2
The U.S. Blood Supply System

INTRODUCTION

The U.S. blood supply system is comprised of many organizations with different management structures and philosophies. Table 2.1 lists each of the major organizations that function to meet the nation's blood needs. To provide the context for the Committee's analysis, this chapter provides information on blood and blood products, the organizations that collect, manufacture, and distribute them, and the professional and trade associations that represent these organizations. Because of the special role of hemophilia in the Committee's analysis, this chapter also provides background information on the National Hemophilia Foundation and related organizations. Finally, this chapter also presents information on the federal agencies responsible for blood safety, the history of blood and blood product regulations, and the regulatory authority of the FDA.

BLOOD AND BLOOD PRODUCTS

There are two different types of blood collection activities. One blood collection and supply system involves the cellular elements and plasma obtained from whole blood, and the other involves large-scale collection of the plasma portion of whole blood and the subsequent manufacture of derivatives produced from that plasma as a raw material. Before describing these two types of activities, a brief summary of the products produced from whole blood and plasma is helpful.



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HIV and the Blood Supply: An Analysis of Crisis Decisionmaking 2 The U.S. Blood Supply System INTRODUCTION The U.S. blood supply system is comprised of many organizations with different management structures and philosophies. Table 2.1 lists each of the major organizations that function to meet the nation's blood needs. To provide the context for the Committee's analysis, this chapter provides information on blood and blood products, the organizations that collect, manufacture, and distribute them, and the professional and trade associations that represent these organizations. Because of the special role of hemophilia in the Committee's analysis, this chapter also provides background information on the National Hemophilia Foundation and related organizations. Finally, this chapter also presents information on the federal agencies responsible for blood safety, the history of blood and blood product regulations, and the regulatory authority of the FDA. BLOOD AND BLOOD PRODUCTS There are two different types of blood collection activities. One blood collection and supply system involves the cellular elements and plasma obtained from whole blood, and the other involves large-scale collection of the plasma portion of whole blood and the subsequent manufacture of derivatives produced from that plasma as a raw material. Before describing these two types of activities, a brief summary of the products produced from whole blood and plasma is helpful.

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HIV and the Blood Supply: An Analysis of Crisis Decisionmaking Table 2.1 Major Organizations Comprising the Blood Supply System and Their Functions Organization Function Federal Agencies   Department of Health and Human Services Direction and oversight Public Health Service Direction and oversight Food and Drug Administration Regulation and review Center for Biologics Evaluation and Review Blood Products Advisory Committee Regulation, review, and research scientific advice Centers for Disease Control and Prevention Surveillance, investigation, and information dissemination National Institutes of Health Biomedical research Blood Collection Organizations   American Red Cross Blood collection and supply, research Community blood banks Blood collection and supply, information exchange Hospital blood banks Blood collection and patient care For-Profit   Plasma fractionation industry Plasma collection and supply, manufacturing, research Professional and Trade Associations   American Association of Blood Banks Representing blood collection and transfusion services organizations, standard setting (inspection and accreditation program), and education American Blood Resources Association Advocacy for plasma fractionation industry, education

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HIV and the Blood Supply: An Analysis of Crisis Decisionmaking Organization Function Council of Community Blood Centers Representing blood collection, information exchange Nonprofit-Patient Advocacy   National Hemophilia Foundation   Medical and Scientific Advisory Council Advocacy, education, and information dissemination Medical and scientific advice Blood is composed of plasma and several cellular elements which include red cells (erythrocytes), five kinds of white cells (leukocytes, many with important subtypes), and platelets. Either whole blood can be collected or the plasma portion of the blood can be collected with the cellular portion returning to the donor. Whole blood is collected by blood banks, which prepare the cellular products and unprocessed plasma used directly for transfusion. Plasma is collected and used as raw material to commercially produce plasma "derivatives," which are concentrated forms of selected plasma proteins (Figure 2.1). Whole Blood and Components Whole blood is collected by venipuncture from healthy adults into plastic bags containing a liquid anticoagulant preservative solution. About 450 milliliters of blood can be collected as often as every 56 days without harm to the donor. The whole blood is separated into components within eight hours after collection. The components are red blood cells, platelet concentrate, and fresh frozen plasma. The fresh frozen plasma can be used in one of three ways: (1) for transfusion; (2) for further processing into cryoprecipitate (i.e., fresh or frozen plasma) to be used for transfusion, and cryoprecipitate poor plasma, which serves as a source of raw material for further manufacture of plasma derivatives; or (3) as a source of raw material for subsequent manufacture of plasma derivatives as described below. As shown in Table 2.2, among the components prepared from whole blood are red blood cells, platelets, fresh frozen plasma, and cryoprecipitate. Blood banks make many modifications of these components to obtain blood products that will be effective for specific purposes. In addition, blood banks distribute

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HIV and the Blood Supply: An Analysis of Crisis Decisionmaking Figure 2.1 Organization of the plasma and plasma products industry. Reprinted with permission of the American Blood Resources Association.

