Europe has witnessed strong growth in orphan drug approvals over the past decade, yet for pharmaceutical innovators, securing market access for these rare disease therapies remains challenging without the right support. Dozens of new orphan medicines are reaching the market each year under the incentives of the EU Orphan Medicinal Products Regulation, which since 2000 has spurred more than 192 orphan drug approvals through 2022. But behind the celebratory headlines, a sobering reality persists: today, approximately 95% of rare diseases still have no approved treatment options. [1] Rising to this challenge to reap the rewards requires finding the right partner to navigate the complexities.

One recent landmark approval illustrates both the promise and the difficulties. In early 2024, the European Commission granted conditional approval to Casgevy (exagamglogene autotemcel), a first-in-class gene-editing therapy for severe sickle cell disease and transfusion-dependent beta thalassemia. This was a milestone, Europe鈥檚 first CRISPR-based treatment, making roughly 8,000 eligible patients newly hopeful for a cure. Yet Casgevy鈥檚 journey is far from over, and like many orphan drugs, it is now undergoing health technology assessment (HTA) and price negotiations in each country. The road from EMA approval to national reimbursement can be especially difficult for ultra-expensive, first-of-its-kind therapies, even as they hold life-changing potential. To reach the finish line, pharma companies need to have a clear understanding of the challenges to come and find the right support so that they can focus on what鈥檚 most important: life saving science.

Divergent HTA outcomes across Europe

Once an orphan drug is approved at the EU level, its fate splinters across Europe鈥檚 patchwork of national HTA bodies and payer systems. Notably, HTA outcomes for orphan drugs vary widely by country, leading to inconsistent patient access.

A comparative analysis of orphan drug reimbursement decisions from 2013鈥�2019 in major EU markets reveals striking differences [2]:

Germany

Approximately 98% of EMA-approved orphan drugs ultimately received a positive reimbursement decision in Germany. However, 73% of those were assigned a 鈥渘on-quantifiable benefit鈥�, an automatic designation under Germany鈥檚 orphan drug rule, indicating the regulator saw no proven added benefit over existing therapies. Only about a quarter of orphan drugs (25%) demonstrated a minor to major added benefit in the eyes of German assessors. While this policy ensures near-universal coverage (thanks to a special framework waiving full comparative assessments up to a certain revenue threshold), it also highlights the evidence gaps for most orphan drugs at launch. When a company did seek a higher added benefit rating in Germany, it took on average 708 days to reach a price agreement, significantly longer than the 510 days for those accepting the basic orphan designation.

France

Approximately 92% of orphan drugs reviewed by France鈥檚 HTA agency (HAS) from 2013鈥�2019 were approved for reimbursement, and France assessed far more orphans (67 drugs) in that period than most peers. Importantly, only 19% received the lowest added-value rating (ASMR V, meaning 鈥渘o improvement鈥�), and the vast majority showed at least some improvement in medical benefit (ASMR I鈥揑V) according to HAS. Counterintuitively, drugs with higher ASMR ratings (I鈥揑II, indicating major to moderate improvement) actually took longer on average to get reimbursed (585 days) than those with lesser or no improvement (427 days for ASMR IV鈥揤). This suggests that pricing negotiations for high-impact innovations can be protracted in France, perhaps reflecting harder bargaining over price when the therapeutic value is clearly substantial.

England (NICE)

Approximately 91% of orphan drugs appraised by NICE achieved some form of positive recommendation. However, more than one-third (37%) of these were only recommended for a restricted subgroup of patients or with special conditions rather than for the full broad indication. Two key mechanisms used to make orphan drugs acceptable were label restrictions (limiting coverage to certain patient subsets) and Patient Access Schemes (PAS), such as confidential discounts or outcome-based agreements. Companies that agreed to narrower patient populations saw faster positive decisions on average (approximately 407 days vs 505 days without restrictions). Introducing a PAS could improve the chance of approval as well, though it tended to delay the overall timeline (523 days with a PAS vs. 311 days when no PAS was needed).

Scotland

Among these countries, Scotland had the strictest HTA outcomes for orphan drugs. Only approximately 67% of orphan medicines assessed by the Scottish Medicines Consortium were ultimately accepted for use, meaning one in three (33%) were not recommended at all, the highest rejection rate of the group. This is despite Scotland鈥檚 system employing special modifiers for rare diseases (including the Patient and Clinician Engagement, or PACE, process to incorporate patient input in 74% of submissions). The data suggest that even with flexibility measures, a significant portion of orphan drugs fail to convince Scottish authorities of sufficient value to justify their price.

Understanding the evidence gap

But why do orphan drugs so often encounter mixed HTA results and demands for concessions? A major reason is the evidence gap inherent in rare disease drug development. By nature, orphan drugs target small patient populations, making large-scale Phase III trials difficult or sometimes impossible. Many orphan approvals rest on thin clinical packages, often single-arm studies, surrogate endpoints, or historical controls, which leave payers unconvinced about real-world benefit.

