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In April 1998, the National Institute of Allergy and Infectious Diseases (NIAID) convened an expert panel to begin developing guidelines for the design, conduct and monitoring of scientifically and ethically acceptable clinical trials to evaluate the safety and efficacy of new approaches to achieve immune tolerance in transplant recipients. A group of experts in bioethics, law and basic and clinical research in transplantation joined NIH staff and representatives of the Food and Drug Administration and the NIH Office of Protection from Research Risks.
Transplantation is now routine therapy for end-stage renal disease, with one-year graft survival approaching 90% using standard immunosuppressive therapy. However, long-term graft survival has not improved appreciably since the early 1980s and only about 45% of cadaveric kidneys survive ten years post-transplant. For other organs (e.g., liver, lung and pancreas), graft survival does not approach this level. While new immunosuppressive drugs have reduced acute rejection in the first year post-transplant, it is clear that these therapeutic improvements will not significantly alter long-term clinical outcomes. Therefore, much recent attention has focused on the potential for the induction of donor-specific immune tolerance to achieve long-term graft survival without the need for non-specific, life-long immunosuppressive therapy that has deleterious and often life-threatening side effects. Although certain promising tolerogenic molecules have been shown to induce donor-specific tolerance in rodent and non-human primate transplant models and are being tested in humans for the treatment of selected autoimmune diseases, these approaches have not been evaluated for transplantation in humans.
A major ethical dilemma in moving forward with clinical trials for the induction of transplant tolerance results from the growing body of knowledge that standard immunosuppressive therapy blocks the intracellular signals necessary to induce at least some types of tolerance. Therefore, transplantation clinical trials to evaluate the safety and efficacy of tolerogenic approaches will involve withholding standard immunosuppressive therapy or significantly altering immunosuppressive regimens.
The expert panel was asked to address a number of critical questions and issues, including the following:
What is the quality and extent of non-human primate data needed to begin clinical trials in humans: What differences between species need to be taken into account in designing human studies?
What are the options for a scientifically viable and ethically acceptable research design? Under what conditions, if any, can standard immunosuppressive therapy be withheld? Under what conditions can standard immunosuppressive therapy be significantly reduced in terms of the number of drugs, dosage or length of administration?
What reliable markers are available, or need to be developed, for the early detection of graft rejection, assessment of graft function, and assessment of the induction, maintenance or loss of tolerance?
What rescue therapies need to be in place?
Which patient populations are most appropriate from both a scientific and an ethical standpoint?
What safeguards need to be incorporated into the informed consent process?
The panel acknowledged that clinical trials of tolerance induction in the transplant setting is a rapidly evolving field of investigation that will require ongoing review by a similar panel of experts. The risks and benefits associated with decisions to initiate human studies and the design and monitoring of human studies should be reviewed on a case-by-case basis by experts in bioethics, law and basic and clinical research in transplantation.
Long-term graft survival is no better today than it was 20 years ago. The failure to achieve substantial improvements in long-term graft survival rates remains a problem for transplant recipients, clinicians, surgeons and researchers. Therefore, the panel strongly endorses the development and testing of new therapeutic approaches to prevent the process of chronic rejection.
The issues involved in balancing scientific viability with ethical acceptability are not unique to clinical trials of transplant tolerance. These issues have been addressed in clinical investigations of other diseases such as AIDS and cancer. It is possible to design scientifically valid and ethically acceptable clinical protocols despite current limitations in understanding mechanisms of action and incomplete data on safety and toxicity.
Non-human primate models are particularly useful because they more closely approximately the human immune system and physiology. Therefore, non-human primate studies are essential to provide critical data on safety and toxicity that, in many cases, cannot be obtained ethically in human clinical trials and sufficient data from such studies should be available before initiating human clinical trials. However, demonstrated efficacy in non-human primate models does not guarantee "success" in humans. Therefore, data from animal studies, while important, are just one factor in the decision-making process to proceed with human trials. For example, a lack of demonstrated efficacy in non-human primate studies would not necessarily preclude initiation of pilot clinical trials in humans.
It will be important to define success in terms of clinical outcomes. Some measures of success recommended include the absence of acute or chronic rejection without a requirement for globally immunosuppressive agents and long-lasting immunocompetence against infections and tumors.
The projected risk/benefit ratio of any tolerance induction trial in transplant recipients must be at least neutral compared to standard therapy before a clinical trial can proceed. Given the considerable toxicities, side effects, financial burden and poor long-term survival rates associated with global immunosuppression, the projected risk/benefit ratio of a well designed tolerance induction clinical trial would be at least neutral. Furthermore, it is has been demonstrated that 95% of acute rejections can be reversed, providing a reasonable "rescue" therapy for patients enrolled in tolerance induction trials. The design of tolerance induction trials can, therefore, incorporate specific rules for rescue of the rejecting graft and placing these patients on conventional immunosuppressive therapy.
The design of initial clinical trials of tolerance induction must give priority to patient safety. These trials should incorporate a sequential enrollment design in which the enrollment of additional patients is dependent on the results of patients enrolled up to that time. Defined stopping rules and treatment regimens for potential rejection, based on expected failure rates, must be in place to ensure patient safety. The current acute rejection rate using standard immunosuppressive therapy is 20-25% during the period from 3-6 months post-transplant. Therefore, similar acute rejection rates in tolerance induction clinical trials may occur in the clinical trial design.