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HIV and the Blood Supply: An Analysis of Crisis Decisionmaking Table 2.2 Components Produced by Blood Banks and the Medical Use of the These Components Component Medical Use Red blood cells Oxygenate tissues Platelets Prevention or stopping of bleeding Fresh frozen plasma Stop bleeding Cryoprecipitate Stop bleeding Cryoprecipitate poor plasma Plasma exchange Granulocytes Treat infection Frozen red blood cells Store rare blood Leukocyte-depleted red blood cells Prevent reactions and certain diseases many of the plasma derivative products as part of their total supply program for transfusion medicine therapy, but most of these other plasma products are actually manufactured commercially by plasma fractionation companies. Because the United States has a pluralistic system of blood collection, there is no central repository of data about the number of units of blood collected or the components produced or transfused. The American Red Cross (ARC) collects about 45 percent of the 14 million units of whole blood available for use annually in the United States. Other community blood banks collect about 42 percent, hospitals collect about 11 percent, and the remaining 2 percent is imported. In 1989, a total of 12,544,000 units of whole blood were collected by 190 blood centers and 1,685,000 units were collected by an estimated 621 hospitals (Wallace, et al. 1993). Plasma and Derivatives For the manufacture of derivatives, plasma can be obtained as the by-product from whole blood (plasma) or by plasmapheresis (source plasma). Plasma that is a by-product from whole blood collected by community blood banks or hospitals is sold to commercial companies in the plasma fractionation industry, who in turn manufacture the plasma derivatives and sell them in the

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HIV and the Blood Supply: An Analysis of Crisis Decisionmaking pharmaceutical market. See Chapter 4 for a description of the role one such product—antihemophilic factor (AHF)—in the treatment of hemophiliacs. The blood banks' sale of their plasma to the commercial plasma fractionator may, but usually does not, involve an agreement to provide some of the manufactured derivatives back to the blood bank. For example, plasma from whole blood collected by the ARC is fractionated through a contract with Baxter Healthcare, which then returns all of the derivatives produced to the ARC for sale through their blood provision system. The amount of plasma obtained from whole blood is not adequate to meet the needs for raw material to produce plasma derivatives. Therefore, much of the plasma that will be made into derivatives is obtained by plasmapheresis. This plasma is called source plasma, which is ''the fluid portion of human blood collected by plasmapheresis and intended as the source material for further manufacturing use" [C.F.R., 1992]. Automated instruments are usually used to obtain 650–750 milliliters of plasma up to twice weekly from healthy adult donors (approximately 225 cc of plasma can be obtained from 450 ml of whole blood but most plasma is obtained directly through plasmapheresis). An individual can donate up to about 100 liters of plasma annually in the United States if the plasma protein levels and other laboratory tests and physical findings remain normal. The plasma is used as raw material for the manufacture of the derivatives shown in Table 2.3. The production of these plasma derivatives is a complex manufacturing process usually involving large batches of plasma (up to 10,000 liters) from as many 1,000–20,000, or more, donors. The high demand for plasma products and the lengthy and often uncomfortable procedure of plasmapheresis led to the justification and legalization of compensation for plasma in the United States. Up to the early 1980s, plasma collection centers could be located in prisons and other areas where there was a high prevalence of hepatitis and other chronic infections. With the possible emergence of AIDS in the blood supply, plasma fractionators began closing their prison collection sites in December 1982, and in essence all were closed by January 1984. Organizations and facilities need licenses for plasma collection (if shipped interstate) and the manufacture of AHF concentrate and other products from plasma. Plasma Collection Data regarding the plasma fractionation industry are proprietary and thus not readily available. The FDA does not routinely collect data on the nature of plasma donors, the amount of plasma each organization collects, or the number of derivative products produced. According to the American Blood Resources Association (ABRA), the U.S. plasma and plasma fractionation industry employs

