From PICOs to comparative evidence: Preparing orphan medicines for EU Joint Clinical Assessment

The EU Joint Clinical Assessment (JCA) will extend to orphan medicines from 2028, introducing new methodological and operational requirements for evidence generation and submission. At the World Evidence, Pricing and Access Congress 2026, Patrick Hopkinson and Caroline Ling from RTI Health Solutions examined emerging challenges, including PICO selection, comparative evidence limitations, and the role of real-world evidence in rare disease assessments.

The implementation of the EU Health Technology Assessment Regulation (EU HTAR) in January 2025 marked a significant development in how health technology assessment (HTA) is conducted across the European Union’s 27 Member States. By introducing a new framework for Joint Clinical Assessment (JCA) of medicines, the regulation establishes a centralized process intended to produce a single clinical assessment that can inform subsequent national HTA decision-making.

With orphan medicines entering the JCA framework in 2028, developers can begin to prepare their evidence generation and submission strategies while monitoring progress of the early assessments, the first of which is due to report in Q2 2026. However, evidence generation in rare diseases often presents methodological and operational challenges when producing the comparative effectiveness evidence required for JCA assessments. As companies prepare for the integration of orphan medicines into the JCA process, careful planning of evidence strategies will be essential to address these constraints.

At the World Evidence, Pricing and Access (EPA) Congress 2026, the session titled “EU Joint Clinical Assessment for Orphan Drugs: Methodological Challenges, Solutions, and Early Learnings” examined how these emerging challenges are beginning to be addressed in practice. Patrick Hopkinson (Independent Consultant, Founder and Managing Director, PHTA Consulting) and Caroline Ling (Vice President, Value and Access, RTI Health Solutions), shared methodological insights and practical observations drawn from their experience supporting companies preparing JCA submissions. Drawing on early implementation experience and ongoing industry preparation efforts, they provided insight into how developers are adapting their evidence generation strategies in advance of the 2028 inclusion of orphan medicines within the JCA process.

Evidence challenges in assessing orphan medicines under JCA

Many of the challenges associated with rare disease research are well recognized within HTA. Under the JCA framework, however, these issues may become more visible due to standardized methodological requirements applied across all Member States. Importantly, as Patrick Hopkinson explained, the current JCA methodological framework does not include adaptations specifically designed for orphan medicines. Discussions with the HTA Coordination Group (HTACG) suggest that the same methodological approach will be applied across disease areas. As he put it, “the HTACG currently are not planning to adapt the methods for orphans - they are not planning anything different.”

This approach may present additional challenges for developers of rare disease therapies, whose evidence generation strategies often rely on small datasets, surrogate endpoints, or alternative study designs due to the limited number of patients affected by these conditions.

Generating robust epidemiological data also presents difficulties. For rare diseases, natural history evidence may be limited, and assembling reliable epidemiological data across multiple jurisdictions can be challenging. Hopkinson highlighted the scale of this issue, noting that developers must compile comprehensive epidemiological evidence across the EU.

“You need all your epidemiology data,” he said, “but how are you going to get that across 27 Member States for a rare condition?”

The fragmented nature of health data systems across Europe can make it difficult to construct a consistent evidence base for conditions with very low prevalence.

Clinical trial design introduces further constraints. Rare disease studies frequently enrol small patient populations, and randomized head-to-head trials may not always be feasible. Caroline Ling noted that trial sizes in rare diseases are often extremely limited. “Maybe 20 patients are all you're going to have,” she said. “If you're lucky, you might have 100.”

The limited size of clinical datasets can make it difficult to generate robust comparative evidence, particularly when assessments require multiple PICOs (population, intervention, comparator, outcomes) requested by Member States. Variation in treatment practices across Europe means that comparators may differ significantly between countries. Ling noted that treatment pathways are rarely uniform across the EU, with “every country doing something slightly different.”

This variability may result in multiple PICOs being included in a single assessment. While such complexity may be manageable in common diseases with larger evidence bases, it presents challenges for rare conditions where patient numbers are limited. As Ling noted:

“In a rare disease, if you end up with large numbers of PICOs, the chances of being able to get the evidence to support those PICOs are even less.”

Outcome measurement can also present methodological difficulties. Many rare disease trials rely on surrogate endpoints rather than established clinical outcomes. Within the JCA framework, these endpoints must be clearly justified and validated, including demonstrating a strong relationship with clinically meaningful outcomes.

Ling also highlighted additional methodological constraints related to how evidence may be interpreted during assessment. In rare diseases, limited patient numbers can restrict not only clinical trial recruitment but also the availability of observational datasets describing disease progression, symptom burden, or patient-relevant outcomes.

Current methodological guidance suggests that assessors may conclude there is “insufficient evidence” to estimate treatment effectiveness for specific PICOs. Where datasets are extremely small, advanced analytical approaches, such as population-adjusted comparisons or external control arms, may be viewed cautiously due to concerns around uncertainty, transparency and reproducibility. As a result, developers may face situations where robust comparative conclusions cannot be drawn despite considerable analytical effort.

