Appropriate comparator therapy (zVT): relevance for the AMNOG process and benefit assessment

The zweckmäßige Vergleichstherapie (zVT) is the comparator defined by Germany's Federal Joint Committee (Gemeinsamer Bundesausschuss, G-BA) for assessing the additional benefit of a new medicine under the AMNOG process. It therefore has a direct bearing on which clinical evidence can answer the German assessment question.

For international market access teams, the zVT should be understood as a Germany-specific assessment concept. It is not interchangeable with the comparator concepts used in other HTA systems. The zVT can affect clinical development, evidence planning, dossier preparation and the subsequent assessment of additional benefit.

The timing is particularly important: a zVT discussed in early G-BA advice is not necessarily the comparator that will apply at the time of the final G-BA resolution. Treatment standards, new evidence, updated guidelines and new treatment options can change the German assessment landscape over time.

Regulatory status: October 2026. The relevant zVT and current legal and methodological requirements should be checked against the latest German primary sources for each individual procedure.

The zVT affects the wider AMNOG process in Germany: G-BA advice can clarify the expected comparator in advance, the AMNOG dossier guide shows how the comparator shapes the evidence submission, and the guide to written comments and the G-BA oral hearing explains how outstanding comparator issues can be addressed later in the process.

The zVT in the German AMNOG process

The zVT defines the comparator against which additional benefit is assessed in the German AMNOG process. The G-BA determines it for the relevant indication and, where applicable, separately for different patient populations.

For evidence planning, the relationship is straightforward:

clinical evidence → comparison with the zVT → assessment of additional benefit

The question of the zVT therefore does not arise only when the final AMNOG dossier is prepared. Depending on the comparator defined for Germany, the study design, comparator strategy, statistical analyses and later usability of the clinical evidence may already be affected much earlier.

The G-BA defines the zVT using the German treatment context

The zVT reflects the current medical knowledge and treatment situation for the relevant indication in Germany. The G-BA does not simply identify every potentially available treatment option. It determines which treatment is considered appropriate for the specific assessment question.

The relevant criteria include:

1. If a medicine is considered as a comparator, it should in principle be authorised for the indication.

2. If a non-drug intervention is considered, it must be available within the statutory health insurance system.

3. Existing G-BA resolutions, assessments and recommendations concerning medicines and non-drug interventions in the indication are considered.

4. The comparator should form part of the appropriate treatment options according to the generally accepted state of medical knowledge.

The actual treatment situation also matters. Under specific legal conditions, an off-label medicinal use can therefore be taken into account when the zVT is determined.

The zVT does not necessarily have to be a single medicine. Depending on the indication, it can also comprise several treatment options, an individualised therapy, therapy at the physician's discretion, a non-drug intervention, best supportive care or watchful waiting.

The exact wording of the zVT is therefore part of the assessment question and can affect what type of comparative evidence may be required.

Guidelines and medical societies inform the treatment standard

Current evidence-based clinical guidelines are an important source for assessing the medical treatment standard when the zVT is determined. They help establish which treatment options are relevant according to the current state of medical knowledge.

Particularly useful are guidelines based on systematic evidence appraisal with a transparent link between recommendations and the underlying evidence. Currency, evidence quality and applicability to the German treatment context are important.

Medical expertise also contributes to the assessment of the treatment standard. Scientific medical societies and the Arzneimittelkommission der deutschen Ärzteschaft (AkdÄ) may be involved in questions concerning the zVT.

These consultations focus on the treatment standard for the relevant indication rather than on the assessment of a particular new medicine.

For zVT planning, this means looking beyond previous G-BA resolutions. Changes in guidelines, new clinical evidence and developments in routine care can signal that the relevant treatment standard is changing.

The zVT can differ between patient populations

One authorised indication does not necessarily lead to a single zVT. The G-BA can divide an indication into several patient populations and determine different comparators for them.

The assessment structure can therefore look like this:

Indication → Patient population A → zVT A → additional benefit A

Indication → Patient population B → zVT B → additional benefit B

This matters for evidence planning because clinical data need to address the respective German assessment questions. A study can be informative for the overall population while supporting an assessable comparison for only some German populations.

Population and zVT therefore need to be considered together. Changes in population definitions can also change the relevant comparator for a given group.

Different zVT wordings can have different implications for evidence

The zVT is not always expressed as a single active ingredient. Depending on the treatment setting, the G-BA may name several options or define a choice based on patient-specific or physician-based criteria.

For evidence planning, it is therefore important to consider not only which treatments are included in the zVT, but also how the comparator is worded.

The exact wording should always be read together with the G-BA's supplementary notes. These may specify relevant comparators, patient-specific criteria or the type of evidence expected.

An "or" formulation can identify several comparator options

An "or" formulation names several treatment options that may be considered appropriate comparators. For example:

Active ingredient A or active ingredient B or active ingredient C

Depending on the individual resolution, additional benefit may be demonstrated against one of the named options.