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HIV and the Blood Supply: An Analysis of Crisis Decisionmaking over 12,000 people nationwide (Scott 1990). U.S. plasma collection facilities perform approximately 13 million plasmapheresis donor collection procedures annually. Thus, if an average of 700 ml of plasma is obtained from each donation, it could be estimated that approximately 9 million liters of plasma would be collected annually in the United States by plasma centers. Individuals who donate plasma to support the plasma fractionation industry receive between $15 and $20 per donation. According to the ABRA, donors receive compensation of more than $244 million from plasma collection facilities annually (ABRA 1994). This is in contrast to whole blood donors, who donate voluntarily and do not receive compensation. Much of the plasma obtained from whole blood collected by blood banks is also used for production. Blakestone has estimated that in 1990 approximately 12 million liters of plasma were consumed in the manufacture of plasma derivatives (Blakestone 1994). It is estimated that plasma fractionation worldwide sales exceed $4 billion annually, with U.S. firms providing more than 60 percent of the plasma products or $2.4 billion in domestic and export sales annually (ABRA 1994). Of the $2.4 billion in domestic and export sales, $645 million is the estimated export revenue from sales of U.S. plasma products in Europe. Plasma Processing The collected plasma is sent from the collection site to a fractionation laboratory, which in the United States, is either owned by a pharmaceutical company or by an outside company that sells the fractionated plasma to the pharmaceutical company. Fractionation involves further separation of the plasma into proteins such as albumin, immunoglobulin, and AHF concentrates. A pool size of at least 1,000 donors is required by the FDA for the production of immunoglobulin products used in the treatment of infectious disease, because increasing the pool size concentrates the therapeutic antibody portion of plasma. Pooling was more efficient for production in the manufacturing process of AHF concentrates because clotting factor proteins are found in extremely small quantities in plasma. Pooling plasma also has the negative effect of increasing chances for contracting infectious disease (see Chapter 4).

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HIV and the Blood Supply: An Analysis of Crisis Decisionmaking Table 2.3 Plasma Derivative Products and Their Uses Plasma Derivative Medical Use Albumin Restoration of plasma volume subsequent to shock, trauma, surgery, and burns Alpha 1 proteinase inhibitor Used in the treatment of emphysema caused by a genetic deficiency Anti-inhibitor coagulant complex Treatment of bleeding episodes in presence of Factor VIII inhibitor Anti-thrombin III Treatment of bleeding episodes associated with liver disease, antithrombin III deficiency, and thromboembolism Cytomegalovirus immune globulin Passive immunization subsequent to exposure to cytomegalovirus Factor IX complex Prophylaxis and treatment of hemophilia B bleeding episodes and other bleeding disorders Fibrinogen Treatment of hemorrhagic diathesis in hypo-, dys-, and afibrinogenemia Fibrinolysin Dissolution of intravascular clots Haptoglobin Supportive therapy in viral hepatitis and pernicious anemia Hepatitis B immune globulin Passive immunization subsequent to exposure to hepatitis B IgM-enriched immune globulin Treatment and prevention of septicemia and septic shock due to toxin liberation in the course of antibiotic treatment Immune globulin (intravenous and intramuscular) Treatment of agamma- and hypogamma-globulinemia; passive immunization for hepatitis A and measles

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HIV and the Blood Supply: An Analysis of Crisis Decisionmaking Plasma Derivative Medical Use Plasma protein fraction Restoration of plasma volume subsequent to shock, trauma, surgery, and burns Rabies immune globulin Passive immunization subsequent to exposure to rabies Rho(D) immune globulin Treatment and prevention of hemolytic disease of fetus and newborn resulting from Rh incompatibility and incompatible blood transfusions Rubella immune globulin Passive immunization subsequent to exposure to German measles Serum-cholinsterase Treatment of prolonged apnea after administration of succinylcholine chloride Tetanus immune globulin Passive immunization subsequent to exposure to tetanus Vaccinia immune globulin Passive immunization subsequent to exposure to smallpox Varicella-zoster immune globulin Passive immunization subsequent to exposure to chicken pox Blood and Blood Components Distribution Traditionally, some areas of the United States have been able to collect more blood than needed locally and have provided these extra units to other communities. The misalignment of blood use and blood collection is a longstanding phenomenon. To deal with these blood shortages, blood is "exported" from areas of oversupply and "imported" into areas of shortage—a practice called "blood resource sharing.'' The lack of an adequate local blood supply and the need to import blood causes several difficulties including complex inventory management, technical disparities, emergency donor recruitment, higher costs,

