What does it take to consent to islet cell xenotransplantation?: Insights from an interview study with type 1 diabetes patients and review of the literature.

BACKGROUND: The transplantation of porcine islet cells provides a new potential therapy to treat patients with type 1 diabetes mellitus (T1DM). Compared to other biomedical technologies, xenotransplantation stands out in terms of its involvement of animals as graft sources, as well as the possible transmission of infectious diseases. As these aspects are especially relevant for potential xenotransplantation recipients, it is important to assess their opinion regarding this technology, in particular in terms of the requirements that should be met in the informed consent process for xenotransplantation. METHODS: We conducted qualitative interviews with seven T1DM patients to assess their information needs prior to xenotransplantation. Before the interview, the participants received a model informed consent form for a clinical trial with porcine islet cells transplantation. The interviews were transcribed and analysed using qualitative content analysis. RESULTS: In the interviews, we identified several requirements that are crucial for patients with T1DM in order to consider xenotransplantation as a potential treatment option: therapy-related requirements, professional care and supervision, successful behaviour and attitude management, improving quality of life, and managing control/self-determination challenges. Regarding the informed consent form, several of the participants' questions remained open and should be addressed in more detail. The interviewees stressed the importance of personal consultations. CONCLUSIONS: To become a sustainable therapeutic option, patients especially expected an improved diabetes control and a reduction of diabetes-related burdens. Health-related aspects prove to be pivotal for diabetic patients when considering porcine islet cell transplantation. The use of pigs as source for organ retrievals was not considered as problematic.

Justifying clinical trials for porcine islet xenotransplantation.

The development of the Edmonton Protocol encouraged a great deal of optimism that a cell-based cure for type I diabetes could be achieved. However, donor organ shortages prevent islet transplantation from being a widespread solution as the supply cannot possibly equal the demand. Porcine islet xenotransplantation has the potential to address these shortages, and recent preclinical and clinical trials show promising scientific support. Consequently, it is important to consider whether the current science meets the ethical requirements for moving toward clinical trials. Despite the potential risks and the scientific unknowns that remain to be investigated, there is optimism regarding the xenotransplantation of some types of tissue, and enough evidence has been gathered to ethically justify clinical trials for the most safe and advanced area of research, porcine islet transplantation. Researchers must make a concerted effort to maintain a positive image for xenotransplantation, as a few well-publicized failed trials could irrevocably damage public perception of xenotransplantation. Because all of society carries the burden of risk, it is important that the public be involved in the decision to proceed. As new information from preclinical and clinical trials develops, policy decisions should be frequently updated. If at any point evidence shows that islet xenotransplantation is unsafe, then clinical trials will no longer be justified and they should be halted. However, as of now, the expected benefit of an unlimited supply of islets, combined with adequate informed consent, justifies clinical trials for islet xenotransplantation.

The International Xenotransplantation Association consensus statement on conditions for undertaking clinical trials of porcine islet products in type 1 diabetes-- executive summary.

The International Xenotransplantation Association islet xenotransplantation consensus statement describes the conditions for undertaking clinical trials of porcine islet products in type 1 diabetes. Chapter 1 reviews the key ethical requirements and progress toward the definition of an international regulatory framework for clinical trials of xenotransplantation. Chapters 2 to 7 provide in depth and agreed-upon recommendations on source pigs, pig islet product manufacturing and release testing, preclinical efficacy and complication data required to justify a clinical trial, strategies to prevent transmission of porcine endogenous retrovirus, patient selection for clinical trials, and informed consent. It is planned to update this initial consensus statement in a year's time in light of progress in research, changes in the regulatory framework, and comments submitted after publication.

The International Xenotransplantation Association consensus statement on conditions for undertaking clinical trials of porcine islet products in type 1 diabetes--chapter 1: Key ethical requirements and progress toward the definition of an international regulatory framework.

The outstanding results recently obtained in islet xenotransplantation suggest that porcine islet clinical trials may soon be scientifically appropriate. Before the initiation of such clinical studies, however, it is essential that a series of key ethical and regulatory conditions are satisfied. As far as ethics is concerned, the fundamental requirements have been previously reported in a position paper of the Ethics Committee of the International Xenotransplantation Association. These include aspects related to the selection of adequately informed, appropriate recipients; animal breeding and welfare; safety issues and the need for a favorable risk/benefit assessment based on strong efficacy data in relevant xenotransplantation studies in the primate. As most diabetic patients are not at risk of short-term mortality without islet transplantation, only a small subset of patients could currently be considered for any type of islet transplant. However, there are potential advantages to xenotransplantation that could result in a favorable benefit-over-harm determination for islet xenotransplantation in this subpopulation and ultimately in a broader population of diabetic patients. With regard to regulatory aspects, the key concepts underlying the development of the regulatory models in existence in the United States, Europe and New Zealand are discussed. Each of these models provides an example of a well-defined regulatory approach to ensure the initiation of well-regulated and ethically acceptable clinical islet xenotransplantation trials. At this stage, it becomes apparent that only a well-coordinated international effort such as that initiated by the World Health Organization, aimed at harmonizing xenotransplantation procedures according to the highest ethical and regulatory standards on a global scale, will enable the initiation of clinical xenotransplantation trials under the best auspices for its success and minimize any risk of failure.

