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Overview of Regulatory and Policy-Making Procedures in Blood Banking



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Blood Banking and Regulation: Procedures, Problems, and Alternatives I Overview of Regulatory and Policy-Making Procedures in Blood Banking

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Blood Banking and Regulation: Procedures, Problems, and Alternatives FDA Policy and Regulation Michael Beatrice The Food and Drug Administration (FDA) is presently re-examining its regulatory mechanisms in an effort to do more with less. At the same time, matters relating to blood products and blood services are under intense scrutiny by the public. The discussion of regulatory alternatives is therefore quite timely. THE REGULATORY MANDATE The Center for Biologics Evaluation and Research (CBER) is that part of FDA responsible for regulating blood, plasma, and other biological products such as banked human tissue, somatic cells, stem cells, vaccines, allergenic products, and various biological therapeutics. Recently, the Blood and Blood Components Review Program was reorganized by combining the Division of Blood Product and Establishment Applications and Review Policy with the Division of Blood Collection and Processing. This change, accomplished in February 1994, was intended to streamline the review process. CBER operates on the assumption that the public—including the scientific and the professional public—expects more than a passive regulatory bureaucracy. This philosophy and the involvement that CBER has with various components of the blood services complex have made the center a more effective partner in bringing about constructive change and regulation. Regulation should be a thoughtful blend of medical needs, statutory authority, and public expectation. When logic and scientific thinking indicate that there is a need for change, it is the responsibility of the center to find a mechanism to bring about that change. Protection of the public health requires active facilitation, as well as the more traditional restrictive components of regulation. The availability of blood and new and improved blood products, for example, is fully as important as the elimination of poor practices in processing and manufacture. If FDA is to work effectively, it must understand the need for productive interactions with many groups in translating basic scientific data into medical and manufacturing practice.

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Blood Banking and Regulation: Procedures, Problems, and Alternatives REGULATORY MECHANISMS CBER has a number of tools available to it to pursue its mission. One of them is the technical workshop, a natural outgrowth of scientist-to-scientist communication that can result in the issuance of guidelines by FDA for the industry. Recent technical workshops have been on topics of gene amplification technology, to close the window of human immunodeficiency virus infectivity; hemoglobin substitutes; computer validation of blood quality assurance; evaluation of the interim regulations for banked human tissue; and viral inactivation methods to reduce infectivity in plasma products. Additional workshops being planned cover blood licensing and methods of leukocyte reduction in blood components. In these workshops FDA expects to receive input from the industry on regulatory issues, as well as to educate the industry about its standards and guidelines. Another mechanism is the advisory committee, which often is of use in assisting the agency in reaching a regulatory decision. As of January 1995, there were four such advisory committees, each of which comprised physicians, scientists, biostatisticians, and others. The committees provide scientific and medical opinions, and elicit for the agency's consideration public comment on the safety, effectiveness, and appropriate use of the products under CBER's jurisdiction. Several methods of providing regulations and guidance are available. They range from proposed formal regulations, which have their origins with the publication of a notice and invitation to comment in the Federal Register, to the issuance of guidelines and ''points to consider,'' which are documents for the more rapid dissemination of current information. Regulations are binding on both FDA and the industry. Guidelines may be binding if they are recognized as industry standards. "Points to consider" are always regarded as draft documents, subject to revision as additional comments are received. A related mechanism that is also used to indicate agency practice and expectations the is the use of recommendations, which are usually in the form of memoranda to manufacturers. Although these memoranda are not regulations, they are based on regulations and may be issued when necessary as interpretive or explanatory documents to achieve rapid communication with the industry.

