Blood Safety Transcripts - April 1998

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?
Monday, April 27, 1998
8:00 a.m.
Holiday Inn
2101 Wisconsin Avenue, NW
Washington, D.C.

C O N T E N T S

P R O C E E D I N G S

DR. NIGHTINGALE: Good morning. If people could identify themselves for the microphone, beginning with Dr. AuBuchon and moving around, please.
DR. AUBUCHON: Jim AuBuchon, Dartmouth.
DR. BUSCH: Mike Busch, UCSF.
DR. GILCHER: Ronald Gilcher, Oklahoma City.
DR. GOMPERTS: Edward Gomperts, Baxter-Fenwalt.
DR. GUERRA: Fernando Guerra, Director of Health in San Antonio.
DR. HAAS: Paul Haas, Bowling Green.
DR. HOOTS: Keith Hoots, University of Texas, Houston.
DR. KUHN: Dana Kuhn.
DR. PENNER: John Penner, Michigan State University.
DR. SCHIFF: Gene Schiff, University of Miami, Miami, Florida.
DR. GRACE: Marian Grace, Howard University College of Medicine.
MR. WALSH: John Walsh, Alpha-1 Foundation.
DR. CAPLAN: Arthur Caplan, from the University of Pennsylvania.
DR. NIGHTINGALE: The ex officio members are?
DR. MCCURDY: Paul McCurdy, National Heart Lung and Blood Institute.
DR. EPSTEIN: Jay Epstein, Food and Drug Administration.
DR. FEIGAL: David Feigal, Food and Drug Administration.
DR. CHAMBERLAND: Mary Chamberland, Centers for Disease Control and Prevention.
DR. PILIAVIN: Jane Piliavin, University of Wisconsin.
DR. NIGHTINGALE: And, Richard Davey, American Red Cross, who has recently joined us as a member of the committee. Welcome, Dr. Davey.

The agenda for this morning is to determine what has caused the current shortage of plasma derivatives, and what can be done to correct this situation. At its last meeting, the committee recommended, among other things that the Food and Drug Administration work with industry and appropriate consumer groups to relax current Jacob-Creutzfeldt disease guidelines on quarantine and withdrawal of blood products to the extent necessary to relieve product shortages. Implicit in this resolution was uncertainty regarding the relative contribution of these guidelines and other factors to these product shortages. This meeting has been convened to address this question.

To achieve this goal, we have attempted to represent all parties who may have information about this issue, or who may have a stake in the outcome of the committee's deliberations on this. If there are those who feel they have additional information of which the committee should be aware, or who feel their stake in this issue has not been recognized, they have the opportunity to address the committee directly tomorrow morning during the period reserved for public comment. I would request, but not require, that those wishing to speak during that period inform me of their plans.

The following announcements are made as part of the public record to preclude even the appearance of a conflict of interest at this meeting. General applicability has been approved for all participants. Unless particular members will be addressed by this committee on issues dealing with specific products of firms, it has been determined that all interests reported by the committee members present no potential conflict of interest at this meeting when evaluated against this agenda.

In the event the discussions involve specific products or specific firms for which the members may have a financial interest, the participants are aware of the need to exclude themselves from such involvement, and their exclusion will be noted for the public record. With respect to all other meeting participants, we ask in the interest of fairness that they address any current or previous financial arrangements with any firm or product upon which they may wish to comment.

Because the wording of the standard announcement might be confusing in the context of today's agenda in which individual companies are scheduled to make presentations, I will read into the record the portion of the Code of Federal Regulation on which they are based. This is in particular Title XVIII US Code 208(b)(3) which is paraphrased:

A waiver of the disqualification statute may be granted by the employing agency to a special government employee -- that is the members of the committee and the consultants -- serving on an advisory committee if, after review of the SGE's financial disclosure report, the agency officially certifies in writing that the need for the SGE's services outweighs the potential for a conflict of interest created by the otherwise disqualifying financial interest.

This is the blanket waiver that all the committee members have received, but because we have asked committee members to serve us we feel that it is in their best interest that they understand the specifics of the law which are in Section 208(b)(2).

A special government employee serving on an advisory committee, within the meaning of the Federal Advisory Committee Act, may participate in any particular matter of general applicability where the disqualifying financial interest arises from his on-federal employment or non-federal prospective employment provided that the matter will not have a special or distinct effect on the employee or the employer, other than as part of a class.

For purposes of this paragraph, disqualifying financial interests arising from non-federal employment does not include the interests of a special government employee arising from the ownership of stock in by his employer or prospective employer.

Example number one, which is specific to the committee, a chemist employed by a major pharmaceutical company has been appointed to serve on an advisory committee established to develop recommendations for new standards for AIDS vaccine trials involving human subjects. Even though the chemist's employer is in the process of developing an experimental AIDS vaccine and, therefore, will be affected by the new standard, the chemist may participate in formulating the advisory committee's recommendations. The chemist's employer will be affected by the new standards only as part of the class of all pharmaceutical companies and other research entities that are attempting to develop an AIDS vaccine.

At this point, I will turn the microphone over to Dr. Arthur Caplan, who is the chairman of the committee.

DR. CAPLAN: Well, good morning. As you recall from our last hearing, we spent time both talking about where the policy was with respect to our recommendations on hepatitis C look-back, and we engaged in an examination of some of the challenges posed by the safety of the blood system by transmissible spongiform encephalopathies, TSEs.

Among those were Jakob-Creutzfeldt, and that let us to a discussion about blood products that might be in short supply. We took a position at that time about the recall practices that had been used out there, and might be implicated in creating shortage of immunoglobulin and other blood products. At the end of the hearing, after much discussion, the committee was very insistent that we try and understand why there is a shortage.

I can tell you that the chair has listened very carefully to that, and asked staff, particularly Steve, to work hard to put together a hearing where we would get a fair review of the issue of scarcity. So, that is what we are going to do. I think we owe it to those who rely on blood products to understand that issue. I think the American people expect an answer about why a vital set of substances might not be in adequate supply to meet demand. So, I think the staff has done a great job of working hard to put together what I think will be an important couple of days of testimony, and I hope we get progress in understanding exactly what the reasons are behind the shortage of blood products so that we are not put in a position to have to make choices, if they can be avoided by having an adequate safe supply of blood and blood products.

At this point, if Eric is ready to go, I am going to ask him -- he is standing in for Dr. Satcher today, not speaking for him but speaking as him, or something. Eric is someone who has been serving as liaison for this committee to the administration and Sec. Shalala. He is the Director of the Office of HIV/AIDS Policy and handles many matters pertaining to blood at HHS.

DR. GOOSBY: Welcome to the meeting. I apologize for being a little late. I had a lot of trouble finding this place, but that is my problem, not yours. I also have strep throat.

I want to welcome you to the meeting. Dr. Satcher has been called to the White House this morning for a tobacco discussion, and discussion about some problems they are having around that dialogue, unexpectedly, and he asked me to express his regrets for not being here with you today. This has been a high priority on his new list of activities, and I think you will see from Dr. Satcher a real sustained interest in the issues of this body.

I cannot overemphasize the importance of the subject of this meeting today. We simply cannot tolerate a shortage of life-sustaining blood products, whether they be blood cells, platelets, immunoglobulins, clotting factors or whatever. The human resources that are needed to create these entities, as well as recombinant technology or a combination of the two must be better understood, both in their ability to serve the needs that are currently present and the demands that are being made, but also be in a position to anticipate unexpected demands.

It has been a long and difficult struggle to develop these products, beginning with the work of Dr. Charles Drew, in the '40s, and continuing today through the work of those who are guarding our blood supply against the potential threat of newly emerging infections. Their contributions, however, are no less important than those of the individuals who voluntarily donate blood and plasma each year.

It is partly because of our blood supply demands that they depend equally on the very best of our medical research establishment and on the voluntary contributions of so many members of our society that blood is unique in the public trust. However, blood is also unique because all members of society realize that they may need this resource at any given point in the future in an unexpected fashion, and they trust us to ensure that it will be available to them when needed. We cannot betray this trust.

It is obvious that blood is not a single compound like penicillin. We fractionate blood and clone the genes that code for its components because different people need different parts of it. When we do this, we must be sure that these components are distributed equitably. Our obligation is to ensure that all members of our society have access to the component of blood that they need. Shortage of one blood component is of no less concern that the shortage of all blood components.

I want to review some of your questions and issues around the hepatitis look-back. Last August, the advisory committee considered, at your request and our request, the subject of how to best deal with transfusion recipients who may have been inadvertently exposed to hepatitis C. This risk arose because the donors who had tested negative for hepatitis C at the time of the donation subsequently tested positive for this infection.

In January, Dr. Eisenberg, who is the Acting ASH, communicated Sec. Shalala's response to your recommendations, which was to support them fully and, as you will recall, to go beyond them.

On March 20, 1998, the Food and Drug Administration published a guidance to industry which informed the industry and the public of its intent to require direct notification of all those who received blood from a donor who subsequently tested positive for hepatitis C, by a multi-antigen test which became available in mid-1982. The FDA is committed to proceed with the development of this guidance in accordance to established regulatory policy into a notice of proposed rule-making by the end of July, and to work with the Health Care Finance Administration to prepare as soon as possible a regulation for the blood banks that the HCFA administration is responsible for.

You also recall that Sec. Shalala's directive was for us to reach all patients at risk for hepatitis C, and not just one group of prior transfusion recipients. The Centers for Disease Control and Prevention submitted to Dr. Satcher, on April 10, a comprehensive plan for the prevention and control of hepatitis C virus infection that outlines the national strategy to prevent and detect hepatitis C virus infection, control hepatitis C-related chronic disease, and evaluate the effectiveness of these efforts. Dr. Satcher and the Blood Safety Committee is committed to support this plan and to help identify the funds necessary to implement it.

In January of this year, you considered at our request the potential threat of the transmissible spongiform encephalopathies to the safety of the blood supply, and you made five specific recommendations to us.

The first of these was that an expert Public Health Service group prepare a comprehensive report on this issue. That expert group is now being established. There is much happening in the field right now, and it may be advantageous to defer completion of this report until some of these issues are clarified or settled, however, we will complete this task as soon as circumstances permit.

Second, you recommended that the Public Health Service, professional groups and patient advocates emphasize the importance of postmortem examination to the protection of the public health, and that they support the training of physicians to recognize new pathological patterns of emerging disease and autopsy tissue.

We agree with this recommendation, and we would respond that these are components of existing Public Health Service policies and programs, including our direct surveillance of morbidity and mortality in hemophiliac populations. We will reemphasize the importance of these recommendations whenever the opportunity presents itself.

Thirdly, you recommended nationwide standardization procedures for screening donors at risk for transmissible spongiform encephalopathies. As you know, the FDA did establish criteria for this activity in 1985, and they are working actively with the National Heart, Lung and Blood Institute of NIH to develop and test the effectiveness of additional screening procedures.

Fourth, you recommended that the NIH specify its needs for research and infrastructure support necessary to promote research on the transmissible spongiform encephalopathies, with particular reference to human and animal tests which can discriminate among those conditions within each specie.

We struggled a bit with this because the NIH is usually not reticent at budget time but, in all seriousness, we share your perception of the importance of this research, and we will ensure that this subject remains among the highest research priorities at the institute.

Finally, you recommended that during the next year the FDA work with industry and appropriate consumer groups to relax current CJD guidelines on quarantine and withdrawal of blood products to the extent necessary to relive product shortages.

This is a complex recommendation, as I am sure you realized when you made it. First of all, it was not completely clear to all of us last January to just what extent these quarantines and withdrawals had actually contributed to product shortages. That is why we asked you to address this subject in your meeting today and tomorrow. At the same time, the FDA is exploring a variety of options to achieve the effect that both you and we desire to increase availability without compromising safety.

Let me conclude with a comment about the role of the advisory committee in the development of blood policy. In the past, as I see it, blood policy has been largely driven by concerns over safety, availability and trust. At present, blood is extremely safe from known pathogens. Genomic amplification technology appears capable of closing the so-called window between the time a donor becomes capable of transmitting HIV, hepatitis B, or hepatitis C and the time when immune response to these pathogens can be detected. Furthermore, the federal government has devoted substantial resources towards surveillance for, and developing effective countermeasures against emerging and reemerging pathogens that might be transmissible through blood or blood products.

In the meantime, further developments in donor evaluation, and the prevention of human error in blood processing may be possible, and these are areas that I would encourage the advisory committee to consider.

Availability, as we have talked about before, and I will repeat myself only briefly here -- we simply cannot tolerate shortages of life-sustaining blood components. It is fully recognized that availability is a complex interaction among manufacturing, marketing and regulation, but this interaction must not be allowed to fail. I appreciate your efforts to advise us how best to correct this situation and prevent its recurrence, and I look forward to receiving any recommendations you may have.

However, to be clear, we are committed to working with the recipients of these products, the manufacturers and the regulators to position ourselves optimally to be in an anticipatory posture around issues of availability. It is our hope that the deliberations today will further this effort.

The third and final issue that has driven blood policy ever since the AIDS epidemic is the issue of trust. An important lesson that we have learned from the AIDS epidemic is the importance of the public's trust in the blood supply, both perceived and real, and how difficult it can be, once transgressed, to restore it.

All the principles that combine to develop an atmosphere of trust around an issue, each component and each principal who participates in that -- the industry, the recipients of the blood, as well as the regulatory overlay, play an important role, a critical role in establishing the foundation of trust, that issue being truth. To fully inform, to be honest without certainty, and to be willing to accept responsibility for the outcome are the essential components that we must bring to our dialogue and keep in our dialogue.

I urge you in your discussion today and tomorrow, and in your actions thereafter, to do whatever, and to do everything in your power to support and, when necessary, improve trust in the safety of the blood supply, trust in its availability, and trust between its producers and recipients. Thank you.

DR. CAPLAN: Art, will you take questions?

DR. GOOSBY: Certainly.

DR. CAPLAN: Questions? Comments? [No response]

Well, thank you, Eric. I think you have gotten us off to a great start in terms of particularly emphasizing the issues of trust. I think the committee understands full-well that one way to cement that trust is to make sure that the discussions move in a public and accountable fashion. I hope we get progress over the next two days in answering some of the questions that have arisen with respect to shortage and availability.

MS. CHAMBERLAND: Would it be possibly for Dr. Goosby to make that statement available to the committee since he was reading it?

DR. GOOSBY: Certainly.

DR. CAPLAN: Mary wanted to make sure you all had a copy of the statement, and we will get that to you.

All right, without further ado then, in the interest of what is going to be a full day of information provided to the committee, why don't we ask Dr. Winkelstein, our first witness and presenter today. Jerry Winkelstein, Professor of Pediatrics at Johns Hopkins. He has graced us with his presence before, and it is good to have him come back. He is going to talk to us just a little bit about how immunoglobulin is used in the battle against immune deficiency disorders.

DR. WINKELSTEIN: Thank you. My job is easy over the next two days, which is to simply inform you about how this product is of benefit to patients with immune deficiency diseases. If I can have the first slide? And, I think I will need to have the lights down and the slides moved ever so slightly.

What I am going to do in the next 20 or 25 minutes is refresh your memory of what the immune system is like; how immune globulins function; what are some of the primary and secondary immune deficiency diseases; give you an example of two of the different primary immune deficiency diseases since that is an area that I work in; and then give you the evidence that this product works very effectively in both helping patients with primary immune deficiency diseases, as well as some of the secondary immune deficiency diseases.

For those of you who are far distant from your basic science course in the immune system, I will refresh your memory and say that the basic function of the immune system, the function that ties all disparate components together, is to recognize foreign material which may be bacteria, viruses, transplanted organs, pollens, whatever is foreign to the body and then to react against that foreign material by either killing the bacteria, rejecting the transplanted organ, or creating inflammation under a variety of conditions.

The component of the immune system which is of special interest to this group are the immunoglobulins. These are produced by B-cells, eventually through plasma cells. Three different major classes of these kinds of protein molecules are produced. This is the prototypic immunoglobulin G molecule. As an aside, this is the molecule which makes up well over 99% of the content of intravenous gamma globulin. It has two different ends, if you will. On the left is the portion of the molecule that combines with the foreign antigen, as I said, whether that antigen be the pneumococcal germ, polio virus, pollen or even a transplanted organ. When the two different antigen combining sites that you see on the left combine with the antigen physically, much as a lock and key or a three-dimensional crossword puzzle, there is a perfect fit for certain microorganisms, depending on the kind of gamma globulin or immunoglobulin molecule. This translates into changes in the right side of the molecule, which then allows it to subserve a number of different protective functions.

For those of you that are chemically oriented, there are two heavy chains and two light chains, and the variable portions of the heavy and light chains, in the cross-hatching on the left, is actually a three-dimensional picture, or should be a three-dimensional picture that fits perfectly with a variety of different kinds of microorganisms. That is immunoglobulin G.

Immunoglobulin M, you can see, has the same sort of bilateral symmetry with two heavy and two light chains, but it is five molecules put together through a "J" or joining chain. This is a much more efficient molecule and it is made quicker than IgG but lasts a much shorter periods of time.

The third major class of immunoglobulins is immunoglobulin A. This is the secretory form of the molecule which also has bilateral symmetry, with the left two molecules joined, one of the left and one on the right, into a secretory immunoglobulin. This immunoglobulin is specifically designed, if you will, to make its way to mucous membranes and surfaces of the body. Whether that be tears or pulmonary secretions, the middle ear, uterine cavity, the gallbladder and intestine, this comes out into secretions. But it is the first one which is found predominantly in IVIG.

Now, there are four major protective functions of these immunoglobulin molecules, and for the most part now I will be talking about IgG, or the first one that I showed you. One is opsonization, whereby the molecule fits on top of some microorganism, such as a pneumococcus or H. influenzae, and makes it more readily available and more readily ingestible by phagocytic cells. But immunoglobulin can also neutralize viruses, much the way immunoglobulin in the '40s and '50s was used passively to protect young children from polio. So, it may neutralize a virus and not allow it to enter into the host cell.

Yet a third way in which immunoglobulin works to protect us against infection is to neutralize toxins that are produced by certain microorganisms, the best known of which would be perhaps tetanus as well as diphtheria. Here it doesn't protect us against infection but, rather, it neutralizes the toxin that the infectious agent, such as tetanus, releases which will cause damage at a distant site.

The fourth function that is protective of immunoglobulin is that it activates a mediator system, called the complement system, which expands, if you will, by a factor of 2000 or 3000 its ability to do its job. The complement system is an important mediator. Some people have said that immunoglobulin is like the starter motor and the complement and phagocytic systems that depend on immunoglobulin for recognition are more like the real car or the engine.

This is a graphic representation. In fact, these are pneumococcal germs that have been incubated in immunoglobulin specific for this kind of pneumococcus, and then stained with a dye that fluoresces. This is really a very graphic representation of the pneumococcal germ, a very common cause of meningitis and pneumonia, middle ear disease and sinusitis in children and adults, and this is the pneumococcus that has been coded with immunoglobulin. This is just a graphic representation, if you will, of one way in which this immunoglobulin works because, after coding the microorganism, it causes its ingestion by phagocytic cells, or lends this phagocytic cell a leg up, so to speak, in its ability to ingest the bacteria. The cell right in the middle, which happens to be mine if you are interested, is a phagocytic cells that is ingesting the antibody-coded or immunoglobulin-coded pneumococci which, you can see, is the diplococcal forms around the nucleus.

Once this has occurred, for most part the battle has been won. So, immunoglobulin is critically important in giving the host or the individual with the infection an advantage over the microorganism, and this is the way, for the most part, that it does it.

Now, there are two general categories of patients who are either born or acquire abnormalities in their immune system or deficiencies. The first, although not the first recognized but the first that I will speak about are called primary immune deficiency diseases, and these are disorders or deficiencies of the immune system in which the primary defect is intrinsic to the cells or tissues of the immune system. Many, but not all, are genetically determined.

Some of the examples of these -- there are over 70 -- are listed on this slide. As a matter of fact, these have been selected not for this talk, but it turns out they have also been selected for this talk for listing on this slide because most of these -- no, all of them are treated with intravenous gamma globulin. These are just six or seven of the 70 that are known to exist however.

The secondary immune deficiency diseases are also disorders or deficiency of the immune system in which the defect in the cells or tissues of the immune system is not intrinsic but is secondary to an extrinsic agent. You are all very familiar with examples of some of these secondary or extrinsic deficiencies, or deficiencies due to extrinsic factors.

One of the leading causes of secondary immune deficiency diseases is cancer. Chemotherapy used for either cancer or other disorders can cause secondary immune deficiency. Radiation, whether intentional or whether by accident, can cause an immune deficiency disease. Certain medications, such as steroids, can cause a secondary immune deficiency. Even burns can cause a secondary immune deficiency and, of course, viral infections can cause a secondary immune deficiency.

An example of cancer that I will talk about later, in which IV gamma globulin is used in which there is an immune deficiency that can be corrected, at least in part, is chronic lymphocytic leukemia. Certainly, an example of a viral infection that causes an immune deficiency disease in which IV gamma globulin has been shown to be of some help is HIV infection. But I should mention that this is not the only viral infection that can cause a secondary immune deficiency disease.

Well, that puts everything, I hope, into context. What I do mostly is see patients with primary immune deficiency diseases. So, for obvious reasons, I will focus the middle third of this discussion on some of the primary immune deficiency diseases.

There are over 70 different disorders. The list grows. Last week two or three new ones were added at the federation meetings in San Francisco. These deficiencies, in one form or another, will involve virtually every functional compartment of the immune system. These were originally felt to be very uncommon, if not rare, disorders, and they are really not. In fact, when taken as a group of disorders, which is operationally the proper way to view these diseases, these diseases are as common or possibly more common than childhood leukemia and lymphoma put together.

Originally these diseases, because they were originally viewed as very serious diseases and the worst cases were initially evaluated or discovered first -- these diseases were felt to be limited to infancy and childhood. That too is not true. In fact, well over 50% of the patients in the United States are well into their 20s, 30s, 40s, 50s and 60s. So, over half of these patients, even though many of the diseases are genetically determined, are clearly well into adult life.

The third problem that people have, or the third conception is that these symptoms were originally felt to be only severe; that a relatively well person who limped along in a job or school could not have one of these diseases. Nothing, again, could be further from the truth. In fact, the symptoms can vary from relatively mild to relatively severe, depending on the disease and how well they are treated.

Now, the first disorder I am going to go through quite briefly is X-linked agammaglobulinemia. I am presenting it for two reasons. One is that it was the first primary immune deficiency disease to be discovered, published actually out of Walter Reed Army Hospital, just a few miles from here, by Dr. Bruton. This was a landmark case and opened up the field, if you will.

The children are characterized, all boys of course because it is X-linked recessive, by markedly reduced levels of immunoglobulin G, A and M, the three molecules that I showed you. They have a marked decrease in function. They cannot do opsonization or toxin neutralization by antibody, and they are missing a certain cell in their body called B-lymphocytes, which is the progenitor of immunoglobulin- producing cells.

I thought I would show you what this actually looks like. By contrast, you can see what the normal molecule might look like and what the deficiency looks like. In the upper right-hand portion we are looking down on a glass slide, not under a microscope but just visually with our eyes under normal conditions. What I am showing you here, on the bottom, are some of the different serum proteins, using a technique called immunoelectrophoresis. You can see that immunoglobulin G is the large band furthest to the right. Immunoglobulin A is a little hidden by it, and you can see the spur coming down, and IgM is the fuzzy line running parallel to the bottom of the slide, which is barely discernible because I wasn't as good a photographer as I should be. The normal material that is found in IV gamma globulin is the IgG that you see as the band on the right in the lower portion of this slide. A patient with X-linked agammaglobulinemia is missing G, A and M, and his serum is on the upper portion of the slide, and you can see what is missing in the right portion of the upper part of the slide.

These are the kinds of infections that these children and adults used to get before there was intravenous gamma globulin. This is the result of a patient survey through doctors that we did about ten years ago because we wanted to get a more complete clinical picture of this illness. Recurrent pneumonia occurred in nearly 4 out of every 10 patients; meningitis or encephalitis occurred in a quarter of the patients; and blood stream infections or sepsis in 1/6.

These patients, at this point in time historically, were not being treated IV gamma globulin. It was not yet available in the United States. And, this gives you a retrospective indication of what these diseases looked like, if you will, in terms of impact on life before the days of IV gamma globulin.

The slide that I didn't get this weekend, and I apologize, and better left unshown though is that about 13% of these 96 patients died, and they died of either a very bad viral infection caused by very common viruses, or chronic lung disease from recurrent pneumonias.

These are the children that lived. Most of the children -- not most but 46% of the children, and this is in the pre-IV gamma globulin era, developed chronic lung disease -- no oxygen content or hypoxemia in their blood, and secondary heart defects from the pressure caused by the lung on the heart. Neurologic disorders, because of the meningitis and the recurrent ear infections, were not uncommon as well. Again, I would emphasize that although this slide is only 11 years old, it does reflect, unfortunately, the pre-IV gamma globulin era with only immunoglobulin by intramuscular injection was available.

This is one small example of a boy who is no longer with us, who was treated with intramuscular gamma globulin but, because of a lot of reasons, continued to have chronic lung infections and died in 1980. But this is the kind of problem that these patients have without adequate therapy.

Now, the prognosis of this disease is excellent -- with a big "if." They have to be diagnosed early. That is my job. And, they have to be treated relatively early as well. The earlier the therapy, there can be little doubt, the better the chance.

This is what can be expected now. We really have very positive feelings and very positive outcomes about this one disease and many of the other immune deficiency diseases as well. Most of the children end up getting IV gama globulin at home. There is a limited number of doctor visits. In fact, they do so well that I have to beg them or insist that they come back to see me. There is little, if any, school absenteeism; no special diets or restrictions; full activity; competitive sports. Many of my patients actually are playing college lacrosse and/or soccer.

The disease in the adult is somewhat different. Many of the patients learn to self-infuse. Most find full employment; normal activities. Their major problems is health insurance, as you can imagine, and the implications of having an X-linked recessive disease where all of their daughters will be obligate carriers and half of their grandsons will be affected -- a new set of problems, if you will.

Now, common variable immune deficiency is the second disorder that I wanted to talk about, perhaps more briefly than the first, and this is a primary hypogammaglobulinemia, or deficiency of gamma globulin in the serum, of which the etiology is not known. There are many more patients with this diagnosis than with the X-linked form of the disease. This disease affects, both in its initial onset and later years, adults equally, if not more so, than children. These are the kinds of infections, and this is from a relatively recent article out of New York City in a clinic in which both children and adults were seen. That is why I have elected to use this series as an example. These were about 103 patients. You can see that recurrent sinusitis, conjunctivitis, pneumonia were all very common; some meningitis, some hepatitis, severe viral infections such as zoster, and an occasional patient with a T-cell kind of infection, Pneumocystis carinii pneumonia.

These are the reasons that those patients in that series died. As you can see, mortality is not insignificant. There is pulmonary insufficiency from recurrent infections; hepatitis; measles and other viral kinds of encephalitides. Then this disorder, not necessarily the previous disorder, but this disorder does have a significant risk for malignancies of the same system which is abnormal, i.e., the immune system. So, lymphomas and B-cell leukemias are not uncommon, unfortunately, among patients with this disease.

In the recent three or four years, recombinant technology and the kind of revolution that has occurred in molecular genetics has made its impact on this family of 70 diseases. I have selected for you examples of seven or eight of the diseases which up till 1993 were known to be inherited but the basic molecular or genetic defect was not understood.

I won't bore you by going through the initials of different genes that have been identified, except to say that X-linked agammaglobulinemia discovered a gene and a protein that had never been known to exist until it was found to be deficient in these patients. One form of X-linked SCID capitalized on another kind of advance. The autosomal recessive form of SCID ADA deficiency has received a lot of press because it is the disease for which gene therapy was first initiated. And, the list goes on.

This has allowed molecular diagnosis so that prenatal diagnosis and carrier detection of sisters who might have a 50-50 chance of being carriers and having children of their own with these diseases -- molecular diagnosis has improved considerably our ability to understand the pathophysiology and bring genetic services to these large numbers of diseases. But it really has not yet changed the way in which we treat some of these disorders and, unfortunately or fortunately, IV gamma globulin remains the mainstay for may of these diseases, that and bone marrow transplantation.

I made this slide specifically for you. It shows some of the primary immune deficiency diseases and some of the secondary immune deficiency diseases which are treated very effectively, if not helped partially or almost completely cured by this kind of therapy. X-linked agammaglobulinemia, on the left upper portion of the slide, we have talked about. The third one down, common variable, I also showed you an example of that. I will give you some examples of the way in which this therapy has been shown to be beneficial in two of the three secondary immune deficiency diseases as well, and I think I am going to make my time slot and leave time for questions.

Intravenous gamma globulin has lots of advantages. It had to live through intramuscular gamma globulin where two or three people had to hold these children down because of the painful nature of the injections. If any of you have gotten intramuscular gamma globulin, make sure that you remember that you got a very small amount compared to the amount that would be necessary to treat these children and adults.

The advantage of IV gamma globulin is that I virtually can give any amount that I wish. It is relatively painless. It can be infused at home, but its big advantage is that it attains absolutely normal levels of gamma globulin in the patient's serum, and we could not do this with the intramuscular material.

There are some disadvantages, but they have proven to be not of any great consequence, at least up to this point in time. The material that is commercially available is intravenous gamma globulin composed almost exclusively of IgG, the first molecule that I showed you. The disadvantage is that it does not contain IgA for your secretions or IgM, and we seem to do better than people might have expected in spite of that limitation.

It does not supply as high a level of antibody or active material as you might have after being immunized either through natural infection or through one of your normal routine immunizations.

It doesn't supply antibody to uncommon organisms that those of us in this room might not have been exposed to, because this material is obtained from normal individuals rather than individuals exposed to very uncommon or rare infections. And, it is very expensive.

I will show you my last four or five slides to show you some of the clinical studies that have looked at the degree to which this material helps in these different primary and secondary immune deficiency diseases.

This is a retrospective study. There have never been controlled studies done on this material, but this is a retrospective study done out of England. You can see on the left side of the slide that they looked historically at the number of hospital days that children and adults with X-linked agammaglobulinemia had with either no therapy -- historically 14 hospital days per patient per year; or intramuscular gamma globulin at a very low dose, 16.7 -- it is actually more but not significantly so. Then when we first started to use IV gamma globulin at 200 mg or less per kilogram per month, it reduced somewhat. Then, when we finally learned to use it properly, to give the patient enough material, it really made a dramatic improvement.

There is another way of looking at this, which is the degree to which the patient was reconstituted. In the left column is the lowest level they would reach of this material after it had been given to them before they got their next infusion -- the lowest that it would reach. You can see that when you get up to greater than 500 mg/100 mL, the incidence or prevalence of pneumonia, all infections and days in hospital is remarkably lower than when you give a dose that results in a lower level of immunoglobulin in the blood.

This is a study done in Toronto, by one of my colleagues who looked at whether or not this translated into improvement in pulmonary function. On the left part of the slide is the amount of air that a patient can get out, FEV-1, in the first second. On the right side of the slide is the amount of total air that the patient can exchange in their lungs with any given breath.

You can see patients before and after therapy from six months to a year with high-dose gamma globulin. These are patients with either X-linked agammaglobulinemia or common variable, and you can see that, for the most part, the patients had a quite remarkable improvement in their lung function simply by allowing some of the ongoing infections to slowly resolve and calm down.

This is a picture out of the New England Journal article reporting the NIH collaborative trial, not in a primary immune deficiency disease, but this is actually a prospectively randomized trial for children with pediatric AIDS. The specific subset that is represented on this slide is a special subset that makes the point perhaps most dramatically. These are children that entered this controlled trial with some AIDS-defining infections and entry criteria into this group, and also with CD4 or T-cell helper counts above a certain threshold. So, they were somewhere in the middle clinically, if you will. These were children that they felt could be analyzed for the most benefit because they were not quite as sick as some other children.

This is not survival. This is really survival without a life-limiting or serious infection. This is really not mortality on the vertical axis. It is really infection-free survival, if you will. As you would guess, the individuals who received IV gamma globulin are the solid line, who had much better "survival" than the individuals who received placebo, and they are on the dashed line. This trial was stopped at the appropriate time apparently because the results were so dramatic. And, this is one of the reasons that this material is now indicated for pediatric HIV.

This is a different end of the age spectrum. These would be older individuals with chronic lymphocytic leukemia. This is my last slide. This is older individuals with chronic lymphocytic leukemia, the subset which develop a secondary hypogammaglobulinemia, become immunodeficient as a result of their CLL and, as you can see again, this is not survival but this is infection-free interval, and there is a significant improvement in statistical terms, if not human terms, between the individuals who received the IV gamma globulin, the solid line, and the individuals who did not.

I think that is my last slide. So, I will just summarize and say that this material is of great benefit in both patients with primary immune deficiency diseases and patients with secondary immune deficiency diseases. I hope I did okay with time. Thank you.

DR. CAPLAN: Exactly. Thanks, Dr. Winkelstein. What we are going to do is open the floor for comments and questions. If you will just stand there, we will let the panel direct questions to you.

DR. WINKELSTEIN: Sure.

DR. HOOTS: In the review article that we were supplied by Drs. Buckley and Schiff, in 1991, in the New England Journal, it was talking about the original World Health Organization recommendations being at minimum 1000 donors. We need to get, obviously, a lot of heterogeneity of the antibody species. But it also said that on the average it was a minimum of 3000-6000, but it requested that some sort of standardization be undertaken. Has that been undertaken? Do we have a sense of what the minimum number of donors is who would provide that kind of heterogeneity?

DR. WINKELSTEIN: That is an important question. To the best of my knowledge, there have been committees like this that have been formulated, at least one or two that I am aware of, to address that question and I don't know whether they have been able to come to a determination. In the extreme, one person is too few and one million is too many. I am not trying to be glib; I am just saying that it is going to be a difficult question to know what the answer is, and there are pressures at both the minimum estimate and the upper estimate of what pool size should be that relate to both biological as well as economic considerations. But I would not be able to give you an estimate.

DR. CHAMBERLAND: Dr. Winkelstein, could you provide us with a little bit of demographics in terms of what percentage of the population is affected with these conditions?

DR. WINKELSTEIN: I can give you estimates but, unfortunately, I can't give you precise numbers, except for one disorder which I am involved in, in an NIH contract, to look at what the minimum estimate of that disease is. That is a disease in which IV gamma globulin is not used, and I will use it only as an example of how much underestimate there has been. It was assumed that the incidence per live birth was 1/1 million, and we know of enough patients through a registry that the NIH supports where the estimate is 1/200,000, and this is a minimum estimate. So, we would guess that the estimates that I am going to give you are at least a factor of 5-10.

Having said that, it has been estimated that there are 20,000 to 40,000 patients with primary immune deficiency diseases. That excludes one important group of patients which does not receive IV gamma globulin under most circumstances. The most dramatic figure, although it does not relate to the use of IV gamma globulin, would be that 1/500 individuals have a complete absence of immunoglobulin A. If you say that is too generous an estimate and you say 1/5000 you are still talking about a quarter of a million people in the United States with that disorder. But that disorder in some patients will not be as significant as the ones that I have shown you. So, my estimate of 20,000 go 40,000 would be of the kinds of patients that I have shown you.

DR. CHAMBERLAND: Thank you.

DR. GUERRA: Dr. Winkelstein, thank you very much for a very enlightening presentation. Would you comment about the perhaps additional survival or survival that can be attributed to the use of some of the antimicrobials and antivirals that we think of as part of adjunctive therapy?

DR. WINKELSTEIN: The slide that I didn't include because of time -- I have a slide on improvement on therapy of these kinds of disorders that I show both to medical students and, if you will, lay organizations on occasion. There is a pediatric handbook, called, The Harriet Lane Handbook, which I edited in 1968 as a senior resident at Hopkins, and I compared the number of antifungals in that edition compared to the edition that came out a year ago, and the difference is 1 to 7. The number of antivirals is 1 to 15. The number of antibiotics or microorganisms is 12 or 15 to well into 100. In addition, bone marrow transplantation has occurred during my professional lifetime; better nutrition -- there are all sorts of things for the most severely affected children and adults that have helped.

Perhaps the most dramatically obvious is intravenous gamma globulin, but there is no question that other therapies that we tend to take for granted, like the newer antimicrobials, have made a significant impact, absolutely.

MR. WALSH: In one graph, Dr. Winkelstein, that showed increased efficacy with increased dosing strategies, at least to decrease the amount of hospitalization, would you suggest there is a level at which, during the shortage, there would be a minimal amount that would be appropriate?

DR. WINKELSTEIN: I wouldn't want to suggest what should be done in a shortage, sir, but I will tell you that we make every effort to keep the lowest level before the next infusion about 400 mg or 500 mg/100 mL of blood, and I would be uncomfortable telling you whether or not that can be compromised or not. But I make every effort to maintain a nearly normal trough level.

DR. GOMPERTS: Dr. Winkelstein, could you provide a little perspective? Are there side effects of this therapy, complications?

DR. WINKELSTEIN: There are side effects, and there is a very rare patient who actually may not be able to receive it although I personally, fortunately, have not had such a patient. If the infusion is given too quickly, then the patient can have fluid shifts and have flu-like symptoms of backache, heaviness in the chest even though they are not wheezing, fever, terrible headache and nausea. That is solved by slowing the infusion. Most people tend to give it too quickly because they want to get out of the room, as well as the people that are infusing it.

There can be anaphylactic reactions where you actually have IgE, the immunoglobulin I didn't show, that is responsible for most allergic disease, reacting against some of these foreign proteins. That is distinctly uncommon, if not very rare. I, thankfully, have never had a patient with that.

There can be anaphylactoid reactions, that resemble but are not the same as allergic reactions, if the material is improperly reconstituted and aggregates are given rather than completely solubilized material. In some individuals that causes the same sort of problems as an anaphylactic reaction.

There are some patients that receive very large doses for other indications than the ones that I have explained, for instance ITP or idiopathic thrombocytopenic purpura or immune-mediated thrombocytopenic purpura. Those patients on very high doses of material can develop a sterile inflammatory response in their central nervous system that resembles meningitis but is not infectious which, fortunately, resolves over a period of days but causes the patient tremendous problems in terms of how well they feel.

So, there are lots of different reactions. We have been very fortunate. We find the brand that the patient tolerates, and there are different patients who can tolerate different brands for reasons that we are not sure of, and we are able to find the proper brand for most patients, or the proper formulation, and most patients have relatively little, if any, problem with it.

DR. CAPLAN: I am going to take a question for myself and then do one more, and then we will let Dr. Winkelstein move on.