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HIV and the Blood Supply: An Analysis of Crisis Decisionmaking decreased independence, and higher risk-management costs (Scott 1990). Some blood centers import blood because they can obtain this blood for less than their own costs of production (Anderson 1990). For years, blood banks have participated in systems to exchange blood among themselves to alleviate shortages. Blood banks in metropolitan areas that serve large trauma, tertiary, and transplantation centers most frequently experience shortages of whole blood, components, and type-specific blood units. Although experience has demonstrated that the American public is ever-willing to donate blood in times of local disaster or national emergency, this same public has often not donated blood in sufficient supply to meet the daily needs of the local community. Less than 5 percent of the U.S. population donates blood and in certain communities the percentage is even lower. Without resource-sharing networks, many individuals would not receive the blood transfusions necessary to maintain or restore their health. BLOOD COLLECTION ORGANIZATIONS The United States blood collection system is heterogeneous owing to the "random development of blood centers without regard … to patient referral patterns" (Scott 1990). The American Red Cross (ARC) collects approximately half the blood in the United States. In the non-ARC covered areas, blood is collected by one or more community or hospital blood banks. In most areas of the United States, there is only one local organization that collects blood. However, in some communities, including these where the ARC operates a blood program, blood may be collected by more than one organization. When this occurs, usually several hospitals and a community blood center (ARC or non-ARC) are involved. The adequacy of the nation's blood supply varies at different times of the year and in different parts of the United States, but, in general, the United States is almost 100 percent self-sufficient in its blood supply. Approximately 2 percent of the U.S. blood supply is imported from western Europe (Wallace, et al. 1993). Sufficiency, however, varies among geographic areas of the United States on a continual basis. The extent to which the adequacy of the blood supply is related to the public image of blood banks and the association of blood with AIDS is not clear. Public opinion surveys indicate strong support for blood banks (Gallup 1991), and despite major public education efforts by blood banks, a high (35 percent) percentage of people believe they can contract AIDS or HIV by donating blood (CDC 1991).

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HIV and the Blood Supply: An Analysis of Crisis Decisionmaking Community Blood Banks Blood is collected by blood centers and hospitals. Blood centers are freestanding organizations, virtually all of which are nonprofit. These centers are governed by a board of local volunteers and are organizations whose sole function is to provide the community's blood supply. Each blood center collects blood in a reasonably contiguous area and supplies the hospitals within the blood collection area. The blood center may or may not supply the total needs of the hospitals in its area or may supply hospitals in other areas as well. The area covered by each center is determined by historical factors and did not develop according to any overall plan. Rather, local interests dictated whether, how, and what kind of community blood program developed. Not every area of the United States is necessarily covered by a blood center. There are a total of approximately 180 blood centers in United States (Scott 1990). Approximately 45 of these (25 percent) are operated by the ARC and the remainder are community blood centers as described above. The American Red Cross Service The ARC is the organization that collects the largest number of units of blood in the United States. The ARC Blood Service is one of many humanitarian programs operated by the ARC. The ARC is a nonprofit, congressionally chartered (but not government sponsored or operated) organization that conducts programs supported by donated funds and through cost recovery. The mission of the ARC Blood Service is to "fulfill the needs of the American people for the safest, most reliable, most cost-effective blood, plasma … services through voluntary donations." In addition, the organization attempts to be the "provider of choice for blood, plasma … services … by commitment to quality, safety, and use of the best medical, scientific, manufacturing, and business practices" (ARC 1994). Hospital Blood Banks Some blood is collected by blood banks that are part of hospitals. These blood banks usually collect blood only for use in that hospital and do not supply other hospitals. Very few (possibly no) hospitals collect enough blood to meet all their needs. They purchase some blood from a local or distant community blood center. Most U.S. hospitals do not collect any blood but acquire all of the blood they use from a community center. Of those that do collect blood, there are no good data available to define the proportion of their needs that they collect. This can be presumed to be quite variable.

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HIV and the Blood Supply: An Analysis of Crisis Decisionmaking advisory committees must be chartered, and their charters must be renewed biennially unless otherwise determined by law. The CBER has four different standing advisory committees, one of which is the Blood Products Advisory Committee (BPAC), which provides evaluation of data related to safety, effectiveness, and labeling of blood and blood products and makes appropriate recommendations to the Secretary, the Assistant Secretary for Health, and the FDA commissioner (IOM 1992). Advisory committee nominations include candidates from relevant professional and scientific bodies, medical schools, academia, government agencies, industry and trade associations, and consumer and patient organizations. Committee members are appointed to terms not to exceed four years. Reappointment to a committee requires that one year elapse between appointments. The general way in which an agenda is set for an FDA advisory committee involves two stages: (1) a meeting is formally scheduled and announced in the Federal Register; and (2) several days prior to the meeting, the FDA staff sends advisory committee members a detailed agenda and a list of specific questions on which their advice is sought. The FDA releases this list of questions to the public on the morning of the meeting (IOM 1992). An advisory committee meeting operates with the following separable portions: an open public hearing; an open committee discussion; a closed presentation of data; and closed committee deliberations. The BPAC's topics include investigational new drugs that meet the criteria of important diagnostic therapeutic, preventive, or other advances; novel and improved methods for product delivery; potential or apparently significant safety hazards; involvement of new biotechnology; and issues requiring additional expert review or clarification of study protocols. Product licensing agreements considered at BPAC meetings include those meeting the criteria of being a significantly new product; posing new uses for marketed products; having significant potential for risk compared to narrow therapeutic benefit; needing or being considered for postmarketing studies; presenting potential for withdrawal from market because of safety or questionable efficacy; and posing issues requiring additional expert review or clarification of study protocols. The BPAC has 13 voting members and 2 nonvoting members. All voting members, consultants, and experts to advisory committees receive compensation for each day worked, travel, and per diem, unless waived. Industry and consumer representatives receive a salary if they have been cleared under the FDA's conflict of interest regulations as a special government employee. During the 1980s the BPAC was comprised of experts in relevant professional, scientific, and medical establishments, including academic blood banking, transfusion services, anesthesia and pharmacology, state public health departments, general medicine, biochemistry, pediatrics, laboratory medicine, infectious diseases, virology, hematology, and oncology.

