the longer term are going to have less of a priority?

DR. CAPLAN: No, no, they can start tomorrow morning, too.

MR. WALSH: That is definitely a longer term issue.

DR. NIGHTINGALE: This is the proposal that you see on the board as written by Dr. Hoots. It had a preamble which I read because it doesn't fit on the overhead.

The preamble states that acknowledging decisions about donor pool size may impact different recipient populations differently, and that the theoretical risks regarding TSE's appear to be alleviated by use of recombinant rather than human products, and that similar deliberations in the United Kingdom have acceded to the preferability of recombinant clotting factor concentrates in the face of local incidence of new variant CJD.

The committee recommends that every effort be made to make recombinant clotting factors available to all hemophiliacs who would benefit from them, and to remove all barriers to such conversion.

DR. PENNER: We need a couple of whereases.

DR. CAPLAN: Okay. This is an attempt obviously to try and push forward a thorough exploration and minimization of barrier to recombinant.

DR. KUHN: Can we extend that besides just hemophilia and say bleeding disorders, because that is going to encompass future recombinant --

DR. CAPLAN: Sure. I understand.

DR. HAAS: Are any of the other diseases amenable to the recombinant factor, is anything out there?

DR. CAPLAN: I don't think the IVIG is.

MR. WALSH: And alpha-1, hopefully, it will be in one of our long -- it definitely will be in one of our long-range objectives.

DR. HOOTS: And that is the reason. I figured there would be a specific one for that, because it is a different time line, because here we are talking about licensed products, and there you are talking about developmental products.

MR. WALSH: So move.

DR. CAPLAN: There is a motion.

Is there a second?

DR. HAAS: Second.

DR. CAPLAN: Any other discussion? All right. Al in favor?

[Show of hands.]

DR. CAPLAN: Opposed? That is a unanimous.

DR. PENNER: You may want to be more specific about the bleeding disorders since there are a lot of bleeding disorders that have nothing to do with clotting factor, but that can be remedied.

DR. CAPLAN: We will wordsmith that to be relevant bleeding disorders.

DR. HOOTS: One of the reasons, in response to that, John, that I didn't, because there are a couple of products that are awaiting licensure.

DR. PENNER: We don't have to be specific, but those which are dependent upon or who have deficiencies --

DR. HOOTS: Right.

DR. CAPLAN: Mac, can I ask you to go up there with one of the overheads? I have a feeling that John is going to propose something about NIH strategy. We might try to write down what you started to say while we are incubating another proposal up there, but --

MR. WALSH: I have to acknowledge I am not nearly as good as you on the fly, Mr. Chairman, but we recommend that the NHLBI immediately evaluate alternative dosing strategies with respect to alpha-1 protease inhibitor augmentation therapy to include --

DR. CAPLAN: You can just way with respect to alpha therapy. We will spell it out.

MR. WALSH: -- to include prophylactic use in cases of acute exacerbation in infection and evaluation of dosing 60, 90, 120 a day milligrams per kilogram.

DR. CAPLAN: You don't have to get that specific. They will do it. That is under the dosing strategies.

MR. WALSH: All right.

DR. CAPLAN: Do you want to make that just the NHLBI or NIH -- not that other institutes can't get in there --

MR. WALSH: Unfortunately, NHLBI isn't doing anything on alpha-1 right now with the exception of Dr. Brantly. Just as a little background -- and somebody might be able to help with the drafting of this -- there is definite theories that demonstrate that if we take product, if are going to have a shortage until year 2001, when we have an acute infection, we need product, as Dr. Brantly said yesterday, you lose lung function, you don't get it back, and there is no studies to substantiate that, and the only package insert at this time states 60 milligrams per kilogram per week. Some docs won't --

DR. CAPLAN: Just add to that, Mac, we recommend that the NHLBI -- no, no, sorry -- this is just a little insert. See where we have NHLBI up top there? You can just draw an arrow down and say other appropriate agencies. There are some other places that might actually do clinical studies besides NHLBI.

DR. PENNER: You want them to also consider recombinant?

