Taking on the access hurdles for orphan drugs: preparing for EU HTA

In recognition of Rare Disease Day 2025, I was reflecting on how variable reimbursement of orphan drugs is across Europe. Whilst some countries such as Germany are reimbursing a large proportion of orphan drugs approved by the EMA, a significant portion of the EU is failing to reimburse more than half of all such therapies. For patients, this means significant disparities continue to exist in access to the latest treatments. [1,2,3]

The new EU HTA Joint Clinical Assessment (JCA) aims to address some of these problems by accelerating access to patients, introducing greater uniformity and streamlining the HTA processes for all 27 member states. For these reasons, the changes have been largely welcomed by patient, physician and industry associations. [4, 5, 6] 

However, despite extensive guidance being published by the EU HTA Coordinating Group, there is very little specific to orphan drugs; most of the guidance does not differentiate between non-orphan and orphan drugs. This is problematic because:

• Clinical evidence for orphan drugs is usually subject to high levels of uncertainty due to low numbers of patients, determining the right clinical/surrogate end points, understanding the natural history, characterising disease heterogeneity etc.,
• Establishing the economic value is often difficult, particularly if the drug is the first to treat a disease with no clear standard of care, as well as the high prices associated with orphan drugs

JCAs are now live for oncology and advanced therapy medicinal products and the scope will expand to cover all remaining orphan drugs from January 2028. This means that companies currently with orphan drugs in Phase 2 or 3 should be planning for this now.  

In the rest of this article, I focus on 4 key areas that each require specific considerations for orphan drugs:

1. Planning for EU and National-Level market access
2. Addressing data uncertainty
3. Navigating the process
4. Engaging with stakeholders

1. Planning for EU and National-Level Market Access

For orphan drug developers, a well-defined market access plan is essential, and this requires balancing EU-level JCA requirements with national HTA expectations. Unlike in the past, where HTA submissions were country-specific from the outset, JCAs will now provide a centralised clinical assessment that must then be followed by national reimbursement decisions. To prepare effectively, companies should:

Anticipate the expected scope of the JCA: Population, Intervention, Comparator, Outcomes (PICOs) 

Since PICOs define the comparative assessment, their early simulation is critical. For orphan drugs this may include off-label treatments as comparators, particularly if no authorised standard of care exists. Care must also be taken to identify relevant patient sub-populations as these will also generate separate PICOs. 

In the JCA process itself, the scoping process is likely to generate multiple PICOs as the assessment is required to meet the policy needs of all member states. For example, in a recent PICO simulation, EFPIA identified:

• 16 PICOs for an orphan oncology therapy in solid tumours and 
• 22 PICOs for an orphan ATMP in haematological tumours [7]  

The JCA assessors will expect to see evidence provided (where available) for all the available PICOs. The upshot is that this may create a substantial evidence burden and hence early planning is essential.

Map national value assessment frameworks 

Member states within the EU have different methods for their national HTAs. For example, ‘Social Healthcare Insurance’ oriented systems tend to have a greater focus on budget impacts, whereas ‘National Health Systems’ focus on cost-effectiveness criteria. Some of these frameworks have specific conditions that can support orphan drugs such as:

• Waiving all or part of the assessment should the budget impact be under a certain threshold e.g., Germany, Netherlands 
• Flexibility in the Incremental Cost Effectiveness Ratio thresholds (ICER) to accommodate greater uncertainty on outcomes, costs of development, level of unmet need etc., [8]

Model pricing scenarios early 

High price points typical of orphan drugs will be scrutinised and will need to be justified with supporting value arguments. It is crucial to assess price scenarios considering the JCA scope and value assessment frameworks mentioned above. 

Plan for different scenarios in the use of the JCA 

At this stage it is still unclear to what extent the JCA reports will be used in national level decision making. Some countries may integrate them fully into their processes, whilst others may use them more as directional inputs. 

One country to watch is Germany, which currently assumes the added clinical benefit as proven for orphan drugs upon approval (and thus reimbursement), provided that the in-country sales do not exceed €30M in any 12-month period. If an orphan drug’s JCA report concludes that there is no clinical improvement relative to the standard of care (or indeed delivers poorer clinical outcomes), then automatic reimbursement of that drug at a premium price will likely draw criticism. At present, the German authorities have not proposed any changes to their pricing and reimbursement policies on this issue, however this may be revisited once the JCA process is embedded. 

2. Addressing Data Uncertainty

One of the biggest hurdles in HTA for orphan drugs is data uncertainty and particularly the use of single arm trials. Whilst not every rare disease pivotal study will have this design, their use in rare conditions is common. This is due to the difficulty of recruiting patients for the study and/or for ethical reasons. HTA assessors consider the quality of evidence from these trials as low compared to randomised controlled trials as they are more prone to bias and provide no direct comparative evidence. Nevertheless, JCA assessors still want to see the evidence of comparative effectiveness and safety, which means it needs to come from indirect means. 

