Registries for rare diseases provide a tool for obtaining an overview of the clinical situation and can be used to discover points of improvement and to monitor long-term safety. Registries could also become a powerful tool to provide supporting information for marketing authorization. There is an urgent need for a pan-European or global strategy that supports consistent data. Therefore, transparency in data collection, harmonization of the database structures, and the convergence of scientific approaches are required.

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Emerging treatment options for hemophilia, including gene therapy, modified factor products, antibody-based products, and other nonreplacement therapies, are in development or on their way to marketing authorization. For proof of efficacy, annual bleeding rates (ABRs) have become an increasingly important endpoint in hemophilia trials. We hypothesized that ABR analyses differ substantially between and within medicinal product classes and that the ABR observation period constitutes a major bias. For ABR characterization, an internal factor VIII (FVIII) treatment database has been built based on confidential clinical trial data submitted to the Paul-Ehrlich-Institut (PEI). Furthermore, anonymized data from 46 trial protocols submitted for review to the PEI were analyzed (FVIII replacement, n = 27; antibody-based, n = 12; and gene therapy, n = 7) for methodology. Definitions of bleeding episodes and ABR observational periods differed substantially in clinical trials. In the initial observation phase, individual ABRs of patients, treated prophylactically for 1 year, vary by about 40% (P < 0.001), which finally led to a significant reduction of the ABR group mean by 20% (P < 0.05). Furthermore, the high variance in ABRs constitutes a major challenge in statistical analyses. In conclusion, considerable heterogeneity and bias in the ABR estimation in clinical trials was identified, which makes it substantially more difficult to compare the efficacy of different treatment regimens and products. Thus, awareness of the important pitfalls when using ABR as a clinical outcome is needed in the evaluation of hemophilia therapies for patients, physicians, regulators, and health technology assessment agencies. www.cts-journal.com Annual Bleeding Rates in Hemophilia Patients Keipert et al.

Hemophilia is a rare heredity bleeding disorder that requires treatment for life. While few therapeutic options were available in the past, multiple recent breakthroughs have fundamentally altered and diversified hemophilia therapy, with even more new therapeutic options forthcoming. These changes are mirrored by significant regulatory and legal changes, which have redefined the role of hemophilia registries in the European Union (EU). This dual paradigm shift poses new regulatory, scientific but also structural requirements for hemophilia registries. The aim of this manuscript is to enumerate these significant challenges and to demonstrate their incorporation into the redesign of the German Hemophilia Registry (Deutsches Hämophilieregister, dhr). To identify the spectrum of hemophilia therapies and the degree of regulatory changes, a horizon screening was performed. Consequently, a core dataset for the dhr was defined by harmonization with regulatory guidelines as well as other hemophilia registries and by heeding the needs of different stakeholders (patients, clinicians, regulators, and scientists). Based on this information, a new registry structure was established, which is optimized for capturing data on new and established hemophilia therapies in a changing therapeutic and regulatory landscape

Vesicular V-ATPase (V-type H+-ATPase) and the plasma membrane-bound Na+/K+-ATPase are essential for the cycling of neurotransmitters at the synapse, but direct functional studies on their action in native surroundings are limited due to the poor accessibility via standard electrophysiological equipment. We performed SSM (solid supported membrane)-based electrophysiological analyses of synaptic vesicles and plasma membranes prepared from rat brains by sucrose-gradient fractionation. Acidification experiments revealed V-ATPase activity in fractions containing the vesicles but not in the plasma membrane fractions. For the SSM-based electrical measurements, the ATPases were activated by ATP concentration jumps. In vesicles, ATP-induced currents were inhibited by the V-ATPase-specific inhibitor BafA1 (bafilomycin A1) and by DIDS (4,4'-di-isothiocyanostilbene-2,2'-disulfonate). In plasma membranes, the currents were inhibited by the Na+/K+-ATPase inhibitor digitoxigenin. The distribution of the V-ATPase- and Na+/K+-ATPase-specific currents correlated with the distribution of vesicles and plasma membranes in the sucrose gradient. V-ATPase-specific currents depended on ATP with a K0.5 of 51+/-7 microM and were inhibited by ADP in a negatively co-operative manner with an IC50 of 1.2+/-0.6 microM. Activation of V-ATPase had stimulating effects on the chloride conductance in the vesicles. Low micromolar concentrations of DIDS fully inhibited the V-ATPase activity, whereas the chloride conductance was only partially affected. In contrast, NPPB [5-nitro-2-(3-phenylpropylamino)-benzoic acid] inhibited the chloride conductance but not the V-ATPase. The results presented describe electrical characteristics of synaptic V-ATPase and Na+/K+-ATPase in their native surroundings, and demonstrate the feasibility of the method for electrophysiological studies of transport proteins in native intracellular compartments and plasma membranes.

Previously performed CTs in PUPs were divergent, which prevented a direct comparison of outcomes. However, this study demonstrated that data from CTs and carefully designed registries may complement each other in the establishing of sufficient safety information for single products to improve clinical insights and support regulatory decisions.

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There is a broad range of factor products approved in Germany for haemophilia A treatment. Since the introduction of recombinant coagulation factor VIII (FVIII) products in the 1990s, there has been substantial debate whether there is a difference in inhibitor incidence between single FVIII products or product classes. Neither haemophilia registries nor clinical studies, including a randomised controlled clinical trial, provided a consistent and definite answer. The reasons were mainly related to methodological challenges in conducting controlled studies in a rare disease. In this analysis, the most relevant epidemiological challenges and main problems were examined, including study bias, potential overlap of individual studies and advanced development of therapy and methods in the course of time. Meta-analyses on two levels showed that therapies using recombinant products resulted in different event rates when compared to plasma-derived products. These results are accompanied by substantial study heterogeneity evidenced by Cochran’s Q tests. Only three studies have been identified that meet the standards of current clinical guidance. To finally resolve this ongoing and disputable safety issue of replacement therapy, collaboration among registry owners, academia and regulators must be fostered.