From Uncertainty to Impact: Regulating Risk in Unmet Medical Need

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.

The project builds on three prior ITINERARE research strands: research on epistemic uncertainty in regulatory decision-making; work on trial design and oversight in cell and gene therapies; and research on innovation incentives in pharmaceutical law, especially the concept of UMN and its role in justifying evidentiary flexibility and post-authorisation obligations.

Work package 1 (WP1) systematises EU and Swiss regulatory-law approaches to epistemic uncertainty across three lifecycle decision points – trial approval, safety-signal response, and initial marketing authorisation – through doctrinal analysis of legislation, regulatory guidance and policies, jurisprudence, and case-based regulatory decisions. It is illustrated through three case studies developed with KISPI/ITINERARE partners Janine Reichenbach, Johannes Häberle, and Georg Stettner. WP1 will produce a pharmaceutical regulatory law paper and a practitioners’ guide.

WP2 applies the WP1 framework to two key gene-therapy governance problems. WP2.1 examines under which conditions earlier paediatric inclusion may be justified in UMN gene-therapy trials, in cooperation with KISPI/ITINERARE partners Janine Reichenbach and Johannes Häberle. WP2.2 – in partnership with Janine Reichenbach and Georg Stettner – analyses SAE-triggered clinical holds and resumption decisions in US and European gene-therapy trials (2016–2025) through an event-mapping database capturing triggers, duration, lift conditions, and post-resumption restrictions. Together, these studies identify how evidentiary flexibility is operationalised in high-stakes practice contexts and which safeguards are needed to preserve patient protection and scientific validity.

The project will generate three peer-reviewed research articles, a practitioners’ guide, and an optional policy piece on clinical-hold transparency and SAE disclosure and re-consent. For ITINERARE, the outputs are designed to feed directly into planned rare-disease clinical trials, including regulatory strategy, regulatory and ethics submissions, paediatric-development strategy, and SAE response. The project will help build sustainable capacity in pharmaceutical regulatory law and rare-disease trial governance within ITINERARE, with significance for current Swiss legal reform processes (e.g., planned revisions of the Federal Act on Medicinal Products and Medical Devices and the Federal Act on Research involving Human Beings; preliminary-draft Federal Act on Measures to Tackle Rare Diseases).