5
Conclusions and Recommendations

The following conclusions and recommendations are based on workshop presentations and discussions, as well as review of relevant materials and extensive discussions among the committee. This chapter presents those conclusions and recommendations along with the key points that underlie them, but it does not duplicate in detail material presented in previous chapters of this report.

The progress of basic science in the field of xenotransplantation has been rapid, and clinical trials of specific applications of xenotransplantation are under way. Xenotransplantation may also be valuable for the treatment of human diseases. However, it is well recognized that infectious agents can be transmitted from animals to humans and that organisms benign in one species can be fatal when introduced into other species. Further, it is known that the pathogenicity of infectious organisms can change under a variety of conditions and that the effects of infection by some organisms, such as the human immunodeficiency virus, are delayed for years or even decades. Because xenotransplants involve the direct insertion of potentially infected cells, tissues, or organs into humans, there is every reason to believe that the potential for transmission of infectious agents (some of which may not even now be recognized) from animals to human transplant recipients is real. If established in the recipient, the potential for transmission to caregivers, family, and the population at large must be considered a real threat. The committee concludes that, although the degree of risk cannot be quantified, it is unequivocally greater than zero.

The committee discussed various alternatives for oversight or regulation of clinical trials in light of the risk of transmission of infectious agents to the



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--> 5 Conclusions and Recommendations The following conclusions and recommendations are based on workshop presentations and discussions, as well as review of relevant materials and extensive discussions among the committee. This chapter presents those conclusions and recommendations along with the key points that underlie them, but it does not duplicate in detail material presented in previous chapters of this report. The progress of basic science in the field of xenotransplantation has been rapid, and clinical trials of specific applications of xenotransplantation are under way. Xenotransplantation may also be valuable for the treatment of human diseases. However, it is well recognized that infectious agents can be transmitted from animals to humans and that organisms benign in one species can be fatal when introduced into other species. Further, it is known that the pathogenicity of infectious organisms can change under a variety of conditions and that the effects of infection by some organisms, such as the human immunodeficiency virus, are delayed for years or even decades. Because xenotransplants involve the direct insertion of potentially infected cells, tissues, or organs into humans, there is every reason to believe that the potential for transmission of infectious agents (some of which may not even now be recognized) from animals to human transplant recipients is real. If established in the recipient, the potential for transmission to caregivers, family, and the population at large must be considered a real threat. The committee concludes that, although the degree of risk cannot be quantified, it is unequivocally greater than zero. The committee discussed various alternatives for oversight or regulation of clinical trials in light of the risk of transmission of infectious agents to the

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--> general population by xenotransplantation. There was strong feeling among a number of committee members that special regulation of xenotransplant research is not justified because other types of research, including allotransplantation, also involve substantial risks. Other members of the committee argued that the potential for transmission of new infections to humans is a unique risk, justifying special regulations. However, all members of the committee agreed that some mechanism is needed to ensure attention to and reduction of the risk of infectious disease transmission. One mechanism acceptable to all committee members was the establishment of national guidelines. The committee was aware of and commends the efforts of the Food and Drug Administration (FDA) and the Centers for Disease Control and Prevention (CDC) in developing the first set of guidelines, which are soon to be released, but were not final before this report was complete. The development of these guidelines involved discussions with other federal agencies and representatives from stakeholder groups. The importance of such guidelines should be emphasized. Hence: Recommendation 1: The committee recommends that guidelines for human trials of xenotransplantation address four major areas: (1) procedures to screen source animals for the presence of infectious organisms and consideration of the development of specific pathogen-free animals for use in xenotransplants; (2) continued surveillance throughout their lifetimes of patients and periodic surveillance of their contacts (families, health care workers, and others) for evidence of infectious diseases; (3) establishment of tissue banks containing tissue and blood samples from source animals and patients; and (4) establishment of national and local registries of patients receiving xenotransplants. Special efforts should be made to coordinate with international registries and databases. These areas were discussed at the workshop as key elements for the effective monitoring of infectious disease transmission. For example, screening of source animals should focus first on those organisms known to infect that animal species and known to be pathogenic in humans. However, screening broadly for a wide range of organisms should be performed while conducting early trials until evidence is provided that screening for a particular organism is unnecessary. Screening of donor tissue must be complemented with mandatory active surveillance of patients receiving xenotransplants, as well as their contacts, for the sole purpose of determining the safety of xenotransplantation. Such surveillance will require collection of tissue and serum samples and coordination of information in a central database or registry. The requirement of lifelong surveillance certainly raises dangers from potential

