By Christopher Gyngell and Julian Savulescu.
At 57, David Bennett was dying. He had a decades long history of heart disease. Prior treatments, including surgery, had proved ineffective. In November 2021, he was diagnosed with uncontrollable arrhythmia and was admitted to the University of Maryland Medical Centre. Despite the best efforts of clinicians, his condition continued to deteriorate.
Mr Bennett’s best chance at long-term survival was to get a new heart. Unfortunately, he had a history of not following medical advice. His medical records showed instances of taking medications incorrectly and missing medical appointment. He was deemed to have poor adherence to treatment, which was an exclusion criterion for receiving a human heart for transplantation.
Just when it seemed he had no hope, Mr Bennett was approached with an unusual offer. While the Maryland transplant team couldn’t acquire a human heart for transplant (allotransplantation), they could offer him a heart grown inside a pig (xenotransplantation). The heart would come from specially bioengineered pigs, which have been genetically modified to ‘humanise’ their organs, and minimize the chance of patient’s immune system rejecting it.
Mr Bennett had limited options. “It was either die or do this transplant,” Mr Bennett said before his surgery. “I want to live.”
The clinical team was granted approval to conduct the surgery via the Food and Drug Administration (FDA) Expanded Access program and Mr Bennett’s underwent xenotransplantation. For the first week, it seemed like the operation was a stunning success. Doctors reported that the heart was beating well and performing like ‘a rock star’. Unfortunately, this success would be short lived. Forty-nine days after the transplant, the heart had begun failing. Sixty days after he received the xenotransplant, Mr Bennett’s life support was turned off and he passed away.
Although Mr Bennett only lived for 60 days after the surgery, the xenotransplantation itself has been considered a success. The heart showed no signs of rejection, a key determinant of long-term survival in xenotransplantation. Rather, Mr Bennett’s heart failure was suspected to be caused by an underlying viral infection. Following Mr Bennett’s case, there have been calls for clinical trials of porcine xenotransplantation, and in June 2022 the FDA took initial steps to initiate clinical trials into xenotransplantation.
In this blog, and a forthcoming paper, we explore two ethical controversies relating to Mr Bennett’s case. The first focuses on eligibility for xenotransplantation, and Mr Bennett being denied human heart transplantation. The second concerns Mr Bennett’s informed consent to undergo the procedure.
Should Mr Bennett have been on the FDA’s Expanded Access program?
The FDA’s Expanded Access program is designed to facilitate access to investigational medical products for patients who have life threatening medical conditions. There are several criteria that must be meet for a procedure to be authorized under this scheme. The most controversial of these in Mr Bennett case is “there is no comparable or satisfactory alternative therapy to diagnose, monitor, or treat the disease or condition.”
Allotransplantation would have been a satisfactory alternative treatment for Mr Bennett. He was denied access to this treatment, not because he would not be physically suitable, but rather because he had a prior history of poor compliance. Unfortunately, there is a shortage of available hearts from deceased donors. As the need for human hearts outstrips their demand, it is necessary to make decisions about how to best allocate available hearts. A standard practice is to exclude individuals who have a prior history of non-compliance. This is based on consequentialist reasoning. After an organ transplant, patients must take a regime of drugs to make sure the organ is not attacked by their own immune system (called rejection). Patients who are unlikely to comply with medical orders are unlikely to get much benefit from a heart. Furthermore, allowing a heart to go to someone who is unlikely to live very long, can be seen as disrespectful to the donor and their families, who often donate with the assumption their gift will provide many additional years of life for others.
But using history alone as an exclusion criterion for allotransplantation seems unfair. It is the future behaviour of a recipient that will determine how much benefit is gained from an organ donation. There are many contexts when previous non-compliance would not predict future non-compliance. Consider Mr Bennett: his previous instances of non-compliance were for medical non-life threatening conditions years early, where the risks of non-compliance were not as high as there were now. Now that his life depended on taking medications, he would have had a much higher motivation to comply with medical orders.
There are even more fundamental problems with using a history of non-compliance as an exclusion criterion when allocating organs. Several factors contribute to non-compliance, including one’s social circumstances and underlying health. Individuals who have a more severe illness may find it harder to move about their community and be less likely to access medications and attend follow-up appointments. A policy which excluded individuals from the organ transplant lists because of non-compliance may disproportionately exclude those who are already disadvantaged.
The limits of informed consent
A key requirement of informed consent is that it must be given voluntarily and not under duress. Was Mr Bennett under duress when he consented to xenotransplantation? Comments like “it was either die or do the surgery…I want to live”, support the view that he was under pressure when choosing xenotransplantation. But here we must distinguish choosing an option under duress, and having very poor options to begin with. Xenotransplantation may have been the best of two poor choices for Mr Bennett. It will often be the case that people have limited options with regards to late-stage medical treatments. If a patient must choose the lesser of two bad options, it does not mean that their consent to that option should be questioned.
However, Mr Bennett’s case shows why we need to look beyond consent with assessing ethically controversial research. A central moral function of consent is to protect or promote autonomy. But in Mr Bennett’s case, the prior decision not to offer him allotransplantation or long-term circulatory support, took valuable options away from him. Being deemed ‘non-compliant’ reduced his capacity to be the author of his own life and make choices in accordance with his preferences and values. Although it is good that he is given the option of xenotransplantation over certain death, the overall situation is not one where Mr Bennett’s autonomy is being promoted.
This shows the need to move to formal clinical trials of xenotransplantation, where rules around eligibility and suitability can be transparently assessed in all subgroups of patients. For instance, it now appears that neonates and infants with severe congenital heart malformations may become the best candidates for cardiac xenotransplantation because of the immaturity of their immune system and current poor alternatives to xenotransplantation. Xenotransplantation may also be used as a bridge to allotransplantation in these young children. We must carefully consider the different ethical issues that will arise in trials in each of these different patient groups.
As the demand for organs outstrips availability and calls for clinical trials of genetically modified porcine xenotransplantation intensify, there is an urgent need to discuss and agree upon clear frameworks around patient selection and consent processes.
Paper: Ethical Analysis of the First Porcine Cardiac Xenotransplantation [Under consideration]
Authors: Christopher Gyngella,b,c, Megan Munsie b,d, Misao Fujitae,f, Carrie Thiesseng, Julian Savulescub,c,h,i, and Igor Konstantinov a,b,j
Affiliations: a Department of Paediatrics, University of Melbourne, Melbourne, Australia b Murdoch Children’s Research Institute, Melbourne, Australia c Melbourne Law School, University of Melbourne, Melbourne, Australia d Melbourne Medical School, University of Melbourne, Melbourne, Australia e Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan f Institute for the Advanced Study of Human Biology (WPI-ASHBi), Kyoto University, Kyoto, Japan g Department of Surgery, University of Wisconsin School of Medicine and Public Health, Wisconsin, United States of America h Faculty of Philosophy, Oxford Uehiro Centre for Practical Ethics, Oxford, United Kingdom i Centre for Biomedical Ethics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore j Royal Children’s Hospital, Melbourne, Australia
Competing interests: None declared