Proposals for studies of pig organ xenotransplantation could be submitted to IRBs soon. Informed consent will be a central consideration in these study protocols.
As a xenotransplantation researcher, Luz Padilla, MD, MSPH, recognized existing policies for human research subject protection probably were not adequate for these trials. Mainly, it is because there are so many unknowns with outcomes in humans.
“Whenever a team submits a protocol to the IRB for an initial clinical trial of xenotransplantation, they would need to think of as many potential problems as possible, to have the patient be as informed as possible before making a decision,” says Padilla, an assistant professor in the departments of epidemiology and surgery at the University of Alabama at Birmingham.
Padilla says IRBs should put themselves in the shoes of the potential xenograft recipient. Is maintaining the safety of the recipient reflected in the study design? Is there a plan to address the potential risks, such as zoonotic infection (an infection from the pig)? Is there any possibility of coercion from sponsors or principal investigators?
Padilla was the lead author of a recently published paper that outlined important points for informed consent for xenotransplantation clinical trials.1 These points include the fact subjects cannot withdraw from the trial, and that there will be restrictions on the subject’s reproductive rights. Also, the patient might need to quarantine if researchers determine there is a risk of infectious disease transmitted from the pig to the patient. “Obviously, with xenotransplantation, as with any new procedure, you need to explain carefully to the patient and family that it is experimental, and that there are risks involved, but also potential benefits,” says David Cooper, MD, PhD, a senior investigator in transplant surgery at the Massachusetts General Hospital in Boston.
Cooper says there are two groups of patients for whom it would be ethical to suggest considering a pig organ transplant instead of waiting for a human organ. One group is patients age 55 to 65 years, particularly if they have Type O or B blood, who might wait many years to obtain a kidney from a deceased human donor. Five or 10 years later, when an organ does become available, the reality is many of these patients will be deceased or will have developed comorbidities that make them ineligible for a transplant.
“It’s ethical for researchers to be transparent about this to patients, and present the option of accepting a pig kidney transplant while waiting for a human kidney to become available,” Cooper explains.
Some patients might agree to participation based on the potential benefits, including the fact dialysis will not be needed during that time frame, which could improve quality of life.
“It is currently unknown how long the pig kidney will function, but the patient would remain on the waiting list for a deceased human organ,” Cooper says.
If the patient rejects the pig kidney or develops an infection that proves difficult to treat, then the pig kidney could be removed, all immunosuppressive therapy discontinued, and the patient put back on dialysis until a human kidney became available. “There is a Plan B if things don’t work out as you hoped,” Cooper adds.
Pig organ transplantation also is an ethical option for babies born with complex congenital heart disease.
“For those patients, if you can carry out a human heart transplant within the first month of life, they do extremely well — better than any age group with any organ,” Cooper observes. “At that age, their immune system is very malleable, so it adapts to this new graft and doesn’t reject it as strongly as an adult.”
The problem is that it takes an average of four months to obtain a human heart, and infants are at risk of dying sooner. “The pediatric cardiac surgeons don’t really feel they have any really successful treatment that is suitable for these children,” Cooper laments.
One option is to implant a pig heart shortly after birth and keep it there while waiting for a human heart.
“I think that would be ethical, since the infant has a high chance of dying otherwise,” Cooper offers.
Patients will have to accept potentially serious risks when consenting to xenotransplantation. One is the risk of acquiring a zoonotic infection, the likelihood of which is unknown. “There is concern that an infected patient might transfer a pig virus to others, such as family and other close contacts. I think it’s unlikely, but we don’t know for certain,” Cooper cautions.
If it happens, the patient might have to be put into quarantine. Even if the graft fails and surgeons remove the pig kidney, the patient still would need to be followed for the rest of his or her life due to public health obligations, as well as concerns about the subject’s own health. That means the subject can never really withdraw from the clinical trial.
“That’s the biggest difference between other clinical trials and this one. The patients cannot really opt out of it, because they may possibly be a potential risk to everybody else,” Cooper says.
Based on the recommendations from the informed consent paper, Cooper compiled a sample consent form.2 “We now have an example of what the consent form would look like, and what the patient would be agreeing to,” Cooper reports.
The patient would be asked to sign the consent form twice — once after an initial discussion with the transplant team, and again (after a period of several days or even weeks) to reflect on the decision. “It’s important to give the patient and the family the opportunity to reconsider it,” Cooper says.
Informed consent for xenotransplantation has been a contentious issue, and remains so, observes Daniel J. Hurst, PhD, ThM, MSc, director of medical professionalism, ethics, and humanities at Rowan University School of Osteopathic Medicine in Stratford, NJ. IRBs typically only consider individual risks to the research participant. “But xenotransplantation research presents some risk to the larger community, so this may also fall under an IRB’s remit,” Hurst says.
The consent process must address the risk of zoonotic infection in the xenograft recipient that could spread to a wider community. “Some have recommended that potential xenograft recipients consent to lifelong testing for disease,” Hurst notes.
Participants must be made aware of this possibility. In the context of a clinical trial, this means the participant would not be able to withdraw from this aspect of the trial.
“This goes against research ethics guidelines since Nuremberg, as well as against federal guidelines, notably the Belmont Report,” Hurst says. “How to enforce such a requirement is also anybody’s guess.”
Considering all these challenges, Hurst would like to see informed consent forms released publicly. This would open the documents to peer review by the entire xenotransplantation community.
“I do not see any reason not to release a blank copy of the form without the patient’s identifying information,” Hurst says.
REFERENCES
1. Padilla LA, Hurst D, Maxwell K, et al. Informed consent for potential recipients of pig kidney xenotransplantation in the United States. Transplantation 2022;106:1754-1762.
2. Cooper DKC. Patient informed consent for a clinical trial of gene-edited pig kidney transplantation: A representative consent form. Xenotransplantation 2022; Nov 26:e12790. doi: 10.1111/xen.12790. [Online ahead of print].
Existing policies for human research subject protection might not be adequate for these trials, mainly because there are so many unknowns with outcomes in humans.
You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
- Award-winning Medical Content
- Latest Advances & Development in Medicine
- Unbiased Content