title: Inconsistent approaches of the G-BA regarding acceptance of primary study endpoints as being relevant to patients - an analysis of three disease areas: oncological, metabolic, and infectious diseases.
abstract: Previous evaluations of oncological medicines in the German early benefit assessment (EBA) procedure have demonstrated inconsistent acceptance of endpoints by regulatory authorities and the Federal Joint Committee (G-BA). Accepted standard endpoints for regulatory purposes are frequently not considered as patient-relevant in the German EBA system. In this study the acceptance of clinically acknowledged primary endpoints (PEPs) from regulatory trials in EBAs conducted by the G-BA was evaluated across three therapeutic areas.
  
  
  
  Medicines for oncological, metabolic and infectious diseases with EBAs finalised before 25 January 2016 were evaluated. Respective manufacturer's dossiers, regulatory assessments, G-BA appraisals and oral hearing minutes were reviewed, and PEPs were examined to determine whether they were considered relevant to patients by the G-BA. Furthermore, the acceptance of symptomatic vs asymptomatic PEPs was also analysed.
  
  
  
  A total of 65 EBAs were evaluated. Mortality PEPs were widely accepted as patient-relevant but were only used in a minority of EBAs and exclusively in oncological diseases. Morbidity PEPs constituted around 72 % of assessed PEPs, but were excluded from the EBA in over half of the corresponding assessments as they were not considered patient-relevant. Symptomatic endpoints were largely deemed patient-relevant, whereas acceptance of asymptomatic endpoints varied between therapeutic areas.
  
  
  
  This evaluation identified inconsistencies in patient relevance of morbidity-related PEPs as well as in acceptance of asymptomatic endpoints by the G-BA in all three disease areas examined. Better harmonisation between the regulatory authorities and the G-BA is still required after 5 years of AMNOG health technology assessment in Germany.
authors.affiliation: Roche Pharma AG, Emil-Barrell-Str. 1, 79639, Grenzach-Wyhlen, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Staab
authors.affiliation: Roche Pharma AG, Emil-Barrell-Str. 1, 79639, Grenzach-Wyhlen, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Isbary
authors.affiliation: Medical School of Hanover, Hanover, Germany.
authors.forename: Volker E
authors.initials: VE
authors.lastname: Amelung
authors.affiliation: Roche Pharma AG, Emil-Barrell-Str. 1, 79639, Grenzach-Wyhlen, Germany. joerg.ruof@bluewin.ch.|Medical School of Hanover, Hanover, Germany. joerg.ruof@bluewin.ch.
authors.forename: Jörg
authors.initials: J
authors.lastname: Ruof
mesh_terms: D017277:Drug Approval; D005858:Germany; D006801:Humans; D007239:Infections / Q000188:drug therapy*; D008659:Metabolic Diseases / Q000188:drug therapy*; D009017:Morbidity; D009369:Neoplasms / Q000188:drug therapy*; D013673:Technology Assessment, Biomedical
keywords: AMNOG; Early benefit assessment; HTA; Marketing authorisation; Morbidity; Primary endpoint