The International Xenotransplantation Association consensus statement on conditions for undertaking clinical trials of porcine islet products in type 1 diabetes--chapter 7: Informed consent and xenotransplantation clinical trials.

This essay explores the meaning and implications of informed consent in xenotransplantation clinical trials from both ethically justifiable and international perspectives. In international and national codes and guidelines involving human subject research and in the laws of many nations, the informed consent of research subjects is obligatory. Its moral foundations include and also extend beyond respect for individual persons as autonomous agents in Western nations. Axioms regarding the value of human life and duties to protect innocent and vulnerable persons from harm, duress, and deceit underlie Western individualism and are broadly shared in many non-Western cultures. Accents on family and/or community consent in China and other nations are compatible with individual consent as long as family and community consent supplement, rather than replace, individual consent. Reflecting its moral foundations, informed consent in medical research is rightly characterized as "voluntary" or "freely given" informed consent because it encompasses researchers' disclosure and subjects' comprehension of all the relevant information about the protocol that reasonable persons would want to know in order to freely and affirmatively enroll in the research. The interplay between these conceptual foundations of informed consent and the realities of xenotransplantation research defines what the nature and functions of consent should be in xenotransplantation clinical trials. Because these trials involve a complex body of medical information, numerous procedures, numerous risks (associated with failure rates, immunosuppression, xenogeneic infections, and so on) and the subject's obligation to abide by extensive national and international precautionary guidelines, informed consent should be enacted as an organized, sequential, thoughtfully paced, jargon-free process of communication. The features and functions of consent forms or consent documents should accord with this process. Rather than being virtually equated with informed consent, consent documents should be utilized as templates of relevant, essential, and understandable information that contribute to comprehension and voluntary enrollment. In xenotransplantation clinical research, the consenting process must cover a large number of topics, including treatment choices, participation information, study procedures, information about risks associated with immunosuppression, xenogeneic infections, discomforts, and other matters. In addition, due to infectious risks, subjects are obliged to 10 post-protocol responsibilities. Two of the three unique moral issues regarding informed consent in xenotransplantation trials involve what to do to minimize post-protocol infectious risks and what to do about international and national guidelines that affirm the subject's right to withdraw from participation in medical research at any time. The third moral issue centers on issues involving the enrollment of children and mentally incapacitated adults. The other chapters in this consensus statement demonstrate that, morally and logically, favorable harm-benefit determinations precede considerations of informed consent. When these harm-benefit assessments are favorable enough to warrant the onset of clinical trials, informed consent emerges as a pivotal moral precondition for these trials.

Presente y futuro del trasplante de islotes pancreáticos / Present and future of pancreatic islet transplantation

El protocolo de Edmonton supuso un salto cualitativo en los resultados del trasplante de islotes, consiguiendo en el primer año postrasplante que el 60-90% de los pacientes suspendiera el tratamiento con insulina, y que en un plazo de 5 años el 80% mantuviera un injerto funcionante que les permitía, aunque con el requerimiento de dosis generalmente bajas de insulina, un control metabólico óptimo sin hipoglucemias graves. En la actualidad, el tratamiento puede ofrecerse tan sólo a una minoría de pacientes, debido fundamentalmente a la toxicidad de la inmunosupresión y a la escasez de islotes disponibles para el trasplante. En esta revisión se analizan los recientes resultados del trasplante de islotes, los riesgos y beneficios del procedimiento, sus indicaciones actuales y los retos que la investigación debe afrontar para conseguir que el trasplante de islotes o, de forma más general, la terapia celular pueda ser un tratamiento generalizable a la mayoría de la población diabética (AU)

The Edmonton protocol has been a major step forward in the field of islet transplantation. In the first year after transplantation 60-90% of patients achieve insulin-independence, and after 5 years around 80% of patients maintain graft function and excellent metabolic control, even though they require low doses of insulin, with minimal o no episodes of severe hypoglycaemia. Currently, islet transplantation can be offered only to a minority of patients, basically due to the toxicity of immunosupression and the scarcity of islet tissue available for transplantation. In this review we analyze the current results of islet transplantation, the risks and benefits of the procedure, current indications, and the challenges that research must face to achieve that islet transplantation or, in a more general way, cell therapy of diabetes may became a common treatment available to most diabetic patients (AU)

The xenotransplantation narratives of nine type 1 diabetic patients with renal failure.

Within the research project ''Treatment of Diabetes by Transplantation of Porcine Islets'' that was run by the Swedish Xenoislet Transplantation Network between 1998 and 2003, a partner project called ''Cultural Perspectives on Xenotransplantation'' investigated attitudes toward xenotransplantation development among the patients and their relatives as well as the medical personnel at a transplantation clinic in Sweden. In-depth interviews were done with 37 individuals: nurses, doctors, researchers, patients, and relatives. All interviews were taped and transcribed verbatim. In this presentation the interviews with the nine type 1 diabetic patients with renal failure that took part in the project are focused. The personal and embodied narratives of these nine patients illustrate the ambivalent situation of individuals who are both patients and (potential) experimental subjects simultaneously. Both as actual practice and as biomedical information xenotransplantation research triggers a certain kind of cultural identity of the chronically ill patients--an identity related to how the patients ''translate'' scientific information and, at the same time, counter risk and uncertainty as well as promises of remedy. A central dimension in this cultural identity is a positive but still reluctant embodied attitude toward what spearhead science can bring about.