Ethical decisions under uncertainty? Guidance for initiating first-in-human trials involving genome editing

First-in-human studies involving gene transfer or genome editing give rise to complex uncertainties. There is a broad acknowledgment that the current scientific guidelines should be supplemented with ethical guidance, particularly with regard to decisions about whether to initiate such trials. As a first step toward this goal, we present a three-tiered conceptual framework that operationalizes ethical principles to provide researchers with guidance on this decision. In the first “diagnostic” step, researchers are invited to identify the drivers of uncertainty in their study and to collaboratively reflect on the value judgments commonly taking place in the evidence assessment. Here, the principles of research validity and integrity are operationalized. The second “decisional” step outlines elements for the ethical deliberation about initiating a trial, formulated as benchmarking questions related to the principles of beneficence, nonmaleficence and their proportionality. The third “communicational” step offers guidance for communication about the study during planning, submission and, eventually, with potential participants, operationalizing the principles of honesty and respect for participants. This conceptual contribution is expected to stimulate further work on the relevance, practicality and adaptability of such an ethical framework in research settings characterized by complex uncertainty.