Informed Consent Is Central Ethics Concern with Xenotransplantation Clinical Trials

By Stacey Kusterbeck

The field of xenotransplantation is developing rapidly, with several pig kidney and heart xenotransplants recently performed through the U.S. Food and Drug Administration (FDA)’s Expanded Access/Compassionate Use pathway.¹ Additionally, the first-ever clinical trials of nonhuman animal organ — a genetically modified pig kidney — recently were approved by the FDA.²

As transplant programs are moving forward with designing first-in-human pig kidney xenotransplant clinical trials, researchers are facing some unprecedented ethical questions. Many of those ethical concerns involve informed consent. “There is a need to have an open discussion about what these trials question about our understanding of clinical trials, clinical equipoise, and expectations. In addition, we need to have guidance from the larger xeno-society about surveillance and observation for public health risks,” says Savitri Fedson, MD, MA, a professor of the Center for Medical Ethics and Health Policy at Baylor College of Medicine.

There also is a need to update existing ethical guidance. The Nuffield Council on Bioethics published ethical guidance on xenotransplantation in 1996, followed by the World Health Organization in 2008, and the FDA in 2016. “We wanted to ensure that guidelines accounted for updates in ethical considerations regarding the conduct of such first-in-human pig kidney xenotransplant clinical trials,” says Elisa J. Gordon, PhD, MPH, a professor in the Department of Surgery and Center for Biomedical Ethics and Society at Vanderbilt University Medical Center.

Gordon and colleagues interviewed interested parties about xenotransplantation, including patients, transplant clinicians, translational scientists, regulators, institutional review board (IRB) members, and experts in human research protections.^3,4 One transplant surgeon emphasized how important it was for the entire transplant team to share the same understanding of the ethical issues the clinical trial raises. “Being on the same page is essential for efficiently progressing in this scientific endeavor that holds great promise for relieving the organ shortage,” Gordon underscores.

The researchers also developed four case studies for transplant teams, which are conducting pig kidney clinical trials or preparing to do so. Researchers can use the case studies to reflect on the ethical issues that these trials generate. The researchers also created a checklist for IRB members to evaluate the unique ethical issues raised by first-in-human pig kidney xenotransplant clinical trial protocols.

Next, Gordon and colleagues interviewed 28 waitlisted kidney transplant patients about the kind of information they would want to make a decision on participating in a first-in-human pig kidney xenotransplant clinical trial.⁵ Patients wanted this information:

• The potential of contracting or transmitting infection. Patients expressed concern about whether the human body could defend itself against a potential infection from a pig kidney and whether it could be transmitted to somebody else.
• The risks, benefits, and effect of xenotransplant trials. Patients wanted to know if the kidney was going to work, how long it would last, and how the transplant would affect their overall quality of life.
• Xenotransplant clinical trial and recipient experience. Patients wanted to know how many people before them had undergone a pig kidney xenotransplant, their life expectancy, and what the post-operative treatment was like.
• The logistics of the clinical trial. Patients wanted to know how long they would have to be monitored, the number of tests and appointments they would need to go to, and what would happen if a rejection was to occur.
• The pig and its kidney. Patients wanted to know if the pig was free of diseases and whether it was screened well.

Based on this feedback, the researchers developed an informed consent form prototype and solicited feedback from 16 patients. Those patients suggested adding some more details — about the pig’s age and life expectancy, the length of time patients would be monitored for, whether the surgeon has done a pig kidney transplant before, and insurance coverage.

Gordon outlines these important ethical considerations for transplant teams when recruiting study participants for xenotransplant clinical trials:

A need for transparency about the goals of the clinical trial, to avoid therapeutic misconception. Patients considering participation in xenoplant trials may be particularly vulnerable because of limited or no available treatment alternatives for end-stage kidney disease. “Therefore, study participants may conflate the goals of clinical research with the goals of therapeutic treatment in the hopes of receiving therapeutic relief,” says Gordon.

Transplant teams need to be sure that patients understand that the primary goal of a first-in-human clinical trial is to determine the safety of the pig kidney transplant. Researchers want to know if the pig kidney is transmitting infectious diseases, for example. A secondary goal may be to evaluate the effectiveness of the intervention — whether the pig kidney is working. “The informed consent process must carefully review this point and ensure that patients/participants are making a voluntary decision about participation,” says Gordon.

In some ways, xenotransplant trials are similar to Phase I chemotherapy trials. In both cases, it is unknown if there will be any benefit for the participants. “In addition, we do not know how a xenotransplant might then affect an individual’s ability to get and maintain an allotransplant. There are some primate studies in process looking at delayed antibody response, but these are small,” observes Fedson.

The need to disclose the “exit strategy” for xenotransplantation. Researchers need to address what happens if the pig kidney no longer works after transplantation. “We already saw that happen with one pig kidney xenotransplant recipient, obtained through the FDA Expanded Access pathway: She had to return to dialysis. This is one of many pieces of information that patients need to be informed about so that they are well-prepared and can make a voluntary, informed decision,” says Gordon.