My question is this, in some of the material that we have looked at about the use of IV gamma globulin there is a suggestion that part of the reason it might be in short supply is that we are seeing more diseases for which it is appropriately used, but perhaps there is some use out there of this substance for which it is not clearly appropriately used. I am just wondering, from your clinical perspective as someone who has watched this supply over time, do you think that part of the reason shortage may arise is that we simply find more appropriate indications, or how does that weigh against people looking for new and possible uses, or even inappropriate use?

DR. WINKELSTEIN: I think you have touched on all three elements of the consumer side problems, and forgive me for calling it that. Number one, more of the patients for which this is genuinely indicated are being diagnosed. That is our job, fortunately, and we are getting better at it, and primary care physicians are slowly beginning to realize that these disorders are not as uncommon as they thought. So, they are finding more patients; they are looking more.

Number two, there are more other indications than immune deficiency diseases for which this is licensed, approved and recommended. Those patients are growing in number.

The third reason it is being used would be, I guess, indications that are either unproven but may be appropriate or unproven and not appropriate, and I think probably that might be an area, if society knows how to address that kind of problem -- I certainly don't, but if society knew how to address that kind of problem, it would be of benefit to the individuals in whom this material is genuinely life-saving.

DR. PENNER: You didn't address the anti-idiotypic properties of gamma globulin. Could you comment on that?

DR. WINKELSTEIN: Well, I am not an expert on that. That is one of the reasons I shied away from it. The anti-idiotypic value of immunoglobulin is one reasons that it has been proposed for working in disorders of inflammation and autoimmune disease. Since in the patients that I have discussed this is not a problem, not the indication, I did not include that, but it is one of about four or five mechanisms by which this material might work in either autoimmune diseases, such as ITP or lupus, but it is only one of the three or four postulated mechanisms by which the apparent paradox of giving a patient with what appears to be, if you will, an overactive immune system by having this material used as an immunomodulatory component.

DR. PENNER: And, don't some of the products have IgA in them?

DR. WINKELSTEIN: They all have a measurable amount of IgA. It is a matter of to what degree they have it, and some do have more than others. But I think it is nearly impossible to chemically purify this material, even if you were doing it in small, 10 cc aliquots, and make sure that every molecule of IgA is gone. One or two of the products are as close probably as it is possible to get it free of IgA.

DR. PENNER: Thank you.

DR. WINKELSTEIN: Thank you, sir.

DR. CAPLAN: Our next panel is going to bring a perspective of people who rely on IVIG to treat some of the medical problems that Dr. Winkelstein has been telling us about. I have John Boyle, Larry Tabor and Karen Gurwith, Roger Kobayashi, Mike Grote, Miriam O'Day and Tom Moran. What I am going to ask is that we really try to watch our time. I am not sure that every individual there is going to speak themselves. We certainly do want to hear these perspectives but, at the same time, we have to make sure that we leave room to get through the data. So, I am going to ask John Boyle to step forward.

DR. BOYLE: Good morning. The way we are trying to arrange this panel in order to get through the necessary time is that I am presenting the results of two surveys, and I will take ten minutes. Each of the other presenters will be limited to five minutes, which should still give us five to ten minutes worth of questions. In order to make sure that we are able to get through all of this, what we would prefer to do is hold the questions until we get through the entire presentation.

I am going to move back and forth between slides and overheads, and if I could begin with slide number one, very quickly I am going to present the results of two surveys. The first is a survey of physicians, the purpose of which is to be able to give you some sense of the dimensions and implications of the current shortage.

Very quickly, I want to show you that last year the Immune Deficiency Foundation conducted a survey of 15,000 specialists who are likely to treat patients with immune deficiency diseases, primary immune deficiency diseases. The survey was of approximately 1500 physicians who treat 23,000 patients with primary immune deficiency diseases. Since only 1/6 physicians returned the survey, we believe it is an underestimate. A very quick way to get some estimate of the number is that we took those physicians who we know treat patients with primary immune deficiency diseases, saw the number of returned forms, which is about half, and basically multiplied by two to say that we probably have about 50,000 patients with primary immune deficiency diseases who are treated by specialists.

To put that into perspective, in a patient survey of 3000 we found 70% of patients with primary immune deficiency diseases get IVIG. So, we are probably talking about 30,000 to 35,000 patients with primary immune deficiency diseases who are treated with IVIG.

Out of the 15,000 physicians, those who had 25 or more patients treat 15,000 compared to those with less than 25 patients who treat 8000. Consequently, we stratified the sample and took all physicians who had 25 of more patients and a random sample of those with less than 25. The total drawn sample is approximately 500, 251 with 25 or more patients and 265 with less than 25.

Of those who completed and returned that survey, which was conducted between mid-March and early April, we have 147 of the large number of patients, 101, of less than 25. Of those, 121 of the 25-plus, use IVIG; the under 25, 76. We have 197 physicians with patients using IVIG.

We asked during the past six months, did you have any difficulty in obtaining intravenous gamma globulin for your patients with primary immune deficiency diseases. Approximately 9/10 physicians treating patients with primary immune deficiency diseases, 87%, said yes, they had problems.

I am going to skip over this, but I can show you a map of the United States because we charted where these physicians are. These physicians are in every state in which we have any reporting physicians. We had no states in which physicians report they have no problem, and no other physician reports they do have a problem. This demonstrates that it is clearly a national, not a regional or area, problem.

We asked the physicians, as a result of the shortages in IVIG during the past six months, which of the following, if any has happened to you.

As you can see, those who had to contact new suppliers was 64%; had to contact manufacturer directly to get IVIG, 42%; had to change usual IVIG product, 75% --

DR. CAPLAN: John, go right back to that mike.

DR. BOYLE: Okay. Did not receive IVIG orders from usual sources, 49%; received less IVIG than orders, 48%; made special arrangements, 49%. Basically you have only 15% who had none of these problems. That includes those who report no problems. This is all physicians with IVIG patients.

More importantly, as a result of the shortages in IVIG in the past six months, which of the following, if any, has happened to your patients? Postponed scheduled infusions, 68% switched to different IVIG brand; 70% switched to less preferred brand; 51% interval between infusions increased; dosage reduced, 39%; unable to obtain product for indigent patients, 15%; substituted alternative therapies for IVIG, 18%; none of these things, only 16%.

To date, has the shortage of IVIG supply had a negative effect on the health of any of your patients? And, 45% of all treaters said yes, it has.

How much difficulty are you experiencing now -- This is late March to early April -- in obtaining normal supplies of IVIG? A lot of difficulty, 40%; some difficulty, 42%; normal difficulty, 5%; and this is 14% of those who have not had problems in the past obtaining it. The bottom line is that 4/5 physicians are still having some and 1/5 are having a lot of difficulty.

We conducted a second survey. We had an ongoing survey of 2000 patients. In April we had about 800 ready to go out. So, we included the same type of form for patients. They went out April 9 so, as you can imagine, we have not had a lot of response yet, but we do have 158 responses to date and since this is a sub-sample of a national sample, these responses may be of importance here.

Of the 158 respondents, 133 are IVIG users. Of the 133 IVIG users, 80% reported problems in obtaining IVIG in the last six months -- the same questions we asked the physicians basically.

Out of the 107 who reported problems in obtaining IVIG, 56% report adverse health effects. These 60 patients include 31 reporting that they had more infections; 9 adverse reactions to a new brand; 6 pneumonia, bronchitis and lung infections; 7 reported only stress and anxiety; and 7 said adverse health effects without telling us exactly what they were.

In summary, one of the things I would really point out is that 80% of patients report problems in obtaining IVIG, which is not that far off from the number of physicians reporting. And, 45% of all IVIG patients responding report adverse health effects. That 45% is the same as the proportion of physicians treating patients with IVIG who report that their patients are having adverse health effects.

The bottom line is that the problem is national. It is affecting the 30,000 to 35,000 immune deficient patients who are receiving IVIG. Based upon both physician report and patient report, nearly half of those patients are already reporting adverse health effects.

Thank you. We will move to the next.

DR. CAPLAN: Thank you, John.

MS. GURWITH: My name is Karen Gurwith, and I am the Director of Pharmacy at Texas Children's Hospital.

Texas Children's Hospital is the largest free-standing pediatric hospital in the United States. In addition to our inpatient setting, members of our medical staff provide primary care to 90 immune deficient patients, including HIV, 65 ITP and another 50-70 children receiving high-dose chemotherapy and undergoing bone marrow, as well as numerous other illnesses for which IVIG may be used.

As a result of our affiliation with a buying group, our purchases of IVIG have been through a single-source contractual agreement. Based on our historical review of required routine care, we established a routine shipment of 2000 gm a month, at a cost per gram of $27.50. Any additional amount we may have needed we have obtained either from the same vendor, but usually through other means such as specialty wholesalers.

In November of 1997, the routine committed shipment was unable to be delivered. In the first week of December I was on my way to a national meeting, hoping to learn more about this problem and to identify if, indeed, it was a nationwide one. I left the Assistant Director of Pharmacy in charge of what IVIG we had left, 200 gm, with the comment, "that should be okay for the week." The day after I left we admitted two patients with Kawasaki, one with Guillain-Barre, and two bone marrow patients had their need for IVIG per protocol. The physicians were asked to choose which patients were to receive the last of what we had.

Immediately, I began contacting the local manufacturer's representatives and educated them about our needs, and sought assistance in obtaining whatever supply I could. I primarily looked to companies which we currently purchase other blood products from, and hoped that this preestablished relationship would support our ability to obtain small supplies of IVIG.

Utilizing specialty wholesalers was considered. However, the price of IVIG increased as much as three to four times the average cost, if the supply was available. Once specialty company provided a package deal. You could purchase 20 vials of albumin and then you could buy 10 gm of IVIG at two to three times the average cost.

While pursuing alternative sources of product, I asked members of the medical staff to assist in determining the best method for managing this shortage. Dr. Tabor will explain this work.

DR. TABOR: Good morning, Dr. Chairman and members of the committee, and everyone else who could find a chair. I am Larry Tabor. I chair the Pharmacy and Therapeutics Committee at Texas Children's Hospital, and I am a professor of pediatrics, microbiology and immunology at Baylor College of Medicine.

Ms. Gurwith advised us of this shortage. Of course, we did what anybody else does in this country, we formed a committee --

[Laughter]

This was a subcommittee of our P&T committee, and members of this committee included key prescribers on our medical staff and, of course, legal counsel and the director of our pharmacy. We discussed this problem and tried to determine a solution, hoping that it would be temporary, of course.

Ms. Gurwith gathered together the historical review of our usage of IVIG in all patients, regardless of their diagnosis. Our legal counsel advised that we might have two alternatives. One was to use whatever IVIG we had on a first come, first serve basis. The other was for this representative committee of our medical staff at Texas Children's Hospital to serve as a triage committee and prioritize the use of IVIG.

Had we elected to the first, we would have had a three-week supply of IVIG, looking at our historical use of IVIG. So, these were our priorities. The first group was the group that Dr. Winkelstein told you about. Those were children with deficiencies of IVIG who were receiving replacement therapy. The next group of children were those with immune thrombocytopenic purpura who had platelet counts of 20,000 or below -- it makes you nervous, doesn't it? And children with Kawasaki's disease and children with Guillain-Barre. These are all proved conditions, obviously, where IVIG is effective in their therapy, and these children -- these four groups of patients represented 60% of our use.

We sent out a memo to all of our medical staff. We asked the pharmacists to serve as police officers. We had a pre-printed form, and on that form you indicated the use for which you were ordering the IVIG. If the patient did not fall into that category, the pharmacist called the ordering physician and said, "you cannot have it." The physician could ask for peer review. Peer review was a call to either Ms. Gurwith or to myself. Most usually, we turned most of the physicians down because we simply did not have the product. When this process first started, almost every physician in the hospital called, wanting some IVIG. That has tapered off as of late because they realize they will not get it.

The other thing we did, we did have a supply of Cytogam, which contains a high titer of antibody to cytomegalovirus, and we used this as an alternative for a while. But it was going fairly rapidly. So, we had to develop criteria for its use. The subcommittee and the P&T committee and the executive committee of Texas Children's Hospital all approved that any IVIG product would be interchangeable.

Dr. Winkelstein told you about some of the problems in his overall talk that we have because, as you know, individual patients may tolerate one product and not another product, and to some of the children you want to give a product that has as little IgA as you can get in a product. We could not do this. We could not be brand specific as we had been able to do in the past. So, we handled these cases individually.

The other thing we did, we requested the laboratory to do STAT IgG levels, as STAT as possible, so that we could prolong the time interval for giving children replacement therapy. Instead of giving it q. monthly, perhaps give it every five to six weeks.

Now, the use of IVIG has diminished over this last year and in 1998, with the primary decrease occurring since November of 1997. We have had a 75% decrease in patient use. Our usual usage includes 30% to children with immune deficiency; 11% to children with ITP; 15% for children with Kawasaki's disease; 4% to children with Guillain-Barre. This represents 60% of our total usage. Other usages include children who have lymphocytic leukemia or who have allogeneic bone marrow transplants; children who have some infection, such as a premature infant with overwhelming sepsis, etc; and then some other non-label or off-label uses, and that was 18%.

Because of the prioritized patient list that we established, all of our immune deficient patients have been able to receive their IVIG. That is 45 patients. We have added 10 patients to that group because they were not able to receive IVIG from their usual means.

The patients who have been primarily affected by our criteria is the hematology-oncology patient group, and our bone marrow transplant group where, as you know, IVIG is given weekly for about 100 days and then monthly thereafter. We no longer gave them routine IVIG. That was 10 patients. Children who had lymphocytic leukemia who were getting standard infusions of IVIG, we had to eliminate their use of this product. All of our children who have HIV also were eliminated from routine infusion of IVIG. So, you can see that a considerable number of our patient population was just eliminated from receiving this product so that we could give the IVIG to those children we thought absolutely were priority.

Since we initiated this, we have only given IVIG to four patients who did not meet criteria. All these patients underwent peer review, and one physician we turned down and he went to our physician-in chief, who is also chairman of our department and president of the medical school, and he was given IVIG for use in his patient. Another three children were very critically ill in the pediatric intensive care unit, and eventually received IVIG as a last therapeutic alternative by the critical care physicians.

Other children in whom we have not used IVIG have been children with systemic lupus erythematosus, in which it has been proved to be a benefit; children who came in with bacterial Group A strep infection associated with toxic shock syndrome; as I have noted, premature infants who had bacterial sepsis, etc.

The last two sentences are the most important sentences in what I have told you, and this will bring it down to you, any of you in this room who have children who may need IVIG, or even if you have children who may potentially need IVIG, we had adverse effects that we can document in a medical sense, and we are looking at this more specifically at the present time. But one of the most difficult situations for us was to explain to parents whose children had been routinely -- routinely -- routinely receiving IVIG that they were no longer able to receive IVIG. A parent understands when you tell them that something is wrong with a product and we can't deliver that product to your child. They don't understand why in this country suddenly we have no IVIG to give their children who had been receiving this IVIG on a routine basis. Certainly, these parents were very much concerned about this lack of specific therapy, and how it would adversely affect their child's overall health. Thank you.

DR. CAPLAN: I think we have Dr. Kobayashi next.

DR. KOBAYASHI: Yes. Thank you, Mr. Chairman. Permit me to adjust the microphone. I have a Japanese defect, called short stature.

[Laughter]

Good morning, Mr. Chairman, members of the committee and guests. My name is Roger Kobayashi, and I am a practicing allergist and immunologist, from Omaha, Nebraska, and on the clinical faculty of UCLA.

Thank you for allowing me to tell you that a significant shortage also occurs in the Heartland. You have heard about the statistics regarding the national shortage. You have heard about the impact on a large teaching institution in a big city, where rationing has occurred and prices have risen. You have heard about a survey where 87% of nearly 200 doctors queried reported having difficulty receiving IVIG for patients affected with primary immune deficiency.

Permit me to put a personal face on this problem. It is difficult to ration IVIG when you are personally caring for these patients on a close and intimate basis, worrying where and whether adequate supplies will be available to meet the needs of these patients. I have been a practicing immunologist-allergist in Omaha for seven years, after leaving full-time academic medicine, and have begun to serve as regional care giver for patients requiring intravenous immunoglobulin. I am privileged to care for approximately 75 to 80 children and adults receiving IVIG in a five-state area. I have been fortunate in being able to receive supplies directly from some of the manufacturers. I have also been privileged to be on their highest priority list for receiving IVIG.

However, in the fall of last year, and continuing to the present time, I have experienced significant shortages where, from day-to-day, we are worried whether we will have enough IVIG to infuse our patients. After considerable consternation, a letter, dated February 21, 1998 -- and a copy is provided to the committee -- was sent to our patients.

Several points were made. The first was that the situation had become critical. The second was that we could not guarantee that we had enough IVIG for our patients. Thirdly, we have had to ration, switch products, increase intervals or decrease the amount of IVIG given.

In addition, Omaha hospitals were often unable to obtain supplies for their patients, and those who I follow who are receiving IVIG at hospitals at distant sites were also having great difficulty in obtaining supplies.

I received a letter from one of my patients, from Kingman, Kansas who, incidentally, played football and was a halfback on the high school team which is located just out of Wichita, Kansas, whose son has hyper-IgM syndrome, which Dr. Winkelstein described, and she wrote as follows: "The blood specialist doctor was unable to receive supplies. Therefore, T.A. was infused in the hospital. However, the hospital did not have enough and called three other hospitals in Wichita, Kansas, and t hey were all out. T.A.'s doctor in Wichita has put him on a priority list, but it still worries me that one of these times he'll go in and there won't be any. This is a life and death deal with T.A. because he does not make any antibodies."

Another one of my patients, and it is interesting to note because this patient probably had common variable immune deficiency during World War II because he was excluded from the military because of chronic pneumonia. He was subsequently diagnosed, and is a patient of mine, and was admitted to a major local hospital for pneumonia and fever, and he required IVIG. However, the hospital had no supplies and, therefore, we volunteered part of our clinic's stock to provide him IVIG in the hospital.

In Omaha, a third patient that I have followed for seven years since I returned from Los Angeles, has been unable to secure IVIG from a large pharmaceutical chain where she had been getting her supplies. She writes as follows: "I've always had the product available until now, and it is a deep concern for me. My pharmacy hasn't been able to get IVIG as before. I have had to rely on my physician to secure supplies."

This patient happens to be the president of the Nebraska Immunodeficiency Foundation, and had been previously hospitalized on a number of occasions for pneumonia and other infections. Her husband is an officer within this large pharmaceutical chain in Omaha and has not been able to secure product for her. She has related to me that she asks her husband every day whether and when her IVIG has come in today.

It is the uncertainty of not knowing whether IVIG will become available when you come in for monthly infusions that causes fear and anxiety among patients, and worry among physicians. As stated in my letter to the patients, our group has begun rationing product, and the personal turmoil of having to make decisions which might compromise the best care I can give my patients has been a disturbing burden.

In ending, I would like to emphasize that even in a small state like Nebraska we are feeling the effects of the shortage similar to our brethren in Texas, California, New Jersey, Florida and elsewhere. Thank you.

DR. GROTE: Good morning, everyone. My name is Michael Grote. I am a practicing pharmacist. I have been a practicing pharmacist for greater than 20 years, and I currently work for Corum Health Care in the clinical services department, and I am currently working on special projects within the department. My main job responsibility is IVIG at this point.

Corum Health Care, headquartered in Denver, Colorado, is a provider of alternate site patient care, that is, patient care provided outside the hospital. Through our local branches, IVIG therapy is provided to a number of patients nationwide. In November of 1997, due to our inability to obtain sufficient IVIG product from manufacturers and wholesalers, restricted allocations for our company and in order to try to ensure continued supply for our patients, Corum decided to procure and distribute IVIG product using a centralized approach versus relying on a regional and local availability of product.

In addition, much like our friends at Texas Children's Hospital, a clinical decision on an IVIG process was developed to assist clinical and operational staff at the branches to triage patients to provide IVIG to patients based on medical necessity, using clinical classification codes, otherwise known as ICD codes. This prioritization is, classification 1, primary immune deficiency patients; classification 2, transplant patients; classification 3, autoimmune disorder patients.

Due to the lack of availability, IVIG product switching has occurred, whereby one brand of IVIG is substituted for another. I have been told that this has resulted in certain patients having adverse reactions to different IVIG product, resulting in hospitalization of these patients.

Currently, only two manufacturers have provided consistent allocations of IVIG product over the past six months. IVIG from one manufacturer is currently only available through an emergency hotline process. The price of IVIG from manufacturers has increased over the past 12 months anywhere from approximately $2 to $33 per gram. Specialty wholesalers have contacted our branches and me directly to distribute IVIG at prices greater than $90/gram.

I continue to coordinate and assist branches with IVIG product procurement for existing patients and new IVIG referrals. Our branches continue to receive these referrals, which we are not able to accept due to our inability to obtain product. In other words, we must turn away those patients for lack of IVIG product. This inability to obtain product is an ongoing problem, and coordinating IVIG product procurement and distribution continues to be one of my major job responsibilities. Thank you.

MS. O'DAY: Good morning. My name is Miriam O'Day, and I am vice president of the Immune Deficiency Foundation, and I am here to represent the activities of the Foundation on behalf of our patient population.

During the month of November, the Foundation began receiving calls from patients who could not obtain IVIG. We handled these requests on a case-by-case basis. Shortly before Thanksgiving, we received a call from a doctor who treats upwards of 200 patients, and she was having difficulty obtaining the product.

As we became aware that the shortage was nationwide, we sent a letter out to all of the manufacturers, requesting that they put aside an emergency allocation. Each manufacturer responded with their own protocol.

Between December 15 and February 15, we directly assisted 2100 patients with a diagnosis of primary immune deficiency disease in obtaining IVIG. Since February 15, IDF has met with manufacturers, regulators, IPPIA, treaters and other plasma consumer groups in an attempt to identify causes and play a constructive role in resolution. Thank you.

MR. MORAN: I will be mercifully short in my remarks. I am Tom Moran. I am president of the Immune Deficiency Foundation. Just to summarize the presentations that you heard this morning, there is a shortage of IVIG in the marketplace. It is severe, and it is causing substantial cost with respect to human suffering as a result of the shortage.

We are really here representing the interests of our community of patients, between 25,000 and 30,000, who use IVIG, with a couple, I think very simple, requests. The first is that I think that collectively we all have to work in a cooperative fashion to try to resolve the issues around the IVIG shortage. Political leadership, patient organizations, regulators, industry -- we need to roll up our sleeves, work together in a cooperative fashion and resolve this issue. Divisiveness and unnecessary blame-finding I think is going to slow down the process of resolving the problem, and slowing down the process of resolving the problem is going to prolong it, and if it prolongs it, people are going to get sicker than they are today.

The second thing I would ask the committee is to find out why there is a shortage of IVIG. Our primary request this morning is to ask industry, perhaps supported by FDA, to answer some questions related to that. We are now in the sixth month of the IVIG shortage. It would be nice to know why it is happening.

As a guideline, and certainly industry representatives can edit this if they care to, but fundamentally we would like to know the amount of IVIG available in the U.S. marketplace in 1996, 1997, 1998 and start with what is produced, subtract out IVIG exported, quarantined, released to the U.S. market, withdrawn from the U.S. market. It seems to me that some simple data of this type would go a long way to answering a lot of the questions. I think this data is available, and we are hoping that industry and FDA can comment on it this afternoon and tomorrow.

This is a two-day meeting and before we leave this meeting, it would be very helpful, in our effort to explain to immune deficient patients why there is a shortage of IVIG, to have this kind of data available.

The second need of our community, and I am sure we share it with other communities, is that obviously we need more IVIG in the marketplace. So, there are questions related to what is inhibiting, if you will, the ability of manufacturers to make more IVIG available on the marketplace. Certainly, it would be interesting to hear some estimates with respect to demand, projecting future demand, projecting the future production of IVIG targets in industry in 1999 and beyond, and finally some discussion from industry related to the factors that affect their ability to increase production, such as the rate of return, profitability to the industry, future of the plasma derivatives, other than IVIG, whatever factors might limit or might cause expansion of IVIG production.

So, as a final note, our comment is that there are significant medical effects of the IVIG shortage in our community. We would like to know why there is a shortage of IVIG, and we would like to know what impediments or incentives can be offered to expand the production of IVIG. Thank you.

DR. CAPLAN: Thank you. Why don't we keep Tom up there and let's open it up for the panel.

MR. MORAN: Sure.

DR. KUHN: I guess this is a question I have for Dr. Boyle. It seems like the standard of care over the past five to eight years in immune deficiency patients has been IVIG, and if there are approximately 40,000 patients requiring IVIG treatment. Has there been a time over the past five years when product was in shortage, and has the growth of new diagnoses and usage of your population caused a significant increase in product to impact upon a shortage?

Then, the other question I have, and I didn't hear anybody allude to this, what is the morbidity and mortality due to the difficulty in obtaining IVIG most recently?

DR. BOYLE: Well, I can respond to some of that question. We are guessing at the total number of IVIG users because at least three of us come up with slightly different estimates, but it is probably somewhere between 25,000 and 40,000, somewhere in there. But we are doing things like multiplying by 2.

There is absolutely no question, if you listened to Jerry Winkelstein's discussion, of the improved health and the decline in mortality among immunodeficient patients as a result of IVIG, and the improved diagnosis so that over time the number of patients using IVIG continues to go up, and will continue to go up, and the amount being used is also going up as higher levels are being found to have greater effects.

To what extent the growth in our community contributes to the shortage, five or seven years ago we were the only ones using it so at some level, as we expand, we are a factor in the demand curve. There are other factors and we don't know the components. We don't know how large they are. It is very hard to get a handle on that.

In terms of issues of actual mortality, I am not the person to respond to that. I do surveys.

DR. CAPLAN: We will let someone else get to that mortality question, if someone wants to comment on it. John Penner?

DR. PENNER: I have a question for Drs. Tabor and Kobayashi. Are either of you using plasma replacement as an alternative in some of those patients? Reflecting on the fact that there is a volume problem with it, it is still an effective measure for providing gamma globulin.

DR. KOBAYASHI: The answer to that, whether plasma is being used as a replacement for primary immune deficiency, I am not using it and I don't think very many people in the country would be using it. Dr. E. Richards, under whom I trained, pioneered, I think, part of this therapy about thirty years ago. This has been abandoned sometime ago because of its lack of effectiveness in treating primary immune deficiency.

DR. HOOTS: Dr. Gurwith mentioned that in her efforts to procure IVIG several instances of potential price gouging or bundling of other products. Has this been documented across the U.S., or is this one particular aberrant occasion, do you think?

MS. GURWITH: It is across the United States. The specialty wholesalers are located across the United States, and you will get fliers via fax from all over the country.

DR. GOMPERTS: I have a question for Dr. Tabor. Dr. Tabor, if the supply situation were to disappear today, having looked at the spectrum of patients across your institution who are receiving IVIG, would all of those patients be put back on at the previous level of treatment, or have you identified a group of patients who would require less treatment and some patients who would not require treatment?

DR. TABOR: I will be very honest with you. The P&T committee was already looking into the use of IVIG at our hospital, particularly what we call the non-label or off-label uses. We will continue to do some policy effort to try to discourage physicians from using IVIG with the extreme theoretical implication that it might work.

The four groups that we prioritized, remember, they got 60% of our IVIG, and then when you consider the children with lymphocytic leukemia and bone marrow transplants, in which this is now standard therapy of course, that is another 15%. Then the children with AIDS add another 13% or 7%.

So, for the most part, for the children who really are receiving IVIG we are trying to look at some morbidity/mortality. We have had one child with AIDS who has been admitted three times with infection since this child has not been receiving routine IVIG. We have a child that had a protein-losing enteropathy that got a level down below 200, and that child came in with overwhelming sepsis before we could give some replacement therapy.

So, we have had some morbidity associated. We are trying to find out in our bone marrow transplant patients and our children with lymphocytic leukemia if this has adversely affected their hospitalization rate.

DR. CAPLAN: Dr. Tabor, if you would just stay up there for a second, I want to follow-up one point. Have you had any discussion with fellow pediatricians, with people in pharmacy, with people in immunology at a nationwide level to get at the issue of physician or pharmacy use of this substance to set out guidelines in the face of the shortage? Has there been any professional society statement, consensus conference, any type of activity at the national level to help make sure that the product, as it stands today, is being used appropriately?

DR. TABOR: I don't know of any that have come across my desk specifically. There are some very good outlines though of approved uses of IVIG, potential benefits, probable benefits, and then the latter group falling into kind of case reports. Keith, do you know of any guidelines issued nationally?

MR. MORAN: Dr. Tabor, the American Academy of Asthma, Allergy and Immunology, their basic and clinical interests immunology section is currently developing some guidelines with respect to use.

DR. TABOR: The recent Red Book of the American Academy of Pediatrics has a nice section that talks about the proved benefit, in those children in which it has been proved to benefit them as far as morbidity and mortality.

DR. CAPLAN: The reason I ask is because I wondered if you would want to comment that, while it is very helpful to have different procedures in place for rationing and allocating supply at each institution, if we have a lot of off-label use in the current climate we may need to get a clear statement from organized medicine nationally about what is going on here.

DR. TABOR: I agree with you one hundred percent. I think that we should have a committee of experts --

[Laughter]

DR. CAPLAN: You can suggest that to us!

DR. TABOR: -- of experts in this field who will offer us some specific guidelines. It would be helpful to us as physicians in dealing with individual patients and parents, as you can understand. And, this has a medical-legal problem associated with it. That is why we had legal counsel on our committee and in our deliberations.

DR. GUERRA: Dr. Tabor, in a given year at Texas Children's, how many children with immune deficiency disorders are coming in as new patients, and how many are leaving your roster because of early death and/or because of other important therapeutic type of modalities that are also being used, including the stem cells and marrow transplantation, etc.?

DR. TABOR: Well, I can only tell you that presently, with primary immune deficiency we have 55 children who are receiving IVIG. I know 10 of those entered rather recently because, as I told you, they could not get IVIG from the regular supplier. So, they are now part of our primary care patient population at Texas Children's Hospital, and receive their IVIG there as outpatients. But I wish I could give you some information, and I should have thought about getting that together about how many we lose and how many we enroll, but presently we have 55.

MR. MORAN: I think the trend is for these children to survive and live through adult life. So, you are constantly getting children who are treated by IVIG and that becomes a life-long therapy, surviving into adulthood.

DR. WINKELSTEIN: You have to also factor in that if they do well, and most do, they not only last longer but they gain weight. It is a per kilogram dose, and so it might be 2 gm in a 2-year old and 30 gm in an adult.

DR. TABOR: They also run and play in sports and go dancing, and do those kinds of things which they did not do before.

MR. WALSH: In your efforts to triage, do distributors or health care providers differentiate newly diagnosed patients from those that have been on product for a substantial period of time?

DR. TABOR: I don't think we would with primary immune deficiency. We excluded, as I told you, a group of children who had been receiving IVIG -- the bone marrow transplants, the AIDS and the lymphocytic leukemias -- from getting it. They were excluded because we simply didn't have a supply for them.

DR. CAPLAN: Let me take maybe one more question over on the panel side. Then I saw that Jay Epstein had a question, on this side.

MR. ALLEN: What I wanted to ask, and this is kind of a general question here, is in regards to the price increase for these products and the indigent care patients. Are the patients on indigent care getting alternative therapy, or are they being allowed to use the IVIG regardless of cost?

DR. TABOR: I am proud to say that at Texas Children's Hospital there are no patients on indigent care. We have no idea how the patient pays when we see a patient.

MR. MORAN: I think there is a profound effect on that issue. There is one example that we learned of about a month ago, in Florida, where the price at the University of Florida Gainesville, for example, exceeded the price that Medicaid would reimburse in that state. It is our opinion that the availability of indigent care has plummeted dramatically as a result of the shortage, and that health care institutions and hospitals are just reacting differently. But the fact is that the prices that treaters have to pay to get this material is now exceeding, in some cases, the rate of reimbursement from publicly funded programs. I think that the idea of free care, at least as we have anecdotally been told, is basically out the window in a lot of locations.

DR. TABOR: Children in our hospital who are Medicaid patients receive any product, any care, any surgery, anything that they need regardless of whether Medicaid will reimburse it fully or not.

DR. CAPLAN: Well, at the risk of cutting off this nirvana-like description of Texas --

[Laughter]

-- let me go over here, to Dr. Epstein. I am going to take two more comments and I am going to warn our next speaker up that we are still going to go to Prof. Gervais after this, but I am going to ask her to see if she can take her remarks down to maybe ten minutes so that we can ask questions, because we are going to get way off schedule if we don't do that. So, Jay?

DR. EPSTEIN: Thank you. I would like to ask the panelists whether they perceive any trend regarding availability at this time. There is a perception at FDA, based on the decrease in the number of calls requesting aid in getting supplies, that the availability seems to have improved in April. I would like to know whether at the level of care providers or pharmacies there is any trend that you would like to comment on.

DR. BOYLE: Let me go first because I have the national survey data. What we are seeing is that in late March to early April, which is when the survey was conducted of 179 physicians, there were only, I believe 3% of those, 3% who said they had had problems in the past six months but had no trouble getting it now. There are 15% of all physicians saying that they were having a lot of trouble getting it now, which is late March, early April, and another 40% saying they were having some trouble.

So, I think that the conclusion from the survey data has to be that it is still a major problem. It still is in all states, and if there has been any change, any improvement, it is obviously not been very dramatic.

MR. MORAN: I think, Jay, there may be a frustration factor involved. IDF noted that its calls dropped off when we were no longer able to help individual patients get IVIG and, as a result, the calls dropped off. I would guess that if we started doing that kind of service again tomorrow the phones would suddenly start ringing off the hook again. My impression is that there is still a significant shortage in the marketplace.

DR. GROTE: And, I think I can echo that from Corum's perspective because on a routine basis we do get new referral requests. You know, we obviously classify patients and take care of the primary immune deficient patients first. At this current time, our allotments have still decreased over the last six months. So, it is nowhere near where it even was a month ago.

DR. CHAMBERLAND: I have a question for Dr. Boyle, a couple of questions. First of all, the panel members got copies of the patient survey results. The physician survey -- it would be helpful if we could get hard copies at some point.

DR. CAPLAN: They are outside.

DR. CHAMBERLAND: Great! You presented data in the patient survey regarding the types and numbers of specific adverse effects that patients noted. Do you have comparable data in the physician survey?

DR. BOYLE: No.

DR. CHAMBERLAND: It was just a general question, have your patients had effects?

DR. BOYLE: We were trying to make sure on the physician survey that it all fit on one page. For that reason, when we got to the health effects it was yes/no. We did not have a "specify" with it. There were people who wrote little comments, but it was more the exception than the rule. In the patient survey we were able to eliminate a few things. We had to keep it on one page but, because we knew the health effects were critical, we have them a space to explain what they were, and most did; a few did not.

DR. CHAMBERLAND: Also, can you tell us a little bit about how patients distribute themselves across the United States? Obviously, I would imagine it is very homogeneous but in terms of treatment I would imagine that patients tend to cluster at larger medical centers, or whatever. Can you give us anything about that?

DR. BOYLE: The closest we can get is that we do have a survey of 3000 patients. Unfortunately, like anything else, the only way you get to it is effectively by referral. So, you take it with a grain of salt. There may be some maldistribution. They are in every state in proportion to the population. If you look at it, you know, urban/rural, it looks like the population because most of our patients are not being treated in tertiary care facilities. Most of them are out, just like you and me. It wasn't necessarily true 20 years ago but it is true now. Their distribution, if you look at them by race, by geographic distribution, but almost anything -- there may be some effects by income just because some portion are, in fact, disabled though it is small -- they are going to be with the general population.

DR. CHAMBERLAND: But what you said is that most of them, in terms of treatment, are not clustering in tertiary care centers.

DR. BOYLE: Right. One of our problems in terms of my numbers on patients is that that is done exclusively through 15,000 physicians and specialty organizations. Many of these patients are treated by primary care doctors because it is a straightforward matter of giving them their IVIG and monitoring them.

DR. CHAMBERLAND: Thank you.

DR. CAPLAN: Richard?

DR. DAVEY: Yes, I have a question for perhaps Dr. Kobayashi or maybe Dr. Winkelstein. We know that gene therapy has been useful in ADA deficiency and perhaps, you know, is under investigation for some of there other disorders. Do you see gene therapy as being useful adjunctive therapy or corrective therapy in the near enough future to help alleviate some of these shortages?

DR. WINKELSTEIN: That is an important question because it would offer some real change for the future. The answer, unfortunately, and my personal opinion is that we should not depend on that for a number of reasons. One is that at this moment ADA deficiency, and soon chronic granulomatous disease, and soon thereafter perhaps X-linked SCID would be amenable to gene therapy. But those are genes in which either a receptor and/or an enzyme important in the metabolic pathway needs to be fixed.

To fix X-linked agammaglobulinemia, for instance, you would be fooling around with a gene that is a member of the tumor suppressing family of genes. People are a little nervous about doing that for obvious reasons. So, for many of these diseases and, in fact the most common, common variable immune deficiency, either gene therapy will not be immediately be available, and I mean within a 10- or 15-year period, or for common variable, since it is not known to be caused by a single gene defect, there is no hope at this point in time or the near future for gene therapy for that.

So, I think the impact on IVIG use will be somewhat -- there will be an impact but it will not be as significant perhaps as I would like or you would like.

DR. CAPLAN: Well, thank you. Thank you, those on the panel for excellent presentations. I am going to ask Prof. Gervais to come right up to the microphone. Karen Gervais is a bioethicist with the Minnesota Center for Health Care Ethics, in Minneapolis.

DR. GERVAIS: Hello. Thank you. Yes, I am Karen Gervais and, in addition to directing the center that was just described, I am serving as an ethicist for the Allina Health System in Minnesota. It is a very large health system. It is the largest we have.

I am presenting the work of an interdisciplinary team from the Minneapolis-St. Paul area that developed an approach to rationing IVIG, and instituted this approach in January. The need to do so was originally noted by the ethics committee at Minneapolis Children's Hospital. The ethicist at the end of the list was the leader in that effort. You can see it is an interdisciplinary effort. We have people from pharmacy, physician staff of Allina represented and myself. I am just going to give you a thumbnail sketch of how we proceeded and show you the triage questions that we developed.

This has the dimension that the initial or the earlier report didn't have. We were not just one hospital trying to allocate; we were six hospitals. The Allina metro hospitals consist of four large hospitals. In addition, there are two children's hospitals, one in Minneapolis and one in St. Paul. These Allina and children's represent two distinct health systems, but they are joined at the hip, as it were, by a pharmacy purchasing group. So, it seemed appropriate to come up with a way of sharing the resource that was becoming increasing scarce.

