A shifting European policy landscape: How will Europe’s new incentives reshape rare-disease clinical development?

Europe has introduced a flurry of policy initiatives to strengthen its life-sciences ecosystem. This comes against a backdrop of declining European competitiveness: a report commissioned by EFPIA and Vaccines Europe found that between 2013 and 2023, the EEA’s share of global Phase I–IV clinical-trial starts fell from 18% to 9%.¹ 

The Biotech Act is one of the core policies announced to change this tide by seeking to mobilise private investment across the development pathway. During consultation on the Biotech Act, stakeholders recognised that Europe’s competitiveness challenge extends beyond investment, with barriers identified across clinical development, regulation, commercialisation and manufacturing.^2,3 

So what else is the EU doing to build this ecosystem? The Joint Clinical Assessment(JCA) and the Pharmaceutical Package add two further dimensions, connecting decisions made during clinical development with regulatory incentives and downstream HTA requirements. This article asks whether these policies work coherently and what sponsors should consider while clinical programmes can still be shaped.^4,5  

Creating incentives for breakthrough therapies 

The Pharmaceutical Package announced a revision of the regulatory protection and market exclusivity offered to developers, with potential consequences for clinical trial design. Under the previous framework, an authorised orphan indication generally received ten years of market exclusivity. Under the new agreed framework, technologies that meet the definition of a “breakthrough orphan medicinal product” will receive 11 years of exclusivity, while standard orphan medicines would receive 9 years. To qualify for ‘breakthrough’ status, no medicinal product must already be authorised in the EU for the relevant orphan condition, and use of the new medicine must result in a clinically relevant reduction in disease morbidity or mortality for the relevant patient population.^6,7 

One immediate concern is that there is currently insufficient clarity on how “clinically relevant reduction in disease morbidity or mortality” will be measured to attain breakthrough status. Developers should seek this clarification urgently, because it could influence clinical trial decisions, for example: 

• Impact on endpoint selection: Will demonstrating an effect on a surrogate endpoint (which is common for rare diseases) be sufficient, or will more direct evidence of an effect on morbidity or mortality itself be required? 
• Impact on evidence strategy: Similarly, where a single-arm programme is clinically appropriate, sponsors will need to consider whether the evidence generated will be sufficient to demonstrate the magnitude of benefit required to be considered a clinically relevant reduction or whether additional external evidence will be needed to contextualise the effect

This is a tangible example of the interplay between clinical trial design choices, regulatory protection, and the associated long-term commercial opportunity. Separately, from an ecosystem perspective, a key question is whether the new framework will ultimately act as a pull incentive. If a meaningful proportion of orphan medicines achieve breakthrough status, the Pharma Package could offer an additional year of market exclusivity and thereby act as a real incentive. However, if relatively few products meet the threshold, more orphan medicines would receive nine years, one year less than under the previous framework. Without greater clarity on how the breakthrough criteria will be applied, it is difficult to know whether the Package represents a stronger pull incentive for rare-disease development or a reduction in the existing incentive.

Rewarding clinical development choices through market protection

Changes to market protection also extend beyond orphan innovations. Before the EU Pharmaceutical Package, non-orphan medicines benefited from eight years of regulatory data protection followed by two years of market protection (8+2), with a potential further year for a qualifying new indication. Under the new Package, this would become a baseline of 8+1. Sponsors can gain an additional year of market protection through several conditional routes: 

1. Medicinal product addresses an unmet medical need; or 
2. Relevant/evidence-based comparator + early EU filing; or 
3. Relevant/evidence-based comparator + trials in >1 Member State; or 
4. If the comparative trial is not possible/appropriate: >1 Member State + early EU filing

A further year remains available for a qualifying new indication providing significant clinical benefit, with overall data and market protection reaching a maximum of 11 years. The conditional criteria are particularly interesting from a clinical-development perspective because they explicitly link choices made during clinical trial planning to market-protection outcomes. Two practical considerations for sponsors include:

• Comparator strategy: Where a comparative trial is planned, sponsors need to consider a relevant and evidence-based comparator in accordance with EMA scientific advice; an important outstanding question is how this requirement will operate in practice, including whether scientific advice must be sought and how different comparator choices will be treated
• Feasibility and site selection: The multi-Member State incentive could become an additional consideration when selecting and prioritising sites; for example, a European site that previously sat just below the selection cut-off could become more attractive once the potential market-protection benefit of recruiting across multiple Member States is factored into the decision

Implementing a coherent policy landscape

One aspect worth examining is how the evidence expectations across these policies interact. As noted earlier, the Pharmaceutical Package may potentially reward comparative trials; similarly, comparative data is also the cornerstone of the JCA process. JCA has been operational since January 2025, with orphan medicines entering scope from 2028. The JCA assesses the relative effects of a new intervention against comparators relevant to EU Member States.

