Blood Safety Summary - April 1998

DATE: July 23, 1998

TO: Interested Parties

FROM: Stephen D. Nightingale, MD, Executive Secretary Advisory Committee on Blood Safety and Availability V

SUBJECT: Summary of the Advisory Committee on Blood Safety and Availability Meeting on April 27 and 28, 1998

The Advisory Committee on Blood Safety and Availability met on April 27 and 28, 1998 at the Holiday Inn Georgetown, 2101 Wisconsin Ave. NW, Washington, DC 20007. The agenda of the meeting was to consider what had caused the current shortages of plasma derivatives and what could be done to correct this situation. Members present were Dr. Arthur Caplan, Chairman; Mr. Larry Allen, Dr. James AuBuchon, Dr. Michael Busch, Dr. Ronald Gilcher, Dr. Edward Gomperts, Dr. Fernando Guerra, Dr. Paul Haas, Dr. Keith Hoots, Dr. Dana. Kuhn, Ms. Carolyn Jones, Dr. John Penner, Dr. Jane Piliavin, Dr. Eugene Schiff, Dr. Marian Secundy, and Mr. John Walsh. Ex officio members present were Dr. Mary Chamberland, Dr. David Feigal, Dr. Eric Goosby, and Dr. Paul McCurdy. Also present were Dr. Richard Davey, a consultant to the Committee, Dr. Stephen Nightingale, the Executive Secretary, CDR Lawrence McMurtry, the Deputy Executive Secretary, and approximately 200 members of the public.

The meeting was called to order at 8: 10 AM. After roll call, a statement of the meeting's agenda, and announcements related to potential conflicts of interest, Dr. Goosby addressed the Committee on behalf of Dr. David Satcher, the Assistant Secretary for Health and Surgeon General. Dr. Goosby emphasized the importance of the topic before the Committee, and updated the Committee on the responses of the Department of Health and Human Services to the Committee's prior recommendations regarding hepatitis C and Creutzfeldt-Jakob disease.

Dr. Jerry Winkelstein then reviewed the immunology relevant to the agenda for the Committee. He described the three major inununoglobulin classes and the mechanisms by which they protect the body; the primary (congenital) immune deficiencies such as x-linked agammaglobulinemia or common variable immune deficiency (primary hypogammaglobulinernia) and the secondary (acquired) immune deficiencies such as those produced by cancer chemotherapy. He then described the responses of representative patients (with x-linked aga.mmaglobulinen-iia, AIDS, and chronic lymphocytic leukemia) to treatment with intravenous inimunoglobulin. Dr. Winkelstein estimated that there were 20,000 to 40,000 patients, children and adult, in the US with primary immunodeficiency disorders. In response to a question from Dr. Caplan, Dr. Winkelstein suggested that increased consumer demand for intravenous immunoglobulins could be due to increased numbers of patients diagnosed with immune deficiencies, increased use of intravenous immunoglobulins to treat diseases other than immune deficiencies for which treatment was clearly beneficial, and increased use to treat diseases for which the benefit of treatment was unproven.

Representatives of the immune Deficiency Foundation then presented their perspective on the current shortage of intravenous immunoglobulin. Mr. John Boyle presented the results of two surveys, one of patients and one of physicians, in which 80% of patients and 90% of physicians reported difficulty obtaining intravenous immunoglobulin within the last six months. Ms. Karen Gewurth and Dr. Larry Tabor of Texas Children's Hospital then described the triage system they had established at their institution to respond to the shortage of intravenous immunoglobulins, which prioritized delivery to patients with immune deficiencies, immune thrombocytopenic purpura, Kawasaki's disease, and Guillain-Barre syndrome, which accounted for about 60% of use under triage conditions. The next category was patients with lymphocytic leukemia and bone marrow transplants, patients with AIDS, and patients with unique circumstances such as protein- losing enteropathy. They noted that children with bone marrow transplants, lymphocytic leukemia, HIV infection, systemic lupus, toxic shock syndrome, and prematurity had been denied treatment with intravenous immunoglobulin. In response to a question, Dr. Tabor was supportive of efforts to reach a national consensus on prioritization of intravenous immunoglobulin use.

