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Although the role played by general practitioners (GPs) is historically consolidated, continuous changes have been recently introduced in Europe because of the increasing multimorbidity and complexity of patients. Here we try to compare the roles played by GPs in the four major countries of Europe. In France GPs are self-employed medical doctors, and their remuneration consists of a payment scheme for the services provided. The weekly opening hours of French GPs are on average approximately 48. In Germany primary care is mainly provided by GPs and outpatient internists, and patients are free to choose the facility and the professional. German GPs are self-employed professionals mainly remunerated for each consultation, who work for an average of 50 opening hours per week. In Italy GPs are self-employed professionals mainly paid on per capita basis, who have their own list of patients and must guarantee a minimum number of clinical opening hours per week, which has often become the average number in practice. Accordingly, the patients' weekly access to Italian GPs' clinics is very limited. In Spain GPs are civil servants who work in multifunctional facilities with multi-professional teams. The weekly hours worked by Spanish GPs are 38 hours, as for any other civil servant. Trying to draw positive lessons from the comparison, the Spanish facilities seem to be the most advanced examples of horizontal-integrated organizations able to fulfil the expectations of a growing population of ageing people. The range of generalist professionals could be enlarged beyond GPs, as the German example shows., (© 2023. The Author(s), under exclusive licence to Società Italiana di Medicina Interna (SIMI).)

A price stems from the intersection between supply and demand curves in any common market. However, there are special markets where consumers do not pay for goods directly, and prescription drugs are a well-known example in healthcare. Drugs are mainly funded by public expenditure in well-established welfare systems like those of the Western European countries. However, the present era of austerity in public funding has made financial resources scarce in most European nations. Currently, the leading tendency for pharmaceutical pricing in Europe is direct negotiation with pharma companies. However, these negotiations are administratively burdensome, with costs not necessarily offsetting savings. Moreover, since any trade negotiation implies some degree of confidentiality to be effective these strategies are scantily transparent. When prices are set for many products through unavoidably arbitrary decisions, the final consequence is an irrational allocation of financial resources. Here, we raise a proposal to restore a reasonable balance between public equity objectives of health authorities and private profit incentives of the pharma industry in Europe, switching from pricing to budgeting. The underlying rationale of our proposal is to stop setting arbitrary prices in a context of market failure., (© 2022. The Author(s), under exclusive licence to Società Italiana di Medicina Interna (SIMI).)

The regulatory process is currently designed to ensure drug safety during the pre-marketing process. Due to limitations of the pivotal studies owing to their short duration and small number of highly selected cases, some adverse drug reactions (ADRs) are not detected, particularly the rarest and those which appear a long time after exposure. Thus it is essential to foster pharmacovigilance run totally independently from marketing authorization holders in order to attain transparent surveillance. This challenge is relevant for hemophilia drugs, after recent advances offered innovative replacement and non-replacement medicines that warrant monitoring due to the occurrence of predicted but also unexpected and rare ADRs. This article contains an overview of pharmacovigilance systems in the European Union and USA, describing the main ADRs related to traditional and recently available hemophilia medications and suggests how to involve stakeholders other than marketing authorization holders for an independent and transparent pharmacovigilance targeted to detect not only early ADRs but also those emerging post-marketing., (Copyright © 2021. Published by Elsevier Ltd.)

The COVID-19 pandemic has put under pressure all the health national systems in Europe and telemedicine (TM) has been an almost unavoidable answer for primary care (PC) services to constrain the contagion. PC includes all the healthcare services that are the first level of contact for individuals. General practitioners (GPs) are the pivotal providers of PC throughout Europe. Although GP costs are mainly covered by public services or social insurances in Europe, they are still self-employed physicians everywhere, differently from their colleagues in hospitals who are traditionally employees. TM is a very general term open to various interpretations and definitions. TM can now be practiced by means of modern audio-visual devices and is an alternative to the traditional face-to-face consultation in general practice. Although the adoption of TM seems to be compelling in our era, its practical dissemination in PC has been quite slow so far, and many different concerns have been raised on it. On the whole, TM widespread adoption in PC seems to be more a matter of labor organization and health care funding than of technology and ethics. Larger-scale organizations comprising a wide range of health professionals have become a pressing priority for a modern PC, because working together is crucial to provide high-quality care to patients, and co-location should boost teamwork and facilitate the management of information technology. A national network of large organizations in PC could be rationally managed through local budgets and should increase efficiency by adopting tools such as TM.

