From Uncertainty to Impact: Regulating Risk in Unmet Medical Need
Regulating risk under epistemic uncertainty in conditions of unmet medical need: An integrative analysis of pharmaceutical regulatory law, research ethics, and clinical trial practice in Switzerland and the EU
Across Europe, medicines regulators increasingly accept evidentiary concessions in settings of clinical urgency and unmet medical need (UMN), including small or non-randomised datasets, surrogate endpoints, limited follow-up, and expedited routes such as conditional marketing authorisation (CMA). In rare and ultra-rare diseases, these shifts reflect feasibility constraints – small, heterogeneous patient groups, time-sensitive disease courses, and outcomes that may take years to mature – as well as a policy environment that has made addressing UMN a priority.
Crucially, this is not simply a matter of risk-benefit balancing. The core governance problem is epistemic uncertainty: relevant unknowns that persist because the available evidence cannot yet resolve them, even though decisions on trial authorisation, serious adverse event (SAE) management, and initial marketing authorisation must nonetheless be made.
Gene therapy medicinal products (GTMPs) are a particularly sharp stress test for governing epistemic uncertainty in UMN rare-disease contexts, because they combine high clinical urgency with limited evidence, long-term uncertainty, potentially irreversible intervention, platform dynamics, and expanding access routes beyond conventional trial pathways.
This ITINERARE Junior Grant aims to develop a framework for how European Union (EU) and Swiss pharmaceutical regulatory law should govern epistemic uncertainty in UMN settings, and to translate that framework into practical guidance for rare-disease trial design and oversight. It asks when evidentiary concessions are justified, and which safeguards and follow-up obligations they require.