JCA discontinued: Why EU-HTA assessments are stopped and what this means for Germany

The first discontinued Joint Clinical Assessments (JCAs) show very clearly where the practical risks of the new EU-HTA procedures lie. The relevant question is not only whether the clinical evidence is convincing. The procedure may already become vulnerable if the evidence has not been completely identified, prepared in line with the relevant PICOs, methodologically justified and documented in a reproducible way.

For pharmaceutical companies in Germany, this creates an additional preparation point at the interface between the JCA dossier, the delta dossier and the AMNOG dossier. The German procedure remains national. The JCA does not replace the early benefit assessment, and a discontinued JCA does not reduce the requirements for national evidence preparation.

**“JCA discontinued” means that a Joint Clinical Assessment was not completed with a final JCA report.** The term initially describes the procedural status, not automatically the underlying reason.

Based on the cases reviewed so far, at least two different constellations can be distinguished:

This distinction is important. A discontinued JCA is not automatically equivalent to “insufficient clinical efficacy”. In some cases, the regulatory withdrawal is the main issue. In others, the official documents show very clearly that the JCA dossier did not meet the requirements for completeness, transparency and methodological traceability.

Based on the documents reviewed, three cases are particularly relevant: Zumrad / sasanlimab, catequentinib and Tacquell.

These cases should therefore not be grouped under a single category such as “JCA failed because of poor evidence”. A more precise interpretation is this: the first discontinued JCAs show that the EU-HTA procedure can become vulnerable both from a regulatory and a methodological perspective if either the authorisation process or the JCA dossier basis does not hold.

**The JCA for Zumrad / sasanlimab was discontinued because Pfizer withdrew the EMA marketing authorisation application.** Zumrad was intended for adults with BCG-naive, high-risk, non-muscle-invasive bladder cancer. The active substance sasanlimab was intended to be used in combination with Bacillus Calmette-Guerin (BCG).

The EMA had already assessed the application and prepared questions for the company. At the time of withdrawal, the EMA was evaluating the company’s responses. The Agency expressed concerns about the study and the conclusions derived from it.

The relevant points included:

1. major changes made while the study was ongoing,
2. a change in the statistical method,
3. uncertainties regarding the appropriateness of the primary endpoint,
4. assessment of the endpoint by investigators in an open-label study setting,
5. the question of whether the observed effect represented a clinically meaningful benefit for patients,
6. lack of support for the primary result from other important endpoints, including survival data,
7. more side effects and more interruptions or discontinuations of BCG treatment under the combination with Zumrad.

Pfizer justified the withdrawal by stating that additional data and analyses were needed to address the CHMP’s questions.

For the interpretation of discontinued JCAs, Zumrad therefore represents a distinct type of case. The case does not primarily show an incomplete JCA dossier under Article 9, but the direct dependency of the JCA on the central authorisation procedure. If the marketing authorisation application is withdrawn, the regulatory basis for completing the JCA no longer exists.

**Catequentinib and Tacquell show a different type of risk: the JCA was not classified in relation to a withdrawn marketing authorisation application, but in relation to missing information, data, analyses and evidence in the JCA dossier.** Article 9 of Regulation (EU) 2021/2282 is central here.

Article 9 requires a JCA dossier to contain complete and up-to-date information, data, analyses and evidence to assess the parameters defined in the assessment scope. In addition, the submitted evidence must be complete, analysed using appropriate methods, presented transparently and supported by underlying documentation that allows verification.

The Commission documents on catequentinib and Tacquell show that these requirements are assessed in very concrete terms. It is not sufficient to submit a clinical study or selected results. The JCA dossier must provide a complete, PICO-specific and methodologically traceable basis for assessment.

Catequentinib: Why missing evidence completeness became a JCA risk

**For catequentinib, one central problem was the lack of transparent and comprehensive identification of the available evidence.** The Commission criticised that the available evidence had not been presented and synthesised in a way that allowed assessors to evaluate the completeness and validity of the methodological approach.

For catequentinib, the documented deficits included:

1. no transparent and comprehensive identification of all available evidence,
2. no sufficient justification for the inclusion or exclusion of evidence,
3. insufficient presentation of the PICOs in accordance with the Commission’s first request,
4. missing explanation of why no relative effectiveness and relative safety results were submitted for certain PICOs,
5. missing justification for not conducting feasibility assessments for indirect comparisons,
6. insufficient documentation of literature searches and study selection,
7. missing or incomplete information on study characteristics,
8. missing results according to the assessment scope,
9. incomplete information for assessing the certainty of results,
10. missing underlying documentation in the appendices.