So, there was an agreement to pool supplies of the drug to ensure that it would be available for critical patients throughout the systems, and each site though continues to maintain its ordering and storage of the supply. They engage in daily communication, periodic sharing, and pharmacists enable the movement of material to a needing hospital immediately.

How did we do this? Basically, we had a three-part process that we followed. First of all, the physicians and pharmacists consulted widely and developed a tier system of disease categories. I will just show you the slides of these.

Category 1, very critical; potentially life-threatening. You can read quickly down the list.

Category 2-A, in general it was about imminent morbidity. We realized that we needed to distinguish imminence. So, category 2-A, imminent morbidity likely within one week became the crucial criterion.

Category 2-B, within one week or longer.

Category 2-C, greater than one week.

Category 3, prophylactic or unclear evidence of the efficacy of IVIG.

Category 4, ineffective, that IVIG is not considered effective therapy and/or alternative therapy is available and preferable. Medication would not be dispensed, and a few disease categories are indicated there.

So that was the first part, the creation of these disease categories. The second part of our effort was led by the pharmacists who assessed system usage patterns, and drew conclusions about the system supply levels we needed to address the needs of patients in the disease categories.

This slide shows the supply data for the six hospitals combined from December to mid-January. Similar to what Dr. Tabor presented, when we first began eliminating prophylactic and non-indicated uses, we reduced our usage to only 25% of what we had been using. We reduced our usage by 75%, which was significant. But, as you see, we were at very low levels in December and then the system level rose.

In any event, the pharmacy group studied our usage patterns carefully and came up with these supply level categories. Level I would be less than or equal to 1000 gm for the system as a whole. So, this would be all six hospitals. The idea became that we coordinated the disease category level I with level I supply category. So, if we only had level I in supply, then only disease category 1 patients were eligible to receive it.

So, at level II, again the amount of grams that we felt that we needed to be able to supply both category 1 and category 2 patients. Then level III was medication freely available after that point.

The third part of our process was the ethics piece. We were really in a crisis position in December. So, we didn't sit around and think very hard. We went immediately to the AMA guidelines on the allocation of scarce medical resources.

The criteria that they provide for resource allocation -- these are, first of all, the inappropriate criteria, and these are the ones that we used to develop our triage questions, the acceptable criteria for resource allocation among patients. So, basically we tried to reflect each of those in our list.

There was a bit more ethics work that we did, but in the interest of time I will spare you that. Basically, it was to come up with some underlying principles, much like the National Commission for the Protection of Human Subjects, done so many years ago that grounded the use of the criteria.

The patient selection questions -- and I will make it brief by suggesting we assume that we are looking at a patient with a category 1 disease. The triage questions go like this: First of all, what disease does the patient have? So, knowing the disease. Then, determine the disease category. Is the disease category 1, life-threatening or very critical? If yes, go to question 3 of allocation level I questions. If no, consider category 2.

So, you can see that you would proceed then to go down these categories to determine which disease you are looking at. So, assuming that it is a category 1 disease, you would move to our allocation 1 questions, first of all looking to the issues of whether there are appropriate alternative treatments that could be used. If they have already been tried, continue to question 4. If no, do not dispense drug and recommend an alternative. If the threat to the patient's life is very critical; morbidity immediate, if yes, continue to question 5.

Is IVIG likely to be effective in saving the person's life or preventing very serious morbidity associated with the disease? We wanted here to rule out life-threatening co-morbidities that would prevent the patient's life from being saved even if the IVIG would be effective in achieving its intended goal.

Our way of trying to represent the quality of life issue -- is IVIG likely to improve the patient's life? I will comment a little bit about that in a minute but, if yes, continue to question 7.

Are the improvements in the patient's condition likely to be more than transient? If yes, complete documentation form and dispense. If no, collect information but do not dispense product. If two patients with the same status present simultaneously, go to question 8.

Here, I have to tell you that as far as we have gotten, and thank goodness, we haven't gotten to this situation yet, we haven't had simultaneously presenting patients who can't all be served, but we would resort to some procedural approach to being fair at that point.

What has happened to us, when we first presented these selection criterion both physicians and pharmacists were unhappy because they felt, first of all, that they were being asked to make quality of life assessments for people and also to name the duration of the effect that the IVIG would have. We tried to emphasize that it was the question of improvement in the patient's quality of life, and not some absolute judgment we were asking of them, and also a kin of minimalist requirement here is if you know it is only going to be a transient impact that is an important consideration.

But we still continued to tinker with the right way to phrase these questions so that we are not putting physicians and pharmacists in any more difficult of a position than we have to. These questions become the basis for a dialogue then between any physician who needs the drug for a patient and the pharmacist.

Just in summary, what have we learned and what work remains for us? First of all, we learned that developing a rationing mechanism is one thing but implementing it is quite another. At first we encountered resistance, as I said, from pharmacists and physicians, but by now, given the shortage, they are beginning to acknowledge that the only responsible thing to do is to tighten our questions.

The whole issue of implementation in the health system -- first of all, it is a good idea but, secondly, it is encumbered by the fact that health systems aren't really thinking like health systems yet. They don't know how to do it. So, it is unclear often who is in charge; who sets the agenda; who makes the final decisions; who owns the responsibility of making sure that the protocol is implemented consistently throughout the system.

Finally, we know that if the shortage deepens we have a lot more drilling down to do with our patient selection criteria, and that is going to be a very tough thing to do.

But I guess the good news, and this is why I feel quite positive about what we have done so far is that by instituting this procedure, this mechanism, in January, we have managed our shortage. We have had some deep troughs in the availability. At present, each hospital of the six hospitals continues to get supply. So, we are keeping the multiple access routes open. Currently we have a very high amount. We have 7000 gm in the system. However, two hospitals are receiving nothing and have been receiving nothing. So, this is coming to the two larger hospitals that are directly linked to the two children's hospitals.

Apparently, in January and February they got a very large supply but they have been told by their suppliers that there will be no more product available possibly for many months. So, we don't know exactly what we are looking at. The supply is inconsistent to each of the six institutions. They continue to share the product, and this triage method has been very useful.

The first and most disabling feature is the uncertainty of the supply, not so much that the supply has been limited. I think that is the point I would want to emphasize. We have often hesitated to distribute it even when our system levels have been higher because when we do, the supply immediately drops to dangerous levels. Yet, sometimes we feel we aren't benefiting patients when we could be. Again, it is not knowing when the supply will be there.

Based on my experience so far with these hospitals, it seems that systematizing distribution and prohibiting the development of secondary markets that further drive up the cost would be big steps forward because there are ways of managing shortage pretty effectively, as our experience has shown us so far.

DR. CAPLAN: Thank you, Karen. Questions? Jim?

DR. AUBUCHON: Your system very dramatically reduced the use of IVIG in these hospitals. How much of the reduction in use was due to patients that would otherwise have gotten the IVIG in categories that were low down on your list and, therefore, didn't meet criteria because of the status of the inventory, as opposed to those who just really weren't going to get any benefit out of it in any case?

DR. GERVAIS: The only figure they were able to give me was 75%, and we can't discriminate right now who is who. We don't know which are the non-indicated uses and which are the prophylactic uses. What we did find out though when our system levels rose and we began to allocate at level II and a bit into level III is that it just dropped our supplies so fast because we were on a waiting list. So, the problem of not knowing when to expect supply is just the real dilemma. I think you could stage these things rather intelligently if you knew that.

DR. SCHIFF: In those individuals who were denied the IV gamma globulin but where there was some indication that they were just low priority, did you utilize any kind of informed consent in giving the alternatives, although we know that alternatives are scarce but so they could look out for themselves even though you are not giving it to them?

DR. GERVAIS: My understanding, and I wasn't really close to that piece, was that they were always given alternatives, and there was a great effort made to help them find supply elsewhere. Informed consent -- this committee that I was working with did not develop an informed consent protocol. We only developed the triage protocol and a questionnaire that the pharmacists were using so that we could begin to track what was being done, who was being denied the drug, and we haven't been processing that fully as yet. So, I can't fully answer your question. The worst problem we felt we were in ethically was this informed consent dilemma of how do you really talk to the patients and families that you are now denying the product to?

DR. CAPLAN: Let's do one more question. We'll go to Keith.

DR. HOOTS: I applaud what you have done. Have you begun to develop liberalization strategies? You alluded to it a little bit, how difficult it is to do that when you don't know what the future holds. But, have you actually thought about what your question would be for the highest categories in terms of reserve before you start liberalizing down to the lower categories towards 2 and 3?

DR. GERVAIS: Yes. We began, actually, very conservatively and found that we could open it; that 1000 gm was what we needed for the category 1 patients. Right now, the whole system seems to be adequate and we have a breakdown of the number of grams we need to be able to allocate effectively for each category. We have been trying to solve this problem. My suggestion has been that we adopt the notion of a savings account and actually put away the amount of IVIG that we know we need for the emergency patients, just put it aside and then count. Forget that we even have that in our savings account and then count with the system we are now using. We haven't done that yet.

DR. CAPLAN: Thank you, Karen.

DR. GERVAIS: Thank you.

DR. CAPLAN: We are going to take a break until 11:00 sharp. I am going to ask the next group of panelists to be ready to go at 11:00. I am going to ask the committee to come back sharp at 11:00.

[Brief recess]

DR. NIGHTINGALE: Could the committee please return to their seats? We are running slightly behind schedule.

DR. CAPLAN: I think our next presenter is Corey Dubin, the Committee of Ten Thousand, and a member of the Blood Products Advisory Committee to the FDA that we have heard something about. Corey?

MR. DUBIN: Members of the panel, Mr. Chairman, guests, I am Corey Dubin. I am the president of the Committee of Ten Thousand. We are at our root an AIDS advocacy and support organization, primarily for people with hemophilia infected with HIV and AIDS through obtaining blood products. We have also done some reaching out with the transfusion community in some work. But I think, as some of you sitting on the panel know, we have also for the last five years played a rather prominent role in the discussion of blood safety from the consumer side of the fence.

Let me say this up front, and I will try to move through the areas, I want to say that Dr. Nightingale asked me for the landscape. So, I am going to attempt in a short time to put that landscape on the table to the best of my ability.

One of the things we would say up front is something that has been said, that we have been saying for four years, and I will do it quickly. We believe a new paradigm is in order in looking at the regulatory and supply and safety climate for blood and blood products. We believe in some ways we have started to move in the direction of that new paradigm with committees like this, the reconstituted BPAC, where we sitting at the table, especially here, representatives of the medical community, treaters, the industry, the Red Cross, the independent blood banking industry, government, and we think that needs to continue, but we think it needs to continue in a better climate of mutual trust and respect. We think we have done the early dance part of the game, if you will, where we feel each other out and it is time to really get down to some serious business together where mutual respect, and respect for perspectives is the issue. I think anybody can talk about science, and one member's science may be another member's rhetoric, or vice versa.

What we want to say is that everybody is coming to the table prepared and ready to do their job. The consumer/patient organizations all have medical committees and, as I think you have begun to see, they have very good medical committees and are doing solid work. So, I think it is really time we move in that direction and take the next step beyond kind of dancing around together.

That said, let's jump right in. We have seen the issue of safety and supply, from our perspective, constructed on a bipolar graph. At one pole is safety; at the other pole is supply. We, over the years, have consistently heard if we go too far on the safety side of the equation, guys, you are not going to have enough factor. It is just that simple. The opposite, of course, is if the supply rises, it is at the expense of safety.

We have heard this a number of times, expressed in a number of different ways. I would say that at the Committee of Ten Thousand we categorically reject that construction. We think we can maximize both safety and supply, and do it well and create a pool of safe and efficacious products, and enough of those products to treat the people out there. And, that is certainly our goal and we will see that goal met.

In terms of pool size -- let's talk a little bit about pool size because Steve had asked us to address that and it hasn't come up yet this morning. I think it is pretty clear that we have called for greatly reduced pool sizes. We were shocked, to say the least, at last summer's revelations of pool sizes in the range of 100,000; with some products larger. With other products we heard up to 300,000 in some pools that were involved in the production of immune globulin IV. "Shocked" may be an understatement. We had been led to believe for 25 years that in assessing our risk, our donor exposure was about 20,000.

I think it is interesting to note that when Don Francis sat in on the "60 Minutes" program a year ago to talk about these issues, he used the number 20,000. That is what key and other medical research had believed. So, we had somewhat of a sense of shock at those revelations. We recovered from that and decided to go to work.

At the September BPAC, almost as if to add insult to injury, we were presented with a new voluntary safety program. Now, we wouldn't say that we don't welcome a voluntary safety initiative from the industry; we absolutely do welcome them taking steps in that area. However, we had a little problem with the way it went down and "we're going to do the right thing now and reduce the pools to 60,000 as our upward limit." And, it was done in the context of nothing being said about the revelations that we had heard just a couple of months before that.

We think pool size reduction has to go down. We do not believe that there is good medical and scientific bases for pool size numbers of 60,000, 80,000, 100,000. We have yet to see a demonstration of the need for pool sizes of that size, for instance, to reach efficacy for immunoglobulins which, of course, is one of the most important issues in discussing pool size. We think the issue is manufacturing economies of scale. It is just that simple. It has been that issue right along.

Now, we want to say very clearly, from the Committee of Ten Thousand, that although immunoglobulins IV are not our main product, although a number of our HIV-infected individuals are being treated with this product, this is an issue we take very seriously because we believe that immunoglobulins drive the plasma derivative market. We have been hearing that for years. Factor has a smaller marketplace, even though it is a highly priced product, and immunoglobulins drive the market. So, we very clearly see the need to be clear about that.

We also support the Immune Deficiency Foundation's call for adequate supply. We are shocked, again, at the level of shortage we are seeing right now and what we heard today because I think they put a human face on the numbers that we have been hearing, and have given us some sense of what this shortage means out there in the community.

So, we see that as an important issue. In our research, we have heard that efficacy is in all probability reached somewhere in the vicinity of 15,000. That is a number we have been hearing quite a bit around the efficacy of immunoglobulins. If that pans out to be true, then clearly we support the FDA's call to move to 15,000, with an eye towards 5000. We think that is absolutely imperative.

Now, another issue that comes up for us when you talk about pool size is the so-called high titers, donors with a high titer for HBV antibody, which, of course, are some of the critical donors for immunoglobulins. In the 1980s it was the pooling of those donors from communities known to be at high risk of AIDS that we believe played a central role in the infection of nearly 10,000 people with hemophilia. I will remind you that no one in hemophilia was warned that those high titer, high risk donors were being pooled into those pools.

Now, do they present a risk today? FDA has taken the distinction that the line is drawn between high-titer donors with a history of risky behavior, behaviors associated with the transmission of virus, and those without that risky behavior. We have kind of defined that hypothetically as the housewife in Des Moines versus a prisoner who has a history of intravenous drug use. Our concern is the level of enforcement and the level of vigilance around that barrier. We have concerns that that boundary is not necessarily being enforced to a degree that we would like.

That, mixed with the fact that if it turns out that pool size, in order to reach efficacy for immunoglobulins turns out to be higher than the 15,000 number, then maybe it is time to institute dual production lines. When we read the 1976 FDA regs on biologics and donors, let's say in the production of biologics, only healthy and normal donors who do not have a history of viral hepatitis can be used, we have always interpreted that to indicate the need for dual production lines. What happened in the 1980s only drives that home further for us. So, that becomes an important issue when looking at pool size. Obviously, the application of viral inactivation technologies impacts that equation very seriously.

When it comes to viral inactivation, clearly with lipid-envelope viruses the question is not whether or not it works. We know it works. The question is good manufacturing procedures and standard operating procedures, GMPs and SOPs, and the enforcement of those to a degree that ensures that application takes care of lipid-envelope viruses that might sneak through the donor screening process.

But the application of technology isn't always the answer. So, we still have concerns. I think depending on where the recommendations which, we hope, are going to be coming from NIH and NIAID about what is an efficacious pool size for immunoglobulins, that those recommendations will impact our position. But, we certainly think that the discussion of dual production lines, essentially segregating the high-titer donor pools for immunoglobulins, is one that has received not enough attention at the Food and Drug Administration or anywhere else in the regulatory structure, and we would urge that we begin to look at that in a much more serious way.

In the studies we have seen and the presentations we have seen regarding the pool size question, but not only the pool size question, we see a consistent focus on HIV, HBV and HCV. Now, these are clearly viruses, due to some very work being done, that we have come to understand rather intimately -- window periods, things of this nature, infectivity. These are things that we have a pretty good handle on, and we understand that. What we are concerned about in these presentations and in discussion is what we believe is a lack of modeling for emerging threats, a lack of modeling, and serious looking and, analysis to the best degree possible when dealing with the unknown. Because, if we focus on those three viruses, we are basically speaking to the choir in the sense that we have learned how to deal with them, both at the front end and the rear end through screening the application, genome amplification testing, PCR and obviously through viral inactivation.

So, the question becomes not if emerging threat will happen but when. If that emerging threat is a non-lipid-envelope killer, so to speak crudely put, then will the system respond? Are in place to deal with that? We would suggest that much more modeling of emerging threat needs to occur, and it needs to occur now rather than later. We think this is a critical point in discussion, and we consistently believe that it is not being done and that it can be done.

Let's talk a little bit about the regulatory climate. I think when we are talking about HIV, HBV and HCV, as we said, the regulatory climate is the key issue. Good manufacturing practices and standard operating procedures, are they being enforced? We think, well, we are not looking down the barrel of the gun of the 1980s, and that there is still a large degree of distance to be covered in this area. We have come to refer to something as, in essence, the culture of decision-making in the regulatory system at FDA and elsewhere. A culture that has historically built its decisions on consensus building, discussion, dialogue, obviously in some instances that can be a very effective way to approach regulatory affairs. But we also think there needs to be wielding, strong wielding of the power invested in the FDA by the United States Congress and, of course, the ultimate power which is licensure, which Congress gave the FDA as an enforcement tool which, very clearly, is not used.

Let me give you two examples that concern us, and one is in '83 and one is in '97. The '83 one was a letter that emanated from the Baltimore field office that called for a class I recall based on HIV. The inspector, whose name slips me at this moment but I would be glad to give it to anyone who would like to know -- the inspector laid out a pretty bleak picture, and called for a class I recall -- the style of recall where somebody is at your door, saying give me your factor; the stuff is dangerous.

When that letter processed through FDA, it came out as a market withdrawal. Most of you I think know the difference between a market withdrawal and a class I recall -- quite a bit of difference. And, I don't need to belabor the point of what the result of market withdrawal versus recall is.

Then we have a situation in the '90s where there is a problem with Baxter-Fenwalt division collection boxes with saline, and possibly the saline affecting the testing of collected units. FDA apparently agrees to refer it to a committee. At a later date, the field office spot-checks Baxter, probably because they were concerned if there were front end problems there might be rear end problems that they should stay on top of. A temperature variation is discovered in the clean room roughly six months previous that was not reported to FDA. Again, a memo goes to central, basically saying we ought to take very serious and aggressive action, potentially licensure action to get them on line with this.

Obviously, there are differences between the context, and I don't mean to compare HIV with this problem. What I am trying to talk about is a style of decision and an approach to things. We believe FDA has to take a stronger independent usage of the power invested in it, mixed with the kind of discussion and dialogue that goes on here, and what we do at the BPAC, but there has to be that point where the buck stops. There has to be that point where people are told, "the following shall happen," not "we are recommending." We see a lot of "we are recommending" and not a whole lot of "we shall." Now, I think there are instances where that is not necessary, but I think there are instances where it is necessary, and we do not believe that power is being wielded enough by the agency.

The question we would ask is if the FDA believes they do not have that power, then what work do we need to do with the relevant congressional committees to see that power invested in FDA? Because that is one of the last lines of defense.

I will give you another example which concerns us. Obviously, the transmissibility of CJD in blood is still open to debate. The question of food is a different one. We have already seen an outbreak in Great Britain of mad cow. We have many products, from melatonin to vitamins, to other food products, where brain tissue and spinal cord tissue from cows is being used in those products. Now, are some of those people going to be blood donors who are consuming those products? And, why aren't those products labeled accordingly? If we want to see change in the marketplace, wouldn't a requirement to label the presence of those components in those products be a way for the public to move the equation by saying they are not going to buy those products with those components in it? Those are issues we can be proactive on, that we know about, where some proactive activity would really make a difference.

The other area I want to talk about is data collection. I have sat on the BPAC now for three and a half years roughly, and we keep coming to one issue. We are asked to consider public policy and regulatory policy options regarding margins of safety. How do we do that if we do not understand as members of the panel what the impact of a given policy will be on the availability of product?

I consistently feel under-equipped to do the job, not because I don't think I can handle it or learn what I need to learn, but because I don't think there is enough information on the table. I think when we consider the CJD recommendations that came out of the special advisory panel, or other safety margin options, we ought to have production data. We ought to have data about what the impact of a given policy will be.

When the special advisory committee met, and a member of our board, Dr. Rich Calvin sat on that panel, we were told repeatedly, "you guys aren't going to have enough product if you keep pushing this equation." Well, that is vague. It is rhetorical, and it doesn't really serve our ability to understand the issues in a way that allows us to consider and make intelligent decisions. We believe FDA obviously has the ability to get that data. We have heard many times that some in industry consider it proprietary. Well, I think the unique character of blood and blood products changes the proprietary equation a bit for a number of reasons. We are not dealing with an automobile, for instance. Consumers don't really have a lot of choice. In some communities, like alpha-1, there is no choice at this time. There is one product. In hemophilia there are a few choices, but they are not the same kind of choices you have if you are buying a toaster, a washer or a car.

The other issue that should modify the proprietary question is this concept of cost shifting, societal costs. If I go out and buy a new Ford Bronco, that is coming out of my pocket. What is being paid for these products in hemophilia, primary immune, alpha-1, are societal costs. In some instances there are direct societal costs being paid for by Medicaid, Medicare. In others, they are indirect, the insurance carriers. But any way you stack it up, they are societal costs. We think those issues ought to modify this question of proprietary, and we think it is imperative that we get this kind of data on the table because we just don't think we are going to be able to make intelligent decisions until we get to that point.

Now, one of the things that we are a little bit confused about is the whole federal coordination and linkages, landscape, if you will. We, obviously, played a role in getting Congress to ask for the IOM report, and then we played a role in the report itself. As we understood the recommendation for setting up a committee such as this one, one of the important issues was to look at the landscape of the federal government in blood and blood safety and availability, and ascertain where the system might be weak, where the system needs coordination, and how do we coordinate if we get into a situation of a rapidly moving, emerging threat.

I don't know that we have done that yet, but we sure think it needs to be done. We think there is a hodge-podge of federal agencies both directly and indirectly involved. Where is the authority? Where is the coordination? Who really coordinates the response of the different federal agencies to emerging threat?

One of the things we looked at in emerging threats was kind of constructing this triangle where research and surveillance feed public policy and regulatory decisions in a very formal way.

Let me give you an example of that. During the 1980s we had a lot of death certificates in the hemophilia and HIV community marked "dementia." We weren't doing surveillance. We weren't doing a lot of autopsies. The education wasn't done. And did we miss a golden opportunity to collect more data on the potential presence of CJD? We think we did. And, we think when we move to a surveillance program, more specific in each of the user communities, that will also entail a lot of internal education, both for the treaters and the patient communities.

We think any program of surveillance has to include that. This is just a look at research. Obviously, we think research needs to be coordinated and well funded. We look to this committee for that coordination.

This is the surveillance, and again, we looked at CDC and all the communities, and we think what is missing is some very serious education. In hemophilia we are still not sure all the treatment centers are getting this message clearly and understanding the need for surveillance around issues like CJD.

So, we are hopeful that this committee will look at that, but we think that is something that should happen here. We think it is a critical issue because, again, we are talking about when, not if; and when is the important issue. Coordination is the critical issue. Will we have casualties in the tens or hundreds or multitudes of thousands again? We believe we can hold them down. We believe we have the people and we can do it. We saw things like turf wars get in the way in the '80s and we would like to see that go away.

Let me close by addressing the shortage which seems to be the biggest thing on everybody's mind. Obviously, we are troubled by the shortage, even though a small amount of it has come our way, but we are concerned when we hear about primary immune deficient patients not getting their product and getting sick. This shouldn't be happening. This should not be happening. And, we would ask a series of questions. Why is it happening? Is it happening because of poor planning in the demand side of the equation? Because the industry didn't see the off-label demand and other kind of demands happening? Is it happening because more of this product is going to Europe? We are hearing from our sources in Europe that there is not a shortage on the Continent; there is American product to be had.

Whatever the reason is, we need answers. We need to know why because we have to begin to solve these equations, and if we have production numbers and that kind of data we are better equipped, all of us together, to solve these problems because we really don't want to see any of our communities, not alpha-1, not hemophilia, not primary immune, none of the communities that depend so critically on these products should be faced with these kinds of shortages where you are talking about life-threatening criticality.

We have been subjected to that in hemophilia a couple of times. It is no fun, folks. I was told I had to stop working at one point because there wouldn't be enough factor to support the kind of work I was doing. But, beyond that, it is life and death. So, I think we need to come together in that climate of mutual respect and dialogue but, at the same time, we need to greatly strengthen the federal system. We need to strengthen coordination and linkages. We need to strengthen FDA's ability to wield an independent hand and, at the end of the day if the FDA is not getting what it needs so they have the power to say you will be here at such-and-such a date and time with the following data set, and they will go on the table, and we will then make decisions based on an understanding of what the impact of those decisions will be. This is the climate we want to see. This is the climate we believe everybody in this room is capable of because we do believe one thing, we do have a shared goal in this country, and that shared goal is to get enough product out there, safe and efficacious product to take care of our people. I don't think there is anybody in this room that would dispute that goal. But we seem to have a problem collectively getting there, and we seem to have a problem understanding what the real problem is, where the logjam is and why. I think part of creating this paradigm, this new climate, means that we all come with our cards and we put our cards on the table, and we have honest and good discussions about where we are going to go to make sure that our people, hemophilia, alpha-1, primary immune, have the kind of product they need to get the job done.

The last thing I want to say is we would hope, even though it is not in the committee's jurisdiction, that the committee might help us nudge NIH a little and push the standard of care in hemophilia towards recombinant. We think that is certainly something that we are interested in, as well as supporting gene therapy research in hemophilia.

Dr. Caplan, Dr. Nightingale, I am very thankful for the amount of time you provided us, and we are very appreciative.

DR. CAPLAN: Stay up there just a second, and we will take time for maybe just a couple of questions before we go on to Jan Hamilton. Jim?

DR. AUBUCHON: A couple of points of clarification, one on something you said and one that I may need from industry. You indicated that it was your impression of the data that a pool size of approximately 15,000 donors would provide an efficacious IVIG product. If 15,000 is appropriate, you then said that you would support a move to a pool size of 5000. If 15,000 is efficacious, why would we go to 5000?

MR. DUBIN: What I said was we would support FDA's recommendation, which is to currently go to 15,000 with an eye towards moving towards 5000, but I also said in the context of understanding the need to hit a level that is efficacious for immunoglobulins. If we find out at the end of the day that that number is significantly higher, then we might suggest dual production lines.

DR. AUBUCHON: Related to dual production lines, is that not in effect what we already have? I am asking this as a question because I don't understand the ins and outs of the details of the production process. But when, I believe, a two-plus-three paste is made that comes out of the end of the Factor VIII production line, aren't multiple lots of the two-plus-three paste then combined in making the IVIG product? In essence, there is greater exposure for IVIG recipients than for Factor VIII recipients. I am asking that as a question. I don't know the answer.

MR. DUBIN: I would like to see the industry answer the question, rather than me.

DR. CAPLAN: We will come back to that this afternoon. You will have a chance to ask that question.

DR. KUHN: Mr. Dubin, you are saying two production lines and, ideally, you are saying a pool size of 15,000. How would this impact safety as it relates to emerging threats, and how would it impact cost to industry?

MR. DUBIN: Well, I think one thing that has never been on the table is this cost-benefit analysis. We have looked at economies of scale from a manufacturing perspective, and historically the large pools have looked attractive. We believe in a heightened regulatory climate, which we are clearly moving towards, smaller pool sizes will become a more effective economy of scale for the industry because if you have a recall the amount of units you have to bring in the door will be smaller. So, we think that as the regulatory climate is heightened you could actually see the smaller pool sizes become a better manufacturing economy of scale than the large pools that we currently have. So, that addresses the question. What was the other side of the equation?

DR. KUHN: How that relates to emerging threats, a smaller pool size.

MR. DUBIN: And, this is a somewhat simplistic analysis, but if you have pathogen X out there and the incidence is one in a million in the society, and you have a pool size of 100,000 the risk is 1/10. If you lower that pool size to 10,000 you risk factor goes down significantly. And, I think in that analysis also we have been hearing from FDA that reduced pool sizes do not impact heavy users, but for the sake of discussion let's say we accepted that argument. We don't want to see classes of users created in the discussion of safety. We want to up the margin of safety for small users, medium users, and large users. And, we keep hearing that that reduction in pool size won't impact heavy users. If we accept that, it still begins to kind of look in the direction of creating classes of users vis-a-vis the safety margin discussion.

DR. CAPLAN: Why don't we do one more, and then we will move on? Oh, excuse me for one second. If a black Volvo, Maryland EXW-737 doesn't move, it will be towed!

[Laughter]

MR. WALSH: Corey, good presentation, but with regard to recombinant, obviously that impacts safety and availability. Where are we in the hemophilia community with respect to availability of product and research?

MR. DUBIN: Well, I think clearly, as we said, we would like to nudge the committee towards at least something in the way of a recommendation but even standard of care does not really reside here. We have heard some rumblings about NIH discussions about standard of care. I think it was Dr. McCurdy that spoke to me at a BPAC meeting recently about this issue. We, obviously, want to move hemophilia as much as possible to recombinant. I don't think that means we want to abandon the safety discussion but I think, for us, our best risk position is on recombinant product. We have asked the question and are still asking the question why is there not enough recombinant on the street? Why are we not able to access the level of recombinant that demand will support? Was demand underestimated? That is a distinct possibility.

DR. CAPLAN: A quick question, Corey, to your knowledge has the United Kingdom now gone to recombinant only?

MR. DUBIN: Canada has gone to that standard. I think the United Kingdom is still in process, but Canada has absolutely gone to that standard.

MR. WALSH: Is it economics?

MR. DUBIN: I imagine it could be, but there are a couple of ways to look at this, and I would love to hear from the industry later today about this. But, I think there are two ways one can look at this. They may have underestimated demand. It may just be that simple, that they are not operating at full capacity because of an underestimation of demand.

One of our science and medicine teams raised the issue that the per unit cost is lower if a certain segment of the hemophilia community remains on human-derived factor because they will still have a domestic market for that cryo in the pools. If we are all on recombinant they won't have that domestic market. Obviously, some people have said, well, they could sell that overseas but, again, that is an issue we would love to hear from the industry because the demand is there; it is strong. We want to see our people on recombinant; they want to use recombinant. So, let's find out why we can't get enough product on the street and try to solve that problem.

DR. HOOTS: Just in response to your question, hemophilia treaters, in conjunction with the U.K. blood oversight organization, have recommended that for hemophiliacs in the U.K. American recombinant products be purchased because of stabilization with albumin and, since no new variant disease has been uncovered yet in the U.S., that was the choice that they have made. It is important not only for this question, but it will also become important in the discussions later in terms of demand, increasing demand.

DR. MCCURDY: I have a question and then a comment. The question is whether this recommendation to move toward recombinant was blanket or for those who are under the age of, say, 16. It was my understanding that in the U.K. it had an age on it; Canada, I don't remember.

DR. HOOTS: My understanding was that it was prioritized for people under 16 but it wasn't limited. Is that your understanding, Corey?

MR. DUBIN: Yes.

DR. MCCURDY: I doubt if it would be limited --

DR. HOOTS: Yes, I think it was unlimited. It was an unlimited recommendation. There were no stipulations specifically put on it.

MR. DUBIN: The Canadian recommendation was unlimited, with a goal towards moving their entire hemophilia population to recombinant.

DR. MCCURDY: My comment is that the Heart, Lung and Blood Institute has under discussion now the possibility of a workshop, or something similar to that, to look at the relative safety of recombinant versus plasma derived. I think that since these are made in animal cells or bacteria or some other cells than human, it is not a one hundred percent given that they will be totally safe. We are considering looking into that in a workshop format.

DR. CAPLAN: Thanks, Corey. Let's have Jan Hamilton come up.

MS. HAMILTON: Thank you. In the interest of time, I am going to refer to my notes because I have a tendency to get a little long-winded if I leave it up to myself to just talk to you.

Dr. Nightingale, Dr. Caplan, members of the advisory committee, and guests, it is once again a privilege to address this distinguished panel. The purpose of the discussion for today and tomorrow, "what has caused the current shortages of plasma derivatives and what can be done to correct this situation," if of extreme importance to members of the hemophilia community. We acknowledge that we are not the only community affected by these shortages.

The hemophilia community and the immune deficient community are both extremely dependent upon an adequate and safe supply of plasma derivatives. Patients who undergo transplants, receive treatment for leukemia, and many other forms of cancer, sickle cell patients, and John W. Public, all depend upon a safe blood supply. Many of those use plasma and plasma derivatives. However, the two communities who truly depend upon plasma derivatives being pure and always available in an adequate supply are those with hemophilia and immune deficiency.

When there is a discussion of pool size many questions arise. When there is mention of product shortages many questions arise. In respect to pool size, several facts come to mind.

For years we were led to believe, as Corey mentioned, that pool sizes varied between 10,000 and 10,000 units. Then we discovered, and it was reported through the Shays Commission hearings last July that pool sizes were really up to 250,000, and sometimes even 400,000.

BPAC recommended a 15,000 pool size. Industry said it was totally impractical and couldn't be done. Industry agreed to limit pool size to no more than 60,000. Do we know if this limit has actually occurred? Are all pools limited to no more than 60,000 as of this date?

We have been told that smaller pool size will result in shortages of plasma derivatives. However, if there happens to be a recall and the pool is smaller, wouldn't it follow that there would be less product to recall and, therefore, less to replace, causing less of a shortage?

There probably are some legitimate additional costs for producing smaller pool sizes, additional testing, and so forth. Do these additional costs warrant the larger, riskier pool size? Two decades ago, industry chose not to utilize the heat treatment procedure proposed to them because it would cost 13 cents per unit. Was that 13 cents worth the thousands of lives we have lost?

My intention is not to dwell on the emotions at this point, but to stress the obvious. In July of 1995, the Institute of Medicine issued its report which was a result of their intense study of HIV and the blood supply, "An Analysis of Crisis Decisonmaking." Many, if not most of those 14 recommendations have either been implemented or at least addressed. We would like to emphasize a few of the items which directly pertain to the subject under discussion today.

To quote from the support language for recommendation number 2, "pooling of plasma obtained from numerous donors, although permitting some economy of scale, also increases the risk that a large fraction of manufactured blood products will be contaminated by a single infected donor." Their recommendation that the Blood Safety Council consider this issue and address the safety and efficiency trade-offs in changing the minimum pool size is part of the basis for today's meeting.

Because blood products are derived from human beings and may contain harmful biologic agents present in the blood of a donor, blood products are inherently risky. This was the basis for recommendation number 5 regarding the establishment of a systematic, ongoing surveillance system within the CDC to detect, monitor, and warn of adverse effects in the recipients of blood and blood products.

In recommendation number 6, IOM urged FDA to encourage, and where necessary, require the blood industry to implement partial solutions that have little risk of causing alarm.

We have been told that pool size has no impact on the transmission of transmissible spongiform encephalopathy. It was pointed out that the last meeting of this panel that we can't prove that TSE is transmissible by blood, but we can't prove that it isn't. Perhaps we should be listening to the recommendations from the IOM and be cautious. The incidence of CJD is said to be one in a million. If it could be proven to be blood borne, then the risk in a pool size of 100,000 would be 1.10. However, the risk in a pool size of only 10,000 would be 1/100.

On the subject of shortages, last January we heard that recalls and product holds because of possible CJD contamination were causing shortages, especially in the immune deficient arena. We are now hearing that reducing pool size could be a reason for shortages. What will be the next reason? Possibly a shortage of healthy donors? What will eliminate shortages? Must we compromise safety to eliminate shortages? Why is it that there doesn't seem to be a product shortage in Europe or Japan? Could it be because manufacturers receive 50% more in Europe and 150% more in Japan for the same product?

There have been shortages reported because of all of these, plus the fact that a manufacturer has had to close their plant due to poor manufacturing practices, as was mentioned earlier. Why must hospitals determine a scale of which patients are the sickest to allot the much needed products when it has been proven that many, if not most of the manufacturers have adequate products in storage which they will not release? Are our communities being held in a blackmail situation?

Intelligent regulatory decisions regarding recalls, holds, etc., need to be made taking into account the way they affect the safety of the product, as well as the effect upon production and shortages. Good management practices and standardized operating procedures need to be used in all areas of production, including distribution and recall. You have already heard this at least two or three times today, and I am sure you will hear it again before we are through. We must base all of our actions on good science and not on political groups.

Each of our consumer advocacy organizations relies on advice fro their various medical and scientific advisors so that we may better inform our constituents. We participate in sessions like this one, attend BPAC meetings and Congressman Shays hearings on various phases of blood safety. We stay tuned as much as we possibly can to all of the things which affect our community and relay that information to our constituents so that they may be comfortable in using products which can help them to live a better life, thereby avoiding those which could cause them harm or death.

We must urge groups such as the Advisory Committee on Blood Safety and Availability, BPAC, the FDA and CDC to use extreme diligence in enforcing research, regulation and surveillance in decision-making regarding blood product manufacturing and distribution, which could result in another disaster for our communities.

We certainly advocate the continuation of stringent testing practices in the blood collection process. However, perhaps we should look very closely at the plasma treatment method proposed to the FDA by companies like V.I. Technologies, which has been called blood scrubbing. It is our understanding that V.I. Technologies hopes to gain approval this summer and follow rapidly with availability of products treated in this manner. We also learned, however, of other biotechnical companies which have similar processes in their ongoing research protocols. If these biotechnology methods are as wonderful as proposed, then we would urge the FDA to grant licensure as soon as possible, or look elsewhere for other solutions.

A few years ago, I was privileged to make an extensive trip to Alaska and found it to be a beautiful, basically pure expanse of nature. One of the many things that stuck with me about that trip was a visit, as near as we could get, to the site of NORAD, our national early warning system upon which we relied so greatly during the period when we feared the threat of Russian attack or invasion. Our country relied upon this safety net, this now defunct system provided to our peace of mind. We need our regulatory agencies to provide that same sense of peace and safety to our communities. If we close our eyes to the dangers arising from pool size and/or shortages, they won't go away but we will pay the price in human lives lost.