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HIV and the Blood Supply: An Analysis of Crisis Decisionmaking BLOOD AND BLOOD PRODUCT REGULATION Statutory Background The history of blood and blood product regulation in the United States includes both congressional enactments (public laws) and rulemaking procedures of the FDA. The FDA regulates blood, blood components, and derivatives under two separate but overlapping statutes, one governing "biologics" and one governing "drugs." The biologics law requires that any "virus, therapeutic serum, toxin, anti-toxin, or analogous product" be prepared in a facility holding a federal license. A separate law, for food and drugs, includes drugs intended for the "cure, mitigation, or prevention of disease" and, thus, includes biologics such as blood and blood components or derivatives. Thus, blood banks and plasma product manufacturers are also subject to this drug regulatory process. Biologics Act In 1902, following several outbreaks of disease from contaminated vaccines, Congress enacted the Biologics Act [32 Stat. 728] which provided the framework for federal regulation of biological products for human use. The law required that biological drugs sold in interstate commerce must be licensed and produced in licensed establishments. The term biologics includes vaccines made from or with the aid of living organisms that are produced in animals or humans. Biologics also include antitoxins used to protect against diphtheria, tetanus, and whooping cough; serums for the treatment of disease; products for the treatment of allergies; and blood for transfusion and other medical purposes (Hutt and Merrill 1991). In 1944, the Biologics Act was reenacted as part of the recodification of the Public Health Service Act [58 Stat. 682, 702, 1944], and is now codified at 42 U.S.C. § 262 (Hutt and Merrill 1991). The recodification hearings focused on the issue of possible duplicative regulatory authority of biological products under the Federal Drug and Cosmetics Act. Under the original act, the Public Health Service (PHS) licensed and controlled the manufacturing of virus serums, toxins, and other biologics. At the hearings, while PHS control of biologics was viewed as effective, the wording of the new act was seen to be suggestive of duplicative administrative control of the PHS and the FDA. In the event that some product dangerous to human life inadvertently entered the market, the FDA would have power of seizure [Section 351 of the PHS Act, referred to as the Biologics Act] (Hutt and Merrill 1991). Prior to 1970, the Biologics Act did not specifically include blood products. In 1970, Congress amended the Biologics Act

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HIV and the Blood Supply: An Analysis of Crisis Decisionmaking "specifically to include vaccines, blood, blood components or derivatives, and allergenic products [84 Stat. 1297, 1308]" (Hutt and Merrill 1991). Public Health Service Act In 1974, the FDA promulgated regulations governing good manufacturing practices in the collection, processing, and storage of human blood components [39 Federal Register 18,614, 1974; 40 Federal Register 53,532, 1975]. By combining the jurisdictional and regulatory provisions of the Biologics Act and the Food, Drug, and Cosmetic Act, the FDA brought all blood and blood products produced and used in the United States under uniform federal requirements (Hutt and Merrill 1991). Blood Shield Laws During the 1950s and 1960s, blood shield laws were adopted by 47 different jurisdictions. The blood shield laws were developed to exempt blood and blood products from strict liability or implied warranty claims on the basis that blood and blood products provide a service, not a sale. Accordingly (as stated in the California Health and Safety Code 1606), the procurement, processing, distribution, or use of whole blood, plasma, blood products, and any blood derivatives for the purpose of infusing the same, or any of them, into the human body shall be construed to be, and is declared to be, for all purposes whatsoever, the rendition of a service by each and every person, firm, or corporation participating therein, and shall not be construed to be, and is declared not to be, a sale of such whole blood, plasma, blood products, or blood derivatives, for any purpose or purposes whatsoever (Westfall 1986). Only four jurisdictions (New Jersey, District of Columbia, Rhode Island, and Vermont) did not adopt statutes protecting hospitals or blood donor services from strict liability or breach of implied warranty (Lipton 1986). Even in these jurisdictions, however, the likelihood that a court would hold a hospital or blood donor service liable under either breach or implied warranty or strict liability theories was considered remote (Lipton 1986). In 1976 blood banks received exemption from liability under protection of blood shield law as providing a service and not a product. The court ruled that there was a rational basis for blood bank's exemption from liability, based on weighing the need for an available blood supply for surgery and other medical procedures against the "relatively minor risk of hepatitis which the blood

