Early insights for orphan drugs and rare diseases

In 2028, treatments for rare diseases will fall within the scope of Joint Clinical Assessment (JCA) in the European Union (EU). This means treatments for rare diseases, traditionally assessed under more flexible national frameworks, will face a centralized, multi-country health technology assessment (HTA) process.

For manufacturers this represents both a challenge and an opportunity:

Rare diseases and why they bear greater burdens

As we mark Rare Disease Day on February 28, 2026, a day of raising awareness about how rare diseases affect the lives of individuals and families worldwide, it’s worth noting that pharmaceutical manufacturers are redoubling their efforts to bring new treatments through stringent health technology assessments under the European Union Health Technology Assessment Regulation.

In the European Union (EU) between 27 and 36 million people live with a rare disease, defined under Regulation (EC) No 141/2000 on Orphan Medicinal Products as a disease affecting no more than 5 in 10,000 people. Seventy percent of these rare diseases begin in childhood and 80% have a genetic cause.¹ Other causes include bacterial or viral infections, allergies, degenerative, proliferative causes, chemicals, radiations or a combination of these factors.² Nonetheless, for the majority of rare diseases, research is ongoing to fully understand why rare and ultra-rare disease happens and how these conditions develop at a biological level.

For pharmaceutical manufacturers, rare disease treatments often qualify for orphan or ultra orphan drug designation because they address conditions affecting these very small patient populations. While this designation offers certain regulatory incentives, it also comes with distinct challenges, that will be even greater under Joint Clinical Assessment (JCA).

One of the major hurdles manufacturers will face is the limited size of the patient population, with few patients and limited clinical expertise in treating the condition, conducting large, randomized clinical trials is often impractical, but more likely impossible. Care pathways and availability of treatments can vary significantly across EU countries, increasing the complexity of the evidence dossier that manufacturers need to submit for JCA.

Evidence generation poses further difficulties. In rare diseases, single‑arm trials are common, and surrogate endpoints may be used; however, these endpoints are often unvalidated from an HTA perspective, potentially weakening the perceived robustness of results and therefore the perceived value of the product. Compounding this, there may be limited evidence and understanding in a number of areas, including treatment pathways, current disease burden, costs associated with managing and treating the condition, etc. This scarce or incomplete natural history data makes comparative effectiveness more challenging, especially in the context of single-arm trials. Given this, there is often a need to rely on input from clinical experts or real-world evidence to fill these gaps in the evidence base.

Given these obstacles, manufacturers cannot afford to be reactive. Under JCA’s expanded scope and heightened stringency, resorting to last‑minute fixes may not be possible. Preparation must begin years in advance to ensure that the evidence package meets the demanding cross‑EU country requirements from the outset.

Manufacturers must overcome challenges

From both regulatory and practical experience, the main hurdles orphan drug manufacturers will face from 2028 will include:

Evidence Scope – Disease recognition and diagnosis, lack of familiarity with rare diseases, heterogeneity in disease presentation and geographic variation in existing treatments

Trial Design Limitations – Lack of sufficient and robust clinical data, no established standard of care and heterogeneity of prognosis and treatment effect

Endpoint Validation – Lack of validated instruments to assess efficacy and effectiveness end points

Insufficient Knowledge – Insufficient knowledge of the natural history of the disease

Quality of Life (QoL) Data Deficits – Proxy data or vignette studies are sometimes used, but these are suboptimal for HTA

Increasing Evidence Strictness – Ongoing debate in Germany on the abolition or restriction of the orphan drug regulation could mean orphan drugs needing a full benefit assessment³

No time to waste: a JCA action list for manufacturers

The EU JCA process is based on comparative clinical evaluation of new oncology, advanced therapy medicinal products (ATMPs) and high-priority medicines. The assessment is prepared jointly by designated HTA bodies from several Member States and is coordinated by the EU HTA Coordination Group. At Phase 3 of the process the medicine’s pivotal trial results should be available. This is the phase at which a full comparative clinical assessment will be made ahead of national pricing and reimbursement decisions. Our advice for getting ahead of JCA changes for orphan drugs and rare disease is:

Start early – do not wait for Phase 3

• Begin now: Allow enough time to generate the evidence JCA will demand
• Do contingency planning to be able to meet last-minute requests on short timelines
• Avoid the common trap of only considering HTA needs late in Phase 3 when options are limited
• Set out internal processes for review/sign-off etc to ensure a smoother submission process

Define a strong evidence plan

• Population, intervention, comparator, outcomes (PICO) simulation: Map PICOs early to anticipate the JCA scope
• Scope mapping: Account for diverse EU standards of care – this determines comparator selection and dossier complexity

Validate endpoints early

• Identify what is a clinically meaningful change for your indication
• Link surrogate endpoints clearly to patient-relevant outcomes; avoid “… so what?” gaps
• Start validation in early clinical phases – do not leave to do after Phase 3

Strengthen comparative evidence 

• External Control Arms: Where randomized controlled trials (RCTs) are not possible, use broader, representative real-world evidence (RWE) to create comparators
• Plan for prospective natural history studies if retrospective datasets are not adequate
• Build clinical support from the start by engaging with a wide range of clinical key opinion leaders (KOLs) from different countries to establish what the standard of care should be before starting data collection
• As far as possible establish a clear understanding of the disease’s natural history – how does the condition evolve and how does it progress
• Clearly define the unmet need
• Develop a publication plan to shape conversation as early as possible. Having a strong clinical understanding from the start and publicizing this understanding as an early part of any communication plan is critical

Address RWE & QoL gaps early

• RWE: Identify and secure usable datasets early; if unavailable, initiate your own registry
• QoL: Avoid proxy-only solutions; integrate validated patient reported outcomes (PROs) into trials whenever possible; consider exit interviews to understand the patient experience with the product and if appropriate the caregiver experience.

Engage regulators & HTA bodies early

• Joint Scientific Consultation: Use early advice to refine design, comparators, and endpoints
• Build relationships and anticipate national nuances

Improve efficiencies and reduce risks

• Early evidence planning improves internal processes and reduces costly last-minute activities
• Having detailed and robust cross-functional evidence plans can help to reduce uncertainties and improve the likelihood of achieving commercially acceptable prices across markets

By investing early in more integrated evidence planning, manufacturers will be able to unlock significant advantages. Patient access to new treatments will benefit as comprehensive, validated evidence will increase the likelihood of positive reimbursement decisions following a JCA. Manufacturers who dedicate their time and effort in preparing for JCA will help to ensure improved internal processes and will likely avoid the need for reactive evidence generation during the final Phase 3 stage of JCA.

Conclusion

The JCA’s inclusion of orphan drugs in 2028 will mark a turning point for rare disease treatment. The landscape will be more demanding and the need for robust evidence will be greater than ever. On February 28, 2026, the day when we raise awareness about rare diseases, celebrate the work of researchers, and acknowledge the challenges faced by patients and carers, the message for manufacturers is clear:

Start preparing now. Do not lose sight of the underlying science and the importance of evidence-based decision making in the excitement of the innovation – ensure that the science is robust and clearly communicated and supported by a strong evidence package that clearly demonstrates the value of their product to stakeholders.

How Can Lumanity Help

At Lumanity we constantly strive to stay ahead of policy changes and what they mean for manufacturers bringing new treatments to a global market. As leaders in the field, we have supported several of the first oncology medicines and ATMPs to go through the JCA process. Our team of experts is ready to help you ride the next JCA wave and support bringing new orphan drugs to market.