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Background: Vaccine market access (VMA) pathways across the European Union (EU) and the United Kingdom (UK) are complex, lengthy, and heterogeneous, particularly when compared with pharmaceuticals. The knowledge base to inform recommendations for optimization of VMA is lacking. We therefore conducted a comprehensive evaluation of EU VMA pathways. Methods: Research in two phases included: (1) mapping VMA pathways in each EU member state (including the UK) based on a literature review, expert interviews, and mathematical archetyping; and (2) interviews with vaccine experts to identify barriers, drivers, and recommendations for regional VMA alignments. Results: Key steps in VMA across the EU include horizon scanning, early advice, National Immunization Technical Advisory Group (NITAG) recommendation for inclusion in national immunization programs, health technology assessment (HTA), final decision and procurement. We found significant complexity and heterogeneity, particularly for early advice, and in the roles, decision-making criteria, and transparency of NITAGs and HTA bodies. The most important drivers for rapid VMA included demonstration of disease burden and vaccine benefit (e.g., efficacy, safety, economic). Key barriers were budget limitations and complexity/clarity of VMA processes (e.g., need for national-regional consensus, clarity on process initiation, and clarity on the role of HTA). Recommendations for alignment at EU and member-state levels include information sharing, joint clinical assessment, initiatives to address funding and political barriers, and improved transparency by decision-making bodies. Early engagement with vaccine stakeholders was a key recommendation for manufacturers. Conclusions: There is significant potential for alignment, collaboration, and improvement of VMA across the EU. Roles, responsibilities, and transparency of key bodies can be clarified. The COVID-19 pandemic response should stimulate policies to improve access to all vaccines, including routine ones, and form the foundation upon which a consistent vaccine ecosystem can be created for the EU, one that is resilient, consistent between member states, and fit for purpose. (c) 2021 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http:// creativecommons.org/licenses/by/4.0/).

Introduction There are clear treatment options for mild psoriasis where topical therapies are the mainstay, and for severe psoriasis where systemic therapy (biologic or non-biologic) is necessary. However, there is less clarity in the ‘grey zone’ of patients in the moderate or so-called ‘beyond-mild’ segment. There are frequent delays to the initiation, discontinuation, switching and dose change in treatment, and many patients fail to continue treatment because of concerns about safety or lack of efficacy. Treatment with topical therapies, such as calcipotriol and betamethasone dipropionate (Cal/BD) combinations, may be suitable for these patients. Method These consensus recommendations on the use of topical therapies including Cal/BD foam for beyond-mild psoriasis originated from a modified Delphi process of European clinical experts. In the process, the experts iteratively refined a series of draft statements, which had to receive ≥ 80% approval to be incorporated into the consensus. Results The experts identified three main themes: Cal/BD foam as monotherapy, as an add-on to non-biologic systemic therapies and as an add-on to systemic biologics. The consensus emphasises disease factors and patient preference in treatment choice, summarises the evidence base for Cal/BD foam monotherapy for flare treatment as well as long-term management, and identifies the potential for improved treatment outcomes, such as reduced time to onset of action and reduced systemic dose to minimise side effects for add-on Cal/BD therapy to non-biologic systemics. The recommendations regarding add-on Cal/BD foam to biologics are similar to those for non-biologic systemic therapies, but also include suggestions for patients on biologics who are late responders. As clinical choices of Cal/BD combination vary, we have here often used ‘Cal/BD’ without reference to any particular formulation. Conclusions These recommendations aim to give practical guidance to those treating patients with beyond-mild psoriasis, to support patients’ use of topical preparations and to optimise treatment outcomes.

Resume L’evaluation medicoeconomique estime, pour une technologie de sante donnee, le surcout et le benefice clinique par rapport a une strategie de reference. L’objectif est d’analyser les criteres de mesure de benefice clinique qui fondent les decisions d’acces au marche et de remboursement des medicaments en oncologie, en France et en Europe. L’amelioration de la survie globale est le critere privilegie pour demontrer le benefice d’un medicament anti-cancereux ; un gain de survie de 2 a 3 mois ou plus serait considere comme pertinent pour un nouveau produit par rapport a un comparateur. En l’absence d’amelioration de la survie ou de donnees matures sur la survie, survie sans progression ou survie sans symptomes et la possibilite d’acceder a des alternatives therapeutiques a visee curative, la reduction des toxicites et l’amelioration de la qualite de vie peuvent etre prises en compte. Les differences d’appreciations du benefice clinique entre les agences d’evaluation et les payeurs ne sont pas specifiques pour la France. Les etudes de cas montrent qu’il est difficile de trouver une ligne claire dans les decisions de remboursement et de prix mais aussi qu’il est difficile d’identifier les facteurs qui expliquent les decisions de remboursement lorsque le benefice en survie globale n’est pas demontre.

