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Blood Safety Summary - April 1999

DATE: May 13, 1999

TO: Interested Parties

FROM: Stephen D. Nightingale, M. D., Executive Secretary

Advisory Committee on Blood Safety and Availability

SUBJECT: Summary of Advisory Committee Meeting of April 29 and 30, 1999

The Advisory Committee on Blood Safety and Availability met for the eighth time on April 29 and 30, 1999 at the Holiday Inn Bethesda, Bethesda, MD 20814, to discuss The Reserve Capacity of the Blood Supply. Members present were Dr. Caplan; Dr. Albrecht; Mr. Allen; Drs. Aubuchon, Busch, Chamberland, Feigal, Gilcher, Gomperts, Goosby, Guerra, Haas, and Hoots; Ms. Jones; Drs. Kuhn and McCurdy; Ms. O'Connor; Drs. Penner and Piliavin; CAPT Rutherford; Dr. Secundy; CAPT Snyder; and Mr. Walsh. Also present were Dr. Davey, Consultant to the Committee; Dr. Epstein, Director of the Office of Blood Research and Review, Food and Drug Administration; CAPT Lawrence McMurtry, Deputy Executive Secretary to the Committee; Dr. Nightingale; and approximately 60 members of the public.

The meeting opened at 8:00 AM with the reading of a statement of the conflict of interest laws that governed it. Next were welcoming remarks from the Chairman, followed by an address by Dr. David Satcher, the Assistant Secretary for Health and Surgeon General.

I REMARKS BY THE SURGEON GENERAL

Dr. Satcher reported that the recommendations of the Advisory Committee on January 28, 1999 regarding hepatitis C lookback had been unanimously endorsed by the Department's Blood Safety Committee, and then accepted by the Secretary and himself. He announced that the FDA will publish, in May 1999, a Guidance to Industry that will incorporate these recommendations, but not change any previous lookback effort, or any of the time frames allotted for their completion. Dr. Satcher noted that the American Association of Blood Banks (AABB), America's Blood Centers (ABC), and the American Red Cross (ARC) had recently informed the Department that their direct notification efforts were on schedule. He then announced that the CDC would hold a press briefing to describe its public education program for hepatitis C on May 5, 1999.

Dr. Satcher then asked the Committee to turn its attention from looking back to looking forward. Dr. Satcher noted that it might be necessary at some time in the future to defer, at least temporarily, some portion of the donor pool, and that this needed to be done in a way that would minimize its impact on those who depend on blood transfusion for their health, and even for their lives. He charged the Committee to review the state of the reserve capacity of the blood supply and to make recommendations how it might be strengthened, and to do so before, and not after, circumstances might require use of this reserve capacity. Dr. Satcher emphasized that we should never be in a position, as some have suggested we may have been in the past, where we would feel obligated to release a unit of blood if we had any doubt about its safety.

Dr. Satcher then asked the Committee, in a future meeting, to explore the potential impact of the dramatic economic changes in health care financing on the safety and availability of blood. He noted that we, as a society, have determined that our blood supply must be unequivocally safe, and that the technology to insure this, at least for known pathogens, is developing rapidly. He also noted, however, a concern whether the current system of reimbursement will allow funds to pay for these advancements in a timely manner. Dr. Satcher emphasized that we should never be in a position, as some have suggested we may have been in the past, where we might permit a delay in the introduction of a needed safeguard to the blood supply simply because funding had not been arranged to support it.

II THE CURRENT SAFETY PROFILE OF BLOOD AND PLASMA PRODUCTS

Dr. Harvey Klein of the National Institutes of Health then provided an overview of the current safety profile of blood products. Dr. Klein began by contrasting the rate of fatal hemolytic transfusion reactions in the 1940's, roughly one per thousand, with the current rate of one in less than half a million as a way of measuring progress that had been made in blood safety. However, he noted that as many as one in 12,000 units of blood may still be given to the wrong patient. Dr. Klein observed that screening procedures had largely confined the residual risk of transfusion-transmitted infection to the coincidence of an asymptomatic but pathogenemic host, a highly adapted pathogen, and a susceptible recipient. He reviewed the milestones, from voluntarism to pooled nucleic acid testing, in the continuing efforts to eliminate the risk of transfusion-associated hepatitis C infection and of HIV infection. Dr. Klein then noted the limited but persistent threats of malaria, yersinia, and other emerging infections to blood safety, and the obstacles that these pose to the attainment of a truly zero risk blood supply. He concluded by cautioning against the adoption of safeguards that might have the unintended but net effect of increasing rather than decreasing the risk of transfusion-transmitted disease.

