Orphan medicinal products (OMPs) will enter the EU Joint Clinical Assessment (JCA) process from 2028. While still a couple of years away, first published JCA reports include assessments of four OMPs, and are therefore giving early insights into how comparative evidence is being assessed under this new framework. For manufacturers developing treatments for rare diseases, these reports provide a valuable opportunity to anticipate future evidence expectations and begin preparing accordingly.
In our recent JCA for Orphan Medicines webinar, our expert panel explored the emerging themes from the JCA reports on tovorafenib, tarlatamab, lurbinectedin and onasemnogene abeparvovec, and discussed what they could mean for evidence planning. Below, we share the key takeaways from the discussion, followed by our recommendations for orphan medicinal manufacturers.
The first reports provide a clear picture of the high bar, the ‘methodological gold standard’, that will be used as a benchmark by assessors. Local health technology assessment (HTA) submissions and negotiations may provide opportunities to contextualise the evidence for national decision making. However, for manufacturers, the public critique of evidence quality within JCA reports reinforces the importance of considering JCA requirements long before submission.
Where the terms “rare” or “orphan” appear in JCA reports, they provide descriptive background only and are not linked to evidence expectations. The difficulty of overcoming small sample sizes, low effective sample size (ESS) and restricted covariate adjustment in rare diseases is sadly not acknowledged.
The JCA reports also did not acknowledge circumstances in which a randomised controlled trial (RCT) may be impractical or a placebo-controlled trial may be unethical. This is consistent with an approach that assesses comparative evidence against a defined methodological standard.
The JCA process is prioritising methodological consistency over disease-specific context, raising important questions about how the unique realities of rare disease evidence generation will be considered in future evaluations, when JCA reports are leveraged to support local HTA negotiations.
Both direct and indirect comparative evidence was subject to thorough methodological critique. Across the first four JCA reports for OMPs, assessments focused on robustness and completeness of evidence, rather than interpreting the evidence within the wider context of the rare disease indication or drawing conclusions on treatment value (the latter being a responsibility for local HTA bodies).
Uncertainties were consequently listed in the reports, but rarely quantified. Even where they were quantified, as in the spinal muscular atrophy (SMA) report, the implications for decision making were not discussed and were instead those judgements have been left to local HTA bodies.
The reports therefore provide an early indication that assessors are focused on evaluating the strength and reliability of the evidence itself, leaving interpretation of the resulting uncertainty largely to national HTA bodies.
Matching adjusted indirect comparisons (MAIC) based on conference publications, along with all non-comparative evidence, were excluded rather than critiqued. Several further MAIC results and analyses were omitted owing to methodological concerns. The threshold between evidence that will be “presented with caution” and evidence that will not be presented remains unclear. Assessors frequently critiqued methods or omissions without raising them for discussion with the manufacturer during the clarification process.
Perhaps most notably, the reports suggest that evidence may not simply be viewed less favourably because of methodological limitations, but may be excluded from consideration altogether, increasing the consequences of evidence-generation decisions made early in development.
Population, intervention, comparator and outcomes (PICO) coverage varied widely across the four reports: tovorafenib addressed 1 of 8 PICOs, tarlatamab 7 of 7, lurbinectedin 1 of 1 and onasemnogene abeparvovec 7 of 12. Each PICO result is presented descriptively, with no overall conclusion on evidence quality or treatment value, no weighting of PICOs by importance and no synthesis across them; these tasks are left to local HTA bodies.
This reinforces that the JCA should not currently be viewed as a replacement for national HTA assessments, but rather as a common clinical evidence foundation that individual markets will continue to interpret through their own decision-making frameworks.
Accurate and early prediction of decision problems at a national level will ensure all pre-launch evidence generation aligns with HTA needs. The standard of care can vary widely across markets in rare diseases, so mapping treatment pathways in key markets is essential. Pathway mapping will feed into PICO simulation, a central tool in the development of a pan-European strategy. PICO simulation in rare diseases may require a combination of approaches, including literature reviews, expert insights, and real-world evidence studies.
Rare diseases often lack validated and disease-specific outcome measures. Consensus building and validation take time but strengthen the case for chosen outcome measures. Scientific advice can help further refine an outcome strategy. This validation may be particularly important in markets such as France and Germany, where patient-reported outcomes are influential in decision making.
Where ITCs will be needed, assess the suitability of comparator sources by conducting early feasibility studies, before the pivotal trial is designed.
Single-arm trials are common in rare conditions. The first four reports indicate that unanchored analyses based on IPD may be viewed more favourably than unanchored comparisons based solely on published cohort data. Manufacturers should therefore consider the potential role of external/synthetic control arms, where single-arm trials are felt to be most appropriate. Payer validation, such as advisory boards and scientific advice, can be used to gauge how gaps in comparative data may influence local decision making and access outcomes.
Gathering expert insights is critical to preparing an effective launch strategy and robust evidence base in a rare disease indication. In rare diseases with a limited pool of clinical experts, manufacturers should plan engagement carefully and transparently, taking account of applicable conflict-of-interest requirements. Surveys or written contributions may reduce some forms of interaction-related bias compared with interviews or advisory boards, although the appropriate approach will depend on the objective and context of the engagement. With a limited pool of experts in many rare diseases, decisions made early in evidence development may influence the availability of expert input throughout the evidence-generation and assessment process.
Robust comparative evidence should reflect local decision problems and focus on clinically meaningful and patient-relevant outcomes. Manufacturers should consider national HTA requirements in priority markets alongside potential JCA evidence expectations from an early stage of development.
As orphan medicinal products move closer to entering the JCA framework, understanding emerging evidence expectations will be critical. Watch the JCA for Orphan Medicines webinar recording to hear our expert panel discuss the first JCA reports and their implications for rare disease manufacturers.
If you would like any further information or advice on the themes presented above, please get in touch, or visit our EU Joint Clinical Assessment page to learn how our expertise can benefit you. Issy Newell (Head of Rare Diseases), Keval Haria (Consultant, Rare Diseases) and Maddie Judge (Senior Analyst, Rare Diseases) created this article on behalf of Costello Medical. The views/opinions expressed are their own and do not necessarily reflect those of Costello Medical’s clients or affiliated partners.
