Five theses on the Delta-Dossier: why references alone will not be enough for Germany

Instead, it is becoming the test of whether clinical trial evidence, European and German HTA requirements, and tight procedural timelines can be brought together at an early stage.

There is still only limited practical experience with real Delta-Dossiers. All the more important, then, are the signals coming from Germany's Federal Joint Committee (Gemeinsamer Bundesausschuss, G-BA), the country's highest decision-making body in joint self-government and a central institution in the national HTA framework. Its spring 2025 events already made clear where the key requirements are likely to emerge and which questions pharmaceutical companies should be addressing now. The G-BA itself views the planned adjustments in the national setting, including the adaptation of the AMNOG dossier module templates, as a first step and intends to assess further developments on the basis of the first practical experience.

Here, we share five theses on the Delta-Dossier.

Thesis 1: The EU JCA will not replace the German benefit assessment

A central point is often underestimated in the current debate: the JCA does not replace Germany's early benefit assessment. The G-BA makes it clear that alignment with the European assessment does not change the assessment standards applied in the German benefit assessment. Decisions will continue to be taken at the national level. The JCA dossier is intended to inform national decision-making, but it does not itself provide a conclusion on additional clinical benefit compared with the national appropriate comparator therapy (zVT) - the foundation for the subsequent price negotiation.

This also clarifies the role of the Delta-Dossier: the objective is not simply to pass through European content in a formal way, but to prepare it in a manner that is robust and usable for the German procedure.

Thesis 2: The Delta-Dossier is about translation, not cross-referencing

The G-BA describes very specifically how the JCA dossier is to be used. References are possible, but only to clearly identified sections. General or dynamic references are not sufficient. At the same time, it remains the responsibility of the pharmaceutical company to determine whether the contents of the JCA dossier are sufficient for the German benefit assessment or whether updated or supplementary evidence is required. There will be no separate dossier template. The structure of the AMNOG modules will remain in place.

This is precisely where the quality of a good Delta-Dossier becomes visible: it is the national translation of the European assessment process and brings the JCA dossier and the AMNOG dossier together. This is achieved not through references alone, but above all through the targeted selection of content that is truly robust and the addition of missing data needed for an evidence-based national assessment.

One point is particularly important here: the G-BA makes it clear that a full national AMNOG dossier may still be submitted. There is therefore no obligation to use the Delta-Dossier as a lean referencing solution. What remains decisive is not the format, but the quality of the national dossier preparation.

Thesis 3: The real work starts well before the Delta-Dossier

The determination of the relevant PICOs (PICO scoping) for the JCA already begins when the marketing authorization application is submitted to the EMA, and therefore well before the start of the national AMNOG procedure. The PICOs fed back by Germany are intended to reflect the relevant research questions for the later AMNOG procedure, but - just like, for example, the outcome of an early G-BA consultation on the appropriate comparator therapy - they are not legally binding. This creates a risk scenario, particularly for the national procedure, that must be anticipated and taken into account in strategic planning. Any company that only starts to structure populations, comparator therapies, endpoints and potential subgroups when preparing the national dossier is already too late.

European scientific consultation on PICO scoping also takes place at a point when studies are still being planned. National consultations remain possible, but parallel duplicate structures are to be avoided. For manufacturers, this means that the real strategic work does not begin with the Delta-Dossier, but with PICO scoping, study design and early evidence planning.

Thesis 4: The biggest risks sit in comparator selection and endpoints

Translation into the German setting already becomes particularly demanding at the scoping stage. The first key question is which PICO, or which set of PICOs, actually reflects the requirements of the German benefit assessment. This determines which comparator therapy is relevant for Germany and whether the evidence addressed in the JCA will in fact support the national assessment. This is precisely where preparation for a strong Delta-Dossier begins: with the early identification of the PICOs relevant for Germany, the selection of robust content and the supplementation of evidence wherever European materials are not sufficient for the national assessment.

In addition, European JCA scoping may include endpoints that are not necessarily recognized as patient-relevant in the national procedure. The G-BA explicitly distinguishes between endpoints included at the European level and the criteria for patient relevance that apply in the German AMNOG procedure. The same applies to analytical methods: national requirements - such as the 15% relevance threshold for responder analyses - remain in place.

For this reason, the Delta-Dossier is particularly demanding from a scientific and methodological perspective wherever European evidence must be made robust for German comparator therapies and nationally relevant endpoints.

Thesis 5: Timing and evidence updates will be decisive

In addition to scientific issues, procedural management is becoming more important. The G-BA continues to require that the underlying systematic literature review on relevant clinical evidence must not be more than three months old at the start of the procedure. Additional data cuts and newly completed studies may therefore become relevant in the AMNOG procedure even if they were not addressed in the JCA dossier. This means that the dataset underlying the national AMNOG dossier may differ from the dataset underlying the JCA dossier.

The timing of the publication of the JCA report is also particularly important. If it is available in time, it will be taken into account in the benefit assessment. If it becomes available later, it may still be considered during the written comments procedure or, at the latest, in the final resolution. However, if it is published only after the start of the written comments procedure, it can no longer formally be taken into account. At the same time, the G-BA points out that there is as yet no reliable practical experience in this regard - another source of uncertainty for pharmaceutical companies.

From JCA dossier to Delta-Dossier: Cytel combines global perspective with local execution

Cytel occupies the critical interface between European clinical assessment and national benefit assessment in Germany. Together with the German team at co.value, a Cytel brand, Cytel combines experience in PICO scoping, JCA dossier development and statistical evidence generation with in-depth local AMNOG expertise. This means support does not begin only at the point of translating into the Delta-Dossier, but much earlier: in evidence planning, the selection of robust comparator therapies and the targeted shaping of European evidence for reliable use in the German AMNOG procedure.

The Delta-Dossier as the true test

The first Delta-Dossiers are only now beginning to emerge. But the substantive guardrails are already clearly visible, and they point in a clear direction: within the framework of European clinical assessment, the German AMNOG procedure will not become a process that can be handled through references alone.

What will matter instead is how early clinical trial evidence, European and German HTA requirements, and tight procedural timelines are brought together. The Delta-Dossier is therefore not merely a new format. It is the clearest expression of whether this translation work has been accomplished in time.