To address this companies should first perform a systemic literature review to understand what data is available and whether there exists the possibility of performing indirect treatment comparisons from existing studies. All potential sources of data should be considered, not only prior trials but also real-world data as an external control e.g., from registries and natural history studies. 

In using evidence from prior studies and or from real world settings, it is important to minimise the risk of bias by matching the patient populations between the data sources at an individual patient level. Various statistical methods are recommended by the HTA Coordinating Group to perform this; however, the group recognises the limitations of these methods and may continue to be concerned over the risk of bias should the assumptions underpinning these methods not be met. Companies must plan these studies with expert health economic statisticians to determine the best course of action. [9, 10]

Given the challenges and risks outline here, it is advisable companies seek advice in the planning stage of their pivotal trials from either the HTA Coordinating Group (via Joint Scientific Consultations JSCs), or from national level HTA bodies. It is worth noting however that available slots for JSCs are extremely limited in the near term (up to 10 will be available in 2025) and will be allocated based on published prioritisation criteria. 

Finally, companies should look at options for ensuring long-term follow-up data as this can provide critical insights into durability of effect, particularly for ultra-rare diseases where initial trial data may be limited. Indeed, it is likely that regulators will demand follow up studies should pivotal trial data be limited.

3. Navigating the Process

While the JCA framework aims to harmonise clinical assessments across Europe, the process itself presents significant challenges for orphan drug companies.

PICO Selection 

In addition to the comments on PICO simulation mentioned in the planning stage, we must bear in mind that during the scoping phase of the JCA, companies will not have the opportunity to challenge the PICO selection; the PICOs will be determined by the JCA sub-group leading the assessment. Therefore, companies must anticipate potential PICOs in advance and prepare accordingly and have back up scenarios to hand.

Resource-Intensive Process with Tight Timelines

JCA submissions will require significant resources, and the preparation timeline will be strict—especially for those seeking accelerated assessment. This is likely to disproportionately affect smaller companies, placing strain on available resources. This, coupled with the fact that JCAs are to be undertaken at the same time as the EMA’s assessment for the marketing authorisation, means work preparing for the JCA should begin early. Companies should build close working between their market access, HEOR and Regulatory Affairs teams to ensure agile responsiveness. 

4. Engaging Patients and Physicians

Rare disease patients and their physicians will play a key role in the JCA process since information on what it is like to live with and to manage these conditions is usually scarce. Testimonies and opinions from these individuals are likely to play a critical role in both the scoping and conclusions of the assessment. Companies should therefore:

• Build strong relationships with patient advocacy groups and clinical experts to understand their unmet needs and pain points. This should be undertaken long before the JCA process begins
• Ensure patient-relevant endpoints are integrated into trials: these are key for the JCA and will be considered during the scoping phase of the assessment
• Capturing real-world perspectives on disease burden and treatment impact, which can strengthen the case for reimbursement

Conclusion: Start Preparing Now

With JCAs for all orphan drugs set to launch in 2028, companies developing orphan drugs in Phase 2 or Phase 3 should act now to ensure they are prepared. This includes:

• Aligning EU and national-level market access strategies
• Anticipating and mitigating data uncertainty
• Understanding the process challenges, particularly around PICO selection and resource demands
• Engaging early with patients and physicians to incorporate meaningful evidence into assessments

Contact

If you are interested in discussing any of the issues above, please contact me through my email address dniven@nivenbiopharma.com. Feel free to also visit my website at www.nivenbiopharma.com for more information.

Sources

1. An international comparative analysis of public reimbursement of orphan drugs in Canadian provinces compared to European countries, Ward et al, Orphanet Journal of Rare Diseases, 2022
2. Percentage of orphan drugs approved by the EMA available to patients in Europe, as of 2024, by country, Statista
3. Availability and Accessibility of Orphan Medical Products and Medical Devices for Rare Diseases, Rare 2030
4. Response to the consultation on the Implementing Act on Joint Clinical Assessments, EURORDIS, March 2024
5. EUCOPE’s Feedback to the public consultation on the draft implementing act on JCA of medicinal products, EUCOPE, March 2024
6. EFPIA Response to JCA Implementing Act public consultation, EFPIA, April 2024
7. EU HTA Regulations for Oncology Medicines: Learnings from the simulation of the impact of proposed EUNetHTA21 methods, EFPIA, March 2024
8. HTA Criteria Adopted in different models of public healthcare systems for orphan drugs: A scoping review, Felippini et at, Elsevier, June 2024
9. Guidance on Validity of Clinical Studies, HTA CG, July 2024
10. Methodological Guideline for Quantitative Evidence Synthesis: Direct and Indirect Comparisons, HTA CG, March 2024