For evidence planning, the key question is whether the comparator used in the clinical programme corresponds to one of the relevant options and reflects the German assessment question in terms of population, dose and treatment implementation.

An individualised therapy uses defined patient criteria

With an individualised therapy, the choice of comparator depends on explicitly defined patient-specific criteria. These can include prior treatment, disease severity, tumour location, mutation status or other clinically relevant characteristics.

The choice of treatment therefore depends on the criteria set out for the zVT.

Where several comparator options form part of an individualised therapy, the comparative study needs to accommodate that treatment choice appropriately. The timing of the comparator decision can also be relevant.

A single-comparator study may therefore cover only part of the assessment question in some settings. The evidence strategy should establish which patient populations can actually be addressed by the available data.

Therapy at the physician's discretion represents a different treatment choice

Where the zVT is defined as therapy at the physician's discretion, treatment selection depends more strongly on the treating physician's judgement and the individual care situation. The relevant treatment options may not be linked to the same explicit patient-specific criteria used for individualised therapy.

The short label alone does not determine which therapies are suitable comparators. The exact G-BA wording and supplementary notes need to be considered.

Depending on the treatment setting, both authorised medicines and, under specific conditions, off-label use can be relevant.

The evidence strategy should assess whether the study design reflects the treatment choices encountered in routine care. A single comparator may not be sufficient for the full assessment question in every case.

Off-label use can be relevant to the zVT

Under specific legal conditions, off-label use can be taken into account when the zVT is defined. The key issue is whether the treatment is part of the generally accepted medical standard in the relevant German care setting.

Off-label use is therefore not automatically part of the zVT simply because a medicine is used in routine practice. The statutory requirements and the specific G-BA determination are decisive.

This can be relevant when there is a discrepancy between authorised medicines and treatment options recommended in guidelines or used in routine care.

The zVT should be addressed in G-BA advice

G-BA advice provides an opportunity to discuss the expected German comparator and its implementation in the clinical programme before dossier submission. This is particularly relevant while there is still time to incorporate implications into study design, evidence planning or dossier strategy.

Two questions should be distinguished:

1. Which treatment or treatment options constitute the expected zVT based on the current knowledge?

2. Does the comparator in the relevant study adequately reflect that zVT?

The second question can be as important as the first. A generally appropriate comparator will not automatically result in an AMNOG-relevant study if dose, population or treatment implementation differ from the German assessment question. Process, preparation and possible questions are covered in the guide to G-BA advice.

A zVT discussed early can change before the G-BA resolution

A zVT discussed in G-BA advice is not necessarily the comparator used for the final benefit assessment and G-BA resolution. The assessment reflects the medical and scientific knowledge and treatment situation relevant at the respective stage of the procedure.

Potential drivers include:

Not every change in wording represents a completely new clinical comparison. The important question is what therapeutic and methodological consequences the change creates.

Dynamic indications increase the risk of zVT changes

In rapidly evolving indications, uncertainty increases over which comparator will be relevant when the German benefit assessment takes place. New medicines, changing guidelines and new evidence can alter the treatment standard during a multi-year clinical development programme.

This creates a timing challenge. Clinical development may require long follow-up, while the German treatment standard can change during the same period.

A high-quality randomised study may therefore be relevant for regulatory approval but no longer provide the direct comparison expected in the German benefit assessment if the zVT changes.

This does not mean that future zVTs can be predicted with certainty. It means that plausible changes in the treatment standard should be identified early and their implications for the German assessment question considered.

A change in the zVT can change the usability of clinical evidence

When the zVT changes, the question of which clinical evidence can directly answer the German assessment question may change as well. The critical issue is whether the available studies still provide a suitable comparison against the new zVT.

Where the study comparator and zVT match:

Study comparator = zVT → direct comparison may be available

Where they differ:

Study comparator ≠ zVT → alternative comparative evidence should be assessed

This can require checking whether:

• a direct comparison with the new zVT exists,

• an adjusted indirect comparison is feasible,

• an appropriate common bridging comparator is available,

• relevant studies have been identified comprehensively,

• populations, endpoints and study designs are sufficiently comparable,

• the required data are available for the relevant populations.

A zVT change can therefore trigger additional searches, analyses or a reassessment of the available evidence network.

Multiple zVT scenarios can matter for evidence planning

Where the future treatment standard is uncertain, evidence planning can consider several plausible zVT scenarios. The aim is not to model every possible future, but to identify changes that could materially affect the usability of the evidence.

This type of scenario planning can help identify evidence gaps earlier, particularly in dynamic indications.

Indirect comparisons can become relevant when the study comparator differs from the zVT

When no suitable direct comparison with the relevant zVT exists, an indirect comparison can be a potential evidence option. Its feasibility depends on the available study network.