In the early '80s we waited for proof that HIV/AIDS would be a threat to our community. We waited too long and look where we are. We must be more diligent and more assertive. As I mentioned at our last meeting, in Europe patients with hemophilia were warned about the possibility of danger from CJD in the blood supply. In our country, we were told it is no threat. Between 1985 and 1995, we had roughly a thousand deaths due to AIDS dementia which could possibly have been CJD. Surveillance did not happen. We must step up surveillance in such matters wherever a death occurs. Let's look ahead and prevent another disaster instead of reacting after the fact.

Let us make a positive statement and address the real reasons for shortages in plasma derived products. We have two communities with different needs who both rely on plasma and derived products. One has needs possibly in contradiction with the other. Neither community should be at risk because of the needs of the other.

We would advocate for separate production lines which would protect both communities because unnecessary risks are unacceptable to both. We hope for a continuation of a heightened regulatory climate with recalls when necessary for safety.

We have been led to believe small pool sizes increase shortages. It would seem more likely that the larger the pool size, the larger the recall and, therefore, the larger the shortage. We urge the FDA to continue with their recommendation to BPAC to encourage a pool size of 15,000 now with a potential to possibly get down lower, if at all possible.

With a reminder that we subscribe to the basic premise that good public policy should be rooted in science, there is no way to justify the large pool size for hemophilia products in terms of safety. We urge consideration of pure recombinant products as a national standard for all clotting factor used in hemophilia treatment.

Once again, we stress that it is not our wish to request standards for hemophilia products to the detriment of the immune deficiency community. Good manufacturing practices, standard operating procedures with high quality assurance goals, and active, enforced surveillance practices will only spell success for all parties resulting in a healthier nation. Thank you.

DR. CAPLAN: Jan, what I am going to do is ask Glen Pierce if he can step forward. I will ask you and him to then be available for some questions, just in the interest of time.

MS. HAMILTON: Sure.

DR. CAPLAN: I am hoping too that Dr. Pierce can be as concise as possible in the interest of time. Also, while I have the mike for a second, I will warn Dr. Morgan that he will face the ultimate triage test of abutting lunch.

DR. PIERCE: Thank you. What I would like to do in the time I have is to thank you for the invitation to speak on behalf of the National Hemophilia Foundation on blood safety and availability. The NHF is 50 years old this year. It has 43 chapters and staff in New York, and hundreds of volunteers, like myself, who work at the national level to move the agendas forward for the community, which include research, outreach, as well as advocacy. Much of this in recent years has focused on blood safety and availability. In addition, we have a number of projects ongoing with the CDC, as well as the NIH, which also have an effect on this.

On the first slide, what I would like to do is to just give you a brief overview of the different coagulation factor concentrations that are available for the treatment of hemophilia. The first slide shows plasma-derived clotting factors. You can see that there is a variety of them that are used to treat various types of bleeding disorders.

What has occurred in more recent years is the availability of recombinant DNA produced products. There are two manufacturers of Coagulation Factor VIII that have been on the market for a little over three years. Now there is a Coagulation Factor IX that has been on the market for about a year. So, that covers the majority of individuals with hemophilia, but not everyone. There are products in development that would cover most of the rest of the individuals, including patients with inhibitors as well as individuals with severe von Willebrand's disease, and we are anxious to see those get developed.

There are a lot of opportunities for improved treatment at this point, but the goal is to prevent bleeding episodes, not to treat bleeding episodes. So, when you think about it, in the hemophilia community much of the treatment is reactive; it is not proactive, and that is a problem.

I would like to go through a number of the recommendations that the Medical and Scientific Advisory Council for the NHF has proposed over the past few years. This is a group of leading hemophilia treatment center physicians -- Keith Hoots actually is vice-chair of this group at this point -- as well as a number of consumers, who meet on a regular basis to consider recommendations for the treatment of bleeding disorders. I think you have all received a copy of the latest recommendations.

What I would like to do is to highlight a few of these recommendations with regard to the standard of care and recombinant products, because we actually do have a standard of care out there. The first one, in October of 1995, says individuals with hemophilia A and their care providers should consider the use of recombinant-derived clotting factor as the first choice for replacement therapy. This came out several months after recombinant was first available.

In addition, another bulletin in February of '98 was the most recent update, which is what you got, says that the risk of human viral contamination is definitely lower than for plasma-derived products. With regard to Factor IX, because of differences in manufacture and how the product is treated during manufacture, we have said that the risk of human blood-borne viral contamination is essentially zero.

Then finally, to cover the issue of reactive versus proactive treatment, several years ago, in 1994, MASAC recommended that prophylaxis be considered optimal therapy for children with severe hemophilia A and B. That has become a standard.

These kinds of recommendations have been used by a number of insurance companies at hemophilia treatment centers to get reimbursement for the products, but it is not uniform at this point and there are a number of cost concerns that prevent everyone from using the products.

I would like to cover the supply shortages. This is a partial list of products over the past year or so that have been in short supply in our community. Supply shortages are not of the magnitude at this point that the Immune Deficiency Foundation reported, but we can sympathize with that because about ten years ago we had severe supply shortages, very much along those lines.

At this point, it has been a cyclical thing. In other words, some products are available; others are not. Later on, as supplies open up for manufacture, the first product becomes available and the second one is in short supply. So, it has been a little bit of a juggling act this past year but, as you can see, it affects a wide variety of products including the recombinant products, for reasons that I will get into.

What is causing those supply shortages? We are going to hear quite a bit more about that from industry as well as the FDA. From our point of view, we do think that insufficient product is being made as a result of consent decrees on two manufacturers, as well as inadequate manufacturing capacity, inadequate prediction of the move to recombinant product in our community. We do know that a lot of product, both plasma derived as well as recombinant product, is exported, as you have already heard. There are some off-label uses, such as the use of some of these products to treat patients with von Willebrand, but that is really not a major burden on supply in this country. Then, a minor contribution is from withdrawals and recalls.

I guess from our point of view, we are unclear as to why over the past 6-12 months we have been unable to get better numbers to understand exactly what the causes of the supply shortage are. It seems to us that the FDA does have the regulatory authority to obtain those numbers. We will look forward to hearing them from industry as well as the FDA later.

I want to briefly cover pool size because every time that is mentioned the question of supply also gets mentioned. I think we are all very familiar with the FDA data that was published a few years ago. Not surprisingly, we would have a different interpretation of that data. We believe that smaller pools do afford significant protection against both prevalence and emerging threats.

In addition, we are not sure that there is really an issue between serving the needs of the Immune Deficiency Foundation patients and the needs of the hemophilia community. In my discussion with manufacturers, and this may be very naive so I would very much hope for some clarification, small pools are put onto manufacturing runs, and then for both products they are pooled into much larger sizes for lots. Well, all that means is that you are pooling different amounts of these small runs for coagulation products and IVIG products. IVIG products could be as large as they need to be, and coagulation products can, in general, be at least 15,000 L or less, just on the basis of that. I would be very interested in hearing if I am incorrect in that assessment. So, that means that there really is not a dichotomy between what is good for immune deficiency patients and individuals who use coagulation products.

We think that smaller pools would lessen the impact of withdrawals. No one seems to have agreed with us on that. So, maybe from the industry perspective that is not true. We will just have to find that out.

Lastly, common sense dictates establishing limits. Whether you call it common sense, or good scientific practices, or epidemiology 101, when you have an emerging threat the thing to do is to contain that threat, and it is not contained when you start mixing a little bit of this pool and a little bit of that pool, and before you know it you have over 100,000 donors. That doesn't work.

Well, I have covered a little bit of this before. Why is viral elimination important? You have heard about the unprecedented loss of life in our community. I would just like to point out that in addition to the synergy that has been identified between HIV and hepatitis C, where one makes the other much worse, there is also a synergy between hepatitis C infection and new hepatitis A infection. We took a lot of criticism a couple of years ago for urging that some potentially contaminated product with HAV in it be removed from the market immediately, and the reason for that was that no one thought that HAV was much of a risk. We had found some studies in China that suggested that there was a risk, and now, in the January issue of the New England Journal, there is a more definitive study that says that if you have HCV you are much more likely to die from HAV infection. So, that is just one example of the need for caution and the need to make the assumption that you are dealing with a patient population that is infected with multiple viruses and, for that reason, one needs to have even more caution.

Another dichotomy here is really the kind of elegant studies that have been done by Jim AuBuchon and Mike Busch, looking at cost-benefit ratios for single-donor components and individuals who have to receive those. Those are very, very different for people who start life-long infection in infancy and potentially become infected in infancy. So, even things like parvovirus, which may be relatively benign in most individuals -- it is relatively benign in most individuals, but what is the effect of infection during infancy and then repeated exposure to parvovirus, which is exactly what is occurring in plasma-derived concentrates?

What is wrong with this picture? I think that these are issues that we have been discussing for the past few years and, although there has been some movement for them, for the most part there has not been much movement. The inactivation methods, as you are all well aware, are not effective on non-lipid envelope viruses, and although we are concerned about those, what we are more concerned about are undiscovered agents that are going to emerge in the blood supply that aren't going to be inactivated. That is where individuals who chronically use the blood supply over a period of a lifetime can really be impacted, as we have seen.

In addition, I think everyone would agree that transmission of the transmissible spongiform encephalopathies is poorly understood at best. A number of predictions have been made. A number of conclusions have been drawn on the basis of very incomplete facts, and I will cover that in a few minutes.

I would also like to point out that we continue to have morbidity and mortality from actual bleeding episodes. Treatment costs are exorbitant, in the range of $50,000 to $100,000 a year, and if I were to prophylax the treatment cost would be two to four times that amount. It is almost untenable for adults to prophylax with these kinds of costs.

There is insufficient recombinant Factor VIII. The supply is not in any way meeting the demand. In addition, the recombinant Factor VIII continues to contain a human serum albumin stabilizer. From our point of view, that has made no sense over the past several years. We are encouraged that the manufacturers are making progress to remove the blood product from the synthetic product.

Finally, I just want to point out that recombinant Factor IX has been available for a year. There are now a number of anecdotal reports from the field that suggest that its efficacy is not uniform; that in some cases it takes up to 600% as much material to treat a bleeding episode as it does the plasma-derived material, and it is premium priced. It is higher than any other of the commonly used factors.

So, there are a number of concerns that are beginning to emerge that the Factor IX patients, as we move toward recombinant product, are not going to be uniformly brought along because of this.

In the final few minutes, I would like to turn back to CJD and just refresh our memories about how we got involved in this. It started at that December, 1994 BPAC meeting where the recommendation was to destroy single-unit components that were contaminated by a CJD donor, but to release the pooled plasma products. I think what amazed us the most at that meeting was that there was absolutely no data to suggest that the pooled product was safer than the single-unit components but, in fact, the question became it is either safe or it is not. If it is safe, then why are you withdrawing the single-unit components?

So, we felt that that was a contradiction, an enormous contradiction. A lot of questions were raised about the cost of those withdrawals and the supply, but there was absolutely no data presented, and decisions were made on the basis of no data. To us, as we read the transcript from ten years earlier, the transcripts for that December 1994 meeting looked remarkably similar.

After that meeting, we felt that products should be guilty until proven innocent if they are implicated, a very new way of looking at it, and not a way that has been traditional in the over the past 20 or 30 years since these products have been used.

We also called for research to answer three questions, much of which has been done and you have heard about. Is there any CJD in chronic blood product recipients? The answer at this point is no, but the incubation times are low and the numbers are very small when you are dealing with a very rare disease.

Is the CJD agent transmitted in animals by blood products? Yes. Does it partition the specific plasma fractions? Unfortunately, yes. Can CJD in plasma products be inactivated or removed? We initially thought that that may not occur but there has been some recent work done by several labs including the Red Cross that suggests that maybe there is a way to inactivate or sterilize these plasma products for CJD agents.

There are a lot of scientific reasons that the potential exists for transmission of CJD, and I won't spend much time on this except to say that there are components in the blood that can metabolize the normal pre-N protein to the abnormal protein. It is clear from the work of Drone, Brown and Rhor that you have already heard about that plasma and plasma fractions can transmit it. In at least one case there has been transmission via transfusion to animals. It sets the precedent for that concern in human beings as well. In addition, it has been well established the oral and parenteral routes, including the iatrogenic CJD.

The new variant CJD is a new concern. It has jumped two species already. It clearly behaves differently than CJD and, as we have heard alluded to, the European authorities are taking a very aggressive approach on the use of plasma from the U.K. in this regard, and don't believe that it should be used.

Our feeling is that although there may be no risk of new variant CJD to chronic U.S. recipients, it is certainly a marker for TSEs and the next one that may come along. Given our level of understanding, it is probably naive to think that it is going to behave identically to a CJD agent.

There are some solutions to this and to future dilemmas regarding safety. We need to further promote the development of reliable donor screening tests for TSEs. Some of that work is being done by industry in collaboration with academics, and it should continue to be encouraged.

We need to call for universal sterilization of blood products. This is something that the federal agencies have not taken a strong stand on and could make a much stronger stand on.

In terms of the hemophilia community, we should to continue to eliminate dependence upon plasma-derived coagulation products, but there are cost and reimbursement issues, as well as supply issues that impact that statement at this point.

Long-term or intermediate term our goal would be a cure, and you will hear more about that from Rick Morgan. So, we would like to see national plans, more inter-agency cross-talk to address these issues. We need a little bit more leadership from the FDA and the NIH, especially when it comes to new inactivation techniques, as well as moving toward better screening tests for these newer agents.

Finally, I would like to finish up by just pointing out a number of the recommendations that were in the February, 1998 MASAC statement that you received. These were specifically to the industry and FDA. We want to see this voluntary initiative from the ABRA and the IPPIA enhanced. We would like to see it taken by FDA and time lines put to it in order to move it forward and get it implemented, including establishing upper limits for viral rate markers at plasma donor centers.

We applaud the fact that genome amplification is being introduced through INDs. We would like to point out that it is being introduced for agents right now that are already inactivated by plasma products, and it would be nice to see it introduced for agents that can still be transmitted by plasma products, such as parvovirus B19 and potentially HAV.

We would like to see coagulation product pool sizes decreased immediately to 15,000 according to an FDA recommendation from a couple of years ago. I have discussed the inactivation removal of these agents. We think that it is up to the FDA to regulate the manufacturers much more proactively. We have read the Code. We think that the FDA has the ability to do it, and to develop and enforce timetables for implementation of these other measures to increase the safety and the availability of blood products. Thank you.

DR. CAPLAN: Thanks, Glen, for that concise presentation. Why don't we open the floor up for some comments and questions? I am going to try and bring us to a halt around 12:35 for a lunch break but we do have time for a little bit.

Maybe I can grab the floor for just one question to either Glen or Jan, whoever wants to wrestle with it. One of the things we heard at the previous meeting about CJD in particular was that it seemed likely that it was endemic in the blood supply; that while we do find donors postmortem who are implicated as CJD cases, that may just be the tip of an iceberg without an effective screening test. Forming a recall policy for something that may be out there, facing anyone who receives blood products, especially people who rely heavily on them, may not be consistent with the best good science. I am just curious about your comment on that.

DR. PIERCE: I think there are two points to make with regard to that. The first point is that in experimental studies there is evidence for increased infectivity as you get closer toward symptomatic disease. So, that is point number one.

The other point is does it make any sense to take something that is obviously infectious and continue to use it despite the fact that there may be some level of infectivity prior to that? I don't think it does.

MR. DUBIN: Just a short comment, I think in the '80s we learned that -- let me back up. We all want to root what we do in good science. What do we do when science doesn't keep pace with emerging threats? CJD seems to present one of those instances. I think we err on the side of caution. We take the cautious regulatory steps. We commit the dollars to research, and if we find out we were too cautious we back off but we don't have a big casualty list when we back off.

DR. CAPLAN: Other questions? Comments?

[No response]

Well, let me try one more. It seems to me we have heard about the pool size issue for sometime now. One of the ways to deal with uncertainty is to try to minimize it perhaps by following pool sizes that seem to pose the least risk and allow for the most convenient and easiest withdrawal of things that potentially might be risky. I would like any of you who have testified to just comment about what has been the hang-up on this pool size matter. Where is the glitch that continues to keep us from following what the recommendation is? I mean going down to the 15,000.

DR. PIERCE: I think it is the refusal by the manufacturers to do that, pure and simple.

MR. DUBIN: I just want to underline what Glen said. I believe when their economy of scale changes because of a potential heightened regulatory climate you will see them jump toward smaller sizes. And, we are concerned that a lot of medical people sit on these panels, and when we watch it is clear that most of them would probably not think this is the safest approach for their patients, and we have been having, as Glen says, this discussion for 10 years, 15 years, and the manufacturers on this one have stood in the way. They have dug their heels in and said no.

MS. HAMILTON: I think one of the ways that we can get closer to agreement on this is in what you have done and what BPAC has done recently, putting more consumers on panels such as this so that we can get our two cents' worth in before it gets to the reactionary stage. Thank you.

DR. GUERRA: How close are we to the cutting edge of technology to try to ensure the elimination of some of these emerging agents that have not yet been identified, you know, beyond just the detergents and vapor treatment? What is the technology there, and at what cost?

DR. PIERCE: The manufacturers have been working on this, and I think that there have been small companies also that have been interested in pursuing this in the hope of selling that kind of technology to the manufacturers. There are a number of approaches out there that should not cost much, won't destroy protein, and may be more universal inactivation agents than the ones that we currently have, or may be additive to the ones that we currently have. Iodine is one approach. There is irradiation. There are a number that have been looked at. But what hasn't occurred is for any sort of a national agenda to appear, either by the NIH or by the FDA, to say this is important and this needs to be implemented by the year 2000 or 2001. And, that is what we need. When we have a deadline you wind up getting results.

MR. DUBIN: I think, again, it gets back to the question of linkages and coordination, and where does the buck stop. Red Cross presented their numbers at the NHF meeting, their early numbers on iodine. They were promising. And, I think you all were looking at transitioning from a lab to a production line at that point and what that might look like in terms of your results. I think there have been promising things on the horizon for sometime now. There has not been the will, regulatory will, the political will to get this job done. Frankly, we don't really want to stand up here any more and hash out pool size. We know that anyone in the same frame of mind would agree that 60,000 donor exposures is not the best way to treat our people. So, we would really like to get on with the business, get this out of the way and get on to some other things that we have to tend to, besides this one, because we have been hashing this one out for an awful lot of years, folks.

DR. CAPLAN: I am going to go to Dana after Jan speaks, and then I will ask Dr. Morgan to get ready to go.

MS. HAMILTON: I just wanted to make one comment regarding some things that were in the press this weekend. It is very disturbing to me that something that is new, emerging technology that could be solutions to some of our problems of the viruses in the blood, could be possibly controlled by an agency that might cause the whole thing to backfire and make shortages again and have different agencies fighting against each other for control of technology. I hope that something can be done to keep that from happening.

DR. KUHN: One of the concerns that I have, and have had all along, is how would a smaller pool size have an effect persons who are using IVIG and alpha-1 product, i.e., also hemophilia? It sounds to me like your medical and scientific councils have really looked into this if they are recommending a 15,000 pool size along probably with recommendations that come from the FDA.

I think what has helped me realize that this is very credible is also the article that we received in our packet of information, the New England Journal of Medicine, authored by Dr. Buckley and Dr. Schiff, in which they said that effective immune globulins have to come from a pool size of 1000-6000 donors, and that was necessary. So, it sounds to me like all of this can line up and is a great possibility. Is this what your medical and scientific councils are also concluding?

DR. PIERCE: Well, I think they can line up, but the conclusion is a little bit different, and I hope that the panel will ask industry this afternoon very directly. Our understanding is that pool sizes are very small during the manufacturing process. They may not be down to 5000 but they are a heck of a lot less than 60,000. In intermediate points in that process they are pooled together to form large lots. So, as best as I can tell, and as best as any of us who have interacted industry and asked specific questions about this can tell, these are unrelated issues. If I am wrong about that, let's get into a discussion about it. But I think it is unrelated. So, whatever the immune deficiency groups need for pool size can be done. Whatever the coagulation factor needs are, that can be done too, down to a certain limit before you have to make changes. But I am not even talking about making changes in manufacturing.

MR. DUBIN: I think we would underline what Glen said, and again say that to us this is a question of will, a question of making the right demands in the right place in the federal system to get this job done and reduce the risk, and stop the debate that just keeps cycling. As Glen, we hope that the industry puts it on the table this afternoon. We are certainly going to be here listening.

DR. CAPLAN: Al right, if I can thank the people for their excellent presentations, and I will ask Dr. Morgan to come forward and try to model himself in the conciseness we have seen exhibited.

DR. MORGAN: I am going to do my best. I am going to whet your appetite for lunch and also for the future therapies for some of the disorders we have been talking about today. Specifically, I was asked to talk about hemophilia gene therapy but the same applies, as already mentioned, for immune deficiency where the first gene trials took place, and also could be implemented for the alpha-1 antitrypsin deficiencies.

So, gene therapy, in its simplest definition, is the introduction of new generic material into the cells of an individual with the resulting therapeutic benefit to that individual. So, you can think about this technology as really engineering the cells of a patient to produce their own drugs. They are no longer administering IVIG; they are no longer administering clotting factor but their body is, in a sense, producing what they need.

For hemophilia, the rationales are profound. I have listed a few here. When you talk about engineering a cell to produce a constant amount of the factor you are going to have a prophylaxis, and certainly we know that for a majority of diseases, if not all, prophylaxis is better than reactive therapy. It should lead to an improved life style. There should be no risk of viral pathogens. Is there a possibility of a cure? We think so; that is why we are doing this work. Will it be less expensive? I don't have a handle on that yet.

There are different approaches by which gene therapy is carried out. In the ideal sense, we would like to do direct delivery where literally the gene delivery vector is injected directly into a patient, or administer by some other route directly to the patient.

There are also protocols which use what we call the ex vivo approach, where cells are removed from a patient and brought into the laboratory. In the laboratory the gene transfer event occurs. The cells are then collected and returned to the patient. Both of these are in clinical practice today.

Because of the shortness of time, I am going to talk probably just about a couple of these approaches to gene therapy for hemophilia, and I have listed four of them here, retroviral, vector mediated, gene transfer, the adenovirus as a gene transfer system, the adeno-associated virus and, lastly, using a skin fibroblast to potentially deliver clotting factor genes.

I am going to talk first about the retroviral vector delivery system, just as a way of introducing the way you modify these existing viruses to deliver therapeutic genes.

So, with all the viral vector systems, the idea is essentially the same. We are going to take an animal virus or even a human virus and adapted to transfer genetic material. If you look at the red box, up in the top left-hand side, that is what we call a vector or a way to shuttle genes around. You can take an animal virus, use recombinant DNA, remove the viral gene and insert your gene of interest.

The trick with most of the viral systems is to take this naked DNA and get it into an appropriate system that produces a viral particle which can then be used for a therapeutic benefit. So, you take this vector DNA, put it into a cell in the laboratory to produce what is known as a helper cell or a producer cell, and now inside this cell you have the retroviral vector which, in this case, makes an RNA, which is shown in red. That then gets assembled around what looks like a normal virus protein coat in a lipid envelope. So, what comes out of the cell, in the bottom right-hand of the figure, is this hybrid biological entity. On the outside, for intents and purposes, it looks like a virus particle, but on the inside all the viral genes are gone, and now we have something that can deliver, in the case of our research, a clotting Factor IX or a clotting Factor VIII to a hemophiliac.

So, some of the data that has been generated, and what are the pros and cons for using this type of system? The advantages of the retrovirus as a gene transfer agent is that after you expose a cell to a retrovirus you get a stable gene transfer. The gene actually goes in and sits itself down into the chromosome. So, it is stable. There is now almost a ten-year old proven safety record on the use of these agents in the clinical setting.

The disadvantage of the current generation viruses is that they require the cells to grow and divide. So, most of the cells in your body aren't growing, so that sort of limits where we can put our current class of gene transfer vectors, and that limits how we can use them in the body or in vivo.

Data from hemophiliac studies have been sort of mixed. We know that the dog model is a nice animal model for hemophilia, and there is in dogs a similar, if not identical diseases as in humans. You can get long-term expression of these clotting factors but they are probably not at the levels you need to be therapeutic. So, they are suboptimal but we can get long-term expression, particularly of Factor IX. Data on Factor VIII are still limited at this date.

One more vector system I would like to mention, just because you may be seeing it clinically soon, is the adeno-associated virus. It is very similar to the retrovirus in design.

The advantage of adeno-associated virus, or AAV for short, is that you can probably get stable gene transfer. So, once you do the gene transfer, it is not a recurrent therapy that you have to do over and over again. We have a potential for in vivo delivery, directly injecting it into the patient, and this is a non-pathogenic virus. Adeno-associated virus is not associated with any human disease.

The disadvantage is that it is a tiny little thing. It is a small virus. So, we can't put the clotting Factor VIII in there without some manipulations which may or may not be possible. But we can do Factor IX probably fairly readily. And, you can make large amounts. For clinical use you may have to make a large amount of this virus and that may test the current production methods. But we have some encouraging data from some of the studies in animal models for application to hemophilia. We know that you can administer AAV vectors to both the liver and to the muscle in animals models and you can get long-term therapeutic levels of this clotting factor. So, there is a lot of encouraging new news on using the adeno-associated virus as a gene therapy vector for hemophilia.

I just want to touch briefly on some of the new directions where we think the field may be going. There are a lot of new viral vectors out there which we will be able to treat for clotting factors back and forth to the appropriate tissues. We have actually taken the HIV virus and adapted it to use to transfer clotting factors. I know that scares the hemophiliac community for obvious reasons, but there is potential for doing this safely, and I think there will be a lot of interest in this vector as a method of transferring genes in the next several years, and we have a lot of data on that.

I want to mention something that our lab has been in interested in, a different way of thinking about gene therapy -- not using a virus, not taking a cell out, culturing it and introducing a gene, but actually ingesting, if you will, your gene therapy agent. So, I will just mention oral gene delivery as a potential for hemophilia therapy.

The rationale for looking at the gut as a target for gene therapy is enormous. There are huge numbers of cells lining your intestines. The small intestine alone has greater than 1011, or probably more like 1012 cells which are targets for gene therapy. So, even if you get a very, very small efficiency of gene transfer, you potentially can hit many, many cells. You have a tissue with is accessible by non-invasive methods of administration. You have rapidly dividing cells that may make them amenable to certain classes of gene transfer agents. And, this organ tissue system is well invested with capillaries and lymphatics which should be able, once the cell is engineered, to deliver the clotting factors readily to the circulation.

We have done some preliminary experiments and show that in animal models you can literally give some of these gene transfer vectors. This is a picture of the small intestine. The dark little blotches are successful gene transfer. So, ideally, in the next few years we want to turn this whole stretch of the intestine blue. For now, we can hit little patches. So, the efficiency is still low but you can deliver these things orally. We will certainly continue to look at that as a method of gene transfer.

Another very interesting and new direction for gene therapy is actually not just giving a gene but actually going in and correcting the defect. So, there is now the potential technology to try to do gene correction. This has been based on studies involving what is called homologous recombination. That is a biochemical term just to look at how DNA molecules mix together and how one molecule can replace another molecule or recombine to form a new molecule.

There has been the use of a non-viral system of gene transfer based on little pieces of DNA, actually a chimeric or hybrid molecule between RNA and DNA. It turns out that in certain contexts these can be engineered and given to cells, and you can induce DNA repair or gene correction.

The way this works is something like this. The gene correcting agent is on the very top. It is the oval, the stretched out oval which is yellow. It has green pieces. The green is RNA and the yellow is DNA. Below that, the squiggle would be a DNA molecule. It is potentially possible to get that chimeric -- chimerplasty is the term picked for this procedure. You can potentially get that gene-correcting molecule to go in between the DNA strands, shown in the middle. Based on the mechanism of how cells repair their DNA when you get random damage, which is what you would do if you went out this weekend and got some nice sun on Saturday, at least if you live here, and you would get certain low levels of DNA damage. There are mechanisms in your cell to repair that. These molecules potentially induce repair. This has actually been done now and reported in a couple of settings, one of which was exciting enough to make the Time magazine a few weeks ago. This is exciting potentially for the people in this audience because the target was the Factor IX gene.

What this group out of the University of Minnesota did in animals was not to correct a hemophilia mutation but to use the same technology to actually induce hemophilia in small animal models. These chimeroplastic ligonucleotides were actually administered to the liver of rats, and that actually potentially induced a defect in the normal rat, such that you turned the normal Factor IX gene into a mutant Factor IX gene. The obvious step is now going on in the laboratory to go into animal models for hemophilia and try to actually go and physically correct that genetic defect. So, there are very exciting technologies on the horizon in the next few years.

Let me summarize this brief overview with this last slide. There is going to be no one universal hemophilia gene therapy or gene therapy for any specific disease. There is going to be a variety of gene transfer vectors which would be necessary to engineer cells to produce clotting Factor IX or clotting Factor VIII. You are probably not going to necessarily use the same virus to treat a hemophilia B Factor Factor IX deficient patient versus a hemophilia A Factor VIII deficient patient.

Based on our current research and what I know is out there, we expect to have pilot clinical trials to be proposed this year or next year at the latest. AAV vectors are certainly on the fast track and there is interest in using skin fibroblasts as a method of delivering clotting factors.

I have introduced some of these new directions on the use of new viral vectors, oral gene delivery and gene correction which are a great promise to the future application of gene therapy for hemophilia.

While our future is clearly bright for the initiation of these gene therapy trials for hemophilia, it is very unlikely that these methods will become the standard of treatment in the next five years or so. But I am convinced, and I am really dedicated to this, that these technologies will eventually be a cure for hemophilia. I will leave you with that optimistic note to go on to lunch.

DR. CAPLAN: Thank you. It is great to see what work is being done. It gives some reason for excitement and optimism. I want to ask you something that isn't related to gene therapy per se and these mechanisms, but just on the use of recombinant DNA technology to make different factors, can you comment on where you think that is relative to the safety issues and so on in terms of genetically engineering the intermediate step before we get there and actually alter somebody's DNA permanently to effect a cure?

DR. MORGAN: Certainly, recombinant Factor VIII and Factor IX are available. Because of the cells they are made with, whether it is the tissue culture cell lines or bacteria, there are subtle differences between the factors which may affect their biological utility. But, certainly, if it is done correctly these can be directly utilized by people with bleeding disorders to correct that phenotype. So, I think a bridge for the next several years would be an appropriate metaphor for these recombinant factors. If the scale-up issues and production capacity are met, they certainly will be an effective bridge and a safe bridge until these new and emerging gene technologies come on line.

DR. AUBUCHON: Could you comment on the potential applicability of gene therapy for treating sickle cell disease, where there is a known and usually single genetic defect that causes all cases of sickle cell disease?

DR. MORGAN: The sickle cell disease and any disease which has as its underlying basis a small, defining mutation is potentially amenable to the last technology that I talked about, the technology which induces gene correction or DNA repair. Even though it was controversial at the time, and still is, the first application of that gene correction technology was to a similar model where we are thinking of targeting genetic defects. There, you would ideally you would be able to go into a hematopoietic stem cell and make the correction which would then be a progenitor for the red blood cells.

DR. AUBUCHON: Is it possible it could induce an immune reaction in that individual, it being a different protein than the one that is usually formed, or would this possibly induce a tolerance situation? Has that been discussed?

DR. MORGAN: There has been some discussion. There was a large hemophilia gene therapy meeting last September, I believe, at the University of North Carolina at Chapel Hill, where a lot of these issues were discussed. Whether, if you are delivering a clotting factor via a viral vector, would that potentiate an inhibitor formation, for example. Certainly, we know that there are some classes of viral vectors that are particularly immunogenic. So, it would certainly not be a first choice to deliver a clotting factor using an adenovirus vector because you know it is going to potentiate immune response and, therefore, you might have more potential to develop inhibitors. There are laboratories including ours, trying to get a handle on this now to ask in animal models for inhibitor formation if you deliver the clotting factor via a direct intravenous infusion versus delivering the same factor via a viral vector, do you see any difference in inhibitor formation? Clearly, it is necessary to address that very important issue.

MR. WALSH: Your opening comment, Dr. Morgan, regards IVIG and also alpha-1 antitrypsin deficiency in gene therapy. Alpha-1 is obviously one of the simplest genetic deficiencies identified. Where do you see gene therapy on the horizon for alpha-1 antitrypsin deficient patients?

DR. SCHIFF: Along the same lines, genetic disorders, such as Wilson's disease, will be corrected in the future by cell transplants rather than liver transplant corrects hemophilia. Do you see a place for cell transplants, and in this case we would have to embrace endothelial cells, as a solution to diseases like hemophilia?

DR. MORGAN: Yes, there is a lot of research already involving transfer of alpha-1 antitrypsin gene. The main obstacle there is the level that you need, which is a fair amount. Cell and organ transplantation -- I think have the same limits for using them for gene correction as they do when you need an organ transplant for other reasons. I think if you could come up with the appropriate delivery method of perhaps mass producing a certain tissue which could produce clotting factor and then administer that factor so you had a generic cell type which you could then use in multiple patients -- the key here for all of these therapies is that, unfortunately, a lot of the gene therapy strategies are individualized. So, even though we may provide a cure for a patient, you are still going to have to deal with a patient for each treatment, and perhaps even sequence that patient to individual mutation. So, if you could get some delivery system where you could perhaps have even an implantable device which could have a cell in it which produced clotting factor, that would be great way of treating a variety of disease.

DR. CAPLAN: Thank you. We are going to reassemble at 1:30. We will be right on time. Let me ask that when we come back the people in the first session, just so we try to keep ourselves roughly on schedule, be prepared to go at 10 minutes maximum presentations. What we are going to do today is, instead of having our general discussion as indicated on the agenda at the end, we will try and build it back in to allow for more questions at the specific presentation times, because we do have time to talk tomorrow too about these issues. See you at 1:30. [Whereupon, at 12:50 p.m., the proceedings were





recessed, to be resumed at 1:30 p.m.]



AFTERNOON SESSION





DR. CAPLAN: We are going to begin the afternoon panel with an overview of another area where blood product is needed and where shortage may impact, and that is alpha-1 antitrypsin, and the material used to treat that. Mark Brantly, who is a senior scientist at the National Heart, Lung, and Blood Institute of the NIH is going to be our first speaker.

DR. BRANTLY: Thank you, Dr. Caplan, and members of the advisory board. What I would like to do is give you an overview of alpha-1 antitrypsin deficiency. I am sure that Dr. Walsh has given us a good description in the past alpha-1 antitrypsin deficiency but I would like to review it with you, to sort of give you some background.

Alpha-1 antitrypsin deficiency is a relatively common inherited disease, with at least 50,000 to 75,000 individuals in the United States that are affected. It is along the frequency of cystic fibrosis. It is a very easy disease to make a diagnosis of. Typically, the alpha-1 antitrypsin deficiency levels are about five-fold lower than normal. In contrast to cystic fibrosis, it is predominantly a single gene defect. PIZ is the major genetic abnormality associated with the profound deficiency.

The disease is most often characterized by having lung disease, emphysema, and asthma in about 45% of the individuals. It is also the second most common reason for liver transplants in children in the United States. The average FEV-1, that is, the amount of air that you can force out in one second has a decline of approximately 83.5 ml per year in a group of individuals who have FEV-1s between 35% to 79% of predicted.

To sort of give you a perspective on how much increase in rate of decline in lung function that is, a normal individual loses around 50 ml of lung function or about an ounce of lung function per year from about age 22. So, these individuals have a 4- or 5-fold faster decline in lung function. As you can imagine, we only have about 4 L to start off with and it doesn't take very long to get down to the state of breathlessness.

The asthmatic component oftentimes correlates with rapid decline in the lung function, and we have had IV augmentation therapy in the form of alpha-1 antitrypsin or Prolastin for approximately 10 years now.

This is a high resolution thin section CT scan of an individual with alpha-1 antitrypsin deficiency. What is really impressive about this individual is that basically he was totally asymptomatic until he developed a pneumonia. Immediately following pneumonia, as you can see at the far right-hand corner there, he basically dissolved his lung in a period of about 3 or 4 weeks. This gentleman went from being a normal individual to basically an individual that was essentially a pulmonary cripple within about a year or so. Again, the profound effects of the absence of protection of alpha-1 antitrypsin are sort of illustrated on this type of a picture.

The reason why this occurs, and if you were to cut that lung and look at it, what you would see is sort of almost in the dead center there are some normal air sacs, but as you can see on the top, there are air sacs that are greatly dilated. That is basically what you see in the lung of these individuals after the ravages of infections.

Alpha-1 antitrypsin is a sugared protein that is made predominantly in the liver, and it is an acute phase reactant. What that means is that basically it is an endogenous anti-inflammatory molecule which basically goes up in response to lung infections or any other type of infections. It has sort of a loop that sort of sticks out that has oxidizable methionines on it. Basically, the function of the molecule can be inhibited by different types of oxidants.

It inhibits a whole array of proteases or destructive enzymes. Probably the most important destructive enzyme that it inhibits is the omnivorous protease neutrophil elastase, which can basically degrade just about all types of lung tissue, including cells that protect the lung from infections also.

The way it does this it acts as a molecular trap. That is, the alpha-1 antitrypsin, which is on the left side there, basically has a loop that sort of sticks out acting as bait. It is cleaved right there when the neutrophil elastase interacts with it and it basically hugs onto the molecule with a sort of kiss of death. It basically takes out this neutrophil elastase molecule so that it can no longer degrade tissue.

The concept of why this causes lung damage is basically sort of engendered in this protease, anti-protease homeostasis hypothesis. That is, if you can imagine inside the lung there is a balance. Typically, the balance is the other way with alpha-1 antitrypsin basically tipping it far in favor of anti-proteases. In alpha-1 antitrypsin deficient individuals over time, they begin to accumulate neutrophil elastase in their lungs, which is then sort of the onset of degrading of their lung tissue.

Indeed, what happens is that basically over time, in the normal lung when the neutrophil releases neutrophil elastase there is no damage to the air sacs. In a deficient lung there is no protection, and when there is no protection basically that portion of the lung can be damaged.

What we are left is, instead of the normal air sacs on the left-hand side, you basically have dilatation of the air sacs and loss of the functioning units that allow for exchange of oxygen.

