4
Product Treatment

INTRODUCTION

Plasma products can be treated by a variety of physical and chemical processes to reduce the risk of contamination from viruses and other infectious agents, thus increasing the safety of their use. Currently available product treatment procedures use physical heat or chemical detergents to virally inactivate plasma products that will be used in medical treatment of clotting disorder diseases such as hemophilia. Owing to a variety of technical obstacles that remain today, there are no effective methods to inactivate viruses present in whole blood or in nonplasma blood components such as cellular blood products (e.g., red blood cells and platelets) used for transfusion purposes.

Shortly after the development of the technology to manufacture antihemophilic factor (AHF) concentrate, it was recognized that blood products carried a substantial risk of hepatitis to their recipients. Although some blood derivative products (e.g., albumin) have been treated with heat to destroy live viruses since the late 1940s, Factor VIII and IX AHF concentrates in the United States were not subjected to procedures of viral inactivation until 1983–1984. In fact, the methods used to manufacture AHF concentrate can also inadvertently concentrate certain viruses, present in the original plasma donation, within the final product preparation. The fact that AHF concentrate is prepared from pooled plasma from thousands of donors greatly increases its risks for transmitting disease.

This chapter describes the development and implementation of treatment methods used to inactivate viruses in AHF concentrate. The events leading to the development and implementation of these methods unfolded over the period from 1970 to March 1983, during which time AHF concentrate became widespread



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HIV and the Blood Supply: An Analysis of Crisis Decisionmaking 4 Product Treatment INTRODUCTION Plasma products can be treated by a variety of physical and chemical processes to reduce the risk of contamination from viruses and other infectious agents, thus increasing the safety of their use. Currently available product treatment procedures use physical heat or chemical detergents to virally inactivate plasma products that will be used in medical treatment of clotting disorder diseases such as hemophilia. Owing to a variety of technical obstacles that remain today, there are no effective methods to inactivate viruses present in whole blood or in nonplasma blood components such as cellular blood products (e.g., red blood cells and platelets) used for transfusion purposes. Shortly after the development of the technology to manufacture antihemophilic factor (AHF) concentrate, it was recognized that blood products carried a substantial risk of hepatitis to their recipients. Although some blood derivative products (e.g., albumin) have been treated with heat to destroy live viruses since the late 1940s, Factor VIII and IX AHF concentrates in the United States were not subjected to procedures of viral inactivation until 1983–1984. In fact, the methods used to manufacture AHF concentrate can also inadvertently concentrate certain viruses, present in the original plasma donation, within the final product preparation. The fact that AHF concentrate is prepared from pooled plasma from thousands of donors greatly increases its risks for transmitting disease. This chapter describes the development and implementation of treatment methods used to inactivate viruses in AHF concentrate. The events leading to the development and implementation of these methods unfolded over the period from 1970 to March 1983, during which time AHF concentrate became widespread

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HIV and the Blood Supply: An Analysis of Crisis Decisionmaking as the standard medical treatment for individuals with hemophilia. Although inactivation of hepatitis viruses was the goal of the first product treatment methods developed to increase the safety of AHF concentrate, review of the history of their development is important to consider for several reasons. First, because the product treatment methods used to inactivate hepatitis viruses also inactivate HIV, their availability prior to 1981 would have minimized, if not prevented, the widespread HIV infection of persons with hemophilia. Second, consideration of the development of viral inactivation methods helped shed light on important aspects of the prevailing scientific, medical, and regulatory environments of the early 1980s. The Committee framed its analysis of the development and implementation of viral inactivation methods of four questions: When did the information that facilitated the development of viral inactivation methods become available? Could the technology to accomplish viral inactivation of AHF concentrate have been developed earlier to decrease the transmission of hepatitis and AIDS? What were the internal and external pressures that influenced the rate at which viral inactivation methods for AHF concentrate were developed and implemented? What was the role of the Food and Drug Administration and the National Institutes of Health in encouraging or supporting research on viral inactivation methods to improve the safety of AHF concentrate? The Committee developed two hypotheses to explain the actions that were taken during the period from 1970 to 1983: Plasma fractionators and other organizations responsible for the safety of blood products did not begin research on viral inactivation of AHF concentrates until the onset of the AIDS epidemic. Hepatitis was viewed as an acceptable risk by the government regulatory agencies responsible for the safety of blood and blood products, the plasma fractionation industry, the physicians who treated the individuals with hemophilia, and the individuals with hemophilia. As a result, little incentive was available to improve AHF product safety through the expeditious development and implementation of viral inactivation technologies. Testing these hypotheses against the evidence gathered through documents and fact-finding interviews, the Committee concluded they were able to reject the first hypothesis but unable to reject the second.