An adjusted indirect comparison can connect the relative effects of the new medicine and the zVT through a suitable common bridging comparator.

The assessment should consider:

• whether a suitable evidence network exists,

• whether relevant studies have been identified comprehensively,

• whether the included studies are sufficiently similar,

• whether populations and endpoints are comparable,

• whether the necessary data are complete.

Feasibility should be assessed early. If the mismatch between study comparator and zVT is discovered shortly before dossier submission, time and data availability can further restrict the options.

Methods and requirements for direct and indirect comparisons are covered in the AMNOG dossier guide.

Orphan drugs follow a specific assessment framework

Orphan drugs are subject to specific rules for demonstrating additional benefit in the simplified AMNOG procedure. As long as the statutory conditions are met, medical additional benefit is considered established by the marketing authorisation.

In this setting, a regular comparative proof of additional benefit against a zVT is not required. The assessment focuses in particular on the magnitude of additional benefit.

If the relevant statutory revenue threshold is exceeded, a regular benefit assessment with evidence against the zVT may become necessary.

The zVT can therefore still matter for longer-term evidence planning even when it does not have the same function for proving additional benefit in the simplified procedure. The specific dossier requirements are explained in the AMNOG dossier guide.

EU HTA does not replace the German zVT

The comparators considered in a Joint Clinical Assessment (JCA) do not replace the German zVT. A JCA assesses relative clinical effects within the European assessment scope, while the German benefit assessment determines additional benefit within the national AMNOG framework.

For medicines subject to EU HTA, European and German comparator questions therefore need to be aligned:

JCA PICO and comparators → German population → zVT → national AMNOG assessment

A comparator relevant in the JCA is not automatically the German zVT. Conversely, a German zVT may address only part of the European assessment scope.

The key evidence-planning question is therefore which European comparisons already support the German question and where additional or differently structured evidence is needed.

Reviewing the zVT throughout the AMNOG process

The zVT should not be treated as a one-off decision made at the start of AMNOG preparation. Its relevance and the available evidence should be reviewed as the development and assessment process progresses.

The zVT therefore connects several stages of the AMNOG process. Early G-BA advice can provide orientation, but it does not remove the need to monitor treatment standards. Likewise, an early comparator strategy does not automatically answer the later evidence question.

For AMNOG preparation, the key point is whether the zVT relevant at a given stage remains compatible with the available clinical evidence.

Frequently asked questions about the zVT

What is the zVT?

The zweckmäßige Vergleichstherapie (zVT) is the comparator defined by the G-BA for assessing additional benefit in the German AMNOG process. Additional benefit is assessed for the relevant patient populations against the applicable zVT.

Who defines the zVT?

The zVT is defined by the G-BA. The determination reflects the indication, current medical knowledge, the German treatment situation and the applicable criteria under German AMNOG law and procedure rules.

What criteria does the G-BA use to define the zVT?

The G-BA considers, among other factors, the authorisation status of possible medicines, availability of non-drug interventions within statutory health insurance, existing G-BA resolutions and recommendations, and the generally accepted state of medical knowledge.

Is the zVT discussed in G-BA advice binding?

No. The zVT discussed in G-BA advice reflects the knowledge available at the time. Changes in treatment standards, new evidence, treatment options or population definitions can lead to a different zVT later.

Can the zVT change during an AMNOG process?

Yes. The relevant comparator can change before the final G-BA resolution. For evidence planning, treatment standards should therefore continue to be monitored after early G-BA advice.

Can one indication have several zVTs?

Yes. The G-BA can define different patient populations with different zVTs. Additional benefit is then assessed separately for the respective population and comparator.

What does "individualised therapy" mean as a zVT?

An individualised therapy is a comparator strategy in which treatment selection is based on explicitly defined patient-specific criteria, such as prior treatment, disease severity, tumour location or mutation status.

What does "therapy at the physician's discretion" mean?

It describes a treatment selection that depends more strongly on the physician's assessment of the individual care situation. The relevant comparator options should be interpreted from the specific G-BA wording and notes.

Can off-label use be part of the zVT?

Under specific statutory conditions, an off-label medicinal use can be taken into account when the zVT is defined. The relevant German legal requirements and the G-BA determination are decisive.

What happens if a study does not compare against the zVT?

If no suitable direct comparison with the relevant zVT is available, other comparative evidence may need to be assessed. Depending on the evidence network, an adjusted indirect comparison may be an option.

Does a JCA comparator replace the German zVT under EU HTA?

No. JCA comparators are defined within the European assessment scope. The German zVT remains the national comparator for the AMNOG benefit assessment.

Who supports zVT strategy and evidence planning?

co.value supports pharmaceutical companies in assessing the zVT as part of German market access and evidence planning. This can include comparator assessment, preparation for G-BA advice, evaluation of zVT scenarios and review of available evidence for the AMNOG dossier.