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HIV and the Blood Supply: An Analysis of Crisis Decisionmaking recipient must take" (Westfall 1986). In addition, the court found that exemption of the blood bank from liability was constitutional because protection of blood banks was related to the state's purpose of encouraging the general blood supply. In 1977, the courts extended this protection to blood product manufacturers on the same grounds: the distribution of blood products was a service and not a sale. In a wrongful death suit concerning a hemophiliac who had died from hepatitis after using a blood product [Cutter v. Fogo 1977], the court reasoned that because the blood product was unavoidably unsafe, and because the risk of hepatitis could not be eliminated despite every attempt to screen donors (i.e., through both biological tests and avoidance of high-risk donors), the blood product manufacturers were protected from strict product liability since the blood product had been instrumental in helping many hemophiliacs (Westfall 1986). Federal Licensure of Blood Collection Organizations Federal licensure is thought to ensure that the facility in which the biologic is produced will ensure its purity and quality. In addition to licensing the facility or establishment, this law requires that each biologic product itself be licensed by the government. Thus, to produce a licensed biologic, an organization must have an establishment license describing the facility in which the product is produced and a product license describing the specific product being produced. Over the years, this law has been specifically amended to include the terms blood and blood component or derivative to make it clear that blood and blood products are subject to the biologics regulation. Establishment Licensure and Registration Presently, there are 188 FDA-licensed organizations at 790 locations for collection and interstate shipment of blood and blood components. In addition, a total of 2,900 locations are registered to collect blood but not for interstate shipment. If an organization wishes to ship the components across state lines or engage in commerce by selling the products to other organizations, the organization must obtain an FDA license for this purpose. Even if an organization does not wish to produce blood components for interstate shipment, the FDA law requires that all organizations involved in "collection, preparation, processing, or compatibility testing … of any blood product" register with the FDA (McCullough 1995). This registration allows the organization to collect blood and prepare blood components for its own use. Thus, for practical purposes, most hospitals that collect blood or prepare blood components for their

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HIV and the Blood Supply: An Analysis of Crisis Decisionmaking own use are registered but not licensed since they do not ship blood in interstate commerce. Most blood centers are licensed since they supply multiple hospitals, some of which may be in other states. In addition, blood centers may wish to participate in blood resource sharing with blood centers in other states and thus need to be licensed for interstate shipment of blood. Product Licensure Along with the establishment license, the organization must file a product license application for each product it plans to produce in the facility. For whole blood and components, the product application involves basic information about the manufacturer (organization), establishment, product, standard operating procedures, blood donor screening tests, frequency of donation, donor medical history, presence of a physician, phlebotomy supplies, venipuncture technique, collection technique, allowable storage period, storage conditions, disposal of contaminated units, supplies and reagents, label control processes, procedures for reissue of blood, and a brief summary of experience testing 500 samples. For the manufacture of plasma derivatives, the product license application involves the manufacturer's (organization's) name; the establishment name; procedures for determining donor suitability including medical history, examination by physician, laboratory testing, methods of preparing the venipuncture site, and collecting the plasma; methods to prevent circulatory embolism and to assure return of red cells to the proper donor; minimum intervals between donation and maximum frequency of donation; techniques for immunizing donors; laboratory tests of collected plasma; techniques of preparing source plasma and storing it; methods to ensure proper storage conditions and identification of units; label control systems; and shipping conditions and procedures. Blood banks and plasma derivative manufacturers must submit a report annually to the FDA indicating which products are collected, tested, prepared, and distributed. Other Required Licensure Blood banks are subject to several other requirements or licensure systems in addition to those of the FDA. Because blood banks carry out testing on human material that is in interstate commerce, and because they provide services to Medicare and Medicaid patients, they must comply with the Clinical Laboratories Improvement Act of 1988. Several states also require that blood

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HIV and the Blood Supply: An Analysis of Crisis Decisionmaking banks have a license to operate or provide blood in that state. These licenses usually involve a specific application and inspection. REGULATORY AUTHORITY OF THE FDA Since 1972, the FDA has been the principal regulatory agency with respect to blood and blood products. Its statutory regulatory authority is extensive under the federal Food, Drug, and Cosmetics Act and the Public Health Service Act [codified as 42 U.S.C. § 262]. Compliance with Regulations The FDA depends on the regulated industry for some amount of self-regulation. However, the FDA's enforcement cannot be by self-regulation, and the FDA's General Counsel determines if a violation of legislative mandates constitutes grounds for legal action (Hutt and Merrill 1991) (See Chapter 6, which focuses on FDA's regulation of blood and blood products during the period 1982–1986 when HIV contaminated the blood supply and before the development of a test to detect antibody to HIV, for more information). A formal compliance program for the plasma fractionation industry was established in 1977. The responsibility for annual inspections was transferred from the Bureau of Biologics to the FDA field investigation office (OTA 1985). In addition, there was no ban on commercial collection of plasma at this time because the voluntary donor system could not meet the demand for plasma. To reduce the risks of transmission of hepatitis, source identification (as to whether the donor was paid or volunteer) was required as a federal regulation imposed by the FDA in 1978 for both whole blood and its components. This requirement, however, did not apply to source plasma or derivatives (OTA 1985). In March 1980 a memorandum of understanding was established between FDA and the Health Care Financing Agency (HCFA) for coordination of the inspection of blood banks and transfusion services. The FDA exempted all transfusion services and clinical laboratories that are regulated by HCFA under Medicare [45 Federal Register 64,601; September 30, 1980]. HCFA adopted the FDA's blood regulation to assure uniform and efficient regulation of these facilities.