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HIV and the Blood Supply: An Analysis of Crisis Decisionmaking CRITICAL TIME PERIOD: 1970-1983 Two important elements frame the period from 1970 to 1983: (1) the discovery of hepatitis as an infectious agent associated with the use of blood and blood products, and (2) the development of viral inactivation procedures for increasing the safety of AHF concentrate. With respect to both elements, it is important to establish when certain scientific information was available in relation to decisions about blood and blood product safety. Hepatitis The transfer of blood and blood derivatives between humans is considered one of the greatest and most successful therapeutic practices in modern medicine. However, accompanying the development and increased use of blood transfusion practices, there has been a growth in rates of blood-borne diseases. Iatrogenic transmission of hepatitis has a long history dating back to at least the 1880s when vaccination against smallpox, using glycerinated lymph of human origin was occasionally practiced. So-called serum hepatitis (now known to result from hepatitis B infection) was also seen in many individuals who received preparations of yellow fever vaccine that had been stabilized by the addition of human serum. By 1943, hepatitis had been recognized as a complication following transfusion of whole blood and plasma. Supporting evidence accrued during World War II as the constant demand for blood and plasma administration during battle led to the recognition that a serious transmissible illness was affecting large numbers of soldiers following transfusion. Studies conducted in the United States and England following World War II identified two viruses, one with a short incubation period that could be transmitted both orally and parenterally, and the other with a long incubation period and transmissible only parenterally. The identification of two viruses, made in the late 1940s, was confirmed two decades later with the availability of sera to distinguish between the two types of viruses responsible for the distinct clinical presentations (Seeff 1988). The virus causing hepatitis B (serum hepatitis) was discovered in 1965, and the virus causing hepatitis A in 1973. By 1968, a direct test for the presence of an antigenic component of hepatitis B, or HBsAg (hepatitis B surface antigen) was developed and used to detect individuals suffering from active chronic or acute hepatitis infections. Ultimately, a highly effective vaccine to prevent hepatitis B infection became available in 1982; a second generation recombinant vaccine has been available since 1986. An effective vaccine to prevent hepatitis A has recently been developed.

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HIV and the Blood Supply: An Analysis of Crisis Decisionmaking Despite the widespread use of diagnostic tests for hepatitis A and B, a significantly large number of cases of post-transfusion hepatitis continued to be observed. It was then realized, between 1976 and 1978, that other undiscovered agents were responsible for what became known as non-A, non-B (NANB) hepatitis. Hepatitis A was found to be responsible for a transient infection that causes a self-limited disease of mild to moderate severity. A mortality rate of 0.2 percent or less is seen following hepatitis A infection and the infection never becomes chronic. Hepatitis A is commonly transmitted by a fecal-oral route, either the result of person-to-person transmission or ingestion of contaminated food or water. The virus usually appears in the bloodstream during the incubation period and the early acute phase of hepatitis A infection. Transmission by blood transfusion or by contaminated AHF concentrate has also been reported, however, such instances of blood-borne transmission are rare. Hepatitis B (HBV) infection frequently causes a transient infection that in most cases is cleared by the host immune response and leaves the individual immune from reinfection by hepatitis B upon subsequent exposure (i.e., through development of immunity thought to be mediated primarily by antiviral antibodies). However, acute HBV infection can be severe and sometimes fatal (i.e., there is a 0.2–2 percent mortality rate), and a minority of infected persons experience a persistent infection that is associated with progressive liver disease and a type of liver cancer known as hepatocellular carcinoma. Though HBV infection is less likely to be severe, it is more likely to become chronic in young persons, with 90 percent of infected newborns developing chronic infection while only 2–7 percent of infected adults do so. Transmission of HBV principally results from exposure to blood or blood products, although sexual transmission is also common. During the 1960s, up to 10 percent of persons who received massive transfusions acquired HBV infection and more than 80 percent of individuals with hemophilia were infected through their use of contaminated pooled AHF concentrate. In 1977 another virus, the delta hepatitis virus (HDV) was discovered; HDV is an incomplete RNA virus that can be transmitted only in the company of HBV. Infection with HDV can occur either as a co-infection with HBV or as a ''superinfection" in individuals with pre-existing chronic HBV infection. HDV infection is usually severe with complications of fulminant hepatitis and progressive chronic hepatitis. An overall mortality rate of 2–20 percent has been reported. Chronic HDV infections are seen in 1–3 percent of HBV infections and 70–80 percent of superinfections. The transmissible nature of HDV was established in 1980 by transmission of the virus to HBV-infected chimpanzees. The identification of the viruses responsible for the hepatitis syndromes permitted the development of serologic tests to screen blood donors for potential infection and resulted in a substantial reduction of post-transfusion hepatitis B.

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HIV and the Blood Supply: An Analysis of Crisis Decisionmaking During the years 1970-1972, the HBsAg test was required and implemented in all blood and plasma collection organizations. In July 1975, the use of a third-generation test for HBsAg with a greater degree of sensitivity, utilizing radioimmunoassay or reversed passive hemagglutination, was required by the FDA. In 1977, the World Health Organization Committee on Viral Hepatitis adopted the terms hepatitis A for the hepatitis virus transmitted orally, and hepatitis B (HBV) for the virus transmitted sexually and through transfusion of blood or blood products. As a result of the implementation of HBsAg testing during the period from 1972–1975, AHF concentrate testing positive for HBsAg decreased from 25 percent to 3 percent of Factor VIII lots tested by the FDA, and from 67 percent to 2 percent of Factor IX lots tested by the FDA. After 1975, according to Dr. Robert Gerety, chief of the Hepatitis Branch, Division of Blood and Blood Products in the Bureau of Biologics at the FDA at the time, no lots of either Factor VIII or Factor IX submitted to the bureau contained detectable HBsAg; but despite this, the problem of HBV infection following administration of the AHF concentrate would remain serious (Gerety and Barker 1976). By 1975, even though third-generation testing was in practice, some donations of blood or plasma had levels of HBsAg that were below the level of assay detection and HBV-infected donations continued to enter the pools used in the plasma lots. Even though these lots contained undetectable levels of HBsAg, owing to the extraordinary infectivity of HBV, they were still able to transmit the infection to susceptible recipients of the affected blood products. However, in 1976, although 80 percent of individuals with hemophilia were identified as positive for the antibody to hepatitis B (evidence of previous infection with the virus), the majority did not develop clinically apparent hepatitis. The percentage of individuals with hemophilia with chronic HBV infection ranged from 2.5 to 7.8 percent and the percentage of those who had clinically recognizable hepatitis ranged from 6 to 26 percent. Gradually, it was believed by the medical community treating individuals with hemophilia that many adults with hemophilia had developed an immunity to HBV as a result of prior exposure to the virus (Aledort, Dietrich, Levine interviews). Administration of the AHF concentrate to children and adolescents with hemophilia, however, often resulted in clinical and chronic HBV infections (Gerety and Barker 1976). Once screening for HBV markers resulted in the exclusion of HBV carriers in the donor pool, NANB virus was responsible for 80–90 percent of the hepatitis cases. Prospective studies performed in the late 1970s and early 1980s indicated that the incidence of post-transfusion hepatitis (HBV and hepatitis C [HCV]) was 7–21 percent in recipients of blood from volunteer donors (Barker and Dodd 1989). The infectious nature of NANB hepatitis was first established in 1978 by experimental transmission to