Objectives: Clinical endpoints are defined as valid measures of clinical benefit or harm due to treatment, that describe the impact of treatment on how a patient feels, functions, and survives. The choice of endpoints and the manner in which they are reported have a major impact on the relative effectiveness assessment (REA) of pharmaceuticals. The aim of this article is to describe the guideline development process and the key findings that set a framework for appropriate use of endpoints in REAs in Europe.Methods: A multi-health technology assessment (HTA)-agency collaborative process in EUnetHTA JA1 was used to scope, draft, and finalize methodological guidelines for REA in Europe.Results: Patient-relevant clinical endpoints can be broadly categorized into: mortality, morbidity and health-related quality of life. A clinical endpoint is a main symptom or sign of a disease that is clinically relevant, valid, reproducible and responsive to change. Preference is for long-term or final endpoints whenever possible. Surrogate endpoints may be used when there is compelling evidence of a clear and consistent correlation of treatment effects on the surrogate and final outcome of interest.Conclusions: The relevance and hierarchy of the different types of clinical endpoints depend on the research question, disease, and the treatment investigated. Not only the primary endpoint, but also other relevant endpoints are assessed in comparison to adequate comparator(s). This simultaneous assessment of all relevant endpoints is a hallmark of REA.

In response to a recommendation from the Pharmaceutical Forum, the European Medicines Agency and the European network for Health Technology Assessment initiated a collaboration with the aim to improve the contribution regulatory assessment reports can make to the assessment of relative effectiveness of medicinal products by health technology assessment bodies. This collaboration on improving European Public Assessment Reports (EPARs) started in February 2010 and was performed over 2 years. As a result, the templates for preparing EPARs were revised to better address the needs of heath technology organizations. The better understanding of information needs was a key outcome of the collaboration. To ascertain whether these template changes led to the inclusion of relevant information, a review of a small set of EPARs for recently approved medicinal products was carried out in parallel by both the European network for Health Technology Assessment and the European Medicines Agency. This report provides an account of this project on improving EPARs, which is part of the ongoing dialogue between regulators and health technology assessment bodies on a European level to support policymaker decisions in the future.

Medico-economic evaluations estimate, for a given health technology, the added cost and the clinical benefit compared to a reference strategy. The objective here is to analyze the criteria used to measure clinical benefit as the basis for market access and reimbursement decisions for drugs in oncology both in France and in Europe. Prolonged overall survival is the criterion of choice to demonstrate the benefit of an anticancer drug; a survival gain of 2 to 3 months or more would be considered as relevant for a new product versus the comparator. In the absence of survival benefit or mature data on survival, progression-free survival or symptom-free survival and the availability of alternative curative treatments, decrease in drug toxicity and quality of life improvement may be considered. Differences in clinical benefit assessment between regulatory agencies and payers are not specific to France. Case studies show that it is difficult to find a consistency in reimbursement and pricing decisions and to identify factors that may fully explain reimbursement decisions when survival benefit is not demonstrated.

One of the challenges of the coming years is to personalize medicine in order to provide each patient with an individualized treatment plan. The three objectives of personalized medicine are to refine diagnosis, rationalize treatment and engage patients in a preventive approach. Personalization can be characterized by various descriptors whether related to the field, biology, imaging, type of lesion of the entity to be treated, comorbidity factors, coprescriptions or the environment As part of personalized medicine focused on biological markers including genetics or genomics, the integration of the clinical development plan to obtain marketing authorization may be segmented in 3 stages with a known descriptor identified before clinical development, a known descriptor discovered during clinical development or a known descriptor known after clinical development. For each stage, it is important to clearly define the technical optimization elements, to specify the expectations and objectives, to examine the methodological aspects of each clinical development phase and finally to consider the fast changing regulatory requirements in view of the few registered therapeutics complying with the definition of personalized medicine as well as the significant technological breakthroughs according to the screened and selected biomarkers. These considerations should be integrated in view of the time required for clinical development from early phase to MA, i.e. more than 10 years. Moreover, business models related to the economic environment should be taken into account when deciding whether or not to retain a biomarker allowing the selection of target populations in a general population.