Thus far, eight JCAs have had an outcome: four published reports, three discontinuations and one withdrawal. Across the four published reports, the proportion of requested PICOs that could be assessed varies substantially, as shown in Table 1. Importantly, generating comparative evidence does not necessarily mean generating the right comparative evidence for JCA; the study design needs to anticipate the comparators and questions likely to be relevant to JCA – even an RCT can have gaps as observed in the JCA – for Itvisma, evidence was requested across 14 PICOs, but only 7 could be assessed.⁸ 

Table 1: PICOs required and assessed across the four published JCAs⁹ 

Both reforms therefore seem to place importance on comparative evidence; one risk for sponsors, however, is assuming that a trial designed to support additional market protection will also meet the needs of JCA assessors. Clinical development teams should therefore take a holistic approach to trial design rather than optimising solely for regulatory approval. A well-designed comparative study can potentially serve multiple purposes: supporting regulatory approval and market protection, while also providing the evidence that underpins the JCA as well as the HTA and reimbursement decisions that follow. 

There is also a separate consideration for breakthrough orphan medicines. The Pharmaceutical Package offers breakthrough status for technologies addressing orphan conditions for which no medicinal product is already authorised in the EU. For some rare diseases, small patient populations, limited treatment options and ethical considerations can make randomised controlled trials difficult or impractical, leading developers to rely on single-arm evidence. However, as illustrated in the Ojemda case study in Table 1, this can create challenges for JCA, which seeks to assess relative effects against relevant comparators. A sponsor might therefore reasonably consider a single-arm trial in a first-in-condition programme, particularly where the development objective includes breakthrough status. However, the absence of an authorised treatment does not necessarily mean there is no relevant comparator for downstream JCA or HTA assessors; relevant comparators may include best supportive care or no active treatment. The same programme could therefore be well positioned for regulatory approval and potentially breakthrough status but still leave a substantial comparative-evidence gap for JCA.

Implementing a proactive approach to clinical trial development

An emerging challenge for JCA is its proximity to EMA regulatory filing, which draws resources from an organisation during an already intensive period. This pressure can be compounded when submission teams must work with clinical trial data that was not designed to meet the expectations of JCA assessors or downstream payers in the HTA process. Thus far, three JCAs have been discontinued, and while it is too early to attribute these discontinuations to any single cause, they raise an important question around developer readiness.^10,11 

So what could JCA readiness mean in the context of a clinical development programme? Sponsors should take a proactive approach to anticipate the comparative questions that may come from JCA assessors. One way to do this is through the Joint Scientific Consultation (JSC) process, the EU’s early scientific advice for JCA. It should be noted that sponsors can only access the process during planning of the pivotal trial, when JSC findings can still shape the clinical programme.¹² 

Conclusion

Europe is clearly seeking to create stronger incentives for rare-disease innovation and clinical development, but whether these reforms work will depend on how sponsors respond to them and how coherently the different policies operate together. So, what are the key takeaways? The common thread across this article is timing and alignment; sponsors need to understand Europe’s requirements, incentives and consequences early enough to respond while the development programme can still be shaped.

Three final reflections, for three stakeholders:

• For executive teams: demand a “do it once, do it right” mindset, creating an organisational expectation that development programmes consider the full evidence lifecycle rather than optimising primarily for regulatory approval
• For clinical development teams: understand how the evolving European policy landscape changes the consequences of decisions around endpoints, trial design, comparator strategy and trial geography, and broaden the stakeholders involved in making those decisions while the programme can still be shaped
• For market access teams: use these policy changes to demonstrate why your voice matters during clinical development; educate development teams on the different perspectives through which comparative evidence will be assessed, and use opportunities such as JSC to ensure JCA and downstream HTA requirements are considered before the pivotal trial is fixed

Resources

1. https://www.efpia.eu/media/0ipkatpg/efpia-ct-report-embargoed-221024-final.pdf
2. https://ec.europa.eu/info/law/better-regulation/have-your-say/initiatives/14627-Biotech-Act/public-consultation_en
3. https://health.ec.europa.eu/biotechnology/european-biotech-act_en
4. https://www.consilium.europa.eu/en/press/press-releases/2026/09/28/pharma-package-council-adopts-new-rules-for-a-fairer-and-more-competitive-eu-pharmaceutical-sector/
5. https://health.ec.europa.eu/health-technology-assessment/implementation-regulation-health-technology-assessment/joint-clinical-assessments-medicinal-products_en
6. https://ec.europa.eu/commission/presscorner/detail/en/ip_25_3015
7. https://data.consilium.europa.eu/doc/document/ST-7105-2026-INIT/en/pdf
8. https://health.ec.europa.eu/document/download/d947533e-7e4e-4e82-a9c6-e06830d708f8_en?filename=hta_ongoing-jca_en.xlsx
9. https://health.ec.europa.eu/health-technology-assessment/key-documents_en?f%5B0%5D=topic_topic%3A247
10. https://www.linkedin.com/pulse/two-jcas-discontinued-what-went-wrong-should-sponsors-chowdhury-cotie/
11. https://www.linkedin.com/feed/update/urn:li:activity:7510962473458515971/
12. https://health.ec.europa.eu/health-technology-assessment/implementation-regulation-health-technology-assessment/joint-scientific-consultations_en

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