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Blood Banking and Regulation: Procedures, Problems, and Alternatives LEGAL AUTHORITIES The authority under which blood and plasma are regulated has changed over the years. Today's laws regulating drugs and biological products (biologics) are administered in a coordinated manner, even though they were drafted, passed, and implemented separately. Among the earliest were the Biologics Control Act of 1902, also called the Virus, Serum and Toxins Act, and the Pure Food and Drugs Act of 1906, which established purity standards for food and drugs. Because early vaccines and antitoxins were then administered by direct injection, as compared with drugs, which were largely ingested, legislation related to biologics occurred earlier and was stricter than that for drugs from the outset. The production of biologics requires a licensing process, as it did in 1902 and so does today. With licensing came inspections. In 1902 licensed establishments were inspected by scientists and medical officers from the National Hygienic Laboratory, the forerunner of the present National Institutes of Health (NIH). Today, biologics are also defined as drugs. Therefore, when the biological authorities joined FDA in 1972, all of the provisions of the federal Food, Drug and Cosmetic Act (FD&C Act) became operative. Having the authority to administer both the FD&C Act and the Public Health Service Act (PHS Act) now gives FDA great flexibility and scope. The laws dealing with food and drags originally dealt only with purity, not with safety and efficacy. The drags act was strengthened in 1938 with the birth of the federal FD&C Act, which included safety along with purity. The ensuing years saw consolidations and reorganizations. In 1944 the Virus, Serum and Toxin Act was consolidated with other laws into the PHS Act; and in 1948 biologics regulation was focused in the new National Microbiological Institute. By that time the first blood bank, the Philadelphia Blood Bank, had been licensed, and biologics authorities embarked on the licensing of whole blood and blood derivatives. In 1955 the responsibility for biologics regulation was transferred from the National Microbiologics Institute (now the National Institute of Allergy and Infectious Diseases) to an independent division of the called the Division of Biologic Standards. REGULATION AND ENFORCEMENT AT FDA The Division of Biologic Standards, the DBS as it was known, was transferred to FDA in 1972 and became the Bureau of Biologics. It has remained in FDA ever since, with occasional variations in its size, structure, and affiliations. Today it is an organization with more than 800 scientists, medical officers, and support personnel. Its three offices for product review

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Blood Banking and Regulation: Procedures, Problems, and Alternatives have full authority to review products, from the investigational stage through marketing. The Office of Blood Research and Review currently has a staff of 105 organized into three divisions: the Division of Transfusion Transmitted Diseases, the Division of Hematology, and the Division of Blood Applications. In an earlier day, when the number of licensed blood banks was less than 150 and antibody identification panels were considered high technology, the regulatory climate could best be described as relaxed. Relationships with manufacturers, including blood bank personnel, were professional but collegial. As one commentator observed, "It is not surprising that . . . [being] led by medical personnel whose primary mission was public health rather than law enforcement, a laboratory of blood and blood products of the Division of Biologic Standards carried out the administration of biologic law in the manner of communication among physicians." This environment changed dramatically with the first prosecution of an individual in a commercial blood bank in 1962. The responsible head of the blood bank was found guilty of falsification of records, mislabeling, and adulteration and was permanently barred from practicing blood banking in any licensed facility. The Justice Department at the time elected to prosecute the case under both the drug and the biologies statutes, since prior to that time the courts had held that blood was not a biological product because it was not enumerated specifically in the PHS Act. In 1973 the PHS Act was amended to include blood explicitly. The more frequent administrative actions against a license include revocation or suspension. A license may be revoked at the request of the licensee for various reasons such as the discontinuation of the manufacture of the product. In instances in which manufacturers waive the opportunity for a hearing and request revocation, the revocation is without prejudice. Licenses may also be revoked for cause, such as a failure to allow FDA access to facilities, failure to report in advance significant changes to products or facilities, failure to conform to applicable standards in the license, changes in the manufacturing methods that require a new showing, or producing a licensed product that is not safe and effective for all of its intended uses. The agency may initiate a revocation in either of two ways. It may issue a notice of intent to revoke, which allows a firm the opportunity to demonstrate or achieve compliance within a reasonable period of time. Or the agency may inform the firm of its intention to move directly to revocation, without allowing time for the firm to demonstrate or achieve compliance. The latter course is usually indicated when the violations are considered willful, such as intentional record falsification. Notices of intent to revoke have been issued for documented, repeated significant variations from good manufacturing practices after prior warnings

