Acceptance of Clinically Relevant Primary Study Endpoints In The German Health Technology Assessment Process: Analysis of Five Different Disease Areas.

The introduction of AMNOG law in Germany in January 2011 stipulated an early benefit assessment (EBA) for new medicines. EBAs determine the extent of additional therapeutic benefit that a drug has on patient-relevant endpoints. We examined the acceptance of clinically acknowledged primary endpoints (PEs) from regulatory trials in EBAs conducted by the German Federal Joint Committee (G-BA). For drugs in five disease areas (oncology, diabetes, hepatitis C [HepC], multiple sclerosis [MS] and idiopathic pulmonary fibrosis [IPF]), EBAs and regulatory assessments were reviewed. The G-BA website was used to obtain manufacturers’ value dossiers and G-BA appraisals. Endpoints used in pivotal trials were obtained from the Summary of Product Characteristics available from the European Medicines Agency website. Acceptance of PEs by the G-BA was compared to acceptance by regulatory authorities. In 4 disease areas (diabetes, HepC, MS and IPF), PEs only addressed the dimension of morbidity; in oncology, they covered the dimensions of morbidity and of mortality. Acceptance of PEs by the G-BA differed between the evaluated disease areas. Both the G-BA and regulatory bodies accepted mortality PEs. The G-BA did not accept morbidity PEs in diabetes and IPF and only partially accepted them in oncology and MS, whereas they were fully accepted in HepC. More specifically, widely accepted morbidity PEs were not deemed patient-relevant by the G-BA in three of five evaluated disease areas (progression-free survival in oncology, haemoglobin A1c in diabetes and change in forced vital capacity in IPF). None of the reviewed pivotal trials included quality of life (QoL) endpoints as PEs. Whereas there was largely agreement on the acceptance of mortality PEs (where provided), considerable variability in the acceptance of morbidity PEs was observed between regulatory bodies and the G-BA. Established morbidity PEs were frequently not, or only partially, accepted by the latter.