It is a little bit more complicated in some ways though, and there are probably at least three phases to the lung destruction. There is an initiation phase, which can either be cigarette smoking, infections and probably even allergic components. There is a phase in which the inflammation in the lungs is sort ramped up with recruitment of neutrophils and inflammatory cells. Finally, those toxic metabolites are basically released to damage the tissue. The real issue is how can we prevent the damage that is associated with the effectors of injury?

When you basically have unimpeded damage that is occurring, probably one of the most important things to recognize is the fact -- as you can see on the right-hand side, there is a graph of individuals that have alpha-1 antitrypsin deficiency, and you can see some of the dots. These people are losing as much as 250 mL or their lung function at a time, which is basically more than 10 times faster than normal. You can see at the top there, there are individuals that basically have normal lung function and how fast they lose also.

Oftentimes these major drops in lung function are associated with acute events, primarily pneumococcal pneumonias or viral pneumonias that bring in the neutrophils in response to fighting the infection, but because there isn't any alpha-1 antitrypsin around to control the ravages of the neutrophil elastase, it then goes to damage the air sacs.

To sort of bring home what the consequences of this are, this is a life table analysis from a study we did at the Heart, Lung and Blood Institute about seven or eight years ago, where we compared a Kaplan-Meier life table cumulative survival in individuals. You can see at the top of that curve the normal population, and at the bottom are alpha-1 antitrypsin deficient individuals. What you can see is that normally at age 63 85% of the American population was alive, but if you had alpha-1 antitrypsin deficiency only 16% of the population was alive. So, it profoundly affects, obviously, these people, and the effect is that they develop breathlessness in the prime of their lives, usually in their 30s, when they have young children at home.

The potential therapeutic strategies, the things that can be approached are obviously treating infections early on, the pneumococcal and influenza vaccines, obviously to stop smoking if somebody has been smoking, and avoid dusty environments. This basically will sort of keep the protease as low as possible.

Then, obviously, there are other approaches. One is to stimulate the liver to make more alpha-1 antitrypsin, which has not been particularly successful. There is some pharmaceutical development that is going on, making inhibitors to neutrophil elastase and damaging enzymes but right now probably the major form of direct therapy for alpha-1 antitrypsin deficiency is augmentation therapy with pooled human alpha-1 antitrypsin. Basically, the principle is to replenish the amount of alpha-1 antitrypsin that is absent in alpha-1 antitrypsin deficient individuals.

Basically, what we want to do is convert people to the left side of this particular graph. That is, we want to increase the amount of alpha-1 antitrypsin until this balance tips back over. Again, there is also a burden of neutrophil elastase so sometimes it probably is more likely that we have to push up even more the amount of alpha-1 antitrypsin that we give individuals.

This is one of the original studies that was done as augmentation therapy. The current FDA-approved methodology of giving augmentation therapy is to give 60 mg/kg of alpha-1 antitrypsin, and basically give it once a week in these kind of doses. What you get are these rapid rises in the amount of alpha-1 antitrypsin, dropping down to a nadir and then re-dosing again. This has been sort of the standard for the last ten years.

One of the things that is the most impressive in augmentation therapy at the present time is that it has had a remarkable safety record. There are no reported cases, that I am aware of, of transmission of any viral diseases at the present time. There have been some acute reactions, but primarily they were associated with specific lots very early in the process.

This is basically a scheme of the way alpha-1 antitrypsin augmentation therapy has been developed over time. The 1980s was really sort of the beginning early on in the pulmonary branch of the Heart, Lung, and Blood Institute. Five subjects were initially tested in a primary pilot study. Around 1985 and 1987, clinical trials were done with Cutter, which later became Bayer Pharmaceuticals, and with a weekly trial with Centeon. Subsequently, a whole series of developments have moved along. That is, we have looked at both recombinant and aerosolized alpha-1 antitrypsin. In 1988, FDA approved Prolastin. Then over the last ten years, basically with the onset of the national registry, we have been evaluating the efficacy of augmentation therapy. Finally, in the last two or three years, two other plasma product companies have become interested in also manufacturing alpha-1 antitrypsin, which includes Centeon and Alpha Therapeutics. The hope is that at least in part the entry of other companies into the development of alpha-1 antitrypsin deficiency treatment specifically will enhance our patient community substantially.

Again, obviously the goal is to provide these individuals with the protection they need so that when they have a pneumonia, when they develop an infection it is not a life-threatening infection. In general, when a normal individual gets a pneumococcal pneumonia, if you were to take a look at their lung afterwards and take a CT scan of it, you would find that there is no damage at all to their lung, or very little damage. In an alpha-1 antitrypsin deficiency individual who is not taking alpha-1 antitrypsin that gets a lung infection, basically that portion of the lung where the infection resided is gone. Thank you very much.

DR. CAPLAN: Thank you. There may be time for one or two quick questions. Let's go to Dr. Gomperts.

DR. GOMPERTS: Has the subcutaneous route been evaluated?

DR. BRANTLY: Not that I know of. I don't think anybody has looked at subcutaneous.

DR. GOMPERTS: This could certainly modify your peaks and troughs.

DR. BRANTLY: Indeed, the half-life of the drug is actually about 4.5 days. If you were to look pharmacologically at the area under the curve, in other words, to sort of level out those peaks and valleys, one would consider giving it more often and that would give you higher steady-state doses. The problem is obviously that you want the convenience of giving an IV product more often than that. So, as far as I know I don't think anybody has attempted to do any kind of trials with subcutaneous at the present time.

DR. GUERRA: Any pathology of the liver?

DR. BRANTLY: The pathology of the liver is basically an accumulation of the Z alpha-1 antitrypsin protein. It is actually not a storage disease though. The liver has an exquisite system of being able to degrade misfolded proteins, of which the Z protein is one. In actuality, they don't accumulate very much. So, the pathology is primarily periportal or around the portal veins and the bile ducts. It is not a storage disease per se.

DR. GUERRA: So, there is no way to alter the progression within the liver per se.

DR. BRANTLY: Actually, there are investigators currently working on basically modifying the degradation of the protein at the present time. My laboratory and a couple of other laboratories around the country are actually looking at these particular types of approaches also. I think we are a long ways off as far as therapeutics. We are tinkering with some very basic mechanisms regarding the transport of proteins at the present time.

DR. SCHIFF: Along those lines, two things. One, the histology question is a classic picture that you can see on H&E, cherry spots, where you can spot any alpha-1 antitrypsin deficiency. Them they use a PAS diastase resistant stain and they light up all over. There is more there than meets the eye sometimes. But, anyway, to get at the practical question, when you are treating the people with emphysema with alpha-1 antitrypsin, or prophylactically to prevent it, do you see any either positive or negative effect on the liver since the defect seems to be coming from the liver and I don't think the alpha-1 antitrypsin would necessarily help the liver? I don't know. I am asking.

DR. BRANTLY: Absolutely not. I followed the largest cohort of patients in the United States, in fact probably in the world, and I followed very closely their liver function and we have never seen any adverse effects related to augmentation therapy.

DR. SCHIFF: Good. Have you seen any benefit?

DR. BRANTLY: No.

DR. BUSCH: It is just a question of safety you alluded to, how many patients have actually been treated, and what is the basis for the safety? Do we know? Is it the partitioning during the fractionation?

DR. BRANTLY: I think that, number one, there are more than 2000 people in the United States that have currently been treated with augmentation therapy, and the vast majority of them have been treated up to ten years now. So, we have many, many thousands of infusion sort of experiences regarding augmentation therapy.

Probably the reasons for the safety are, number one, it is from the 4B con-fraction. It is at the end of the purification process and, in addition, there are at least two methodologies that are fairly widely applied, the heat treatment for 10 hours at 60 degrees centigrade using a stabilizer or detergents to basically prevent any kind of viral transmission. Both of these seem to be remarkably effective, at least in our patient population at the present time.

DR. CAPLAN: Okay, thank you.

DR. BRANTLY: Thank you.

DR. CAPLAN: Next we will hear from the Alpha-1 National Association. We have Sarah Everett and Sandra Brandley coming forward.

MS. BRANDLEY: Hon. Chairman and committee members, thank you for allowing me the opportunity to address you today. You have already heard articulate and eloquent comments from members of the immune deficiency community and the hemophilia community. It is our intention to add to the picture of alpha-1 antitrypsin deficiency and the plasma product crisis we are now facing.

My name is Sandra Brandley, and I am the executive director of the Alpha-1 Antitrypsin Deficiency National Association, headquartered in Minneapolis, Minnesota. Our organization was established in 1991 to act as an advocate and to provide support and education for people with alpha-1 antitrypsin deficiency. Alpha-1 is the most common lethal single gene defect of Caucasians in the United States. Nearly 100,000 people are believed to carry the severe form of the deficiency, yet only 5% are identified.

You may ask how can that be. When symptoms of shortness of breath on exertion, cough, wheezing with infections and year-round allergies and frequent lung infections occur in people who are in their peak child-rearing and earning years, health care professionals logically look to more common diseases such as asthma, allergies and smoking-acquired emphysema. Panacinar emphysema is the most common manifestation of alpha-1. It is ordinary for someone with alpha-1 to see several doctors over a dozen years before an accurate diagnosis is made.

For those affected by alpha-1 antitrypsin deficiency, once diagnosed, their lives and hopes and dreams, and those of their families are forever changed. Hope is offered through replacement of the important protein they are missing in the form of Prolastin, a product produced by a single manufacturer, a product with a low yield from a large pool of plasma. This hope comes with a price tag that averages $30,000 each year for the drug alone at current recommended doses. No IV tubing to infuse it; no health care person to supervise; just this small vial of liquid hope, hope that they will be able to be productive members of our society; hope that they will be able to provide shelter, food and clothing for their families through gainful employment; and the simple hope we all take for granted, that they will see their children grow up.

This liquid hope provides a shield to protect those with alpha-1 from simple things, like colds and respiratory infections, things you and I throw off in seven to ten days. For someone with alpha-1 a cold can be a month-long ordeal. A respiratory infection may lead to disability, a transplant list or death.

Now that hope is threatened. Every day I receive calls from those with alpha-1 or their physicians trying to secure their share of this liquid hope; trying to understand the reason behind the shortage. Every day I hear the panic in the voices of alphas who know their lives are healthier because of Prolastin, and who are now denied it. Every day I hear the fear and dread in the voices of those who find their world smaller because of the fear of catching something if they go among friends while not protected by Prolastin.

This fear was magnified by the early lack of information about the reason for the shortage and subsequent mixed communications. In January, we were warned that a shortage was imminent, but it was not until March that the picture was fleshed out. Now we are almost to May and the shortage seems to be at a peak. Rumors are rampant and panic is high.

An example of this fear and dread is illustrated by the change in attendance anticipated at our national conference. Last year, 375 individuals affected by alpha-1 attended the national conference. This year, we hope to see 275. They call to say, "I would love to go but I'm afraid of a crowd; I can't get enough of my Prolastin."

I hear of children with a liver manifestation of alpha-1 antitrypsin deficiency receiving Prolastin, which is an off-label use. I hear stories of pharmacies or home care companies making medical decisions on who gets product and who does not. I hear of wholesalers who are selling to the highest bidder, and distribution decisions based on who will pay.

The northwest seems to be disproportionately affected. I receive two calls from this area for every one from the rest of the country. However, some areas seem to be totally unaware of the shortage as no one has missed a treatment or even had one delayed. Why is there this disparity in distribution? We need a safe, reliable product with equitable distribution.

The threat of CJD hangs heavily in our community, as it does in many other communities, and I understand that research is moving forward in this area. In my mind, this is a warning shot that we will continue to see emerging virus and virus-like infective agents appear. Haste needs to be made in the development of recombinant products, while ensuring the safety of the biological products we currently depend upon.

A national notification program is essential in allowing those with a dependence on biological products the opportunity to make informed decisions and to be proactive in protecting their own health. A system which educates distributors and provides checks and balances to ensure the cooperation needed. The current system falls short as wholesalers and pharmacies may fail to notify users of withdrawals or recalls.

In the most blatant case, an alpha was told by his distributor that they would not exchange or provide a refund to him for vials of Prolastin identified in a recent CJD withdrawal. These vials currently sit in his refrigerator because he refuses to infuse a withdrawn lot. How dare they not abide by the manufacturer's instructions to return for refund or replacement withdrawn product?

For all the darkness the shortage has created, it has also allowed us to bring to your attention the human cost and the critical needs, as yet unmet, in the community of people who rely on biological products.

Thank you again for the opportunity and for your attention.

DR. CAPLAN: Thank you, Sandra. Why don't we hear next from Sarah?

MS. EVERETT: Thank you. My name is Sarah Everett. My purpose here today is to put a personal face on alpha-1 antitrypsin deficiency and the current Prolastin shortage. I am a 55-year old divorced mother of two. I am also the secretary-treasurer of the Alpha-1 Foundation. The mission of our Foundation is to promote research for better treatment and ultimately a cure for alpha-1.

I was diagnosed five years ago, following a hospital stay that resulted from a severe case of pneumonia. I was lucky. I was started on Prolastin immediately, and I have been on it continuously since. My lung function is currently 32% of predicted. My prescribed dosage has been increased twice in five years following infections, and also tests revealing that my Prolastin levels were not being maintained.

My testimony today will focus on the effects of the current Prolastin shortage, on my fellow alphas and me, and I will make a series of requests of both industry and government on behalf of our community.

First, a few brief words as to the progression of the disease from a personal point of view. As Dr. Brantly has previously explained, alpha-1 antitrypsin deficiency is an inherited form of emphysema. It is a progressively debilitating lung disease which eventually results in death. It strikes early, usually in one's 30s and 40s.

The first symptoms, frequently ignored, as I did, are usually shortness of breath upon exertion and/or increased frequency of lung infections. Over time, such symptoms exacerbate generally very quickly until full-time use of oxygen is necessary in order to live. From that point on, only two current options exist, lung transplantation or death.

The effect of augmentation therapy on the progression of the disease -- in the experience of the alpha community, the advent of Prolastin has been life-saving. For some, myself included, who are lucky enough to have had Prolastin already available at the time of diagnosis, we were able to continue to work to support ourselves and our families. For example, Prolastin allowed me to continue to work as a New York assistant attorney general. As a result, my youngest was able to complete her college education. For others, not so lucky but who previously suffered yearly from repeated and severe lung infections, since beginning weekly Prolastin infusions the frequency and severity of such infections has greatly diminished. Finally, for virtually all of us Prolastin has increased both the length and the quality of our lives.

Now the effect of the current shortage on our community -- first, I must point out that the shortage is not evenly distributed throughout the community. There are some of us, for example, as I understand it those who receive their product by direct shipment, who are still receiving 100% of their product. Others of us, such as myself, have been receiving only 50% to 70% of their allocation. For still others of us, Prolastin therapy has been suspended indefinitely.

With respect to those of us whose allocations have decreased, what are our fears? Our principal fear is the fear of infection. With infection, as Dr. Brantly described, elastase levels increase dramatically. In a normal person your antitrypsin levels also increase proportionately. Not so with alphas. The only way to increase antitrypsin levels is to increase the frequency of infusion, the amount infused or both. These are steps, until the current shortage, that many of us have taken successfully, most recently myself this past winter.

There is also a fear, even without infection, of more rapid deterioration with or without increased infections. Without Prolastin, many of us fear that our symptoms will be exacerbated very quickly, leading first to full-time oxygen and ultimately to the Hobson's choice between transplant and death.

Finally, I would like to offer a series of requests both to the committee, to government and to industry on behalf of our community. First, we request that you change the allocation system to a patient allocation system. We realize that this will take time and, of necessity, involve a neutral third party, if I am correct. But we believe this is the only fair way to deal with our community and it must be a first priority.

Second, we request that somehow you increase production of Prolastin sufficient at least to meet patient demand over the short term, and by that I mean over the next 12 to 24 months at least. Don't let us down now. Allow us to continue to lead as healthy and productive lives as we can.

Third, we request that you support efficacy studies with respect to increased levels of augmentation therapy. Such studies would, hopefully, document and verify what many of us have already discovered on an individual trial and error basis.

Fourth, we request that you support and promote development and trials of new therapies as quickly as possible. We all hope eventually for a cure for alpha-1 antitrypsin deficiency. Additional new therapies, however, are a realistic short-term goal.

Finally, I must point out that ours, to date, is a small community. To date, only 5000 members approximately have been diagnosed, 2600 of whom are currently on Prolastin. Because of our numbers, with respect to investment in novel therapies, our community doesn't represent the same profit motive to industry as some other prominent disease communities do. Because of our numbers also, our community doesn't have the political visibility to grab the attention of appropriate legislative and regulative authorities who could provide us with the assistance that we need.

Adding insult to injury, the delivery system for at least one such new therapy, as I understand it, is already available. Within the last week, I was provided with this new Cerevent discus to replace my old Cerevent inhaler. As I understand it, one such new therapy would deliver Prolastin like this as an inhalation powder. It is there theoretically but in fact we don't have it.

All we ask for is a level playing field. Give us the same chance that other larger disease communities have been afforded. Thank you.

CHAIRMAN CAPLAN: Thank you.

Let's go straight to our last presenter, who I think is back there. Yes. That must be Julie.

MS. SWANSON: It is. My name is Julie Swanson, President of the National Alpha-1 Association. I, too, am an alpha. I was diagnosed in 1988 at the age of 31. At that time I had 40 percent of my lung function. I had bronchitis that wouldn't clear up. That's how I was diagnosed.

For two years, I hesitated using prolastin for fear of AIDS, hepatitis, and who knew what else, and also fear of losing my insurance because I, too, have a son with cystic fibrosis, and it was hard getting insurance. But that's going to be another committee, I'm sure.

I was then told in that two years that I had no choice, I had to try the drug. I was down to 20 percent lung function. I was constantly getting sick, getting infections, reoccurring bronchitis; I could hardly walk from one room to the other. So I bit the bullet and got on the product.

Fortunately, I haven't lost my insurance over it. I had to change careers to get the insurance, but that's a different story.

The replacement therapy is mine and many other alphas' hope, hope for a longer life and hope for a better quality life. One of National's missions is early detection, to find people with alpha before the non-reversible disease destruction is done.

Unfortunately, now there is no product to offer the newly diagnosed people. There is only one company that provides our product at this time. I'm asking you to remove some of the blocks that are preventing products from getting products out on the market. But, of course, we are not asking that you compromise safety. We don't want effectiveness compromised. We need to continue the dosage research to see if we are even getting enough to help us. We need to continue research for a better product. You know, it's not fun sticking yourself weekly, as I do. It would be great to have an inhaled product available.

I receive so many calls and e-mails and faxes from people who are terrified--terrified they're not going to live much longer because they don't have any product. They don't have any hope.

We need an allocation system. I have given up some of my own product for alphas who are chronically ill and can't get enough of their own dose. We need a system in place where the product goes with the patient, not the hospital, not the health care companies. I feel this would also add some price control, because I understand out there that some companies are taking advantage of this situation and jacking up their prices extremely high. It's not right.

A company would not be able to discriminate against one person because somebody has a better insurance than the other. I realize there's no easy solutions to all the problems facing all plasma users, but I am asking that we work together to change the current situation for the better. Make it safe, make it cost-efficient, and plentiful. Please, give us hope for a longer life.

Thank you.

CHAIRMAN CAPLAN: Thank you. Julie, why don't you stay up there and we'll ask the other people to come back and see if we've got any questions for the three presenters. Why don't we go to Keith first?

DR. HOOTS: Ms. Brandley, I wondered, we heard from Dr. Brantly that the recombinant was licensed in 1988, I think, if I heard correctly. What's the status of the production of the recombinant prolastin? What percent of the market share does it now represent? It sounds like very--

MS. EVERETT: Zero.

DR. HOOTS: Zero. Okay. And what about the investigation, new drug application for the aerosolized alpha-1 antitrypsin? Where does that stand and what will that--does that require more clinical trials? And if it's licensed, does it represent a relatively net win-win in terms of both supply issues related to plasma and also in terms of relatively lower cost per therapy?

MS. EVERETT: This is definitely a question that Mark can answer.

DR. BRANTLY: Number one, I think the feasibility was well documented by Ron Crystal and our group several years ago about the delivery of recombinant of--or both recombinant and pooled human alpha-1 antitrypsin by aerosol method. There are both some scientific issues that need to be dealt with that can easily be dealt with, and obviously there are some economic issues that need to be dealt with. But, quite frankly, I think that it is almost a crime that we are ten years into the development of this drug and we still do not have anything there. We don't even have clinical trials going on in this particular--in using inhaled alpha-1 antitrypsin at the present time.

I think probably one of the people I admire the most, Gordon Snyder, who is a great pulmonologist, basically said that it is a shame that we've really let down the patient community by not pushing forward and developing alpha-1 antitrypsin as our major priority at the present time.

CHAIRMAN CAPLAN: Paul?

DR. HAAS: I guess I need some help with science, since I am not very scientific. But this product is a blood product, and I guess I'm just trying to follow through the demand-supply side of this thing.

If it's a separate component from the other products that we've been hearing about today, why isn't it--is it being made in the same volume as IVIGs, et cetera? I guess I'm having trouble--

DR. BRANTLY: I think that's a very good question. It's what would be considered a bulk protein. It's probably one of the most plentiful proteins made by the liver that's in the plasma. But the fact is that the lung normally only sees about one-tenth of the amount that circulates in the blood. It basically passes through the circulation and then goes into the epithelial lining fluid that is at the sac and basically protects the air sac from damage from neutrophil elastase.

One obvious approach then would be to deliver it by an aerosol method where you could actually deliver fairly large amounts of alpha-1 antitrypsin to the lung without having to go through the vascular and sort of the drop-down in the amount of alpha-1 antitrypsin that's required. In that sense, it sort of changes the scale of giving alpha-1 antitrypsin to the individuals to deliver it particularly to their lung.

DR. HAAS: So right now the problem is we have an inefficient delivery system. Am I hearing that correctly?

DR. BRANTLY: I think the systems were not as efficient ten years ago, but they were not unreasonable back then. I think that the major problems were the theoretical aspects of whether inhaled alpha-1 antitrypsin would actually be efficacious. And I think that those are the kind of things that we need to deal with very straightforwardly and sort of knock them off as quickly as possible.

CHAIRMAN CAPLAN: Dr. Schiff?

DR. SCHIFF: Yes, would the recombinant form that would be used in the aerosol fall within the category of an orphan drug? In other words, would this make it--give an incentive to industry if it met the criteria of an orphan drug? And I don't know what all the incentives are.

DR. BRANTLY: It's already had orphan drug status. It's already moved through. It's there. In fact, NIH holds the patent for inhaled alpha-1 antitrypsin. It's just not--it has not been given the profile that it probably needs as a therapeutic approach.

I think that the recombinant alpha-1 antitrypsin is a very exciting thing. I would not abandon plasma as an approach, though. Again, I think at least for the next four or five years, we already have large amounts of proven safe plasma product, plasma-derived alpha-1 antitrypsin that can be given inhaled also, with very little problems. It's got a great safety record.

CHAIRMAN CAPLAN: Dana?

DR. KUHN: I guess the question I have on shortage for you all is--I guess anyone from the Alpha-1 National Association could answer this question, or maybe John would answer the question. Does your community have any information from the providers of prolastin as for the reason for your shortage? Is it because it's in the same fractionation process that IVIG comes in? Is it in that same line of production? What have you heard as being the reasons for the shortage that you're experiencing?

MS. EVERETT: Yes, alpha-1 is in that same line. It is the last protein that's removed. It's essentially the sludge at the end of the fractionation process. And what we have been told, it's a low yield, so there's a very small amount of that after you remove the other proteins and the other factors.

That means that many lots of this have to be combined to create the product that goes out to our community. And as the entire production goes down, that one goes down dramatically, also.

The other thing that we have heard is that certainly there is some impact as far as the withdrawals are concerned. But we were told it was only 3 to 5 percent, so that's a fairly small amount as far as that particular side of things are concerned.

The other factor, again, that I mentioned is that we are hearing of some off-label use. We do not know how pervasive that is, and it's not indicated in children with liver disease. It shouldn't do anything good for them at all. And there are some researchers who have indicated that they feel it might be harmful for them.

So we have got--as of Friday, I knew of one adult with liver disease and three children with liver disease who were receiving prolastin, and they shouldn't be.

MS. BRANDLEY: If I could also add one other from my survey of the community, this goes back to the fact that we're not on a patient allocation system. It's my understanding that the allocation system is based on purchasing records of purchasers of prolastin towards the end of last year, and for whatever reason, there were some purchasers of prolastin that made very, very large purchases in November and December of last year, therefore, gaining additional prolastin not only at that time but also as per the allocation system that was based on their November and December purchases.

I do think that this is also a large part of the problem and why you see the inequities across the system.

CHAIRMAN CAPLAN: Let's do a couple more questions. I've got John here. Then I saw Keith, then I saw Larry. Maybe that will get us out.

MR. WALSH: I think either Julie Sally, or Sandy could answer this one. Could anybody elaborate on what has been suggested that some distributors are actually guaranteeing a year's supply of prolastin and actually putting new people on service when we have over 300 to 500 people that aren't able to get product?

MS. SWANSON: We have heard several cases like that, which is a shame. You know, people have been on it ten years and then can't get any, and then somebody new is being put on it. It's--we need a fairer system.

MR. WALSH: That company testified this morning, I believe, on IVIG.

MS. SWANSON: So it's a definite problem, as Sally said. When they bought that big dose in November, December, that really gave them a big advantage on having extra product where other companies have zero.

DR. HOOTS: I want to follow that up. Are these home care companies who have patients on this product who have an affiliation in terms of buying affiliation with the one supplier and, therefore, have an inside track to the persons who are the end users for them and the other people don't have the same access to the product? Is that what you're saying?

MS. SWANSON: Correct. The cases that I've heard, it's all been involved in the home care.

CHAIRMAN CAPLAN: Larry, it looks like you're going to get the last go here.

MR. ALLEN: Actually, this is sort of a continuation. You mentioned earlier that you were told there was going to be a shortage. Who told you? Where are you hearing these things from, specifically?

MS. EVERETT: The January message was directly from the manufacturer saying that, you know, we're looking at things, we think there's going to be a shortage; you need to gear up for that and to essentially prepare us for the fact that there would be a product shortage. And the--

MR. ALLEN: Okay--go ahead.

MS. EVERETT: I'm sorry. And the reason for that was the changes in manufacturing that were mandated.

MR. ALLEN: Okay. They didn't mention recalls at that time as one of the--

MS. EVERETT: Not particularly, no.

MR. ALLEN: And the patient that you said has a recalled product that can't get it exchanged, have you taken any kind of legal measures or anything of that nature to help? I know it's probably a small amount versus overall, but it's the principle behind it.

MS. EVERETT: It is the principle. That was--actually, all kinds of things happened on Friday, and that was one of the things that happened. So we are going to turn that over to our Medical Advisory Committee and then move on from there. And we are going to act on that.

CHAIRMAN CAPLAN: Okay. Thank you.

MS. EVERETT: Thank you. xx CHAIRMAN CAPLAN: Our next panel is the International Plasma Products Industry Association and the American Blood Resources Association coming together. If I can have them come forward, I think we've got the overhead geared up again.

The order I have is Mr. James Reilly from the American Blood Resources Association coming first. xx MR. REILLY: Can you all here me? Thank you, Mr. Chairman and committee members. My name is Jim Reilly with the American Blood Resources Association.

I think what we'd like to do today is, as the agenda indicates, go through a series of four presentations, and they all kind of fit together to describe the entire fractionation process, culminating with a clean description of what we believe the supply issue to be and some sense of where it's going.

What I'd like to try to do, because they all do fit together, is try to go through all the four presentations and then come to questions at the end.

CHAIRMAN CAPLAN: That's fine.

MR. REILLY: First, let me sort of describe why we've broken it up the way we have.

The process includes donor screening, collection, and testing, which is represented largely by American Blood Resources Association, who I'm the President of, and we have about 40 members who are involved in that process. Once the collection process has been finished, the plasma is then passed on, if you will, to the IPPI members, the fractionation side of the business, which handle the pooling, fractionation, removal, and activation, et cetera. And there's four major fractionators in the world, the four largest that are members of IPPI, and they will follow me.

First, let me start with the plasma supply. If you go all the way back to 1982, we had about 390 centers, and I won't take too much time to go through it in detail because we are a little late. But when you get up to 1997, the number of FDA-licensed centers has risen dramatically. In fact, the supply has gone up a little bit higher than the chart might indicate because it has gone up on three fronts. The centers that we are operate are now larger than they were back in 1982. The yield of plasma per donor is larger, and the number of centers is larger.

One thing that I need to make mention of because it will be important a little further on is that of the 452 that are licensed in 1997, about plus or minus 50 of those are actually very small tax-exempt organizations like the Red Cross. So they produce a fairly small or moderate amount of the total.

So where are we in 1997? Well, roughly, we have about a million and a half donors. That's about 13 million donations, approximately 11 million liters. We expect that in 1998 that number will actually decline slightly. It should not affect the supply of the finished products that would be absorbed through existing inventories, and then we will rebound, I think, in future years.

I throw this one up because we always get this question. Source plasma is the paid-donor industry. That is our principal recruitment activity, and at the recent BPAC meeting we got plenty of questions about what are the numbers. So I thought it was useful, rather than waiting for the questions, to address them up front.

A typical donor will get $15 to $20 per donation, and then we use a variety of additional special incentives. If it's a unique product or some type of rare antibody, the donor may receive some additional compensation. We sometimes will have programs to try and encourage repeat donations. If we're trying to expand the donor base, we may, if you will, add additional compensation to do that. And then a variety of companies have all experimented with other things: going out to large groups, community groups or church organizations, and trying to recruit active participation out of those groups.

Now, let me just sort of describe a philosophy that we're trying to employ in our collection process.

If you would just sort of imagine this axis here s the collection process, starting with the general population as potential donors, it moves all the way through to the product and ultimately to the patient. Our objective is to move down on this relative risk scale as early in the recruitment process or in the manufacturing process as possible.

If you look, for instance, I saw a recent article that showed the prevalence of HIV in the population at being somewhere around 320 per 100,000, what you'll see in a little while is that by the time we get down to donor screening, we've got it down to less than 1 per 100,000. So that's the objective, is pull this safety line down to zero as early as possible and not allow it to trend down over the process.

This chart is a little busy, and I think we have some handouts which you will all get, if you haven't gotten them already. But what I wanted to do is walk you through the donation process. It gives you an idea of how complicated and how much safeguards have been put in up front.

When the new donor comes in, if he is, in fact, a brand-new donor to us, which would be anybody who we have not seen in the past six months--so we may well have a file on him, but if we haven't seen him in six months, we start him over as a new donor. We'll take a donation history. Assuming that he passes through that without any problems, he moves on to the first-time donor category here.

If he's a first-time donor, we check him against the National Donor Deferral Registry, which coordinates the Donor Deferral Registries of all the companies for all the viral marker tests. Assuming that he's not on the registry, he moves on and he would receive a drug test. Continue the assumption that that would be negative. He gets a physical exam by the center's physician or a properly trained physician substitute.

It is not until that part does he actually make a donation, which is then put in quarantine while tests are run. Assuming that the tests are negative, that first unit goes into quarantine. Then you wait for the donor to return. And only if the donor returns is the unit released. The point that he returns, he has to go through the process again, only because he's not a first-time donor, you're allowed to skip the deferral registry, the drug, and the physical exam, and you just go through the donor screening health history exam. He makes a donation, and, again, it is used--or it is tested and entered into an additional inventory hold of 60 days, which I'll describe in a few minutes.

At the centers, for all of those things to occur, we've recently--I shouldn't say recently. In 1991, we began a program called QPP certification where centers are agreed to abide by a series of additional standards beyond the regulations, and they submit to an inspection every other year by an independent third party. Those centers that are currently certified number about 380. That's why I said it was important to note that 450 total. The discrepancy is largely the tax-exempt organizations, although there is a small number who are not certified. They typically fall into one of three categories.

The very smallest number, numbering only a few, are centers that provide products into marketplaces where they don't view these as necessary to their product line.

A second line is centers who provide largely diagnostic or non-injectable products where this is not necessarily a factor.

And the third are usually new centers who, in fact, abide by the standards but have not received certification at that point in time.

The standards cover employee education and training, cover facilities standards to ensure professional medical facility operation, additional donor education and exclusion criteria, use of the National Donor Deferral Registry, testing for drugs of abuse in all new donors, insistence on a community donor base--and there's a variety of questions and screening that goes on to ensure that--a viral marker rate standard that currently is based on the entire donating history, including first-time and repeat, and that's something we're looking at changing to have it be more effective; and, finally, the qualified donor standard, which is, in fact, a little bit of that chart that I showed you before where the donor has to come back a second time before we consider him to be a qualified donor.

Those all fall under the QPP certification. There are some additional industry criteria which I think we'll probably get into a little bit more, a little bit by me and a little bit by the other presenters. One is inventory hold, which happens after the center, if you will, further down the process. One is PCR testing, which is intended to close the window period. And the third is donor exposure limits, which was touched on earlier.

To give you a little bit of numbers about some of these safety initiatives, for the National Donor Deferral Registry there's currently about 175,000 donors, or non-donors as it may be, in the registry. It's growing by, I think, a couple thousand a month. We perform on average about 865,000 new donor checks every year against the registry. And roughly 1.6 of those checks result in deferring the donor. That number is overstated, though, because there's a certain amount of quality assurance activity going on performing checks, and we are unable, unfortunately, through our office to distinguish between a quality assurance check and a standard donor check. So I can't tell you exactly what the breakdown is there.

The next series of slides are some I borrowed from a presentation made at the Blood Products Advisory Committee a couple of weeks ago on some of the safety initiatives. As I said before, the seroprevalence within the qualified donor population for hepatitis B is roughly 3.6 per 100,000. It's 0.97 for HCV and 0.91 for HIV. This all came from data collected late last year and earlier this year.

This slide is intended to try to estimate what the value of the qualified donor standard is--in other words, when you exclude that first donation until you have a repeat donation on him, and you have greater confidence in that donor and his commitment to the program.

If you look at our rates before when we were looking at seroprevalence, it would be all the units added to the pool, which was all the donations we took in. Seroprevalence of confirmed positives was roughly 3.68 per 100,000. We had to estimate this because at that point in time we weren't doing confirmatory testing, so we pulled from the literature approximately the confirmatory rate and tried to estimate it.

So for HIV, we were using units for all donations, and that was the seroprevalence. Now we're using only the units from the qualified donors, and the seroprevalence is now down to 0.91.

For hepatitis B, it's a similar--in fact, greater increase, from 30 down to 3. And for hepatitis C, it moves from about 183 estimate down to 0.97.

So we've made a dramatic impact on the quality or seroprevalence amongst the units that we're actually utilizing.

Inventory hold is the next one in the manufacturing step where we hold the units for 60 days in inventory, waiting for, if you will, the donor to return. If the donor does not return at the end of the 60 days, the unit would be released. If he does return and there's any negative or positive test results or any other subsequent reason for deferring him, we're able to reach back through that 60-day inventory and pull the units out.

For HIV, where the window period is something in the neighborhood of 22 days, we have 100 percent effectiveness, essentially.

For hepatitis C, we were at roughly 54 percent effectiveness because the window period was longer than the 60 days. But with the addition of PCR testing, we closed that window period down inside the 60 days, and we moved to 100.

For hepatitis B, the window period I think is estimated at about 59 days, and so we're not quite at 100 for that.

The next stage in the exercise of estimating probability of a window period entering the pool, let's go through an incidence calculation where you take those seroprevalence numbers and you add in, if you will, a factor for inter-donation interval, the time period between donations.

For HIV--and we also factor in the 60-day hold in the PCR. The blue column is without PCR. The clear column is with PCR.

For HIV, where we were already inside the window, we're down at a 0.6 factor number. For hepatitis C, the addition of the PCR closed the window sufficiently that we get that factor down to 0.8. And for hepatitis B, where the PCR is not employed at the moment, it's still up at 34.

I'm going to take a little detour for a minute because there's been some discussion about the use of going--or the gold standard of going beyond inventory hold and looking at a full-scale quarantine. What I wanted to do is just describe the difference between the two briefly.

For an inventory hold, what we are employing is 60 days where I described before we would hold the units in inventory. The release would be based on having those subsequent deferral causes. It's effective for all repeat donors. The catch in it is that you may not catch those window units from a non-returning donor. So the donor who comes in, donates several times, and then was possibly in the window period and then stopped, we obviously would not have detected him.

For a quarantine, what has been proposed is to base it on the window period. I'll show you some assumptions we made assuming that the window is roughly 30 days. The release would only be based on having subsequent test results, so if the donor doesn't return, the units would not be usable, in the estimates we are going to present to you, for 30 days.

It's effective for known viruses, but it has two substantial problems. One is a substantial loss of product, which we've tried to estimate, and the other is substantial new logistical management issues, which may be overcome-able but are not in the short term.

This tries to use the incidence calculation that I described before to look at what it would look like in a quarantine versus the hold. The center column is effectively 60-day hold with PCR. The column to the right would be the 30-day quarantine. So for HIV, we're moving for a factor of 0.2 to theoretically zero; for hepatitis C, 0.7 to theoretically zero; and for hepatitis B, because the window period is actually longer than the 30 days, it actually would go up, in theory.

The logistical issues can be described this way: Right now we find roughly 15,000 donors industry-wide positive for a viral marker rate, and we have to actively track those 15,000 donors and link them to the roughly 150,000 donations that they make. If you go to a full quarantine, what happens is we have to move from passively tracking all million and a half donations or donors, and there are 13 million donations. That is a substantial change in the way that we would have to go about doing that.

Finally, the supply issue. If you assume that we're going to maintain a constant supply of 11 million liters which we're currently at, we have the 150,000 units which we would try and find, and that represents that small bar at the top that would be lost on an ongoing basis every year.

If we move to the full quarantine, what happens is every time a donor drops out, we lose the previous 30 days of inventory from that donor. Now, there are a variety of variables, trying to increase repeat donations, trying to incentivize the donor in some way to give a sample back, and those are all variables that are very difficult to estimate. But we've been running some computer models and trying to come up with more precise estimates, and so far every way we run it, what we come up with is a minimum of 25 percent loss of production, and the higher numbers are up in the 40, 50 percent range.

Let me just kind of close giving a sense of where we're going because we don't see these programs as static. Within the context of the QPP and outside of the QPP program, there are under discussion or development a variety of things. We have already this year increased employee training in the areas of GMP. We are exploring a donor interviewing and screening workshop and, in fact, are also looking at the donor screening and interviewing process to see if there aren't modifications to improve that process.

The deferral registry will be expanded to include additional causes for deferral such as high-risk activities. The viral marker rate, we are trying to put together an ongoing reporting mechanism, public reporting mechanism, as well as reworking the standard to be based on the seroprevalence within the qualified donor population.