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Blood Banking and Regulation: Procedures, Problems, and Alternatives have already been given. FDA may also suspend a license if the Commissioner has reason to believe that one or more grounds for license revocation exists and if a danger to health exists. In such a case the license is immediately suspended, preventing the products from being shipped interstate. Another remedy available to the agency is the voluntary recall, which is used for products in violation of the laws administered by FDA. Recalls may be initiated by manufacturers or distributors or at the request of FDA. FDA-requested recalls are usually reserved for urgent situations, for example, when a firm refuses to undertake a recall requested by FDA, when FDA has reason to believe that a voluntary recall would not be effective, or when violations are continuing and it is necessary to seize the product. A more radical remedy is a seizure, a civil action taken against a product designed to remove it from the market quickly. Products are not seized without prior warning unless there is documented harm to the consumer from their continued use. Similarly, an injunction may be requested from a court to stop or prevent a violation of the law and to correct the conditions that caused the violation to occur again. Appropriate prior notice is required, and the injunction is generally sought only after the agency comes to believe that no other steps will stop the continuing violation. Other types of regulatory actions can follow from inspections of manufacturing facilities. Again, biologics facilities are licensed under authority of the PHS Act, and since they are also drugs, the facilities that manufacture them are also inspected under the authority of the FD&C Act. A preapproval or prelicense inspection is conducted prior to the approval of a facility. Once approved, each facility is inspected on a regular basis thereafter. Since 1988, the inspections have been annual. The results of the inspection, including observations, deficiencies, and violations, are given to the individual responsible for the facility—usually the "responsible head." The report lists the observations that are significant enough to require a response or a corrective action. If the observations are of sufficient magnitude or if they continue after substantial notice has been given, the agency may issue a warning letter specifying the violations and threatening additional legal action if the problems are not addressed within a short time, usually 30 days. Pre-approval inspections are conducted by Center personnel experienced in the review of applications for blood processing facilities. The postapproval annual inspections are done by personnel in the field.

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Blood Banking and Regulation: Procedures, Problems, and Alternatives ENSURING BLOOD SAFETY AND AVAILABILITY IN THE FUTURE The future of blood safety and availability lies at least partly in technical innovation. Advances in testing, such as gene amplification, may yield better sensitivity. Hemoglobin-and non-hemoglobin-based blood substitutes may also be developed, as may recombinant and other molecular techniques for producing substitutes for products now derived from blood. Better methods of evaluating donor safety and recruitment are also being investigated, and as important as scientific advances are, there may be even more potential in donor recruitment and systems efficiency. From a regulatory perspective, strategies must be developed by FDA and industry to provide quality assurance, to prevent errors and accidents, and to ensure conformance with legal requirements without losing the identity of blood banks as both a needed medical service and as manufacturers of biological products. This will require the development of more meaningful partnerships between the federal government and the private sector and between the public and members of the health professions.

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Blood Banking and Regulation: Procedures, Problems, and Alternatives CDC Recommendations Lyle Petersen CDC'S MISSION The mission of the Centers for Disease Control and Prevention (CDC) is to be the national leader in disease prevention and control in the United States. It serves this mission partly through public health-related research, facilitated by a unique integration among epidemiology, statistics, and laboratory science. That research provides the basis for CDC's voluntary guidelines and recommendations. CDC also provides consultation and assistance to federal agencies, state and local health departments, other nations, and international agencies. This consultation and assistance function has been notable in the blood arena, where CDC has provided data and expert opinion to the Food and Drug Administration (FDA). EFFECTIVENESS OF CDC The influence that CDC has in national health policy can be attributed to several factors. First, CDC is not a regulatory agency and has no regulatory authority, even though it does have a public health mandate. Thus, the only way that CDC can exert influence is to build consensus. Accordingly, the emphasis is on data-based decision-making and an intense effort at consensus building as the basis for its recommendations. Second, CDC enjoys a strongly positive public perception. Third, it has developed the ability to disseminate data and recommendations rapidly through scientific publications and, more importantly, through the Morbidity and Mortality Weekly Report (MMWR).

