Rare Diseases at a European Crossroads: Which Way Forwards for Patients?

Will Overhauling the European Union (EU) Pharmaceutical Legislation Create Gaps in the Competitive Landscape?

The upcoming reform in EU pharmaceutical legislation, the first of its kind in twenty years, has the potential to bolster Europe’s orphan drugs market competitiveness and also to pose challenges. One positive proposal was the reduction of the European Medicines Agency market authorisation pathway from 210 to 180 days,1 facilitating quicker access for patients in need. However, proposed changes such as alterations in incentives and attenuated market exclusivity assurances may deter companies from launching within the EU (as opposed to the United States [US]).

The EU pharmaceutical legislation reform sparks a new chapter for rare diseases. Tighter restrictions can be seen as a reaction to some stakeholders taking advantage of incentives to push unreasonably high prices, unjustifiably salami-sliced indications and poor-quality evidence. Undoubtedly these restrictions may disincentivise manufacturers from prioritising investment in European markets. Arguably these measures will enforce commitments to wider evidence generation, offering an opportunity for more frequent use of methods such as the application of real-world data (including external control arms), more robust elicitation of expert opinion and improved methods for evaluating health-related quality of life.2, 3 With these changes to EU legislation provoking industry criticism, and the launch of the new Medicines and Healthcare Products Regulatory Agency (MHRA) regulatory reliance routes imminent,4 the United Kingdom has a chance to further its ambitions to be seen as an innovation hub in life sciences. Increased MHRA independence, such as the world-first approval of the CRISPR-based Casgevy® for the treatment of sickle cell disease and beta thalassemia, shows the kind of world-leading advances that are possible.5

International Collaboration for Improved Data Quality

Surrogate outcomes are often required in rare disease studies, which increases clinical uncertainty as the relationship between the surrogate and final clinical outcomes may not be validated. One promising development was an international collaboration of health technology assessment (HTA) agencies proposing to publish draft guidance on best practices for using surrogate outcomes. The collaboration group acknowledged the current reliance on surrogate outcomes due to data immaturity and considered that appropriate surrogate outcomes can reliably predict clinical outcomes when long-term data from randomised controlled trials (RCTs) are not available. Although these developments move closer to a consensus on the use of surrogate outcomes, the collaboration group acknowledged that even validated surrogates require cautious application and may not be universally accepted, due to potential inconsistencies (e.g. geographies, clinical settings).

Cross-border collaboration was also evident in the European Health Data Space. The benefits of collated European data must be weighed against the quality and comparability of data across different health systems. The lessons learnt from established federated data networks abroad, such as in the US, could inform strategies to address the complexities of pooling data at an EU level.

As Rare Communities Drive Real-World Evidence (RWE) Innovation, Are They Carrying Its Burden?

In the last five years, RWE has become more widely accepted by payers to address data gaps for rare disease indications, and it is particularly crucial when an RCT is not feasible and/or would be unethical to conduct. Moreover, RWE can provide unique insights into natural history and patient experiences when these data are unattainable through conventional methods (e.g. when a prospective natural history study is no longer feasible due to widespread treatment uptake). However, challenges must still be overcome to ensure robust RWE can be obtained from different settings. Considering the unique features of individual health data systems across Europe, stakeholders need to be cautious about the validity of findings derived from amalgamated datasets. There is therefore an urgent need for standardised methodologies and stronger collaboration across Europe to harmonise RWE practices. While ongoing pilot studies, such as DARWIN EU’s natural history study in rare blood cancers,6 may promote consensus among HTA bodies on the use of RWE, manufacturers will need to strategise and engage early to ensure RWE data sources are relevant and useful.

European Reference Networks (ERNs) have helped to generate robust RWE for rare disease management and research, as highlighted at the World Orphan Drug Congress 2023. ERNs, connecting over 1600 healthcare units and 400 hospitals,7 form a unique component of the European healthcare ecosystem. By addressing regional governance and institutional barriers, ERNs position Europe as a leader in real-world data collection for rare diseases. The conference spotlighted the Together for Rare Diseases (Together4RD) initiative, targeting tangible and perceived barriers to ERN-industry collaboration, for example by consolidating good practices from disease-related pilots to demonstrate how ERNs can work with industry.8 Graham Slater of EURORDIS described this opportunity to advance ERN research as significant, given the >30 million people in the EU living with a rare disease.9

The increasing development of advanced therapy medicinal products, with claims of long-term (or lifelong) effectiveness, leads to a growing need for RWE to demonstrate sufficient clinical value to justify high one-off treatment costs. With smaller populations requiring fewer resources to support this evidence generation, RWE efforts often centre in the rare disease space. This threatens rare disease communities with the increased burden of supporting RWE innovation, particularly given that rare conditions are often complex and heterogeneous. This creates the risk that already underserved rare disease communities bear the brunt of failed experimentation or substandard methods for RWE analysis; it is therefore critical that the HEOR community as a whole works to further best practices for use of RWE, to ensure its application in the rare disease setting is appropriate and fully realises its potential to benefit these patients.


  1. DLRC Ltd. EU Pharmaceutical Legislation Proposal: an Overview. 2023. Available here. Last accessed: 21 November 2023.
  2. Member Group Meeting. ISPOR Good Practice Task Force Recommendations on Valuing HRQoL of Children & Adolescents in Economic Evaluation Open Meeting (Pediatric Utilities). ISPOR Europe Congress, Copenhagen, Denmark, 2023.
  3. Breakout 152. Measuring Health Related Quality of Life in Pediatric Life Limiting Progressive Diseases: Whose Perspective Are We Measuring? ISPOR Europe Congress, Copenhagen, Denmark, 2023.
  4. Medicines and Healthcare Products Regulatory Agency. MHRA announces new recognition routes to facilitate safe access to new medicines with seven international partners. 2023. Available here. Last accessed: 27 November 2023.
  5. British Broadcasting Corporation. Casgevy: UK approves gene-editing drug for sickle cell. 2023. Available here. Last accessed: 20 November 2023.
  6. European Network of Centres for Pharmacoepidemiology and Pharmacovigilance. EUPAS50800 – DARWIN EU® – Prevalence of rare blood cancers in Europe. 2023. Available here. Last accessed: 20 November 2023.
  7. European Commission. European Reference Networks. 2023. Available here. Last accessed: 21 November 2023.
  8. Hedley, V; Bolz-Johnson, M; Hernando, I et al. Together4RD position statement on collaboration between European reference networks and industry. Orphanet J Rare Dis. 2023;18(1):272.
  9. Open Access Government. Help 36 million people in Europe with rare diseases. 2023. Available here. Last accessed: 21 November 2023.

If you would like any further information on the themes presented above, please do not hesitate to contact Tom Gleeson, Senior Analyst (LinkedIn), or Annabel Griffiths, Global Head of Rare Diseases (LinkedIn). Tom Gleeson and Annabel Griffiths are employees at Costello Medical. The views/opinions expressed are their own and do not necessarily reflect those of Costello Medical’s clients/affiliated partners.