Pharmacy has been historically regarded as a discipline between health and chemistry devoted to drug development, production, and compounding. These tasks have been almost lost with the industrial manufacturing, and dispensing remains the main activity of pharmacists. Hospital pharmacists are usually employees in their workplace, while the professional framework of community pharmacists is very different, being pharmacies predominantly private shops in almost all European countries. In the last years pharmacists have strongly advocated that the focus of their services should switch from 'product' to 'patient'. Clinical pharmacy and pharmaceutical care are the two most cited concepts to support this shift. Clinical pharmacy was originally defined as the area of pharmacy concerned with the science and practice of rational medication use, pharmaceutical care as the responsible provision of drug therapies to achieve definite outcomes. The practice of clinical pharmacy should embrace the philosophy of pharmaceutical care. The new wave of pharmacists' patient-centered care in Europe still seems to be a reaction against the loss of their traditional professional role after the drug manufacturing revolution. To depict a realistic scenario for progress, it is worth differentiating between hospital and community. Hospital pharmacists should strengthen their pivotal role of medication gatekeepers to improve among clinicians the appropriateness of drug prescriptions and generate savings in expenditures. Any proposal for clinical services provided by community pharmacists is inevitably affected by the issue of their potential remuneration, especially in countries where the remuneration for reimbursable drugs is still a proportion of the retail price.

This report contains the updated consensus recommendations for optimal hemophilia care produced in 2019 by three Working Groups (WG) on behalf of the European Directorate for Quality of Medicines and Healthcare in the frame of the Kreuth V Initiative. WG1 recommended access to prophylaxis for all patients, the achievement of plasma factor trough levels of at least 3-5% when extended half-life factor VIII (FVIII) and FIX products are used, a personalized treatment regimen, and a choice of chromogenic assays for treatment monitoring. It was also emphasized that innovative therapies should be supervised by hemophilia comprehensive care centers. WG2 recommended mandatory collection of postmarketing data to assure the long-term safety and efficacy of new hemophilia therapies, the establishment of national patient registries including the core data recommended by the European Medicines Agency and the International Society on Thrombosis and Haemostasis, with adequate support under public control, and greater collaboration to facilitate a comprehensive data evaluation throughout Europe. WG3 discussed methodological aspects of hemophilia care in the context of access decisions, particularly for innovative therapies, and recommended that clinical studies should be designed to provide the quality of evidence needed by regulatory authorities, HTA bodies and healthcare providers. The dialogue between all stakeholders in hemophilia care and patient organizations should be fostered to implement these recommendations., (Copyright© 2020 Ferrata Storti Foundation.)