Dr. Roger Kobyashi then described similar problems with intravenous immunoglobulin shortages in his practice in Omaha, Nebraska, as did Mr. Michael Grote, a pharmacist with Corum Health Care. Ms. Miriam O'Day summarized the efforts of the Immune Deficiency Foundation to

help patients locate intravenous immunoglobulin. Finally, Mr. Thomas Moran presented the request of the Foundation to the Committee for an explanation of the current shortage and for a plan for the solution to it. Discussion following these presentations addressed spot prices of the product and whether a decrease. in the number of telephone calls to hot lines or federal agencies was indicative of an amelioration of the current shortage. Finally, in response to a question from Dr. Davey, Dr. Winkelstein was not optimistic about the short term prospect of gene therapy alleviating the need for intravenous immunoglobulin among the immune deficient.

Dr. Karen Gervais then described the process used at Allina Health System in Minnesota to ration intravenous immunoglobulin. The first phase was to prioritize use by a combination of severity of illness and known benefit of therapy; the second was to identify availability; and the third was to evaluate this strategy based on ethical principles as enunciated in American Medical Association guidelines. The effect of the process was to systematize distribution of scarce products throughout this health care system; it was associated with a 75% reduction in the use of intravenous immunoglobulin by this health care system.

After a break, Mr. Cory Dubin of the Committee of Ten Thousand addressed the immunoglobulin shortage issue from the perspective of the hemophilia community. He rejected the inevitability of a tradeoff between safety and availability of blood products. He suggested that if optimal pool size and donor populations differed for different users of blood products (for example, high-titer donors for specific antisera) that separate production lines would be appropriate. He expressed specific concern about emerging infectious threats to the blood supply, such as non-lipid enveloped viruses, that might in the future overcome current safeguards, and he encouraged FDA to make stronger independent use of the regulatory power invested in it to insure public confidence in the FDAs capacity to respond to emerging infectious threats to blood safety, such perhaps as mad cow disease, as they emerge.

Mr. Dubin then decried the limited amount of data on production of blood products that was available to those who advise the government on these matters, and the process by which societal costs of blood safety are disproportionately borne by users of these products. Finally, Mr. Dubin emphasized the need for coordination of separate government blood safety programs, and gave as examples of this need both the surveillance of hemophiliacs for Creutzfeldt-Jakob disease and the current immunoglobulin shortage. He concluded with a request that the standard of care for hemophiliacs be "nudged" toward recombinant products. In response to a question from Mr. Walsh, Mr. Dubin responded that "We, obviously, want to move hemophilia as much as possible to recombinant. I dont think that means we want to abandon the safety discussion but I think, for us, our best risk position is on recombinant product."

Ms. Jan Hamilton of the Hemophilia Federation, who spoke next, also raised the issue of pool size in relation to blood safety, and raised the question of whether in the long run smaller pools might increase both safety and availability of blood products. Ms. Hamilton questioned why there were shortages of intravenous immunoglobulin in the United States but not in Europe or Japan, where the prices paid for these products may be higher. Ms. Hamilton called for action based on good science rather than political groups, and noted that organizations such as hers relied on their medical and scientific consultants for advice on how to counsel their constituents; she expressed the hope that regulatory agencies could provide the same peace of mind for consumers of blood products as the NORAD radar system did during the cold war. She urged consideration of pure recombinant factors as a national standard for all clotting factor used in hemophilia treatment, and she stressed that it was not the wish of the hemophilia community to request standards that would be to the detriment of any other treatment community.

Dr. Glen Pierce then spoke on behalf of the National Hemophilia Foundation. He joined previous speakers in supporting the use of recombinant clotting factors for treatment of hemophilia, and emphasized the importance of prophylaxis as well as treatment in the management of bleeding disorders. He did not feel that adequate data was publicly available to completely determine the causes of the current immunoglobulin shortages, and he requested that it be made available. Dr. Pierce also repeatedly expressed concern about pool size and Creutzfeldt-Jacob disease as threats to the safety of plasma derivatives. He cited continuing concerns within the hemophilia community about the cost of care, residual human plasma derivatives in recombinant products, the development of additional recombinant products to treat patients with clotting factor inhibitors, and effective sterilization of all blood products.

In the following discussion, Dr. Caplan asked for comment on the presenters request that blood policy decisions be based on science when, in the case of Creutzfeldt-Jakob disease, the available science was perceived to be inconclusive, and why pool size had persisted as an issue for so long a time. In response to the former question, Mr. Dubin called for caution until the issue was resolved; in response to the latter question, Ms. Hamilton called for more consumer representation on groups that advised the government.