Mr. James Reilly of the American Blood Resources Association (ABRA) then began an overview of the current safety profile of plasma products. He acknowledged that the plasma industry relied heavily on paid donors, while the blood industry is based on volunteer donors, and he described ongoing industry efforts to respond to this difference. Mr. Reilly's presentation focused on the evolution of ABRA's Quality Plasma Program (QPP) from 1991 to the present. The QPP now includes extensive criteria that must be satisfied before a candidate becomes a qualified donor, including two separate donations within a six month period; the first donation is not released until a second donation is made. QPP also specifies maximum acceptable viral marker rates in donor populations, facility standards, and procedures for internal audits; internal audits are to be replaced by independent, external audits in the near future. In addition, it is now an industry standard to hold each unit of plasma for sixty days after collection before releasing it, so that the unit can be withdrawn if additional information about that donor becomes available during this interval. ABRA also sponsors a donor deferral registry, employee training programs, and research such as donor dropout studies. Mr. Reilly mentioned the relationship of the QPP to United States and international regulations, and he raised the possibility of further harmonizing these relationships.

Mr. Dennis Jackman of the International Plasma Producers Industry Association (IPPIA) continued this discussion by noting that IPPIA members use only QPP-certified plasma in the United States, and that nucleic acid testing of this plasma plus viral inactivation/clearance procedures during manufacture make additional contributions to the safety of the finished product. Mr Jackman stated that there had been no transmission of HIV, hepatitis B, or hepatitis C since the introduction of current screening tests and viral inactivation procedures - as long as these have been performed properly. Mr. Jackman then discussed recent product shortages and industry plans to alleviate them. He mentioned the regulatory and reimbursement climates as two areas of ongoing concern to the industry.

In the discussion that followed, Mr. Reilly noted that 95% of all plasma donor deferrals were in patients who never returned for a subsequent donation, and that donors who returned only once, regardless of the interval, appeared to be as suitable as donors who returned more than once and/or at longer intervals after their initial donation. Mr. Reilly also noted that the duration of the industry's inventory hold, 60 days, was based on actual data on the time frame in which window-period transmissions occurred.

III THE RESERVE CAPACITY OF THE BLOOD SUPPLY

After a break, Ms. Marian Sullivan of the National Blood Data Resource Center, an affiliate of the American Association of Blood Banks, spoke on current trends in blood donation and utilization. She presented results from the Center's 1998 blood collection and utilization survey. In 1998, 12.6 million units were collected, and 11.5 million units were transfused. Ninety-three percent of allogeneic units were transfused, 2% were discarded because of screening test results, 4% became outdated, and 1% were unaccounted for. Total blood collections decreased by 5.5% between 1994 and 1997, while the total number of whole blood and red cell transfusions increased by 3.7% during the same period. Extrapolating current trends, Ms. Sullivan estimated a total supply in 2000 of 11.7 million units, and a total demand of 11.9 million units.

In the discussion that followed, Dr. AuBuchon noted that many of the outdated units were group AB or unused autologous donations. Dr. Klein noted that an overall annual surplus did not preclude the development of spot shortages. Dr. AuBuchon noted that one reason for the trend Ms. Sullivan described was the aging of the population. About half of all transfusion recipients are over 65; as a result, as the population ages, there will be proportionately fewer donors and more recipients.

Dr. George Schreiber of Westat then spoke on frequency of blood donation and the reserve capacity of the blood supply. His analysis was based on data collected by the NIH-sponsored Retrovirus Epidemiology Donor Study (REDS). He began by noting that while almost half the adult population of the United States has donated blood at some time, only about 5% donate in a given year. In 1995, about 32% of the roughly 8 million donors were first-time donors. Half of these new donors never returned, and two thirds of those that did return did so within one year of their initial donation. He estimated that if the rate at which first-time donors return for a second donation within one year could be increased by 15%, the blood supply could be increased by 10%. Dr. Schreiber also found that those who donated two times or more had a lower incidence of HIV and hepatitis C than those who donated only once, and that those who donated only twice had no higher incidences of these infections than those who donated more than twice.

In the discussion that followed, Ms. O'Connor asked if people who moved and continued to donate, but at a different center, were counted as new or repeat donors, and what effect this would have on Dr. Schreiber's estimates. Dr. Schreiber responded that they would be new donors, and that he did not have an answer to Ms. O'Connor's second question. Dr. Gilcher asked if there were not a frequent repeat donor group, such as apheresis donors, who had even lower incidences of HIV and hepatitis C than the average repeat donor. Dr. Schreiber responded that he could not confirm this observation, but that the number of frequent repeat donors in his sample was small.