Essentials A residual factor VIII synthesis is likely to be protective towards inhibitor (INH) development. Mutation type-inhibitor risk association was explored in 231 patients with severe hemophilia A. A 2-fold increase in INH development for in silico null vs. non-null mutations was found. A 3.5-fold increase in INH risk for antigen negative vs. antigen positive mutations was found., Summary: Background The type of F8 mutation is the main predictor of inhibitor development in patients with severe hemophilia A. Mutations expected to allow residual synthesis of factor VIII are likely to play a protective role against alloantibody development by inducing immune tolerance. According to the expected full or partial impairment of FVIII synthesis, F8 variants are commonly classified as null and non-null. Objectives To explore the mutation type-inhibitor risk association in a cohort of 231 patients with severe hemophilia A enrolled in the Survey of Inhibitors in Plasma-Product Exposed Toddlers (SIPPET) randomized trial. Methods The genetic defects in these patients, consisting of inversions of intron 22 (n = 110) and intron 1 (n = 6), large deletions (n = 16), and nonsense (n = 38), frameshift (n = 28), missense (n = 19) and splicing (n = 14) variants, of which 34 have been previously unreported, were reclassified according to two additional criteria: the functional effects of missense and splicing alterations as predicted by multiple in silico analyses, and the levels of FVIII antigen in patient plasma. Results A two-fold increase in inhibitor development for in silico null mutations as compared with in silico non-null mutations (hazard ratio [HR] 2.08, 95% confidence interval [CI] 0.84-5.17) and a 3.5-fold increase in inhibitor development for antigen-negative mutations as compared with antigen-positive mutations (HR 3.61, 95% CI 0.89-14.74] were found. Conclusions Our findings confirm an association between the synthesis of minute amounts of FVIII and inhibitor protection, and underline the importance of investigating the residual FVIII antigen levels associated with causative variants in order to understand their clinical relevance., (© 2018 International Society on Thrombosis and Haemostasis.)

This report summarizes recommendations relating to haemophilia therapy arising from discussions among experts from 36 European countries during the Kreuth III meeting in April 2013. To optimize the organization of haemophilia care nationally, it is recommended that a formal body be established in each country to include the relevant clinicians, national haemophilia patient organization, health ministry, paying authority and (if appropriate) regulatory authorities. The minimum factor VIII consumption level in a country should be 3 I.U. per capita. Decisions on whether to adopt a new product should not be based solely on cost. Prophylaxis for children with severe haemophilia is already recognized as the optimum therapy. Ongoing prophylaxis for individual adults should also be provided when required based on clinical decision making by the clinician in consultation with the patient. Children with inhibitors who have failed, or who are not suitable for, immune tolerance therapy should be offered prophylaxis with bypassing agents. Single factor concentrates should be used as therapy wherever possible in patients with rare bleeding disorders. Orphan drug designation for a factor concentrate should not be used to hinder the development, licencing and marketing of other products for the same condition which have demonstrably different protein modification or enhancement., (© 2014 John Wiley & Sons Ltd.)

Introduction: Work Package 4 Development of the standardisation criteria of the European Haemophilia Network project has the main objective of implementing a common and shared European strategy for a certification system for two levels of Haemophilia Centres: European Haemophilia Treatment Centres and European Haemophilia Comprehensive Care Centres in the Member States of the European Union., Materials and Methods: An inclusive and participatory process for developing shared standards and criteria for the management of patients with inherited bleeding disorders has been carried out. The process has been implemented through four different consultation events involving the entire European community of stakeholders that significantly contributed in the drafting of the European Guidelines for the certification of Haemophilia Centres., Results: The Guidelines set the standards for the designation of centres that provide specialised and multidisciplinary care (Haemophilia Comprehensive Care Centres) as well as local routine care (Haemophilia Treatment Centres). Standards cover several issues such as: general requirements; patient care; advisory services; laboratory; networking of clinical and specialised services., Conclusions: The drafting of the European Guidelines for the certification of Haemophilia Centres was performed adopting a rigorous methodological approach. In order to build the widest possible consensus to the quality standards, the main institutional and scientific stakeholders have been involved. The resulting document will significantly contribute in promoting standardisation in the quality of diagnosis and treatment in European Haemophilia Centres.