As progress continues toward clinical applications in human recipients, infants and young children are among the groups of patients being considered for early clinical application. However, there are additional ethical concerns for obtaining informed consent from parents.⁶ “While xenotransplantation has an number of overall ethical considerations, when children are involved, there are few more nuances that should be considered,” says Fedson.

One is the main difference between substituted judgment and best medical interest. “For children, we are supposed to make decisions based on the best medical interest standard — which, for the purpose of trials, is a sense of clinical equipoise. It is difficult to argue for children that an experimental kidney is better or equal to dialysis, and that parents are supposed to make decisions based on this,” explains Fedson. In the setting of xenotransplantation, there currently is no clinical equipoise. There is no genuine uncertainty on the part of the researchers on the effects of the treatments when compared to mechanical circulatory support, Fedson explains. That poses a challenge for researchers in terms of compliance with the standard conceptions of informed consent.

“In addition to their children, parents are also vulnerable subjects in this setting,” says Fedson. Parents often have to make decisions about their children in the absence of clear data, limited options, and a significant number of unknowns. Participating in the xenotransplant trial could affect future opportunities in ways that currently are not understood. The effect of immunization for childhood diseases for a xenotransplant recipient is unknown, for example.

“One of the reasons we wrote our paper was to prompt people and institutions to think of the questions that need to be addressed. Ethicists can certainly help with these discussions,” says Fedson.

At least one biotech company announced plans to begin a pediatric cardiac xenotransplantation clinical trial.⁷ “The FDA could say that pediatric cardiac trials should not proceed until more data [are] collected in adult cardiac xenotransplantation patients,” says Daniel J. Hurst, PhD, ThM, MSc, director of Medical Professionalism, Ethics, & Humanities at Rowan University School of Osteopathic Medicine in Stratford, NJ. On the other hand, the FDA might allow for pediatric cardiac xenotransplantation as a compassionate use in certain limited circumstances, similar to what has been done in adults. “It’s unknown at this point, since that information is not publicly available,” says Hurst.

In a recent paper, Hurst and colleagues outline important ethical considerations with pediatric cardiac xenotransplantation.⁸ “One such consideration, in a pediatric context, is the informed consent conversations with the surrogate — usually the parents. Xenotransplantation is a very novel and experimental therapy. It’s important that parents truly understand this and are aware of the known and unknown risks,” says Hurst.

IRBs need to try to ensure that risks are minimized and potential benefits are maximized. “Xenotransplantation comes with unique problem sets. IRBs should have relevant expertise to judge the merits and risks of the proposed study. But, should they not, outside review is essential,” says Hurst. The IRB will have to determine whether they have the expertise to review xenotransplantation study protocols. One mechanism that is available is the International Xenotransplantation Association’s ethics committee. “This committee allows investigators to submit proposals to their team of experts for review,” says Hurst.

Stacey Kusterbeck is an award-winning contributing author for Relias. She has more than 20 years of medical journalism experience and greatly enjoys keeping on top of constant changes in the healthcare field.

References

1. Bobier C, Hurst DJ, Rodger D. Xenotransplantation under the Food and Drug Administration’s Expanded Access pathway. Am J Transplant. 2024;24(10):1911-1912.

2. Deeley M. FDA greenlights first clinical trials for genetically modified pig kidney transplants in humans. American Kidney Fund. Published Feb. 6, 2025. https://www.kidneyfund.org/article/fda-greenlights-first-clinical-trials-genetically-modified-pig-kidney-transplants-humans

3. Maschke KJ, Gordon EJ, Gusmano MK. Executive summary: Informing ethical translation of xenotransplantation clinical trials. The Hastings Center. Published May 2025. https://www.thehastingscenter.org/wp-content/uploads/Xeno-Executive-Summary-6-23-25.pdf

4. National Institutes of Health Research Portfolio Online Reporting Tools (NIH RePort). Informing ethical translation of xenotransplantation clinical trials. https://reporter.nih.gov/search/nNpK-gyQD0G6jLBC8eRN1A/project-details/10895485

5. Gordon EJ, Gusmano MK, Gacki-Smith J, et al. Patients’ information needs for informed consent to participate in first-in-human pig kidney xenotransplant clinical trials: A mixed methods study. Xenotransplantation. 2025;32(1):e70016.

6. Urschel S, Benden C, Fedson S. Considerations of ethical aspects of xenotransplantation in pediatric patients. J Heart Lung Transplant. 2025; Mar 19. doi: 10.1016/j.healun.2025.03.013. [Online ahead of print].

7. Hamzelou J. This company plans to transplant gene-edited pig hearts into babies next year. MIT Technology Review. Published July 17, 2023. https://www.technologyreview.com/2023/07/17/1076392/this-company-plans-to-transplant-pig-hearts-into-babies-next-year/

8. Hurst DJ, Bobier C, Merlocco A, et al. Pediatric cardiac xenotransplantation and expanded access: Ethical considerations. Pediatr Transplant. 2024;28(7):e14876.