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--> needs for enforcement and limitation of individual freedom. Thus, individual information should be strictly confidential and should not be used to screen patients for any diseases not directly caused by xenotransplants. A collection of animal donor tissue and serum samples should also be archived to allow later testing if new or unusual infectious diseases are identified in xenotransplant recipients. Special efforts should be made to coordinate the development of a national database or patient registry with efforts already under way internationally. For example, the International Islet Registry in Germany contains information on patients who have received xenotransplants of pancreatic islet cells. Cooperative links with such registries may constitute a valuable resource for surveillance and research. Guidelines, however, do not carry the full weight of law and, thus, can function only as one part of effective oversight of individual clinical trials. There was much discussion among committee members about the role of local institutional review boards (IRBs) and their capacity to address the multiple issues related to xenotransplantation. A requirement that individual trials be approved by a national committee, analogous to the Recombinant DNA Advisory Committee (RAC), was considered unacceptable by a number of committee members. The entire committee agreed that IRBs could, with specific augmentation and required adherence to national guidelines, provide the appropriate consideration of individual clinical trial protocols. Therefore: Recommendation 2: The committee recommends that adherence to specific national guidelines be required of all experimenters and institutions that undertake xenotransplantation trials in humans. Local institutional review boards and animal care committees, in consultation with outside experts, are appropriate vehicles for review of proposed protocols, provided that they are required to conform to the national guidelines for minimizing and for continued surveillance of infectious risks. The committee is well aware that placing the authority for the approval of xenotransplantation trials within local IRBs and IACUCs will require an increase in, or augmentation of, the existing capacity of some of these groups. For example, conformity to the national guidelines may require expert outside advice from Physicians, infectious disease experts, and veterinarians trained in microbiological screening. Ensuring appropriate surveillance procedures, including tissue banking and data filing in patient registries, may also require a local IRB to consult with outside experts. In addition, IRBs will require input from patients and their families. Transplantation of animal organs also raises new ethical and social questions. To assist local IRBs, IACUCs, and society at large to address new ethical and social questions:

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--> Recommendation 3: The committee recommends further investigation into the special ethical issues that are raised by xenotransplantation, particularly those related to informed consent in light of the requirement for lifetime surveillance of patients and those related to fairness and justice in allocating organs, as well as research into the psychological and social impact of receiving animal organs on recipients, their families, and members of the society as a whole. Addressing the multiple areas that require attention, however, will necessitate ongoing review and the cooperation of federal agencies, universities, and the private sector. One mechanism could be the establishment of an advisory committee comprised of representatives of federal agencies and other relevant groups, such as basic and clinical researchers, ethicists, lawyers, and private industry. It also would be important to include patient groups and the public. An advisory committee could be charged to coordinate, but not to regulate, research in xenotransplantation. Rather, the mandatory adherence to the soon to be released FDA and CDC guidelines would provide the needed safeguards at the local IRB level, which could be overseen by the advisory committee without establishing a complex and, possibly costly, new regulatory structure. In addition, the advisory committee could regularly review and advise the Department of Health and Human Services on guidelines in the light of evolving knowledge. Coordination within a single federal agency is difficult because the establishment of guidelines for xenotransplants involves addressing a broad range of questions of science, ethics, and public policy currently addressed handled a number of agencies. For example, federal agencies that address the basic and clinical science of xenotransplantation and infectious disease include the FDA, the NIH, the CDC, and certain components of the Department of Agriculture, but the duties of each of these agencies do not often overlap. Monitoring adherence of local IRBs and IACUCs to national regulations, and possibly to the guidelines proposed here, is the responsibility of the Office for Protection from Research Risks. Coordination will also be required between the proposed national patient registry and the archival collection sites for patient and animal donor tissue and serum samples. Given the evolving nature of this field, tracking of research progress is required so that guidelines can be amended as new data emerge. Also, developments in other public or private sector areas, such as the establishment of specific-pathogen-free breeding colonies and advances in genetic manipulation of animal cells, will have to be considered in a broad context that includes the clinical, scientific, ethical, and social implications of new discoveries and developments. An advisory committee could also be the focal point for initiating international cooperative agreements in order to share data resources

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--> from ongoing clinical trials involving xenotransplants. To deal with these considerations: Recommendation 4: The committee recommends that a mechanism be established within the Department of Health and Human Services to ensure needed coordination of the federal agencies and other entities involved in development, oversight, and evaluation of established guidelines. At least one scientist who participated in the workshop believed that the risk of infectious disease transmission is high enough to preclude any further human xenotransplantation trials. After considerable discussion of this view and consideration of the issues listed above that will be required to assess the risk of infection, the committee concluded that the potential benefits of xenotransplants are great enough to justify this risk. Hence: Recommendation 5: The committee recommends that, when the science base for specific types of xenotransplants is judged sufficient and the appropriate safeguards are in place, well-chosen human xenotransplantation trials using animal cells, tissues, and organs would be justified and should proceed. Clinical trials with cellular xenotransplants are already under way, and a real danger exists that the commercial applications of xenotransplant technology will outstrip both the research base and the national capacity to address special issues raised by xenotransplantation, including the risk of disease transmission. The committee considered the total expense associated with research and technology development, especially in light of current fiscal restraints. Substantial, stable resources are needed to support research, such as virus discovery, better understanding of the physiology of transplanted organs, and mechanisms of rejection; to perform diverse, well-designed clinical trials; and to maintain patient registries, tissue and serum sample collections, and surveillance for disease in patient populations. The committee concludes that the potential of xenotransplantation is great enough to justify funding, by federal agencies, private industry, and other sources, of research and other programs (e.g., tissue banks and patient registries) necessary to minimize the risk of disease transmission.