MR. WALSH: Yes, and also the dosing strategies, and other delivery alternatives, e.g., aerosol.

DR. CAPLAN: You don't even have to spell it out.

DR. HOOTS: Could we say specifically to accelerate the development and implementation of recombinant, because that is not even an exploration. That is actually an acceleration as far as replacement therapy.

DR. CAPLAN: If you go under that, Mac, and just write the word "accelerate," we will put that in.

MR. WALSH: Make sure you get recombinant in there, too, Mac, please, after accelerate.

DR. CAPLAN: It looks a little messy, but the general idea of this is that we are recommending that NHLBI and other appropriate agencies evaluate alternative dosing strategies with respect to alpha therapy, that we also are recommending that other delivery methods be explored and development be accelerated for recombinant. That is what you are being asked to vote on here.

Motion?

DR. HOOTS: I move.

MR. WALSH: Second.

DR. CAPLAN: Discussion? All in favor?

[Show of hands.]

DR. CAPLAN: Opposed? No. You can write unanimous on the bottom there, and we will wordsmith that one up a little bit. It is still in the long term arena.

DR. NIGHTINGALE: I believe that No. 3 was voted on while I was writing it. I think I will take off No. 3, and No. 2, I will leave with the shorthand, and I have another blank piece of paper that I can write on about developing and managing reserves for times of shortage.

DR. CAPLAN: What I thought we could do for a very simple recommendation, under No. 2, is that we pursue the development of strategies for reserves and their allocation. This gets back to what Paul was asking about, about having a model, but it does seem to me if shortages -- shortage is something we want to get away from, but at the same time, we do need to develop a policy about reserves.

This reminds me a little bit about the oil crisis of some years ago when we sort of wanted to have a reserve, and what we are trying to get at here in pretty short language is that we want to recommend the development of a strategy for the development of a reserve for our blood products.

It is pretty straightforward, but it seems to me that would be a reasonable thing to be exploring. Basically, we are trying to say pursue strategies for the development of reserves, plasma and blood products, and for their allocation.

DR. PENNER: So moved.

DR. CAPLAN: Second?

MR. WALSH: Second.

DR. CAPLAN: Any other discussion? All in favor of what is now 3?

[Show of hands.]

DR. CAPLAN: Opposed? Okay.

DR. NIGHTINGALE: What is now No. 4 -- it is still No. 4 -- industry and NIH should support the scientific evaluation of the various indications for intravenous immunoglobulins and the doses appropriate for each indication.

DR. GOMPERTS: I think scientific research at the present time is going to take away product for questionable uses, uncertain uses, away from the acute emergency situation. So, this should be prefaced once the supply shortage is dealt with, but in reality, this is ongoing anyhow.

DR. PENNER: I think this is redundant. This is part of the strategies that industry is going through constantly, as well as the number of investigations around the country, to determine what is effective and to try to establish efficacy. I don't think they need any urging, but maybe the committee feels differently. Would you agree?

DR. GUERRA: I am not sure that it is entirely the responsibility of industry. I think that the scientific and the clinical, therapeutic community probably needs to also have some input into that process.

DR. CAPLAN: We can certainly add on the development encouragement of the evaluation here for industry and clinical community. I think what we are trying to get at here is remember, we had this huge battle -- discussion now about whether off-label uses and experimental uses were impacting the supply adversely and one of the sources of shortage, so I think what we are trying to call for with this recommendation is some attempt to evaluate the use of that particular substance rather than seeing people experiment with it or stay off-label or never subject it to assessment. At least that is what is intended here. It may need a little rephrasing to get that clear, but what we are trying to suggest is development of strategies for the appropriate use, clinical use of IVIG.

DR. KUHN: Were you kind of heading towards guidelines, strategies and guidelines for off-label use?

DR. CAPLAN: Yes. Well, I don't want to have guidelines for off-label use because that probably makes me illegal or something.

