The European orphan drug landscape has witnessed remarkable growth over the past decade, with more than 192 orphan medicinal products approved through 2022 under the EU Orphan Medicinal Products Regulation. Despite this progress, a sobering reality persists: approximately 95% of rare diseases still have no approved treatment options, leaving millions of patients without therapeutic solutions.
The recent conditional approval of Casgevy (exagamglogene autotemcel), Europe's first CRISPR-based gene-editing therapy for severe sickle cell disease and transfusion-dependent beta thalassemia, exemplifies both the promise and challenges in this space. While the approval offers hope to approximately 8,000 eligible patients, Casgevy now faces the complex journey through country-specific health technology assessment (HTA) processes and price negotiations—a path that can be particularly difficult for innovative, high-cost therapies.
Divergent HTA Outcomes Across Europe
Once an orphan drug receives EU-level approval, its fate fragments across Europe's patchwork of national HTA bodies and payer systems, resulting in inconsistent patient access and reimbursement decisions.
Germany: High Approval, Limited Recognized Value
Germany leads with a remarkable 98% approval rate for orphan drugs. However, this statistic masks a critical nuance: 73% of these approvals received a "non-quantifiable benefit" designation—an automatic classification under Germany's orphan drug rule indicating no proven added benefit over existing therapies. Only about 25% demonstrated minor to major added benefit.
The German system ensures near-universal coverage through a special framework that waives full comparative assessments up to a certain revenue threshold. However, companies seeking higher benefit ratings face significantly longer price negotiation periods—averaging 708 days compared to 510 days for those accepting the basic orphan designation.
France: Balanced Approach with Value Recognition
France's HTA agency (HAS) approved approximately 92% of reviewed orphan drugs between 2013-2019, assessing more orphan products (67) than most peer countries. Notably, only 19% received the lowest added-value rating (ASMR V, meaning "no improvement"), with the majority demonstrating at least some improvement in medical benefit.
Interestingly, drugs with higher ASMR ratings (I-III, indicating major to moderate improvement) took longer to secure reimbursement—585 days on average versus 427 days for those with lesser improvement ratings. This suggests that pricing negotiations for high-impact innovations can be more protracted, possibly reflecting harder bargaining when therapeutic value is substantial.
England: Conditional Approvals and Access Schemes
NICE, England's HTA body, achieved a 91% positive recommendation rate for orphan drugs. However, more than one-third (37%) of these approvals came with restrictions to specific patient subgroups or special conditions rather than full indication approval.
Two key mechanisms frequently enabled approval: label restrictions (limiting coverage to certain patient subsets) and Patient Access Schemes (PAS), such as confidential discounts or outcome-based agreements. Companies accepting narrower patient populations saw faster positive decisions (407 days versus 505 days without restrictions), while introducing a PAS improved approval chances but extended timelines (523 days with a PAS versus 311 days without).
Scotland: Strictest Assessment Standards
Scotland maintained the most stringent HTA outcomes, with only 67% of orphan medicines assessed by the Scottish Medicines Consortium receiving approval—meaning one in three were rejected entirely, despite Scotland's special modifiers for rare diseases, including the Patient and Clinician Engagement (PACE) process to incorporate patient input.
The Evidence Gap Challenge
The mixed HTA results and frequent demands for concessions stem largely from the inherent evidence limitations in rare disease drug development. Small patient populations make large-scale Phase III trials difficult or impossible, resulting in many orphan approvals based on limited clinical packages—often single-arm studies, surrogate endpoints, or historical controls.
This evidence gap creates significant uncertainty at the HTA stage. Cost-effectiveness modeling for ultra-expensive orphan therapies becomes highly sensitive to these uncertainties, where small changes in assumptions can dramatically alter a drug's perceived value proposition.
Orphan drug developers face a fundamental dilemma: accelerating regulatory approval for patients with urgent unmet needs often requires accepting limited trial evidence, but this very limitation later hinders reimbursement negotiations. Bridging this evidence gap has become crucial for improving orphan drug access.
Real-World Evidence: A Growing Solution
Real-world evidence (RWE)—data gathered outside controlled clinical trials—is emerging as a powerful tool to support orphan drug development and access. RWE encompasses diverse data sources including patient registries, electronic health records, insurance claims, pharmacy data, mobile health apps, and wearables.
For orphan drugs specifically, RWE offers a way to fill the evidence void left by small pre-approval trials, enabling continuous collection of real-world outcomes once a drug enters clinical use. It can also better characterize the unmet needs of rare disease populations, strengthening value propositions for new therapies.
"Harnessing real-world data effectively can shorten development timelines and provide access to medicines earlier for patients by complementing clinical trial evidence," notes Dr. Raymond Huml of Sciensus, a leading rare disease expert.
Regulatory agencies have increasingly embraced RWE as a valid component of evidence packages. Both the FDA and EMA now accept certain real-world studies to support drug approvals or label expansions, through initiatives such as the EMA's Adaptive Pathways pilot and the FDA's Real-World Evidence Framework.
RWE's Rising Industry Prominence
What was once a niche concept is now becoming mainstream in pharmaceutical strategy. In GlobalData's latest industry survey, RWE ranked as the fourth most impactful trend anticipated for 2025.
The industry's pivot toward RWE is evident in corporate communications, with mentions of "real-world evidence" in pharmaceutical company filings surging in recent years. Executive discussions of RWE on earnings calls, in annual reports, and R&D strategy updates have increased dramatically, with consistently positive industry sentiment scoring 0.86 (on a scale of 0 to 1) in 2024.
This trend is translating into concrete action. GlobalData's analysis of clinical trial registries shows a steady rise in RWE-focused studies over the past decade, with consecutive growth since 2012. The COVID-19 pandemic further accelerated RWE generation, as researchers sought to leverage real-world patient data amid the crisis.
Improving HTA Outcomes for Orphan Drugs
Pharmaceutical companies can take several approaches to enhance orphan drug approval chances despite limited data availability:
-
Proactive RWE Planning: Agreeing on methods for ongoing real-world data collection post-launch with HTA bodies can address evidence gaps and uncertainty.
-
Creative Evidence Collection: Developing innovative approaches such as patient and HCP apps can facilitate continuous data gathering in rare disease populations.
-
Broader Stakeholder Engagement: Engaging the wider rare disease community, including patients and healthcare providers, can strengthen value propositions beyond clinical data.
-
Value-Added Services: Offering supplementary services that reduce administrative burden or improve disease management can enhance perceived value, as demonstrated by Amicus Therapeutics' Galafold for Fabry disease, which achieved favorable HTA outcomes partly through additional support services.
Looking Ahead
The orphan drug ecosystem in Europe is evolving into a more evidence-rich, data-driven environment. Pharmaceutical organizations are increasingly investing in real-world data infrastructure, rare disease patient registries, and analytics capabilities, recognizing that future market access may depend on robust evidence generation beyond traditional clinical trials.
For the approximately 30 million Europeans affected by rare diseases, this evolution offers hope that the evidence gap hindering orphan drug development and access may gradually narrow, potentially accelerating both the development and uptake of new therapies for conditions that have long lacked treatment options.