We are looking at or are in the process of developing a proposal for quality assurance standards and systems within the centers to be incorporated into the program. We are looking at additional laboratory testing standards, an inspectional program for the testing laboratories which operate independently of the plasma centers, and we are developing location facility guidelines.

This is the point, if you will, that we will hand it off. We are done making the plasma, and we've tried to pass it off or ship it off to the fractionators, and I think our next--

CHAIRMAN CAPLAN: Mr. Reilly, let me just interrupt you there. I just want to make sure, since some of this was technical, maybe you'd take a couple of questions here just on the description if people want to get something clarified. That's by way of saying I'd like to ask two things to clarify.

MR. REILLY: Ask your question.

CHAIRMAN CAPLAN: One is, when you had the standards up for screening or training or counseling, whatever it is going to be on the donor end, are these followed by the industry on a voluntary basis? What's the enforcement to make them go?

MR. REILLY: They're followed by the industry on a voluntary basis, but it's actually much more rigid than that. Let me describe the process.

They have to apply to us. They send in an application form with certain background information on it where they say we are ready, we abide by all the standards, and if you send the inspector out, he will be able to verify that. At that point, we send an independent third-party inspector out, and he makes a report back to us.

It is very much black and white. They pass all the rules, or they don't.

To the extent that they haven't, we enter into a dialogue with them, and they correct the problems and, generally speaking, we then ultimately grant certification.

That inspection reoccurs at least every other year, and there are provisions for unannounced inspections. It is still voluntary. Centers don't have to sign up. However, nearly every fractionator in the world has made it a requirement of their purchasing practices, so it's virtually impossible to not pursue it.

CHAIRMAN CAPLAN: And one other question. On your hold versus quarantine issue, we've been looking, as you know, at some diseases like CJD or potential TSEs. How do you think the hold versus quarantine would play out in that arena?

MR. REILLY: I have to admit that I'm not a scientist, so what I'll tell you may or may not be true. But from my understanding of the window period, if you will, for CJD, it's years. So I'm not sure that an inventory hold is possible to address that issue.

DR. PENNER: Is the deferral registry at all interlinked with Red Cross, or is there a consideration to at least pool some of that information?

MR. REILLY: It's not presently interlinked with the Red Cross, but I think that's something that we would be interested in doing. It's just a building process, if you will.

DR. PENNER: And the second thing, on full quarantine, would the possibility of the quarantined blood that you couldn't unload then be treated with a detergent approach; therefore, you'd be able to salvage that plasma and it would cut your costs down because you wouldn't have to treat all of the plasma with the detergent method?

MR. REILLY: I'm not sure I completely followed the question.

DR. PENNER: That's all right. You're going to have some quarantined plasma up there. You don't have the donor coming back in again, so you don't know about the window period.

MR. REILLY: So it's not going to clear, right.

DR. PENNER: So you could wash the plasma and do a detergent treatment to eliminate possibilities of hepatitis C and HIV at that point, which would, again, reduce the infectivity significantly.

MR. REILLY: And shift it over to fresh frozen plasma for transfusion?

DR. PENNER: That's right.

MR. REILLY: I suppose that's a possibility. It's not one we have explored.

CHAIRMAN CAPLAN: Okay. We're going to go quick here. Just a couple more of these, and then we'll come back.

DR. KUHN: As I'm looking at your inventory hold versus quarantine, what comes to my mind--and maybe I'm not reading this correctly, or maybe it's not in here--out of the 11 million liters collected per year, what would you say would be the percentage that is annually on hold or annually on quarantine?

MR. REILLY: Well, the hold, every unit passes through the hold at some point.

DR. KUHN: But it's a hold of--

MR. REILLY: The hold is 60 days.

DR. KUHN: Sixty days.

MR. REILLY: And our loss of product, when we find a donor positive, is roughly a hundred--estimated. I don't have the hard figure, but I think a very good estimate is in the neighborhood of 150,000 units which have to be retrieved from that hold and are destroyed. All of the other units are released.

For the quarantine, the number was more like 25 percent of the total.

DR. HOOTS: We hear a lot about volunteer versus paid donors, and obviously at some point in the scale of things, there has to be a competition for those donors.

Have you done any prospective looks geographically across the United States to say what is our potential, what is your potential to expand paid donors without impacting significantly voluntary donors, American Red Cross, American Blood Centers sorts of capacities and requirements? And do you think we're close to that kind of point where, if we just borrow--if we build any more donor centers, we're going to start compromising the voluntary donor pool? Or can we continue to expand, particularly in the face of a supply problem for virtually every component we've talked about today?

MR. REILLY: I would say we have not consciously addressed that, but to date, we have not run into any serious conflict. There may be an individual community where there might be a problem, but generally speaking, it is not a problem.

CHAIRMAN CAPLAN: I've got Dr. Guerra, and then we'll go to Ron.

DR. GUERRA: Can you tell us a little bit about the companies that set up the plasma collection centers? Are these entrepreneurial type of businesses? What are the ethical standards? And I raise the question because on occasion, we have individuals that show up in our public health clinic with a note that is given by one of these centers saying you've been found to have a positive test for--whatever--syphilis or for HIV or hepatitis C, and just sort of leave them on their own without getting them connected to any--or to have any assurance for follow-up.

I just wonder what the standards are on that side of the industry.

MR. REILLY: Well, there are FDA standards on donor counseling when you find a positive test result, and obviously, all the centers are required to follow those. That's really the basis by which most--in fact, all the centers must operate. So when they find a donor positive they would follow whatever the FDA guideline is.

That generally follows the philosophy of you notify the donor to the extent that you have additional information, for instance, a confirmatory testing of some sort that would affect the counseling in one way or the other. And then you try to make sure that the donor is adequately referred out either to his personal physician or, if he doesn't have one, to the health care--the Public Health Service in some format in the local community.

Does that answer that question?

DR. GUERRA: I guess that there's no way, though, that they can be tracked to see if, in fact, they have, you know, followed up with that recommendation.

MR. REILLY: No, we have not pursued that.

DR. GILCHER: Jim, how widely used is the age 50 cutoff now by the plasma industry? First question.

Second question. What percentage of the total donor base was lost by using the 50-year-old cutoff, and how are you, in fact, making that up? Because we see that in the volunteer sector as having an impact on us.

MR. REILLY: I don't have any hard data. This is somewhat anecdotal. I think that most of the centers now--and maybe someone can correct me from the fractionators if I'm wrong. Most of them have some kind of an age cutoff. Our donor population demographics, though, are slightly younger than what you're used to seeing. I think if my memory serves me, the impact was not more than a few percentage points.

DR. GILCHER: For example, when this came out, we looked at it within our own blood center, and actually, about 32 percent of our donors--not donations now, but donors--were over the age of 50.

MR. REILLY: In our case, it's a little bit the reverse. I think over the age of 50 we're looking at 1 or 2 percent as ours.

CHAIRMAN CAPLAN: Jay?

DR. EPSTEIN: Jim, of the 11 million liters collected, do you have any estimate what proportion is fractionated by U.S.-licensed fractionators?

MR. REILLY: No, I don't know the answer to that, Jay.

DR. EPSTEIN: Any kind of ballpark?

MR. REILLY: I know that--and I think you will see it in the data that the fractionators have on their production--the plasma fractionated here exceeds--historically had exceeded demand here.

DR. FEIGAL: I wonder if I could push you a little further on that. We have heard figures in the past that the U.S. market is approximately 6 million liters, so that the plasma collection centers are collecting almost double of what the U.S. demand is. So that is clearly not the cause of the shortage. Is that a statement that is in the ballpark?

MR. REILLY: From what I can recall, that would be roughly in the ballpark.

DR. FEIGAL: Do the plasma centers sell their plasma outside of this country directly?

MR. REILLY: Some does go out directly, yes.

CHAIRMAN CAPLAN: Okay. Thank you.

MR. REILLY: Thank you.

CHAIRMAN CAPLAN: I think we've got Sue Preston from Alpha Therapeutic. xx MS. PRESTON: Dr. Caplan, Dr. Nightingale, members of the committee, and ladies and gentlemen of the audience, I am pleased to be able to speak to you today on behalf of IPPIA. I would like to acknowledge Jean Huxall and Bayer Corporation for the presentation today as they usually do this portion of this presentation.

Next overhead, please.

I will speak to you directly about pooling, fractionation, and preparation of final containers.

Next overhead, please.

The steps in the manufacturing process are usually divided into six. We have just heard from Mr. Reilly about the first, collection and testing of plasma; the second step is the inventory hold, which Mr. Reilly has also touched on. Pooling, fractionation, preparation of final container, and testing and release of products make up the rest of the steps.

Next overhead. Thank you.

When we talk about fractionation, I'm always very excited to talk about that because it was a process that was developed by Cohn in the early 1940s in response to the war effort. It is the Manhattan Project of biochemistry.

During that time, Dr. Cohn and his colleagues--and you'll hear us refer to the intravenous immunoglobulin preparation as Cohn-Onkley(?) Method 9--developed several ways in which to fractionate the many proteins that there are in plasma.

One of the things to remember is that plasma has over 100 different proteins in it, and each of these proteins has some responsibility for some function in the body. Right now we only utilize a few of those in therapeutic products.

In the fractionation process, there's a cold ethanol precipitation in which plasma is exposed to sequentially different process parameters resulting in a systemic separation of the various components. The separated product is then concentrated and processed into individual components, and each product type is removed as a separate entity.

This diagram is an example of what happens in the fractionation process. So we'll start with pooling, and the first step is really the separation of the cryoprecipitate. The cryoprecipitate paste, the precipitate from that, goes on through many different purification steps to factor VIII that is utilized to treat the hemophiliacs. After the cryoprecipitate paste is removed, this effluent from that may be utilized to produce factor IX or thrombin that is used in an as yet unlicensed fibrin glue.

Fraction I paste is the next separation in the sequence, and that could lead to fibrinogen, another component of clinically--a product under clinical trials. Further, fraction II plus III separation goes to the fraction II plus III paste. That precipitate is then purified into fraction II, and let me just say that fraction II is about 90 percent IgG. It goes on, though, for further purification to the intravenous immunoglobulin form.

Fraction IV-1 separation will lead eventually to alpha-1 PI; fraction IV-4 separation, which is removed and has other proteins; and then fraction V precipitation, which leads to albumin. And at the fraction V step it is 99 percent pure albumin.

So the Cohn colleagues developed a very fine way of precipitating the protein, and then after the cold ethanol fractionation, each of the manufacturers has taken different steps to further purify those proteins and to formulate those into products that are suitable for injection.

Next overhead.

Let's just take an example pool, and this represents the industry average with respect to the yields that I will present. But let's just say that we have a pool size of 4,000 liters, and that means actually how many units get pooled or how much volume gets pooled from the individual donations. At 800 mL per container, this would represent about 5,000 source plasma individual donations in the pool. Please remember that plasma is 85 percent water, and the protein content then is 200 to 300 kilograms in the 4,000-liter pool.

Next slide.

When we look at the amount of final container material that is available to us, when we look at albumin, there is an estimated 32 grams of albumin per liter, yielding a theoretical potential of 125 kilograms of albumin. The normal yields, however, through the purification process are 70 to 95 kilograms from this 4,000 liters of plasma.

For immunoglobulin, there is an estimated 8 grams per liter, yielding a potential of 32 kilograms of immunoglobulin. Our normal yields are about a third of that, 10 to 11 kilograms per the 4,000-liter pool.

For factor VIII, it has about 0.0001 grams per liter of factor VIII with a potential of about 0.4 grams. But our normal yields are about 0.2 to 0.3 grams from that 4,000-liter pool.

Alpha-1 PI is also a protein where there is about 0.27 grams per liter of alpha-1 PI, yielding a potential of 1.08 kilograms from the 4,000-liter pool. But as Bayer pointed out in the slide, the therapeutic dose of alpha-1 PI is 4 grams; thus, it takes 16 liters to produce one therapeutic dose.

Next overhead.

So now let's go to the individual steps to which I wanted to speak today. Pooling is where an individual unit of plasma, which can be either in a bag or bottle, that has been received from a qualified donor and has been held for not less than 60 days is combined with other units. The plasma units are selected for pooling based upon specific acceptability criteria, including the length of time that they have been held in inventory. The number of individual units that are combined at the pooling stage varies with manufacturer and is dependent upon the process that has been validated and approved for that manufacturer. The validated process would include such items as equipment utilized and the planned lot size.

The intent of pooling is to combine individual units into one homogeneous pool for fractionation, and for immunoglobulin preparations, a broad spectrum of antibodies is desired.

Next slide.

The process variables for the Cohn-Onkley fractionation or the Cohn fractionation includes temperature, protein concentration, alcohol concentration, the ionic strength, pH, time, the equipment size, the equipment type, and our starting pool size.

Next slide.

After we have taken the fractionation and we have also purified the proteins into highly purified products, we will combine the intermediates by like types to achieve the minimum amounts required for the subsequent manufacturing. The number of combined intermediates is dependent upon FDA-approved and -validated process and the design and the size of the equipment, and the concentrated intermediates are further processed and purified into a single product batch.

Next slide.

Each product is formulated for stability. This could include addition of a plasma product such as albumin. Processing includes viral inactivation and partitioning steps, and we'll hear about that in a little more detail from my colleague in a minute.

The solution is then filled into vials, and some products may be lyophilized for stability, and these lyophilized products would be subsequently reconstituted prior to administration.

It's also worth, I think, pointing out that since these are proteins, they cannot be terminally sterilized like some other intravenous proteins, so we do take very much care in terms of the aseptic processing to assure a sterile product.

Next slide.

But we are still not through. Even though we may have the product in the vial, there are many other pieces that we need to put into place. Quality assurance testing is ongoing throughout the process, and I'm going to talk a little bit more in detail because it covers the components, the plasma pool, intermediates, bulk, final product, CBER testing, and also final release of product.

Next slide.

When we think about the components, the components are not only the plasma where we've heard that we have a number of criteria for plasma; the chemical also are tested, and if they are USP, they are tested by USP tests. If not, there are specifications that each manufacturer has approved through the FDA that is based on the purity and the intended use of the chemicals. Such things as filters, our vials, our bottles, our stoppers and our labels, all undergo quality control.

The pool itself is usually tested for relevant tests. Some of these might include microbial load. And then each intermediate may have specific tests to help formulate it into the final lot, and those include purity, if it's a dry powder it may include moisture, and relevant tests that are dependent upon the type of product, the type of intermediate it is.

When we get to the bulk stage, which is prior to the sterile filtration or right at sterile filtration, things such as potency, visual inspection, specific activity, things looking at pyrogen, sterility, maybe osmolality, or sodium or calcium may be important. And then there could be other excipients that we've added, other reagents during the processing that we want to test, or other relevant tests that we'd like to conduct.

Next overhead.

For final containers, again, a lot of the same tests that we performed on the bulk, but now this is looking at sterility specifically. Some of these tests are one-day tests. Some of them are much longer. A sterility test, for instance, takes 14 days to complete.

After we've completed all of our testing and we find the lot is suitable for release, and if we have lot release requirements from CBER, we will submit the results of our tests as well as samples to CBER. And CBER will review the test results and elect whether they wish to do testing or not and then provide us with a release.

After we receive the CBER release, then we again make sure that we have everything in place for the final release of that product into the distribution inventory.

Next overhead.

In summary, the fractionation process is complex, with additional purification steps after the ethanol precipitation steps. Many proteins are separated at the same time with specific equipment in different areas of the plant. Process and yields are a delicate balance for the adequate purity of all proteins desired from the plasma, and the lot size and throughput are dependent on the specific processes and equipment.

Now I'd like to turn it over to Dr. Baker.

CHAIRMAN CAPLAN: While Dr. Baker is coming up, let me tell the panel about a slight change that I have been noodling here with watching the clock. I've asked James McPherson and Christopher Lamb to talk to us tomorrow. When we're done with these presentations, we'll take a break. Then I'm going to ask the people who are on the section called Industry Comments on our agenda to come back--that's some of the people we're listening to now--so that we have time for questions. So we'll get the other two presentations tomorrow, just so you know. You may be looking at your watches saying, Am I ever going to get out of here? So we'll have time to do this and get the information about how things work and then address the scarcity questions.

Okay, Dr. Baker. xx DR. BAKER: Good afternoon. I have been asked this afternoon to speak from a manufacturer's perspective on the issue of viral safety and on the very complex relationship between viral safety and availability. I'd like to key off a comment that I think was made by Corey Dubin this morning that we need a new paradigm in discussing the viral safety of plasma derivatives, and I couldn't agree more.

Our current generation of products are very, very safe with respect to those serious blood-borne pathogens that we know. Quantifying this safety, my estimate is that the risk of transmission of these serious pathogens is in the neighborhood of less than one instance of transmission per million vials utilized. This is a level of risk that is far below the community exposure that one would see for these agents, and it's a level that's generally considered insignificant.

Now, we got there, and how we got there was not by accident. This was a deliberate process in which multiple barriers to exclude pathogens, that is, to exclude contaminated donations, exclude problematic donors, and for those pathogens that did manage to enter at the manufacturing stream, to put in place processes that would eliminate and remove them.

This defense in depth has proved to be very, very effective. However, where do we go from here, and how do we make our next initiatives? And here I think we face the dilemma that is seen in, for example, national defense. Our society, in fact, every society, recognizes the need for a strong national defense. This is a dangerous world we live in. However, at some point, you reach a realization that you cannot layer defense system upon defense system. At some point, the incremental burden becomes greater than the benefit, and trade-offs have to be made. And these trade-offs ideally are made in an environment of rational discussion in which ineffective measures are set aside and new technologies are brought into play.

With that, I would like to talk a little bit about some of the exclusion methodologies that we use and what they cost and what their impact is. And, again, we heard a request from the patient groups this morning to present some data, and I think that's a very legitimate request. We should talk about what do we get for our money, what do we see when we implement these measures.

You heard Mr. Reilly describe the plasma hold initiative. That was something that was brought forward by the industry. We initiated that mid-year last year, the 60-day plasma hold, and I took a look for our company. What did that mean in terms of the first quarter of this year, the first three months of this year? How many donations did we kick out by this plasma hold?

The total was 71 donations, January, February, and March, and that's on a little under half a million that we processed. That works out to, based on a number of calculations that I won't go through, but the cost for us was approximately $6,100 per donation that we kicked out.

Now, these problematic donations, the vast majority of them, are seroconversions that were recognized down the road after we went back and pulled out. Some were lifestyle issues, behaviors that were incompatible with being a plasma donor.

Now, is $6,100 good? Is that effective? I don't know. I think that's a good topic for discussion. Just how much should you pay to kick out a donation? But I can put it into perspective with, say, P24 antigen testing. Again, using the data from my company, in just under a million donations which I took a look at, it cost us approximately $660,000 to uniquely identify a problematic donor by P24 testing.

Now, I think we can talk about whether or not $6,100 is cost-effective, but $660,000 to kick out a problematic donor, keeping in mind that our inactivation processes will easily handle the minuscule viral burden brought by a single HIV donation, that strikes me as a safety measure that we ought to take a hard look at. Are we getting the bang for our buck?

Next, let's take a look at CJD. We've heard a lot of discussion about CJD. I think this is an exclusion measure that we should take a very, very hard look at its cost-effectiveness and whether or not an appropriate change in the criteria should be used.

Data has continued to accumulate that CJD, the chance of CJD being a blood-borne disease under normal circumstances, something that you could get from transfusion, the chance is either zero or very remote. Our own studies in our laboratories with TSE as a model system indicate that the TSE agent is cleared by a number of very, very simple processes which are used in our fractionation system.

In terms of the cost of this initiative, what does it cost us, that is very hard to calculate, and I have to say that in this case I have defaulted to the eminent journal, the Sunday New York Times, in which they indicated that something like 1,000 kilograms of IGIV has been kicked out of the system based on CJD withdrawals. That seems to me to be a tremendous expenditure for a zero or remote risk, and I think we should talk about that.

In summary, I would absolutely agree from what I've heard from the patient groups today that we need rational, fact-based discussion in a respectful atmosphere in which we take a hard look at these initiatives. We need to cast aside the ineffective to make room for the effective. This committee, with its breadth of experience and with the mandate that it has for safety and availability, I believe is an excellent entity to show leadership in this direction.

Thank you.

CHAIRMAN CAPLAN: Any quick question, clarification?

All right. Then let's go to--oh, sorry. Jay, go ahead.

DR. EPSTEIN: Yes. Dr. Baker, you cited 1,000 kilograms of IGIV, quote-unquote, out of the system. Are you saying that's an estimate of material that was retrieved due to withdrawal? Or are you saying that that's an estimate of the lot size of what was affected and you're not sure what was withdrawn?

DR. BAKER: You know, Jay, that's a good question. All I can say is that's what I saw in the New York Times. I struggled to find a number on the CJD withdrawals because, as you know, this occurs--this is sort of like a defective exclusion mechanism. It occurs after the fact, and we withdrawn product or we do not continue to produce product. So I really can't speak to whether that was a total number of material that was withdrawn or just how they came up with that figure. I think it's certainly something that we need to look at, though.

I know our own company's experience has been certainly well in excess of $10 million with regard to CJD withdrawals.

CHAIRMAN CAPLAN: That's what I was going to ask you. Could you speak to your own experience?

DR. BAKER: Yes. I don't have the exact figures, but I do know the last time I looked it was in that neighborhood.

CHAIRMAN CAPLAN: Which would be roughly, in terms of grams?

DR. BAKER: No, I'm sorry. That's total plasma product.

CHAIRMAN CAPLAN: Oh, total plasma product withdrawn. Okay. Got it.

Larry? And then we'll go on to Mr. Bult.

MR. ALLEN: Now that we're talking about money--which seems to always be an issue here, and I understand that. But since money has been brought up, and you mentioned the cost of certain testing, would it be fair, since you're explaining the cost of this, to also explain to consumers and other people interested what the mark-up is on these products from the moment you bring these--you get the donors in and you pay them the $20 or whatever other incentives you pay them, from that point on to the time it's out the door and you get money back from these products? Can we talk about those numbers?

DR. BAKER: First off, I'm not the person to talk about mark-up and marketing, and I have to say honestly I don't even know how to address that question. That's just beyond my expertise.

MR. ALLEN: Okay. Secondly, in regard to the $6,100, I think you mentioned, for one of the tests, being a consumer and having children that consume blood and blood products, you can come to me and explain to me on several different fronts problems you've had providing these products. But when you start talking about the cost of it, then you kind of lost me, if you understand what I'm saying, as a consumer. We're not concerned about the cost. We're going to pay for it one way or another. I think that's part of business. Someone's going to pay for that extra cost. But the actual effect it has on that individual who may or may not contract something as a result, is that--you know, these fears have to be put in the proper perspective. You're talking about money. We're talking about livelihood. We're talking about the effects it has on families. Those are issues that I personally, through 20 years of going through this, haven't been able to put a dollar amount on.

So I understand your need to talk about money, but there has to be some understanding also that, as a consumer, that's the last thing we want to hear from you in regards to safety.

DR. BAKER: You know, let me go through a few of those points, because I think I want to be absolutely clear on this. We are talking about a multi-layered defense system. I am not saying we're kicking out one $6,100 donor exclusion criteria so that we will risk transmission. I'm saying we've got multiple, multiple layers, and we need to look at which ones are more effective.

Regretfully, I think we have to recognize there are limits to the amount of money the system can avoid--the system can bear in terms of making safer products. If one takes the analogy you've never seen a weapons system you didn't like, we should devote all of our GNP to national defense. But I don't think anyone would agree with that. At some point we say we have to take a rational approach to this. We have to balance the risk and the cost.

The only truly safe plasma derivative is the one that you don't make and don't administer, and that's a reality we have to recognize.

CHAIRMAN CAPLAN: Okay.

DR. FEIGAL: A more useful way to describe the cost is actually describe the cost for the units that are actually used rather than the ones that are kicked out, or the number that you gave was for a total system. And if my math is right, it looks like the cost of the plasma hold was a little bit under $1 per unit of plasma. So that's the incremental cost that we're talking about, and I think those units are a little more understandable when we're talking about having to bear the brunt of cost, and similarly for P24. I think you do--it is legitimate to look at the yield, but I think the cost is going to be borne not by the units that are kicked out, but by the units that are actually used.

CHAIRMAN CAPLAN: That must be profound because I think I followed it. Okay.

Let's go to Mr. Bult. xx MR. BULT: Good afternoon, Mr. Chairman and members of the committee. My name is Jan Bult, and I'm the executive director of the International Plasma Products Industry Association, IPPIA, the international trade association representing the commercial producers of plasma-based therapies.

IPPIA members produce approximately 80 percent of the plasma products for the U.S. market and include the four largest commercial fractionators, which are Alpha Therapeutic, Baxter Health Care, Bayer Corporation, and Centeon.

IPPIA is aware that during the past few months many hospitals, pharmacies, and, most importantly, patients have experienced a shortage of intravenous immunoglobulin, IVIG, therapies. Our members share an interest in providing accurate information about the current shortage of IVIG, particularly to the patients who depend on the life-enhancing qualities of these products.

For many years, worldwide demand for therapies made from human plasma, including IVIGs, sometimes exceeded the supply. In all these events, industry was able to deliver the plasma therapies to the patients in critical need. For most of 1997, the supply of IVIG by our members was on track. We believe the current shortage that occurred in late 1997 is due to a number of factors occurring simultaneously, and these include: better diagnosis and treatment of patients leading to a continually increasing use of these therapies by physicians seeking to enhance and lengthen the quality of life of their patients; product withdrawals due to the industry's and the Food and Drug Administration's conservative and prudent approach to reducing the theoretical risk of Creutzfeldt-Jakob disease transmission; and temporary production decreases resulting from the implementation of facility system enhancements and efforts to ensure continued compliance with current good manufacturing practices. I will explain each of these factors in turn.

While we are not able to quantify the actual demand for these products, studies by the Marketing Research Bureau indicate the market for IVIG has increased around 9 percent every year for the last several years. At this time, we have no reason to expect any changes in this outlook for the near future.

Manufacturers' withdrawal of IVIG from the market due to a theoretical increased risk of CJD transmission--we will call them CJD withdrawals--has had some impact on the supply of this therapy. The following table, which is a part of a data-gathering effort I will describe in more detail, shows the impact of withdrawals for CJD on IPPIA members. What you will find in this table is the numbers for 1996, 1997, and the forecast for 1998, and in all the data that I'm going to show you in a minute, we follow the same pattern.

You see that in 1996 we had four withdrawals; in 1997 we had seven; this year so far none. The volume of IVIG returned from the market in both years was 16 kilograms. We express all the quantities from now on in kilograms to be consistent.

The volume of IVIG that could not be released in kilograms in 1996 was 166 and 1,050 for 1997. The total for 1996, therefore, is 182 kilograms and 1,066 for the year of 1997. This year so far we have not seen a withdrawal.

These data include the volume of IVIG actually returned from the market for these withdrawals as well as the volume of in-process and unreleased material. And as you can see, over 1,000 kilograms of IVIG, and take an average dose of 25 grams, representing over 40,000 doses, was not available due to CJD withdrawals in 1997.

It is important to point out that additional CJD withdrawals are not included in this table because they affected non-IPPIA members for whom we cannot speak.

Until a serological test for CJD becomes available, withdrawals for this cause will most likely continue to affect the IVIG therapy. Further, IPPIA members have experienced recent temporary production decreases as a result of several factors that can be broadly categorized into three areas: quality control, quality assurance enhancements, a changing regulatory environment, and specific production and technical issues. A sample list of these factors would include increased and intensified FDA inspections, resulting in a personnel shift to respond to these FDA questions, subsequently leading to longer than normal production slowdowns to address compliance issues.

Some changes in the manufacturing process resulted in a lower yield of finished product, such as incorporation of additional viral inactivation procedures, the adoption of a donor exposure limitation, commonly referred to as pool size reduction, as announced at a congressional hearing the 31st of July 1997, and change of plasma supply sources, and other company-specific technical issues. Each of these factors resulted in significantly increased production time with a new result of less IVIG production in 1997 and projected for 1998.

The single most important question is: What can we do to improve the current situation?

IPPIA members have undertaken an intensive data-gathering effort with the help of Georgetown Economic Services to begin to understand how all these factors affect this complex situation. The following table summarizes our initial findings. What I would like to do at this moment is walk you through to a number of slides and graphs that we have made from this table. But I think since there is so much interest in the data, I think this is a very important part that I would like to explain.

First of all, again, you will see the same exercise from 1996, 1997, and forecast 1998. What you see is in 1996 there was a possible supply of over 14,000 kilograms, 14,300 in 1997, and almost 14,000 in 1998.

Now, what happened? We have seen withdrawals, recalls, and other losses, adding up in 1996 to 465, leading to a net result available supply in 1996 of 13,752 kilograms. If we do the same for 1997, we find 12,994 available IVIG in 1997. For 1998, the forecast is a little over 13,000 kilograms.

If we look at the available supply, then another important question is: What has been used for domestic supply? Here are the numbers. For use in the United States, 11,400, 10,300 in 1997, and almost 10,500 in 1998 forecast. Here are the export numbers: 2,352 in 1996, 2,663 in 1997, and forecast 2,588 in 1998. I think these are the accurate data, and I think that is very important. We have heard over the last week many questions and many assumptions. These are accurate data.

This has been prepared with the Georgetown Economic Services, and I'm going to tell you in a minute what our ongoing data collection effort is going to be, because we need to understand more.

Another very important question is: What is happening with inventory? And what we have done, we have looked at the inventory with a target date of the 1st of January of every calendar year. What we see is in 1996, 1,886 kilograms inventory, going down to 1,260 in 1997, and at this moment, 763. Within that number, in response to an FDA request, the industry has built up an emergency supply to ensure delivery to the patients in most critical need. And what we see is in 1997 we had an emergency supply of 105, going up to 430 in 1998.

Now, once you've seen the numbers and they are part of the testimony, I think it's important to look at the next graph that will put everything in context.

What you see here is the total available supply--and I gave you the numbers a minute ago--for 1996, 1997, and 1998. What you see is a drop down in 1997, and it also shows you what has been used for domestic supply and what was exported.

Next slide, please.

Now, I explained to you that we have seen losses, and if you look at the losses in the manufacturing process, there are several reasons. We have to deal with recall and withdrawal, and we have to ask the question: What was returned from the market? And I can tell you what we've seen so far is that number is pretty low, and this expresses the quantity that has been returned from the market after withdrawal or recall.

The most important reason in 1996 here, but more importantly in 1997, was because of withdrawals, and I gave you the number. The third factor is because of additional losses which are technical operations, reconstruction, those kinds of issues. And what we see is that in this year we already see the consequences of technical operations. We have not seen an impact of Creutzfeldt-Jakob disease-related withdrawals so far.

Now, talking about Creutzfeldt-Jakob disease-related withdrawals, again, this graph brings it in context because what you see here is the total available supply, and you see what the impact was because of the CJD withdrawals in 1997. Of course, that is the result here in this case when the numbers go down, but that tells you how this relates.

I would like to come to one other very important issue because that has been addressed over the last couple of weeks several times, and that is, what can we do--and I will come back to that in my testimony, but I would like to explain the graphs at this moment because I think that's important. What can we do to ensure that the patients who need the treatment have a way to get the treatment? That's why in response to an FDA request we have started to build up an emergency supply. And in 1997, that means that every day that is the minimum available supply inventory in the industry. There is always a minimum inventory of 105 in 1997, and this year this went up to 430 because we want to respond to the urgent questions of the physicians and the patients.

Now, the next one, which is the last slide, I think is very important. We have seen over the last couple of days questions, allegations, assumptions, critical remarks about the inventory in the industry, and I hope that this graph is going to explain to you that this industry is not stockpiling, because what you see here is that there is a significant reduction of inventory over the last couple of years, 1996, 1997, and 1998, and at the same time we built up an emergency supply. I think that's very important, and that will certainly answer some critical questions.

What I would like to do now--and I don't need a microphone for that--is that if I go to the questionnaire which was developed and presented to you this morning by the Immune Deficiency Foundation, I think we have a very clear response.

You have all the questions here. If you look at this, you have all the data you asked for. We have more. I am going to show you in a minute what we're going to do.

IPPIA members are committed to the health of the patients who depend on these therapies. We are working continuously to resolve the current IVIG shortage, just as we have always done. However, it is important to note that the current shortage is a result of many factors, and there is no single solution. With this in mind, our members have identified both short-term and long-term initiatives that could be taken in an effort to reduce the impact of the current shortage and reduce the threat of future shortages.

Let's talk about short-term initiatives.

IPPIA members have implemented emergency programs to assist patients in need. Each of the IPPIA members is working with the FDA, hospitals, physicians, and patient groups to try to ensure those patients in critical need that they will have access to these life-enhancing therapies. For this reason, IPPIA members in response to this request keep an emergency supply that is reserved for patients in critical need of this therapy. Special telephone numbers provide access for providers and patients to these emergency reserves. Earlier, I told you that in 1998 430 kilograms is reserved for this purpose.

Once released through each company's normal quality control procedures--and you heard in detail by Sue Preston about it--our members are using innovative strategies to quickly bring the therapy to the patients. These efforts include providing a larger proportion of sales directly to hospitals and pharmacies. IPPIA members are actively working with the FDA in an effort to get additional IVIG to the market. Through this cooperative effort, FDA's release time for IVIG lots has been shortened from the normal two to three weeks to two to seven days, without compromising safety.

Our members have expended the resources, both human and financially, to ensure continued compliance. It would be extremely useful to expedite the FDA review and approval process.

Long term. The industry is also pursuing long-term advancements to address the future needs for this life-enhancing therapy. IPPIA members are investing millions of dollars in an effort to expend over-capacity at our manufacturing facilities to meet increased demand for IVIG and other life-enhancing plasma therapies. Each of our member companies will address the specific action undertaken to relieve this current situation later this afternoon.

Another long-term initiative is to develop new yield-improving technologies. It is extremely important that we develop new technologies resulting in new plasma therapies for the patients who need treatment. Reasonable clinical trial expectations will be instrumental in achieving this outcome.

The members of IPPIA are working continuously to provide patients with a safe, adequate supply of IVIG and other life-enhancing plasma therapies. At this time, we cannot estimate how long the current shortage will last. IPPIA understands the critical need for IVIG and the seriousness of the current shortage. In this light, we commit at this time to continue our data collection effort. We will collect and make public production data--and you've seen the examples--every three months so that all interested parties will be able to understand the current production trends, and we anticipate that this information will allow us to better understand, predict, and respond to the threat of any future short supply situations.

Thank you for allowing me to address these very important issues. The members of IPPIA are dedicated to producing safe, effective therapies to enhance patients' lives. I would be happy to answer any questions in a minute.

CHAIRMAN CAPLAN: All right. Let's go to questions for all of our presenters at this point in time, and I'll start down with Jim AuBuchon, and I'm going to work around this way.

DR. AuBUCHON: Could any of you provide an estimate as to the increased loss in yield that is associated with reduction in pool size? I understand that your equipment, your processes may have initially been set up for larger pool sizes, but just how much of a loss in yield is there when you have gone to a smaller pool size?

MR. BULT: Let me respond in general. For today, it's clear we have fully concentrated on the IVIG issue because we think that is the most critical issue at this moment. As you know, we have had a congressional hearing on the 31st of July 1997. We have had two NIH panels recently to address the same issue. We anticipate more meetings, and at that meetings we will certainly come up with the data that you are asking for. At this moment, I can't provide you with the hard data, but that there is an impact, that is for sure.

MR. REILLY: I think that type of data was presented previously to the Blood Products Advisory Committee by the association and Fred Feldman. Maybe we could figure out how to retrieve it.

CHAIRMAN CAPLAN: Larry?

MR. ALLEN: As with any other business, I'm sure you have projections. I'm not talking about the numbers you gave in terms of supply for 1997 or whatever. Do you have projection numbers in terms of needs for this particular product for 1996, 1997, 1998? Because, obviously, you have to have a bill-to number in order to make your inventories. That's the first question.

Secondly, what is the pool size now? That's another question. And apparently, from 1998, from one of the graphs, it shows that almost twice the amount of losses from the previous year were for production changes or whatever. Is that correct?

MR. BULT: I would like to answer the first question first before I get lost with the series of questions that certainly will follow today.

The first question that you asked, please?

MR. ALLEN: Projections.

MR. BULT: Projections. We have collected the data from 1996 and 1997, and what you have seen here for 1998 is forecasted data for 1998. We further have committed to collect on a quarterly basis the further data, and that will show you exactly where the trend is going to be.

We felt it was extremely important at this moment to come forth with accurate information, and that's what we have tried to do.

MR. ALLEN: Okay. I understand that. But what I'm saying is you have to have a bill-to number. You have to know at the beginning of the year throughout the year we are going to need X amount of kilograms. You have to have that. Every business has some kind of projections in order to know what you need to make per year, per three months, however you do it. You have to have those numbers.

MR. BULT: Those data are not available in this presentation. I don't have these data. These are the numbers that we have collected.

MR. ALLEN: Okay. What about the pool size?

MR. BULT: The second question about pool size, you know that industry has committed to implement the donor exposure limit for 60,000 in the first quarter of 1998, and our members have implemented and begun to implement, and at this moment we are in the second quarter, have implemented that donor exposure reduction.

MR. ALLEN: Okay. Down to 60,000.

MR. BULT: That's correct.

MR. ALLEN: From where? What were the numbers?

MR. BULT: There were different numbers. I am not a manufacturing specialist, but what I can tell you is that the industry has committed to reduce donor exposure to limit within the regulatory framework without having to change licensing applications, so that's what happened.

MR. ALLEN: Okay. But no one up here can give us any numbers on what the donor pool sizes were?

MS. PRESTON: As I recall the congressional hearing last July, we had broad numbers presented. I don't recall the exact upper limit, but I believe it was 100,000 or greater, and I think there was mention of one lot that might have been manufactured from around 400,000 from recovered plasma units which are about one-quarter of what you can collect with source plasma. That's to the best of my memory.

But I would like to reiterate what Jan Bult said. We have presented some of these data before, very recently, in fact, at an NIH expert panel, so we can certainly make that data available.

MR. ALLEN: Okay. And just--

CHAIRMAN CAPLAN: Larry, I'll come back to you. Let me go slightly around to this end.

Dana?

DR. KUHN: There's something that I'm just not understanding here. If industry was aware of the increased demand of IVIG for clinical usage in 1989 and 1990 due to the various journal articles, and also the projections of off-label use, and we know that it takes five years of time from the building of new plants or production lines before products come off the line, and taking into accountability also the past history of recalls and withdrawals, and FDA inspections through consent decrees and so on and so forth, then assuming that industry has marketing analysts monitoring the projected demand, should we be experiencing a shortage eight or nine years later?

