One procedure. A closer look.
In the donidalorsen procedure, berotralstat remained part of the appropriate comparator therapy (ACT). Garadacimab was not included, even though the German Federal Joint Committee (Gemeinsamer Bundesausschuss, GBA) had already found an indication of a major added benefit of garadacimab versus berotralstat.
The case shows how substantially the evidence landscape can change between an early determination of the ACT and the subsequent GBA decision.
The ACT for donidalorsen was based on the situation in March 2025
For donidalorsen, the GBA determined routine prophylaxis with a C1 esterase inhibitor, lanadelumab or berotralstat as the ACT. The underlying comparator set dates back to a consultation in March 2025.
The treatment landscape subsequently evolved:
- 21 August 2025: Garadacimab receives an indication of a major added benefit versus berotralstat.
- 1 March 2026: The donidalorsen procedure starts.
- 20 August 2026: The GBA adopts its decision on donidalorsen. The ACT remains a C1 esterase inhibitor, lanadelumab or berotralstat.
By the time of the donidalorsen procedure, garadacimab had therefore already been approved and assessed for added benefit. In its final decision, the GBA explicitly considered garadacimab but did not include it in the ACT. The GBA referred to the lack of guideline-based recommendations and concluded that the role of garadacimab in clinical practice could not yet be conclusively assessed
Berotralstat as the ACT was questioned during the procedure
The issue was also raised during the oral hearing.
For NICE, the pharmaceutical company had conducted an indirect comparison of donidalorsen versus garadacimab. During the German procedure, the question was raised why a corresponding indirect comparison against garadacimab had not been submitted.
The GBA also explicitly addressed the existing ACT, asking whether berotralstat was still the ACT.
Ultimately, berotralstat remained part of the ACT, while garadacimab was not included.
The national guideline situation adds another layer to the case: The German guideline on hereditary angioedema has been expired for several years. An update was registered in 2023 but has not yet been published. Newer treatment options such as garadacimab are therefore not yet reflected in the currently available German guideline.
Donidalorsen illustrates the dynamic nature of the ACT
The case highlights a relevant issue for AMNOG evidence planning: An early ACT consultation reflects the appropriate comparator therapy at a particular point in time. The evidence and treatment landscape may continue to evolve afterwards.
For pharmaceutical companies, it may therefore not be sufficient to consider the ACT only at the time of the consultation. New approvals, GBA decisions and guideline updates can change the situation before the benefit assessment begins.
In the donidalorsen procedure, these developments did not result in an adjustment of the ACT. They do, however, raise a broader question: When has the evidence and treatment landscape changed sufficiently to warrant reassessment of an already determined ACT?