Pharmacovigilance is an essential element of any drug treatment and considering the history of adverse events due to products used to treat inherited bleeding disorders, it should be an integral component of modern haemophilia treatment. Because inherited bleeding disorders and adverse events are rare, a multicentre, preferably multinational, adverse event reporting scheme for all clotting factor products is required. EUHASS is a European, prospective, multicentre adverse event reporting scheme in the field of inherited bleeding disorders., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Current challenges facing haemophilia care were identified and reviewed by an interdisciplinary group of experts in haemostasis and thrombosis, infectious disease, epidemiology, pharmacoeconomics and public health who met in February 2005 in Brussels. The outcome of this meeting was a series of consensus recommendations proposed to address the following three challenges: (i) developing the next generation of haemophilia specialists; (ii) reducing the risk that emerging pathogens present to safe haemophilia care and (iii) providing haemophilia care in an environment of cost constraint. It is intended that these consensus recommendations will form the basis of a concerted effort by leading haemophilia clinicians to secure future resources for the development and improvement of haemophilia care throughout Europe.

This study prospectively evaluated the rate of biologic response to desmopressin (DDAVP) in 66 patients with type 1 or 2 von Willebrand disease (VWD), each of whom had, on the basis of available records, a clinically significant bleeding history and at least one of the following laboratory abnormalities: bleeding time (BT) longer than 15 minutes, ristocetin cofactor activity (VWF:RCo) less than 10 IU/dL, factor VIII coagulant activity (FVIII:C) less than 20 IU/dL (severe VWD). Before the study, responsive patients were defined as those who, 2 hours after infusion of 0.3 microg/kg DDAVP, had increased baseline values of VWF:RCo and FVIII:C by at least 3-fold and achieved levels of at least 30 IU/dL for both and a BT of 12 minutes or less. The rate of biologic response varied according to VWD types and was higher in type 1 (7 of 26, 27%) than in type 2 (7 of 40, 18%) (type 2A [1 of 15, 7%], type 2M [3 of 21, 14%], type 2N [3 of 4, 75%]). Mutations in the VWF gene were previously known or newly identified in most patients with types 2A (n = 15 of 15), 2M (n = 15 of 21), and 2N (n = 4 of 4), but in none of those with type 1 VWD. Genotype provided more information than phenotype in predicting individual responses to DDAVP only in patients with 2A and 2N VWD. This prospective study showed that the rate of biologic response to DDAVP is relatively low not only in type 2 but also in type 1 VWD when uniform and stringent criteria for patient selection and responsiveness are applied.

Four functional assays for protein S were evaluated by 4 different laboratories, each center using its own method. The aim of this study was to compare these different assays and to establish a relationship with results of immunological assays of total and free protein S antigen and C4bBP. The same plasma samples were distributed to each center and tested in blind. In 47 normal subjects, there was no significant difference between the 4 functional assays, with mean values ranging from 93 to 100%. These values were in good agreement with those of free and total protein S antigen. In 34 patients with a quantitative congenital deficiency of protein S the mean values of protein S activity were decreased with the 4 assays, ranging from 25 to 40%. Free protein S antigen was reduced to a similar extent, whereas total antigen was either normal or decreased. The correlation of protein S activity with free protein S antigen was satisfactory for 3 methods, with coefficients of correlation varying from 0.84 to 0.92 whereas it was only 0.70 in one lab. When total protein S antigen was reduced, protein S activity was decreased in all the patients with the 4 assays. In contrast when total protein S antigen was normal an important overlap of protein S activity between normals and patients was observed in one lab with 12 patients misclassified. In 8 patients with a functional defect, results of protein S activity differed substantially according to the assay used and about half of these patients were misclassified.(ABSTRACT TRUNCATED AT 250 WORDS)

The prevalence of von Willebrand's disease (VWD) in Western European countries and Israel was assessed. Possible patients were identified initially by questionnaire and those with plasma levels of von Willebrand factor antigen ( WFAg ; factor VIII related antigen) less than 1 u/dl (less than 1%) were confirmed by immunoradiometric assay performed at four reference centres. The prevalences of severe VWD in Scandinavian countries were similar to each other and about 10 times greater than those in other Western European countries. The prevalence in Israel was intermediate. The Registry will form the basis for future non- invasive epidemiological studies of atherosclerosis in these individuals.