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Blood Safety Summary - August 2000

DATE: September 12, 2000

TO: Interested Parties

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

SUBJECT: Summary of August 24, 2000 Meeting

The Advisory Committee on Blood Safety and Availability met for the twelfth time on August 24, 2000 at the Hyatt Regency Capitol Hill Hotel, 400 New Jersey Ave., N.W., Washington, D.C. 20001. Voting members present were Dr. Caplan, the Chairman; Mr. Allen; Drs. AuBuchon, Busch, Davey, Gilcher, Guerra, Haas, Hoots, and Kuhn; Mss. Lipton and Pahuja; Drs. Penner and Piliavin; Mr. Walsh; and Dr. Winkelstein. Non-voting member present were Drs. Chamberland and Epstein; COL Fitzpatrick; and Dr. McCurdy. Also present were Dr. Nightingale, the Executive Secretary; CAPT McMurtry, the Deputy Executive Secretary; and approximately 30 members of the public.

Dr. David Satcher, the Assistant Secretary for Health and Surgeon General, opened the meeting at 8:10 A.M. by acknowledging the contributions of the Advisory Committee to the development of policies on hepatitis C virus (HCV) lookback, the transmissible spongiform encephalopathies (TSEs), shortages of plasma derivatives, shortages of blood products, reimbursement for blood products and plasma derivatives, and management of error in transfusion medicine, but he cautioned that this is not the time to relax our vigilance or lessen our efforts to assure the safety and availability of the blood supply. Dr. Satcher discussed his recent "Dear Citizen" letter on HCV infection, and ongoing efforts to assure its distribution. Dr. Satcher acknowledged that there are not adequate federal funds to support the desired response to this letter, but he expressed hope that the desired response would lead the government forward to make those resources available. Dr. Satcher thanked Mr. Allen and Drs. AuBuchon, Gomperts, Penner, and Secundy, whose appointments to the Advisory Committee conclude in September 2000, for their services. Dr. Satcher concluded with a discussion of the health indicators that are the focus of the Department's Health People 2010 project.

In response to questions from the Committee, Dr. Satcher reiterated his commitments to work with Congress to distribute his "Dear Citizen" letter, and to obtain funds necessary for the state and territorial health offices to respond properly. He expressed hope that the November 2000 meeting of the Global Collaboration for Blood Safety in Geneva would identify how the United States and the World Health Organization could best contribute to blood safety worldwide.

Dr. Harold Margolis then updated the Advisory Committee on the CDC's national strategy for prevention of HCV infection. He reviewed public education efforts directed towards the various groups at risk of HCV infection, and towards providers who care for members of these groups. Several members raised concerns about individuals whose risk was prior intravenous drug use; Dr. Margolis' response included comment about states that are integrating drug treatment programs into the mainstream of their public health efforts.

Dr. Nightingale then called attention to the Department's solicitation of nominations for membership on the Advisory Committee. He noted that 5 CFR 2640.203, which deals with conflict of interest by members of an advisory committee (and is read in part or in full at each Advisory Committee meeting); the Charter of the Advisory Committee; and the Notice published in the Federal Register, Vol. 65, No. 105, p. 34705 would be guides to the selection process. He noted that while committee members were chosen from the classes of individuals specified in the Advisory Committee charter, there was no specific class of individuals, other than the non-voting government representatives, that the Charter directed be represented on the Advisory Committee. He said that the Department wished the total membership of the Advisory Committee to be as inclusive as possible, and that this goal would continue to be a factor in the selection process. Dr. Nightingale also noted the continued desire of the Department to include all interested parties in the public discussion of matters before the Advisory Committee, and he complemented Dr. Caplan for his efforts to achieve this goal.

Dr. Nightingale then noted that the agenda of the meeting, the role of various considerations in decision making related to new and additional safety measures, could be restated as a question, what are the principles on which a blood policy to assure a safe, available, and affordable blood supply should be based?

