The diagnostic odyssey describes the long journey that patients with rare diseases go through, starting from their first symptom up until a confirmed diagnosis, spanning several years and misdiagnoses along the way. Diagnosis is the foundation for patients’ access to care, social support, and potentially treatment. In Europe, the average wait from first symptoms to confirmed diagnosis is around five years, while 60% of patients are initially misdiagnosed, as mentioned at the 13th European Conference on Rare Diseases and Orphan Products in Prague, Czech Republic, on 3–4 June, 2026.
At one of the symposiums, Dr. Holm Graessner, Managing Director of the Centre for Rare Disease at University Hospital Tübingen German and co-chair of the Aspire4Rare Diagnosis Expert Group, discussed Aspire4Rare Diagnosis, an initiative built around an archetype-based framework. Within this initiative, there are seven recurring patterns of diagnostic challenges, including awareness and referral, access to technology and knowledge, the social context of diagnosis, its dynamic and non-linear nature, economic burden, standardisation, and the role of research in unlocking answers. The aim of this initiative is to turn complexity into recognisable situations that non-rare disease specialists, particularly the policymakers and funders, can engage with. One speaker compared the diagnostic odyssey to a maze that patients need to navigate, and depending on a patient’s economic and geographical status, they may never enter the maze at all.
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Fragmentation is limiting the progress of rare disease diagnosis, rather than scientific knowledge, in the pharmaceutical industry. There has been a rapid accumulation of knowledge in recent decades, especially in genomics and diagnostics. However, the challenge is that this expertise and data are scattered across too many disconnected places. A potential solution to this could be high-end, networked centers capable of comprehensive diagnosis, with European Reference Networks empowered rather than replaced. Digital tools should not be used as a substitute for clinical judgment, but to direct patients to the right center. Also, systems must carry the load over individual clinicians, as these healthcare professionals cannot be expected to memorize thousands of conditions. Then, the framework’s real value is as a shared language across clinical, social, economic, and political domains. The bigger challenge is no longer knowing what to do, but working out how to deliver it.
Innovative clinical trials for rare diseases
Rare disease drug development has rapidly progressed, with the number of orphan drugs more than doubling over the past decade.
Orphan drugs now make up roughly a third of the pharmaceutical pipeline due to innovation and advancements within genomics and targeted therapies. Despite this, testing rare disease therapies through clinical trials remains a challenge. Rare diseases are usually found in small and geographically dispersed populations, and are often early-onset genetic conditions, making traditional clinical trials a poor fit. Danielle Dong, ScM CGC, Global Medical Scientific Advocacy Lead, Rare Diseases at Sanofi, discussed IHI RealiseD at the 13th European Conference on Rare Diseases and Orphan Products in Prague, Czech Republic, on June 3–4, 2026.
IHI RealiseD is a multi-stakeholder public-private partnership aimed at improving how clinical trials are run and evaluated in rare and ultra-rare diseases. With very small samples, randomisation cannot reliably balance the two arms of a traditional clinical trial, so a difference in outcome may reflect chance rather than the effect of the treatment being tested. Patient heterogeneity adds to the challenge, and while knowledge on several rare diseases remains scarce, trials often use endpoints from related common diseases that ultimately fail to capture what matters. Therefore, RealiseD works by extracting more from each patient through repeated measurements and multiple endpoints, adjusting for imbalance using non-parametric techniques rather than randomisation alone. Also, where a placebo cannot be used, this initiative can build synthetic control arms from registry data that model how patients would otherwise have progressed.
Additional challenges exist from a regulatory and health technology assessment (HTA) perspective. Marketing authorisations question whether a drug’s benefit outweighs its risks, while the HTA asks whether it is worth funding relative to existing options, which is especially difficult in rare diseases, where a relevant comparator may not exist. RealiseD aims to push dialogue between developers, regulators, and HTA bodies so that methods are agreed on before the evidence is generated, rather than contested at a later time. Ultimately, RealiseD encourages patients, clinicians, regulators, and HTA bodies to collaborate in tackling the same problem collectively.