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HIV and the Blood Supply: An Analysis of Crisis Decisionmaking chimpanzees. The virus itself was not identified until 1989, and is now referred to as HCV. Following the identification of the etiologic agent of the majority of cases of NANB hepatitis in 1988, the natural history and severity of this infection became better known. In prospective studies, 50–70 percent of persons with acute hepatitis C infection were shown to become carriers of chronic HCV. It is known now that chronic hepatitis C infection is often silent, is one of the major causes of cirrhosis, hepatocellular carcinoma, or both, in the United States, and is a common precipitant of liver failure necessitating liver transplantation. Viral Inactivation of AHF Concentrate Early Methods According to a Department of Health, Education and Welfare Conference on Hemophilia in 1976, research at that time had already begun to develop alternate means, other than testing for HBsAg, of removing HBV from final products while maintaining the therapeutic activity of the clotting treatment. Pilot studies had been undertaken to evaluate two methods of viral removal: solidphase immunoabsorption and polyethylene glycol precipitation. However, results of inoculating chimpanzees with the treated products were equivocal (Barker and Dodd 1989). In 1978, hepatitis continued to present a major risk in the use of pooled plasma products, including fibrinogen, AHF concentrates (i.e., Factors VIII and IX), and Factors II, VII, and X (Trepo, et al. 1978). Two other methods of viral inactivation were also being developed during the 1970s. These methods provided the foundation for most of the subsequent development in this area. First, Dr. Edward Shanbrom, the codeveloper of Factor VIII concentrates, who by this time had left Hyland Laboratories (Baxter Healthcare) and was self-employed, developed a nonionic detergent method for treating plasma before it was fractionated into Factor VIII and the other plasma derivatives (Shanbrom interview). Second, a German pharmaceutical company, Behringwerke, A.G., initiated studies in 1977 on heat inactivation methods for AHF concentrate (Weidmann and Hoechst 1993). Dr. Shanbrom's method required adding a detergent to the fractionation column, and this method was chosen for experimentation because it was known that viruses containing lipid membranes are readily inactivated by detergentinduced disruption of membrane integrity (Shanbrom pers. com. 1995). The application of the inactivation process before the plasma was fractionated, however, would have required relicensure of all the products of fractionation (Bacich, Shanbrom interviews). Although Dr. Shanbrom tried to interest the

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HIV and the Blood Supply: An Analysis of Crisis Decisionmaking various plasma fractionation companies in his detergent process, for several reasons none responded favorably (Shanbrom interview). According to one of the plasma fractionators, they were already involved with heat-treated viral inactivation research, and interrupting these research efforts to begin experimentation on the effectiveness of the detergent method would delay licensing (Bacich interview). There was also a question whether there were sufficient data to support the effectiveness of the detergent process against HBV (Mozen interview). Further, Dr. Shanbrom approached both Armour Pharmaceutical and the federal Centers for Disease Control to test the procedure in chimpanzees to confirm its ability to inactivate hepatitis viruses, but was told that there were too few chimpanzees and that confirming the efficacy of this process was not a priority (Favero 1992). The process used by Behringwerke was (and still is) a pasteurization procedure that requires the heating of AHF concentrate at 60°C for 10 hours, using sucrose and glycine as stabilizers, before lyophilization. Behringwerke's "heat sterilized" Factor VIII was licensed in Germany in May 1981 (Weidmann and Hoechst 1993). Behringwerke claimed (at that time) that the loss of potency or yield (i.e., factor protein) of the treated Factor VIII was approximately 50 percent, but U.S. manufacturers claimed the loss was 90 percent or more according to their internal studies (Feldman pers. com. 1994). The reasons for the discrepancies in the results obtained by different companies in testing this method are not clear. However, owing to the loss of activity resulting from this process, the cost of the Behringwerke product was approximately 10 times that of non-heat-treated concentrate (Feldman pers. com. 1994). Although Behringwerke's pasteurized Factor VIII was used in Germany upon its licensure, the company was simultaneously producing non-heat-treated material; also, Germany continued to import Factor VIII from the United States. The loss of yield due to the application of heat resulted in the need to obtain larger plasma volumes according to testimony from a Behringwerke representative. This led to significant supply problems, as larger plasma volumes were difficult to obtain at the time (Weidmann and Hoechst 1993). In 1981, there was only enough pasteurized product to treat about 50 patients, and in 1982 only 100. In addition, while the Behringwerke pasteurized product was shown to be effective against HBV, it remained unknown whether it was effective against non-A, non-B hepatitis. The heat-treated Behringwerke product was not universally accepted for use among the German hemophilia population for several reasons, including the limited supply. One reason was the belief by some physicians that the stabilizer added to the product during the heating process would also stabilize the virus, hindering full viral inactivation (Feldman interview). There was also a concern about the risk of heat-induced alterations in the structure of the treated Factor VIII preparation (neoantigenicity). Neoantigenicity can lead to the formation of inhibitors, or antibodies, to the altered product after infusion into the patient.

