Despite affecting nearly 30 million people in Europe and more than 300 million worldwide, rare diseases remain one of the most underserved areas of medicine. The numbers are stark: while between 6,000 and 7,000 rare conditions have been identified, the vast majority still lack targeted therapies. But why, with so many affected, are there still so few therapies for rare diseases? While scientific advances continue to identify new conditions, progress in developing and evaluating treatments has been far slower—raising difficult questions about how clinical trials are designed, conducted, and assessed.
A recent webinar series organised by the IHI-funded RealiseD project brought together over 1,150 participants—including patients, regulators, clinicians, academics, and industry representatives—to examine where rare disease clinical trials are falling short, and how they might be redesigned to better reflect biological reality, regulatory expectations, and lived experience.
Why conventional trial models fall short in rare disease
At the heart of the challenge lies scale—or the lack of it. Rare disease trials typically involve small, geographically dispersed patient populations, making recruitment slow and conventional statistical power difficult, if not mathematically impossible, to achieve. At the same time, genetic and clinical heterogeneity means that patients with the “same” diagnosis may experience markedly different symptoms, disease trajectories, and treatment responses. Speakers across the webinar series agreed that trial designs developed for common conditions are often ill-suited to these realities.
Long diagnostic journeys further complicate matters, delaying both early intervention and opportunities to participate in research. Add to these, limited commercial incentives and regulatory frameworks that still assume large populations, and it becomes clear why progress has been uneven.
Aligning feasibility with scientific rigour
The opening session of the webinar series set the scene by outlining the RealiseD project’s ambition: to develop methodologies and regulatory pathways that are proportionate to rare disease contexts while maintaining scientific integrity. Panel discussions highlighted practical constraints, the need for regulatory alignment, and the importance of building data infrastructures capable of supporting evidence generation in very small populations.
A recurring message stood out: in ultrarare diseases, flexibility is not a compromise. It is a prerequisite.
Evidence assessment in a changing regulatory landscape
The second webinar addressed critical challenges in rare disease evidence assessment within the context of EU HTA Regulation implementation. The discussion revealed a constructive tension between methodological rigor and practical realities. While some panelists emphasized that robust evidence generation remains essential, —with no convincing practical and scientific rationale for different evidentiary standards across disease types—, others articulated how traditional frameworks often prove inadequate for rare diseases.
The dialogue acknowledged a complex equilibrium: maintaining scientific integrity while recognizing that traditional statistical power is mathematically impossible in rare disease contexts. The consensus was not about lowering standards but adapting methodologies to become solutions rather than barriers to equitable access.
“Different approaches” was framed not as “less rigorous,” but as rigor applied in a contextually appropriate way. Panelists emphasized the importance of early multi-stakeholder dialogue, the use of innovative and flexible methodological designs, consideration of alternative regulatory pathways, and the central role of patient perspectives in guiding evaluation frameworks.
The concept of "totality of evidence" emerged as a potential solution—enabling comprehensive assessment through joint regulatory-HTA consultations rather than applying fragmented standards that delay patient access.
Rethinking trial design: beyond the two arm RCT
With traditional two arm randomised controlled trials (RCT) often proving not feasible in the context of rare diseases due to ethical, logistical, or recruitment constraints, a later session explored what alternatives might look like in practice. Single arm trials, RCTs, Bayesian approaches, and the use of real-world evidence were all discussed as potential tools—provided their limitations are clearly understood.
Single arm trials, for example, could be appropriate when treatment effects are substantial or placebo use would be unethical, but they also pose challenges for causal interpretation. Speakers cautioned against assuming that external controls or real-world data automatically strengthen evidence.
Panellists from regulatory agencies, industry, and patient organisations discussed that no single design fits all situations. Instead, they argued that trial design in rare diseases should be determined case by case, balancing feasibility, methodological rigor, and stakeholder needs while ensuring transparency about uncertainty.
Putting patient priorities at the centre of trial endpoints
A recurring thread across all sessions was the central role of patients—not only as participants, but as partners in defining meaningful outcomes. This was the focus of the fourth webinar where several speakers emphasised that outcome measures must capture what matters most to patients’ daily lives, rather than relying solely on clinical or surrogate endpoints.
The use of hierarchical endpoints in Generalised Pairwise Comparisons (GPC), which measures treatment effect as Net Treatment Benefit (NTB), was proposed. Rather than relying on a single primary endpoint, this method allows multiple outcomes to be prioritised and assessed together, reflecting the trade-offs patients often face in real life. This approach, which performed well even in small samples as seen in paediatric epilepsy, helps ensure trials remain both statistically robust and meaningful for rare disease communities.
The central role of patients in defining outcome hierarchies was also highlighted as a clear opportunity to improve quality of life measurement, while speakers emphasised that early and ongoing dialogue with regulators will be essential to ensure acceptance and consistent interpretation.
Lessons from the RealiseD webinar series to rethink clinical trials for rare diseases
The RealiseD webinar series highlighted a growing consensus: the need to use smarter designs to make evidence generation possible—and meaningful—in rare diseases. Earlier and closer alignment between regulators and HTA bodies can reduce fragmentation and uncertainty. Structured patient involvement can help ensure trials measure what truly matters. And shared learning—through ERN-led pilots across rare disease areas—offers a way to move from isolated solutions to transferable standards.
Indeed, methodological innovation, regulatory dialogue, and patient engagement are increasingly converging—but translating these discussions into routine practice remains the next challenge. For patients still waiting for effective treatments, progress will depend not only on scientific discovery, but on the willingness of the research ecosystem to rethink how evidence is generated, assessed, and valued.
This project is supported by the Innovative Health Initiative Joint Undertaking (IHI JU) under grant agreement No 101165912. The JU receives support from the European Union’s Horizon Europe research and innovation programme and COCIR, EFPIA, Europa Bío, MedTech Europe, and Vaccines Europe. Views and opinions expressed are those of the author(s) only. They do not necessarily reflect those of the Innovative Health Initiative Joint Undertaking and its members, who cannot be held responsible for them.