The AMNOG dossier is the structured evidence submission prepared by the pharmaceutical company for the early benefit assessment under Section 35a SGB V. It consists of five modules and combines information on the medicinal product and the German healthcare context with the clinical evidence on added benefit and the underlying documents and supporting evidence.
Formal completeness alone is not sufficient. The available clinical evidence must be able to address the German assessment question. Particularly relevant are the appropriate comparator therapy (zweckmäßige Vergleichstherapie, zVT), the patient population relevant to Germany, patient-relevant outcomes, subgroups and the required statistical analyses.
An AMNOG dossier is therefore not a transfer of the regulatory dossier into a different template. Module 3 must reflect the German healthcare context, Module 4 must present the evidence for medical benefit and added benefit, and Module 5 must make the underlying information and analyses traceable. The five modules serve different functions. In international market access, the AMNOG dossier is often referred to as the German value dossier or the HTA dossier for Germany. Unlike a global value dossier, it follows binding national templates and the assessment framework of Section 35a SGB V.
Regulatory status: September 2026. Module templates, formal requirements, statutory thresholds and other dynamic requirements should be checked against the applicable primary sources for each individual procedure.
The AMNOG process guide provides the overall framework; G-BA advice can clarify comparator, population and endpoint questions in advance, the appropriate comparator therapy guide explains the comparator that shapes the assessment, and the written comments and oral hearing guide covers the steps after publication of the assessment.
AMNOG dossier at a glance
The AMNOG dossier consists of five modules with different functions in the early benefit assessment. They range from administrative information and the description of the medicinal product and German healthcare context to clinical evidence and underlying documentation.
|
Feature |
AMNOG dossier |
|---|---|
|
Legal basis |
Section 35a SGB V |
|
Submitted by |
Pharmaceutical company |
|
Responsible institution |
G-BA |
|
Structure |
Modules 1 to 5 |
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German healthcare context |
Main focus of Module 3 |
|
Clinical evidence |
Main focus of Module 4 |
|
Documentation and supporting evidence |
Module 5 |
|
Comparator |
Appropriate comparator therapy (zVT) |
|
Function |
Evidence basis for early benefit assessment |
In practical dossier development, the modules are interdependent. Patient numbers in Module 3 require appropriate source documentation, clinical analyses in Module 4 require the corresponding supporting documentation, and new information on study recruitment in Module 3 creates additional documentation requirements in Module 5.
Preparation and timing of the AMNOG dossier
Preparation of an AMNOG dossier typically starts well before the actual submission date and runs in parallel with the marketing authorisation process. A typical planning horizon for compiling the dossier is around twelve months before market launch.
During this period, several workstreams need to be brought together:
clinical evidence,
statistical analyses,
systematic information retrieval,
target population information,
epidemiology,
zVT,
healthcare context,
annual treatment costs,
references and underlying documentation.
Dossier planning should therefore not start only when final marketing authorisation is imminent. Early decisions on the zVT, population and endpoints can be clarified in G-BA advice.
Submission date for the AMNOG dossier
For a medicinal product with a new active substance being placed on the German market for the first time, the benefit dossier must be submitted no later than the time of market launch. For an indication extension, submission takes place within four weeks after authorisation of the new indication.
The submission date is therefore the end of a longer preparation process rather than its beginning.
Regulatory timing, market launch, availability of clinical data and completion of the required analyses need to be planned together.
Formal completeness check before AMNOG submission
A formal completeness check by the G-BA can be used before final dossier submission. As a planning benchmark, the documents should be submitted for this check no later than three weeks before final submission.
Formal completeness should be distinguished from the methodological strength of the dossier.
A formally complete dossier can still contain substantive uncertainty regarding the zVT, population, outcomes or statistical analyses. Methodological preparation should therefore be largely complete before the formal final check.
Structure of the AMNOG dossier: Modules 1 to 5
The five modules of the AMNOG dossier combine administrative information, medicinal product information, the German healthcare context, clinical evidence and underlying documentation. Their substantive focus differs considerably.
|
Module |
Main focus |
Practical function |
|---|---|---|
|
Module 1 |
Administrative information and summary |
Consolidates key information and results |
|
Module 2 |
Medicinal product and indication |
Defines the subject of the assessment |
|
Module 3 |
zVT, target population, healthcare context and costs |
Reflects the German healthcare context |
|
Module 4 |
Medical benefit and added benefit |
Clinical and statistical evidence |
|
Module 5 |
Documents and supporting evidence |
Makes information and analyses traceable |
Modules 1 to 4 are published on the G-BA website as part of the benefit assessment procedure.
Module 1: Administrative information and summary
Module 1 contains administrative information and summarises the central content of Modules 2 to 4.