In this context, real-world evidence (RWE) may help complement clinical trial data by providing additional insights. However, Ling noted that the same constraints affecting clinical trials can also limit the availability of observational data.

“The limited patient numbers really means that there's often not that much RWE in terms of the disease course, symptoms and what's really important to patients,” she said.

Methodological solutions: Evidence planning and preparation for JCA

While the methodological challenges associated with assessing orphan medicines are substantial, both speakers emphasized that many elements of JCA preparation remain grounded in established HTA practices. The key difference lies in the level of coordination, early planning, and methodological rigor required to support a centralized clinical assessment across multiple Member States.

Hopkinson noted that many companies have already begun internal preparation activities in anticipation of JCA requirements. These include organizational readiness programs, PICO prediction exercises, mock JCA submissions, and preparation for Joint Scientific Consultations (JSC). Such activities allow organizations to test internal processes, assess evidence strategies, and identify potential data gaps well before the formal submission stage.

From a strategic perspective, he advised companies to carefully evaluate whether participation in JSC is appropriate for their development program.

“If you're thinking of doing a JSC, I just encourage you to stand back first of all and do a strategic review of whether that’s the right thing for your asset or your organization.”

While JSC can provide valuable feedback on clinical trial design and evidence generation, it also requires significant resources and may introduce additional strategic considerations. Some organizations are therefore exploring mock consultations or internal simulations as alternative approaches to anticipating JCA requirements.

As Hopkinson emphasized, companies must consider early in the development process how additional evidence may be generated to support submissions. “What are you going to do in terms of supplementing the data that will be required for your submission?” he asked.

Ling explained that evidence preparation begins with the familiar PICO framework, although the process becomes more specific under JCA.

“It’s not that different from what we've all been doing for many years in terms of looking at the PICOs,” she said. “It’s just a more formalized process.”

A key element of preparation therefore involves anticipating how national treatment practices may influence the PICOs included in the assessment. To address this, companies are increasingly conducting PICO prediction exercises early in the evidence planning process to identify potential comparators and evidence requirements before the formal scoping stage.

Systematic literature reviews (SLRs) also remain central to the evidence package. Ling emphasized that these reviews should be designed to support both the JCA submission and subsequent national HTA assessments. “Think about what you're going to need for JCA but also what you're going to need for your national HTA,” she advised. Designing SLRs with both purposes in mind can reduce duplication and enable efficient updates as new evidence emerges.

Ling also highlighted the importance of assessing the feasibility of indirect treatment comparisons (ITCs). Where randomized head-to-head trials are not feasible, ITCs may be used to support comparative effectiveness assessments. However, determining whether such analyses are methodologically appropriate requires careful consideration. Assessing both the need for, and the validity of, potential ITCs is therefore an important step in preparing a JCA submission. Where robust comparative analyses cannot be conducted, companies may need to provide a clear scientific rationale explaining why an ITC cannot be presented for specific PICOs. In these circumstances, a SLR is required to demonstrate the absence of suitable comparative evidence.

Ling reinforced the growing role of RWE in supporting JCA submissions. Planning RWE generation early in the development process may help supplement clinical trial data and address potential evidence gaps.

“If you've got single-arm trials, if you need additional data, RWE planning from early on is going to be key for orphan diseases,” she said.

A final, important component of JCA preparation is stakeholder engagement. Hopkinson emphasized that input from patient groups and clinicians can play an influential role during assessments.

“Stakeholder mobilization and engagement is critical, especially if you think of orphans. The patient voice, the clinician voice is very powerful in terms of assessments.”

However, strict conflict-of-interest rules within the JCA framework require organizations to manage stakeholder engagement carefully and plan interactions strategically rather than reactively.

Five steps to preparing the JCA evidence package for orphan medicines

To help companies navigate the evolving framework, Ling outlined a practical preparation framework consisting of five practical key steps.

1. Early planning. Evidence generation strategies should be considered well before submission, ideally while pivotal trials are still being designed. Anticipating potential PICOs at this stage can help ensure that trials generate the evidence needed for comparative assessment.
2. Developing a clear evidence strategy. As clinical development progresses, companies should assess the potential risks associated with different PICOs and identify where evidence gaps may emerge.
3. Preparing the evidence base. This includes conducting SLRs, assessing the feasibility of network meta-analyses, and identifying opportunities to generate RWE.
4. Preparing the JCA submission dossier. Ling noted that the submission template contains extensive reporting requirements and structured tables. Completing as much preparatory work as possible in advance can help reduce pressure during the formal submission window.
5. Consider the relationship between JCA and national HTA submissions. Although the clinical assessment will be conducted centrally, national agencies will continue to evaluate economic evidence and country-specific considerations. As a result, developers must ensure that their evidence strategies support both stages of the market access process.

Early learnings from the first wave of JCA implementation

With orphan medicines entering the JCA framework in 2028, many companies are already using the intervening period to strengthen internal readiness and refine their evidence strategies. Hopkinson noted that organizations are undertaking activities such as PICO prediction exercises, internal submission planning, and evidence gap assessments to prepare for the methodological and operational requirements of the new framework.

