The German AMNOG law (roughly translated as the Pharmaceuticals Market Reorganization Act) has been in place since 2011, and introduced the early benefit assessment. This meant that in addition to regulatory requirements (efficacy, safety and pharmaceutical quality) which an authorized medicine has to meet, it also needs to have a patient-relevant added benefit.

Unlike in other systems, early benefit assessment does not represent a “fourth hurdle.“ New medicines are reimbursed as soon as they are available on the market. However, the AMNOG kicks off as soon as the medicine is authorized and available. After one year, there is a negotiated reimbursement price and the added benefit is the basis for price negotiations.

There are two Health Technology Assessment (HTA) bodies in Germany: the G-BA (Federal Joint Committee), which is the decision-maker, and the IQWIG (Institute for Quality and Efficiency in Healthcare), which is usually ordered to perform the benefit assessment.

German law states that the added benefit assessment is based on the principles of evidence-based medicine. Therefore the assessment process is focused on the evaluation of clinical trials, which differentiates it from other HTA systems like the UK, where the focus is on health economics.

This means that clinical trials and their design face a set of challenges and requirements that must be met in order to achieve a favorable benefit assessment. In order to anticipate these requirements, it makes sense to seek early advice with the G-BA.

What´s the ideal time point for early advice and what does the process look like?

Ideally, early advice should be sought at a point where the study design of the pivotal trials can still be influenced by the feedback. On the other hand, it is not advisable to engage too early because there should be at least a solid draft of the study protocol. This is important because in order to receive useful feedback, the pharmaceutical company should be able to provide a solid position of the approach that they are proposing.

As a first step, an advice request with the questions for the G-BA is prepared. There is a template provided by the G-BA which has to be used. The advice request is in German. For each question, the company needs to provide a position. Additionally, a summary of the proposed study design has to be submitted.

Once the advice request is submitted, the G-BA takes eight weeks to prepare the feedback. After this time, a face to face meeting takes place. It´s important to note that the meeting is not held directly with the decision-makers, but rather with the committee´s office. This means there is very little room for negotiation during the meeting and that all relevant information should be submitted beforehand with the advice request so it can be included in the G-BA´s decision.

Two weeks after the face to face meeting, the G-BA provides written minutes that the pharmaceutical company can provide comments on.

It should be noted that the advice is a) treated confidentially and b) is not legally binding.

Frequently asked questions

There are, among others, two main topics that are crucial for a successful benefit assessment in Germany – comparator and endpoints.

The comparator is so important because the added benefit of a new medicine is measured against the Appropriate Comparative Therapy (zVT, zweckmäßige Vergleichstherapie). This means that if the study comparator does not reflect the appropriate comparative therapy, no added benefit can be shown.

The G-BA determines the appropriate comparative therapy by systematic literature research according to the following set of criteria:

  • Marketing authorization in the proposed indication
  • If it´s a non-medical treatment, it needs to be reimbursed by statutory health insurance
  • The G-BA has already determined a patient-relevant benefit
  • It’s included in current treatment guidelines

It should be noted that the appropriate comparative therapy can change between the time of early advice and when the product is actually authorized. This can happen because there might be a revision of medical guidelines. Also, the indication of the new product can change during the marketing authorization procedure, narrowing or widening the field of potential aapropriate comparative therapies.

Besides the comparator, it´s important to make sure that the endpoints in the study are accepted as patient-relevant by the G-BA.

Patient relevance is defined by German socallaw: it´s something that the patient feels or experiences directly – mortality, morbidity or health related quality of life. Added benefit can only be determined based on patient relevant endpoints – laboratory or imaging endpoints are not accepted unless they can be validated as surrogates according to IQWIG methodology.This can be an issue because the G-BA´s demands on endpoints differ from regulatory requirements.

It´s important to note that in the added benefit assessment, there is no differentiation between primary or secondary endpoints. Each endpoint is regarded separately and can generate an added benefit. Crucially, quality of life endpoints are also gaining in importance.

Other frequently asked questions can be the study duration, quality of life instruments or different elements of the study design.

What´s the benefit of G-BA early advice?

The German system poses some unique challenges to study design. For instance, endpoints that are perfectly acceptable for regulatory purposes are not suitable to show an added benefit. When designing studies, it´s no longer enough to ensure they meet regulatory purposes – added benefit is just as important in order to make sure the medicine can eventually reach patients.

This is where G-BA early advice comes in and is so extremely helpful; it´s the only opportunity before the benefit dossier is actually submitted to enter into an interaction with the G-BA and to get advice on the study program.

Of course, clinical studies have to fit into the global picture and need to meet a multitude of requirements from different regulatory and/or HTA systems.While it´s not always possible to incorporate the G-BA´s feedback, actually seeking the feedback gives us the opportunity to make an informed decision.