Second and third Joint Clinical Assessments published, addressing all Member State PICOs with comparative evidence

The publication of the second and third Joint Clinical Assessment (JCA) reports provides further insight into how evidence is being generated and assessed under the EU HTA Regulation. Assessments of lurbinectedin and tarlatamab demonstrate broader PICO coverage and more extensive use of comparative methods.

The Baseline

• The second and third JCAs include comparative evidence across all PICOs defined by Member States.
• Both assessments are supported by randomized controlled trials, supplemented by indirect comparisons where needed.
• The dossiers include a broad range of analytical methods, particularly in the tarlatamab assessment, reflecting increased methodological complexity.

The European Commission has published the second and third Joint Clinical Assessment (JCA) reports, covering Zepzelca (lurbinectedin) and Imdelltra (tarlatamab) for extensive-stage small cell lung cancer (ES-SCLC). The assessments were conducted with the involvement of the Institute for Quality and Efficiency in Health Care (IQWiG), alongside INFARMED, I.P. (Portugal) for lurbinectedin and the National Public Health and Pharmaceutical Center (NNGYK) for tarlatamab as the co-assessors.

The publication of these reports follows the first JCA released in early June and provides further insight into how the framework is being applied in practice, particularly in relation to evidence generation and the ability to address Member State-defined PICOs (population, intervention, comparator, outcomes).

Both assessments relate to orphan indications in ES-SCLC, but with differing scopes. For PharmaMar’s lurbinectedin, Member States defined a single PICO, reflecting a more narrowly specified population and treatment setting. In contrast, the tarlatamab assessment required seven PICOs across multiple subpopulations, illustrating how the breadth of the claimed indication influences the complexity of the assessment scope.

In both cases, randomized controlled trials (RCTs) formed the basis of the evidence package. For lurbinectedin, the comparator in the RCT aligned directly with the comparator specified in the PICO, allowing for a straightforward direct comparison.

For tarlatamab, developed by Amgen, the evidence base was more complex. Subpopulations within the pivotal trial were used to inform multiple PICOs, supplemented by indirect comparisons where direct evidence was not available. These included network meta-analyses, anchored indirect comparisons, and unanchored matching-adjusted indirect comparisons (MAICs), depending on the data available for each scenario.

Comparative analyses were therefore available across all PICOs in both assessments, representing a notable difference from the first JCA, where evidence was available for only one of eight PICOs. This issue was also discussed at the recent GetReal conference, where speakers highlighted the difficulty of aligning available evidence with multiple PICO requirements and the challenges of generating comparative data in small or heterogeneous populations.

A key difference highlighted by the first JCA was not the number of PICOs defined, but the availability of comparative evidence to address them. As discussed in an editorial by Sreeram Ramagopalan and Annie Jullien Pannelay in the Journal of Comparative Effectiveness Research, even a relatively limited scope resulted in most PICOs remaining unaddressed due to a lack of suitable comparator data. In contrast, the second and third JCAs demonstrate that where comparative evidence is available, whether through direct comparisons or a combination of indirect methods, it is possible to address the full set of Member State-defined research questions.

Commenting on the publication, Beate Wieseler, Head of IQWiG’s Drug Assessment Department, reflected on the experience of delivering the assessments, saying:

“These assessments have expanded our understanding of the new European process. In gaining these insights, we have particularly benefited from our collaboration with our Portuguese and Hungarian colleagues.”

Referring to the tarlatamab assessment, she highlighted the range of analytical approaches applied within the JCA framework: “The assessment of tarlatamab specifically highlights the wide variety of methods available for a JCA – and that these can also be applied to orphan drugs.”

Wieseler also emphasized the importance of transparency, noting that the publication of unredacted reports and dossiers “enables the evidence to be used for decision-making purposes in EU Member States and beyond.”

As both medicines received marketing authorization from the European Medicines Agency at the end of May 2026, JCA outputs can now be used to inform national HTA procedures. The availability of comparative evidence across all PICOs, supported by a combination of direct and indirect methods, provides a broader evidence base for Member States as they move towards pricing and reimbursement decisions.

These assessments also provide an indication of how submissions align with the expectations of the framework when comparative evidence is available and clearly documented. Reflecting on the first JCA, Anne Willemsen, Co-chair of the JCA Subgroup, highlighted the importance of transparent justification where evidence is limited or absent. In this context, the second and third JCAs illustrate how the combination of available data and clearly described analytical approaches can support assessment across multiple PICOs.