Compounding this, orphan trials often use surrogate endpoints or short-term outcome measures due to practical timelines, when what payers want is evidence of long-term survival, quality of life improvement, or healthcare cost offsets. The result is a high degree of uncertainty at the HTA stage. Cost-effectiveness modelling for ultra-expensive orphan therapies, which frequently come with six-figure price tags, is highly sensitive to those uncertainties, and a small change in assumptions can swing a drug from an acceptable value proposition to an untenable one.

In short, orphan drug developers face a Catch-22: to get regulatory approval quickly for patients with unmet needs, they often must rely on limited trial evidence; but that very limitation later hinders their reimbursement negotiations. Bridging this evidence gap is crucial to improving orphan drug access. Increasingly, all eyes are turning to one approach as a potential solution: real-world evidence (RWE).

Orphan drug access with real-world evidence

Real-world evidence, which refers to data gathered outside the controlled confines of randomised trials, is emerging as a powerful tool to support drug development and access, especially in rare diseases. RWE comes from a broad range of sources, including patient registries, electronic health records (EHRs), insurance claims, pharmacy data, mobile health apps, and wearables. Essentially, any information about how patients fare in everyday clinical practice can contribute to RWE. These data streams can provide insights across the healthcare ecosystem, from clinicians and researchers to payers, regulators, and policy makers. For orphan drugs, RWE offers a way to fill the evidence void left by small pre-approval trials, enabling the collection of real-world outcomes once the drug is in use. It can also be tapped as a way of better understanding the unmet needs of a rare patient population and thus the value that a new therapy could bring.

Importantly, regulatory agencies have begun to embrace RWE as a valid component of the evidence package. The FDA and EMA now both accept certain real-world studies to support drug approvals or label expansions. This regulatory openness has been growing in recent years through initiatives such as the EMA鈥檚 Adaptive Pathways pilot and the FDA鈥檚 Real-World Evidence Framework, which encourage manufacturers to augment clinical trial data with real-world data. As a result, RWE is expected to play an increasing role in drug development and approval of new medicines going forward. We are already seeing marketing applications where real-world data on historical disease progression or patient quality of life have helped convince regulators to approve a drug under exceptional circumstances, a trend that could especially benefit rare disease therapies.

RWE on the rise

Not long ago, real-world evidence was a niche concept, discussed mostly in the context of pharmacovigilance or post-marketing commitments. Today, it is becoming mainstream in pharma strategy. In GlobalData鈥檚 latest industry survey, RWE was identified as one of the top emerging trends for the near future, ranked fourth-most impactful trend for 2025 by respondents. By comparison, areas such as anti-obesity drugs and immuno-oncology topped the list.

An internal analysis by GlobalData even noted that the industry鈥檚 pivot to RWE is evidenced by the growth of the phrase 鈥渞eal-world evidence鈥� in company communications, with mentions of RWE in pharmaceutical company filings surging in recent years. Executives are discussing RWE on earnings calls, in annual reports, and in R&D strategy updates more than ever, with the analysis revealing a consistently positive industry sentiment for the trend, which scored 0.86 (on a scale of 0 to 1, with 1 being the strongest positive sentiment) in 2024.

Moreover, what was once mainly a talking point is now seeing concrete adoption. GlobalData鈥檚 analysis of clinical trial registries shows a steady rise in RWE-focused studies over the past decade. Year by year since 2012, the number of new trials explicitly leveraging real-world data has increased, demonstrating a consecutive growth trend through 2022. Notably, the COVID-19 pandemic catalysed an explosion of RWE generation, with 2020 and 2021 seeing the highest numbers of RWE studies registered as researchers sought to harness real-world patient data amid the urgency of the crisis.

RWE鈥檚 promise for the orphan drug landscape

Looking ahead, the growing role of RWE offers a pathway to overcome some of Europe鈥檚 orphan access barriers. By continuously generating evidence in the post-launch period, companies can address the uncertainties that caused HTA hesitation with evidence for cost-effectiveness and value-based pricing. This evidence can be used to support expansion in new indications or geographies.

The orphan drug ecosystem in Europe is evolving into a more evidence-rich, data-driven arena. Pharma organisations are investing in real-world data infrastructure, rare disease patient registries, and analytics capabilities, knowing that market access in the future may depend on it. As Dr. Raymond Huml of Sciensus (a leading rare disease expert) has pointed out, harnessing real-world data effectively can shorten development timelines and 鈥減rovide access to medicines earlier for patients鈥� by complementing clinical trial evidence. Indeed, for rare disease patients desperately awaiting new treatments, every month counts, and if RWE can expedite both development and uptake of new therapies, its impact will be profound.

[1] Trends in orphan medicinal products approvals in the European Union between 2010鈥�2022 | Orphanet Journal of Rare Diseases [2]https://pharmaphorum.com/views-analysis-market-access/how-does-hta-for-orphan-drugs-differ-across-europe