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HIV and the Blood Supply: An Analysis of Crisis Decisionmaking Recall Policy The FDA's recall authority lies within the Public Health Service Act under the Biologics section [21 C.F.R. Part 7]. The FDA can issue a mandatory injunction to place the blood bank back into compliance with the regulations (Dubinsky, Falter, Foegel interviews). The FDA's Regulatory Procedures Manual requires CBER's technical staff to prepare a health hazard evaluation of a product before a recall action is initiated (FDA 1988). (A less formal discussion of recall appears in Chapter 6 and focuses on FDA's regulation of blood and blood products during the period 1982-1985 when HIV contaminated the blood supply and before the antiviral HIV test was developed.) A recall is a method for removing or correcting marketed products that violate the laws administered by the FDA. The recall methods provide efficient and timely protection to the consumer, especially when a product has been widely marketed. Voluntary recalls may be undertaken at any time on the initiative of manufacturers to carry out their responsibility to protect the public health. The recall process is usually a voluntary action taken by a firm to remove a product from the market and may be taken as a result of FDA findings during inspections, reports from consumers, or scientific data indicating a risk (OTA 1985). If the firm decides against market withdrawal, the FDA can seize the product. A market withdrawal is when a firm voluntarily removes a distributed product which involves a minor violation for which the FDA would not initiate legal action or which involves no violation. Requested recalls are initiated in response to a formal request from the FDA (FDA 1988). It is FDA policy that a recalling firm has the responsibility to determine whether the recall is progressing satisfactorily through the use of effectiveness checks. Because each recall is unique and requires its own strategy, the FDA reviews and/or recommends the firm's recall strategy and will develop its own strategy based on the agency's hazard evaluation and other factors, such as type or use of the product. The recall strategy is separate from, and not tied to, the class of recall selected (FDA 1988). Recall classification is a numerical designation assigned by the FDA to a product recall to indicate the relative degree of health hazard presented by the product being recalled. There are three classes of recall: Class I is defined as situations in which there is a strong likelihood that the use of, or exposure to, a violative product will cause serious, adverse health consequences, or death. Class II is defined as situations in which the use of, or exposure to, a violative product may cause temporary or medically reversible adverse health consequences or where the probability of serious adverse health consequences is remote.

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HIV and the Blood Supply: An Analysis of Crisis Decisionmaking Class III is defined as situations in which the use of, or exposure to, a violative product is not likely to cause adverse health consequences. Once the recall has been classified, FDA determines the depth of the recall, which depends upon the product's degree of hazard and the extent of distribution. The recall strategy will specify the level to which the recall should extend as follows [see 21 C.F.R. § 7.45]: consumer or user level, which may vary with the product, including any intermediate wholesale or retail level; retail level, including any intermediate wholesale level; or wholesale level. The FDA issues a warning to alert the public that a product is being recalled and presents a serious hazard to health. This is usually reserved for urgent situations where other means for preventing the use of the recalled product may appear inadequate [21 C.F.R. § 7.45]. The FDA also surveys and monitors recall actions for all biologics by following up to make sure that the recall message (i.e., a letter to the manufacturer) was received and acted upon. The FDA can implement stronger enforcement actions if the manufacturer is not acting in accordance with the recall. However, there must be scientific and medical evidence to justify stronger enforcement actions such as a court injunction or product seizure. FDA staff must present evidence to the FDA General Counsel and the Department of Justice on the necessity of such an action (Dubinsky, Falter, Foegel interviews). SUMMARY The nation's blood and plasma are collected by two distinct systems that are based on different donor sources and produce different products. The blood segment of the collection system is primarily not for profit, the plasma segment is primarily for profit. The federal government regulates blood banking, monitors the safety and efficacy of blood products, and promotes research on blood diseases. Both systems are regulated by the FDA in a similar manner, although the specific requirements differ because of differences between blood and plasma products. Since the period 1982–1986, it appears that the number of units of whole blood collected in the United States has stabilized or slightly decreased. It also appears that the substantial increase in the collection of autologous blood that occurred during recent years is slowing. There is a slight decrease in the number of community blood centers and an increase in the average number of units collected, implying that the decrease in the number of centers may be due to

