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Humans change the climate in many ways. In addition to greenhouse gases, climate model inputs thus include a number of other forcings like land-use change. While studies typically investigate the joint effects of all forcings, we here isolate the impact of afforestation and deforestation on winds in the lowermost 350 m of the atmosphere to quantify the relevance of the lower boundary condition for large-scale wind energy assessments. We use vertically resolved sub-daily output from two regional climate models instead of extrapolating near-surface winds with simplified profiles. Comparing two extreme scenarios, we report that afforestation reduces wind speeds by more than 1 m/s in many locations across Europe even 300 m above ground and thus remains relevant at hub heights of current and future wind turbines. We show that standard extrapolation with modified parameters approximates long-term means well but fails to capture essential spatio-temporal details, such as changes in the daily cycle, and is thus insufficient to estimate wind energy potentials. Using adjacent climate model levels to account for spatio-temporal wind profile complexity, we report that wind energy capacity factors are strongly impacted by afforestation and deforestation: they differ by more than 0.1 in absolute terms and up to 50% in relative terms. Our results confirm earlier studies that land use change impacts on wind energy can be severe and that they are generally misrepresented with common extrapolation techniques. [ABSTRACT FROM AUTHOR]

Drug development for children presents unique challenges and is highly regulated. Novel approaches, such as the use of extrapolation to address, for example, the need to avoid unethical studies, whilst supporting robust evidence generation have been developed in support of benefit/risk considerations by regulatory authorities. This is only one step in the decision-making process towards access, which in Europe also includes health technology assessment (HTA) bodies. Discussions related to evidentiary requirements in small populations using scientific evidence transfer have been identified as a priority action by European Medicines Agency/European Network for Health Technology Assessment 21 (EMA/EUnetHTA 21). We describe the outcome of this work and reflect on the discussions that had taken place on how to leverage prior knowledge through identifying and addressing uncertainties during life cycle management to support regulatory and HTA decision-making. Using examples, we explore the range of applications for evidence generation and offer regulatory and HTA insights on key design considerations for producing better evidence, reflecting our shared ambition. Early interactions with all respective stakeholders, particularly between regulators and HTA bodies are key to optimise data generation and utility in children. In Europe, the HTA regulation will offer opportunities for collaborations, which are important for all development efforts. We collaboratively explored the unique specific challenges relating to paediatric drug development, ethically and in its ability to leverage prior knowledge, as exemplified using extrapolation. Learnings from these offer opportunities to further develop methodology on how to leverage uncertainties across a product's life cycle for small populations generally., (© 2024 The Author(s). British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

To examine the prevalence and incidence of diabetic eye disease (DED) among individuals with diabetes in Europe, a systematic review to identify all published European prevalence and incidence studies of DED in individuals with diabetes managed in primary health care was performed according to the MOOSE and PRISMA guidelines. The databases Medline, Embase and Web of Science were searched to 2 September 2017. Meta-analyses and meta-regressions were performed. The pooled prevalence estimates were applied to diabetes prevalence rates provided by the International Diabetes Foundation atlas and Eurostat population data, and extrapolated to the year 2050. Data of 35 prevalence and four incidence studies were meta-analyzed. Any diabetic retinopathy (DR) and diabetic macular edema (DME) were prevalent in 25.7% (95% CI 22.8–28.8%) and 3.7% (95% CI 2.2–6.2%), respectively. In meta-regression, the prevalence of DR in persons with type 1 diabetes was significantly higher compared to persons with type 2 diabetes (54.4% vs. 25.0%). The pooled mean annual incidence of any DR and DME in in persons with type 2 diabetes was 4.6% (95% CI 2.3–8.8%) and 0.4% (95% CI 0.5–1.4%), respectively. We estimated that persons with diabetes affected by any DED in Europe will increase from 6.4 million today to 8.6 million in 2050, of whom 30% require close monitoring and/or treatment. DED is estimated to be present in more than a quarter of persons with type 2 diabetes and half of persons with type 1 diabetes underlining the importance of regular monitoring. Future health services need to be planned accordingly. [ABSTRACT FROM AUTHOR]

Because sexual orientation concealment can exact deep mental and physical health costs and dampen the public visibility necessary for advancing equal rights, estimating the proportion of the global sexual minority population that conceals its sexual orientation represents a matter of public health and policy concern. Yet a historic lack of cross-national datasets of sexual minorities has precluded accurate estimates of the size of the global closet. We extrapolated the size of the global closet (i.e., the proportion of the global sexual minority population who conceals its sexual orientation) using a large sample of sexual minorities collected across 28 countries and an objective index of structural stigma (i.e., discriminatory national laws and policies affecting sexual minorities) across 197 countries. We estimate that the majority (83.0%) of sexual minorities around the world conceal their sexual orientation from all or most people and that country-level structural stigma can serve as a useful predictor of the size of each country’s closeted sexual minority population. Our analysis also predicts that eliminating structural stigma would drastically reduce the size of the global closet. Given its costs to individual health and social equality, the closet represents a considerable burden on the global sexual minority population. The present projection suggests that the surest route to improving the wellbeing of sexual minorities worldwide is through reducing structural forms of inequality. Yet, another route to alleviating the personal and societal toll of the closet is to develop public health interventions that sensitively reach the closeted sexual minority population in high-stigma contexts worldwide. An important goal of this projection, which relies on data from Europe, is to spur future research from non-Western countries capable of refining the estimate of the association between structural stigma and sexual orientation concealment using local experiences of both. [ABSTRACT FROM AUTHOR]

