Furthering Deceased Donor Intervention Research in Canada and the United Kingdom

Research is important to improve the quality and availability of transplantable organs. Deceased donor research has been hindered by ethical and practical challenges. This applies particularly to deceased donor intervention randomized control studies (RCTs). A handful of good-quality RCTs have been undertaken and enhanced the evidence base for donor physiological support. There may be fewer barriers when the research intervention is already in use, for example, thyroid hormone therapy. A recent US multicenter study involving 852 heart donors has challenged the notion that thyroid hormone given in the setting of donation after neurological determination of death (DNDD) is effective in replenishing a deficiency and restoring cellular metabolism, thereby improving cardiac function and hemodynamic stability.1 Thyroid hormone resulted in no better organ utilization or early graft survival but more cases of potentially injurious hypertension and tachycardia. More contentious may be studies with donor interventions not in current use, such as cooling. Targeted hypothermia has been used in intensive care for controlling raised intracranial pressure and to reduce brain injury post cardiac arrest resuscitation. Its application in deceased donation might be considered low risk for causing harm to the deceased donor or organs for transplant. A US RCT published in 2015 found mild hypothermia (34–35 °C) in DNDD reduced delayed kidney graft function in recipients.2 It precipitated a public controversy because of what was considered a failure of regulatory oversight to adequately protect human subjects. The relevant institutional research board (IRB) had deemed the trial was not human subjects research as the intervention was occurring in deceased donors. Recipient consent was considered not necessary because hypothermia represented minimal risk to organs and no additional recipient data were to be collected, with outcomes determined from registry data.3 The concerns and debate have usefully focused attention on the many challenges and possible ways forward, although the negative public attention has likely stymied advancement in donor intervention research. Impressively, the researchers have since published a further study that included a similar intervention, apparently without the same outcry.4 The scrutiny that interventional donor research faces is only likely to increase given the range and complexity of possible interventions. There is potential for novel pharmacological agents, immunomodulatory and genetic therapies, and invasive deceased donor interventions, including those applied before death in the setting of donation after circulatory determination of death. Interventional donor research raises issues beyond those encountered in standard human research.5 It involves potential donors who are dying or recently deceased and there may be uncertainty about the legality of, and consent requirements for, interventions occurring prior to and after death. There may be lack of clarity about who are the research “participants,” with implications for consent requirements, as participants may include the deceased donor, recipients of the organ for transplant under study (target) and recipients of nonstudy (nontarget) organs in multiorgan donation. There is the potential for the donor family as surrogate decision makers to be impacted by being burdened by additional information and decision making and for the research intervention to alter their experience at the end of life of their relative. Current human research frameworks are not designed to cater for these elements.6 IRBs are likely to have little understanding of the donation and transplantation landscape, and may have difficulty assessing proportionate potential benefits and harms. If recipients are considered participants, would transplant centers also require IRB review? It may not be feasible to obtain adequate recipient consent given the donor intervention will most likely precede organ allocation, there is only a short time available to consider an organ offer, and coercion may be difficult to minimize if the organ offer is conditional on agreeing to participate in the study. Care must be taken that donor intervention research does not alter allocation systems in ways that create or exacerbate inequities in access to transplantation.6 In this issue of the Transplantation, Slessarev et al7 report on the outcomes of a Canada-United Kingdom workshop held as a first step to developing guidance for donor intervention RCTs. The authors convened a hybrid virtual and in-person workshop at the 2022 Canadian Donation and Transplantation Research Program Annual Scientific Meeting in British Columbia, Canada. Thirty participants included experts in donation and transplantation, intensivists, ethicists, researchers, government representatives, and transplant recipients. Expert presentations and panel discussion covered topics including the ethical and regulatory landscape, core outcomes datasets, and “lessons learned” from existing trials. This publication report summarizes the main workshop outcomes. Researchers from these countries are also taking steps to provide precedent in navigating the undertaking of RCTs. The United Kingdom SIGNET trial (Statins for Improving Organ Outcome in Transplantation) will be the largest RCT in organ donation.8 The aim is to include 2600 patients planned for DNDD and provide a simple intervention being a single dose of simvastatin administered after family consent. The successful conduct of the study may be more important than any result such a minor intervention might be expected to have, given the composite primary outcome of death, use of renal replacement therapy or mechanical cardiac support in heart transplant recipients at 28 d. The first Canadian donor intervention RCT, the CINERGY trial (Calcineurin Inhibitor in Neurologically Deceased Donors to Decrease Kidney Delayed Graft Function), has also been launched.9 This pilot will test the feasibility of administering tacrolimus to deceased donors with the aim of reducing ischemia–reperfusion injury and improving kidney transplant function. As well as a prelude to a national study, it seeks to establish an avenue for other innovative donor intervention studies. Addressing the barriers to undertaking research in deceased donors is imperative. Donors and their families want their gift to result in the best possible donation and transplant outcomes. Those in need of transplantation want to see maximized the chance of receiving a well-functioning organ transplant. Many current practices could be suboptimal or even harmful and there are potential beneficial interventions yet to be adequately studied. Advancing knowledge is important for improving the quality of the donation process and safely expanding donation and transplantation. This collaborative initiative between Canada and the United Kingdom is a promising step toward achieving this.

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