Dr. Richard Morgan then described prospects for gene therapy in hemophilia. He described various viral vector systems that hold promise for transferring new genetic material into cells, including retroviruses and adeno-associated viruses, and mentioned encouraging studies in rodents and in dogs. Dr. Morgan described some of his own work with oral delivery systems which transfect gastrointestinal cells, and work on in situ repair of genetic sequences known as "chimeroplasty". Dr. Morgan anticipated that many different approaches would be necessary for gene therapy of different conditions. He concluded by summarizing preliminary human trials scheduled for initiation later this year, but he cautioned that development of them would take at least five years. In response to a question from Dr. AuBuchon, Dr. Morgan noted that there were concerns that altered genetic products might be immunogenic, and that this issue was under study in animal models.

After lunch, Dr. Mark Brantley gave an overview of alpha-I antitrypsin deficiency and its treatment. Alpha-I antitrypsin is an endogenous anti-inflammatory molecule which is synthesized in response to infections of the lung and other organs; it inhibits enzymes such as neutrophil elastase, which degrades lung tissue. In the absence of alpha-I antitrypsin, the normal degradation of lung tissue and lung function are accelerated, ultimately to emphysema. Dr. Brantley pointed out that, at age 63, 85% of the American population is alive, but only 16% of the alpha-I antitrypsin deficient population is alive. In response to a question from Dr. Schiff, Dr. Brantley noted that replacement therapy with alpha-I antitrypsin did not seem to change the course of the liver disease in alpha-I antitrypsin deficiency.

Ms. Sandra Brandley, the Executive Director of the Alpha-I Antitrypsin National Foundation, then described the current shortage of alpha-I antitrypsin in the United States and its effect on patients. Ms. Sarah Everett then described the shortage from a patients perspective, which was to raise her fear that suboptimal treatment would increase the chance of recurrent pneumonia and accelerate the destruction of her lungs. She requested the Committee consider changing allocation of alpha-I antitrypsin to a patient-based system, that production be increased to meet demand, that studies be performed to determine the optimal dose of alpha-I antitrypsin therapy, and that development of new therapies, such as recombinant alpha-I antitrypsin and inhalation therapy with alpha-I antitrypsin, be supported. Ms. Julie Swanson, the President of the National Alpha-l Association, described in more detail the burdens imposed on patients by the current shortages.

Mr. James Reilly of the American Blood Resources Association then described the current plasma collection and processing system in the United States for paid donors. In 1997 there were about 1.5 million donors who gave 13 million donations which totaled approximately 11 million liters of plasma. Mr. Reilly noted that the screening process for potential donors decreases the incidence of I-HIV infection from 320 per 100,000 in the United States population as a whole to less than 1 per 100,000 selected donors. He described this process and the additional procedures, such as quarantine of new donors, that contribute to the safety of plasma derivatives. In response to a question from Dr. Feigal, Mr. Reilly agreed that the United States market for paid plasma was approximately 6 million liters per year, so more than enough plasma was being collected to meet this demand.

Ms. Sue Preston of Alpha Therapeutics then spoke on behalf of the International Plasma Producers Industry Association about fractionation, pooling, and preparation of final containers. She noted that plasma is 85% water. An initial pool of 4000 liters from about 5000 donors contains 200 to 300 kg of proteins, only a few of which are used therapeutically. In the 4000 liter pool there would be about 125 kg albumin, but the fractionation process only yields 70 to 95 kg; for immunoglobulins, while there would be 32 kg, only 10 to 11 kg are retrieved. There would be about 400 grams of Factor VII, of which 200 to 300 grams would be retrieved. There would be approximately 1 kg of alpha-I antitrypsin, but since a single therapeutic dose is 4 grams, the 4000 liter pool yields only about 250 doses. Ms. Preston noted that the relatively low yields of some plasma derivatives, the need to prepare uniformly therapeutic products, and the amount of product used to test for efficacy and safety were all reasons why industry pooled outputs of individual lots.