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HIV and the Blood Supply: An Analysis of Crisis Decisionmaking The medical community feared that the formation of such inhibitors to the product would render the patient more difficult to treat effectively (Aledort, Dietrich, Levine interviews). Behringwerke's heat-treated product was also considerably more expensive, and German insurance companies covered its cost only for special circumstances (Weidmann and Hoechst 1993; Federal Minister of Health 1992). Behringwerke initiated testing the pasteurized product for inactivation of NANB hepatitis in 1985, and a successful clinical trial was completed during 1986–1987 (Weidmann and Hoechst 1993). Studies by U.S. Plasma Fractionation Companies There were basically three methods utilizing heat for viral inactivation used by U.S. manufacturers in the early 1980s: (1) In 1979, the Baxter Healthcare company initiated studies on heat inactivation of AHF concentrate using a "dry heat" process. The dry heat process involved the application of heat at a specified temperature and time to the concentrate in the lyophilized (freezedried) state (Persky pers. com. 1995); (2) the "wet heat" process, a term coined by Alpha Therapeutics, involved suspending powder of lyophilized concentrate in heptane solvent and heating at 60°C for 20 hours. Following the heating process, the solvent was removed and the concentrate revialed (McAuley pers. com. 1995); and (3) in liquid pasteurization, Factor VIII, albumin, or other proteins in the completely soluble liquid state were heated with the addition of various stabilizers. By the early 1980s, all of the plasma fractionators had initiated studies on inactivation by application of various amounts of heat for different durations of time (McAuley pers. com. 1995; Persky pers. com. 1995; Leahy pers. com. 1995; Hammes pers. com. 1995). They also began experimenting with the addition of different stabilizers and organic solvents to protect the protein and enhance the heat effect. There was, however, little if any communication between the different manufacturers regarding the results of the ongoing experiments, because of antitrust laws, regulations, and the normal business consideration of competitive advantage (Bacich pers. com. 1994; Feldman pers. com. 1994; Hammes pers. com. 1995). Problems of Viral Inactivation Development As the Behringwerke experience illustrates, to some extent the possibility of using heat to inactivate viruses in AHF concentrate, as used in other plasma derivatives (e.g., albumin), would be accompanied by three major concerns that impeded progress. The first concern was that heat would denature the labile

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HIV and the Blood Supply: An Analysis of Crisis Decisionmaking factor protein to varying degrees depending on the amount and duration of the heat. Denaturing of the factor protein could cause the development of new antigens that would stimulate blocking antibodies (inhibitors) and reduce the amount of active factor protein in the recipients. Subsequently, this would further increase the amount of factor protein required to obtain a normal clotting response. The second concern was the potential additional cost of implementing the process. In addition to the heating process itself, a lower yield of active concentrate would increase the need for plasma, resulting in added cost. Finally, there was a concern about the adverse effects on the patient of a possibly unstable heat-treated product with varying degrees of purity. Higher-purity products, those in which extraneous proteins such as fibrinogen were removed (e.g., the Behringwerke product), were found to be less stable at room temperature after reconstitution, according to the analysis conducted by one manufacturer (Feldman pers. com. 1994). Impact of the First Reported Cases of AIDS in Individuals with Hemophilia One of the purposes of the July 27, 1982, meeting of the PHS Committee on Opportunistic Infections in Patients with Hemophilia was the need to determine if certain blood products, particularly AHF, were risk factors for AIDS (see Chapter 3). The group issued a recommendation to urgently determine practical techniques for decreasing or eliminating the infectious risks from AHF concentrate. Meeting participants discussed several viral inactivation methods that were under study and that a meeting of the FDA's Blood Products Advisory Committee (BPAC) later in the year would discuss and evaluate the various approaches (Foege 1982). During a December 3–4, 1982, meeting of the BPAC there was discussion of a minimal criterion for virus inactivation in high-risk products such as AHF concentrate. Dr. Aronson, the director of FDA's Coagulation Branch in the Division of Blood and Blood Products, described several experimental methodologies, including heat inactivation, inactivation with propiolactone and ultraviolet irradiation, removal by affinity chromatography, antibody inactivation, immunoabsorbence by immobilized antibody, and polyethylene glycol precipitation. Hepatitis B was selected as a marker to determine the degree of inactivation per method because materials and methods were not yet available for NANB. The CDC convened a meeting, held in Atlanta in early January 1983, to which those concerned with blood and blood products were invited (see also Chapter 3 and Chapter 5). The recommendations that stemmed from the meeting, however, made no mention of changing the current usage of AHF