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Blood Banking and Regulation: Procedures, Problems, and Alternatives RESEARCH ON HIV Although many of CDC research efforts concentrate on the human immunodeficiency virus (HIV), they are applicable to other transfusion-transmissible diseases as well. In one such interview-based study funded by CDC, HIV-seropositive donors at 20 blood centers are interviewed for HIV risk factors, their motivations for donation, and other behavioral characteristics. CDC has also funded a national database with information from 19 American Red Cross blood centers, including all infectious disease marker, demographic, and donation history data. These investigations have proven vital for studying the risk of HIV transmission by transfusion. Another study of seroconverting blood donors has helped to define the "window period of infectivity. These activities occur in conjunction with ongoing investigations of disease outbreaks, including individual transfusion-associated instances of hepatitis as well as HIV. Internationally, through a cooperative agreement with the U.S. Agency for International Development, CDC investigates the degree and quality of blood screening in other countries and assesses the feasibility of recruiting low-risk donors and developing methods for rapidly evaluating blood safety and transfusion practices. HOW CDC AFFECTS POLICY In addition to its formal recommendations and published policies, CDC influences policy regarding blood safety in a number of ways. One is the collection and publication of scientific data from studies such as those just described. Such data can have a significant impact, particularly when they are presented to venues such as the Blood Products Advisory Committee or when they become part of the CDC's congressional testimony or expert opinion to congressional staff. For example, largely on the basis of surveillance data on HIV type 2 (HIV-2) presented at the Blood Products Advisory Committee, FDA decided to defer HIV-2 screening until the HIV-1/HIV-2 combination screening enzyme immunoassay was licensed. CDC also supports research in public health intervention, much of which directly affects transfusion medicine. For example, HIV counseling and testing sites were funded by CDC in 1985, partially to dissuade HIV-positive people from going to blood centers to be tested.

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Blood Banking and Regulation: Procedures, Problems, and Alternatives FORMAL RECOMMENDATIONS There is no set formula for issuing formal recommendations, although there are some common steps. The first is to identify the problem. CDC has a national mandate to conduct infectious disease surveillance. State and local health departments and other agencies report unusual disease occurrences, particularly those that involve multiple states. Thus, CDC can rapidly identify large or unusual public health problems and, if appropriate, conduct an epidemiological study. One recent blood-related example was the matter of idiopathic CD4+ T-lymphocytopenia (ICL). Once the potential problem was identified, CDC acted as a convener of transfusion experts and other relevant scientists to discuss it and implemented a surveillance system. Occasionally, CDC will create interagency task forces within the public health service, such as the AIDS Executive Task Force which coordinated many of the early AIDS activities. These groups can then act as the sites for policy formulation. Once the relevant information is gathered, recommendations are issued in draft form. CDC then tries to achieve consensus on the draft recommendations by, for example, hosting a meeting of experts and other relevant parties. A draft copy of the consensus is often sent to various constituency groups, and the draft recommendations are published in the Federal Register, particularly if the issue is one with a high profile. Public meetings may be held to discuss the issue further. A final recommendation may then be made and may be published in MMWR or in a scientific article. (The advantage of MMWR is that CDC can disseminate the recommendation and background information within 2 days.) The recommendations concerning donor screening made and published in MMWR prior to 1985 were formal recommendations by the U.S. Public Health Service, although notice was given that there was not a full consensus about them. Other recommendations have addressed HIV antibody testing of blood and plasma, including topics such as interpretive criteria for Western blots, recommendations for screening, and what to tell and what not to tell a person who has been tested. Other recommendations concerning phlebotomy and laboratory procedures have been issued, such as universal precautions.