It combines formal information on the medicinal product and pharmaceutical company with a structured summary of the content relevant to the benefit assessment.
Module 1 primarily consolidates results. The underlying scientific derivations are provided in the subsequent modules.
Module 2: Medicinal product and authorised indications
Module 2 describes the medicinal product, its mechanism of action and the authorised indications.
The authorised indication defines the regulatory framework within which the German benefit assessment takes place.
Changes to the final wording of the indication can therefore affect the relevant patient population, the zVT and the evidence required in Module 4.
Module 3: zVT, target population, healthcare context and costs
Module 3 places the medicinal product within the German healthcare context.
Its main content includes:
determination of the appropriate comparator therapy,
description of the disease and target population,
therapeutic need,
prevalence and incidence in Germany,
number of patients in the target population,
patient groups with therapeutically relevant added benefit,
treatment costs for statutory health insurance,
requirements for quality-assured use,
information on trial participants within the scope of SGB V.
Module 3 is therefore considerably more Germany-specific than the general clinical description of the medicinal product.
Module 4: Clinical evidence and added benefit
Module 4 contains the methodological and clinical derivation of medical benefit and added benefit.
It describes the methods and results, relevant patient groups and the evidence used to support an added benefit claim. Systematic literature searching and information retrieval are also part of Module 4. Analyses for the benefit dossier can additionally be submitted as a separate Appendix 4-G file.
Module 4 is particularly important for dossier strategy because it requires an assessment of whether the available clinical evidence can actually answer the German assessment question.
Module 5: Documentation and supporting evidence
Module 5 provides the documents needed to trace the information and analyses in the other dossier modules.
These can include:
full texts of cited references,
relevant sections of the regulatory dossier in CTD format,
assessment reports from regulatory authorities,
documentation of information retrieval,
programming code for indirect comparisons,
study reports,
further documents required for formal completeness.
Module 5 is therefore not merely a document archive. The submitted documents must make the derivations and analyses in the other modules verifiable.
Module 3 of the AMNOG dossier: Germany-specific evidence
Module 3 translates the authorised indication into the German healthcare context. In addition to the zVT, the target population, epidemiology, statutory health insurance population and costs are particularly relevant.
Since 2025, additional requirements apply to selected information on the target population and participation in clinical trials in Germany.
Target population and epidemiology in Germany
The size of the German [target population](/en/insights/real-world-evidence-amnog-dossier) must be derived transparently and supported by appropriate sources.
The derivation can involve several steps, from prevalence and incidence through patient groups relevant to the authorised indication to the number of patients covered by statutory health insurance.
Different data sources may be relevant depending on the question. Assumptions, calculation steps and uncertainty should remain transparent.
Compare patient numbers with previous G-BA decisions
Since 2025, patient numbers in Module 3 should be contextualised against previous benefit assessment decisions in the relevant indication. The corresponding page numbers of the underlying references must also be provided.
This means that a current epidemiological derivation should not be considered in isolation.
Where new patient numbers differ from previous G-BA decisions, the data, assumptions or changes in the healthcare context explaining the difference should be transparent.
Five-year development of the statutory health insurance target population
Since 2025, Module 3 requires information on expected changes in the number of patients covered by statutory health insurance in the target population over the following five years.
This makes the expected development of the target population relevant in addition to its current size.
The forecast should be consistent with the underlying epidemiological derivation. Changes may be influenced by demographics, diagnostics, healthcare delivery or other factors where these can be substantiated for the specific derivation.
Trial participants at German study sites
For medicinal products first placed on the market from 2025 onwards, Module 3 includes additional information on participants in clinical trials conducted at sites within the scope of SGB V.
The number of participants at German study sites and the total number of participants across all sites must be reported for each study.
The requirement covers studies submitted in the dossier and studies submitted for marketing authorisation where the specified conditions are met.
This requirement does not affect Module 3 alone. The corresponding supporting evidence also needs to be included in the underlying documentation.
Module 4 of the AMNOG dossier: Evidence for added benefit
Module 4 must show whether the available clinical evidence can answer the German assessment question against the relevant zVT.
A clinical study does not automatically become suitable evidence for early benefit assessment simply because it was pivotal for marketing authorisation.
Regulatory studies are not automatically suitable for AMNOG
A pivotal clinical study is not automatically suitable for the early benefit assessment. Several conditions affect its usability.
In particular, the following should be assessed:
Does the study population correspond to the authorised indication?
Is treatment consistent with the relevant product information?
Is the evidence transferable to the German healthcare context?
Are the collected outcomes patient-relevant?
Is the relevant zVT adequately represented?
Are the required subgroup analyses available?
Are the statistical analyses required for benefit assessment available?
The most straightforward situation is an appropriate randomised controlled trial against the zVT. Where no such direct comparison is available, it must be assessed whether another form of comparative evidence is methodologically suitable.