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HIV and the Blood Supply: An Analysis of Crisis Decisionmaking concentrate. On the other hand, it was mentioned that viral inactivation procedures for Factor VIII were on the horizon (Foege 1982). Federal Research Support for Viral Inactivation The National Institutes of Health is the major federal source of funding to support research in areas relevant to health. Within the NIH, the institute with primary responsibility for blood research is the National Heart, Lung, and Blood Institute (NHLBI), and in particular its Division of Blood Diseases and Resources (DBDR) (see Chapter 2). A charge of the DBDR is to support research to improve the quality, safety, and availability of blood and blood products for therapeutic use. Consistent with this charge, the five-year plan published by the DBDR in 1982 identified as a research priority, the development of methods to decrease the transmission of infectious pathogens, particularly the hepatitis viruses, via AHF concentrate and other blood products. However, the Committee did not find any evidence that the NHLBI actually provided any support for intramural or extramural research between 1982 and 1983 to develop viral inactivation methodologies to limit hepatitis transmission by AHF concentrate. Beginning in 1982, NHLBI did support several studies aimed at evaluating the potential transmission of the etiologic agent of AIDS through blood and blood products. These efforts included an interagency agreement with the CDC to evaluate immunologic abnormalities in recipients of blood and blood products, initiated in November 1982, and investigation of the possible transmission of the etiologic agent of AIDS to chimpanzees in May 1983. In July 1983, a request for applications was released by the NHLBI for the development of tests (so-called surrogate markers) to identify individuals who might act as carriers of the AIDS agent. Seven grants, totaling $1.5 million, were awarded for the purpose in April 1984; their utility was eclipsed, however, by the discovery of HIV at about the same time, and the money was devoted to studies of more specific test methods. In October 1984, the NHLBI issued a request for proposals for the development of HIV inactivation methods for plasma derivatives. Although the NIH and NHLBI might have been expected to take similar action with respect to viral inactivation methods focused on hepatitis, there is no evidence that the agency devoted any substantial effort to this end. Specific Viral Inactivation Methods By February 1983, all the major plasma fractionators had results from their research on the development of a heat-treated AHF concentrate. The major, if not exclusive, goal of these inactivation methods was the elimination of hepatitis

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HIV and the Blood Supply: An Analysis of Crisis Decisionmaking viruses in AHF concentrate. Each plasma fractionation company subjected the AHF concentrate to varying temperatures and conditions for different durations. Each company used stabilizers to protect the Factor VIII against the heat, but there was uncertainty whether the stabilizers also provided protection for pathogens as well. Using stabilizers such as sucrose resulted in a less than 20 percent loss of potency (Hwang 1982). Each of the manufacturers also initiated chimpanzee studies to determine if the hepatitis virus had been inactivated. Alpha Therapeutics reported that they had also looked for evidence of neoantigenicity but found none after heat treatment (McAuley 1994). Testing for the Effectiveness of the Inactivation Process As stated above, the major rationale for developing a viral inactivation procedure for AHF concentrate was to eliminate the hepatitis viruses. Proof that hepatitis had been inactivated, however, required inoculating the treated AHF concentrate into chimpanzees, a time-consuming, expensive, and resource-intensive effort. From 1981 through 1984 each of the plasma fractionators initiated chimpanzee studies to determine whether their viral inactivation processes inactivated HBV and NANB hepatitis virus. The results of initial studies conducted by Armour Pharmaceutical indicated that HBV was not completely inactivated by their heat treatment process, but that NANB was (Feldman pers. com. 1994). Armour Pharmaceutical was licensed for a process in January 1984 that was proven to inactivate NANB hepatitis in chimpanzee studies; but the company was unable to successfully inactivate HBV with their initial heat treatment process (Leahy pers. com. 1995; Rodell interview). FDA Approval and Licensing of Treated Factor VIII Table 4.1 summarizes the dates of license application and the FDA's approval of each plasma fractionator's heat-treated Factor VIII concentrate. Baxter's licensing was accomplished in only 8 months and licensing for the other fractionators took about 12 months from initial application. All plasma fractionators were licensed for sale of Factor VIII concentrate by February 1984. Upon licensure of the change in processing of the AHF concentrate products, the plasma fractionators immediately began producing a proportion of their production output using the added heat treatment step (Hammes pers. com. 1995; Leahy pers. com. 1995; McAuley pers. com. 1995; Persky pers. com. 1995). The four relevant plasma fractionators claim to have begun processing and distributing heat-treated AHF concentrate immediately after obtaining FDA licensure. However, none of the companies had entirely converted their

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HIV and the Blood Supply: An Analysis of Crisis Decisionmaking Table 4.1 Chronology of Fractionator License Applications and Approvals Plasma Fractionator and Method for Heat-Treated Factor VIII Concentrate Date Applied for FDA Licensing Date License Granted by FDA Baxter Healthcare (dry heat, 60°C for 72-74 hours) June 1982 March 1983 Miles, Inc. (formerly Cutter Biological) (liquid pasteurization, 60°C for 10 hours) August 1983 January 1984 (dry heat, 68°C for 72 hours) November 1983 February 1984 Alpha Therapeutics (wet heat, 60°C for 20 hours) December 1982 February 1984 Armour Pharmaceutical (dry heat, 60°C for 30 hours) December 1982 January 1984   SOURCE: Persky 1995; Rodell 1982; Petricciani 1983; Hammes 1995; Mozen 1995; McAuley 1995; and Feldman 1994. manufacturing processes to produce only heat-treated products at the time they were licensed by the FDA to produce heat-treated AHF concentrate. ANALYSIS AND CONCLUSIONS As with other areas of scientific investigation, technical advances to improve the safety of blood and blood products relies on the imagination and abilities of individual researchers, the availability of sufficient financial resources to encourage and support new research directions, and the encouragement or pressure applied by regulatory agencies or consumer advocates. Progress in improving the safety of AHF concentrate could have potentially been encouraged by a variety of sources including the plasma fractionation industry, the NIH, the FDA, and the National Hemophilia Foundation. In evaluating the adequacy of the response of each of these groups, the Committee reviewed the sources of technical innovation and research funding for viral inactivation technologies for