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Blood Banking and Regulation: Procedures, Problems, and Alternatives characterization. Surely if these organizations had not worked together the lawsuits would have claimed that each was irresponsible, going its own direction rather than working together to attack the problem. Joint statements are no longer issued, but the four organizations still meet to discuss from time to time policy issues and to identify areas where they can work together and can engage in useful dialogue with FDA, CDC, and others in an effort to keep their activities moving in concert. Typically, there will be a liaison from CCBC on the important committees of AABB, as there will be from the American Red Cross and, where appropriate, ABRA. CCBC's scientific/medical/technical committee frequently brings individuals from FDA to speak at its meetings, again, to ensure that there is effective dialogue. OTHER STANDARDS AND GUIDELINES In addition to AABB standards, the American Red Cross Blood Service Directives can be significant for other blood centers as well. ABRA, too, has recently developed a certification program—the Quality Plasma Program—to ensure that the manufacturers of source plasma adhere to a certain standard of quality. Generally, however, ABRA has not set standards. Plasma collection has a smaller number of standard operating procedures. Because plasma collection is dominated by larger manufacturers, with their responsibility for ensuring the quality of the source material, these firms' actions tend to be the origin of standards as they are approved by FDA. ABRA has had a formal FDA liaison committee for a number of years. This committee has been successful in improving the relationship between plasma collectors and regulators. In 1989 or 1990 AABB followed suit and established such a committee for the blood collecting part of its activity. CCBC and the American Red Cross also participate, so that active liaison occurs from both the blood and the plasma portions of the blood banking community. The College of American Pathologists (CAP) also conducts laboratory accreditation programs and surveys. These are of greater importance to hospitals than to blood banks. Almost all hospital transfusion services participate. For many years CAP has had deemed status with the Joint Commission on Accreditation of Health care Organizations for conducting the laboratory portion of hospital accreditation. CAP inspections therefore have great importance for hospitals that perform transfusion activity. CAP also conducts the surveys that are of great importance to CLIA certification, which blood banks also must have (until such time as FDA makes any changes). Like AABB, CAP uses volunteer inspectors, and like AABB, CAP has been

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Blood Banking and Regulation: Procedures, Problems, and Alternatives having more trouble in recent years finding adequate numbers of volunteers to conduct the inspections. Overall, self-regulating activity has certainly been an active area for blood banks. The emphasis is on adherence to standards and a regulatory mind-set on the part of the people who work in this field. The volunteer organizations believe that they do a good job of self-regulating and would like to emphasize that role and its importance as much as possible. It is an activity that has gone on more recently in concert with and in cooperation with federal regulatory activities to ensure that they are consistent.

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Blood Banking and Regulation: Procedures, Problems, and Alternatives Opportunities and Venues for Dialogue Merlyn Sayers THE CHANGING CLIMATE IN BLOOD BANKING The climate within which alternative regulatory opportunities are being discussed has changed recently. The federal agencies that have an impact on decisions relating to blood safety are all agencies of the U.S. Public Health Service, and as such, they are headed by political appointees. Most political appointees are subject to the influence of those who appoint them. Agency budgets largely depend on the goodwill of the members of the U.S. Congress. What is the character of that goodwill today? Republicans in the House of Representatives want a 6-month moratorium on federal regulatory activity. The Republican ''Contract with America'' included proposals to require federal agencies to go through an elaborate process not only of risk assessment but also of cost-benefit analysis before any future rules or regulations are promulgated. This is very different from what prevailed until even quite recently. Other influences have also changed the climate in blood banking. There is a national blood shortage of alarming proportions. A recent American Red Cross press release reported severe shortages in 10 major cities, including Boston, Los Angeles, and Washington, D.C. The Red Cross reported that some 300,000 additional blood donations were required in the next month for the national inventory to be rendered safe. The climate is also a little different on the legal front. Although litigation with regard to transfusion-transmitted AIDS may be in the eclipse, lawsuits are being brought elsewhere. In Australia, for example, individuals have brought lawsuits that have to do with the tardiness of the Australian Red Cross in introducing surrogate testing for non-A, non-B hepatitis. That retrospection may be visited upon U.S. blood programs in the not too distant future. The Canadian Red Cross has recently undergone a painful and thorough outside review investigating inadequacies and inefficiencies in its performance. In the United States, the Food and Drug Administration (FDA) recently