Resume La personnalisation de la medecine est un des enjeux des prochaines annees afin qu’a chaque patient corresponde une prise en charge individualisee. La medecine personnalisee a pour triple objectif : affiner le diagnostic, rationaliser la prise en charge therapeutique et engager le patient dans une demarche preventive. La personnalisation peut etre caracterisee par differents descripteurs qu’ils soient lies au terrain, a la biologie, l’imagerie, au caractere lesionnel de l’entite a traiter, aux facteurs de comorbidite, aux coprescriptions, ou a l’environnement. Dans le cadre d’une medecine personnalisee centree sur les marqueurs biologiques incluant la genetique ou la genomique l’integration du plan de developpement clinique en vue d’une autorisation de mise sur le marche (AMM) peut etre segmente en 3 temps avec un descripteur identifie avant le developpement clinique, un descripteur decouvert pendant le developpement clinique ou un descripteur connu apres le developpement clinique. Pour chacun des temps il est important de bien definir les elements d’optimisation technique, de preciser les attentes et objectifs, de regarder les aspects methodologiques de chacune des phases du developpement clinique et enfin tenir compte des aspects reglementaires tres evolutifs compte tenu du peu de therapeutiques disposant d’une AMM repondant a la definition de la medecine personnalisee ainsi que des sauts technologiques importants selon les biomarqueurs retenus et selectionnes. Ces considerations sont a integrer compte tenu du temps de developpement clinique en vue d’une AMM superieur a 10 ans entre la phase precoce et l’AMM. Par ailleurs les modeles economiques lies au contexte economique sont a prendre en compte dans les choix pour retenir ou non un biomarqueur permettant de selectionner des populations cibles dans une population generale.

Based on the observation that over the last 30 years the cost of development has risen regularly as the number of new chemical entities reaching the market has fallen, how can "savings" be made in terms of clinical development, the objective being more rapid access to a drug for medical needs that are not covered? Several instruments exist to enable innovative products to be made available more quickly: temporary use authorisations, which are not concerned by this work (ATUs), conditional marketing authorisations (MAs) and MAs under exceptional circumstances. These aspects have been taken up in the European medicines agency (EMA)'s "Road Map", which states "A key issue for Regulators will be if a more "staggered" approval should be envisaged, characterised by a better defined/more restricted population of good responders, followed by a broadening of the population post-authorisation when more "real life" data are available. In addition, maximising the value of information generated in the post-authorisation phase should be developed through the use of cohorts and other prospectively collected use data, especially in the case of conditional marketing authorisations." The rules of procedure of the Transparency Commission for their part provide for the notion of preliminary examination: in order to prepare as best as possible the examination of dossiers of products assumed to be innovative and to limit delays, the office can undertake a preliminary study as soon as the dossier has been filed at the Committee for medicinal products for human use (CHMP). It may, at this time, request the firm to provide further information and may call on external experts. The implementation of this preliminary study does not exonerate the firm of the obligation of filing a complete dossier. The post inscription studies requested by the Transparency Commission (ISPEP - public health benefit and post-marketing studies) are usually requested in the case of hesitations regarding the level of improvement of the medical benefit (ASMR) [level II/III or IV/V]. Such requests mainly concern uncertainties regarding the transposability, the patient profile or correct usage in real life. Among the studies whose results were provided, in 15 cases the results were in line with expectations, in 6 cases they resulted in downward re-evaluations and the final 3 cases were inconclusive. The final recommendations of the round table were: Defining the medical need that is not covered by working in consultation (Industry and Health Authorities); Providing a Complementary Investigations Plan (PIC) after the MA at a very early stage to reinforce the early MA, and/or HTA (health technology assessment) preparation and monitoring (possible constraining actions); Enhanced use of modelling techniques and their transposability; "Intussusception" of phases to optimise the development of a complete dossier; Early "scientific opinions" (EMA, French Health Products Safety Agency [Afssaps], French Health Authority [HAS]); Raising the awareness of the authorities, industry, doctors and patients with regard to controlled observational studies; Developing the use of public data bases.