Dr. Alan Williams of the American Red Cross then discussed the use of incentives to increase blood donation. He presented preliminary results of surveys of previous and current use of incentives in blood centers, the effectiveness of various incentives, and the influence of incentives on disclosure of deferrable risk. Dr. Williams reported that donors who reported receiving some non-token compensation increased from 26.1% in 1995 to 62% in 1998. Donors reported that future blood credit was the incentive that would most strongly encourage them to donate blood. Medical testing was also a favorable incentive. However, using lottery tickets as an incentive might even discourage some donors. Also, the data suggest that cash awards might encourage some donors not to disclose a deferrable risk. In the discussion that followed, Dr. Gilcher pointed out the distinction between incentives, benefits, and recognition of donors, and the potential for each to enhance donation rates.

Dr. Michael Busch of Blood Centers of the Pacific then discussed differences in disease markers among blood donor groups. Dr. Busch emphasized the difference between prevalence and incidence of disease markers in donor populations because new infections, which are measured by incidence but not prevalence, may be preceded by window periods in which a donor is infectious but not detectable by current tests. Overall, Dr. Busch has found greater prevalence of transmissible diseases in new than in repeat donors, but less difference between the incidence of these diseases in new and repeat donor populations. Dr. Busch noted that prevalence reflects lifetime exposure to an infectious risk, whereas incidence reflects recent exposure. To illustrate this point, he presented data that showed the incidence of infectious disease markers was lower in the 78% of United States donors who have previously been transfused than in donors who have never been transfused. A deferral of donors who had previously been transfused, such as is practiced in France, would have the net effect of increasing the overall risk of the donor pool.

Dr. Ronald Gilcher of the Oklahoma Blood Institute then discussed new techniques to increase yield per donation and their associated costs. He described new apheresis equipment that can approximately double the yield of a donation, and he noted that collections that do not achieve a full doubling of yield can still be used in some settings, e. g., pediatric units. He noted that increased costs of disposable materials (e. g., bags) for double collections were somewhat balanced by decreased donor testing costs.

To place these costs in context, Dr. Gilcher stated that the current cost of collecting a unit of blood is between $120 to $125. Leukoreduction presently adds $20 to $22 to the cost of a unit of red cells. Red cells are sold for about $80 per unit. Plasma is sold as either fresh frozen or recovered plasma, and nets about $9 per unit. Platelets generate about $16 per unit. However, the market for random-donor platelets is rapidly shifting to single-donor apheresis platelets. As a result, the market price for blood is currently below its production cost. Dr. Gilcher noted that, when red cells are collected by apheresis, two units are harvested instead of one, so $160 rather than $80 is recovered from the donation. However, disposable costs also rise, so this procedure only breaks even. The same considerations apply if two units of plasma are also collected along with two units of red cells.

In the discussion that followed, Dr. Gilcher noted that the cost a hospital charges a patient for a blood transfusion may be substantially more than what the blood center charged the hospital for that unit. He also noted that the charge for a cross-match averages $40 to $50, a substantial fraction of what the blood itself costs. He also noted that fiscal constraints imposed on hospitals by third party payers was limiting efforts to introduce new safety measures such as pooled nucleic acid testing. However, Dr. Gilcher expressed the view of the consumer as follows:

I want the same kind of risk with a blood transfusion that I want when I fly in an airplane. I want that risk to come as close to zero risk as possible, and I'm willing to pay for it.

Dr. Hoots then commented that, when demand exceeds supply,

... the rules change, and suddenly a not-for-profit right becomes a bidded commodity. It seems like we have a tremendous challenge her to make sure that this just never happens, because the quickest way for you to get what you deserve for a unit of blood is for it not to be available to everybody every time.

Dr. Gilcher responded that businesses are generally thought to require a 4% profit margin to replace capital equipment, and we haven't seen 4% on the bottom in the last 5 years. Dr. Busch noted the influence of competition among blood centers over the past 5 years as a factor limiting cost recovery. Dr. Penner questioned the effect of this competition, and the waning of regionalization, on the willingness of citizens to become volunteer blood donors. Dr. Gilcher then concluded the discussion by noting a tendency to treat blood as a commodity rather than as a community resource, and he queried whether this is in society's best interest.

IV INVITED AND PUBLIC COMMENT

Representatives of the blood industry were invited to comment on the reserve capacity of the nation's blood supply and, in particular, the resources that would be necessary to implement any recommendations that the Advisory Committee might make. Dr. Susan Wilkinson, President of the American Association of Blood Banks, immediately raised the question of how the nation would pay for improvements in blood safety. She told the Committee that

  • blood is collected in the United States largely by non-profit community-based organizations. Such organizations have limited access to capital;
  • blood services are not reimbursed directly, but instead through capitated payments to hospitals. The hospital industry itself is in a critical financial position;
  • the cost of blood, adjusted for inflation, has increased minimally in the past 25 years.