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Blood Banking and Regulation: Procedures, Problems, and Alternatives uncovered a whole range of flaws in the quality assurance programs of a major manufacturing company particularly with regard to the specificity of diagnostic products that are in wide use in blood programs. FDA believed that the rate of false-positive results in these diagnostic products was unacceptable, and because of the deficiencies found during FDA inspections, the agency has withheld approval of some of the company's newer diagnostic devices. There are some bright lights, however. In January 1995 FDA held a public meeting to hear comments on the agency's regulations for blood products and establishments. The meeting is part of FDA Biologics Regulatory Review Project that started in June 1994 with the publication of documents reviewing general biologics and regulations for blood products and blood establishments. According to FDA, the purpose of the public hearing is to help the Center for Biologics Evaluation and Research to identify regulations that are "outdated, burdensome, inefficient or otherwise unsuitable or unnecessary in the interests of regulation. VENUES FOR DIALOGUE Opportunities for dialogue with FDA certainly exist. The process open to written public comment is flawed, as is anything that must move through the Federal Register. Even items that are a high priority can take 3 years to move through the system. That process is too lengthy for public influence to be of any real benefit. The national blood banking organizations are themselves venues for dialogue. They have annual meetings, they have standards committees and scientific, medical, and technical committees, and they are platforms for dialogue between blood banking organizations and FDA. The American Association of Blood Banks (AABB) teleconferences are a good example. AABB organizes these teleconferences, linking as many as 80 or 90 blood banks around the country and discussing topics pertinent to blood banking. THE BLOOD PRODUCTS ADVISORY COMMITTEE FDA initiated advisory committee systems in the early 1970s to provide technical assistance related to the development and evaluation of drugs, biologics, and medical devices. The system was also designed to lend credibility to the agency's decisions and its decision-making processes. In addition, it was a means by which FDA could provide a forum for public discussions of controversial issues. In 1976 the Fountain Committee believed that the advisory committees might be too independent of FDA, and might be

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Blood Banking and Regulation: Procedures, Problems, and Alternatives subject to the influence of drug sponsors. Curiously, by 1990 the concern was exactly the opposite. It was claimed by some that advisory committees were excessively influenced by FDA. In fact, however, the Blood Products Advisory Committee (BPAC) has always striven to be an independent source of information. Still, there was a perception that the BPAC's invited experts were under the heel of FDA. The high stakes associated with FDA decisions means that parties disappointed by the agency's action have strong incentives to charge that the independence of advisory committees is compromised by undue FDA influence. Although incorrect, the criticism was nonetheless addressed in a number of ways. For one, FDA position papers that had been distributed to BPAC members in the past were discontinued, largely because, some suspected, a position paper would be evidence of the undue influence of FDA over the committee. The committee is also reminded that everything must be conducted in a fishbowl. There are no preliminary discussions among committee members and FDA. There is no discussion among committee members themselves prior to BPAC meetings. This has left the committee on some occasions a little uncertain as to exactly what the issues are, what FDA's position is, and in what area FDA best needs advice. BPAC has now maintained an unblemished reputation, although it may have been earned at the expense of the Committee's being able to give good and sound advice to FDA. Although the advice of the advisory committee is not binding on FDA, its recommendations are widely regarded as a predictor of agency action. As a result, FDA advisory committees have become highly visible to the public, the U.S. Congress, and to the media. Some of the issues considered by BPAC in recent years include the following: Yersinia. Combination tests for HIV-1 and HIV-2. Reducing red blood cell shelf-life. Lookback for human T-lymphotropic leukemia virus types 1 and 2. Recombinant factor VIII. Use of "fresh" blood. RIBA and reentry procedures. Internal controls for antibody screening tests. Bacterial contamination of platelets. Idiopathic CD4 lymphocytopenia syndrome. Postdonation "call back." Hepatitis C virus testing relative to screening of plasma for fractionation.

