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 i