Europe has made real progress in rare disease innovation, supported in part by incentives for R&D in rare-disease therapies under frameworks, such as the 2000 Orphan Medicines Regulation. Before 2000, the number of EU-approved rare disease treatments (or ‘orphan medicines’) was in the single digits; by 2026, there are now well over 250. Yet, for the vast majority of rare diseases, effective treatment options still remain limited.
Two decades on, these rules have been revised. In that context, the new EU General Pharmaceutical Legislation introduces a more formal, criteria-based definition of Unmet Medical Need (UMN) and links incentives to new medicines addressing UMN to guide investment and innovation specifically towards areas where it is needed most. Under the revised framework, a treatment is considered to address UMN where it targets a life-threatening or severely debilitating disease for which no treatment exists, or where it delivers a clinically relevant improvement in outcomes. Importantly, orphan conditions are automatically included within scope.
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To ensure this works in practice, the European Medicines Agency (EMA) is now tasked with developing guidelines to operationalise this definition. Here, the stakes are high for people living with rare diseases. While orphan medicinal products do automatically qualify within the EU framework, the broader framing of UMN will influence how rare diseases are interpreted, prioritized, and valued in practice.
Over time, newborn screening and lifelong dietary management have improved outcomes, but they have not eliminated the burden
Against this backdrop, Phenylketonuria (PKU) is a useful test case. PKU is a rare inherited metabolic disorder that prevents the breakdown of phenylalanine (Phe). Without treatment, Phe accumulates to toxic levels, causing severe and irreversible brain damage and lifelong neurological impairment.
Over time, newborn screening and lifelong dietary management have improved outcomes, but they have not eliminated the burden. Many children and adults still experience fluctuating blood Phe levels, executive function difficulties, anxiety and depression, and other comorbidities.
As a result, if EMA guidelines are defined too narrowly – focusing primarily on clinical endpoints, or the presence of treatment alone – this could discourage further innovation in areas that matter most to patients, including quality of life, cognitive outcomes, and reduction of treatment burden.
Before 2000, the number of EU-approved rare disease treatments (or ‘orphan medicines’) was in the single digits; by 2026, there are now well over 250
In practical terms, for many people affected by PKU, daily life involves a relentless lowprotein diet, synthetic protein supplements, frequent blood monitoring, and social limitations. Psychological support is often limited despite clear mental health needs.
Compounding this, PKU is still too often treated as a ‘childhood disease’, with inadequate transition from pediatric to adult care. Studies on ageing with PKU, including risks and management of comorbidities, is limited, leaving patients under-supported later in life. These gaps persist across the lifespan – shaping study, work, relationships, families, social lives, and aging. PKU is far from ‘solved’.
With this in mind, the EMA has committed to consulting patients and industry when developing UMN guidelines. We believe that engagement should deliver an approach that:
Ultimately, UMN guidelines will influence which innovations are pursued and which therapies reach patients in Europe. It is important to get them right to sustain Europe’s rare disease leadership and to enable the incremental progress patients need for lifelong, meaningful health.
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