Dr. Donald Baker then discussed the relation of viral safety and availability from the manufacturers perspective. He noted that the manufacturers 60-day quarantine cost $6100 per unit rejected, whereas p24 antigen testing cost $660,000 per unit rejected. He estimated that Creutzfeldt-Jakob disease recalls had cost his company approximately $10 million. Dr. Feigal suggested that an alternative way to express these costs would be in terms of units actually used rather than units rejected, and estimated that the costs were approximately $1 per unit of plasma.

Mr. Jan Bult of the International Plasma Products Industry Association then presented the industry analysis of the causes of the current shortage of plasma derivatives. These were increased demand, Creutzfeldt-Jakob disease-related withdrawals, and manufacturing shutdowns. He estimated that demand for intravenous immunoglobulin was growing at about 9% per year. He stated that the volume of intravenous immunoglobulin that could not be released because of Creutzfeldt-Jakob disease-related withdrawals was 186 kg in 1996 and 1066 kg in 1997 (an average dose is 25 gin). The net available supply of intravenous immunoglobulin, based on figures compiled by Georgetown Economic Services, was 13,752 kg in 1996, 12,994 kg in 1997, and a projected 13,000 kg in 1998; exports were 2352 kg in 1996, 2663 kg in 1997, and a projected 2558 in 1998. Mr. Bult emphatically denied that the industry was stockpiling product. He then presented a table of the data requested by the Immune Deficiency Foundation, and pledged to update this data on a quarterly basis. Mr. Bult then described short term initiatives to minimize the impact of the shortage on patients, and long term plans to increase production of the product. In response to questions from Mr. Allen and Dr. Kuhn, Mr. Bult felt that the current shortage had been precipitated by a number of factors, and that the major factor manufacturing shutdowns was something that the industry could not reasonably have anticipated. Dr. Jay Epstein of FDA asked if industry would be willing to release the approximately 1000 kg of intravenous immunoglobulin withdrawn if it were appropriately labeled, and Mr. Bult responded that most of this material was still in intermediate rather than final product form.

The Committee then heard from an industry panel. The first presenter was Ms. Preston of Alpha Therapeutics, who described Alphas current capacity, amount of final product exported, improvements in distribution, plans to increase capacity, and research activities. She described the approximately 130 day production schedule of intravenous immunoglobulin, which includes the industrys voluntary 60-day hold on plasma products prior to manufacture; she noted that different fractions completed production at different times. She then announced that the amount of Alphas intravenous immunoglobulin sold through wholesalers had decreased from 67% to 16% in the past year, and that their inventory was minimal. Alpha plans to raise its production of intravenous immunoglobulin by 40 to 50% by 2003. In response to a question by Mr. Walsh, Ms. Preston hoped that Alphas alpha-I antitrypsin product could be launched by 2001, and that Alpha was willing to consider sharing its Fraction IV. 1 paste with other manufacturers who were licensed to produce alpha-I antitrypsin. In response to a question from Dr. Chamberland, Ms. Preston confirmed that Alpha did release, at the request of FDA, a lot of intravenous immunoglobulin labeled to indicate that one donor had been exposed to human growth hormone; she also noted that there was "quite an internal debate" at Alpha regarding this action because of its legal risk.

Next, Dr. Larry Guiheen of Baxter discussed that corporations response to the immunoglobulin shortage. He denied that Baxter was stockpiling product; he said that ordinarily Baxter would carry a two month inventory, but that the current inventory was only sufficient for about 14 days. Mr. Guiheen stated that approximately 20% of Baxters intravenous immunoglobulin was exported, but he noted that Baxter was taking steps to import some of the product as well; he also noted that Baxters prices for its intravenous immunoglobulin preparations had not increased since 1994.

Dr. David Spencer then described Bayers response. He noted the reasons why Bayers production of intravenous immunoglobulin in 1998 would be only about half of the 1997 level. The shortfall is due to a combination of previous commitments to production enhancements, failure of the heating system in one plant, and Creutzfeldt-Jakob disease-related product recalls. He noted that these events would limit Bayers production of prolastin and clotting factors as well. At the same time, Dr. Spencer cited five projects that demonstrated Bayers commitment to the field: the development of recombinant Factor VIII, building new production facilities, investigating new chromatographic methods to increase yield of immunoglobulins from plasma, purchasing additional production capacity in Italy, and pursuing research on the transmission of Creutzfeldt-Jakob disease. In response to a question from Mr. Walsh, Dr. Spencer indicated that production of alpha-I antitrypsin was running close to capacity, and he was unsure of the increase in production that an alternative source of plasma fraction 4.1 would permit.