The catequentinib case therefore shows very clearly that a JCA dossier must not only contain evidence. It must demonstrate that the evidence was searched comprehensively, selected transparently, analysed by PICO and interpreted using a methodologically robust approach.

For market access teams, this is particularly relevant because these requirements have to be met early in the process. Companies that only assess after the assessment scope whether the evidence base has been documented robustly for all relevant PICOs, comparisons and endpoints risk procedural problems in a very tight timeframe.

Tacquell: Why results presentation and reproducibility became decisive

**For Tacquell, the main issues were missing PICO-specific information retrievals, insufficient descriptions of methods, missing results presentations and missing documentation.** The Commission listed deficits across several dossier sections and appendices.

For Tacquell, the missing elements included:

1. information retrievals for several PICOs,
2. a comprehensive description of the methods for PICO 1, PICO 2 and PICO 6,
3. a justification for the absence of sensitivity analyses,
4. underlying documentation for external comparisons,
5. description of analysis methods for included studies,
6. complete presentation of relative effect measures,
7. Kaplan-Meier curves for time-to-event data,
8. results on relative effectiveness and relative safety according to the assessment scope,
9. search strategies by PICO,
10. documentation of studies, protocols and registry searches,
11. programming code for the unanchored indirect comparison or external comparison.

Tacquell highlights a second point: the requirements do not only concern evidence retrieval, but also the assessability of the results. If relative effect measures, confidence intervals, sensitivity analyses, time-to-event presentations or programming code are missing, assessors cannot adequately verify the results.

For JCA dossiers, reproducibility therefore becomes a practical procedural criterion. The question is not only whether a result is reported. What matters is whether the derivation of that result can be traced and verified within the available timelines.

**The first discontinued JCAs show four recurring risk areas: evidence completeness, PICO coverage, methodological transparency and reproducibility.** These risk areas affect both the operational quality of the JCA dossier and the strategic preparation of the evidence.

Evidence completeness in the JCA dossier

A JCA dossier must capture the available evidence completely and transparently. Depending on the research question, this includes not only randomised studies, but also study registries, results registries, HTA reports, information from the EMA dossier, patient registries and, where relevant, other data sources.

For manufacturers, this means that a systematic literature search must not only be performed, but fully documented. Search strategies, search limits, study selection, reasons for inclusion and exclusion and the PICO-specific allocation of evidence must remain verifiable.

PICO coverage in the JCA dossier

The PICO questions from the assessment scope structure the JCA. Each PICO question must be addressed. If no results are submitted for a PICO question, the omission must be explained transparently.

For Germany, this is particularly relevant because the scoping phase already determines which populations, interventions, comparators and endpoints may later become relevant for the national translation of the evidence. If the PICOs relevant for Germany are not robustly covered, this creates a risk for the delta dossier and the national AMNOG preparation.

Methodological transparency in the JCA dossier

Indirect comparisons, external comparisons, sensitivity analyses and deviations from methodological guidance documents must be justified. A JCA dossier must show why a method was chosen and why other methodological options were not applied.

This applies in particular to feasibility assessments for indirect comparisons. If no indirect comparison is conducted, a mere statement that evidence is missing is not sufficient. A transparent justification is needed to explain why the comparison is not possible or not methodologically acceptable.

Reproducibility in the JCA dossier

Assessors must be able to verify the submitted results. This requires underlying documents such as clinical study reports, study protocols, statistical analysis plans, documentation of evidence syntheses and, where applicable, programming code.

Reproducibility is therefore not a purely technical detail. It determines whether relative effects, indirect comparisons and sensitivity analyses can be assessed reliably within the JCA timelines.

**A discontinued JCA does not mean that the AMNOG procedure no longer applies in Germany. The German procedure remains national, and the pharmaceutical company must still prepare the evidence in a way that meets German requirements.**

The JCA does not replace the German early benefit assessment. National decisions on added benefit, the appropriate comparator therapy, the patient relevance of endpoints and the subsequent price negotiation remain anchored in Germany.

If no final JCA report is available, there is no European clinical report to which the national procedure can refer. This has three practical consequences:

1. The delta dossier can rely less on a completed JCA report.
2. The national evidence preparation must be robust in its own right.
3. Manufacturers need a fallback scenario in case the JCA report is delayed, incomplete or not available at all.