I just am trying to figure this out. You know, did not industry see this coming knowing the history that it has had in the past?

MR. BULT: My response to your question, I think it's a very important question. You have heard other specialists speaking today about the fact that these shortages occurred in November 1997. So what it tells you that up to this time that industry as a whole was able to request the demand for the IVIG therapies.

I think that nobody could predict that all these factors would occur simultaneously. I think that is one of the problems that we are facing at this moment. And that is why it's so important that we have committed to this ongoing data-gathering effort to better understand what's going on.

The other point that I would like to make is that though we represent a majority of the companies in the United States market, we are not 100 percent. There are other parties that also should be involved in this discussion.

CHAIRMAN CAPLAN: I've got Marian.

DR. SECUNDY: Mr. Bult, could you say more about the emergency supply in relation to your references to critical need? I am particularly interested in knowing the auspices by which that decision was made. Who made it? And who defines critical need? What are the processes, the procedures, and the distribution mechanisms for that supply?

MR. BULT: Again, in general terms, if I speak for the four manufacturers, the way it works is, first of all, the industry has built up this inventory, and I told you the numbers. It's over 400 kilograms at this moment.

When questions come to the manufacturer, they will address to the medical department of that particular manufacturer, and in consultation with the physician, the final decision is made by the physician in consultation with the manufacturer. The manufacturer itself does not make the decision. It is the treating physician who is heavily involved.

DR. SECUNDY: How was that made? Who made that decision to put aside emergency supply?

MR. BULT: This was an immediate response of industry to an FDA request to build up that emergency supply. I can't recall the exact month, but I can tell you this was the immediate response of industry.

DR. SECUNDY: Is FDA at all involved in the process of selecting the persons who meet the criteria for critical need?

MR. BULT: I'm not aware of that. You should ask that question to FDA.

DR. SECUNDY: Well, I really want very, very explicit information about that from the members of the industry who are participating in that process. And I would like to know where I can find it.

MR. BULT: Again, what I told you, in general terms, I expect--

DR. SECUNDY: I don't want general terms. I want very specific, and I would like you to let me know--or to direct me in terms of where I can go to get it.

MR. BULT: Okay. What I will do, I will refer this question to each individual manufacturer and talk about it, because I cannot respond for the specific companies. That's not my role.

CHAIRMAN CAPLAN: I have two questions for anybody who chooses to answer them.

First, what can be done in situations of scarcity, whatever the reasons are, to handle not so much stockpiling but speculating? We have heard people tell us today many times that they are being offered supply at high prices, triple prices, quadruple prices. People seem to be able to wire the supply to those in conditions of scarcity. What can be done to prevent this kind of avarice from determining who is going to get supply?

MR. BULT: This question has been raised over the last week, and I can tell you I have been contacted over the last couple of days by many reporters, and I am really angry about this. I'm very angry about this, because I know how hard this industry is working to get the issue resolved. And if you know what we're doing at this moment to get the emergency systems in place--and we have given you now the actual data. I showed you exactly how the inventory is going on. This discussion about whether our manufacturers are stockpiling should be stopped. And that means that if we have other players in the market, find them. It's outrageous. It's unacceptable.

CHAIRMAN CAPLAN: And let me follow that up with one other question to anyone who cares to answer it. If we looked at our collection process, I take it that the plasma that we're getting, at least as depicted up there, comes from Americans. It's manufactured here and then moves.

In situations of scarcity, is there any reason why supply should go overseas if there's no perceptible scarcity there but there is scarcity here? How are we balancing the needs in this nation where donors and donations come from? When I looked at the front end of where plasma is obtained, and I think Americans would assume that they are trying to help their neighbors, first and foremost, if I see 2,000 kilograms moving overseas, what am I to think about how well we're taking care of the needs of people here as opposed to others where there may not be such acute shortage in other places?

MR. BULT: I think there are two parts to the question. You started with plasma. I will ask Mr. Reilly to respond to that. And I will come back to the finished products.

MR. REILLY: On the plasma, what we're seeing is the supply of plasma exceeds the demand on the finished product. But I guess you could ask the question, it goes out and goes to a manufacturer, obviously. Could that product come back?

CHAIRMAN CAPLAN: I mean, if we're collecting, whatever it was, 11 million units, we need six, they're shipping X, we're short.

MR. REILLY: That's then a function of--being able to get the finished product produced by that excess back is a function of FDA licensure. It's not possible for those manufacturers to bring the product into the country without FDA's authority.

CHAIRMAN CAPLAN: Do you want to do Part B?

MR. BULT: Okay. Responding to your question on finished products, most of the people probably have seen the "60 Minutes" broadcast yesterday evening, and I mean what I have said. If you are sick, wherever you are, whether you are in Europe, the United States or wherever, you need treatment. So we need to have a system in place to ensure treatment for all the patients who need it, in respect of where you are.

I can tell you, I have met a lot of Americans. As you know, I am European. But when I am in Europe and I meet all your American colleagues, if they need treatment, they get it.

CHAIRMAN CAPLAN: Let me just ask--

MR. BULT: But the point I want to make, I think, that's more important is that if you look in 1997 we were on track until the very end of 1997. These shortages occurred in the very last two months of 1997, and I think at this moment, with the data we have, we are not in a position to exactly describe where it's coming from. We need to have a better understanding, and that's why we have the ongoing data-gathering effort.

CHAIRMAN CAPLAN: Just quickly on this. Is it true that the burden of shortage is being borne equitably between Americans and elsewhere?

MR. BULT: I have no data to support it, but I would guess that's true.

CHAIRMAN CAPLAN: John?

MR. WALSH: No, I'm burned. I'll wait.

CHAIRMAN CAPLAN: That exhausted you?

John?

DR. PENNER: Okay. If I'm understanding things correctly, then, what you're saying is production capacity is not at least a problem. It's the inspections and other things. You've already said that plasma is not a problem. You've got an excess of plasma in the system. So if production is where the problem's at but you're saying production capacity is not full at this time or is not complete or am I missing something?

MR. BULT: Well, if you talk about production capacity, you have to take into account IVIG production is one part of the whole manufacturing process. Just to respond to that question, what I can do, because we asked that question, but in order to save time, I didn't show you all the data, but I am happy to show it to you at this moment because that immediately responds to your question.

I can show you in a minute in details what the total fractionation capacity is of our manufacturers in 1996, 1997, 1998. Here are the data. So the total fractionation capacity in 1996 was 7.3 million liters, dropped down--you know the reasons--in 1997, and we are back at 7.3 in this year. So it's not the fractionation capacity. What you have to deal with is not the plasma. What we have to deal with is the simultaneous occurrence of multiple factors that suddenly happened.

DR. PENNER: In other words, you could increase production twofold or 50 percent or something of this sort with the machinery and instrumentation you have available right now. Is that right?

MR. BULT: I wish it was that simple. You heard from Sue Preston during her presentation all the parameters that need to be met. We are working in a very, very defined regulatory environment. So if you want to do something about the manufacturing increase, you have to meet the criteria. So you're not that flexible.

If you want to have expanded manufacturing capacity, if you want to build a new plant, that, of course, requires more time, and the total time for a new plant is about five years to build it up and have it operational. So you don't have that sort of flexibility.

DR. PENNER: But then you're saying it's the requirements that are stopping you. You have more capacity in your plants now, or at least you could have more product out, but because of the requirements, the product has been limited. Is that correct?

MR. BULT: What I'm saying is each individual manufacturer is speaking at this moment with FDA to find ways to increase manufacturing capacity within the regulatory framework.

DR. PENNER: And it's the regulatory framework that is what is disturbing you right now. I'm saying--I'm probably one of the few people in this room that has done the Cohn fractionation from the very beginning all the way through, and it's not that difficult, obviously. But you have to have the capacity--

[Laughter.]

DR. PENNER: --to be able to handle this in what you are--so I keep hearing the same thing coming back, that there is a regulatory situation that is reducing the amounts that are coming out.

MR. BULT: I will ask Sue Preston to give further comment on that.

DR. PENNER: Has Sue ever done the Cohn fractionation?

MS. PRESTON: Yes, I have.

DR. PENNER: Very good. I'll be glad to hear how it went for you.

MS. PRESTON: It went very well. It was actually as part of some experiments on HIV removal. But that's a different story.

It is for us an important topic with respect to how can we increase supply. Unfortunately, our plants aren't set up to just be able to stop and do one process completely and not take care of the other products that we manufacture. For instance, let me just speak specifically for Alpha. We have a plant that's located in Los Angeles, so even before we get to any FDA requirements, we have to get through some local requirements on water usage, on plant expansion, and it takes us quite a while to make those kinds of expansions, plus we're limited by the actual land we have on which to put the buildings.

So when we talk about expansion, there are certain things we can do, and I will be able to tell some of those to you in a little while and go through those, and there are certain things that we can't do. So it's very difficult for us to just say, okay, we'll clear our an entire parking lot and put up a new building and increase the supply, as much as we'd like to do that.

We do have the requirements of the different utilities that are very specifically monitored--water, air, et cetera--and all of that usually ties into the plant. SO there are a lot of logistical issues for how one can go about expanding. Most manufacturers, though, I believe--and Don Baker or any of my colleagues can correct me if I'm wrong, but all of us look for ways to increase yield, to increase the purity, and to increase the safety. And we're doing that as a balance, but we definitely have yield in that equation. So that's one way. Additional facilities is another way. So we do try to take the opportunities to meet the market demand.

CHAIRMAN CAPLAN: I'm going to take three more questions, because we've had this group up there a long time. So let me turn to Paul and Mike, who haven't had a shot, and then I'm going to go to Jay over here.

DR. HAAS: In the data on IVIG that was just presented, there have been no recalls this year, so I'm assuming the screening process is working more effectively, but maybe that's not correct.

What's the basis of your projection of the 905 kilograms withdrawal then for 1998?

MR. BULT: Those were numbers occurring from technical problems that occurred in the first quarter.

DR. HAAS: In the first quarter, you didn't show any withdrawals, but this is what you're projecting will happen then from here on out the rest of the year?

MR. BULT: Nobody is able to predict any recall or withdrawal.

DR. HAAS: I understand. I guess I'm just trying to figure out, did you use 1997 experience as your basis then for projecting--

MR. BULT: No. What we did is we used the available supply. That is a number that we can calculate from our manufacturing capacity, and we have put in that column what we know at this moment. I think the important thing is, with the quarterly reporting that we're going to do, we will have immediately information on that, and that's why we feel comfortable doing it this way.

DR. HAAS: I guess just one other comment. I know you're giving us data and you're working hard to get data. But as someone who is not familiar with the industry, I guess I still don't have any clear sense of the manufacturing process. Some of the questions that were called for this morning about why particular pools are necessary, it would be really helpful for me if the industry would lay out as close as they can, step by step, of how this process works when you go to a bigger size pool or smaller size pool or different size column, or whatever, what happens.

With the data we have here, I'm still left with a huge question in my mind as to what really happens in this process.

MR. BULT: Well, I think two responses. The first question is what are the accurate data, and that's what we presented today. Your first question is: Would there be a way to help you better understand how the manufacturing process works. I think that's an issue that we can take up with your Chairman. I think that should not be the issue for today.

DR. BUSCH: My question relates to the marginal status of the inventory. Even though as you've stated, you've managed to maintain supply pretty well in the last few years, clearly it's relatively marginal. My understanding is all of these products have long shelf lives. These are not products that would be expiring and you need to constantly replenish the supply. So I'm trying to wonder what the motivations are to maintain a fairly marginal inventory. Obviously these products, once manufactured, the volume, et cetera, to maintain them and freeze them in whatever conditions they're retained can't be that substantial.

So I'm wondering, is it the cost of the inventory? Specifically, what is the impact of concern over eventual potential regulatory recalls, et cetera, of inventory product on your--the industry as apparent designer of this system to maintain fairly marginal inventories?

MR. BULT: Well, I think the response to your question is the following: First of all, money is not the issue. What we want to do is bring the product to the patient as soon as possible. These are just the factual numbers. And if you know that you're working in a period of shortage, then I would gather it being unethical to have large inventories. I've shown you that we have very small inventories. The operational inventories at this moment are below three weeks, but if you look at the annual manufacturing capacity--and let's take round numbers--you will find that on average you will have every month 1,000 kilograms available, and with this small inventory, you are able to maintain that level and to deal with the supply issue. So it's not the money. It's just the facts.

DR. BUSCH: It would seem like for many of these products we could have built up five years' worth of inventory and just constantly have that to fall back on if there weren't some concern over eventual problems with that inventory.

MR. BULT: But the reality is that the demand is so big at this moment, there is no way to build up this inventory because it's needed.

MR. REILLY: I think, Mike, the other thing that you I'm sure realize is five years, as an example, is an awfully long time out. And the regulatory requirements are changing on a frequency level that far exceeds or is far shorter than five years. There are major ethical questions if you add a new test or you change the requirements in some substantial way in the interim, what you do that inventory.

MR. BULT: As a practical point of view, the shelf life of immunoglobulin is below five years. You talk about two to three years, depending on the circumstances.

CHAIRMAN CAPLAN: Jay?

DR. EPSTEIN: Jan, you shared with us the estimate that the amount of IVIG not released because of CJD-related issues was about 1,000 kilograms. And my question is: Does that material still exist in quarantine? And would industry consider releasing it with a suitable label telling users of the theoretical risk? This is a question that came up in the January meeting of the Advisory Committee, and there was a general suggestion that it would be useful to move in that direction. I know that there has been one instance by Alpha where such a thing has been done. But I would just draw attention to the fact that that inventory, if it still exists in a quarantine, is potentially releasable and is, in fact, larger than your projected annual decrement of inventories.

MR. BULT: I think, Jay, that is an excellent question. What you have to realize is that the number that we've shown to you, we also calculated the impact of the phase two and three that was lost because of--and that had not reached the final stage of manufacturing. And I think it's very important because, as you have seen from the CBER reports, also phase two and three was withdrawn for that same reason.

The instance that you just mentioned is absolutely correct, and in the numbers that we have shown to you, the January numbers, the inventory numbers, did not include the numbers that you mentioned as a very specific issue, and Alpha and FDA worked out a way to make that product available.

CHAIRMAN CAPLAN: So it is there, or it isn't there?

MR. BULT: In this case, I'd like Alpha to respond, but I think that it--what Jay just mentioned, Alpha and FDA discussed this and made it available, and it was distributed to the market.

DR. EPSTEIN: No, I'm asking whether the 1,050 kilograms that are listed as not released under 1997 could be moved into releasable in 1998 with suitable labeling. You're saying they are not currently counted in the 1998 column, and I'm asking how much of that can be counted.

MR. BULT: I would like to separate the two questions. Let's not talk about the company-specific issue you just mentioned. Let's focus on the 1,050.

The 1,050 is the total of products withdraw, but also including the phase two and three that could not be further processed. And what we used here is a calculation to determine what the yield will be and the impact on the market. That's what happened.

CHAIRMAN CAPLAN: I see. So it actually isn't in IVIG form. It's in raw material.

MR. BULT: Yes. And that's why we also used the term possible supply, because that is important. It's an intermediate but a very relevant intermediate.

DR. PILIAVIN: Was that paste destroyed?

MR. BULT: I can't answer that question. I just have to go back to the--I can't answer that.

DR. CHAMBERLAND: The individual companies, would they be able to provide that information about what they have in inventory in terms of--that's been quarantined in terms of finished product and precursor products?

MR. BULT: I can't respond to that. You have to ask the individual companies.

DR. CHAMBERLAND: So we would have to query each of the individual companies.

CHAIRMAN CAPLAN: Well, that's a great moment to switch to the next session. Thank you. Thank you all for those presentations. We have industry comments coming up next, and in some challenge to the world of urology, I think we're just going to plod on here. I understand the panelists may want to stretch or move a bit, but I'm going to try and drive us through because I think we have a window at the other end of human tolerance for all our activities today. So I want to get us out by 4:45.

So let me ask the next panel to come up. Sue Preston is already up there. The other members, Larry and David, Deborah.

[Pause.]

CHAIRMAN CAPLAN: Let me urge the panel not to go far because I'm going to launch us in a minute.

[Pause.]

All right. I think we're ready to get underway for our next session. Sue Preston, who already graced the podium, is going to be coming back up there. Again, let me urge all those presenting to try and be concise. I know the panel has lots of questions and issues that it may better address by questions than presentations. Let me urge you to try and be as concise as possible. Sue? xx MS. PRESTON: Concise. I will try.

Dr. Caplan, Dr. Nightingale, members of the committee, ladies and gentlemen, guests, I am Sue Preston, Vice President of Quality and Regulatory Affairs for Alpha Therapeutic Corporation. We appreciate the invitation to speak to you today on the steps that we have taken to assure available product and rapid distribution of our immunoglobulin intravenous human product. Our trade name for that is venoglobulin-S.

I will discuss the current capacity, the amount of final product exported, the distribution improvements, plans to increase capacity, and our ongoing research activities related to the product.

This overhead is a chart of the production of IGIV over the last three years with a forecast for 1998. The total amount for each year represents the amount of final container IGIV fractionated and the amount of material that is fractionated into an intermediate product, fraction II plus III paste.

The first point to note is that the final container intravenous immunoglobulin, venoglobulin-S, is approximately the same. We saw an increase in our capacity in 1996, and we have forecast an increase in our ability to release final container IGIV in 1998. We also manufacture, as I mentioned, fraction II plus III paste. Some of that paste goes to other U.S.-licensed manufacturers in the United States, and some of it is exported to our business partners. And the top part, the red bar, is the amount of working inventory, and we can see that that has decreased significantly over this past three years, with a forecast for very little in 1998.

Next overhead.

This next overhead relates the amount of IVIG distributed domestically or exported for the last three years and a forecast for 1998. Alpha Therapeutic Corporation does not export significant amounts of final container venoglobulin-S. For 1997, we exported less than 7 percent, and we forecast less than 3 percent in 1998.

Next overhead.

This overhead represents our fractionation time line. It is important to understand that plasma collected does not yield the final product for distribution for approximately 130 days. The steps will involve a minimum of a 60-day inventory hold, which we can see here, after plasma collection. Immediately after collection and during the inventory hold period, samples are sent to our Memphis laboratory for testing for viral markers such as HBSAG, anti-HCV, anti-HIV I and II, HIV I, P24 antigen. More recently, samples have also been subjected to polymerase chain reaction, PCR, for detection of viral nucleic acid to HCV and HIV under an investigational new drug application sponsored by the National Genetics Institute.

Once the 60-day inventory hold period has elapsed and we have checked each donation against the test records, plasma units will be pulled and the fractionation process begins. The fractionation and purification process typically takes 30 days for completion. Some product lines require a week or 10 days longer than other product lines for the same plasma pools. Final product testing and quality assurance review requires approximately 20 days.

If the product is subject to lot release requirements, the lot will be released typically within 10 to 20 days by CBER staff. And I'm speaking for all product lines. Certainly for IVIG we've seen an increase--actually, shortening of the time for release from CBER.

We immediately perform our final release checks and move the product to inventory released for distribution. The shipping of most of our product occurs Monday through Wednesday of each week, with either overnight or two-day shipping schedules.

Next overhead.

So one of the things that we could so, since we are constrained by the capacity of our plants, one of the things that we did look at over 1997 were ways to improve the distribution channel. And we wanted to get our venoglobulin into the hands of the end users directly. So this is a comparison of the first quarter of 1997 to the first quarter of 1998, and what we can see here, there are three types of end users or users that we--consignees that we ship our product to. We have home care as represented in the blue, home care companies that will get the product directly to the patients that need it, and then what we call direct accounts. These are hospitals, pharmacies, or doctors' offices, and then what we call the wholesalers or indirect accounts. And it's important to note that the wholesalers may provide a valuable inventory service for their customers.

But as we look at what we have been able to accomplish over the 12-month period, we can see that we have shifted our production from 67 percent to 16 percent over 12 months in terms of going to wholesalers. So although the change in the distribution channel has resulted in more sales activities to support, we believe that the change will be beneficial to the patients in that in the time that it takes to get product to the patients, physicians, and medical staff is decreased by approximately 30 days.

Next overhead.

One of the things that we touched on, that Mr. Bult touched on, was the inventory, and when we look at the last six months of final container product shipped and the amount in inventory available for distribution, we showed that we averaged 240 kilograms per month--this is final container venoglobulin-S--and a little over 2 grams a month in inventory. That does not include the 335 kilograms of IGIV that was quarantined for three months and released during the January through March time frame.

Another measure is the amount of the final container product in inventory for the last three years. In 1995, we had 1.5 percent of our final container production, or 37 kilograms of venoglobulin-S, in inventory at year end. This was reduced to 1.5 kilograms in 1996 and was 0.1 kilogram in 1997. This correlates well with the previous graph showing the reduction in the working inventory of fraction II plus III paste as well.

Next overhead.

Alpha Therapeutic Corporation does have plans to expand the IGIV availabilty over the next five years. This overhead provides a forecast of our plans. This year we will be able to increase availability about 375 kilograms beyond 1997's numbers. In 1999, a process enhancement will enable us to add 500 kilograms of venoglobulin-S to the market. Another 500 kilograms are planned to be added in 2000 with new facilities and process enhancements. And then a significant increase will be realized by 2003 with an additional 935 kilograms available.

Alpha Therapeutic Corporation continues to fund research activities in areas of immunoglobulin therapy. This includes clinical trials for a new formulation to provide better safety and a new process that will add to the safety margin as well as increase purity and yield. We are in the final report stage for an already approved indication for treatment of idiopathic thrombocytopenia purpura, and Alpha is preparing a submission on our clinical trials with venoglobulin-S as a preventative measure for acute graft versus host disease in bone marrow transplant recipients.

Alpha Therapeutic Corporation has been aware of a periodic shortage of intramuscular immunoglobulin preparations. We are nearly complete with a trial of the venoglobulin-S 10 percent formulation administered by the intramuscular route. When the route of administration is submitted to and approved by CBER, we will be able to make more immunoglobulin available for intramuscular administration in times of need.

Next overhead.

In summary, in addition to what you've heard with respect to the distribution channel improvements, we are committed to providing high-quality, safe and effective products to serve the public health and the patient needs. And we're doing that--we've demonstrated that commitment in several areas: First, over $20 million have been invested in safety enhancements over the last five years. Second, in the last five years, Alpha Therapeutic has invested all of its profits, plus an additional $33 million, in facility upgrades and expansions. Another $75 million project is now under construction for additional facilities. Third, assuming no reduction in production lot size, we are planning a 40 to 50 percent increase in venoglobulin-S availability by 2003.

Thank you for your attention to Alpha's presentation. We would like to encourage cooperation to assure adequate supply of safe products, and I will be glad to take any questions. Thank you.

DR. NIGHTINGALE: Thank you very much, Ms. Preston. This is Steve Nightingale in Dr. Caplan's absence. I'll be the temporary Chair.

Would the members wish to ask questions of Ms. Preston? Raise your hands and all of you will be permitted to ask all the questions that you wish. Dr. Hoots begins.

DR. HOOTS: What happens to your fraction IV-1 since you told us it takes 16 liters to make the average amount of supply for one alpha-1 patient?

MS. PRESTON: Currently, our fraction IV-1, some of it is processed into alpha-1 proteinase inhibitor, which is an ongoing clinical trial for Alpha for that product. We may at the request of other licensed manufacturers provide them with that fraction, and if there are other uses, I'm not aware of it right now.

DR. NIGHTINGALE: Are there any other questions by Dr. Hoots?

[No response.]

DR. NIGHTINGALE: Mr. Walsh?

MR. WALSH: I've got just two questions, Ms. Preston. How do you apply an allocation program to your distributors or customers at this time in this shortage?

MS. PRESTON: I'm not sure I'm the most expert, but I can tell you what my understanding is. With some of our customers, we do have contracts, and we fulfill those contracts. I think that we try to satisfy first the customers that have been longstanding customers for us, and then we try to--I don't know that we have an exact allocation program, if you will.

I will answer the question about the emergency fund. However, I don't think the person who asked that is here.

MR. WALSH: Just one step further. Alpha Therapeutic Services, Inc., for example, does that get favorable treatment over home health care company XYZ for IVIG?

MS. PRESTON: I don't know exactly how we allocate that, but I know that they don't have any inventory either because they're always complaining. So I assume they're in the same boat as all of them.

MR. WALSH: Second question. Regarding your A1PI product development, perfect-case scenario, we cooperate collectively with the FDA and get that through as quickly as possible. What would you anticipate the time frame to be for market?

MS. PRESTON: I think that we anticipate that it would be in 2001 in terms of product launch, early 2001.

MR. WALSH: And did I hear you say earlier that you would offer a manufacturer that's licensed by the FDA some IV-1 paste now if it would help them meet demand?

MS. PRESTON: Yes. That is, I think, some business opportunities that have to be decided by the business partners.

MR. WALSH: We appreciate that consideration.

DR. NIGHTINGALE: Moving down the line, Dr. Guerra.

DR. GUERRA: Does Alpha have any federal contracts to supply, for example, the Department of Defense with so many kilograms of your product? That's one question.

And another question is: I suspect that there probably are also some specific research uses for the immunoglobulin IV products. For example, in the hyper(?) immunoglobulin that is presently being used as prophylaxis for preventing respiratory (?) virus infections in at-risk prematurely born infants, that demand has increased very significantly in the last year. Is your company one of the suppliers for that product?

MS. PRESTON: No, we have not been a supplier for that particular product, at least that I'm aware of.

Would you repeat your first question, again?

DR. GUERRA: In terms of Department of Defense contracts.

MS. PRESTON: Oh, yes. We do have some federal contracts. I don't know if it's for venoglobulin or whether it might be for albumin or other products, but I do know we have some federal contracts. I think the VA hospitals we have a contract with.

DR. NIGHTINGALE: Mr. Allen?

MR. ALLEN: A couple of things, ma'am. Do you have any procedures in place for wholesalers to make sure they don't price gouge per se, so to speak, during these times of shortages? That's the first question.

MS. PRESTON: I think that that's something that we've tried to address by switching our distribution so that it really does go to the hands of people, the physicians and the patients, as rapidly as possible. I don't know of any way to put a procedure in place that's enforceable, unfortunately, with any distributor.

As I've listened to our sales and marketing vice president, he very strongly makes statements in our Management Committee that we are actively avoiding anyone we know who might be doing that kind of--having that kind of behavior.

MR. ALLEN: But you've had instances in the past where you know that this has happened?

MS. PRESTON: I don't know that we know of any particular instance, but it's something that if we would hear of it, we would certainly want to take--we certainly would want to discourage that.

MR. ALLEN: Could you explain why--and this was mentioned earlier today. I may have misunderstood this, so excuse me if I'm wrong here. But could you explain why some patients have had adverse effects to using the same--

MS. PRESTON: That's a very, very good question and one that has taken a lot of research, and probably Dr. Epstein or Dr. Weinstein could address this. But I can tell you my experience with this.

Typically, when primary immunodeficient patients--and maybe even some of the physicians could answer this better, but with primary immunodeficient patients, when we see them in clinical trials, we'll see their initial infusions result in more adverse events, and when they switch products.

Now, people have speculated as to why that might be. Perhaps because they're immunodeficients they just have--their body has been accustomed to a certain formulation, a certain pattern of immunoglobulin sub-classes or characteristics, and then when it's switched, they have to readjust, just like they would in their initial infusions.

MR. ALLEN: But since there are guidelines that you all must follow when you manufacture these products, shouldn't they all be basically the same, for the most part?

MS. PRESTON: I think one can talk about the products being the same. We certainly have similar, if not the same, specifications with respect to potency and with respect to safety. But each patient is so individual, and that's one thing that I think I noticed in reviewing intravenous immunoglobulin products in clinical trials, is that there's a lot more individual variability with the infusion of intravenous immunoglobulin than maybe with some of the other products.

I wanted to answer the question about the emergency fund. You had asked that, and I wanted to address that.

It's very difficult, at least we at Alpha found it very difficult to try to deny certain accounts or certain patients or certain calls for product ourselves. How could we adequately triage that? We are not in the health care advising. We provide product. So what we elected to do with our emergency fund is first we worked with the Immunodeficiency Foundation, and then we worked with a company called Triple F. And we have allocated--they know our emergency supply allocation. They are the ones that triage the calls. They call us and tell us where to ship it. So that Alpha ourselves do not know the specific patients or the triage, but we have made those kinds of--the emergency fund--

DR. SECUNDY: Can you tell me something about Triple F, who they are?

MS. PRESTON: I don't know much about them myself, but our company--there are experts within our company who do. It's my understanding that they have a distribution network, and they have elected to participate in this emergency supply, not only for our company but I believe at least one other company. And they've set up the triage of calls based on that.

DR. SECUNDY: Are they health care providers?

MS. PRESTON: Yes, they are--well, they've distributed product. I do know that.

CHAIRMAN CAPLAN: Just to follow up on what Marian's asking about, I think if possible--you know, we had a lot of discussion this morning on attempts by individual hospitals to allocate their supply, and we heard the Minnesota experience within their health system about distribution there and prioritization. And I think for many people it's going to be of concern that wherever the emergency supply is stockpiled that it be available equitably. And so it is of keen interest, and this committee would certainly like to have information given to it. I understand that Alpha is not in the business of allocating and providing that way, but whatever the intermediaries are, whatever the procedures are, that's going to be very important for us to know about because, again, the public trust in an emergency supply is only going to go so far as its perception that it's fair and equitable. So that's just something I would urge all the companies and anyone else who has information to get to Dr. Nightingale. I know the committee is going to want to hear more about that. We should. It's just going to be very important to understand how that squares with what those hospitals and systems are doing.

While I've got the floor, would you care to comment--I don't mean to hold you accountable for this, but, again, I'm coming back to this issue of supply going overseas, supply being used here. We hear about that a lot. People are concerned that there's a shortage here that doesn't appear to be in Europe. If you look at the numbers, to some extent, that we saw from the industry, it looks more perhaps like there might be more supply going overseas maybe for uses that might not be as vital--let's try it that way--in the American context.

MS. PRESTON: I don't know that I can comment for all of the industry. I can share that we do have a business partner located in Spain, that they had been contacted by the Spanish Ministry inquiring whether they could increase their production in order to satisfy potential Spanish demands. So I don't know that I can answer any other questions but that.

CHAIRMAN CAPLAN: Okay.

DR. CHAMBERLAND: I guess I wanted to return to the question that we left right before the break, which was the issue that Jay Epstein brought up about what might be available I guess on an individual firm basis that, apparently, the amount of product, of IVIG, that has been returned to manufacturers related to CJD and how much product you might have in quarantine, either complete product or precursor. And then there was also an allusion to the fact that apparently I think it was your firm had released product with a specific CJD warning label, and I wanted to hear a little bit more about those details and how that went.

MS. PRESTON: Okay. Would you permit me to show another overhead that might elucidate that?

First off, I'll just tell you a little bit about this particular product, and this was an overhead that was utilized at the NIH expert panel.

We had one donor who had made a donation. Seven months later, that donor returned, and this is before the implementation of the inventory hold. The donor returned and said at that time, "I think I used growth hormone in the early 1980s." And, in fact, we did the investigation, and that donor did appear to have used pituitary-derived human growth hormone.

But the unit that had been utilized several months before had been in one plasma pool, and when we look at this plasma pool, we see how many things are affected by this one unit in one plasma pool. In the IVIG process itself, we were able to catch the fraction II plus III precipitate. There would have been two lots from each of these precipitates, so a total of four lots. Those precipitates have been discarded already because our immediate thought on this was not to carry those forward.

However, we also used this in a number of albumin lots that come through fraction IV or fraction V, et cetera, and there were ten albumin lots that had been manufactured to final container, and two of the precipitates had been discarded.

But one of these albumin lots was utilized in our IVIG purification process, not as a final container excipient but actually a reagent during one of the purification steps. And that affected 25 lots of venoglobulin-S. Five of those had already been placed out in distribution. Those were recalled. We then had the remaining 19 or 20 that were still in-house, and at the same time, it was when we all, I think, became aware that there was a shortage, and the FDA asked us would we be willing to release this product. Well, that, I will share with you, caused quite an internal debate because this is a litigious society and there are concerns about this, and as long as there's a theoretical risk and so forth.

But as we were also realizing the significance of the shortage, we agreed that we could do that with the appropriate labeling so that recipients would know exactly the occurrence of what had happened and so forth, and we did release that. A good portion of that went into the emergency fund because that was also at the same time that the FDA was asking us about setting up an emergency fund, and we really didn't have any inventory at the time.

Alpha has routinely been back-ordered for IVIG for at least the past two years. So it was something that for us was a fairly routine occurrence.

I hope that answers your question.

DR. CHAMBERLAND: Do you currently have any finished IVIG that is available to you that has been withdrawn from the market because of other CJD-related recalls?

MS. PRESTON: We did recall five lots. Of those five lots, of the material that we placed out there, I believe about 18 percent was returned, has been returned to us to date. It's very difficult for us to think about releasing something that's already been withdrawn. So that would be--and also, there's not very much amounts of those. It's only 16 or 18 percent.

CHAIRMAN CAPLAN: Last question, Larry. Then we'll move to Mr. Guiheen.

MR. ALLEN: Could you tell us--and I know you may not have the answer to this, but how long did it take to build up this emergency inventory?

MS. PRESTON: Well, that had been about seven months in terms of when that plasma pool was processed, and it affected--it just happened that because that was an excipient and it affected so many lots.

MR. ALLEN: No, not that particular one. I'm talking about in terms of the emergency inventory you have now based on what the FDA came to you about.

MS. PRESTON: We tried to set aside--there's very little flexibility, but some flexibility to try to move production around and scheduling activities to try to increase that ability. When we do that, we usually short another product. So, for instance, alpha-9 we didn't manufacture in order to manufacture some additional IVIG.

MR. ALLEN: So there's 430 kilograms here, which is industry-wide, I understand. It took about how long for them to collectively come up with this amount?

MS. PRESTON: I really couldn't answer that question. I don't know how long it takes. It takes us about 130 days just to manufacture a lot.

MR. ALLEN: And one brief, quick question. The kilograms that were exported, is there a price variance between what you get for it here versus what you get over in Europe for it?

MS. PRESTON: Well, I'm not, again, the price expert, but I did ask that question thinking that some--and we had heard a little bit that people were concerned that actually people were getting more for their venoglobulin in other countries. Alpha does not export venoglobulin to Europe, and it would be very--it would be an emergency kind of use situation. But we have a little bit of export that goes to other countries, in South America, perhaps, or into Asia. And there the price that we obtain for venoglobulin is--you know, the price that we charge is either equivalent--it's not more than, I can tell you that. It's not more than.

MR. ALLEN: Okay, but that's not going over to Europe per se.

MS. PRESTON: Right.

MR. ALLEN: Can anyone else answer that?

MS. PRESTON: How about if I sit down?

CHAIRMAN CAPLAN: All right. We'll let you sit down, and we'll bring--

MR. BULT: I would like to respond to one of your questions about the building up of the emergency supply, and, Jay, maybe you can help me. But I think that the request from FDA to build the emergency supply was in August last year?

DR. EPSTEIN: No, it was in December.

MR. BULT: Okay. Well, at first instance, the industry built up an inventory hold for 100 kilogram, and as from the 1st of January this year, we have 400. So this went very quick.

CHAIRMAN CAPLAN: And why don't we bring Mr. Guiheen up there. We'll let Larry's question about pricing hang. He may want to say something about that later. I'm sure we'll come back to it again. xx MR. GUIHEEN: Good afternoon. My name is Larry Guiheen. I'm the Vice President of Sales and Marketing for Baxter Health Care Corporation. I've had 25 years' experience in health care, and 20 of those have been with Baxter. I appreciate the opportunity to address this advisory committee.

As you've heard today, immunoglobulins are life-saving products. The production of immunoglobulins transplants the immune system from healthy donors to patients who are immune deficient, and without these products, the consequences for these patients are life-threatening.

We at Baxter take this responsibility very seriously. We are constantly made aware of our responsibility by the frequent communications, especially recently, with patients, their parents, and their physicians.

As an example, one call recently received was from a mother--I'll call her Mary--whose son Billy had just come home from the hospital having survived a vicious infection. Mary was desperate. She was crying on the phone that her son could not survive another infection. Billy needed a regular infusion of IGIV and his normal immunoglobulin was not available.

It's calls like this, especially in the last six months that we receive over 50 to 100 times a week, that drives us to try to solve this shortage. In this case, we were able to supply from our emergency reserve this patient with Gammaguard SD.

What I'd like to do is really review the timetable of last year and what we did as these events showed themselves. This began, as we all are aware, in early 1997 when one company, as a precaution, temporarily stopped production. As a result, we at Baxter implemented a system of monitoring our shipments and orders in order to make sure we balanced our distribution throughout the United States.

By late 1997, the supply had not improved. Calls increased from patients who were unable to obtain their usual product, and it was at that time we decided to expand our emergency supply of Gammaguard SD. We had always kept a small reserve for patients who are IGA sensitive, but expanded this to 14 days of inventory to meet this growing demand for patients in critical need.

In order to supply this emergency reserve, we first deferred all new clinical research that would reduce the supply, and we shortened the time, much like Alpha, it took to take a finished product and get it to the patient. That's a one-time bolus of product you get by compressing that time period. That was what we did to stock our emergency reserve.

After taking care of this immediate need, we additionally attempted and followed up on the following projects that were identified to substantially increase the amount of supply in the United States. A license amendment was prepared and submitted to the FDA for our Rochester, Michigan, plant. This plant was initially acquired as part of our immuno-acquisition earlier in 1997. This plant, when approved, could produce an additional at least 150,000 vials of Gammaguard SD for the second half of 1998. We believe the FDA will be responsive in approving this supplement.

Number two, we've had a lot of talk about exports. Baxter is arranging to import endobulin. This is an IGIV that is manufactured and distributed by us in Europe. The FDA is also reviewing this application, and we again believe they will be responsive.

MR. GUIHEEN: Baxter is making additional process improvements utilizing new technology to increase the availability of IVIG. We are committed to increasing this supply.

I would like to take one moment to address the allegations in the media. We at Baxter are absolutely not stockpiling. We prefer to have 2 months of inventory under normal circumstances. However, today, we struggle to maintain this 14-day emergency supply.

On the question of export, over 80 percent of Gammaguard stays in the United States. We do export the rest overseas. However, what has not come out is that we do import. We import a product called IVGamm today, and we, again, as I mentioned earlier, are looking to increase our importation.