The cost of insuring its safety, however, has increased substantially;

  • HCFA has statutory authority to anticipate costs of new technologies.

It is rarely used;

  • safety improvements generally have the effect of decreasing the donor pool.

The cost of replacing these donors is substantial, between $15 and $30 per unit;

Dr. Wilkinson noted that the only response blood establishments can take to revenue shortfalls is to reduce staff, and this would inevitably impact on blood safety. She therefore requested that HCFA identify a funding mechanism to reimburse the blood industry for the costs of nucleic acid testing, leukodepletion, and any other safety measures that the government may subsequently mandate.

Dr. Celso Bianco of America's Blood Centers spoke to the issue similarly. He noted that the increased use of incentives by blood establishments in recent years reflected increasing concerns about donor recruitment. He agreed with each suggestion that had been proposed to increase the reserve capacity of the blood supply. However, he also noted the effects of safety measures, corporate downsizing and diminution of their support for community services, negative media exposures - even advertisements for certain plasma products - on donor turnout and retention, and he noted the limited financial resources of the blood industry to respond to these challenges. He concluded by stating that reimbursement had to keep pace with innovation, and that

... a strategy such as recalibration of blood-related DRGs can bring America closer to a zero-risk blood supply goal that all of us share.

Dr. Richard Davey of the American Red Cross (ARC) then spoke of his agency's efforts to increase both the number of donors and the rate of their donations per year. He noted that ARC first-time donors had increased between 1997 and 1998 from 14% to 16%, but that the percentage of the population that donates decreased from 6.4% to 5.7%. Dr. Davey is concerned that moving from an ear to a finger stick, a measure necessary to reduce costs, may identify an increased number of potential donors whose hematocrit will be below the limit permitted for donation, and that other developments - donor consent for nucleic acid testing, deferral of British donors, extensive questionnaires - may cause further decreases the available donor pool. Dr. Davey suggested that streamlining screening questionnaires, development of a pedigreed or even, in very careful and restricted manner, a paid donor pool, and facilitating second donations would all be potential approaches to expanding the reserve capacity of the blood supply.

In the discussion that followed, Mr. James McPherson of America's Blood Centers spoke about the perception that the donor shortage might not be as real as previously expressed. He noted that the blood industry had in the past been accused of crying wolf, because so far it has been able to recover from any events that threatened the donor supply. This time, however, Mr. McPherson pointed out,

... we're all standing up here and saying this time we really mean it, and this time there really are severe shortages, and this time there really are some problems. And so I think that we're hoping our credibility is restored, to some degree, but the unanimity of the voices.

After a break, Ms. Julie Swanson addressed the Committee on behalf of the Alpha-One National Association to express her opposition to the proposed medicare outpayment prospective system, because of the negative effect it would have on a patient community that is already under a 60% allocation system. Mr. Rich Vogel, of the Hemophilia Federation of America, expressed concern that blood safety might be sacrificed for profit.

The Committee then discussed the issue. Several members commented on the developing separation of the blood industry from the individual communities is serves, and raised concern that this separation might be a factor that limited the reserve capacity of the blood supply.

V BLOOD DONATIONS BY INDIVIDUALS WITH HEMOCHROMATOSIS

Dr. Vincent Felitti of the Southern California Permanente Medical Group opened the second morning of the meeting with an overview of hemochromatosis. He began by noting that hemochromatosis is caused by a genetic defect that is found in 1 of every 250 Americans. This defect increases iron absorption from the intestine by about 1 milligram a day. Humans do not excrete iron after it has been absorbed, so this excess iron is slowly deposited in the liver, heart, skin, joints, bone marrow, and brain. The treatment of hemochromatosis is to remove iron from the body; this is most effectively accomplished by therapeutic phlebotomy. Initially this is performed about once a week; after body iron levels fall below toxic levels, therapeutic phlebotomy has be performed only often enough to prevent iron overload from recurring.

Dr. Felitti emphasized that hemochromatosis is not a transmissible disease, and that blood from patients with hemochromatosis is perfectly normal; the defect in hemochromatosis is confined to the increased intestinal absorption of iron. For these reasons, there is no intrinsic reason why blood from individuals with hemochromatosis could not be used for any therapeutic purpose.

CAPT Mary Gustafson of FDA then discussed FDA regulations that related to use of blood from individuals with hemochromatosis. 21 CFR 640.3(d) reads

Blood withdrawn in order to promote the health of the donor, otherwise qualified under the provisions of this section, shall not be used as a source of whole blood unless the contained label conspicuously indicates the donor's disease that necessitated withdrawal of blood.

