How will EU JCA impact HTA for orphan/rare diseases?

Although each rare disease affects only a small number of people, taken together rare diseases impact a substantial and often overlooked patient population. More than 7,000 distinct rare diseases are recognised worldwide, yet around 94% still lack a disease-specific treatment, and roughly one-third of patients have never received a therapy directly targeting their condition.¹

For this community, where treatment options are limited, health technology assessment (HTA) is pivotal: positive recommendations support reimbursement and routine adoption of novel therapies, while negative outcomes or prolonged review processes can deny or severely delay access even when effective treatments exist. The new EU Health Technology Assessment Regulation (HTAR Regulation (EU) 2021/2282) brings the Joint Clinical Assessment (JCA) to the centre of this process. From 2025, JCAs are mandatory for new oncology medicines and ATMPs; from January 2028 they will extend to all orphan medicinal products; and from 2030 to all other centrally authorised medicines.²

JCAs promise to provide a single, streamlined, EU-level assessment of the relative clinical effectiveness for new medicines, however the evidence requirements have largely been defined around more established, non-orphan therapeutic areas, where large randomised studies are likely to be feasible. For patients with rare diseases and companies developing new therapies, this raises an important question: will the JCA improve access, or add another complex hurdle on top of already challenging evidence requirements to achieve reimbursed patient access in Europe?

In this context, it is important to consider what the JCA means for rare diseases and feasible steps health technology developers can take to navigate the new environment.

1. What the JCA changes – and what it does not

Under the HTAR, the JCA will provide a European level joint assessment of the comparative clinical effectiveness and safety of new medicines versus relevant comparators, based on PICOs (Population, Intervention, Comparator(s), Outcomes) agreed by Member States.³

However, several aspects remain national responsibilities:

• Member States retain autonomy over added benefit or clinical value ratings (e.g. France’s SMR/ASMR, Germany’s added-benefit categories) ³ ⁴ ⁵
• Economic evaluation, budget impact analysis and pricing & reimbursement (P&R) decisions remain national level responsibilities³
• Countries may place different weight on JCA conclusions, and some may still conduct additional local analyses⁴ ⁵

For orphan/rare disease health technology developers, the JCA will therefore provide the common European backbone for the evaluation of clinical data, but not a complete replacement for existing national level assessment processes. The challenge will be to develop evidence packages that are robust enough for the European JCA, and flexible enough to withstand potential divergent national interpretations.

2. PICOs challenges for orphan/rare diseases

Considerations for defining the PICOs are likely to differ between new drugs in established therapeutic areas and orphan/rare diseases, with the latter facing distinct challenges within each element of the PICO. This is likely to increase uncertainty regarding the scope for the JCA and implications for evidence generation requirements.

2.1  Population (P)

Rare diseases can often be classified into several subpopulations, with the potential for significant variation in phenotypes, symptom profiles and disease trajectories. Furthermore, standards of care may differ markedly for individual subpopulations between and within jurisdictions.⁶ This can make it challenging to define and stratify a coherent target population and can result in a proliferation of distinct ‘Populations’ within the scoping for the JCA.

2.2  Comparator (C)

On the one hand, comparator selection can appear more straightforward in rare and orphan diseases, where few or no established therapies may exist, unlike in areas such as oncology, where multiple active comparators may be available across several lines of treatment.⁷ On the other hand, standard of care for rare and orphan diseases can often be poorly defined and highly variable both across and within Member States. For example, depending on the therapy area this may consist of best supportive care, surgery, devices, off-label medicines, or new branded medicines with varying availability/reimbursement between Member States. Uncertainty can also be amplified by the absence of harmonised EU treatment guidelines for many rare diseases.

