Vulnerability, protection and fairness: ethical and regulatory limits in small-N gene therapy trials

International ethics frameworks emphasize both the protection of vulnerable participants and the importance of equitable inclusion in research. In ultra-rare gene therapy trials, extensive safety monitoring, long-term follow-up requirements, and specialized treatment infrastructure are necessary to ensure participant protection and scientific validity. However, these requirements operate within healthcare systems characterized by geographic, financial, and social inequalities, raising concerns about whether all eligible patients have a fair opportunity to participate. Recent regulatory reforms in the European Union (EU), United Kingdom (UK), and United States (US) increasingly promote methodological flexibility for small patient populations through adaptive trial designs, risk proportionate oversight, and alternative evidentiary approaches.

This commentary examines the extent to which existing clinical trial guidance for gene therapy promotes fair inclusion while safeguarding participants. We analyze binding and non-binding guidance from the European Medicines Agency (EMA), United States Food and Drug Administration (FDA), Medicines and Healthcare products Regulatory Agency (MHRA), International Council for Harmonisation (ICH), Council for International Organizations of Medical Sciences (CIOMS), and United Nations Educational, Scientific and Cultural Organization (UNESCO), alongside illustrative examples from Zolgensma®, Roctavian®, and Hemgenix®. Current frameworks provide substantial methodological flexibility with natural history data, external controls, decentralized approaches, and proportionate evidence requirements. Emerging initiatives such as FDA Diversity Action Plans, the UK Inclusion and Diversity Plan, and recent EU regulatory reforms further reflect growing attention to procedural fairness. Nevertheless, operational barriers remain. Long-term follow-up obligations, geographic concentration of expertise, financial burdens, and reliance on patient advocacy networks continue to shape who can realistically participate in research. While regulators increasingly recognize these challenges, guidance rarely requires concrete measures to mitigate them.

Current gene therapy trial frameworks largely succeed in supporting methodological flexibility for ultra-rare conditions but insufficiently operationalize fair inclusion. Ethical concerns arise not because participant protections are excessive, but because the burdens associated with necessary scientific and regulatory requirements may disproportionately affect patients facing structural disadvantages. Ensuring justice in ultra-rare gene therapy research requires extending proportionate, risk-based approaches beyond evidence generation to include the identification and mitigation of foreseeable barriers to participation.