DR. FEIGAL: No, it's not. Consensus statements are very useful. There is as lot of indications which will never be pursued for marketing, because the economics are not there, and the consensus statement process is very useful. What the companies can't do is promote it and advertise it unless we agree that the same evidence that the Consensus Conference accepted, we can accept for labeling, as well.

I think you have to decide what your goals are here. Are your goals to take the iffy, off-label uses for which there is really not very much evidence, and put some of those to rest by systematically studying them, or is to get together a panel of experts to help us in the interim, in the short term, to help prioritize based on our best knowledge, or is to encourage industry to seek the proper kind of scientific evidence that will lead to marketing indications for this half a billion dollar product. This is not a product that doesn't have some income to support its development in more traditional drug development.

I think those are sort of related, but different goals.

DR. CAPLAN: The goal here is one and three off that list, and it is try and develop appropriate evaluation for non-standard or non-accepted use, and to encourage industry to collect information that would lead to appropriate marketing.

DR. GOMPERTS: There was a consensus conference, I think back in '95, or was it '94? Thomas Peck has a lot more information, such as Guillain-Barre, a number of the other unusual diseases. Multiple sclerosis, for example, there are a number of Phase II studies that have been carried out and reported.

So, it is probably a good idea to reconvene either that group or a similar group to re-look at that list of diseases, and some diseases, such as chronic fatigue syndrome, almost certainly IVIG will not -- further study will continue to confirm that it doesn't work. Similarly, acute renal failure.

It is probably a good idea to reconvene --

DR. CAPLAN: I understand what you are saying. Does that phrasing that is up there capture that? I think it is developing and supporting the evaluation of appropriate indications for IVIG use, and we can add what I just said, and for marketing, appropriate marketing.

Would that fall in there

DR. GOMPERTS: The manufacturers cannot market for off-label use. We cannot distribute scientific articles in that regard.

DR. CAPLAN: Right. I understand that, but it is making sure that their marketing reflects the latest knowledge, and so forth, about appropriate marketing. Well, maybe not, maybe if we just get the appropriate marketing information, it will be there, and it will be used.

DR. DAVEY: I am wondering if we are heading towards something maybe like this, in collaboration with CDC and other appropriate agencies, develop and disseminate recommendations for the appropriate clinical use of IVIG, so that again we can capture what is new in the field, work with MMWR, if that is appropriate, and move it forward.

DR. CAPLAN: We can call that the Davey alternative.

DR. CHAMBERLAND: Actually, again, I think that just reiterates the point that Dave Feigal made, which is I think there are two different things here that are getting confused and integrated, and I think they are very separate.

One is the development of guidelines for the appropriate clinical indication, you know, here and now, whenever you do them, and then the other, which is how I read what is up there currently, is the promotion of scientific studies, clinical trials, whatever, to evaluate the effectiveness of IVIG, and those are two different things.

DR. SCHIFF: What is wrong with an NIH consensus conference on the use of IVIG, do you think it is too broad of a topic, Paul? I mean those usually are -- I am very impressed with them, having participated in one for hepatitis C

DR. McCURDY: Actually, one of the major goals or major requirements for a consensus conference is that there be a reasonable amount of data on which a so-called unbiased panel can base recommendations. What I think I am hearing here is that there are relatively little in the way of good control data on many of these indications.

What you have basically is a series of anecdotes without much in the way of controls, and one of the recommendations that is almost certainly going to come out is do some suitably controlled trials.

DR. CAPLAN: So, that is that recommendation, that is what that is supposed to capture then, to try and encourage the evaluation of appropriate indications for IVIG use.

DR. McCURDY: You could reconvene -- it wouldn't be reconvening -- but convene a new consensus conference on that, but whether it would be really very useful in the absence of good data, I don't know the field well enough to know what kind of data there are, but I suspect it's limited.

DR. SCHIFF: Well, there may be enough negative data, for example, we heard from Ed on chronic fatigue syndrome, where that was widely used, and that has not panned out, so that is sort of -- we have enough data to say -- I mean perhaps we have enough data to say these people shouldn't be treated off-label. That doesn't mean you have a consensus conference, but there may be negative data.