Additionally, when the standard of care is non-pharmacological (e.g. surgery), designing a head-to-head RCT can be operationally challenging or deemed unethical. Combined with very small and geographically dispersed patient populations across Europe, this means that indirect treatment comparisons and the use of historical/real-world datasets for comparator arms are far more common for orphan medicines than for other conditions. A recent analysis of EMA orphan medicinal products showed that across 418 comparisons, indirect comparisons were used in 44% of cases, qualitative comparisons in 39%, and direct head-to-head comparisons in only 18%.⁸

The JCA Methodological Guideline for Quantitative Evidence Synthesis, while acknowledging that for some interventions “single-arm or non-randomised evidence may be the only evidence available”, also emphasises that such evidence may be “insufficient for estimation of the relative treatment effectiveness in the context of JCA”.⁹ This is despite the HTAR itself calling for methods to be adapted to the specificities of technologies such as orphan medicinal products.³

2.3  Outcomes (O)

Of all PICO elements, outcomes are arguably the most challenging for rare diseases.

In more prevalent conditions, outcomes are often well defined, standardised and widely measured in routine practice. In rare diseases, by contrast, there may be no consensus on validated clinical endpoints, and outcomes are often disease-specific, non-standardised, and clinician-reported. Also, given the small patient populations and potential gradual rate of progression (depending on the indication), capturing a statistically significant improvement in long-term outcomes (e.g. survival, irreversible progression, major functional milestones) can be challenging. Clinical trials therefore often rely heavily on biomarkers or surrogate endpoints to demonstrate the clinical effect of treatment within a feasible duration of follow-up.

The JCA Guidance on Outcomes for Joint Clinical Assessments sets stringent expectations for the use of surrogate endpoints.¹⁰ Health technology developers are expected to:

• Describe whether the association between the surrogate and the outcome of interest has been studied in the specific disease, stage, population and intervention, and indicate whether patient-centred outcomes are likely to become available at a later date
• Use only surrogates with previously established validity whenever possible
• Justify the choice of surrogate, specify the true patient-relevant outcome and quantify the strength of association
• Recognise that, although no universally accepted threshold exists, a correlation of ≥0.85 between surrogate and final outcome is often cited as “high”, as suggested by IQWiG¹¹

For rare diseases, meeting these standards may be challenging as large validation datasets rarely exist.⁷

3.     No JCA methodology/guidance for orphan drugs

Taken together, the PICO-related challenges outlined above illustrate that the rare disease space poses methodological constraints for the JCA and substantially increases residual uncertainty. Against this backdrop, the absence of orphan-specific JCA methodology seems problematic.

A key question is whether the 2028 European Commission review of the HTAR implementation will lead to revised JCA guidance that includes orphan-specific methodological provisions, which many stakeholders regard as essential.

The legal framework clearly anticipates the need for tailored methods. Article 4(1) of the HTAR mandates that the Coordination Group ensures joint work “follows international standards of evidence-based medicine” and explicitly requires that, when developing procedures, it “consider the specificities of the health technology (…) including orphan medicinal products, vaccines and advanced therapy medicinal products”.³ This creates both a mandate and an opportunity to evolve the JCA methodology for rare diseases.

The European Expert Group on Orphan Drug Incentives (OD Expert Group) has outlined what such an approach could look like⁷; an EU HTA framework for rare diseases with explicit criteria and clinical evidence requirements that distinguish orphan medical products for which “gold-standard” data (large RCTs, long-term hard outcomes) are not feasible, and that defines what a feasible yet decision-grade dossier should contain (including evidence types, acceptable methodologies, and significance thresholds).

The EU JCA could also consider examples from a number of other HTA agencies such as England's National Institute for Health and Care Excellence (NICE) and Canada's Drug Agency (CDA-AMC), which have developed methodological guidance on the use of real-world evidence. For example, NICE and CDA-AMC have developed frameworks to minimise bias when using real-world evidence as an external control arm (e.g., suggesting the target trial emulation approach).¹² These frameworks are already having an impact on decision making, with NICE's framework allowing for the acceptance of real-world evidence with external control arms.¹³

4. Strategic considerations for health technology developers¹⁴

4.1 PICO prediction

Health technology developers may leverage Joint Scientific Consultations (JSCs) or early scientific advice from national HTA bodies to refine early assumptions around the patient population definition/stratification, comparators and relevant outcomes. However, a risk assessment is critical as the JCA submission may be challenged if JSC advice is not followed; where this is a concern, running a “mock JSC” internally can help stress-test assumptions and make trade-offs explicit.