CAPT Gustafson also discussed the labeling regulations in 21 CFR 606.121(c), which states that

The container label shall include the following information, as well as other specialized information as required in this section for specific products:

(1) The proper name of the product in a prominent position, and modifier(s), if appropriate;

...

(5) If the product is intended for transfusion, the appropriate donor classification statement, i. e.,., 'paid donor', or 'volunteer donor', in no less prominence than the proper name of the product.

(i) A paid donor is a person who receives monetary payment for the blood donation.

(ii) A volunteer donor is a person who does not receive monetary payment for a blood donation.

(iii) Benefits, such as time off from work, membership in blood assurance programs, and cancellation of nonreplacement fees that are not readily convertible to cash, do not constitute monetary payment within the meaning of this paragraph.

CAPT Gustafson noted that this rule did not explicitly require that a blood donation from an individual with hemochromatosis be labeled 'paid donor'. However, she noted FDA concern whether being able to donate a unit of blood for transfusion as opposed to having to pay for a therapeutic phlebotomy might provide an undue incentive to not be candid in the donor interview about risk factors unrelated to hemochromatosis.

Dr. Alfred Grindon of the American Red Cross then presented his perspective on this issue. Dr. Grindon provided data from two papers in press in Transfusion on the quantity of blood that the hemochromatosis community might be able to contribute to the blood supply. The first paper reports that an average of 2.6 units/month are drawn from patients during acute treatment, and an average of 0.5 units/month are drawn from patients during maintenance treatment. The second examined what percentage of units drawn would be eligible for use by American Association of Blood Banks (AABB) criteria. Only 59% of acute treatment units would have met these criteria, compared with 88% of volunteer control units, largely because of the lower hematocrits of these patients during frequent therapeutic phlebotomy. However, a larger percentage of chronic treatment units would meet the AABB criteria. Dr. Grindon also pointed out that 25% of all patients with hemochromatosis would be under age 17, the minimum age for donation, that women would be less likely to be symptomatic than men, and that not all men would be symptomatic, either. Given these uncertainties, Dr. Grindon estimated that the number of units that individuals with hemochromatosis might contribute to the blood supply could be anywhere from 300,000 (2.5% of the current supply) to 3,000,000 (25% of the current supply), with his own estimate on the lower side.

Dr. Grindon noted that the reported patient charge for therapeutic phlebotomy ranges from $52 to $90. Thirty-nine percent of the respondents had full insurance coverage and no out-of-pocket costs, but the mean out-of-pocket cost for the whole group was $45 per therapeutic phlebotomy. The AABB policy on incentives is that one is unacceptable if it is sufficient to entice someone who, acting solely on the basis of altruism, would not give blood; this is considered such an enticement.

Dr. Grindon then discussed what might be done to permit use of blood from hemochromatosis patients. He noted that the FDA regulations and the AABB policies could be changed, but he raised the question whether recipients had a right to be informed solely of the fact that a unit of blood had been obtained from a therapeutic rather than a non-therapeutic phlebotomy.

In the discussion that followed, Dr. Grindon stated that, in one of the papers he cited, 29% of patients with hemochromatosis had donated blood before their hemochromatosis had been diagnosed.

Dr. Victor Herbert of Mount Sinai School of Medicine then provided his perspective on this issue. Dr. Herbert emphasized the number of undiagnosed individuals with hemochromatosis who presently donate blood, and he pointed out that some ethnic groups have extremely high frequency of this gene; one in five Irish, for example, are heterozygotes. Dr. Herbert then cited the practice of Dr. Gilcher (and Dr. Grindon), who at their blood centers offer free therapeutic phlebotomy as a community service.

In the discussion that followed, Dr. Gilcher stated that he had initiated free therapeutic phlebotomy as a possible first step towards utilizing this donor pool, but that he had not proceeded beyond this first step so far. Dr. Gilcher did express support for continuing in this direction, but he noted that other changes would have to be made to achieve this goal.

In the public comment period, Dr. Margaret Krikker of the Hemochromatosis Foundation noted that 39% of individuals with hemochromatosis whom she had studied had donated blood before their diagnosis. She expressed the dismay and anger that individuals with hemochromatosis have felt when they are compared to paid blood donors. Mr. Randy Alexander of the Iron Disorders Institute, who identified himself as an individual with hemochromatosis, spoke to the same point. He emphasized that patients with hemochromatosis understood the need for safety in the blood supply, and that they wished to make their contribution to society within that framework. Dr. Roberta Crawford of the Iron Overload Diseases Foundation requested that blood banks screen for hemochromatosis, particularly those with low hemoglobin concentrations.