Resume Partant de la constatation que depuis 30 ans, le cout du developpement augmente regulierement a mesure que le nombre de nouvelles entites chimiques atteignant le marche decroit, comment faire des « economies » en termes de developpement clinique, l’objectif etant un acces plus rapide au medicament, pour les besoins medicaux non couverts ? Plusieurs instruments existent pour permettre une mise a disposition plus rapide de produits innovants : les autorisations temporaires d’utilisation ou ATU (qui ne sont pas concernees par ce travail), les autorisations de mise sur le marche (AMM) conditionnelles, les AMM sous circonstances exceptionnelles. Ces elements sont repris dans la « road map » de l’Agence europeenne du medicament, (European Medicines Agency ou EMA), qui dit : « A key issue for Regulators will be if a more “staggered” approval should be envisaged, characterised by a better defined/more restricted population of good responders, followed by a broadening of the population post-authorisation when more “real life” data are available. In addition, maximising the value of information generated in the post-authorisation phase should be developed through the use of cohorts and other prospectively collected use data, especially in the case of conditional marketing authorisations. » Le reglement interieur de la Commission de transparence pour sa part prevoit la notion d’examen preliminaire : afin de preparer au mieux l’instruction des dossiers des produits presumes innovants et de limiter les delais, le bureau peut engager une etude preliminaire des le depot du dossier au Comite des specialites pharmaceutiques humaines (CHMP). Il peut a cette occasion solliciter de la firme des elements d’information et faire appel a des experts externes. La mise en oeuvre de cette etude preliminaire n’exonere pas la firme de l’obligation de deposer un dossier complet. Les etudes post inscription demandees par la commission de transparence (ISPEP) le sont souvent dans le cas d’hesitations sur le niveau d’amelioration du service medical rendu ou ASMR (niveau II/III ou IV/V). Ces demandes concernent essentiellement des incertitudes sur la transposabilite, le profil patient ou le respect du bon usage. Parmi les etudes dont les resultats ont ete rendus, dans 15 cas les resultats sont en conformite avec les attentes, dans 6 cas elles ont abouti a des reevaluations a la baisse, enfin dans 3 cas elles etaient non conclusives. Les recommandations finales de la Table Ronde etaient : – definition du besoin medical non couvert a travailler en concertation (industriels et autorites de Sante) ; – prevision d’un Plan d’investigations complementaires (PIC) au dela de l’AMM tres tot pour conforter AMM precoce, et/ou preparation HTA et le suivre (actions contraignantes possibles) ; – utilisation accrue des techniques de modelisation et de leur transposabilite ; – « intussusception » des phases pour optimiser le developpement d’un dossier complet ; – « avis scientifiques » precoces (EMA, Agence francaise de securite sanitaire des produits de sante (Afssaps), Haute autorite de sante (HAS)) ; – sensibilisation des autorites, industriels, medecins et patients aux etudes observationnelles controlees ; – developpement de l’exploitation des bases de donnees publiques.

Drug evaluation is based on comparison. Thus, the choice of the comparator for any new treatment becomes a key issue, especially when there are great differences in medical practice and of use conditions of the comparators depending on the geographical zones and their evolution with time. The choice of the comparators must satisfy sometimes different expectations from the registration authorities and for insurance coverage. The universal comparator that allows answering all the clinical assessment questions does not exist. Placebo, when it can be used, remains a reference for the MA (marketing authorisation) application, but does not exclude the use of the reference drug available on the market and prescribed under optimal efficacy conditions. The reference treatment is sometimes a difficult choice due to the absence of validated therapeutic recommendations or if the recommendations vary depending on the countries. The expansion and international harmonization of prescription guidelines (clinical practice guidelines) would reinforce the robustness and efficiency of clinical research efforts with respect to the relevance of the comparison to reference treatments. This principle also applies to the use of a non-drug comparator when it has been recognized as the reference comparator in the treatment of the pathology in question. In as much as possible, the search for a consensus must also aim at defining in the clinical development recommendations significant thresholds for the size of evaluated effects. Optimization of the information made available after clinical trials could also be helped by the development of use of methodologies that allow assessing superiority on secondary criteria during a non-inferiority study on the main criterion. Finally, the development of early scientific consultations by the Haute Autorité de Santé (HAS, French Health Authority) would contribute to adapt phase III clinical trials better to questions concerning the assessment of the clinical added value of the medicinal products evaluated.

