Connecting JCA evidence needs with the target trial framework

The early EU Joint Clinical Assessment reports highlight how decisions made during development affect the comparative evidence available to assessors. Recent publications explore how the target trial framework could support evidence planning, while an accompanying interview with Huseyin Naci places these arguments in the context of emerging assessment practice.

The early Joint Clinical Assessment (JCA) reports under the EU Health Technology Assessment Regulation bring comparative evidence planning into sharper focus. They highlight how decisions about comparators, outcomes and data collection made during development affect what assessors can conclude later. Defining the comparisons needed is an essential starting point and is where most effort has gone so far. Designing studies capable of answering them requires planning well before dossier preparation, yet has received far less attention.

As part of our Spotlight “After the first JCA reports: Getting comparative effectiveness right”, developed in assocation with Adigens Health, we explore publications examining this challenge, the contribution of the target trial framework and the practicalities of translating a causal question into an observational study.

What the first JCA reveals about comparative evidence

In their recent NEJM perspective, Huseyin Naci and Beate Wieseler examine the implications of the first JCA, which assessed tovorafenib for pediatric low-grade glioma. Evidence was available for only one of the eight research questions in the assessment scope, with substantial uncertainty limiting the conclusions that could be drawn.

The authors argue that a shared assessment remains valuable even when comparative evidence is limited. JCAs can provide a transparent synthesis that national authorities would otherwise need to produce independently, while leaving judgments about added therapeutic benefit, pricing and reimbursement at national level. These publicly available assessments could also inform decisions beyond Europe, including those of US payers.

Making evidence gaps visible could also influence evidence generation. Naci and Wieseler suggest that bringing comparative effectiveness assessment closer to regulatory approval may encourage developers to generate relevant comparative data earlier. An accompanying IQWiG commentary reinforces the potential incentive to conduct studies with relevant comparison groups from the outset. Timing makes this pressing. JCA runs in parallel with the regulatory assessment, so evidence on the new medicine itself comes almost entirely from clinical trials. Real-world data can enter only on the comparator side, for instance as an external control arm.

In our accompanying interview, Naci observes that the early assessments have applied the Coordination Group’s published methods consistently. His answers highlight the importance of anticipating these requirements during development, when decisions about trial design and data collection can still be addressed.

How the target trial framework could support JCA evidence planning

The article The target trial framework and the HTA reckoning presents the framework as a bridge between defining a comparison through population, intervention, comparator and outcomes (PICO) and designing a study that can credibly answer it.

“A submission can be fully PICO-compliant with the right population, the right comparator, the right outcome and still produce a treatment effect estimate that is systematically wrong. JCA’s focus on PICO gets a company to the right question. The target trial framework is what produces a trustworthy answer to it.”

The framework makes the intended study and its assumptions explicit, although it cannot guarantee a trustworthy estimate. In his interview, Naci notes that the Coordination Group’s validity guidance already refers to the approach. Its practical contribution is to translate anticipated evidence needs into decisions about what to measure, in whom and over what period.

The article advocates specifying target trials early to guide evidence generation and document changes as comparator requirements evolve. This can help developers identify the information a study requires, assess whether existing data capture it and plan additional collection where necessary.

Naci’s interview illustrates why these decisions need to precede dossier preparation. Comparator selection can affect whether a pivotal trial supports later anchored indirect comparisons, while access to individual patient data can determine whether differences between study populations can be addressed. Planning also needs to cover outcome collection: he highlights early JCAs in which quality-of-life and safety follow-up ended with treatment, limiting the evidence available beyond that point.

A related discussion with Mona Khalid and Radek Wasiak (Adigens Health) reinforces this emphasis on feasibility. Khalid notes that even a rich dataset may lack the information needed to answer the intended question. Wasiak argues that trial design and external comparator feasibility should be considered alongside one another, before a single-arm trial’s design limits the options for a suitable comparison. Planning the study design and the data infrastructure such design requires must therefore be done together. Judging whether data are fit-for-purpose at so early a stage is hard, and is likely to take several rounds of iteration.  Data access issues have been a clear barrier to this process running efficiently in the past.

Early planning must also accommodate changing clinical practice. Naci describes Joint Scientific Consultations as an opportunity to test planned comparators and outcomes against anticipated assessment needs, while recognizing that advice may become less relevant as treatment options change. He highlights prospectively planned network meta-analyses and platform trials as approaches that can help evidence generation respond to new comparators.

These perspectives place the target trial framework within a broader comparative effectiveness strategy. Understanding its contribution requires a closer look at what it can achieve and how it can be applied to the available data.

What the framework can and cannot achieve

The methodological basis for this approach is explored by Miguel Hernán and colleagues in The target trial framework for causal inference from observational data: why and when is it helpful?

The framework asks researchers to describe the randomized trial they would ideally conduct to answer their causal question, then consider how that trial could be emulated using observational data. This requires specifying eligibility criteria, treatment strategies, time zero, follow-up, outcomes and the causal contrast of interest.

Its contribution includes reducing ambiguity in the research question and helping prevent biases introduced by study design. This allows researchers to focus more clearly on the limitations that remain in the data and how they might be addressed. However, applying the framework does not eliminate confounding or compensate for data limitations.

"The target trial framework can make the reasoning behind a comparison in JCA more transparent, while leaving assessors to judge whether the design, data and assumptions support the resulting conclusions."

Adapting the planned study to the available data

A second paper, Where do target trials come from? Specifying the protocol of a target trial when repurposing data for causal inference, examines how study specifications develop when researchers encounter the realities of existing data.

Hernán and colleagues describe how an initial “index trial” may need to be adapted into a target trial that can actually be emulated. The structure, completeness and limitations of the data can affect which elements of the intended protocol are feasible.

This adds an important qualification to the emphasis on early specification. Planning the intended comparison provides direction, but a fully emulatable protocol may require refinement after data inspection. The authors raise questions about which examinations should inform adaptations, how changes and their rationale should be reported, and whether rules governing these decisions can be specified in advance.

"For JCA dossiers, the implication is that assessors need to understand both the original question and any changes made to produce the final study. Transparent reporting should make clear whether those adaptations affect the relevance of the evidence to the comparison requested."

These resources show how the target trial framework can translate JCA evidence needs into explicit study designs, while making assumptions and data limitations easier to assess. Naci’s interview extends this planning perspective beyond the initial assessment: studies addressing the gaps documented in a JCA could give national bodies a common basis for considering future evidence generation. The practical task is to explain which question each study will answer, how it will answer it and what uncertainty will remain.

Explore these issues further in our interview with Huseyin Naci and join our webinar, After the first JCA reports: How should comparative effectiveness be assessed?, on January 27, 2027.