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Blood Banking and Regulation: Procedures, Problems, and Alternatives OTHER VENUES FOR DIALOGUE Other venues for dialogue include events such as single topic conferences. "Closing the HIV Window" was one recent conference topic. Private-sector conferences are also conducted, although they are sometimes sponsored by manufacturers who have an assay to promote or a product that they want to popularize. Thus, not all conferences are scientific in the fully unbiased sense. The Institute of Medicine forums and the regional blood banking organizations may also be included as other venues for dialogue. Likewise, meetings of other national organizations like the Hemophilia Foundation, College of American Pathologists, the American Society for Apheresis, and the American Society of Hematology may also be opportunities for dialogue among scientists, blood bankers, and regulators. In addition, alternative venues exist. The media is one of those venues, but good news does not earn Pulitzer Prizes. Bad news carries more credibility. The courts of law are venues as well. Most states regard blood as unavoidably unsafe, but blood programs are still vulnerable when it comes to acts of negligence. Hosts of lawsuits related to cases of transfusion-transmitted AIDS have been filed. The result of some of these have been that blood programs have added to their standard operating procedures practice for which there may be very thin evidence but which are done to avoid the risk of litigation. THE VOICE OF BLOOD PRODUCT CONSUMERS One of the criticisms of BPAC has come in the form that the committee represents a gang of cronies. Members of Congress have asked, "Where are the consumers on this committee?" implying that if consumers were represented on the committee, the right decisions would be made. Appointment to BPAC has not exempted its members from possibly requiring a transfusion, nor has it exempted their family members from running the risk of requiring medical interventions, oncology treatment, or coronary artery bypass surgery. It is a hollow criticism to say that the decisions do not reflect consumer input. Everyone on BPAC is, will be, has been, or could be a consumer of the products on which the committee is asked to cast its opinions. Editor's Note: During a later discussion of this topic, Thomas Zuck made the following point: "One difficulty is that we do not know who is going to be a blood recipient. One of four of us will be and some of us already have been. However, except for a few defined groups with hereditary diseases such as hemophilia, the rest are simply not known in advance. The American Blood

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Blood Banking and Regulation: Procedures, Problems, and Alternatives Commission struggled with this issue of who can represent consumers, and we continue to straggle with it. But we are all consumers. It is folly to assume that we do not worry about consumers." ATTENDING TO THE DONOR The more important question is the more general one: "Who needs to be heard? Similarly, patients needing transfusions certainly need to be heard. Patients needing clotting factor concentrate need to be heard, as do blood bankers and manufacturers. The individuals at the cornerstone of blood banking practice and patient transfusion care nationally, however, not heard. These are the blood donors. Any regulatory revision must take into account this neglected group of individuals. Their support of blood programs is probably at the lowest level that it has ever been for reasons largely related to the effects of regulation, which in a number of different areas penalizes them. They are now subjected to a level of scrutiny that none would have expected 5 or 10 years ago. They are subjected to questioning that is nothing short of an Inquisition. They are subjected to an increasing number of tests. Not only are the tests non-specific, but so are the questions. To see the effect of this nonspecificity on donations, consider what statisticians call "contours of constant probability of inappropriate deferral. The bottom axis of such a contour graph is the specificity of the screening test; on the vertical axis is the number of donations. If the tests have relatively high specificity, for example, 98 percent, an uninfected donor still has a 25 percent chance of deferral after 12 or so donations—that is, deferral for reasons of nonspecificity, not for reasons of true positives. If that test specificity decays down to about 95 percent, that same individual has a 25 percent chance of deferral after only five donations. If those tests and questions were to decay in combination to a specificity of perhaps 50 percent, at that point the donor would have a 90 percent chance of deferral after only four donations. This system thus penalizes the very individual most valuable to the process, namely, the repeat volunteer donor. REGULATORY DIFFICULTIES Where are the problems in regulation today? Regulation is tardy. New regulation cannot keep pace with science, and the blood programs sense that regulation is applied inconsistently. Some blood programs have the impression that the attitude of compliance inspectors is sometimes one of disbelief and a suspicion that the blood programs have something to hide.