Resume La comparaison est un fondement de l’evaluation du medicament. Se pose des lors le probleme du choix du comparateur de tout nouveau traitement, ce d’autant plus qu’existent de larges disparites des pratiques medicales et des conditions d’utilisation des comparateurs, en fonction des aires geographiques et de leur evolution dans le temps. Le choix du ou des comparateurs doit repondre aux attentes parfois differentes des autorites d’enregistrement puis de prise en charge assurantielle. Le comparateur universel permettant de repondre a toutes les questions d’evaluation clinique n’existe pas. Le placebo lorsqu’il est utilisable reste une reference pour le dossier d’Autorisation de Mise sur le Marche (AMM) mais n’exclut pas l’utilisation du medicament de reference disponible sur le marche et prescrit dans des conditions d’efficacite optimales. Le traitement de reference est parfois de choix difficile du a l’absence de recommandation therapeutique validee ou lorsque ces recommandations sont differentes selon les territoires. Un etoffement et une harmonisation internationale des referentiels de prescription (de bon usage) renforceraient la robustesse et l’efficience des efforts de recherche clinique quant a la pertinence de l’exercice de comparaison aux traitements de reference. Ce principe est tout aussi applicable a l’utilisation d’un comparateur non medicamenteux lorsqu’il est reconnu comme le comparateur de reference dans la prise en charge de la pathologie en question. Dans la mesure du possible, la recherche de consensus doit de la meme facon viser a definir dans les recommandations de developpement clinique des seuils de significativite de quantite d’effet. L’optimisation des informations mises a disposition suite a essais cliniques pourra en outre etre aidee par le developpement de l’usage de methodologies permettant lors d’une etude de non inferiorite sur le critere principal d’evaluer une superiorite sur des criteres secondaires. Enfin, le developpement des consultations precoces de la Haute Autorite de Sante contribuerait a mieux adapter les essais cliniques de phase III aux questions relatives a l’evaluation de l’amelioration du service medical rendu.

Une demande d’autorisation de mise sur le marche (AMM) d’un medicament repose sur une analyse du rapport benefice/risque (B/R) du produit concerne. Des procedures europeennes sont mises en place depuis pres de dix ans pour assurer l’evaluation optimale et transparente des nouveaux produits. Les dossiers demandes aux industriels doivent etre tres complets, additionnant les etudes animales, les donnees pharmacocinetiques, pharmacodynamiques et toxicologiques, les etudes d’interactions medicamenteuses, les etudes chez le volontaire sain, les dossiers de phases 2 et 3, avec plusieurs etudes « pivot » pour cette derniere phase. Dans le cadre de l’evaluation d’un nouvel anticoagulant, l’efficacite clinique est mesuree en phase 2 principalement sur des criteres de substitution (thromboses veineuses totales phlebographiques asymptomatiques). En phase 3, des criteres plus cliniques sont preferes (thromboses veineuses distales et proximales symptomatiques, thromboses veineuses proximales asymptomatiques, embolies pulmonaires et deces lies a la maladie thromboembolique). Les donnees de tolerance (hemorragies majeures, transfusion) sont confrontees aux donnees d’efficacite lors de ces deux phases, mais ce sont bien sur les etudes pivot de la phase 3 qui vont representer l’element essentiel de la decision. L’exemple du dabigatran est utilise ici pour illustrer cette procedure.

The European patents for epoetin alpha recently expired. Biosimilars (i.e. "a medicine which is similar to a biological medicine that has already been authorized" [EMEA 2007]) of epoetins have thus been released on the market in Europe. Because of the complexity of the processes that are required to produce medicinal products containing biotechnology-derived proteins as active substances and to characterize the physicochemical properties of these compounds, the guidelines that have been developed for generic drugs cannot be used for approval of biosimilar products. The EMEA guidelines do not answer all questions that have been raised for the development of biosimilars, and in some cases, decisions will have to be taken at a national level. This is why the Society of Nephrology (Societe de nephrologie), the French-speaking Society of Dialysis (Societe francophone de dialyse) and the Pediatric Society of Nephrology (Societe de nephrologie pediatrique) established guidelines for the usage of biosimilar epoetins concerning approval, identification, substitution of an innovator drug, post-marketing surveillance, extension of indication and pharmacovigilance plan.