After a break, each member was invited to comment.

Mr. Walsh noted that previous recommendations of the Advisory Committee had been helpful in alleviating the shortage of alpha-1 antitrypsin. He specifically cited recommendations made on April 28, 1998 regarding allocation of scarce products in an equitable manner, reallocating partially processed intermediates from one manufacturer to another, and evaluation of alternative dosage schedules and delivery systems. Mr. Walsh expressed appreciation to FDA for its willingness to discuss issues related to clinical trial design, and to HCFA for its responsiveness to the Advisory Committee's recommendations on reimbursement.

Dr. Winkelstein noted that the recommendations made by the Advisory Committee on April 28, 1998 had also been beneficial to the immune deficiency community. He thanked the FDA for its responsiveness to these recommendations, and to the needs of immune deficient patients for greater availability of immunoglobulin preparations. Dr. Winkelstein also communicated the concern of the immune deficiency community about possible adverse effects of long-term administration of immunoglobulin preparations, and he asked if the Advisory Committee would be willing to consider the merits of a formal assessment or long term study of this issue. Dr. Nightingale responded that because the cost of such a study might not be recognized by the market for this product, and because issues of safety and availability often arose because of costs not recognized by the market, Dr. Winkelstein's suggestion was appropriate and would receive careful consideration.

Dr. Piliavin noted the ambiguity of the definition of the precautionary principle in the materials provided to the Advisory Committee. She specifically cited the requirement of "less than a preponderance but more than a scintilla of evidence" for invoking the precautionary principle as an example of this ambiguity. She then noted the requirement of the precautionary principle that comparable events provoke comparable responses, and she questioned whether current policies on TSEs would meet this requirement. Dr. Piliavin then questioned, given the current level of blood safety, whether resources devoted to marginal improvements in blood safety might be better used elsewhere, for example prenatal care or transportation safety. She recommended that a future administration appoint a committee to assess how our medical dollars are being spent across the spectrum of things that endanger the health of our populations. She concluded by suggesting that we might be pursuing expensive technological and bureaucratic fixes for smaller and smaller risks simply because we can fix them, while ignoring much more critical problems because we can't.

Dr. Penner noted that a recurrent theme of the Advisory Committee deliberations had been, What Price Safety, and he contrasted this approach to the public expectation that the safety of blood be absolute. He acknowledged that the cost of meeting this expectation might be considerable, but he suggested that there was little choice in this matter if we wished the public to respect the fact that we are providing them with something that they don't have to fear.

Ms. Lipton took the opportunity of her presentation to describe the Global Aviation Information Network (GAIN), and its relation to domestic and international blood safety initiatives that had been discussed at the last two meetings of the Advisory Committee. She reported that the most recent GAIN conference, in June 2000, adopted five guiding principles that might be analogous to the precautionary principle or other standards for blood safety. She specifically discussed the first of these principles, that the safety of passengers and workers is of paramount concern to the aviation industry, and the second, that the public perception of aviation safety is as important to the industry as the absolute safety of the industry. Ms. Lipton then commented on the urgency of reimbursement issues currently before congress to the blood industry. She noted that the cost of meeting 100% of demand was disproportionately greater than the cost of meeting 85 to 90% of demand. She pointed out that reimbursement for blood was driven by the cost of meeting 100% rather than 85% of demand, and she acknowledged some diffidence within the health care industry, and among those who underwrite its services, toward the cost of full availability of the blood supply.

Dr. Kuhn took the opportunity of his presentation to request further clarification of the status of the "Dear Citizen" letter. Dr. Nightingale described the procedural concerns had been raised by the House Management Office, and he reported that CAPT McMurtry was working to resolve these concerns.