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HIV and the Blood Supply: An Analysis of Crisis Decisionmaking the hepatitis viruses and HIV. Furthermore, as scientific progress can be greatly facilitated by the open exchange of research findings, the Committee attempted to analyze the communication that took place among these different groups about their efforts to develop effective viral inactivation methods. After reviewing the data on the development of viral inactivation, the Committee concluded that although viral inactivation methods had begun in the late 1970s to eliminate hepatitis, they were not given a high priority for several reasons. First, most individuals with hemophilia had already been exposed to HBV, which led to the perception that these individuals did not need to be protected through viral inactivation of the AHF concentrate (see Chapter 7) and that initial exposure to the hepatitis virus caused the development of protective antibodies in the majority of individuals with hemophilia (Aledort interview). Also, the anticipated availability of a vaccine against HBV led to the expectation that uninfected individuals and infants would be protected against it. This protection, provided by the vaccine, would be accomplished without resorting to methods to improve the safety of AHF concentrate (Pindyck interview). It was not known until sometime between 1976 and 1978, after introduction of the third-generation screening test for hepatitis B in 1976 and continued observation of transfusion-associated hepatitis, that the majority of these transfusion-associated hepatitis cases were due to other agents, especially the virus subsequently identified as HCV. This fact, together with the lack of knowledge of the virulence of NANB hepatitis at that time, further contributed to the limited impetus for and the slow pace of the development of viral inactivation technology. In addition, plasma fractionators, government, the medical community, and society as a whole did not seem to realize that new serious pathogens, or latent agents (e.g. Creutzfeldt-Jakob disease), might also be present in the untreated concentrate. Hepatitis was viewed to be an acceptable risk for individuals with hemophilia because it was considered a medically manageable complication of a very effective treatment for hemophilia (see Chapter 7). According to the record, all of the product treatment methods that were ultimately proven to be effective in inactivating the hepatitis B and C viruses, and HIV, were developed within the laboratories of the plasma fractionators or by individuals closely associated with these industries. With the exception of Behringwerke, A.G., in Germany, each of the major plasma fractionators developed their inactivation methods at approximately the same time and entirely independently of each other. Dr. Edward Shanbrom, once employed by Hyland Laboratories (Baxter Healthcare), advocated a detergent method for viral inactivation after leaving the company. Without adequate support for the development or testing of this method, however, it did not gain widespread attention or acceptance. The record thus clearly indicates that, regardless of potential input or support from other sources, the impelling motive and decision

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HIV and the Blood Supply: An Analysis of Crisis Decisionmaking to develop viral inactivation methods depended almost entirely on the plasma fractionation industry. Given the FDA's role in licensing and ensuring the safety and efficacy of AHF and other plasma-derived materials, it would be natural to expect the agency to have had an interest in fostering, supporting, and possibly even conducting research on ways of inactivating hepatitis viruses and other infectious agents present in these preparations. However, review of the FDA's activities in this area uncovered only limited evidence of proactive effort to encourage industry to develop viral inactivation methods to limit hepatitis transmission by AHF. The FDA had essentially no significant internal research activities in this area. The FDA did convene a BPAC meeting in December 1982 to review the approval process for viral inactivation methods, with a particular focus on the details of the requisite chimpanzee challenge experiments. Several BPAC sessions in 1983 were devoted to viral inactivation and marker viruses (Franantoni 1995); however, this type of activity primarily served to facilitate, rather than actively encourage, the implementation of viral inactivation technologies. The Committee identified several apparent reasons for the limited level of activity by the FDA, but their relative importance is difficult to determine. In discussions with FDA officials, certain useful perspectives emerged (Aronson, Donohue interviews). First, like most other persons with knowledge of this area, officials at the FDA appear to have been complacent about the risk of hepatitis transmission from AHF concentrate. Thus, although viral inactivation was considered a laudable goal, there seems to have been no sense of urgency in encouraging its development. Second, FDA officials believed that the appropriate expertise for developing viral inactivation methods resided in industry and that innovations would eventually emerge. Only a very limited number of personnel were available for the regulatory oversight of coagulation products in the early 1980s, and much of their time and effort was devoted to the emerging methods for thrombolytic therapy for myocardial infarctions. In addition, the FDA had only very modest internal facilities and support for research on viral inactivation technologies. Given these factors, it is perhaps not surprising that the FDA looked to industry to provide the specific direction for progress in viral inactivation. However, the factors that influenced the pace of viral inactivation technologies developed by industry included interest in gaining competitive advantage and concerns over yield and cost. While these concerns are understandable from the perspective of a manufacturer, in the absence of active encouragement by the FDA these concerns probably inhibited expeditious progress in inactivation technologies. Further, with the primary responsibility for the development of viral inactivation methods left to industry, inherent limitations were placed on the free exchange of scientific and technical information that might expedite product development efforts. Operating in a competitive market, manufacturers