The concept of similar biological medicinal products (‘biosimilar’ medicinal products) allows pharmaceutical companies to develop products based on an abridged dossier once the marketing protection of the ‘reference’ biological medicinal product has expired. A biosimilar medicinal product can be granted a marketing authorization provided that its similarity to a reference product is established in terms of quality, safety and efficacy (step-wise comparability exercise). A decision to launch a biosimilar medicinal product on the market is taken if it has a similar efficacy and comparable or better (less) immunogenicity than the chosen reference biological medicinal product. However, this decision is based on limited data and the comparability program may detect substantial differences in immunogenicity profiles but is likely incapable of detecting rare events. This is why clinical experience, through clinical trials and extensive pharmacovigilance programs, remains the most reliable way to assess the immunogenicity and tolerance profile of recombinant therapeutic proteins. Substitution of one biological medicinal product by a biosimilar medicinal product is not currently recommended before long-term clinical efficacy and safety have been acquired in all relevant populations. Here we review recent regulatory guidelines provided by EMEA and comment on the marketing authorizations and risk management plans of two recently approved biosimilar somatropins.

Objective: The objective of this study is to identify the possible barriers and critical success factors for the implementation of European collaboration in the field of relative effectiveness assessment (REA) of drugs. Methods: Data were gathered through semi-structured interviews with representatives from eight European health technology assessment (HTA) organisations involved in assessment of drugs for coverage decision-making (AAZ, AIFA, AHTAPol, HAS, HVB, IQWIG, NICE and ZiN). Results: Potential barriers identified mainly relate to methodology, resources and challenges with implementation in the respective national processes (e.g. legal restrictions). The most critical success factors for production of cross-border assessments were the continuous cooperation of competent partners, and the quality and timely availability of the assessment. Conclusion: Further adaptation of the process and methods is required for optimal collaboration. In the near future it can be expected that cross-border assessments will meet in particular the needs of smaller/middle-sized European countries and also European countries with less developed HTA systems as the potential efficiency/quality gains are the highest for these countries. Therefore, national implementation of cross-border assessments is especially likely in these countries in the coming years. Once more experience is gained with cross-border assessments, and successes become more evident, efficiency/quality gains may also be likely for some larger countries with well established processes.

The objective was to assess the efficacy and safety of all-trans-retinoic acid (ATRA) a retinoid with antitumour activity that inhibits in vitro the growth of Kaposis sarcoma cells in patients with low-risk AIDS-associated Kaposis sarcoma. Design: Non-randomized phase II study using a group sequential procedure to determine whether the response rate to ATRA was above 10%. Setting: Nine referral French centres. Patients: Twenty HIV-seropositive men with CD4 cells ³ 200 ´ 106/l low-risk Kaposis sarcoma [T0I0S0 according to the classification of AIDS Clinical Trials Group (ACTG)] not previously treated with systemic anti-Kaposis sarcoma agents and with at least four measurable lesions were included. Interventions: ATRA was given orally 45 mg/m2 daily for 12 weeks. Main outcome measure: Tumour response evaluated according to ACTG criteria. Nineteen patients were evaluated for response: partial response stabilization and progression were found in eight (42%) seven (37%) and four (21%) patients respectively. Gradual flattening and lightening of lesions was observed in responders after at least 2 months of ATRA. All patients with partial response at week 12 pursued ATRA for another 15 ± 7 weeks. Further improvement was observed in six patients. Median duration of response was 332 days. Cheilitis transient headaches and skin dryness were the main toxicities noted. No significant changes in HIV viral burden or serum interleukin-6 pathways were observed. ATRA is well tolerated and effective enough in Kaposis sarcoma patients to warrant further evaluation. (authors)

Objectives:High-quality clinical evidence is most often lacking when novel high-risk devices enter the European market. At the same time, a randomized controlled trial (RCT) is often initiated as a requirement for obtaining market access in the US. Should coverage in Europe be postponed until RCT data are available? We studied the premarket clinical evaluation of innovative high-risk medical devices in Europe compared with the US, and with medicines, where appropriate.Methods:The literature and regulatory documents were checked. Representatives from industry, Competent Authorities, Notified Bodies, Ethics Committees, and HTA agencies were consulted. We also discuss patient safety and the transparency of information.Results:In contrast to the US, there is no requirement in Europe to demonstrate the clinical efficacy of high-risk devices in the premarket phase. Patients in Europe can thus have earlier access to a potentially lifesaving device, but at the risk of insufficiently documented efficacy and safety. Variations in the stringency of clinical reviews, both at the level of Notified Bodies and Competent Authorities, do not guarantee patient safety. We tried to document the design of premarket trials in Europe and number of patients exposed, but failed as this information is not made public. Furthermore, the Helsinki Declaration is not followed with respect to the registration and publication of premarket trials.Conclusions:For innovative high-risk devices, new EU legislation should require the premarket demonstration of clinical efficacy and safety, using an RCT if possible, and a transparent clinical review, preferably centralized.