Current methods to diagnose rejection are less than optimal and essentially require the clinician to wait until organ damage has occurred before therapeutic strategies to treat and/or reverse rejection can be implemented. The panel recommended that tolerance induction trials incorporate the most sophisticated methods available for detecting and/or predicting rejection prior to severe organ damage, including both pathology and intra-graft gene expression.
Clinical trials of tolerance induction strategies should incorporate studies of new methods to measure the induction, maintenance and loss of tolerance, as well as studies of the underlying immune mechanisms of tolerance induction.
Clinical trials should not be initiated in settings where the failure to induce tolerance would be lifethreatening (e.g., heart and liver transplantation). In contrast, clinical trials of the safety, toxicity and potential efficacy of tolerogenic approaches should be initiated in kidney and islet transplantation. Kidney transplantation and islet transplantation in particular were viewed as appropriate clinical settings since the consequences of rejection are less severe and patients who fail therapy with tolerogenic approaches can be effectively treated with standard insulin therapy or dialysis. Diabetics represent a subpopulation of kidney transplant recipients for whom tolerance induction may be of particular potential benefit, given the poor long-term clinical outcomes of such patients on standard immunosuppressive therapy.
A clear and comprehensive informed consent process is necessary, including a thorough and easily understood informed consent document. To control for conflicts of interest, informed consent should be obtained by independent third parties and should include counseling on all aspects of the risks and benefits of the experimental study. In addition, counseling must continue to be available after informed consent is obtained. Those obtaining informed consent must be knowledgeable about transplantation and capable of answering questions about both standard and experimental therapies and the informed consent process should not be limited to one day. Patients offered enrollment in early trials must be able to understand fully the complex issues involved so they can weigh risks and benefits. In cases of living kidney donation, it may be important to obtain informed consent from the donor as well.
Patient selection must balance the potential risks and benefits in terms of expected clinical outcome for different types of transplant recipients. It was acknowledged that the first-time transplant recipient, i.e., the patient with a "naïve" immune system, would be an appropriate candidate for initial tolerance induction studies versus the patient with severe chronic rejection who may be sensitized and, therefore, not likely to benefit from these experimental approaches. Moreover, the results of tolerance induction protocols for first transplant recipients may not be applicable to sensitized patients, as the patient receiving a second transplant is already immunologically primed to potential donors. Therefore, proof of concept in immunologically "naïve" transplant recipients, along with some understanding of underlying mechanisms, could lead to more effective therapeutic regimens for sensitized patients.
It will be ethical to enroll children in these trials only after proof-of-concept has been demonstrated in adults. Children have the most to gain from tolerance induction since current immunosuppressive regimens are not as successful in children as in adults, and the benefits of donor-specific tolerance could extend longer term in pediatric populations.
Bioethicists and Institutional Review Board representatives should be involved in the design of all clinical trials of transplant tolerance and should assist in the development of ethically acceptable consent forms and processes.
Charles B. Carpenter, M.D., Professor of Medicine, Brigham and Women's Hospital, Harvard University
James Childress, Ph.D., Kyle Professor of Religious Studies, Professor of Medical Education and Chairman, Department of Religious Studies, University of Virginia
David Essayan, M.D., Medical Officer, Pharmacology & Toxicology Branch, Division of Clinical Trials Design and Analysis, Office of Therapeutics Research and Review, Center for Biologics Evaluation and Research, Food and Drug Administration
Norman Levinsky, M.D., Associate Provost and Professor of Medicine, Boston University Medical Center
Bernard Lo, M.D., Professor of Medicine, University of California, San Francisco
Louis Marzella, M.D., Ph.D., Medical Officer, Pharmacology & Toxicology Branch, Division of Clinical Trials Design and Analysis, Office of Therapeutics Research and Review, Center for Biologics Evaluation and Research, Food and Drug Administration
Lee Nadler, M.D., Chairman, Department of Adult Oncology, Division of Hematologic Malignancies, Dana Farber Cancer Institute
Philip D. Noguchi, M.D., Director, Division of Cellular and Gene Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration
Thomas Pearson, M.D., Associate Professor, Department of Surgery, Transplant Immunology, Emory University
Harold Y. Vanderpool, Ph.D., Th.M., Professor in the History of Philosophy, Institute for Medical Humanities, University of Texas Medical Branch
Robert Veatch, Ph.D., Professor of Medical Ethics and Senior Research Scholar, Kennedy Institute of Ethics, Georgetown University
Alison Wichman, M.D., Deputy Director, Office of Human Subjects Research, Office of Intramural Research, National Institutes of Health
Mohamed H. Sayegh, M.D., Director, Laboratory of Immunogenetics and Transplantation Research, Brigham and Women's Hospital, Harvard University
Terry Strom, M.D., Professor of Medicine, Division of Immunology, Beth Israel Deaconess Medical Center
Judy Massicott-Fisher, Ph.D., Health Scientist Administrator, Division of Heart and Vascular Diseases, National Heart, Lung and Blood Institute
Kamal Mittal, Ph.D., Northwest and Compliance Coordinator, Office of Protection from Research Risks, Office of the Director, National Institutes of Health
Camille A. Jones, M.D., MPH, Epidemiology Program Director, Division of Kidney, Urology and Hematology, National Institute of Diabetes and Digestive and Kidney Diseases
Robert Goldstein, M.D., Ph.D., Vice President of Research, Juvenile Diabetes Foundation International
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Last Updated September 29, 2010
Last Reviewed September 16, 2010