Executive Summary

Xenotransplantation involves the transplantation of cells, tissues, and whole organs from one species to another. Interest in animal-to-human xenotransplants has been spurred by the continuing shortage of donated human organs and by advances in knowledge concerning the biology of organ and tissue rejection. In addition, the development of novel strategies to protect animal cells and tissues from rejection has resulted in experimental application of xenotransplantation to treat a wide range of diseases, including diabetes and Parkinson's disease. The scientific advances and promise, however, raise complex questions that must be addressed by researchers, physicians and surgeons, health care providers, policymakers, patients and their families, public health officials, the news media, and the public. These questions include how to manage the risk to the patient and society at large of animal-to-human infectious disease transmission, how to address special issues related to informed consent and organ allocation, and how and whether to provide adequate resources for research and clinical application of the new technology, among others.

As a result of early discussions within the Institute of Medicine (IOM) Council on Health Care Technology, and with sponsorship from a number of federal agencies and two foundations, the IOM convened a committee in October 1994 to plan a workshop to consider the scientific and medical feasibility of xenotransplantation and to explore the ethical and public policy issues applicable to the possibility of renewed clinical trials of xenotransplantation. Another area of focus was added in response to increasing concern about the potential risk of animal-to-human disease transmission through xenotransplantation. The three-day workshop was held in late June 1995 and involved



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--> Executive Summary Xenotransplantation involves the transplantation of cells, tissues, and whole organs from one species to another. Interest in animal-to-human xenotransplants has been spurred by the continuing shortage of donated human organs and by advances in knowledge concerning the biology of organ and tissue rejection. In addition, the development of novel strategies to protect animal cells and tissues from rejection has resulted in experimental application of xenotransplantation to treat a wide range of diseases, including diabetes and Parkinson's disease. The scientific advances and promise, however, raise complex questions that must be addressed by researchers, physicians and surgeons, health care providers, policymakers, patients and their families, public health officials, the news media, and the public. These questions include how to manage the risk to the patient and society at large of animal-to-human infectious disease transmission, how to address special issues related to informed consent and organ allocation, and how and whether to provide adequate resources for research and clinical application of the new technology, among others. As a result of early discussions within the Institute of Medicine (IOM) Council on Health Care Technology, and with sponsorship from a number of federal agencies and two foundations, the IOM convened a committee in October 1994 to plan a workshop to consider the scientific and medical feasibility of xenotransplantation and to explore the ethical and public policy issues applicable to the possibility of renewed clinical trials of xenotransplantation. Another area of focus was added in response to increasing concern about the potential risk of animal-to-human disease transmission through xenotransplantation. The three-day workshop was held in late June 1995 and involved

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--> 43 speakers and presenters and more than 200 participants. The workshop focused on three major topics: the science base; the public health risks of infectious disease transmission; and the ethical and public policy issues, including the views of patients and their families. Based on this workshop and additional deliberations, the committee came to specific conclusions and made recommendations, which are outlined here and summarized in detail in the full report. Recommendation 1 There is ample evidence for the transmission of infectious agents from animals to humans. Transmitted organisms benign in one species can be fatal when introduced into other species. 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. Once an infection is established in the recipient, the potential for transmission to caregivers, family, and the population at large also must be considered a real threat. The committee concludes that, although the degree of risk cannot be quantified, it is unequivocally greater than zero. Hence, 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. Recommendation 2 The committee discussed various alternatives for oversight or regulation of clinical trials in light of the risk of transmission of infectious agents to the general population from xenotransplantation. Several committee members felt strongly 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

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--> transmission of new infections to humans is a unique risk justifying special regulations. All members of the committee agreed that some mechanism is needed to ensure attention to the risk of infectious disease transmission. The committee was aware of and commends the effort 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. Therefore, 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 (IRBs) 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 authority for the approval of xenotransplantation trials within local IRBs and institutional animal care and use committees (IACUCs) will require an increase in, or augmentation of, the existing capacity of some of these groups. Further, 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 through coordinated efforts of the involved Federal agencies (see Recommendation 4) without establishing a complex and, possibly costly, new regulatory structure. Recommendation 3 Transplantation of animal organs also raises new ethical and social questions. To assist local IRBs, IACUCs, and society at large to address such questions, 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. Recommendation 4 The committee is aware of and commends the efforts of the Food and Drug Administration and the Centers for Disease Control and Prevention in developing the first set of guidelines for xenotransplantation, which were not final before this report was complete but developed from discussions with other federal agencies and representatives from stakeholder groups. Addressing

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--> the multiple areas that require attention, however, will necessitate ongoing review and the cooperation of federal agencies, universities, and the private sector. Therefore, 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. One mechanisms to achieve greater coordination 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, policy, and surveillance issues related to xenotransplantation and to suggest modifications of the guidelines based on accumulating information from research and clinical trials. Recommendation 5 Some scientists who participated in the workshop believe 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, 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. A Necessary Caveat 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 constraints. Substantial, stable resources are needed to support research; 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

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--> 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.