A detailed early review of the current and evolving clinical landscape across European Member States and the natural history of disease for target patients will also be highly important, supporting the potential justification for completing a single-arm trial (if required), and informing anticipated PICOs to address decision making requirements across Member States. In the event that large numbers of predicted PICOs are not feasible to address within the clinical development and evidence synthesis programme, early alignment regarding the optimal feasible dataset (and the risk of excluding potential PICOs) will also be required.

4.2 Plan early

Preparation for the JCA should begin at least 24 months before the anticipated submission to allow sufficient time to generate, analyse and document the required evidence. Successful navigation of both the JSC and JCA processes demands a cross-functional model spanning clinical development, biostatistics, regulatory, HEOR, market access and commercial team members.

In particular, considerations on the appropriate clinical comparator(s) should be embedded in the clinical development programme from the outset, and in the absence of an active comparator arm within the pivotal trial, measures should be explored for quantifying the incremental clinical/safety value vs. potential comparators predicted for the JCA scope. This can involve construction of external control arms (e.g. based on natural history datasets/patient registry data), and indirect treatment comparisons using methods aligned with JCA guidance (e.g. anchored Bucher, MAIC, STC, ML-NMR) with explicit modelling of effect modifiers and uncertainty.⁹

In parallel, health technology developers must proactively plan for the relevant endpoints to capture the holistic clinical, safety, QoL and economic value of treatment, the required duration of follow-up and magnitude of effect to support clinically relevant value demonstration. Where surrogate outcomes are required, this should also include clinical consensus building (and publication/dissemination) regarding the patient relevance of a change on the surrogate, with a validation study to inform the association with final patient relevant clinical outcomes.

Importantly, engaging both patients and clinical experts before the JCA invitation is also important to minimise the risk of conflicts of interest¹⁵, particularly in very small rare-disease communities where the pool of available experts and patient representatives is limited.

4.3 Organisational and operational readiness

Study designs should be fit-for-purpose to inform regulatory approval, the JCA, and Member State decision-making, to minimise delays in access and requests for post-launch evidence generation. This will typically require close cross-functional collaboration, including early involvement of country affiliates for scoping likely requirements for national level assessment and potential additional evidence requests outside the JCA report. In this context, ongoing monitoring of country level processes for utilisation of the JCA report and the implications for national reimbursement and pricing decisions will be highly important.

Finally, building an organisation-wide understanding of the JCA process and methodologies will be critical. This should include embedding “HTA-ready” thinking across the development lifecycle to ensure that rare-disease programmes reflect the likely evidence generation requirements to support timely reimbursed patient access across European Member States.

5. Conclusion

Ultimately, the challenge for policymakers is to ensure that the EU JCA evolves into a pragmatic, orphan-sensitive framework that streamlines and clarifies clinical evidence expectations for rare diseases, reducing redundancy and uncertainty rather than adding yet another complex hurdle to an already demanding European HTA environment. In parallel, health technology developers should proactively design “JCA-ready” rare-disease programmes, embedding PICO prediction, comparator strategy, surrogate endpoint validation and RWE planning, and cross-functional HTA expertise from the earliest stages of development.

References

1.     May, M. (2023) Rare-disease researchers pioneer a unique approach to clinical trials. https://doi.org/10.1038/s41591-023-02333-4 (Accessed: January 21, 2026).

2.     Directorate-General for Health and Food Safety (2024) Joint clinical assessment of medicinal products: Submission of early information by health technology developers. https://health.ec.europa.eu/document/download/77476507-9ddc-47e3-ae0d-11c05f89169c_en?filename=hta_%20mp-jca_htd_en.pdf (Accessed: January 21, 2026).