Dr. Hoots noted the ongoing concern of the hemophilia community for the availability of clotting factors. Dr. Hoots thanked all parties, including the Advisory Committee, responsible for the monthly production and distribution reports disseminated by the Plasma Protein Therapeutics Association since 1998. He noted that inventory of clotting factors had previously risen to a nine week supply, but that it had recently fallen to a four week supply, in part because of conversion to a new formulations by one manufacturer and difficulties experienced by another manufacturer in expanding its facilities. Dr. Hoots expressed concern that legal confrontations over average wholesale price-based reimbursement and over the prime vendor component of Section 340B of Public Law 102-585 could have an imminent impact on supply. He stressed a distinctive feature of the clotting factor market, which is that the demand for product by an individual consumer is unpredictable. Hemophiliacs require large amounts of clotting factor in emergencies; and the clotting factor market must be sufficiently capable of responding to these emergency demands. He also pointed out the growing interdependence of the clotting factor supplies in the United States and elsewhere in the world.

Dr. Haas then contrasted the real market for blood products from an ideal market. He noted that in an ideal market there are a large number of buyers and sellers of a homogeneous product, and that entry to and exit from the market by buyers and sellers is free and easy. He noted that government intervention, inelasticity of demand, and the dissociation between the recipient of the product and the entity that pays for it also limit the ability of the real market for blood products to achieve the efficiency, profitability, and equity that an ideal market would, at least theoretically, achieve. Dr. Haas emphasized, from the perspective of both an economist and a consumer, the currently unmet need to define what is meant by safe and available blood, and he argued that these definitions must be compatible with the needs of those who use blood products on a regular and continuing basis.

Dr. Guerra noted the need to strengthen the interface between the public health community and the blood industry. He mentioned the need for better communication by the industry with the public about risk, real and perceived, and the need to support public health initiatives to monitor the safety of the blood supply. He also emphasized the need to insure equitable access to blood products by all members of society.

Dr. Caplan concluded the morning session by suggesting that the role of the Advisory Committee on Blood Safety and Availability is to advise the government how to achieve a safe and available blood supply, rather than to advise the government how much to spend on blood safety and how much on unrelated activities. He noted that the group was called the Advisory Committee on Blood "Safety and Availability" rather than "Availability and Safety," and he suggested that some distinctive aspects of blood, including the altruism of blood donation, the generally involuntary nature of its consumption, and the symbolism associated with the product itself, that might explain this ordering of mission. Dr. Caplan also suggested that these aspects of blood might not be fully appreciated in cost-effectiveness analyses that suggest the benefits of certain safety measures to be marginal. He then remarked on blood donation as a barometer of the strength of a community, and the relation of this to laws limiting liability for its adverse effects. Dr. Caplan concluded by suggesting that the factors he had just enumerated might explain the willingness of at least some segments of society to endorse, and pay for, blood safety measures.

After lunch, Dr. Gilcher observed that the safety of blood products is regarded by the recipient as being of such critical importance that the inherent and perceived risks should approximate zero as closely as possible. He estimated the cost to his system of using nucleic acid testing to prevent one case of HIV transmission to be $7 million, and the cost to prevent one case of HCV transmission to be $1 million. He estimated the cost of universal leukoreduction in his system as $16 per unit. Dr. Gilcher acknowledged the magnitude of these costs, but he stressed the importance of working, and being perceived to be working, towards a zero-risk blood supply. To do less, he said, would fuel the mistrust of both donors and patients, and the end result would be an inadequate and ultimately less safe blood supply.

Dr. Davey suggested, on the basis of his review of the materials provided to the Advisory Committee for review, seven criteria that might be used to evaluate a blood policy. These were:

1. Is the action proportional to the level of protection desired?
2. Is it equitable?
3. Is it comparable to other similar actions?
4. Is it consistent with other similar actions?
5. Is it justifiable by cost-benefit or cost-effectiveness analysis?
6. Is it subject to review in the light of new scientific evidence?
7. Can responsibility for producing the scientific evidence necessary for review be assigned?