Dr. William Barnhart of Centeon then discussed his companys future production plans. Although 1997 production of immunoglobulins had decreased by 70%, he was hopeful that 1998 production would approach 1996 production levels. Dr. Deborah Dunsire of Novartis then discussed her companys attempts to optimize distribution of their intravenous inimunoglobulin, which is manufactured by the Swiss Red Cross. She also noted the impact of Creutzfeldt-Jakob disease-related withdrawals on the availability of her companys product. The four withdrawals in 1998 had achieved a return of only 3.6 kg of intravenous immunoglobulin, but about 15% of the potential supply had to be destroyed because of these regulatory actions.

After a brief discussion, the meeting was adjourned at 5:45 PM.

The meeting resumed the following morning at 8:00 AM. Dr. Caplan encouraged the Committee to consider monitoring production numbers, off-label use, exports, use of recombinant analogs of plasma derivatives, and management of emergency reserves as they formulated their recommendations during the day.

Mr. James McPherson of Americas Blood Centers then discussed the complex economics of plasma obtained from voluntary blood donors, how the threat of Creutzfeldt-Jacob disease-related withdrawals counterbalanced the attractiveness of an American, albeit older American, voluntary pool of relatively infrequent donors, and how such an uncertain economic environment prevented the independent blood centers from investing in the resources necessary to process their recovered plasma into products such as intravenous immunoglobulin. Mr. McPherson noted that all American manufacturers of plasma derivatives preferentially used paid donors because of the risk of Creutzfeldt-Jakob disease-related withdrawals. Dr. Davey supported Mr. McPhersons assertions by estimating that 80% of the plasma used in the United States was from paid donors, but 80% of the Creutzfeldt-Jakob disease-related recalls were for volunteer donors. It was asserted that volunteer donors might be more forthcoming about risks than paid donors, even if only after the fact, but Dr. McCurdy pointed out that no data supported that assertion. In subsequent discussion there was agreement that the current shortages were due to reduced production capacity rather than lack of raw material, but there was no challenge to Mr. McPhersons point that the risk of Creutzfeldt-Jacob disease-related recall may have been a factor limiting investment necessary to create additional production capacity.

Mr. Christopher Lamb then described the American Red Cross plasma program. The Red Cross contracts processing of its plasma with Bayer and the Swiss Red Cross. The American Red Cross collects about 6 million donations per year, which translates into 1 million liters of plasma because the average volunteer donation is 283 ml plasma, whereas the average paid plasmapheresis is around 800 ml. The smaller volume of plasma per donor has an obvious impact on pool size, because more volunteer donors are needed to make an equivalent volume of plasma. He disagreed with assertions by others that a smaller pool size would increase safety and not decrease availability.

Mr. Lamb estimated growth in the market for intravenous immunoglobulin at about 10% per year based on historical trends. He reported that 10% of the Red Cross production of intravenous immunoglobulin was not released because of Creutzfeldt-Jakob disease-related recall, an additional 6% was recalled, and an additional 6% was not processed beyond the intermediate level. Mr. Lamb noted that 80% of the American Red Cross recalls were for reported exposures to dura mater grafts or human growth hormone, and not for Creutzfeldt-Jakob disease itself. Mr. Lamb noted that the American Red Cross had two contractual relationships for distributing its intravenous immunoglobulin, and that they were trying to allocate their remaining supply in the most equitable manner. Like all previous speakers, Mr. Lamb emphatically denied that his organization was hoarding product. Mr. Allen asked Mr. Lamb why the American Red Cross could sell its plasma and Americas Blood Centers could not; in response, Mr. Lamb pointed out that this was largely because the American Red Cross contracts for the production capacity and assumes the risk of Creutzfeldt-Jacob disease-related recalls, which have cost the Red Cross $120 million worth of product since August 1995.

