First EU Joint Clinical Assessment report exposes challenges in generating comparative evidence

The publication of the first Joint Clinical Assessment (JCA) report provides an early indication of how evidence will be evaluated under the EU HTA Regulation. The evaluation of tovorafenib (Ojemda®) sets out how comparative data, indirect analyses, and evidence limitations are handled within the framework.

The Baseline

• The first JCA report includes comparative evidence for only one of eight PICOs defined during the assessment.
• Single-arm trial data were not included where no comparative analysis against relevant comparators could be made.
• Indirect comparisons were included in limited cases, with detailed documentation of methodological constraints and data limitations.

The first JCA report provides a detailed account of how evidence is assessed under the EU HTA Regulation, where demonstrating efficacy must also be supported by evidence of relative effectiveness against relevant comparators. The report, which evaluates tovorafenib (Ojemda®) for pediatric low-grade glioma, outlines the assessment scope, defined PICOs, submitted evidence, and the basis on which analyses were included or excluded. The assessment was led by the National Centre for Pharmacoeconomics (NCPE), Ireland, as assessor, with the Institute for Quality and Efficiency in Health Care acting as co-assessor.

During the scoping phase, EU Member States defined eight PICOs across three populations reflecting the full indication and relevant subgroups. According to the report, comparative evidence was included for only one PICO (PICO 5), while no data were submitted or accepted for the remaining seven (PICOs 1–4 and 6–8).

For the PICOs without comparator data, Ipsen reported that it was unable to identify suitable studies in the target population. The report notes that, in several cases, no studies were available that included the full set of relevant comparators, meaning comparative effectiveness and safety analyses could not be provided.

This is also reflected in the regulatory context. Tovorafenib received conditional marketing authorization from the European Medicines Agency based on less complete clinical data due to unmet need. In practice, this often means reliance on single-arm studies and limited follow-up, which restricts the availability of comparative evidence. This is indicated in the JCA, where comparative analyses were not available across multiple PICOs.

Attempting to address these limitations, the report notes that Ipsen explored the use of external control arms based on real-world data to generate comparative effectiveness evidence for tovorafenib in BRAF-altered, relapsed, or refractory pLGG. A feasibility assessment identified one potential database; however, it was not considered suitable due to insufficient patient numbers and limited follow-up. Ipsen therefore concluded that a “fit-for-purpose and reliable comparator data source was not possible.” Further detail in the dossier appendix highlights the importance of disease-specific registries in supporting the generation of sufficiently robust evidence for external control arm studies.

The report also describes the treatment of single-arm evidence. Data from the pivotal FIREFLY-1 study were submitted across multiple PICOs but were excluded from the assessment where they did not provide comparative information against the specified comparators. The report states that descriptive outcomes without a comparator do not inform relative effectiveness or safety within the scope of the assessment.

For PICO 5, the only PICO for which comparative evidence was included, an unanchored matching-adjusted indirect comparison (MAIC) was conducted comparing tovorafenib with dabrafenib plus trametinib. The report describes the analysis and outlines its limitations, including reduced effective sample size, differences between study populations, and the potential for residual confounding. While such approaches are commonly used in rare disease settings where randomized controlled trials may not be feasible, the assessment shows that unanchored indirect comparisons are examined closely, particularly where supporting data are limited.

The summary report further notes that all results for PICO 5 are based on unanchored indirect comparisons and are associated with “major uncertainties,” including small effective sample sizes, population differences that could not be fully adjusted for, and residual confounding. As non-randomized evidence, these analyses carry a higher risk of bias, and the report states that the resulting effect estimates should not necessarily be interpreted as causal.

By contrast, a second MAIC submitted for PICO 7, comparing tovorafenib with trametinib, was not included in the final report. The comparator study was available only through conference abstracts, and the report states that this level of documentation was insufficient to assess study methods and results. Studies reported only in abstracts or limited summaries are not considered adequate for inclusion, regardless of disease rarity.

The regulatory context is also relevant. Tovorafenib received conditional marketing authorization from the European Medicines Agency based on less complete clinical data due to unmet need. In practice, this often involves reliance on single-arm studies and limited follow-up, which can restrict the availability of comparative evidence at the time of assessment.

The report also highlights the absence of patient-relevant outcomes. No comparative evidence on health-related quality of life (HRQoL) was available across any of the eight PICOs. This was also reflected in stakeholder input, including from patients and caregivers. Within the JCA framework, such outcomes are considered important for assessing relative effectiveness, particularly beyond tumor response, and their absence limits the ability to compare treatments across the defined PICOs.

Commenting on the report, Ipsen noted the absence of a clearly established clinical comparator for much of the patient population, reflecting both the limited availability of treatments and the “challenges of generating comparative evidence in small, heterogeneous patient cohorts.”

Professor Olaf Witt, Director of Translational Pediatric Oncology at the Hopp Children’s Cancer Center Heidelberg, described the constraints associated with evidence generation in this setting:

“Randomized comparative studies… are often unfeasible due to limited patient availability, while withholding potentially beneficial therapy raises ethical concerns. In this context, ensuring timely access to innovation without compromising scientific rigor is critical.”

The JCA report documents these constraints alongside the available evidence, including the absence of comparator data across most PICOs, the use of indirect comparisons in limited cases, and the exclusion of analyses where data were not considered sufficiently robust.

As Member States take this assessment forward into national HTA processes, how they interpret this evidence, particularly in the context of limited comparative data and documented uncertainty, including how uncertainty is weighed alongside unmet need in rare and pediatric populations, will be an important factor in subsequent reimbursement decisions.