Patient-relevant outcomes in Module 4
Patient-relevant effects are central to Module 4; pharmacokinetic data or laboratory parameters alone are not sufficient for the benefit assessment.
The main dimensions include:
mortality,
morbidity,
health-related quality of life,
adverse effects.
For dossier development, it is not sufficient simply to list these outcomes. Their specific operationalisation, measurement instruments and statistical analyses must fit the German assessment question.
Additional analyses for the AMNOG dossier
The Clinical Study Report is generally not sufficient for presenting the evidence in Module 4. Additional analyses for the benefit assessment are often required.
These can include:
additional outcome analyses,
subgroup analyses,
analyses for the relevant German population,
analyses aligned with the zVT,
indirect comparisons,
further AMNOG-specific statistical analyses.
Appendix 4-G allows analyses for the benefit dossier to be submitted separately.
The required analyses should therefore be identified early. The later a methodological gap is identified, the fewer options remain to address it robustly within the dossier timeline.
Direct and indirect comparisons in the AMNOG dossier
A direct randomised comparison against the zVT provides the most straightforward basis for assessing relative treatment effects. Where no such comparison is available, indirect comparison methods may become relevant.
The appropriate method depends on the available study landscape and comparative data.
Direct comparison against the zVT
A direct comparison evaluates the medicinal product under assessment and the zVT within the same comparative study.
Even a direct randomised study is not automatically fully suitable for Module 4. Population, dosing, treatment, outcomes and analyses must adequately reflect the German assessment question.
Early assessment of the zVT is therefore closely linked to clinical evidence planning.
Adjusted indirect comparisons in the AMNOG dossier
An adjusted indirect comparison can be relevant where no direct comparison between the medicinal product and the zVT is available but an appropriate common bridge comparator exists.
In a Bucher adjusted indirect comparison, relative effects are linked through a common comparator.
Methodological suitability of the network, similarity of the included studies and completeness of the required data are particularly important.
Feasibility should therefore be assessed before the final phase of dossier development.
Unadjusted indirect comparisons in the AMNOG dossier
Unadjusted or historical comparisons can be relevant particularly where the evidence is based on single-arm studies, but they are subject to high methodological requirements.
For such situations, a very large or "dramatic" effect is described as necessary; a five- to ten-fold better effect versus the zVT is cited as an indicative magnitude.
A historical comparison is therefore not a simple alternative to missing randomised evidence. The underlying data and the size of the observed effect must allow a sufficiently credible interpretation.
Acceptance of indirect comparisons in previous AMNOG procedures
In one analysis of previous benefit assessment procedures, only a limited proportion of submitted indirect comparisons were accepted.
The dataset comprised 347 indirect comparisons presented in 231 procedures as of early May 2025. Of these, 76, or 21.9%, were accepted. The most frequent reasons for rejection were methodological shortcomings, insufficient similarity between studies and incomplete data.
This historical analysis is not a forecast for any individual future procedure. It does, however, illustrate why the methodological feasibility of an indirect comparison should be assessed early and critically.
An indirect comparison should therefore not be planned only after the lack of a direct zVT comparison becomes apparent in the completed dossier. The evidence network, study similarity and data availability need to be assessed sufficiently early.
Added benefit in Module 4 of the AMNOG dossier
Module 4 links the clinical results to the derivation of the claimed added benefit for the relevant patient groups.
Both the extent of added benefit and the certainty of the underlying evidence are relevant.
Extent of added benefit in the AMNOG dossier
The following categories are distinguished for the extent of added benefit:
major added benefit,
considerable added benefit,
minor added benefit,
non-quantifiable added benefit,
no added benefit proven,
lesser benefit.
"No added benefit proven" does not mean that the medicinal product has no medical benefit. The category refers to whether an additional patient-relevant benefit versus the relevant comparator has been demonstrated within the benefit assessment.
Claimed and assessed added benefit can differ
The added benefit category claimed in the AMNOG dossier is not automatically adopted in the subsequent benefit assessment or G-BA decision.
Module 4 is therefore more than a compilation of positive study results. The methodological derivation must transparently show why the available data support the claimed category for the relevant patient group and comparator.
Differences in population, zVT, outcomes or analyses can result in the submitted evidence being assessed differently from the company's claim.
Module 5 of the AMNOG dossier: Documentation and reproducibility
Module 5 provides the underlying documents and supporting evidence required to review the other dossier modules.
These include in particular:
full texts of cited references,
relevant CTD sections,
assessment reports from regulatory authorities,
documentation of information retrieval,
study reports,
programming code for indirect comparisons.
Documentation should therefore be built in parallel with the substantive dossier modules. Compiling it only shortly before submission increases the risk of missing or inconsistent supporting documents.
