A New Ethical Framework for Assessing the Unique Challenges of Fetal Therapy Trials: Response to Commentaries

The development of fetal therapies is important but requires ethically challenging clinical trials. In our recent Target Article (Hendriks et al. 2022), we argued that existing regulatory and ethical guidance for assessing the risks and benefits of these trials have significant limitations which raise concerns that they may block appropriate trials or permit inappropriate ones. We proposed a new ethical framework to address these concerns. First, to capture all relevant interests, we argued for considering (evidence-based) potential psychosocial benefits and risks of fetal therapies, along with the potential biomedical benefits and risks. Second, we argued against using categorical risk and/or benefit thresholds (e.g., fetal therapy trials should only be conducted for life-threatening conditions), which are common in previously proposed ethical frameworks. Instead, we argue that the individual risks for the pregnant person and the fetus should be justified by the benefits for them and the study’s social value. Additionally, neither the risk-benefit profile for only the fetus or the risk-benefit profile for only the pregnant person should be too unfavorable. Finally, we considered other research ethics challenges for fetal therapies relating to social value, scientific validity, and informed consent. We are grateful to the colleagues who have thoughtfully engaged with our article through their commentaries, further advancing this discourse (Bartlett, Bliton, and Finder 2022, Campo-Engelstein and Loutrianakis 2022, Crombag et al. 2022, Farrell and Michie 2022, Fry and Premkumar 2022, Ibuki 2022, Riggan et al. 2022). We thank Farrel and Michie, Bartlett et al., Campo-Engelstein and Loutrianakis, Ibuki et al, Riggan et al and Crombag et al for highlighting important areas to potentially expand our framework or develop related guidance. In this response, we will respond to the most direct critiques raised by the OPC authors. Ibuki et al suggest that we might be confusing research and clinical care (Ibuki 2022). Though we agree that care needs to be taken to avoid conflating research and clinical care generally, we emphasize that our paper is focused only on research: specifically, conducting clinical trials involving fetal interventions with a prospect of benefit for the fetus. Our framework is actually consistent with several of the suggested amendments from Crombag et al. (Crombag et al. 2022). Specifically (1) We agree that if evidence-based psychosocial benefits are counted, evidence-based psychosocial harms should be counted as well (Hendriks et al. 2022). (2) Our proposal that fetal therapy trials are only acceptable if the risk-benefit ratios for both the fetus and the pregnant person are acceptable, independent of the social value of the study, effectively prevents social value from being able to justify very risky trials. This is consistent with Crombag’s proposal that the risk-benefit ratios for both the pregnant person and the fetus should trump social benefits. (3) We fully agree with Crombag et al. that ethical review is key to ensure that fetal therapy trials are not too risky—our proposed framework is designed to help assess which trials will be conducted and proposed to patients. Like Crombag et al. noted, we acknowledge that there are practical and conceptual challenges with counting a broader range of benefits and risks. However, while Crombag et al. argue that—given their uncertain nature—psychosocial effects should be given less weight than biomedical effects, we think the likelihood and magnitude of both types of effects should be carefully considered. Usually, that will lead to biomedical effects having a larger effect on the risk-benefit profile, but there may be cases in which psychosocial effects should have a