2028 and Beyond: Winning JCA in Rare Diseases

The Joint Clinical Assessment (JCA) centralized process was introduced in January 2025 to provide a unified scientific evidence base for evaluating a product’s relative effectiveness and safety. This process was initially introduced for oncology treatments and advanced therapy medicinal products (ATMPs) and will be expanded to include orphan-designated products/rare diseases in 2028.

Therefore, it will be critical to leverage insights from developing dossiers for oncology products to increase JCA preparedness in rare diseases, while adapting established value‑demonstration strategies from rare disease health technology assessment (HTA) submissions to address evidence gaps and support a coherent JCA narrative.

Since the introduction of JCA, Precision AQ has worked with biopharma manufacturers to develop modular strategies to support the creation of living literature bases, adaptive indirect treatment comparison (ITC) methods, and JCA dossiers for various oncology indications. It is helpful to apply learnings from oncology to address unique hurdles in rare diseases, given that these products typically rely on less traditional datasets and are more sensitive to the rigorous evidence recommendations from the JCA.

Key learnings from these processes that are relevant to rare diseases include:

Learning #1: PICO Predictions are Mission-Critical

Rare diseases typically include small patient populations, which makes it very challenging to conduct trials that address all potential subgroups or comparators of interest. Additionally, the standard of care for rare diseases can widely vary across the European Union (EU) Member States.

This highlights the importance of identifying which Population, Intervention, Comparator, and Outcomes (PICOs) are likely to be included in the scoping assessment to help fill evidence gaps early and to prioritize the universe of PICOs based on payer consultations. Performing PICO prediction three years prior to launch is recommended to enable sufficient time for additional data collection and preparation in advance of the JCA submission. Validation with payer stakeholders and local country teams provides critical insights, but it is important to prioritize essential PICOs over optional ones to focus evidence-generation strategies.

Learning #2: Front-Loading Evidence Strategies Fuels Success

Generating evidence for rare diseases can be challenging due to heterogeneous patient populations, scarce comparative data, and varying endpoint definitions. To address these challenges, it is important to design a living systematic literature review that captures the full evidence base, identifies gaps in generating ITCs, and allows new studies to be incorporated seamlessly over time (well in advance of the critical 100-day period).

Additionally, various phases of ITCs are recommended, including iterations before trial readout, to enable clinical consultations and discussions on which ITC methods are feasible and to develop alternative approaches. A well-designed and comprehensive evidence generation strategy not only identifies gaps and strengthens ITCs but also helps set the foundation for successful JCA submissions in rare disease.

Learning #3: Flexibility is Key When Standard Approaches Are Not Feasible

Sparse or disconnected networks often mean that standard NMAs are not viable, making it essential to plan alternative ITC approaches early in the evidence-generation strategy. In some cases, innovative approaches may be required to build a connected network of evidence in line with JCA guidance. Alternative approaches may include collapsing treatments into comparable nodes (with clinical justification), pooling similar evidence, or developing methods beyond standard network meta-analysis (e.g., component or multivariate network meta-analysis).

Learning #4: Leverage Real-World Evidence for External Control Arms and Adjust Appropriately

JCA guidelines prefer anchored ITCs using randomized controlled trials (RCTs); however, such analyses may not be feasible for specific populations of interest due to limited data availability. External control arms and real-world evidence are often necessary and may allow manufacturers to focus on a specific target population of interest, but their value depends on proper adjustment for prognostic factors and treatment effect modifiers. Clear documentation of assumptions and methods ensures external evidence strengthens the submission rather than introducing uncertainty.

Through structured expert input, manufacturers can identify key covariates and ensure external control arms (ECAs) provide robust, credible comparative evidence. These unanchored ITCs can also be considered to complement anchored ITCs or replace anchored ITCs that are not feasible/require too many strong clinical assumptions.

Learning #5: Engage Patient and KOL Expertise to De-Risk Your Strategy

Insights from patients and key opinion leaders can provide important information on endpoints that capture meaningful changes in the patient experience, which will be important to consider during the PICO preparedness activities. It will be important to consider these endpoints when evaluating the overall benefit of treatments. Additionally, manufacturers will need to engage key opinion leaders to support the communication of findings and the interpretation of results.

For example, analyses involving small patient populations will likely yield wide confidence intervals and no statistically significant results; therefore, it will be necessary to contextualize the clinical significance of the results. Lastly, it would be informative to use Joint Scientific Consultations to assess the validity of surrogate endpoints and to extend their use to the overall evidence strategy for rare diseases, including realistic study designs, data‑gap mitigation approaches, and methods for strengthening the value narrative despite small populations.

Launching a rare disease therapy? Let’s set up a time to connect at World EPA to discuss how early, integrated evidence and access planning can set you up for JCA success.