One procedure. A closer look.
In the donidalorsen procedure, berotralstat remained part of the appropriate comparator therapy (zweckmäßige Vergleichstherapie, zVT). Garadacimab was not included, even though the German Federal Joint Committee (Gemeinsamer Bundesausschuss, G-BA) 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 zVT and the subsequent G-BA decision.
The ACT for donidalorsen was based on the situation in March 2025
For donidalorsen, the G-BA determined routine prophylaxis with a C1 esterase inhibitor, lanadelumab or berotralstat as the zVT. 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.
- May 2026: An updated international WAO guideline includes garadacimab among the options for long-term prophylaxis.
- 20 August 2026: The G-BA adopts its decision on donidalorsen. The zVT remains a C1 esterase inhibitor, lanadelumab or berotralstat.
By the time of the donidalorsen procedure, garadacimab had therefore already been approved, assessed for added benefit and reflected in the current guideline landscape.
Berotralstat as the zVT 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 G-BA also explicitly addressed the existing zVT, asking whether berotralstat was still the appropriate comparator therapy.
Ultimately, berotralstat remained part of the zVT, while garadacimab was not included.
Donidalorsen illustrates the dynamic nature of the zVT
The case highlights a relevant issue for AMNOG evidence planning: An early zVT 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 zVT only at the time of the consultation. New approvals, G-BA 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 zVT. They do, however, raise a broader question: When has the evidence and treatment landscape changed sufficiently to warrant reassessment of an already determined zVT?