Dr. Busch presented an update of the current level of safety of the blood supply. He pointed out that the accuracy of his estimates of residual risk of blood transfusion was limited by the extreme rarity of adverse events. He presented estimates of the rates of transmission of HIV, hepatitis B (HBV), and HCV due to four causes (window period donations, viral variants not detected by current tests, individuals who do not seroconvert, and testing errors). Dr. Busch reported that, in the first year of nucleic acid screening of the United States blood supply, 42 HCV and 4 HIV window-phase infections were detected and prevented from infecting recipients, very close to the numbers predicted. He estimated that the transition from pooled to single unit nucleic acid screening tests would identify an additional two or three HIV and HCV infections, and he discussed the cost of this development. He noted, however, that the availability of a nucleic acid test platform might be very helpful at some future point in time if a new viral threat to blood safety were to be identified in the future. Dr. Busch concluded by contrasting the level of blood safety in the United States with that in the developing world.

Dr. AuBuchon began his presentation by noting that the federal government had repeatedly taken actions over the last decade to limit resources available for health care. He stated that the task of the Advisory Committee should be to highlight what can be done with the resources available, and highlight where the commitment of additional resources may lead to additional benefit. He suggested, however, that when resources are limited and choices have to be made, the Advisory Committee should be willing to prioritize the actions it recommends. Dr. AuBuchon then turned to the specific issue of universal leukoreduction. He compared this intervention to other safety measures implemented at his hospital, namely use of only apheresis platelets and donor-retested plasma, routine culture of platelets, and mechanical barriers to prevent transfusion to the wrong recipient. He stated his view that the data were not yet available from an academic point of view to demonstrate that the safety of blood transfusion will be advanced by universal leukoreduction. He suggested if the push for universal leukoreduction was motivated by a need to recoup the costs of previous safety initiatives, these costs should be addressed directly and not by reimbursement of roughly half a billion dollars per year for an intervention of unproven benefit.

Mr. Allen commented that discussions of blood safety policy such as the one in which he was currently engaged were very different from the ones among patients and their families, and that the perspectives of those patients and families could be quite different from the perspectives of policy makers.

Dr. Epstein began his comments by contrasting responses to known threats with responses to potential threats to blood safety. In respect to known threats, one policy option is zero-risk, intervene at any cost. He noted that a related policy of intervention only if the benefit (or effectiveness) to risk ratio is favorable is essentially the same strategy, because the ratio at which intervention should be undertaken is not specified. He added that FDA, if not other regulators, would be criticized if they attempted to specify this ratio. He then mentioned the as low as reasonably achievable (ALARA) approach to risk management, and efforts to quantitate the level of wellness in society achieved by disparate interventions, such as vaccines versus marginal improvements in blood safety. In respect to potential threats, he noted that policy twenty years ago was to withhold action until there was scientific consensus. More recently, policy approximates that enunciated in the European Union statement of the Precautionary Principle, sometimes with and sometimes without consideration of the consequences of the proposed response. He commented that pending blood safety decisions involved not only the implementation of new safety measures, but also the relaxation of existing standards, such p24 and ALT tests.

Dr. Epstein then noted his general agreement with the European Union statement, and he indicated it should be as applicable to known or quantifiable risks as to unknown or unquantifiable ones. The principles he proposed for development of blood policy were:

1. Acceptance of risk is a political decision.
2. Acceptance of cost is a political decision.
3. Decision making must be transparent if it is to obtain public endorsement.
4. Decision making must include both risk assessment and risk communication.
5. Decision making must include ongoing scientific input.
6. Blood safety decisions should be considered in an international context.
7. Individual contributors to blood safety decisions should independently articulate the scientific, economic, and political bases of their recommendations.

