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Recent developments in gene transfer and gene editing provide promising avenues for the treatment of monogenetic paediatric diseases. First-in-human (FIH) trials are a crucial step towards market authorization. Such trials involve notable uncertainties and risks, and for diseases that manifest in early childhood adult data are often lacking. In research involving minors, an important requirement to allow exposure to more than minimal risks is that there must be a prospect of direct benefit for the minors involved. However, in FIH pediatric gene therapy trials it can be questioned whether a certain therapy meets this requirement for a prospect of direct benefit and when such trials should be allowed, due to the uncertainty that accompanies them. To aid the review of these trials, we investigated definitions of the prospect of direct benefit in the ethical literature and important regulatory documents, such as the European Clinical Trial Regulation, FDA Common Rule and CIOMS guidelines. Additionally, we explored if and how preclinical research can substantiate evidence for the prospect of direct benefit. We found that "benefit" is inconsistently defined in regulatory documents, allowing different types of benefit to influence risk-benefit analysis. In some regulatory documents, direct benefit solely refers to clinical benefits that result from an intervention, whereas other regulations also include other, indirect, benefits in their definition of direct benefit. In addition, we found that what is meant with "prospect" is ill-defined in many regulatory documents. This raises questions on how this requirement for a "prospect" of direct benefit needs to be interpreted. We provide recommendations how this prospect could be understood. To do so, we look at different types of evidence - mechanical and statistical - that are used to substantiate claims of effectiveness, and thus potential direct benefit. Clearly defining and accurately interpreting the requirement for a prospect of direct benefit is crucial for effectively reviewing FIH pediatric gene therapy trials. A failure to do so could lead to mislabeling trials as providing a prospect of direct benefit, fostering therapeutic misconception and accepting trials with an unfavourable risk-benefit ratio. [ABSTRACT FROM AUTHOR]

Competing Interests: Competing interests: None declared.

Regenerative Medicine promises to develop treatments to regrow healthy tissues and cure the physical body. One of the emerging developments within this field is regenerative implants, such as jawbone or heart valve implants, that can be broken down by the body and are gradually replaced with living tissue. Yet challenges for embodiment are to be expected, given that the implants are designed to integrate deeply into the tissue of the living body, so that implant and body become one. In this paper, we explore how regenerative implants may affect the embodied experience of implant recipients. To this end, we take a phenomenological approach. First, we explore what insights the existing phenomenological and empirical literature on embodiment offers regarding the experience of illness and of living with regular (non-regenerative) implants and organ transplants. Second, we apply these insights to better understand how future implant recipients might experience living with regenerative implants. Third, we conclude that concepts and considerations from the existing phenomenological literature do not sufficiently address what it might be like to live with an implantable technology that, over time, becomes one with the living body. We argue that the interwovenness and intimate relationship of people living with regenerative implants should be understood in terms of 'entanglement'. Entanglement allows us to explore the complexities of human-technology relations, acknowledging the inseparability of humans and implantable technologies. Our theoretical foundations regarding the role of embodiment may be tested empirically once more people will be living with regenerative implants., (© 2024. The Author(s).)