3. Regulation (EU) 2021/2282 of the European Parliament and of the Council of 15 December 2021 on Health Technology Assessment and Amending Directive 2011/24/EU (2021). https://eur-lex.europa.eu/legal-content/EN/TXT/?uri=CELEX:32021R2282 (Accessed: January 21, 2026).

4.     Bundesministerium für Gesundheit (2025) Erste Verordnung zur Änderung der Arzneimittel-Nutzenbewertungs-verordnung. Bundesministerium für Gesundheit. https://www.bundesgesundheitsministerium.de/fileadmin/Dateien/3_Downloads/Gesetze_und_Verordnungen/GuV/A/AM-NutzenV-AendV_RefE.pdf (Accessed: January 21, 2026).

5. Règlement Européen sur l’évaluation des technologies de santé (2024). https://www.has-sante.fr/jcms/p_3545447/fr/reglement-europeen-sur-l-evaluation-des-technologies-de-sante (Accessed: January 21, 2026).

6.     Nestler-Parr, S. et al. (2018) 'Challenges in Research and Health Technology Assessment of Rare Disease Technologies: Report of the ISPOR Rare Disease Special Interest Group,' Value in Health, 21(5), pp. 493–500. https://doi.org/10.1016/j.jval.2018.03.004.

7.     European Expert Group on Orphan Drug Incentives (2023) AN EU HTA FIT FOR RARE DISEASES. Copenhagen Economics. https://copenhageneconomics.com/wp-content/uploads/2024/03/EU-HTA-fit-for-rare-diseases-Part-1-Clinical-evidence-in-JCA_CE-FINAL.pdf (Accessed: January 21, 2026).

8.     Windfuhr, F. et al. (2024) 'Which clinical trial designs and statistical approaches have been used in assessments of orphan maintenance by the European Medicines Agency between 2012 and 2022? A cross-sectional study.,' BMJ Open, 14(12), p. e086171. https://doi.org/10.1136/bmjopen-2024-086171.

9.     Member State Coordination Group on Health Technology Assessment (2024) Methodological Guideline for Quantitative evidence synthesis: Direct and indirect comparisons. https://health.ec.europa.eu/document/download/4ec8288e-6d15-49c5-a490-d8ad7748578f_en?filename=hta_methodological-guideline_direct-indirect-comparisons_en.pdf (Accessed: January 21, 2026).

10.  Member State Coordination Group on Health Technology Assessment (2024) Guidance on outcomes for joint clinical assessments. https://health.ec.europa.eu/document/download/a70a62c7-325c-401e-ba42-66174b656ab8_en?filename=hta_outcomes_jca_guidance_en.pdf (Accessed: January 21, 2026).

11.  Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen (2011) Aussagekraft von Surrogatendpunkten in der Onkologie, IQWiG-Berichte. Rapid Report. https://www.iqwig.de/download/a10-05_rapid_report_surrogatendpunkte_in_der_onkologie.pdf.

12.  Castanon, A. et al. (2024) 'EU HTA Joint Clinical Assessment: are patients with rare disease going to lose out?,' Journal of Comparative Effectiveness Research, 13(6), p. e240052. https://doi.org/10.57264/cer-2024-0052.

13.  Bray, B. and Ramagopalan, S.V. (2023) 'R WE ready for reimbursement? A round up of developments in real-world evidence relating to health technology assessment: part 12,' Journal of Comparative Effectiveness Research, 12(7), p. e230092. https://doi.org/10.57264/cer-2023-0092.

14.  Lightning Health insights from ISPOR EU 2025 (2025).

15.  Gentilini, A. and Parvanova, I. (2024) 'Managing experts’ conflicts of interest in the EU Joint Clinical Assessment,' BMJ Open, 14(11), p. e091777. https://doi.org/10.1136/bmjopen-2024-091777.

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