At the same time, the early implementation of the EU HTAR is beginning to generate operational insights. Approximately 16–18 months after the regulation came into force, the first JCA reports are expected to be published in May/June 2026. These initial assessments are widely expected to provide an important indication of how methodological requirements, evidence standards, and comparative analyses will be interpreted in practice.

As Hopkinson observed, “all eyes will be on that submission and that report.”

Some early signals are already emerging from the first wave of assessments progressing through the system (at the time of the session, 13 JCAs were underway, with one discontinued due to withdrawal of marketing authorisation application by the health technology developer). Approximately half of these assessments involve orphan medicines, providing an early opportunity to observe how rare disease evidence is being evaluated within the new framework.

One operational challenge emerging from these early assessments relates to PICO consolidation. Because Member States can request their own PICOs, assessors cannot exclude requests from individual countries. As a result, pilot assessments have included between seven and thirteen PICOs, a pattern that appears to be continuing in current submissions.

The large number of PICOs has implications for both companies and assessors. Ling noted that JCA dossiers can become extremely large as companies attempt to address each requested comparator. “If you’ve got maybe 13 PICOs, you’re probably talking about a thousand-page dossier,” she said.

These extensive submissions also increase the workload for HTA bodies responsible for conducting the assessments. Each JCA is evaluated by an assessor and co-assessor drawn from different national HTA agencies, requiring significant coordination across the EU network. Ling noted that the scale of the task is already becoming apparent, with assessors “realizing it’s a huge amount of work to go through all those PICOs and assess them.” Over time, this may place greater emphasis on efforts to consolidate PICOs where possible, ensuring that the assessment process remains manageable for assessors reviewing increasingly complex JCA dossiers.

Timelines also present another operational challenge. While the formal submission window for JCA is 100 days from receipt of the scope, companies may receive the scope earlier than expected (~day 75 vs. day 120-130), effectively compressing preparation timelines.

“We know the 100-day timeline is tight,” Hopkinson noted, “but it’s being stretched even further.”

This dynamic reinforces the importance of completing key evidence planning activities well before the formal submission stage.

At the same time, national HTA agencies are beginning to adapt their processes to reflect the centralized clinical assessment. Some agencies have started updating submission templates so that national dossiers focus more heavily on economic evaluation and country-specific considerations, rather than clinical evidence already assessed through JCA.

Companies themselves are also at different stages of readiness. While many large pharmaceutical companies have been preparing for the regulation for several years and have established governance structures and dedicated teams, some smaller biotechs remain less aware of the implications of JCA.

As both speakers emphasized, the current period offers a critical window for preparation. The early wave of assessments, along with the first JCA reports expected in 2026, will provide valuable insight into how methodological expectations are applied in practice. For developers of orphan medicines, these early experiences offer an opportunity to refine evidence strategies before the framework becomes mandatory in 2028. As Ling concluded:

“The more you can prepare and plan, then the more prepared you'll be by the time you get to JCA.”

About the speakers

Caroline Ling
Vice President for Value and Access, RTI Health Solutions

Caroline Ling has over 20 years of experience with market access and health economic consultancies, and is able to deliver a broad spectrum of strategic and tactical market access projects for both global and local clients, including JCA and HTA submissions, systematic and pragmatic literature reviews, global value dossiers, , interactive payer tools, value communication materials, and payer research. Dr Ling has experience in a wide range of therapeutic areas, including rare diseases, hematology, oncology, autoimmune disorders, renal disease, diabetes, mental health, and cardiovascular disorders.

Patrick Hopkinson
Independent Consultant, Founder and Managing Director, PHTA Consulting

Patrick Hopkinson is a Global Market Access/HEOR expert with over 30 years experience. He is an independent consultant, founder and managing director of PHTA Consulting. He is a senior leader in the life sciences industry with extensive expertise gained from working across multiple functions in global pharmaceutical organizations at an executive leadership level.

A former Vice President of Global HEOR at Bristol Myers Squibb, Patrick has a specialist focus on Market Access, HEOR, HTA Policy and RWE combined with extensive commercial experience including P&L responsibility. An HTA expert, he has delivered multiple launches, over 400 submissions across ~35 countries overcoming HTA and Access challenges to optimize commercial performance.

As an EU HTAR expert, Patrick led the BMS enterprise readiness, was a member of the EFPIA HTA working group and is a regular speaker at key conferences. Patrick provides support for organizations preparing for JCA/JSC, i.e., embedding requirements into the product development process, cross-functional working, JSC, PICO predication, JCA strategy, stakeholder planning and dossier submission.

He has been a member of key access policy working groups at EFPIA, PhRMA and ABPI, plus he served as a NICE Appeal Panel member for 10 years. Previously he worked at GSK in Global and Country roles and as a Clinical Oncology Pharmacist in the UK NHS. Patrick is a thought leader and regular conference speaker who is passionate about transforming the life science industry and healthcare stakeholder relationship by focusing on value and the sustainability of healthcare.

Sponsorship for this Deep Dive was provided by RTI Health Solutions