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HIV and the Blood Supply: An Analysis of Crisis Decisionmaking are not inclined to share the details of their research efforts; and the FDA is legally barred from sharing a company's research findings among competitors. Companies interacting among each other could be in violation of antitrust laws and face potential criminal charges, fines, and sanctions. Furthermore, the very nature of the competitive world of business is one that normally would cause a company to preserve manufacturing processes and research results for its own benefit, to enable the marketing of products at a competitive advantage. The Committee found that the plasma fractionators did not seriously consider alternative inactivation processes (e.g., the detergent process) because they placed a low priority on developing inactivation procedures for AHF concentrate and because heat inactivation had been successful for other blood products. Further, inactivation of pooled source plasma before fractionation would have required individual relicensure of all plasma products (Bacich, Hammes, Shanbrom interviews). In addition, inactivation methods used on plasma products could cause neoantigenicity, a problem that would negate the clinical effectiveness of AHF concentrate and possibly render the patient untreatable with these concentrates. The difficulty of testing the efficacy of inactivation procedures was due to the lack of correlation between antigen testing and infectiousness, and the absolute need for (and scarcity of) chimpanzees, which slowed progress in developing inactivation methods (Shanbrom pers. com. 1995; Epstein and Fricke 1990). Once the initial inactivation methods were developed and shown to be effective in limiting the transmission of hepatitis B and NANB infection in experimentally inoculated chimpanzees, there was a relatively short interval between the product licensing application submission to the FDA and the licensure of the heat-inactivated products. The fact that the plasma fractionation industry was able to produce an inactivated product for license consideration concurrent with, and shortly after, the first reports of AIDS in individuals with hemophilia suggests that hepatitis infection (rather than AIDS) provided the major motivation for the ultimate development of viral inactivation methods. SUMMARY Overall, the record of the plasma fractionators and the FDA with respect to the development and implementation of heat treatment is mixed. The Committee's analysis focused on whether scientific information and technology was available earlier for the development of viral inactivation methods for AHF concentrate, and whether industry had appropriate incentives (from the FDA, the NIH, the National Hemophilia Foundation, or others) to develop these processes. In the Committee's judgment, heat treatment processes to prevent the transmission of hepatitis could have been developed before 1980, an advance that would have prevented many cases of AIDS in individuals with hemophilia.

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HIV and the Blood Supply: An Analysis of Crisis Decisionmaking Treaters of hemophilia and Public Health Service agencies did not, for a variety of reasons, encourage the companies to develop heat treatment measures earlier. Strong incentives to maintain the status quo and a weak countervailing force concerned with blood product safety, combined to inhibit rapid development of heat-treated products by plasma fractionation companies. Once inactivation methods were developed, the plasma fractionators and the FDA moved expeditiously to license them. Following licensure of the first heat-treated AHF concentrate, however, many treating physicians and the National Hemophilia Foundation were slow to encourage their patients to use the new product (see Chapter 6). AFTERWARD Subsequent Events In 1988, the CDC reported the results of a study of 75 HIV infected recipients of Factor VIII. Among this group of 75, they identified 18 sole recipients of a batch of Factor VIII from a single manufacturer that had been heat treated at 60°C for 30 hours. Subsequently, the manufacturer withdrew the product from the market and the lyophilized Factor VIII treated for 30 hours or less was no longer produced by any of the manufacturers. Armour Pharmaceutical modified their heating process by heating at 68°C for 72 hours (Feldman pers. com. 1994). In 1992, investigators in France and Holland reported the development of a high incidence of inhibitor formation in hemophilia patients treated with a specific European manufacturer's preparation of AHF concentrate (Rosendaal, et al. 1983). This event alerted the medical community worldwide to the possibility of inhibitor formation following treatment with virally inactivated products, which had been extensively discussed previously but had not been reported. Although the development of inhibitors to AHF concentrate (heat-treated and non-heat-treated) had been seen in the first few years of treatment of a hemophilia patient, it was rarely observed in multitransfused patients (Rosendaal, et al. 1983). Current Procedures and Challenges Since the mid-1980s, each of the plasma fractionators has revised their manufacturing and viral inactivation procedures for Factor VIII and IX. Current procedures used in the United States for viral inactivation include (a) heating in solution (pasteurization), and (b) use of an organic solvent such as N-Butyl