New documentation requirements in Module 5 since 2025
Since 2025, Module 5 has included additional documents linked to the new study recruitment information in Module 3.
These include:
SAS outputs summarising study recruitment by country and study site,
the checklist for formal dossier completeness, including information relating to Section 3.6.
New information in Module 3 therefore directly creates additional documentation requirements in Module 5.
Prepare Modules 3 and 5 of the AMNOG dossier together
Modules 3 and 5 should be prepared together for the new study recruitment requirements.
The link can be summarised as follows:
Trial participants in Germany → information in Module 3.6 → supporting evidence and SAS outputs in Module 5
For medicinal products first placed on the market from 2025 onwards, Module 3 requires the number of participants at German study sites and the total number across all sites for each study. Module 5 contains the corresponding SAS outputs and formal completeness checklist.
Dossier planning should therefore establish early which studies need to be covered and whether the required recruitment data are available in the necessary structure.
Orphan drugs in the AMNOG dossier
Specific requirements apply to the dossier modules for orphan drugs under the simplified AMNOG procedure. As long as the requirements for the simplified procedure are met, a comparative demonstration of added benefit against a zVT is not required.
|
Module |
Specific feature in the simplified orphan drug procedure |
|---|---|
|
Module 1 |
Certain sections on zVT, medical benefit and added benefit, and zVT annual treatment costs are not completed |
|
Module 2 |
No change |
|
Module 3 |
Section 3.1 on determination of the zVT is not completed |
|
Module 4 |
Focus on the required information on the extent of added benefit based on marketing authorisation and the studies supporting authorisation |
The simplified dossier structure does not mean that no clinical assessment takes place. Medical added benefit is initially considered established by virtue of marketing authorisation; the procedure particularly assesses its extent.
The revenue threshold for the simplified procedure is EUR 30 million within twelve months; above this threshold, a regular procedure is required.
AMNOG dossier under EU HTA
EU HTA changes the European clinical evidence base available for medicinal products within its scope, but it does not replace the national AMNOG dossier.
The Joint Clinical Assessment and the AMNOG procedure address different assessment questions. The JCA assesses relative clinical effects based on the European assessment scope. The German early benefit assessment evaluates added benefit within the national framework.
JCA dossier and AMNOG dossier serve different functions
The JCA dossier is the European clinical evidence submission for the Joint Clinical Assessment; the AMNOG dossier is the national submission for the German early benefit assessment.
The two dossiers can share clinical content but are neither structurally nor methodologically identical. The methodological requirements of the JCA dossier for RCTs, indirect comparisons and non-randomised evidence are described in the guide on JCA evidence assessment; the implications for Germany are discussed in the insight Five theses on the Delta-Dossier.
The German healthcare context, zVT, German target population and national dossier requirements remain particularly relevant to the AMNOG dossier.
Using European content in the AMNOG dossier
Three workstreams can be distinguished when transferring European content into the AMNOG dossier:
Reuse: Which content from the JCA dossier can be used or specifically referenced for the German submission?
Adaptation: Which European content needs to be selected or adapted for the German assessment question?
Addition: Which national content, analyses or evidence updates need to be added?
Reuse of European content is therefore a targeted assessment rather than a wholesale transfer of the JCA dossier.
National requirements remain in the AMNOG dossier
Even under EU HTA, substantial parts of the AMNOG dossier remain national.
These include in particular:
the zVT relevant to Germany,
German patient groups and target population,
national information on healthcare delivery and costs,
assessment of patient-relevant outcomes,
national requirements for subgroups and analyses,
additional or updated evidence available at the start of the German procedure.
For medicinal products within EU HTA scope, it should therefore be assessed early which European evidence already covers the German assessment question and where additional national work remains necessary. For comparison, the JCA dossier at EU level and the HAS submission in France set different evidence requirements.
Check the AMNOG dossier before submission
Before final submission, the AMNOG dossier should be checked not only for formal completeness but also for consistency of the German assessment question across modules.
Seven questions are particularly relevant:
Is the relevant zVT appropriately addressed for all relevant patient groups?
Does the clinical study population match the German assessment question?
Are the relevant patient-relevant outcomes available and appropriately analysed?
Are the required subgroups and additional statistical analyses available?
Is an indirect comparison methodologically suitable where no appropriate direct comparison is available?
Are Modules 3 and 5 consistent regarding target population, study recruitment and underlying documentation?
Are the studies, analyses and sources used in Module 4 fully traceable?
This review connects clinical evidence, statistics, epidemiology and documentation. It should therefore not be postponed until immediately before the final dossier upload.
The pembrolizumab assessment analysis shows across indications why comparator therapy, biomarkers and endpoints matter in dossier planning.