The European patents for epoetin alpha recently expired. Biosimilars (i.e. "a medicine which is similar to a biological medicine that has already been authorized" [EMEA 2007]) of epoetins have thus been released on the market in Europe. Because of the complexity of the processes that are required to produce medicinal products containing biotechnology-derived proteins as active substances and to characterize the physicochemical properties of these compounds, the guidelines that have been developed for generic drugs cannot be used for approval of biosimilar products. The EMEA guidelines do not answer all questions that have been raised for the development of biosimilars, and in some cases, decisions will have to be taken at a national level. This is why the Society of Nephrology (Société de néphrologie), the French-speaking Society of Dialysis (Société francophone de dialyse) and the Pediatric Society of Nephrology (Société de néphrologie pédiatrique) established guidelines for the usage of biosimilar epoetins concerning approval, identification, substitution of an innovator drug, post-marketing surveillance, extension of indication and pharmacovigilance plan.

The use of LN to freeze and remove the tick attached to the skin has been recently reported. The dose of LN to be delivered depends on the tick size. Cotton-tipped dipstick or LN spray equipment may be used. An application for around 15–20 s is sufficient to freeze a tick, rapid contraction of its body and a complete and immediate detachment of the parasite from the skin. This is an effective, painless, non-invasive, safe, “one shot” simple method of tick removal, especially convenient in case of multiple tick bites in endemic areas.

The principal skin manifestations of carcinoid syndrome are flush, acral pigmentation, cyanosis, and facial telangiectases. We describe herein a patient with carcinoid syndrome whose sclerodermatous lesions of the lower legs, an infrequent manifestation of this syndrome, have entirely subsided with chemotherapy and administration of the long-acting somatostatin analogue octreotide. Report of a Case. A 51-year-old white man was admitted in October 1990 for abdominal pain, diarrhea, and weight loss. On clinical examination, a metastatic liver, ascites, edema of the legs, and failure of the right side of the heart were found. The liver biopsy specimen revealed a poorly differentiated metastatic carcinoma whose origin was initially unknown. The first 5-day course of alternate chemotherapy was administered as follows: fluorouracil, 375 mg/m 2 daily; folinic acid, 200 mg/m 2 daily; and cisplatin, 15 mg/m 2 daily, alternated with streptozotocin, 500 mg/m 2 daily. In December 1990, the patient was referred to the

Background and Design: Early categorization of some acute soft-tissue infections, such as severe infectious cellulitis (IC) without or with secondary abscess formation, necrotizing fasciitis (NF) or pyomyositis, is frequently difficult. The first one requires only medical treatment, the remaining ones require either surgery or closed drainage. To determine the presence and the extent of these infections early, we have prospectively studied the value of magnetic resonance imaging in patients admitted for IC with local or general criteria of severity. Images were analyzed on a blind basis. Definite diagnosis was obtained by reviewing clinical records and, in most patients, the results of an invasive procedure. Results: Twenty-six patients (56 ±23 years old) were included in this study. Among them, 13 received gadoliniumdiethylene-triaminepenta-acetic acid intravenously. The final diagnosis was pyomyositis (five patients), NF ( three patients), or IC with (seven patients) or without (11 pa- tients) subcutaneous abscess. Images specific for these diseases were best outlined with T2-weighted sequences. In patients with pyomyositis or subcutaneous abscess(es), we observed spindle-shaped or round, well-defined areas of high signal intensity within the muscles or subcutis, respectively. Patients with NF exhibited numerous homogeneous, well-defined dome-shaped areas of hypersignal in the deep hypodermis. In patients with uncomplicated IC, these dome-shaped areas of hypersignal appeared ill-defined, heterogeneous, smaller, thinner, and less numerous than those in patients with NF. Conclusions: In patients presenting severe IC, magnetic resonance imaging provided an early clue in the diagnosis of pyomyositis, NF, and abscess-complicated IC. By precisely defining the extent of these infections, it helped to plan surgical treatment. (Arch Dermatol. 1994;130:1150-1158)