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HIV and the Blood Supply: An Analysis of Crisis Decisionmaking mergers. Presently, members of the American Association of Blood Banks account for almost all blood collected in the United States. The number of AABB institutional members who collect blood has increased and those that transfuse blood has decreased. Because this could reflect the changing membership of the AABB, it is not proper to extrapolate these observations to changes in the blood collection or transfusion community. Membership in the Council of Community Blood Centers has increased substantially during the past decade. It is not possible to provide accurate estimates of the amount of plasma or derivatives produced because this is proprietary information. There has been an increase in the kinds of plasma derivative products during the past decade. There has also been an increase in the number of plasma derivative manufacturers during the past decade. Although several companies that produced plasma derivatives in the early 1980s no longer do so, other companies have begun the production of plasma derivatives. REFERENCES American Blood Resources Association. Materials submitted to the Institute of Medicine; 1994. Anderson, K. The Economics of Importing vs Collecting. In Adequacy of the Blood Supply, Council of Community Blood Centers conference proceedings; Clearwater, Florida. February 18, 1990. Blakestone, M.S. Fractionation. Plasmapheresis, vol. 5, 1994. Centers for Disease Control. Morbidity and Mortality Weekly Report , July 3, 1981. Centers for Disease Control. Morbidity and Mortality Weekly Report , July 16, 1982. Centers for Disease Control. Morbidity and Mortality Weekly Report , March 20, 1987. Centers for Disease Control. Morbidity and Mortality Weekly Report , December 18, 1987. Centers for Disease Control. HIV/AIDS Knowledge and Awareness of Testing and Treatment—Behavioral Risk Factor Surveillance . Morbidity and Mortality Weekly Report, vol. 40:704, 1991. CDC, HRSA, and MCHB. Minimal Data Set for Risk Reduction; 1991, 1992, 1993. Chorba, et al. Changes in Longevity and Causes of Death among Persons with Hemophilia A. American Journal of Hematology, vol. 45, 1994. Food and Drug Administration. Policy and Guidance Handbook for Advisory Committees, 1994. Food and Drug Administration. Regulatory Procedures Manual, May 16, 1988. Fratantoni, J., Food and Drug Administration, Division of Hematology. Presentation to Committee, May 16, 1994. Gallup Organization. Attitudes of U.S. Adults Towards AIDS and the Safety of America's Blood Supply. Princeton, New Jersey, 1991. Hagen, Piet J. Blood: Gift or Merchandise? New York: Alan R. Liss, Inc., 1982.

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HIV and the Blood Supply: An Analysis of Crisis Decisionmaking Hoffman, et al. (editors). Hematology: Basic Principles and Practice (second edition). New York: Churchill Livingsone, 1994. Hutt, Peter, and Merrill, Richard. Food and Drug Law: Cases and Materials . Westbury, New York: The Foundation Press, Inc., 1991. Institute of Medicine, Committee to Study HIV Transmission Through Blood Products. Transcript of Public Meeting, September 12, 1994. Institute of Medicine. Food and Drug Administration Advisory Committees . Washington, D.C.: National Academy Press, 1992. Lipton, K. Blood Donor Services and Liability Issues Relating to Acquired Immune Deficiency Syndrome. Journal of Legal Medicine, vol. 7(2), 1986. McCullough, Jeffrey. The United States Blood Collection System, 1995. Office of Technology Assessment. Blood Policy and Technology Washington, D.C: U.S. GPO, OTA-H-260; January 1985. Scott, E.P. Why My Blood Center Imports. In Adequacy of the Blood Supply, Council of Community Blood Centers conference proceedings, Clearwater, Florida, February 18, 1990. Smith, Peter, and Levine, Peter. The Benefits of Comprehensive Care of Hemophilia: A Five-Year Study of Outcomes. American Journal of Public Health, vol. 74(June), 1984. U.S. General Accounting Office [report to Congress]. Problems in Carrying Out the National Blood Policy. Washington D.C.: General Accounting Office, March 7, 1978. U.S. Senate, Committee on Labor and Human Resources, Subcommittee on Health and Scientific Research . Hearing: Oversight on Implementation of National Blood Policy, June 7, 1979. Wallace, E.L., et al. Collection and Transfusion of Blood and Blood Components in the United States. Transfusion, vol. 33, 1993. Westfall, Pamela. Hepatitis, AIDS and the Blood Products Exemption from Strict Products Liability in California: A Reassessment. Hastings Law Journal, vol. 37(6), (1986).

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