Dr. Mark Weinstein of FDA then presented that agencys assessment of the causes of the intravenous immunoglobulin shortage. Dr. Weinstein estimated the shortfall at about 20% of total demand, and he attributed 60% of the shortage to plant closings, 20% to Creutzfeldt-Jakob disease-related recalls, and 20% to increased demand. Dr. Weinstein noted that FDA had been working with industry in a variety of ways to increase product availability. In response to a question from Mr. Walsh, Dr. Weinstein agreed that a decrease in the number of calls to FDA about the shortage should not be taken as evidence that the shortage was abating. Dr. Davey asked if the FDA would look favorably on a generic label for all derivative products, saying there is a theoretical risk of CJD transmission in all derivative products, and if with this label the FDA would be willing to "really aggressively" relax withdrawal policies; Dr. Weinstein responded that the subject was under discussion. Public comment followed a brief recess. Mr. Moran restated the desire of the Immune Deficiency Foundation to work with manufacturers to insure equitable distribution of products. Mr. Dubin restated his constituencys concerns about pool size. Ms. Brandley reiterated her request to FDA to facilitate manufacturing capacity for alpha-I antitrypsin. Mr. Patrick Robert, of the Marketing Research Bureau, presented data on the size of the market for intravenous immunoglobulins, which he estimated at $413 million, and on the market share of the various corporations. Mr. Robert suggested that one reason why there was more of a shortage in the United States than elsewhere was that demand was higher in the United States. Dr. Donald Tankersley then commented on the arguments for and against reduction of the plasma pool size; his conclusion was that reduction in pool size would not improve safety of the finished product.

The Committee then began to formulate its recommendations, which were as follows:

I RECOMMENDATIONS FOR THE SHORT TERM

• The Food and Drug Administration, the International Plasma Producers Industry Association and individual manufacturers and distributers of plasma derivatives and their recombinant analogs shuld, on a monthly basis, collect and disseminate standardized information on production, distribution, and demand for intravenous immunoglobulin, clotting factors (recombinant and plasma-dervied), and alpha-1 antitrypsin.

2. The Department of Health and Human Services should explore, in collaboration with industry, health care providers, and appropriate consumer groups, methods to optimize and standardize allocation of available products in an equitable manner, including management of emergency supplies and programs that distribute products directly from manufacturers to registered consumers.

3. Industry should discuss triage of specific plasma derivatives to specific patient groups with the Food and Drug Administration, the Federal Trade Commission, health care providers, and appropriate consumer groups in order to promote accountability to the public of these practices.

4. Industry should explore with the Food and Drug Administration the possibility of importing additional supplies of intravenous and intramuscular immunoglobulin preparations.

5. Industry should explore with the Food and Drug Administration strategies for reallocating partially processed plasma materials from one manufacturer to another in order to optimize production of alpha-i antitrypsin and other plasma derivatives.

6. Industry should explore with the Food and Drug Administration labeling and disclosure strategies which would increase product availability without compromising public safety and trust.

7. Industry and government should explore the impact of a temporary decrease in exportation of plasma derivatives while they are in short supply in the United States.

II RECOMMENDATIONS FOR THE LONG TERM

Every effort should be made to make recombinant clotting factors available to all who would benefit from them, and all barriers to conversion from human to recombinant clotting factors should be removed.

2. The National Institutes of Health should convene a Consensus Conference on the use of recombinant clotting factors for patients with bleeding disorders.

3. Industry should explore strategies for the development of reserve supplies of plasma derivatives and for their allocation during shortages.

4. The National Institutes of Health and industry should immediately evaluate alternative dosage schedules and alternative delivery systems for alpha-I antitrypsin therapy, including prophylaxis strategies and strategies for treatment during acute exacerbations of disease, and accelerate the development of gene-based products and gene-directed therapies for alpha-I antitrypsin deficiency.

5. The National Institutes of Health and industry should support the continued evaluation of the use and appropriate dose of intravenous immunoglobulins for indications where its benefit requires further delineation, and the results of these evaluations should be rapidly disseminated to the public.

6. Industry should work with the Food and Drug Administration to expand capacity sufficiently to meet anticipated demand for plasma derivatives.

7. Industry and government should jointly explore the antitrust implications of efforts to share data in order to prevent shortages.

The Committee requested an update on the status of all their prior recommendations at the next meeting.

The meeting was adjourned at 3:13 PM.

As required by 4-CFR 101-6.1025(b), these minutes were reviewed and approved by Dr. Arthur Caplan, Chairman of the Advisory Committee on Blood Safety and Availability, on July 23, 1998. The transcript of this meeting can be found at http://www.hhs.gov/partnerfBlood Safety.