Mr. Donald Colburn of the National Hemophilia Foundation then expressed his organization's concern about change in current policy, but he also had learned much from the presentations at the meeting.

After a recess, the Committee discussed the matter, and the following proposal, drafted by Dr. Epstein, was moved by Dr. Hoots and seconded by Dr. Gilcher:

The Advisory Committee recognizes that blood products obtained from persons with hemochromatosis carry no known increased risk to recipients attributable to hemochromatosis, per se, and therefore may be a valuable resource to augment the diminishing blood supply. The Advisory Committee also recognizes that the obligate need for phlebotomy can constitute an undue incentive for blood donation due primarily to financial considerations. For this reason, the Department of Health and Human Services should create policies that eliminate incentives to seek donation for purposes of phlebotomy. As such undue incentives are removed, the Department should create policies that eliminate barriers to using this resource.

The motion was approved unanimously, with no abstentions.

VI THE POTENTIAL CONTRIBUTION OF BLOOD SUBSTITUTES TO THE RESERVE CAPACITY OF THE BLOOD SUPPLY

The first speaker at this session was Dr. C. Everett Koop, the former Surgeon General and now affiliated with Dartmouth College and Biopure, Inc. Dr. Koop stated that the development of alternatives to red blood cells could have a major beneficial impact on public health throughout the world because of the blood safety and availability issues it resolve. He suggested that hemoglobin-based oxygen carriers (HBOCs) might even be superior to human red cells in certain circumstances, such as ischemic states, and that, for this reason, the introduction of HBOCs into clinical medicine could result in major improvements in clinical practice.

Dr. Koop noted the regulatory dilemma facing the blood substitute industry, which is that the compound to which blood substitutes would be compared for efficacy, namely whole blood, has no efficacy criteria of its own. He proposed that blood substitutes should be considered on their own merits. He then cited special benefits that blood substitutes could provide to developing countries and to the armed services, and he urged the Advisory Committee to consider how further development of blood substitutes could be expedited.

Dr. Abdu Alayash of FDA then discussed aspects of the biochemistry and physiology of hemoglobin that impact on the clinical development of HBOCs. He noted that the high concentration of hemoglobin within red cells favors the stabilization of hemoglobin in its natural tetrameric form, and that 2,3 DPG in red cells modulates the affinity of hemoglobin for oxygen. Unencapsulated hemoglobin must be modified, for example by cross-linking and/or by reaction with other compounds, to compensate for the lack of the intracellular environment in which the molecule originally evolved. Dr. Alayash also noted that nitric oxide (NO) is a powerful vasodilator and an antioxidant, and that hemoglobin is a NO scavenger. Excess NO uptake by hemoglobin, which can occur when hemoglobin is not encapsulated in red cells, can cause vasoconstriction and hypertension. Also, free hemoglobin can be toxic to certain cells, and free hemoglobin is more susceptible to oxidation than when it is encapsulated. Finally, free hemoglobin interacts with endotoxin and lipopolysaccharides, and this may have adverse consequences in septic patients. Dr. Alayash indicated that each of these considerations should be addressed in the development of a HBOC.

Dr. Toby Silverman of FDA then discussed the clinical regulatory review of HBOCs. She announced that in September 199 the FDA, Department of Defense, and NIH will cosponsor a workshop on clinical trial issues for this class of products, and FDA subsequently plans to publish a Guidance to Industry on this issue. Dr. Silverman then began her presentation by noting that nature has evolved a very elegant mechanism for oxygen delivery. She stated that the ability of products in development to perform this task effectively and safely is not assumed, and must be demonstrated in clinical trials.

Dr. Silverman stated that mortality would be the end point of choice for clinical trials of blood substitutes in patients with blunt or penetrating trauma, particularly those cases in which hemorrhagic shock or exsanguinating hemorrhage developed. Any surrogate marker of efficacy (for example, a measure of drug activity such as tissue oxygenation) would have to be carefully correlated with this primary endpoint. Dr. Silverman suggested that blood substitutes should be evaluated under controlled circumstances, such as elective surgery, prior to their evaluation in field settings. She also noted that, in poorly controlled field settings, blood substitutes might be used in populations for which it was not formally indicated. For that reason, clinical trials would have to address safety issues in these populations as well.

Dr. Silverman stated that, in perioperative settings, reduction in or avoidance of allogeneic red cell transfusions is an acceptable surrogate endpoint for reduction in the risk of allogeneic blood transfusions. She anticipated that traditional transfusion triggers would be used for initial licensure of some products. She also noted that many perioperative patients would be exposed to blood substitutes and allogenic blood, rather than to blood alone. She indicated that clinical studies should be powered for safety as well as efficacy determinations.