For Germany, the decisive question therefore remains which JCA PICOs reflect the requirements of the German benefit assessment. This determines which comparator therapy becomes relevant and whether the European evidence can support the national assessment. German requirements for patient-relevant endpoints, subgroups, analysis methods and evidence currency also continue to apply.

**The delta dossier is the national translation of European evidence into an AMNOG-ready dossier. If a JCA is discontinued, this translation task becomes more demanding because no final JCA report is available as a reference point.**

The term delta dossier is not an official regulatory term. In the German market access context, it describes the additional content required between the JCA dossier and the national AMNOG dossier. Discontinued JCAs make precisely this interface more relevant.

A robust delta dossier cannot merely refer to European documents. It must assess which elements are actually robust enough for Germany and where updated or additional evidence is required. Without a final JCA report, the emphasis shifts even more strongly to the national evidentiary rationale.

For manufacturers, this creates three operational questions:

1. Which parts of the JCA evidence can be used for the German appropriate comparator therapy and German endpoints?
2. Which evidence is missing for the AMNOG dossier, even though it was not or not fully addressed in the JCA process?
3. Which national dossier strategy is required if the JCA is not completed in time?

These questions do not belong at the end of dossier preparation. They must already be addressed during PICO scoping, evidence planning and methodological preparation.

**JCA readiness begins before submission of the JCA dossier.** The first discontinued JCAs show that manufacturers must assess early whether evidence, methodology, results presentation and documentation can withstand the requirements of the EU-HTA procedure.

For market access, HTA and evidence generation teams, seven concrete review questions arise:

1. Are all PICOs from the JCA assessment scope addressed with evidence or a transparent justification?
2. Is the systematic literature search complete, current and reproducibly documented?
3. Are study selection, reasons for exclusion and PICO allocation described transparently?
4. Are indirect comparisons, feasibility assessments, external comparisons and sensitivity analyses methodologically justified?
5. Are relative effect measures, confidence intervals, Kaplan-Meier curves, safety results and missing data fully presented?
6. Are clinical study reports, study protocols, statistical analysis plans, Appendix D documents and, where applicable, programming code available for verification?
7. Is it clear which JCA PICOs are relevant for Germany and where German requirements for appropriate comparator therapy, endpoints, subgroups or analyses differ?

These review questions do not only concern the European JCA dossier. They also concern the later connection to the German AMNOG procedure. If a PICO question is not properly addressed in the JCA dossier, this can later become a national evidence problem.

**For Germany, the decisive question is whether the European evidence can support the national benefit assessment.** The discontinued JCAs show that this question cannot first be answered at the delta dossier stage.

In the German procedure, the following points remain particularly important:

1. the appropriate comparator therapy,
2. the delineation of relevant patient groups and subgroups,
3. the patient relevance of endpoints,
4. the methodological acceptability of analyses,
5. the currency of the systematic literature search,
6. additional data cuts or new studies,
7. whether a JCA report is available in time and can be considered in the AMNOG procedure.

A discontinued JCA process does not automatically increase the substantive requirements of the AMNOG procedure. However, it removes a potential European reference point from the procedure. This increases the need for national evidence preparation that is robust in its own right.

Cytel and co.value - A Cytel Brand work at the interface between European clinical assessment and national benefit assessment in Germany. The focus is not only the formal preparation of a delta dossier, but earlier preparation: PICO scoping, evidence planning, comparator therapies, indirect comparisons, statistical evidence generation and local AMNOG interpretation.

The first discontinued JCAs show why this early preparation becomes relevant. JCA readiness is not a simple completeness check shortly before submission. It requires an evidence strategy that connects European requirements and national applicability early.

For Germany, this means that the delta dossier remains the visible point at which European evidence is translated into the AMNOG procedure. However, the decisive choices are made much earlier.

**The first discontinued JCAs do not show that EU-HTA as a procedure has failed. They do show that JCA dossiers must be prepared in a procedurally robust way.** Completeness, PICO coverage, methodological transparency and reproducibility are not secondary requirements in the EU-HTA procedure. They can determine whether an assessment can be completed at all.

For Germany, the conclusion is clear: EU-HTA does not reduce national preparation. If a JCA is discontinued, there is no European clinical report as a reference point. The AMNOG procedure nevertheless remains national and requires evidence preparation that is independently robust.

The practical message for manufacturers is therefore this: JCA readiness and AMNOG readiness must be prepared together. Companies that only bring together evidence, PICO coverage, comparator therapies, endpoints, indirect comparisons and documentation in the national dossier start too late.