HTA in Germany

In the German HTA, the G-BA determines the so-called additional benefit of a medical intervention. This is also called the “early benefit assessment“.

Who are the key stakeholders in the German HTA system?

The most important players you should be familiar with are:

• G-BA (Gemeinsamer Bundesausschuss; Federal Joint Committee)
• IQWiG (Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen; Institute for Quality and Efficiency in Healthcare)
• GKV-SV (Gesetzliche Krankenkassen- Vereinigung-Spitzenverband; National Association of Statutory Health Insurance [SHI] Funds)
• EMA (European Medicines Agency)
• BfArM (Bundesinstitut für Arzneimittel und Medizinprodukte; Federal Institute for Drugs and Medical Devices)

Let’s look at the roles of each of these in more detail.

G-BA (Gemeinsamer Bundesausschuss; Federal Joint Committee)

The G-BA has the following main tasks:

• Decides on and publishes binding regulations (=directives) on what is covered by the SHI funds. Thereby, the G-BA specifies which services in medical care are reimbursed
• Assesses new pharmaceuticals, i.e. conducts HTAs according to the regulations laid out in AMNOG law
• Investigates new examination methods and medical technologies
• Defines quality standards for hospitals
• Designs disease management programs for chronic diseases
• Determines reference price groups

The BMG oversees the work of the G-BA.

The G-BA has 13 voting members:

Further information and reference

IQWiG (Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen; Institute for Quality and Efficiency in Healthcare)

The IQWiG has the following tasks:

• Examines benefits and harms of medical interventions
• Provides information about the advantages and disadvantages of examination and treatment methods
• Produces independent, evidence-based reports by conducting systematic searches of the international scientific literature

The following groups make up the IQWiG:

Further information and reference

GKV-SV (Gesetzliche Krankenkassen- Vereinigung-Spitzenverband; National Association of Statutory Health Insurance Funds)

The GKV-SV

• Votes in G-BA meetings
• Is responsible for price negotiations with pharmaceutical companies for new pharmaceuticals
• Sets maximum reimbursement price for pharmaceuticals and medical devices in reference price groups
• Develops framework contracts and reimbursements agreements for hospital, outpatient and dental care
• Represents interests of statutory health insurance (SHI) funds at federal level (at G-BA and BMG) and European / international level
• Supports SHI funds and their subnational associations in fulfilling their tasks

On 1 Jan 2021, 103 SHI funds were registered in Germany.

Further information and reference

EMA (European Medicines Agency)

The EMA

• Evaluates applications for marketing authorization of pharmaceuticals, i.e. it is the regulatory authority at the EU level
• Facilitates development and access to pharmaceuticals
• Monitors the safety of pharmaceuticals across their lifecycle
• Provides information to healthcare professionals and patients

The EMA does not regulate medical devices.

The EMA is structured as follows:

• Management Board (36 members): does not represent any government, organization or sector
• Executive Director: legal representative of the EMA
• Agency staff
• Scientific Committees (7 committees), several working parties and related groups: European experts made available by national competent authorities of the EU Member States

Further information and reference

BfArM (Bundesinstitut für Arzneimittel und Medizinprodukte; Federal Institute for Drugs and Medical Devices)

The BfArM has the following tasks:

• Evaluates applications for marketing authorization of pharmaceuticals, i.e. it is the regulatory authority at the German level
• Collects and evaluates reports of adverse drug reactions and takes the necessary measures for patient protection
• Collects, analyses and evaluates risks arising from use or application of medical devices and co-ordinates the necessary measures to be taken
• Publishes official medical classifications and maintains medical terminologies, thesauri, nomenclatures and catalogues

It has roughly 1,250 employees: physicians, pharmacists, chemists, biologists, lawyers, engineers, technical assistants, administrative staff etc.

Further information and reference

What type of outcome is the result of a HTA in Germany?

The G-BA determines the so-called additional benefit (German: Zusatznutzen) of a medical intervention.

This is based on a benefit in efficacy, safety or health-related quality of life demonstrated with the intervention versus a comparator therapy. Therefore, we can categorize the German HTA system as a comparative clinical benefit market.

If the G-BA identifies an additional benefit, the rating of additional benefit is a combination of a level of likelihood and a level of extent, for example, “Indication of considerable additional benefit”, or “Hint of minor additional benefit”.

If no additional benefit could be identified (most often because the submitted data was not accepted), then the G-BA concludes with “No additional benefit (proven)”.

This additional benefit rating impacts the price of the medical intervention, but it does not impact reimbursement.

Which products does the G-BA assess?

Every pharmaceutical product with a new chemical entity (NCE) that received its marketing authorization on or after 1 January 2011 is subject to an HTA in Germany.

In addition, the G-BA also assesses new indications of products that were first approved on or after 1 January 2011.

Since 15 May 2017, pharmaceutical companies can request to merge the HTAs for two or more indications, if they are expected to be launched within 6 months of each other.

What does the G-BA not assess?

New indications of products that were first approved before 1 January 2011 are not assessed by the G-BA.

In addition, new formulations of an existing drug do not trigger a new HTA in Germany.

Biosimilars are currently not subject to an HTA, as they are considered to be “generics”, for which no further assessment is needed.

Currently, reserve antibiotics, i.e., those effective against infections caused by multi-resistant bacterial pathogens, used in strictly defined indications, with only limited alternative therapy options, are also excluded from an HTA.

Lastly, pharmaceutical companies can also request their products to be exempt from the HTA if the costs to the SHI funds in the outpatient and hospital sector do not exceed the limit of €1 million within 12 calendar months.

What is the process of a HTA in Germany?

