How does the G-BA pick the appropriate comparator?

Welcome! In this post, I am going through the steps on how the G-BA chooses the appropriate comparative therapy (ACT).

I conclude with recommendations for further reading, if you want to revisit the early benefit assessment process or endpoints.

Next time, we will focus on the expected future changes to HTA in Germany.

What is the appropriate comparator?

In a regular early benefit assessment, the G-BA determines the additional benefit of a new product versus the so-called appropriate comparator therapy (ACT). This comparison is not needed in abbreviated, i.e. orphan drug, assessments.

The choice of this ACT is at the discretion of the G-BA. The ACT should reflect the current standard of care (SOC).

The ACT can either be one specific treatment or a selection of treatment options.

If the available evidence does not include comparative data versus the ACT, then the G-BA will conclude that an additional benefit is not proven.

In that case, the manufacturer could conduct an indirect treatment comparison (ITC). However, the G-BA and IQWiG have very high methodological requirements on ITCs. For example, patient populations in the studies included in the ITC would need to match. This is often only possible if patient-level data for all studies were available to the manufacturer. One example of an accepted ITC is the benefit assessment of nivolumab in the adjuvant treatment of melanoma.

How does the G-BA decide on the appropriate comparator therapy?

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

  1. Medicinal products must have a license for use in the same indication.
  2. Non-medicinal treatments must be available to physicians for prescription and reimbursable by SHI funds.
  3. The G-BA prefers pharmaceutical or non-medicinal treatments, for which they have already established a patient-relevant benefit.
  4. The ACT needs to reflect an appropriate treatment for the indication based on the current generally accepted medical findings.
  5. For multiple HTAs within the same active substance class, the G-BA would choose the same ACT. This should allow for uniform and comparable benefit assessments.

Can off-label drugs be an appropriate comparator?

The G-BA might consider products used off-label to be ACTs.

However, where a product with a license for the relevant indication exists, the G-BA would prefer and choose this product 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.

This decision to include off-label drugs can have a big impact on the overall additional benefit, as was seen in the assessment of tucatinib.

Review of early benefit assessments of analogues

The choice of the appropriate comparator is very specific to the indication and early benefit assessment. Thus, in order to understand whether the G-BA or IQWiG might select a certain comparator, I recommend reviewing the early benefit assessments of analogous products in the same indication. However, the treatment landscape and the SOC evolve, so the inclusion of a treatment as ACT in one assessment is no guarantee that the same treatment would be the ACT in another assessment in the same indication.

Therefore, a manufacturer should always consult the G-BA before planning a clinical trial. The G-BA can review the trial plans, and will advise on treatments in the ACT, endpoints, subgroups etc.

These G-BA consultations are hugely valuable to the manufacturers and might help to avoid a resolution of “No additional benefit”. However, the G-BA charges a fee to cover their costs. 

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Anja Pownell

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