Dr. Peter Keipert of Alliance Pharmaceuticals then discussed Perflubron, a perfluorocarbon oxygen carrier. Perflubron is manufactured as a water-soluble emulsion; its shelf life at room temperature is several days. Perflubron has a half-life in the blood of 6 to 12 hours; it is not metabolized, and it is excreted through the lungs. Also, Perflubron does not require human hemoglobin for its manufacture. One difference between perfluorocarbon- and hemoglobin-based oxygen carriers (HBOCs) is the hemoglobin-oxygen dissociation curve for Perflubron is linear. As a result, oxygen delivery to tissues can be increased simply by increasing the inspired oxygen concentration. Another difference is that perfluorocarbons do not cause vascular instability as some HBOCs do.

Perflubron is being targeted for perioperative use, where the majority of blood transfusions occur. Perflubron is intended to be an enabling technology to supplement acute normovolemic hemodilution in elective surgery. (Acute normovolemic hemodilution involves removing blood, nominally 3 units, just before surgery and replacing this blood with fluids. Blood lost during surgery will then have fewer red cells in it, so total red cell loss, and the requirement for red cell transfusion, is reduced. At the end of surgery, the blood previously removed is reinfused.) Perflubron would be used during surgery while blood loss is ongoing; the patient's own blood would be reinfused after hemostasis is achieved. Alliance currently has a Phase III transfusion avoidance study ongoing in Europe, and is planning transfusion avoidance and dose escalation studies in the United States.

Dr. Keipert estimated that full penetration of the Perflubron into the perioperative transfusion market could reduce perioperative blood use by perhaps 60%, which he estimated to be a total of 3 million units per year or about 25% of total red cell use. A 20% market penetration of his product, which Dr. Keipert thought was feasible, would reduce perioperative blood use by 600,000 or 5%. Achievement of this objective would require successful completion of the proposed research and subsequent regulatory review.

Dr. Timothy Estep of Baxter then discussed his company's ongoing research. He reviewed Baxter's previous trials of HemeAssist, a human HBOC, which involved over 1300 individuals. These trials did not demonstrate a survival benefit. They raised concerns about the nitric oxide (NO)-related increases in blood pressure seen with their first generation HBOC, particularly in the lung and gastrointestinal tract. Dr. Estep indicated that Baxter would be focusing its future blood substitute efforts on developing recombinant hemoglobin molecules in order to mitigate vasoactivity seen in other HBOCs. One goal of this research is to determine how variations in the region of the hemoglobin molecule that binds NO affect vasoactivity. Another is to identify differences in response to HBOCs in hemorrhagic and septic shock, and to explore the therapeutic implications of these differences. Dr. Estep discussed the challenge to these studies of using mortality as an endpoint in a population with a high, but also highly variable, inherent mortality.

Dr. Estep pointed out the difficulties of comparing the risks and benefits of blood substitutes to blood when the risks and benefits of blood itself have not been well characterized. He emphasized the need for both sets of investigations to occur, and he suggested that the risks and benefits of both blood substitutes and blood be determined in both experimental and clinical situations, and in different clinical situations such as hemorrhagic and septic shock. Dr. Estep also suggested that FDA consider alternatives to mortality as the primary efficacy endpoint for trials of blood substitutes. He concluded with the hope that Baxter would be initiating clinical trials within several years, and that that the pace of further development would be influenced by the regulatory requirements at that time.

Dr. William Hoffman of Biopure then discussed Oxyglobbin, a veterinary blood substitute now in clinical use, and Hemopure, a human blood substitute now in Phase III clinical trials. Both are polymers of bovine hemoglobin, stable for prolonged periods at room temperature, and ready to administer. The half-life of the product in the circulation is about 24 hours. Hemopure is an isosmotic, low viscosity solution with a P50 of 38 torr that is modulated by Cl rather than 2,3DPG. he endpoint for current trials in orthopedic patients is prevention of allogenic blood transfusion. Dr. Hoffman showed data from a trial of Hemopure in cardiac surgery that showed no difference in blood pressure between Hemopure and control patients.

Dr. F. J. Lou Carmichael of Hemosol then discussed Hemolink, a raffinose-polymerized human hemoglobin that is prepared from outdated human red cells. Dr. Carmichael noted that the raw material has already been approved for human use, and he briefly described its subsequent purification by pasteurization and viral filtration. Like other HBOCs, Hemolink has a prolonged shelf life, does not require cross-matching prior to use. Dr. Carmichael then described Phase II trials of Hemolink to prevent allogenic transfusion in Canadian and British orthopedic and cardiac surgery patients. He stated that there were no limiting adverse events related to Hemolink, that patients were hemodynamically stable, and that end organ function remained normal.