1. When the pharmaceutical company launches their product in Germany, they have to submit evidence on the efficacy, safety and quality of life in a so-called HTA dossier to the G-BA. Many sections of this dossier are publicly available.
2. The G-BA then commissions the IQWiG to evaluate the submitted evidence.
3. After a maximum of 3 months, the IQWiG shares their recommendation on the additional benefit level. This recommendation is publicly available.
4. The pharmaceutical company will now be invited to a meeting, where they can comment on the recommendation from IQWiG and provide additional evidence.
5. In the next 3 months, the G-BA conducts its HTA based on the dossier, any additional evidence submitted by the pharmaceutical company, and the IQWiG recommendation. It then publishes its final resolution on the additional benefit.

In the future, the G-BA may request that pharmaceutical companies flag an expected launch in Germany with a 6 months warning, but this has not been implemented yet.

How does the G-BA determine the level of additional benefit?

The G-BA follows strict criteria to determine whether a product has an additional benefit, i.e., whether it offers a medical benefit over the so-called appropriate comparator therapy (ACT).

These criteria are applied in a hierarchical step-wise manner. Only when the criterion is met, the next one will be reviewed. If the submitted data does not meet one criterion, the resolution automatically is “No additional benefit (proven)”. In that case, the G-BA won’t continue to assess the evidence.

For example, if a study does not compare with the ACT, it is irrelevant whether the product showed a statistically significant reduction in mortality.

As a rule of thumb, the likelihood and extent of additional benefit are determined as follows:

How is the appropriate comparator therapy determined?

The additional benefit of a new product is determined versus the so-called appropriate comparator therapy (ACT). The choice of this ACT is at the discretion of the G-BA and is aimed to reflect the current standard of care (SOC). The ACT can either be one specific treatment or a selection of treatment options.

The G-BA follows several criteria in selecting the ACT:

1. Medicinal products must be authorized for use in the same indication.
2. Non-medicinal treatments must be available to physicians for prescription and reimbursable by SHI funds.
3. Preference is given to pharmaceutical products or non-medicinal treatments, for which the patient-relevant benefit has already been established by the G-BA.
4. The ACT needs to reflect an appropriate treatment for the indication based on the current generally accepted medical findings.
5. For multiple HTAs of pharmaceutical products within the same active substance class, the same ACT should be chosen to achieve a uniform and comparable benefit assessment.

Off-label drugs

• Products used off-label can be considered as ACTs.
• However, where a product with a license for the relevant indication exists, this would be preferred and should be chosen instead.
• If the available evidence suggests that an off-label drug is the preferred treatment choice over licensed treatment options, then the off-label drug can be included in the ACT alongside the licensed drugs.

What are re-assessments?

Several situations can trigger re-assessments:

The indication was altered.

The wording of the product’s indication and the label were amended. The G-BA will re-assess the evidence focusing on the patient population matching the updated indication.

The initial decision was time-restricted.

Sometimes the G-BA applies a time restriction to their resolutions, which means they are only valid for a certain period of time, usually between 1 year to 3 years. Time restrictions are often applied, when

• there is uncertainty in the original data package, and
• studies are still ongoing, which are believed to provide more certain results in the future.

There is new scientific evidence for the product.

The G-BA can request a re-assessment when new scientific evidence has become available.

Since 15 May 2017, pharmaceutical companies can also apply for a re-assessment based on new scientific findings, even if no time restriction was applied by the G-BA to the original HTA. However, this re-assessment process can not begin earlier than 1 year after the publication of the initial resolution.

In all these cases, the G-BA will initiate a new HTA, and the pharmaceutical company needs to submit an updated dossier. This results in a re-assessment of the product, following the same steps again as outlined above.

What is special about the HTA for orphan drugs in Germany?

Medicines for rare diseases are termed “orphan medicines” or “orphan drugs”. The EMA determines which products are awarded the orphan drug designation. The following criteria are used:

• The medicine must be intended for the treatment, prevention, or diagnosis of a disease that is life-threatening or chronically debilitating;
• The prevalence of the condition in the EU must not be more than 5 in 10,000 or it must be unlikely that marketing of the medicine would generate sufficient returns to justify the investment needed for its development;
• No satisfactory method of diagnosis, prevention or treatment of the condition concerned has been authorized, or, if such a method exists, the medicine must be of significant benefit to those affected by the condition.

Further information and reference

These orphan drugs have a special status and undergo an abbreviated HTA in Germany.

HTA process for orphan drugs

The steps of the HTA process for orphan drugs are as follows:

1. When the pharmaceutical company launches their orphan product in Germany, they have to submit an abbreviated HTA dossier to the G-BA. This means that not all sections of the standard dossier are required for the evidence package to still be considered complete.
2. The G-BA then commissions the IQWiG to only determine the treatment costs as well as the size of the patient population covered by the label of the orphan drug.
3. After a maximum of 3 months, the IQWiG shares their reports on treatment costs and patient numbers.
4. After another 3 months, the G-BA publishes its final HTA based on the submitted evidence package.

For an orphan drug, the G-BA does not determine whether there is an additional benefit, as an additional benefit is always automatically assumed.

The G-BA can still define the likelihood and extent of additional benefit, but “Additional benefit not proven” is not an option.

Only when the sales of an orphan product in any 12 months period exceed €30 million or the product loses its orphan drug designation, then the G-BA will conduct a full HTA to determine the likelihood and extent of additional benefit, after requesting a complete dossier from the pharmaceutical company.

Changes to this exemption

Over the last years, SHI funds have often criticized this special rule applied to orphan drugs, as they argue that the assumed additional benefit increases negotiated prices. For now, the G-BA sticks to this beneficial management of orphan drugs, but it might change in the future.