MS. JONES: I think we sort of addressed what I was going to say. I was going to say we could reword it to state that we could convene a consensus conference to evaluate the scientific evidence regarding the indications for use of the product, but if there are specific guidelines as to the purpose and use of a consensus conference, then, I am not so sure that is the appropriate way to go.

DR. McCURDY: There are fairly specific guidelines and usage. They are not always followed.

MS. JONES: Well, maybe we could push this as one instance where it would not be.

DR. HOOTS: Paul, in terms of that, if you were to say that you are going to look for both off-label indications, in which there was -- you know, you needed a little bit more of a consensus in the community, say, multiple sclerosis, for example, and then by contrast, look at the ones for which there was very little or no scientific data to support its use, would that, together, constitute what you are talking about? That is based on data or lack of data in both directions.

DR. McCURDY: It seems to me that you may be describing what was in our packet, a university, a group was outside the NIH sphere of influence, and presumably carried a group of university hospitals or universities as their imprimatur rather than perhaps the NIH and Federal Government.

But that looked to me as though it did just exactly what you described, and it is what, a year old?

DR. CAPLAN: Are you talking about the JAMA piece?

DR. McCURDY: Yes, the JAMA piece that talked about off-label uses and good evidence, lousy evidence, no evidence, et cetera.

DR. CAPLAN: How about this, why don't we try modifying No. 4 to say something like encourage the continued evaluation of IVIG by professional and appropriate government agencies. Again, the NIH isn't the only stopping point, although it is the most likely one.

I would like to encourage the continued evaluation and dissemination of findings, because the other problem is even though we have seen the Dear Doctor letter, even though we have seen the JAMA publication, we clearly have a problem in an area in an area that is liable to shortage about getting people to understand that they are playing dangerously with a scarce resource when they are about innovating.

DR. McCURDY: There is an alternative, which I hesitate to bring up, because it's almost certainly going to be a different institute than NHLBI that would do it, but the NIH, several of the institutes have educational programs which are set for more than one year, often several years, and that usually has a professional and a lay educational aspect to it.

They convene expert panels to go over some of the things that you have done, at least that is the way Heart, Lung, and Blood does it, and that might be -- changing physician behavior is not easy, and not done by one consensus conference.

DR. GUERRA: I think that there are some models that have been quite effective in the past, that impose some restrictions on how one can access some of these products that are in fairly short demand.

The supply and distribution points for accessing [oster] immune globulin, for example, when it was defined for very specific uses in those individuals that were being treated for acute leukemia and lymphoma or cancer, and have been exposed to varicella, and one had to satisfy certain fairly rigorous criteria before you can even access that.

I know that in the time of shortage, for example, of some of the immune globulin products, we have had to jump through a lot of hoops before we could get the number of doses that we needed for rabies exposure or suspected, you know, post-bite incident for rabies exposure, that if you don't satisfy those, you don't get it.

So, I think that one could possibly set up something like that and maybe have some distribution centers on a regional basis, maybe according to the HHS.

DR. CAPLAN: Let me just say here, before I go back to Jay, what I think I want to do is try to encourage evaluation and education about the appropriate use of IVIG. I am starting to hear some good ideas. I don't think we have to recommend them.

We might say there is going to be a restriction on access to supply. We might say there is going to be a professional outreach education effort that is sustained, but we don't have to say any of that. What we have to do is say that we have heard, and I believe, that part of our shortage today is due to off-label use and inappropriate use sometimes -- I am not sure what percentage of the current IVIG shortage is due to that, but something is going on there. We have got make sure that we encourage continuing evaluation and dissemination of appropriate use. That is what I would go for in the recommendation. That may be even shorter, I may have shrunk it, that we want encourage continuing evaluation and dissemination of appropriate use of IVIG.

In other words, I understand what we are into, a discussion about is it the NIH conference mechanism, is it having a restriction on supply. I would leave it to the Secretary to work with her agencies and advisers to tell us what is the best way to try and change physician behavior. When she answers that, we will then allow her to ascend to a lofty perch in the heavens.