Dr. Carmichael noted that the future contribution of Hemolink to the reserve capacity of the blood supply would depend on the availability of the raw product, outdated human blood; on Hemosol's manufacturing capacity; and on regulatory approval of the product. He estimated the current supply of outdated blood at about 500,000 units per year, which would produce 200,000 to 300,000 units of Hemolink. Dr. Carmichael noted that increased collection activities of blood banks often focused on donors with rare blood types, while Hemosol could use blood from the most common donor types. Dr. Carmichael also mentioned a company initiative to grow human red blood cells, but he did not expect this project to achieve commercial status in the near future.

Dr. Steven Gould of Northfield Laboratories then discussed PolyHeme, a glutaraldehyde-polymerized human hemoglobin also prepared from human red cells. The purified final product delivers 50 grams of hemoglobin in 500 ml of solution, approximately the same hemoglobin concentration as in human blood. Dr. Gould described three ongoing trials of PolyHeme. One Phase III trial is in elective surgery. The trial involves acute normovolemic hemodilution and replacement with 6 units of PolyHeme. The primary endpoint is reduction of allogenic transfusion. A second Phase II trial in trauma permits up to 20 units of PolyHeme to be transfused (the adult human blood volume is equivalent to 10 units). A third trial is a compassionate use program.

Dr. Gould stated that the most compelling indication for use of PolyHeme would be life-threatening blood loss when blood is potentially unavailable, and that the most important clinical benefit would be a reduction in mortality in this setting. He noted that while these situations would be anticipated in rural and military settings, unplanned and massive hemorrhage also occurs in urban surgical suites where trauma victims are cared for. Dr. Gould also alluded to patients with religious objections to blood transfusion, and the possibility of shortages of some or all types of blood.

Dr. Gould cited literature stating that, in bleeding surgical patients, mortality exceeds 80% when the hemoglobin is less than 3 gm/dl. He then described his experience with a non-randomized trial in 53 trauma patients who sustained blood loss and were not given blood but instead given 6 or more units of PolyHeme. At the end of the infusion, the amount of hemoglobin in the patient's red cells was measured, and the difference between this and the total amount of hemoglobin in the patient's blood was the amount provided by PolyHeme. Overall, 9 (17%) of the 53 patients died. Twenty-seven of the 53 patients were found to have red cell hemoglobins below 3 gm/dl. Four (14.8%) of these 27 patients died. Their mean pre-treatment red cell hemoglobin was 8.6 g/dl; their mean post-treatment red cell hemoglobin was 1.6 g/dl. Three (15%) of the 20 with red cell hemoglobins less than 2 g/dl died. None of the 5 patients with red cell hemoglobins less than 1 g/dl died.

Based on historical comparisons to patients with similar red cell hemoglobin concentrations, Dr. Gould proposed that the substantial reduction in mortality he observed (80% to 15%) should be considered statistically and clinically significant. In particular, he proposed that the data supported the conclusion that for every 1.41 patients with red cell hemoglobins below 3 gm/dl treated, one life would be saved by PolyHeme. He also noted that, in this setting, there were no serious adverse events related to the infusion of PolyHeme.

Dr. Gould concluded by discussing the potential contribution of PolyHeme to the blood supply. He noted that outdated human blood was the raw material for PolyHeme. He suggested that blood collection, particularly for A and AB blood types that were likely to become outdated, could be expanded sufficiently to meet his needs if waste were not a concern of the collection agencies.

The final speaker was Dr. Robert Winslow of Sangart, Inc. Dr. Winslow reviewed blood substitute research funded by the Letterman Army Institute of Research between 1985 and 1993, and performed under his direction. He described a comparison between one polymerized hemoglobin with a molecular weight of 160,000, a molecular radius of 4.9 nm, a molecular volume of 4,000 nm3, and a viscosity of 1.36 cp (the viscosity of water is 1 cp) and a another polymerized hemoglobin with a molecular weight of 123,000, a molecular radius of 7 nm, a molecular volume of 93,000, and a viscosity of 3.39 cp (the viscosity of blood is 4 cp). The larger molecule exhibited less vascular reactivity than the small molecule in an animal model of hemorrhagic shock. Dr. Winslow described another experiment in which a low concentration of polymerized hemoglobin (2 gm/dl) with a relatively low P50 in an isosmotic hetastarch solution was effective in a similar mouse model. The conclusion that Dr. Winslow drew from these experiments was that it should be possible to produce a relatively economical blood substitute.

There being no further business, the meeting was adjourned a 4:36 PM.