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Blood Banking and Regulation: Procedures, Problems, and Alternatives Discussion It was observed during the Forum's discussions that one of the areas in which safety and risk are affected by standards and practice is the medical decision to transfuse blood. Inappropriate transfusion is, or at least adds to, the possibility of transfusion-transmitted disease. The Forum explored briefly how that aspect of the process is or is not regulated. Richard Shapiro: One of the categories of people who should be involved in the discussion are the people who make the decision to transfuse—he physician. The problems of both undertransfusion and overtransfusion exist. Constraining transfusion to appropriate uses needs to be taken into account as well. Toby Simon: AABB, which includes among its members scientists and physicians in various fields, has been developing guidelines for appropriate utilization. A number of programs going back to the mid-1980s have produced publications, teaching aids, and handbooks on the question, in addition to a number of conferences, lectures, and materials. The National Institutes of Health (NIH) has had a role in two ways. One is the consensus development conference, including some on plasma, platelet, and red blood cell transfusions that addressed the indications for transfusion in an attempt to reduce them to the needed number. NIH also conducted, again in concert with other organizations, the National Blood Resource Education Program. There were a number of activities for physicians, including educational materials. It is clear that the most efficient way to prevent a transfusion complication is not to transfuse, but there has also been concern recently about undertransfusion. It is not clear where the balance is in the physician community between risking inappropriate transfusion and withholding a possibly beneficial transfusion. Both may be now occurring in substantial numbers. Unidentified Participant: There are not many data with which to make solid recommendations about when to transfuse. Wide variations in the practice

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Blood Banking and Regulation: Procedures, Problems, and Alternatives suggest that not everyone is doing it correctly, but we do not yet know enough. More research is needed in this area. Toby Simon: Studies with humans are difficult to do and are usually open to methodological criticisms. They do not fare well in the peer review process, and it has been very difficult to get them funded. Elaine Eyster: Many of the transfusions in this country are initiated by house officers, at least in teaching hospitals. Often, the attending physician does not find out about it until after the patient has received the transfusion. Perhaps there should be efforts to work with medical schools and training program directors to develop algorithms for given situations. Thomas Zuck: Many medical schools face the problem of competition, particularly in the senior year—for educational time. Transfusion medicine must compete with everything else; it is extremely difficult to get the hours. Toby Simon: The Transfusion Medicine Academic Awards was an NIH program supported by the AABB, CCBC, CAP and others that was carried out for a number of years. The literature describes the practice of the "just-in-time" consult, in which a physician expert in transfusion medicine is involved immediately on receiving an order. This could be very effective with house officers in particular. The College of American Pathologists does support the effort through its work in the Joint Commission, by their Requirement for Transfusion Committees and Review. But all of these have fallen short of what we want to achieve, however. Arthur Caplan: In many hospitals the transfusion committees are now called "utilization and review committees." That is, a heavy emphasis is placed on guidelines for transfusion within hospitals. Active program utilization review is short of the ideal, but it does exist and is an ongoing activity. It may now be at the point at which most of the business of those committees is the review of transfusions given outside the guidelines. It is not a total vacuum in terms of utilization review and efforts to teach algorithms or standards. Elaine Eyster: We must take the next steps. Transfusion information has not been well disseminated. Most teaching hospitals are not practicing those steps, and are not likely to find it possible to have a knowledgeable advisor available at the time of every transfusion.