RESUMEN
From 2025, Health Technology Developers (HTDs) have to submit EU HTA dossiers. The joint clinical assessment (JCA) aims to streamline HTA processes and access to medicinal products across Europe. Currently, German HTA bodies IQWiG and G-BA actively shape the JCA methodology. Here we examine if German HTA dossier requirements are suitable for the JCA. We compare the number of safety endpoint and subgroup analyses in German dossiers with analyses considered in IQWIG's benefit assessment and evaluate if these analyses were considered by the G-BA. We further investigated how the number of analyses was affected by the latest change in the German dossier template. With the current template, HTDs report in median 2.6 times more analyses on adverse events (AE) and 1.1 times more subgroup categories than in the previous template. IQWiG does not consider 33% of AE analyses and 73% of the subgroup categories presented by the HTD under the current template. G-BA considered the same AE as IQWiG in 76% of cases. Subgroups were uncommented by G-BA in most cases, independent of the template (previous: 93%, current 85%) and unconsidered in the conclusion on additional benefit (previous: 77%, current 69%). Thus, changes in the dossier template drastically increased HTD workload, but additional analyses seem unconsidered by the HTA bodies. With a broader scope in JCA, this effect could be amplified. To mitigate duplicative efforts and ensure prompt availability of medicinal products as envisioned by the HTAR, we suggest well-chosen and precise dossier requirements, early consultations, and early HTD engagement.
RESUMEN
Death receptors are transmembrane proteins that can induce the activation of caspase-8 upon ligand binding, initiating apoptosis. Recent work has highlighted the great molecular complexity of death receptor signalling, in particular through ubiquitination/deubiquitination. We have earlier defined the deubiquitinase Ubiquitin-Specific Protease 27x (Usp27x) as an enzyme capable of stabilizing the pro-apoptotic Bcl-2 family member Bim. Here, we report that enhanced expression of Usp27x in human melanoma cells leads to the loss of cellular FLICE-like inhibitory protein (cFLIP) and sensitizes to Tumor necrosis factor receptor 1 (TNF-R1) or Toll-like receptor 3 (TLR3)-induced extrinsic apoptosis through enabling enhanced processing of caspase-8. The loss of cFLIPL upon overexpression of Usp27x was not due to reduced transcription, could be partially counteracted by blocking the ubiquitin proteasome system and was independent of the known cFLIPL destabilizing ubiquitin E3-ligases Itch and DTX1. Instead, Usp27x interacted with the E3-ligase TRIM28 and reduced ubiquitination of TRIM28. Reduction of cFLIPL protein levels by Usp27x-induction depended on TRIM28, which was also required for polyI:C-induced cell death. This work defines Usp27x as a novel regulator of cFLIPL protein expression and a deubiquitinase in fine tuning death receptor signalling pathways to execute apoptosis.
