American Journal of Transplantation ( IF 8.9 ) Pub Date : 2020-06-17 , DOI: 10.1111/ajt.16151 Daniel J Hurst 1 , Luz A Padilla 2 , David K C Cooper 2 , David C Cleveland 2 , Wayne Paris 3
To the Editor:
Clinical trials of xenotransplantation (XTx) are likely to begin early this decade. The two major organs that are currently of most interest are the kidney and heart. Broad consensus exists on adults being the candidates for the first‐in‐human clinical trials of kidney XTx, primarily because dialysis is an effective therapy should the xenograft fail. However, similar consensus does not exist on the appropriate population for the first clinical trials of cardiac XTx—adults or children?
Internationally accepted ethical guidelines generally discourage inclusion of children in “first‐in‐man” trials, particularly for high‐risk interventions, unless testing in adults is not feasible. For this reason, inclusion of minors in an initial clinical cardiac xenotransplantation trial would be controversial.1
[I]t would be difficult to justify the involvement of children in major and risky trials as recipients of heart xenografts, for example, before some of the uncertainties have been eliminated in trials involving adults.2
Recently, however, based upon rapid advances in genetic engineering of pigs, long‐term surviving orthotopic heart xenotransplants, and novel immunosuppressive regimens that are yet to be clinically applicable, there have been renewed arguments in support of including children in the initial clinical trial of heart XTx.3, 4
For infants with complex cardiac malformations, such as hypoplastic left heart syndrome (HLHS), there are few options. They do very well if cardiac allotransplantation can be carried out, with an almost 60% 25‐year graft and patient survival, but a suitable deceased human donor organ is often unavailable. In the absence of transplantation, the mortality of an infant on the waitlist is approximately 35%‐40%. Furthermore, the results of support by a mechanical device are very poor. Bridging with a genetically engineered pig heart may be lifesaving.
It is against this background that the ethics of allowing first‐in‐human clinical trials of cardiac XTx in pediatric patients must be considered. We allow parents and guardians to consent for their children to participate in other novel and exploratory therapies, such as clinical trials of cancer therapy, and so why should pediatric patients be excluded from trials of XTx, which could be lifesaving?
To be certain, there are other ethical issues with regard to including pediatric participants in trials of XTx, which we have explored previously.5 The views of pediatric parents and other stakeholders need to be considered by individual programs as part of their preparation for clinical trial implementation. In a recent survey conducted at the University of Alabama at Birmingham with the parents of pediatric heart patients, the majority of respondents favored considering XTx and supported it as a bridge to allotransplantation.6 This does not argue that pediatric trials should commence based solely, or even primarily, on family or community support, for a democratic process alone is not sufficient, but it is an important consideration.
The time seems ripe for a more detailed conversation on the involvement of children in clinical trials of XTx, where current treatment options offer poor outcomes.
DISCLOSURE
The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation.
REFERENCES中文翻译：
小儿心脏异种移植的临床试验。
致编辑：
异种移植 (XTx) 的临床试验可能会在本世纪初开始。目前最受关注的两个主要器官是肾脏和心脏。对于成人是肾脏 XTx 的首次人体临床试验的候选者存在广泛的共识，这主要是因为如果异种移植失败，透析是一种有效的治疗方法。然而，对于心脏 XTx 的首次临床试验的合适人群——成人还是儿童？
Internationally accepted ethical guidelines generally discourage inclusion of children in “first‐in‐man” trials, particularly for high‐risk interventions, unless testing in adults is not feasible. For this reason, inclusion of minors in an initial clinical cardiac xenotransplantation trial would be controversial.1
[I]t would be difficult to justify the involvement of children in major and risky trials as recipients of heart xenografts, for example, before some of the uncertainties have been eliminated in trials involving adults.2
Recently, however, based upon rapid advances in genetic engineering of pigs, long‐term surviving orthotopic heart xenotransplants, and novel immunosuppressive regimens that are yet to be clinically applicable, there have been renewed arguments in support of including children in the initial clinical trial of heart XTx.3, 4
对于患有复杂心脏畸形的婴儿，例如左心发育不全综合征 (HLHS)，选择很少。如果可以进行心脏同种异体移植，他们会做得很好，移植物和患者的 25 年存活率几乎达到 60%，但通常无法获得合适的已故人体供体器官。在没有移植的情况下，候补名单上婴儿的死亡率约为 35%‐40%。此外，机械装置的支撑效果很差。用转基因猪心脏桥接可能会挽救生命。
正是在这种背景下，必须考虑允许在儿科患者中进行心脏 XTx 的首次人体临床试验的伦理学。我们允许父母和监护人同意他们的孩子参加其他新颖和探索性疗法，例如癌症治疗的临床试验，那么为什么要将儿科患者排除在可能挽救生命的 XTx 试验之外？
可以肯定的是，将儿科参与者纳入 XTx 试验还存在其他伦理问题，我们之前已经探讨过这些问题。5作为临床试验实施准备工作的一部分，个别项目需要考虑儿科父母和其他利益相关者的意见。在伯明翰阿拉巴马大学最近对小儿心脏病患者的父母进行的一项调查中，大多数受访者赞成考虑 XTx 并支持将其作为同种异体移植的桥梁。6这并不是说儿科试验应该完全或主要基于家庭或社区支持开始，因为仅靠民主程序是不够的，但这是一个重要的考虑因素。
关于儿童参与 XTx 临床试验的更详细对话的时机似乎已经成熟，目前的治疗方案提供了糟糕的结果。
披露
如美国移植杂志所述，本手稿的作者没有需要披露的利益冲突。
参考
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