At the conclusion of Dr. Epstein's comments, there was further discussionof the Surgeon General's "Dear Citizen" letter. Dr. Kuhn proposed, and Dr. AuBuchon seconded, the following motion:

The Committee actively supports the Surgeon General's efforts to inform the American Public of the risks of HCV infection and transmission. Moreover, the Committee strongly urges the Secretary to seek adequate supplemental funding in Fiscal Year 2001in order to provide the CDC with the most efficacious and widespread means of informing the American public including the consideration of sending a "Dear Citizen" letter to the American public by March 30, 2001.

The motion was approved 11 votes to zero, with two abstentions.

Public comment followed. Ms. Jan Hamilton of the Hemophilia Federation of America asked the Advisory Committee to remain mindful of the recommendations in the 1995 Institute of Medicine report; to maintain vigilance for emerging and reemerging infectious agents in the blood supply; and to continue to address the problem of errors and accidents in transfusion medicine. Ms. Hamilton asked the Advisory Committee to be aware of the looming inequities in average wholesale price for coagulation products.

Ms. Mary Foss of the Mayo Clinic then commented on the economic impact of universal leukoreduction on their facility, which transfuses about 39,000 units of red cells and 46,000 units of platelets. That cost would be $1.2 million per year. Dr. Breanndan Moore, also of the Mayo Clinic, reviewed published evidence that universal leukoreduction would reduce the risk of postoperative infection, and he pointed out the need for further studies of this issue. He also commented that if one was not dealing with "large dollars," universal leukoreduction would have been implemented a long time ago.

Dr. Chyang Fang of Chiron Corporation then updated the Advisory Committee on the impact of nucleic acid testing for HIV and HCV on the safety of the blood supply. He reported that this testing is now performed on approximately 75% of all volunteer blood donations in the United States. By June 2000 62 HCV and 4 HIV infections were identified by this technique alone; an additional 3 HCV infections were identified that had been missed by prior laboratory error.

Dr. Merlyn Sayers then spoke on behalf of America's Blood Centers to request that FDA proceed with formal rule making on universal leukoreduction, rather than waiting for a standard of care to be achieved and subsequent regulation under current Good Manufacturing Practice authority. He stated that only under formal rule making will there be consistent quality control. He also exhorted all branches of government to continue to consider the consequences of unfunded mandates.

Ms. Kay Gregory of the American Association of Blood Banks (AABB) then informed the Advisory Committee of the new AABB task force on the uniform donor questionnaire. This task force includes both private and government representatives. The goal of the task force is to reevaluate the scientific validity of all FDA-required infectious disease questions, to reword questions that might be difficult for the average individual to understand, to identify questions that can be grouped or otherwise simplified, to reorder questions as appropriate, and to evaluate methods for administering the questionnaire. She noted that a public workshop on this issue would be held by FDA on October 16, 2000. Ms. Gregory also spoke in support of reauthorization of the Advisory Committee when its current charter expires in October 2000. Dr. Nightingale thanked Ms. Gregory for that motion, and reported that the process of rechartering the Advisory Committee was well advanced and expected to be completed on schedule.

In the discussion that followed, COL Fitzpatrick discussed the upcoming NATO Civilian-Military Blood Committee meeting scheduled to be held in Washington on November 9 and 10, 2000. The agenda for this meeting is to harmonize donor selection criteria and infectious disease screening for blood to be used by multinational military forces.

There was also discussion about future agenda items for the Advisory Committee. There was consensus that purely scientific issues should deliberated in FDA's own advisory committees, but recognition that issues of availability as well as cost should remain under the Advisory Committee's review. Dr. Caplan added that the Advisory Committee might productively act to encourage scientific investigation of questions for which answers are not yet available.

At Dr. Caplan's suggestion, Dr. Davey moved, and Dr. Guerra seconded, the following motion:

The Advisory Committee directs its staff to develop a matrix out of the presentations to the Advisory Committee as a basis for further discussion of the principles that should underlie a safe, effective, and affordable blood supply.

The motion was approved unanimously.

The meeting was then adjourned at 4:19 PM.

This summary was approved by Dr. Caplan on September 12, 2000