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HIV and the Blood Supply: An Analysis of Crisis Decisionmaking phosphate with a detergent such as Triton X-100 or polysorbate 80. Current techniques for purifying the Factor VIII proteins to reduce the amount of virus in the product, include monoclonal antibody affinity chromatography and processes of intensified ultrafiltration. In addition, individual units of plasma are currently screened with the following tests before pooling: HBsAg, anti-HIV 1 and 2, ALT, anti-HCV 2.0, and syphilis (Leahy pers. com. 1995; McAuley pers. com. 1995; Mozen pers. com. 1995; Persky pers. com. 1995). The production of AHF using genetic engineering techniques is a major advance in blood product safety. Recombinant Factor VIII has been available since 1993 and recombinant Factor IX is currently in clinical trial (Mozen pers. com. 1995). Recombinant factor is produced by synthesizing a glycoprotein from a genetically engineered Chinese hamster ovary cell line, which secretes recombinant antihemophilic factor (rAHF) into a cell culture medium. The rAHF is extracted from the culture medium by immobilizing the monoclonal antibody in a series of chromatography columns to selectively isolate the rAHF in the medium (Persky pers. com. 1995). DNA research in factor proteins had begun at the start of the 1980s and Miles, Inc., cloned the factor VIII gene in 1984 (Mozen pers. com. 1995). In March 1995, two pharmaceutical companies initiated precautionary voluntary withdrawals of immune globulin products manufactured before December 1994 for possible hepatitis C transmission. The FDA's Center for Biologics Evaluation and Research acknowledged that ''there is no epidemiologic evidence of hepatitis C transmission by intramuscular immune globulins" but evidence exists for transmission of HCV by nonvirally inactivated intravenous immune globulin manufactured after the institution of the anti-HCV testing (Council of Community Blood Centers 1995). According to the Council of Community Blood Centers (1995), the FDA began testing samples of immune globulins lots not subjected to a viral inactivation step in December 1994. This testing program follows a May 1993 recommendation to immune globulin manufacturers to develop viral inactivation procedures for all their products. The FDA recommends positive or untested lots be used only if lots known to be negative are not available (Council of Community Blood Centers 1995). Finally, the Committee examined recent modifications instituted by several European countries to improve blood supply safety. It was found that blood supply safety measures adopted internationally included implementation of two-stage viral inactivation processes. Other measures included: decreased reliance on blood products imported from other countries; increased centralized oversight, control authorities and processes; regulation of epidemiological surveillance systems; expert advisory panels for research, testing, and quality control; and establishment of a computerized tracking system for monitoring treatment.

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HIV and the Blood Supply: An Analysis of Crisis Decisionmaking REFERENCES Bacich, John, Baxter Healthcare. Personal communication to the Institute of Medicine; November 16, 1994. Barker, Lewellys F., Dodd, Roger Y. "Viral Hepatitis, Acquired Immunodeficiency Syndrome, and Other Infections Transmitted by Transfusion," from Petz, Lawrence D., Swisher, Scott N. Clinical Practice of Transfusion Medicine (second edition) Churchill Livingsone, Inc., New York, NY; 1989. Council of Community Blood Centers. Newsletter; March 10, 1995. Epstein, Jay S., M.D., Fricke, William A., M.D., "Current Safety of Clotting Factor Concentrates," Archives of Pathology and Laboratory Medicine, Vol. 114; March 1990. Favero, Martin S., Assistant Director for Laboratory Science Centers for Disease Control. Letter to Dr. Edward Shanbrom; September 8, 1982. Federal Minister of Health. Report by the Federal Minister of Health to the Committee on Health of the German Parliament; 1992. Feldman, Frederick, Armour Pharmaceutical. Personal communication to the Institute of Medicine; November 18, 1994. Foege, William H., M.D., Assistant Surgeon General and Director Centers for Disease Control. Memorandum to Assistant Secretary for Health; August 6, 1982. Frantantoni, Joseph C., M.D. Letter to the Institute of Medicine; 1995. Gerety, Robert J., Barker, Lewellys F. "Viral Antigens and Antibodies in Hemophiliacs" proceedings from Unsolved Therapeutic Problems in Hemophilia Conference sponsored by the Bureau of Biologics, FDA Division of Blood Diseases and Resources, NHLBI, and the National Hemophilia Foundation; 1976. Hammes, William J., Associate Counsel, Miles, Inc. Letter to Institute of Medicine; February 13, 1995. Hwang, D. "Hepatitis-Free AHF," Alpha Therapeutics, interoffice memorandum to Dr. C. Heldebrant; September 17, 1982. Leahy, Beth, Director Public Affairs, Armour Pharmaceutical. Letter to IOM ; March 17, 1995. McAuley, Clyde, M.D., Medical Director, Alpha Therapeutic. Letter to Institute of Medicine; February 8, 1995. McAuley, Clyde, M.D. Medical Director, Alpha Therapeutic. "Alpha Information Re: AIDS," submission to the Institute of Medicine; September 8, 1994. Mozen, Milton, Ph.D., Scientific Affairs, Miles, Inc. Personal communication to the Institute of Medicine; January 20, 1995. Persky, Marla, Associate General Counsel, Biotech Group Baxter Healthcare. Letter to the Institute of Medicine; February 24, 1995. Petricciani, John C. Letter to Michael B. Rodell, Travenol Laboratories; March 21, 1983. Rodell, Michael B. Letter to Harry M. Meyer, Jr., Food and Drug Administration; June 14, 1982. Rosendaal, et al."A Sudden Increase in Factor VIII Inhibitor Development in Multitransfused Hemophilia A Patients in the Netherlands." Blood; April 15, 1983.

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HIV and the Blood Supply: An Analysis of Crisis Decisionmaking Seeff, Leonard B. Transfusion Associated Hepatitis: Past and Present. Transfusion Medicine Reviews, Vol 2.; December, 1988. Shanbrom, Edward. Personal communication to the Institute of Medicine; January 19, 1995. Trepo, C., et al. "Different Fates of Hepatitis B Virus Markers during Plasma Fractionation," Vox Sang, vol. 35; 1978. Weidmann, Ernst, M.D. and Hoechst AG. U.S. District Court Northern District of Illinois Eastern Division, Gruca v. Alpha Therapeutic, Co.; November 8, 1993.

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