We do not promote for off-label use. This is illegal.

You have heard reports of pricing increases in the neighborhood of 200 to 800 percent. Baxter's prices today for Gammaguard SD are the same or less than they were in 1994.

Furthermore, we are focussing our supply of the available Gammaguard we have today on hospitals and pharmacies that get this product directly to the patient.

I would like to conclude that we at Baxter acted quickly and decisively to this shortage. We are very concerned about the patients that are affected by this shortage, and we are able to increase supply and are willing to do so as quickly as possible.

I will take any questions.

DR. CAPLAN: The chair is going to note that--the chair has promised to go do something outside of here for this committee that he cannot get out of. So Steve at some point is going to take over traffic control for questions, but I think it very important that we take as much time as needed to get these questions done. So we are just going to keep going.

Keith?

DR. HOOTS: The projections that we heard about the IGIV for 1998, they do not, I presume, include any potential for the import of the immuno-produced product or the Baxter immuno-produced product. Is that right?

MR. GUIHEEN: The number of 150,000 viles is just the Rochester, Michigan, plant producing Gammaguard. Endobulin, if it is approved, would be additional to that.

DR. HOOTS: How much could that potentially provide if it were somehow licensed in 1998?

MR. GUIHEEN: Right now, I would say it is at least 75,000 viles, and that is from U.S.-based plasma. If we were to get approval for European-based plasma, it would be another 75. Both of those are different approvals, as you know.

DR. CAPLAN: John?

MR. WALSH: From what I heard you say or from what I understood you to say, your allocation process is basically redirecting historic distribution to hospitals and pharmacies that deal more directly with the consumer?

MR. GUIHEEN: Actually, there is not much redirecting that was necessary. We mainly distributed directly to hospitals or to home care pharmacies that have always distributed that way.

Our sales to distributors is less than 3 percent and always has been.

DR. CAPLAN: Would you care to comment on this price difference issue between the Europeans and the United States in terms of what can be commanded in the market?

MR. GUIHEEN: Sure. First, Europe is not one country, as we know. It is 13 different--at least 13 different. The pricing is different in each one of them. The supplies are different in each one.

I can say that both in Spain and the U.K., there is a shortage. I cannot speak to all of the countries, but we as a manufacturer believe that, again, our product, endobulin, we can get additional supplies here to the United States by either expanding our capacity in Europe and/or getting it from the European area.

In terms of the pricing around the world, the pricing is different all over the world. Some of it is set by the countries themselves because they are socialized medicine. The reports in Japan that the pricing is very high is true.

DR. CAPLAN: Mary?

DR. CHAMBERLAND: Recently, in response to the cases of human new variant CJD, the U.K. has announced that they will no longer accept plasma from their own donors and will import plasma.

I guess I wanted to get some sense for you because you mentioned the U.K. was "experiencing shortages of IGIV." I guess I wanted to ask you if this heretofore not anticipated need of large volumes of plasma potentially--and I would suspect that the U.S. would be a likely place that the U.K. would look to, to supply this--is that something that has been addressed in projections in terms of production? Do you anticipate, for example, that you will have to export more plasma, be it finished or precursor? Will that then have the domino effect on decreasing the U.S. supply?

MR. GUIHEEN: Yes. I think that what has come up earlier today is that I do not think plasma is the problem. There is available plasma, and from what I understand, that is what the U.K. is doing right now.

Their manufacturing facilities are just procuring some of this plasma that is in excess on the market, and it probably is U.S. plasma, but I cannot say that I know everything about what goes on in the U.K.

DR. CHAMBERLAND: You mentioned that the U.K. and one other country were having product shortages of IGIV. I guess it was Spain. I guess what I am trying to do is to get some sense of--you mentioned that you are getting 50 to 100 calls per week for the last several months, and I guess I want to get some sense of what the urgency and the shortages are in Europe because you export a not insignificant amount of product. You said 20 percent of your product goes--so I am trying to get a sense of what is coming to you from your European contacts in terms of urgency of need.

MR. GUIHEEN: The amount is around 15 percent that we are committing to that, in that neighborhood that we will continue to export. We have exported that amount, again, since Gammaguard was released to the market.

And there are very specific reasons for Gammaguard. It has a very low IGA content, which is one of the reasons that only certain patients could only use Gammaguard because of this low IGA amount.

We look at balance in terms of--we do import IVGamm. We do export Gammaguard. Those are not in balance at this time, but, again, looking at endobulin as a possible alternative, we think we can probably get to a balance so we are able to meet the patients' needs in Europe, while still serving the United States.

Our overall supply over the last 3 years has remained constant. We have not seen a reduction necessarily in the supply of Gammaguard.

DR. NIGHTINGALE: Are there any other questions for Mr. Guiheen?

[No response.]

DR. NIGHTINGALE: If not, thank you very much.

Dr. Spencer?

DR. SPENCER: Well, I was going to say "Dr. Kaplan and members of the Committee." Dr. Nightingale and members of the Committee, on behalf of Bayer Corporation, thank you for asking me to appear before you today.

I will describe Bayer Corporation's history of commitment to plasma therapies and our current situation, and I will tell you what we are doing to help the patients who rely on these life-saving therapies.

We consider this appearance of privilege and an obligation. This is the kind of issue that this Committee was created to deal with. Above all, please know that our relationships with patients are for life, and that we care.

My name is David Spencer, and I am vice president of Product Development for Biological Products in the Pharmaceutical Division of Bayer Corporation. In this position, I have senior responsibility for worldwide product development and marketing for plasma products.

Over the last 20 years, we have seen significant advances in standards of care and well-being of the patients who infuse our products. Bayer remains committed to furthering these advances and doing everything possible to increase the supply of our plasma-derived therapies.

We have been asked to address the issue of plasma product availability and what we are doing to meet the needs of those patients. We are acutely aware that there is a serious supply problem, and we are working around the clock to minimize its impact on patients.

Despite our 7-day-a-week effort--and I assure you, we are not alone in this--Bayer has temporary shortages for some products in the United States and in many markets worldwide. Although our supply situation is improving, there will continue to be spot shortages throughout 1998.

For our immunoglobulin products, Gamimune N, we expect to release about one-half of the total number of units we distributed last year. Supplies of our recombinant DNA Factor VIII therapy for hemophilia will exceed those of last year.

Stocks of our plasma-derived Factor VIII product, Koate HP, are low, but we anticipate that during 1998, we will be able to supply about 90 percent of the units that we made available in 1997.

We will not be able to produce any Factor IX complex this year. Fortunately, at this time, there appears to be sufficient treatment alternatives available for these patients.

Regarding prolastin, our product for the treatment of genetic emphysema, Bayer is expecting periodic delays in deliveries throughout the next several months. We are making every possible effort to produce nearly as much prolastin in 1998 as we did last year.

These temporary shortages, and I emphasize "temporary," have been triggered by at least four events: demand increases particularly for Gamimune N and prolastin; production disruptions stemming from the need to make previously planned improvements as well as to address issues raised by recent FDA inspections; unanticipated breakdown of the heating, ventilating and air-conditioning system at our Clayton, North Carolina, facility, which required replacement and validation of key system components; and, finally, withdrawals by many suppliers of product lots because of possible exposure to the always fatal Creutzfeeldt-Jakob Disease, or CJD.

But the news is getting better. Bayer is devoting every available resource to return to full production as soon as possible. We are also working diligently to address all regulatory and manufacturing issues.

In December of last year, we submitted a detailed implementation plan to the FDA. Dedicated project teams are implementing the agreed changes, and we are providing monthly status reports to the FDA on the facility improvements and on the timelines that we have proposed.

Furthermore, at the request of the FDA, Bayer and all manufacturers of intravenous immunoglobulins, or IGIV, have created special emergency stocks to meet urgent patient needs. This supply is in addition to product that we already provide for children who participated in Bayer-sponsored clinical trials on pediatric AIDS.

We have also reserved an emergency supply for the Immune Deficiency Foundation for patients with primary immune deficiency.

We have three emergency supplies, therefore, the 1,000 grams per month that we put aside distributed through the NIH for pediatric AIDS; 15,000 grams a month that go into our 1-800 number emergency supply, and 40,000 grams a month that we are increasing as much as possible this year that is reserved for primary immune deficiency.

As the sole supplier of prolastin, we recognize our special responsibility to the patients who rely on this product. Aggressive steps are being taken to accelerate production and already have, such as increased reliance on our site in Berkeley, California. The FDA is showing the same sense of urgency and is speeding lot releases.

Mr. Chairman, Bayer took the actions I have just described to respond to a crisis, but our company has long recognized the rise and demand for biological products. Years ago, we began major initiatives to develop new products, increase product supply to patients, and address the ongoing challenges of therapies derived from human plasma.

Five projects show Bayer's commitments to these goals and represent an investment of more than $1 billion. The first project is recombinant Factor VIII. We began this project in the mid-1980's, and it came to fruition in 1993 with the introduction of Kogenate, a leading product for the treatment of hemophilia-A. Today, Bayer leads in the sophisticated cell profusion technology that has been Kogenate available to thousands of patients.

This achievement required a decade-long investment in biotechnology, research and development, and capital expansion. We are putting the same level of commitment into increasing the supply of plasma products, projects which will be completed over the next 1 to 5 years.

Accordingly, our second project is to build new facilities and expand infrastructure so that production capacity and consistency can be improved. This project includes expansion of our filtration capacity to more efficiently product Gamimune N, a new state-of-the-art sterile filling facility designed to increase filling capacity, expansion of high-purity water utilities to provide additional backups in the event of malfunctions, and a redesign of the facility to create physically separated zones that tightly control air, material, and personnel flow, and reduce the risk of cross-contamination.

Third, in response to the steadily growing demand for IGIV, Bayer began a major program in 1995 to greatly increase yield. That is the amount of therapeutic protein that can be produced from a unit of plasma.

We have created a new chromatographic process and are constructing a building dedicated to this innovative purification method. This new process will increase the availability of Gamimune N to patients in the same number of plasma liters by nearly 50 percent.

Fourth, Bayer also has purchased and is modernizing a plasma fractionation plant in Rosia, Italy. When this facility is operating fully, about 5 years from snow, Bayer will have increased its worldwide production capacity by 20 percent.

The fifth project is a major research effort to help answer questions about Creutzfeldt-Jakob Disease, the main one being whether CJD is transmissible in blood or plasma products.

Our preliminary findings suggest that it is possible to trace the presence of prions, that is, the agent thought to be responsible for CJD in plasma, using a new sensitive and rapid assay developed by Bayer.

We have also used this new assay to identify steps in the manufacturing process that may clear prions from plasma. This series of studies provides a unique opportunity to change the way we think about CJD and the risk that it may pose to patients.

It is important to stress, however, that there are still no definitive pieces of evidence that prions are present in plasma or that CJD is transmissible in blood or plasma products.

To that end, we have discussed our CJD research plans with partners at the FDA and NIH, and they have provided valuable suggestions on our research strategy. We now have a much clearer idea of what sort of data would help to clarify policies on product withdrawals related to CJD.

We also encourage and look forward to even more open lines of communication with the FDA and other agencies on such issues as good manufacturing practices. Moving forward together, it would be vital to assure sufficient resources for agency oversight and response. Bayer is eager to meet both the letter and the spirit of agency regulations and directives. The ultimate beneficiary will be our patients.

Mr. Chairman, Bayer's commitment to meet the critical need for plasma-derived therapies is total, now and in the future. For example, a recent shortage of IMIG, intramuscular immunoglobulins, to treat exposure to hepatitis-A prompted the Centers for Disease Control to call us for help. Due to low-market demand, Bayer had not produced IMIG for several years. Nevertheless, we committed to supply 6,000 units. We stand ready to help again.

At Bayer, we know that our relationships with patients, to thousands, young and old, who trust us to provide them with healing plasma therapies are for life. That trust and our care is what motivates us to give our all to restore a dependable product supply. By working together with mutual respect, to quote Corey, we can overcome the current challenges and provide a brighter future for those patients.

Thank you.

DR. NIGHTINGALE: Thank you very much, Dr. Spencer.

Questions beginning with Dr. Kuhn who raised his hand first.

DR. KUHN: Just a point of clarification. I mean, when you were giving your presentation about CJD, something that I heard in one of the presentations--I don't remember who it was--before, did I misunderstand when someone said that the fractionation process inactivates TSEs?

DR. SPENCER: I would not say that it inactivates it. Prions are extremely resilient proteins. What our research is starting to show--and this is with in vitro assays that track the protein rather than infectivity--so all of this is with a caveat so far, but what our studies are starting to show is that specific types of precipitation steps do seem to bring more of the prion protein out. So that, as one goes through the fractionation process, it is starting to look like one can identify where the prion proteins come. So it is a case of partitioning rather than inactivation.

DR. NIGHTINGALE: Dr. Hoots?

DR. HOOTS: What is the rate-limiting step for alpha-1 antitrypsin? Is it source fraction 4-1 or is it the production capacity?

DR. SPENCER: We product prolastin on a continuous basis. The base fractionation occurs at Clayton, and we can purify the product either in Clayton or, to a more limited extent, in Berkeley. The entire process takes about 120 days.

That process is partially limited by the amount of time that the various steps take, the amount of time that QA testing--for instance, to make sure there is no microbial grow-outs and so forth--takes, and also the time that it takes to collect sufficient numbers of intermediates to put together for a full lot size.

DR. NIGHTINGALE: Dr. Guerra?

DR. GUERRA: Before, I think someone had shared with us a distribution graph of the percentage supply that goes to physicians, hospitals, and other percentage to home health agencies, and then I guess directly to wholesalers. Does your company have a similar distribution, and have you observed a similar increase in the volume that is being sent to home health care agencies?j

DR. SPENCER: We, in 1996 and 1997, had a relatively high percent of distribution to distributors. In the end of 1997 and this year, while we are experiencing our own shortage, we have been cutting back and doing far more direct sales. So our percentage to distributors was over 50 percent.

DR. NIGHTINGALE: Are there any other questions? Ex officio members? If not--

MR. WALSH: I just have one.

DR. NIGHTINGALE: Mr. Walsh.

MR. WALSH: Dr. Spencer, Bayer has worked very closely with the patient community to try to flesh out some of the problems related to distribution. I have got two questions related to that.

We have identified some real specific instances where there seems to be some inequities in distribution, and we would like to open up a dialogue offline about that from our patient community perspective.

Secondly, do I understand that you do not need any 4-1 paste from any other? That would not help the current production capacity?

DR. SPENCER: No. As a matter of fact, we could probably increase the amount if we had somewhat more 4-1 paste.

MR. WALSH: Would we have to ask the FDA to help facilitate that with the other manufacturers, or how does that take place?

DR. SPENCER: Well, I think we have to have the kind of discussions that Sue Preston talked about. That is the main issue.

However, we are operating close to our maximum for purification. So we are not talking about big increases here. We would have to get back to you with regard to the exact amount of increase we could have, but we have been putting every possible source of our internal resources behind, moving intermediates through the system. So that is how we know that despite basically a nearly one-quarter slowdown in our filling lines this quarter, as we discussed in Florida, that we are still able to try to meet almost as much as we put out last year.

MR. WALSH: Just for the record, last year's production would not include somewhere between 2- and 300 people that were put on after that same time last year. So we would anticipate that at no time, even if Bayer is at maximum capacity for A1PI for prolastin, would you ever be able to meet demand.

DR. SPENCER: I would say demand has already outstripped our ability to supply.

I mean, as we have discussed, we have gone on with our diagnostic initiatives, and we have gone on with our awareness initiatives because, as you and the association well know, it is so important to identify these patients and tell them what lifestyle modifications they can make to reduce their risk.

We have some things on the books. We have some of these infrastructure changes that I talked about. We will make sure that there is never a throughput problem, never a bottleneck as far as prolastin in concerned in Clayton. We have also looked at similar yield-improving process changes. Unfortunately, that takes us out somewhat in the future.

So, yes, we are struggling to keep up with increasing demand there.

MR. WALSH: And I would like to also emphasize that we feel it is important for the IGIV communities and the alpha-1 community, as well as to an extent the hemophilic community, although they have a more standard level of care, that we focus on disease management programs, and we encourage other manufacturers to come online, although we have heard testimony to the effect that we will not have another A1P1 product online until the year 2001, probably at the earliest.

DR. SPENCER: I would also like to emphasize that clinical research is needed here. I think, John, you know of our Adapt program in the U.K. to try to have a clinical trial to study whether increasing the dosage during an infectious exacerbation really has an impact here, and I think that will be very important moving forward in addition to the disease management concepts that you have raised.

DR. NIGHTINGALE: Dr. Spencer, thank you very much.

William Barnhart of Centeon Corporation.

MR. BARNHART: My name is Bill Barnhart. I am the Centeon vice president for Worldwide Quality. I oversee the quality assurance and quality control functions within the company, and I would like to thank the Advisory Committee for this opportunity to present today on the current shortage of immunoglobulins.

Ensuring that the therapies we produce are of the highest quality and produced in strict accordance with Federal regulations for good manufacturing practices is paramount to Centeon.

GMP compliance is key to process and product predictability. We believe that strict GMP compliance is the sensible path to reliable, consistent product supply, and the avoidance of product recalls and market disruptions.

It is within this context, that is, the GMP compliance yields predictable product supply, that I would like to use the time allocated to me today. I would like to present, first, to the Advisory Committee our perspective on the immunoglobulin supply and our current effort to address the patient needs and our plans regarding the immunoglobulin production and distribution.

As we have heard from the industry trade association, many factors have contributed to the current immunoglobulin shortage. At Centeon, as part of our ongoing commitment to ensure the production of high-quality products, we have been implementing an enhanced quality system. This enhanced quality system and the quality assurance checks inherent in our manufacturing standard operating procedures have increased the time it takes to produce, review, and internally approve product for distribution.

These measures and other activities contributed to an IGIV run rate in 1997 that was roughly 70-percent less than what we had seen in previous years.

I will go into more details about this commitment to quality and about our measures we have implemented, but, first, I want to quickly point out that our production and distribution schedules for this year, 1988, are scheduled to approach a production rate that is comparable to 1966.

This is true for most Centeon products, including IGIV, and in 1988, Centeon will produce an additional 2,000 kilograms of IGIV beyond what was produced in 1997.

Centeon can make this statement today based on the broad range of quality of manufacturing enhancements underway. Many of these initiatives relate directly to achieving our IGIV targets this year. Key actions related to IGIV now underway include, one, an enhanced quality system now in place that includes a strong training program, robust validation capabilities, enhanced operating procedures, a reorganized and enhanced QA/QC function.

Since IGIV production capacity depends on the total plasma fractionated, general CGMP enhancements in place should positively affect the overall IGIV product quality.

Secondly, in addition, we are now internally analyzing possible product or process changes that, if justified, could be submitted as a license amendment to CBER for approval.

Centeon is making all of these changes are rapidly as possible. However, the rate at which such changes can be effected is necessarily paced by our ability to take on the delivery of, install, and then validate new equipment. In addition, these changes depend on, in many respects, people, people to accomplish all that I have mentioned and will mention in a few moments.

Centeon has added many new people to its staff, and as I am sure you can appreciate, bringing on a large number of new personnel, while at the same time installing new equipment, is quite an undertaking that necessarily involves substantial personnel training.

Let me assure you that the rate of spending is not the controlling factor here. Although undertaking these improvement measures, combined to reduce our 1997 volumes of product released, they will help Centeon return to a level of production that will include a more predictable IGIV entering the marketplace over the next several months.

I think it would now be helpful to the Committee and would help put this issue into perspective if I briefly review the efforts that Centeon has undertaken in regards to its commitment to quality and how this effect has had an impact on the amount of IGIV we have distributed over the past year.

As the panel may know, Centeon entered into a consent decree with the Federal Government in January of 1997. After agreeing to the consent decree, we undertook implementation of a wide variety of processes and procedures beyond what I have described a moment ago in our U.S. manufacturing plant.

These additional commitments to quality included: nearly doubling the QA/QC staff; increasing our facilities operations staff by over 25 percent; increasing the amount of training with over 45,000 labor hours being conducted last year and, year to date, over 25,000 this year; four, implementing a significant capital investment at the facility; five, a ten-fold increase in the number of validation professionals involved with new equipment validations and revalidation of existing equipment; and, finally, six, revising several thousand manufacturing and control documents since the beginning of 1997.

In summary, all of these efforts impacted our 1997 volume of product release, but form the basis of our belief that we will meet the 1998 IGIV production commitments.

I also think it might be useful for the Committee if I give an example of a batch manufacturing record that shows the quality steps that each lot of Centeon IGIV undergoes during the manufacturing process.

This record is required by CGMPs and captures the manufacturing steps that go into plasma as it proceeds on its way to becoming final product.

Good manufacturing practices are constantly evolving, as we all know, and as CGMPs have evolved, so has Centeon's batch manufacturing record.

Before me is a typical 1996 batch record for IGIV. Let me show you now a typical record in 1997. Clearly, more detail is being captured, and the data are going through a more demanding review process before final product is released to ensure a predictable steady supply of product.

Please know, however, that Centeon is also working to address the batch record review and approval cycle time needed to review these enhanced batch records. In this regard, we have tripled the number of quality assurance personnel who are solely devoted to batch record review. We will also continue to refine the procedures and assimilate new personnel into the system and continue training that incorporates these elements.

As a result, the time associated with the quality checking system and the ultimate release of final product will be reduced in the future. It is our commitment to continue to work to reduce cycle time, consistent with our number-one priority of releasing only safe and high-quality product.

It is important for this Committee to note that our release procedures also require lot release from the FDA, and we have been actively working with the FDA to obtain releases in an expedited fashion. As the industry trade association representative shows, the FDA has done a very good job facilitating this effort, and we appreciate the assistance.

Concurrent with these quality assurance department activities, Centeon has also been looking to the future and working on other short- and long-term solutions to the supply shortage. While these initiatives are being conducted by other departments within Centeon, I thought I would pass along some items that may be of interest to the Committee.

On a short-term basis, we have been working closely with the medical community in an effort to ensure that patients with critical needs are able to obtain product. Within our Medical Affairs Department, we implemented a program that allocates a monthly emergency reserve of IGIV that is accessible by physicians who have critical-need patients.

We also have a similar program in place working in conjunction with an immune deficiency patient group. In addition, we have worked diligently over the past few months to maintain our shipments to hospitals and multi-hospital organizations who need IGIV on hand for an emergency basis.

On a longer-term basis, beyond our plans to produce and distribute at a level comparable to our 1996 output, we are also exploring scenarios to expand our immunoglobulin production capacity.

In summary, I would like to reemphasize that we are committed as a company to fully comply with CGMPs and the quality assurance procedures we have in place. These efforts will result in a two-fold outcome: first, the manufacturer of high-quality therapies produced in strict accordance with CGMPs; and, secondly, a consistent, reliable, and safe supply of product. Both of these are essential to resolve the IGIV supply shortage situation.

With that, I will take any questions.

DR. NIGHTINGALE: Mr. Barnhart, thank you very much.

In view of the lateness of the hour, I would suggest, unless I see strong objection from the panel, that we proceed directly to Dr. Dunsire.

Dr. Dunsire?

DR. DUNSIRE: Good afternoon. Dr. Nightingale and members of the Advisory Panel, I am Dr. Deborah Dunsire. I am the vice president of the Oncology Business Unit at Novartis Pharmaceuticals Corporation. Novartis is a U.S. corporation affiliated with the leading global group of companies providing health care, nutrition, and agricultural products and services.

I am grateful to have the opportunity to work with the Committee and the many groups that have spoken here today in order to assess the critical shortage of immunoglobulin and to offer the Novartis perspective on the situation.

Novartis, unfortunately, is limited in its ability to contribute to this discussion because it neither collects plasma nor manufactures immunoglobulin. In addition, the immunoglobulin marketed by Novartis, called Sandoglobulin, is the only blood product we sell. For these reasons and because Sandoglobulin is manufactured from plasma recovered from unpaid donations, Novartis is not a member of the IPPIA, and nor is the manufacturer of our product, the Swiss Red Cross.

globulin is manufactured by a non-profit company in Switzerland, the Swiss Red Cross. The Swiss Red Cross has for some time had an agreement with our Swiss affiliate pursuant to which we have the right to market the product in the U.S. and have had this right since 1984. The Swiss Red Cross has independent arrangements with the American Red Cross and independent blood banks here, as well as other organizations abroad to collect plasma.

Novartis does not hold the FDA registration, the PLA, or ELA for Sandoglobulin in the United States. Instead, the Swiss Red Cross does, and they deal directly with the FDA on issues concerning plant inspection, validation, and good manufacturing practices.

Notwithstanding the fact that we do not manufacture Sandoglobulin, I would like to share with you some information about Sandoglobulin, our views on the factors contributing to the current shortage, and what Novartis is doing in this critical situation, where the supply is simply not enough for the critical needs of the patients at hand.

Novartis is proud of the Sandoglobulin safety record. Sandoglobulin, a sterilized lyophilized immunoglobulin, has never been withdrawn or withheld from the U.S. market as a result of manufacturing problems. The amounts available to Novartis for the U.S. market in 1998 constitutes a slight increase over the amounts available in 1997, and are consistent with our forecast of demand of the product.

While we have had our share of CJD withdrawals, which I can address later, Sandoglobulin has never had a documented case of viral transmission. In addition, globulin is manufactured from plasma recovered from the blood of unpaid donors.

As a matter of FDA regulation, the Sandoglobulin sold in the U.S. must be sourced from U.S. blood. We understand from the Swiss Red Cross that currently Novartis Pharma A.G., our affiliate, receives all the IGIV that the Swiss Red Cross manufactures from U.S. blood, although the Swiss Red Cross is clearly the best and most definitive source for the information on that subject.

We also understand that our affiliate is currently sending all of what I will call U.S.-eligible plasma derivative, or Sandoglobulin, back to the U.S.A. By U.S.-eligible, I mean that it is a product produced from U.S. plasma and manufactured in FDA-validated and complying facilities, and otherwise meeting all U.S. regulatory requirements.

In prior years, when product supply was more abundant, small amounts of U.S.-eligible IGIV were shipped to other countries where it served needy patients. Now, that was an amount in the order of approximately 10 percent.

It is very important to understand that while we are now getting all U.S.-eligible IGIV made available to our affiliate by the Swiss Red Cross, this has, and will, put great stress on supplies available to needy patients in certain other countries, most notably the U.K.

I should also point out that once we receive Sandoglobulin here in the U.S.A., we do not sit on it. There are patients that need it, and we send it promptly to our customers. It is extremely misleading for anyone to suggest otherwise.

Despite the facts that our supply of Sandoglobulin has not been severely impacted and should have been sufficient to meet full demand, there is a severe shortage of immunoglobulin overall in the United States. While I do not believe that there is any silver bullet which will miraculously end this crisis, I would like to share my perspective.

I think it is important to understand that this is not the first time the U.S. has had problems in this area, nor shall it be the last. Our experience with Sandoglobulin in the U.S. since 1984 has taught that periodic supply shocks are an unfortunate way of life with blood products.

As the Committee well knows, we are not dealing with synthetic chemicals through the formulation of a tablet. Instead, we are dealing with an organic supply component, blood, which is dependent on the vagaries of human donation. The hepatitis-C withdrawal in 1994 and CJD withdrawals since that time are instructive examples.

While we know that increased production cannot be achieved overnight due to capacity constraints, we have appealed to the Swiss Red Cross through our affiliate to increase our supply. We have made it very clear to them that we will take whatever additional supply they can give us. However, we understand from them that they are operating at maximum capacity with respect to available U.S.-derived material.

Ultimately, we have a vulnerable supply, coupled with a complicated and lengthy manufacturing process. While there is not a simple solution to the current problem, I think we can identify the major contributors which I will discuss as follows: reduction in supply due to compliance issues, the cumulative impact of CJD-related withdrawals, and increasing demand.

First, on the reduction of supply, we began noticing an enormous uptick in phone calls to Novartis requesting the product in the fall of 1997. While our knowledge of the specifics is not extensive, we can report that this phenomenon in our view is most likely due, primarily, to the cumulative effect over time of the manufacturing compliance problems experienced by several U.S. manufacturers, which you have heard described earlier this afternoon. These started in the fall of 1996.

We noticed a gradual increase in demand for Sandoglobulin in early 1997 with a dramatic increase by the end of the year. I believe that although the market could probably have absorbed the impact of one manufacturer's difficulties, it could not adjust to the unexpected problems of the four major U.S. manufacturers, especially in view of the additional factors, such as the CJD withdrawals.

In accordance with the FDA's December 1996 revised precautionary measures to reduce the possible risk of transmission of CJD by blood and blood products, Novartis has experienced approximately 22 voluntary withdrawals since November of 1994, of varying numbers of lots and lot sizes, although the actual amount of globulin returned has been very small.

For example, the four withdrawals that we had experienced thus far in 1998 have resulted in an actual return of only 3.6 kilograms of product. Of more significance, however, is the recent Swiss Red Cross estimate that close to 15 percent of all the Sandoglobulin, which might otherwise have come to the U.S., is destroyed due to these withdrawals and because of the necessary destruction of all intermediates into which the implicated donor's blood is pooled.

While we support all of the FDA's efforts to monitor the blood supply, we also support continuous assessment of the December 1996 guidelines in light of the impact that this is clearly having on supply.

The third contributing factor, increased demand, there has been an increasing demand for immunoglobulin in the U.S. The medical community, as you have heard today, has found the drug to be very versatile.

Based on data available to us, we believe that a figure of 8-to-10-percent increase in the overall U.S. market during each of the past 4 years is a reasonable estimate.

I would like to wrap up by briefly telling the Committee what Novartis has been doing to manage the Sandoglobulin we do have. The first thing we did, and are continuing to explore, is to ask both our affiliate, and through our affiliate, the Swiss Red Cross, for more product. As I have already indicated, we are told we are receiving all U.S.-eligible IGIV from our affiliate, and the Swiss Red Cross tells us they are unable to produce any more at this time.

In addition, we have tried to efficiently and quickly get the product that is available to us to patients in critical need. We are approaching this issue in two ways. First of all, we are trying to continue to get available product out to as many of our existing customers as we can reasonably accommodate in order to enable them to plan their usage during this period.

Our customers are dealing with patients in critical need every day, and as we have seen today, they are in the better position than we are to make judgments about how to distribute Sandoglobulin among their patients.

We are also, as other manufacturers have indicated, drop-shipping product to end users instead of shipping to wholesalers, who can distribute to any buyer. We believe that this limits the development of secondary markets in the product.

In December of 1997, prior to the receipt of the FDA request, we voluntarily established the Novartis Sandoglobulin emergency hotline. Through this program, we have set aside an amount to be available not only to prior Sandoglobulin patients, but to any immunoglobulin patient whose doctor will certify that the patient has a life-threatening need for immunoglobulin. Unfortunately, we are no longer able to satisfy the enormous number of eligible requests. Our hotline is currently receiving over 1,000 calls per week.

We have made a number of adjustments to the program to make sure that as many critical need patients as possible have a chance to get some of the available product.

Through this program, over 3,100 patients have received globulin. Many of our staff have worked tremendously hard to ensure the success of this program.

Finally, we are not supporting any new clinical trials during this period, although that is unfortunate. In addition, the Novartis sales force does not actively promote Sandoglobulin.

I hope my remarks have been useful to the Committee, and I am now prepared to take any questions that you may have.

Thank you.

DR. NIGHTINGALE: Thank you very much.

Are there any questions?

Dr. Penner has one. This will be the last question, then.

DR. PENNER: I'm sorry. I wanted to ask Mr. Bult a question.

DR. NIGHTINGALE: In that case, would you proceed.

DR. PENNER: If I could.

I appreciate those comments, and I would like to bring a question up to Mr. Bult. If I am understanding things from the information that you had put up in front of us on the amounts of product that was made available in 1997, it was perhaps 10 percent or 8-percent less than it was the previous year? Is that about correct? 12,000 versus 13,000, something in this order?

MR. BULT: I think it is in that order. It is in the order of 1,300 kilograms less because of withdrawals, recalls, and technical problems.

DR. PENNER: So that is about 8 percent or so, plus or minus.

Would you speculate that the increased demand is something in the neighborhood of 4, 5 or--what percentage would you think from your figures the increased demand might be in this country?

MR. BULT: I would prefer not to make any speculation. I would like to refer to the data of market research that has shown that the increase over the last year was an average of 9 percent, and as you have just heard from the previous speaker, an average between 8 and 9 was also confirmed in their estimate.

DR. PENNER: So we might say that there is a shortfall of something like 10 to 15 percent in 1997, as compared to 1996, with respect to the increased demand and also the reduction in the amount that was made available.

MR. BULT: I think if you tried to compare numbers--I mean, I think you are not on the end of your question.

DR. PENNER: No, I am not at the end of my question. You are quite right.

What I am seeing, then, with this, perhaps, 10-to-15-percent shortage, as we might say, that it looks like from what we have heard earlier in the morning and from what I have seen in the hospitals that I deal with that this shortage is much greater than 10 or 15 percent. It is something like 50 percent. So, in other words, trying to get that product available for the patients that we now have, there is much more demand, or at least there is much less product available.

So what I am speculating on, and correct me if I am wrong, perhaps what we are dealing with is a fair amount of the product. As you say, it might be, overall, perhaps about 30 percent that is going out to wholesalers and perhaps another 10 percent to home care, and in those places, the product is not easily identified for how it is being used in comparison to the manufacturers that are sending it directly to the hospitals and to the patient care.

So I would wonder, from looking at those figures, that perhaps the wholesalers and the home care programs have perhaps either taken advantage of a situation that perhaps was 10 or 15 percent shortfall and made it appear much greater and perhaps were able to benefit from that.

MR. BULT: That is a speculation.

DR. PENNER: Would you care to comment on that?

MR. BULT: I am not the kind of person who is willing to speculate. I would prefer to stick to the actual numbers, and the numbers are that we have seen that none of our members have been engaged in any stockpiling because that was the first question, and as a matter of fact, what we have done, we have a very significant reduction of our inventory which means that we are operating to very low operational levels.

I cannot comment on any of the speculations that you made, and I think I am not in a position to do that.

DR. PENNER: My only question, and perhaps for some of the other individuals who have spoken, is whether there are just a few wholesalers who have gotten a larger proportion of the product as compared to many, and has there been a change in that in 1997.

MR. BULT: I have no data on that.

DR. PENNER: I know you would not know that.

MR. BULT: So I cannot give any--

DR. PENNER: Perhaps the others might be able to comment on the wholesalers who are getting a major share of the product or portions of it.

MR. GUIHEEN: I think we need to differentiate this whole distribution channel and where things are.

The drug wholesalers, which are represented by McKesson, Bergen, at the hospital request will order product from companies because they hold the inventory for the hospitals. It is my understanding right now that there is no supply in the wholesalers.

I think the people that are necessarily being indicted by the media are the biological distributors. I think that is the class of trade that you need to be looking at in terms of where this product is.

You also should be questioning them in terms of who is supplying them with the product. That is where the answers lie.

As a manufacturer, Baxter, we do not--they are not a big part of our distribution. Most of our sales go directly to hospitals and to home care companies.

To your point on home care companies, they do supply the manufacturers with redistribution reports, and we can see that that product is being distributed.

DR. PENNER: You can see it is being distributed, but you would not know at what cost.

MR. GUIHEEN: No.

DR. PENNER: For example, I was unable to get product for one of my patients on Saturday, but then I finally had a call back from the pharmacist who had called everybody, and he finally got from the spot market something about four times the cost, he would be able to get this 30 grams of IVIG.

Now, previous to that, it was five times the standard cost, and so that is pretty common around the country, from what I have heard from my colleagues. So, obviously, there is a supply out there, and it may be a small amount or it may be a very large amount. From what I have heard thus far, it seems to me, the only areas where product is not coming directly from the manufacturer is the one that goes to wholesalers or apparently to the home care market.

MR. GUIHEEN: Yes. We do get feedback, and from our perspective, we do not see any hoarding in the channels that we have talked about.

I cannot answer where these biological distributors are getting this product. I truly do not know, but they are pretty clear who these people are. That is where the answer lies.

DR. PENNER: It is almost any product. It must be magic, I guess.

DR. NIGHTINGALE: One last question, Dr. Davey, and I think after Dr. Davey's comment, we need to adjourn.

DR. DAVEY: The question maybe is for Mr. Bult or other members. We have heard a lot of international movement of these products, and I can appreciate your comment, Mr. Bult, that we need to be aware of international needs and take care of international customers and patients who need these products.

I am still not clear on why there cannot be some flexibility, though, when shortages are apparent in this country, that in countries where there are no apparent shortages, like Japan, perhaps Germany and France--I am not sure--why there cannot be some flexibility of moving product from countries where supply is adequate to countries where supply is inadequate at any time when shortages occur.

I have not sensed the flexibility in our international opportunities to do that.

MR. BULT: I think it is an excellent question.

First of all, you are absolutely right. If we are facing shortages, we have to take that shortage very serious and to develop measures to improve the situation.

If you talk about flexibility, we have to realize that we always have to work within a regulatory environment. So that means if you talk about flexibility of importing products into the United States, you have heard the example from the Baxter representative of what options are available to introduce IVGamm which is manufactured either in the United States or in Europe.

You heard the Alpha representative speaking about options to explore what the facilities are in Spain. I think all you have to do is work within the regulatory environment, and that needs also discussion with FDA to see what flexibility is available.

The other thing that you have to realize is that if you look in other countries--you mentioned Japan--you can look into Europe--we have different systems in place. We have different regulatory environments. We have different criteria. I think that is part of the answer.

If you look at it in a global point of view, up until November 1997, we were not confronted with these very serious issues. This is an issue that really occurred over the last couple of months, and that is why we haver to look at all available options.

You also could look at flexibility manufacturing capacity. That means if we know that our capacities are available and other countries use that capacity and part of the production process in that country--but, again, that has to be done within the regulatory framework.

DR. DAVEY: What about other international sources and material that is licensed in the U.S.? I am thinking of, like, Winrow, which I believe is licensed, a Canadian product, even though it is a specialized IVIG. Is this something that we can look at more extensively?

MR. BULT: I think we have to explore all available options, and it is just not limited to one specific example. We have to look at all available options.

DR. NIGHTINGALE: And that is, indeed, for the day the last word.

On behalf of the Advisory Committee and the Department and all of its agencies, I do want to thank all of the speakers today for their outstanding and very helpful presentations.

The Committee is adjourned until 8 o'clock tomorrow morning. Thanks again.

[Whereupon, at 5:45 p.m., the Advisory Committee meeting adjourned, to reconvene on Tuesday, April 28, 1998.]