Jay.

DR. EPSTEIN: I have some proposed wording for the same point. I would have the original statement as it stood, industry and NIH should support the scientific evaluation of various indications for IVIGs and dose appropriate for each indication, but then add the sentence, as an interim measure, DHHS should facilitate the development and dissemination of IVIG treatment guidelines. I think we sort of decided there are two points.

DR. CAPLAN: You want to hand that, just pass that over to Steve.

DR. PENNER: I would like to just add that the United States Pharmacopeia has a panel that reviews drugs, medications yearly for the Pharmacopeia, and their panel would be able to provide the information on a non-labeled use.

DR. CAPLAN: AME, statements that come out once in a while on that tech assessment thing they do once in a while, so there are ways to jog it. Jay's statement is coming up to you there in a second.

While we are doing that, not to drive you completely crazy, didn't we have a recommendation up there right under that, about the NIH Consensus Conference on recombinant, which I bet we could vote through pretty quick. This was something that Paul said was being contemplated. You will see it up there, 5, consensus conference by NIH on use of recombinant products for patients with bleeding disorders, that we think this is a good idea, we would like to see it.

DR. HAAS: So move.

DR. GUERRA: Second.

DR. CAPLAN: All in favor?

[Show of hands.]

DR. CAPLAN: Opposed? Okay.

Mac, are you trying to copy that thing from Jay? Okay.

DR. EPSTEIN: How is this different than the short-term recommendation, which is already voted? We have already decided to recommend availability or recombinant products to all those who would benefit.

DR. CAPLAN: Just in tandem with. We could actually move that next to one another. I don't have any problem with that, if that fits in better with the short-term part of that pattern about encouraging, we will move it there. It may fit better there.

What is under there while you are hanging around?

DR. NIGHTINGALE: No. 6 was the recommendation, industry expand capacity to meet anticipated demand. I was not the originator of this. I merely wrote it down.

DR. CAPLAN: We are trying to encourage the industry to quickly expand capacity to meet the anticipated demand. This may be coals to Newcastle phenomena, so I don't know.

DR. PENNER: But it is showing support for their efforts to expand as they have been at identified for us.

DR. GUERRA: I would add to that, because I think it is an important consideration, and it was made by the representative from the American Red Cross, that they probably could get into the marketplace and come out with an array or products that would help to offset some of the shortages. If industry includes the not-for-profit sector, then, I think --

DR. CAPLAN: Yes, it would, for the sake of this.

DR. GOMPERTS: On this particular point, traditionally, industry, when there is a shortage, has responded to the shortage by increasing production and increasing capacity, and there have been shortages in the past, and that is how those shortages have been met.

By and large, this one is unusual on the basis of the duration of the shortage. I think this is an excellent proposal, but I would amend it to say that FDA work with industry in the expansion of capacity, because clearly, the capacity has to be licensed.

DR. PENNER: Move.

DR. SECUNDY: Second.

DR. CAPLAN: Discussion?

DR. EPSTEIN: I would reverse the word order only because it is the industry that does the expansion. Industry should work with FDA to expand. We don't expand.

DR. CAPLAN: With that minor adjustment, all in favor?

[Show of hands.]

DR. CAPLAN: Opposed? Okay.

Have we got the other one written up there, the Epstein version?

DR. NIGHTINGALE: The motion No. 4 now reads industry and NIH support the continued scientific evaluation of various indications for IV immunoglobulins and doses appropriate for each indication and dissemination of the results of these studies. As an interim measure, DHHS should facilitate the development and dissemination of IVIG treatment guidelines.

DR. CAPLAN: Do I hear a motion?

DR. SECUNDY: So move.

DR. CAPLAN: Second?

DR. HOOTS: Second.

DR. CAPLAN: Discussion? All in favor, so signify.

[Show of hands.]

DR. CAPLAN: Opposed? That looks unanimous.

DR. NIGHTINGALE: Finally, No. 7. I wrote down we should explore antitrust implications of efforts to share data in order to prevent shortages.

