Preparing Rare Disease Manufacturers for JCA: The Role of Early Stakeholder Engagement

Introduction

Since January 2025, new oncology medicines and advanced therapy medicinal products (ATMPs) have been subject to the EU’s Joint Clinical Assessment (JCA), a coordinated, EU-level evaluation of a medicine’s relative clinical effects and safety. Orphan medicinal products follow in January 2028. For rare disease medicine manufacturers, this is the most significant structural change to European market access in a generation.

At the heart of JCA is a PICO framework (Population, Intervention, Comparator, Outcomes) scoped by Member States even before formal assessment begins. Manufacturers are permitted to propose PICOs, and those proposals carry weight when grounded in credible clinical rationale and backed by stakeholder input.

In rare disease development, the evidence assessed under JCA is largely determined years before submission. Decisions on trial design, endpoint selection, and comparator strategy shape the evidence package that will ultimately support the PICO framework. Early engagement with national HTA bodies, payers, and clinical experts allows manufacturers to embed local evidentiary standards into PICO proposals and study design from the outset.

This article examines how stakeholder engagement can help rare disease manufacturers prepare for JCA requirements and improve the likelihood of positive market access outcomes. It also shares best practices for early stakeholder management in the context of JCA. With three JCA reports in oncology approved to date (July 2026), we share early observations below that are directionally important and may continue to be refined as more assessments accumulate.  

PICOs: Key Considerations in Rare Diseases

PICO determination for rare disease medicine assessment presents several interrelated challenges:

• The patient populations are inherently small and often heterogeneous.

• On the comparator side, the lack of established standard-of-care treatments in many rare diseases hinders the interpretation of relative efficacy.

• Validated, disease-specific endpoints are frequently absent, and surrogate endpoints must often substitute for long-term clinical outcomes, creating uncertainty on the meaningfulness of patient benefit.

Stakeholder endorsement can strengthen a comparator strategy, making it more likely to be accepted by assessors. A comparator deemed inappropriate at JCA will create challenges for every national appraisal that follows. Conversely, a strategy developed with clinical expert input, validated by KOLs in relevant markets, and acknowledged by patient organizations, enters national appraisal from a position of established credibility.

As for outcomes, surrogate endpoints are unavoidable in many rare disease programs, and the interpretive uncertainty they create will be a focus of both JCA assessment and national appraisal. One approach is to build a body of expert clinical consensus through KOL engagement, advisory boards, and patient organization input that provides interpretive context for the surrogate’s relationship to outcomes that matter. Patient organizations can also provide structured evidence on disease natural history and outcome meaningfulness that quantitative studies alone cannot supply.

A PICO that includes clinically meaningful and measurable outcomes is easier to justify when supported by evidence from clinical experts and patient organizations. This input can clarify why the selected outcomes are relevant, particularly where validated disease-specific endpoints are limited.

Overall, the rarity of the disease means that HTA bodies, clinicians, patients, and manufacturers may each have divergent views on what constitutes a meaningful PICO. Limited evidence, high unmet need, and the emotional weight of decisions affecting very small, vulnerable populations make consensus difficult to reach.

This makes early engagement with HTA bodies, KOLs, and patient organizations vital for shaping a PICO framework that reflects real-world treatment realities and aligns the evidence with national requirements, strengthening the comparator narrative before it is finalized.

Best Practices for Stakeholder Management Under JCA

Build stakeholder engagement into the development plan

Manufacturers should treat stakeholder engagement as a core component of the development plan. HTA bodies, KOLs, and patient organizations should be mapped early, with engagement milestones aligned to key decision points such as trial design, endpoint selection, and comparator strategy. A structured engagement plan with documented outputs ensures stakeholder input that can be referenced in PICO proposals and used to demonstrate the clinical and patient basis for key decisions.

Use stakeholder input to shape and validate PICO proposals

Well-structured proposals, grounded in KOL-validated clinical rationale and patient-informed outcome definitions, are more likely to be accepted. Manufacturers should use pre-submission engagement to test their proposed PICO with KOLs in each relevant Member State, checking whether the population definition, comparator, and outcomes reflect clinical practice. Where concerns are raised, they should be documented alongside how they were addressed. A PICO proposal backed by a clear record of clinical expert input and patient organization endorsement can be substantively more credible in the eyes of assessors.

Invest in endpoint justification collaboratively

Manufacturers should build the interpretive case for surrogate endpoints well before submission, through advisory boards, KOL interviews, and patient organization consultations. Patient organizations can be particularly valuable partners in this context, providing testimony on disease natural history and what outcomes patients consider meaningful. Although this evidence does not replace clinical data, it can provide the interpretive context assessors need to evaluate it.

Treat Joint Scientific Consultation (JSC) as a structured stakeholder engagement channel

The JSC value is maximized when manufacturers arrive having already gathered KOL and patient organization input to support their PICO proposals and comparator rationale. Manufacturers should arrive at the JSC with a pre-formed, stakeholder-supported position, and evidence of patient organization engagement on outcome relevance. It can also be the right moment to probe whether the evidence strategy meets the standards of priority Member States. JSC outputs should be treated as operational guidance and fed directly back into study design and evidence planning.

Map the national market access implications of the JCA outcome before submission

Companies that have engaged national payers, HTA advisors, and clinical experts in key markets before submission can be better positioned to anticipate how the JCA conclusion may be interpreted at the national level. The JCA conclusion feeds into national appraisal processes that vary significantly across Member States. Manufacturers should map their priority markets before submission, identifying how each national HTA body is likely to interpret the JCA outcome and what additional evidence domestic payers require. National KOLs and HTA advisors consulted early can flag misalignments while there is still time to address them.

Conclusion

JCA represents a significant change to European market access, and it underscores the importance of aligning evidence-generation plans with both EU-level assessment requirements and national reimbursement needs.

Pharma companies have opportunities to inform PICO scoping, test comparator assumptions, and strengthen the rationale for endpoint selection before submission. Early engagement with HTA bodies, clinical experts, payers, and patient organizations can help identify potential evidence gaps and areas of misalignment while there is still time to address them.

Companies that integrate stakeholder engagement into evidence planning can be better prepared to submit proposals that reflect real-world clinical practice, develop evidence packages that address national HTA requirements, and present comparator strategies that are supported by relevant clinical and patient input.