DR. CAPLAN: What we are trying to do here is encourage the Secretary to examine the antitrust problems that surround managing the blood supply. I am trying to be careful and not trying to suggest too much because, as I was indicating before, we have a lot of bigger fish out there besides the blood industry when you are into antitrust.

At the same time, we do know that blood is treated somewhat separately, because of the special nature of the product, so that may not be quite the best language, but it is an attempt to sort of encourage an exploration of ways to make sure that antitrust is not hindering the availability of safe, adequate supply.

MS. JONES: Are you asking the companies to share production information among themselves or are you asking them to share this information with the agency?

DR. CAPLAN: Neither. What I want the Secretary to do is explore both those questions. That is to say, I don't know that they can do either.

MS. JONES: They can do one, but not the other.

DR. CAPLAN: Right, and maybe the could do both. After we got together the largest number of lawyers ever assembled in the history of humanity -- I understand what the problem is here. I am just asking that it be explored, whatever the hindrances are. We may get a report back that the hindrances are too big, and they are not going to do that.

MS. JONES: Personally, I don't believe that they can share this information among yourselves. I don't think there is any difficulty in them sharing the information with the agency, and the agency coming out with some report of some sort that does not identify the individual company information.

DR. NIGHTINGALE: I think that part of the original discussion around this proposal implied at least a desire to protect the companies, and that the exploration was to be for their benefit, and not just for the benefit of the public.

DR. HOOTS: Carolyn, in terms of clarification, does that mean that companies, if they are designated as Companies A, B, and C, submit their data, say, to the FDA, and the FDA can make that information public even if there is the possibility, if you know enough numbers, that you could figure out who Company A, B, and C are?

MS. JONES: Generally, if you can figure out who the companies are, you can do it. There must be a way to blind that information.

DR. HOOTS: We have heard enough data here even, in the public arena, that you could probably could put together some sort of surmise if you are following longitudinally.

DR. CAPLAN: Don't say that. We want to continue to encourage the flow of data.

Let me back up here just to ask the question, do we want to encourage an effort to explore the ways in which these -- either call them antitrust, and we could in business issues influence the sharing of data in order to prevent shortage, or do you not want to go there?

DR. SECUNDY: I want to go there, but again, are we specifying who is going there? It an awfully vague, who is going to explore the antitrust?

DR. CAPLAN: On this one, the Secretary would be asked to tell us.

DR. SECUNDY: She would decide. Okay. Or request the exploration. Really, it is not in her bailiwick either, but she could request the exploration of antitrust implications.

DR. NIGHTINGALE: We do have an Inspector General, Ms. Robb.

DR. CAPLAN: In one sense, that is a pretty radical recommendation because it is asking for a look at something that would be very different from the way things are, if you take the exploration fully. I think it is worth doing just as a long-term issue. I don't know, we will get a change, but I think it's worth doing.

Do I have a motion on that one then?

DR. SECUNDY: So move.

DR. PENNER: Second.

DR. CAPLAN: Discussion? All in favor?

[Show of hands.]

DR. CAPLAN: Opposed? No. All right.

Now, I feel duty bound to ask the question -- no, I still have to ask one other question -- we have taken you through a series of recommendations from today, short term and long term. Is there anything else that anyone wants to put forward? Paul.

DR. HAAS: We heard earlier today about some work that Red Cross and others were doing, looking into CJD types of issues and how to detect, et cetera. I think we ought to be thinking about a recommendation to get more NIH or whatever support, so that that research is broadened as opposed to just coming out of one sector.

DR. CAPLAN: We want to recommend broader support for --

DR. HAAS: Government dollars.

DR. CAPLAN: -- broader support from appropriate agencies for CJD and other TSE diseases, is that -- I am just looking for language here.

DR. HAAS: I don't know if we want to put it just there, or other emerging diseases or whatever, but the important thing in my mind is that we shouldn't be just expecting one entity to carry that type of research forward. That is research that impacts broad communities.

DR. CAPLAN: I do remember in our last meeting, as part of the TSE, we did recommend an effort be made to survey and do research on the TSE's across the board.

DR. HAAS: So, reiterate it.

DR. SECUNDY: We need a report back.

DR. CAPLAN: Okay. What we will take there, Steve, is just a note that the committee would like to repeat its concern, go back to the older recommendation, we will put it right back into this one, because we have something actually there. We will just fire it back in and say this continues to be a pressing concern of ours.

DR. PENNER: That does affect this present --

DR. CAPLAN: Present issues about blood product, yes.

DR. PILIAVIN: I would like to get that report, too, if we want to put that in there to see, you know, what have they done since we asked them last time.

DR. SECUNDY: Didn't we specify a time that they were supposed to get back to us?

DR. CAPLAN: I think we did. Six months, I think, I think we did.

DR. NIGHTINGALE: Your first recommendation was report on the risks of TSE's and you requested it within a six-month time frame. What our response, the Department's response was that we anticipate that report in roughly that time frame, however, there are some rapidly evolving issues specifically, there are a number of meetings in early June at which new information is expected to be released which would affect the writing of that report.

So, the Department is not committed to respond to you within a 180-day time frame, but as close to 180 days as is practical.

MR. WALSH: Mr. Chairman, can we look at that allocation, develop the allocation program or evaluate the allocation proposal just real quick? Was that intended to include our specific discussion regards direct consumer allocation for blood derivative products?

I think I made the motion, but I should have clarified whether was intended to mean -- we might want to either make a separate motion to evaluate the structure of a direct consumer allocation program.

We have said to look at allocation programs in the recommendation, but I don't know if that is clear enough.

DR. SECUNDY: Reallocation of raw materials?

MR. WALSH: No, not the raw materials. It relates to --

DR. CAPLAN: I know exactly what you are talking about. I am trying to remember where it was on the overheads.

DR. SECUNDY: The emergency supplies?

DR. CAPLAN: Instead of doing that, since I know what you are trying to get at, and since we are taping and we can catch up to this, you would like to reflect the fact that --

MR. WALSH: That paragraph or that recommendation include a specific reference that we explore a direct consumer allocation of blood derivative products.

DR. CAPLAN: I understand. I don't think that is actually where we were at, Steve. What we will probably have to do is go back -- there was a recommendation that I don't think is on that sheet. What we are looking for to modify it when we find it to make sure that we explore the option of direct consumer allocation. I understand what you are asking for.

MS. JONES: For the retreat in August or whenever it is scheduled, I think it would be helpful for the committee to have a list of the recommendations that we have made in a format and a status report on where they are rather than this open kind of discussion, because I think ti is very difficult to remember what we have decided upon in previous meetings.

I think if we had it laid in some sort of tabular form, we recommended this --

DR. CAPLAN: So, you are asking if staff, by the time the retreat comes, could present all recommendations that have been done on the various topics we have looked at, and maybe have a column that said response.

MS. JONES: Yes.

DR. NIGHTINGALE: You should, and we will anticipate this being provided to you.

MS. JONES: Thank you.

DR. CAPLAN: Any other recommendations? Well, the chair would like to thank the committee for a lot of hard work. I don't think we put it in a recommendation, but I do want to acknowledge the fact that we did get some data for the first time on some of the supply things, and I think that should be commended.

I thought that the presentations we heard were first rate on this, and I think it may have been Adam Smith who said this, I think it was, who said scarcity cements the mind. It got our attention. I think we did a great job pushing these practical recommendations through, and I want to thank all of you for really doing yeoman effort in a tough project, and I hope that some of these things we are recommending really do out to relieve the difficulties that are still going to face people after we leave here, who are going to need IVIG, who are going to need alpha-1 antitrypsin treatment.

Those issues are not going to go away because of what we have done today. I hope we made some steps to alleviate the shortage, and we will try to come back to these issues at our next meeting to see how we are doing, but we are in for some tough times and no one should leave here today thinking that we have solved them, although I hope we have made some headway toward managing them.

Thanks.

[Whereupon, at 3:13 p.m., the meeting was concluded.]

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