The introduction of biologic drugs represents the most significant advance in the management of immune-mediated inflammatory diseases for a decade. However, complex proteins are expensive to produce and manufacture. Biosimilar versions of established biologics are becoming available as another version of the reference medicinal product and are expected to provide substantial cost savings. However, because of their complexity, the approval of biosimilars requires strict controls to ensure that all therapeutically relevant characteristics are comparable to the reference medicinal product. This review summarizes the scientific principles and data requirements underpinning regulatory approval of biosimilars and the assumptions that enable extrapolation of data between indications. These important concepts are exemplified by CT-P13 (Remsima®, Inflectra®), the first biosimilar monoclonal antibody approved in Europe. [ABSTRACT FROM AUTHOR]

The regulatory framework for biosimilars was established across Europe in 2005 based on the concept of biosimilarity. This legislation secures the manufacturing, evaluation, and market authorization (MA) of high-quality safe and efficacious biopharmaceuticals that are highly similar to their reference medicinal product (biosimilars). Demonstration of biosimilarity is documented by full-scale comparability exercises between the biosimilar and the reference product at quality, preclinical, and clinical level. However, the complexity, diversity, and heterogeneity of biosimilars, both in structure and manufacturing, combined with the scientific knowledge accumulated in biotechnological analysis of recombinant therapeutic proteins requires continuous improvement of the regulatory framework based on the evolution and experience gained in this field. This current opinion article presents the concept of biosimilarity, discusses the extrapolation of indications that is acceptable based on a case-by-case basis by CHMP/EMA and uncovers other challenges lying ahead in the development of biosimilars. Biosimilars are still quite 'young' products that require worldwide attention. [ABSTRACT FROM AUTHOR]

The paper presents an interesting analysis of the future economic development of EU countries, offering in the same time some comparisons with USA. Starting with an analysis of the annual dynamic rates of GDP for the EU countries, during 2000-2012, there are identified two periods which are important to consider them for scenarios of Strategy Europe 2020. The trajectories of future economic development until 2015 are extrapolated considering the average dynamic rates both for the period 2002-2007 also for 2002-2008. There are obtained two trajectories: an optimistic one based on average dynamic rate of the period 2002-2007 and a less optimistic the other based on the average dynamic rate during 2002-2008. An analysis of the relative positions of the countries depending on their GDP per capita and their development potential shows which scenario will be viable for the EU development until 2015. [ABSTRACT FROM AUTHOR]

This article analyzes and critiques North American and European "clash literature"--a genre of post-9/11 writings that popularize elements of Samuel Huntington's "clash of civilizations" thesis, with particular reference to putative threats posed to Western civilization by Islam and Muslims. Attention is given to a series of salient themes used by multiple texts and authors, in a manner that creates an overarching narrative of Western moral superiority vis-à-vis a monolithic, authoritarian, and misogynistic Islamic culture; betrayal of Western culture by "politically correct" intellectual elites wedded to ideas of multicultural accommodation; and a cascading threat posed by the rapid influx of unassimilable Muslim immigrants who are poised to mount a demographic takeover of Europe and possibly America as well. The content of clash texts is then analyzed and evaluated in light of its detachment from relevant scholarship, its reliance on highly essentialized identity constructs, its use of demographic extrapolations and alarming anecdotes, and its stark rejection of contemporary pluralism. The article concludes with reflections on how scholars might respond to the identity insecurities revealed by clash literature as they seek to advance alternative narratives based on values of dialogue and coexistence. [ABSTRACT FROM AUTHOR]

The article presents a study which examines the mass balance and ice volume change in glaciers in European Alps from 1900 to 2011. The study performs mass balance extrapolation on data obtained from world glacier monitoring services (WGMS) and field data and modeling for glaciers in France, Austria, and Italy. Result shows that European Alps have mean glacier mass balance of -0.31 ± 0.04 meter w.e. -1 in 1900-2011.

This paper presents a solution for transmission of bulk power over long distances. It allows the interconnection between remote power plants and power grids, which is a common situation in countries with continental dimensions, such as China, Russia, Brazil, and Canada, and also special projects like supergrids in Europe and Asia. This paper also presents an analytical analysis of series and shunt FACTS applications for tapping and power flow control in half-wavelength transmission lines. The proposed FACTS devices are able to drain or inject fractional active power in the half-wavelength line and simultaneously to control the main power flow through the line by means of reactive power compensation, without mischaracterizing its particular principle of half-wavelength operation. Simulation results from a frequency-dependent model of transmission line and the complete models of the series and the shunt FACTS devices were obtained in the PSCAD/EMTDC to demonstrate the feasibility of the proposed systems. [ABSTRACT FROM PUBLISHER]

The world is an unsafe environment, of strong conflicts, where the war is the rule rather than exception. The theoretical roots of this vision can be found in Thomas Hobbes's philosophical work. The concepts of danger, threat, risk and vulnerability have been defined by different doctrinal implicit and explicit theories related to security , but the consensus doesn’t seem to have been done. In the study of these terms we intend to make a conceptual clarification of the areas of security policy across Europe in general and the prospects of the dynamics of these vectors, in particular, without mentioning only the existing trends. While the USA as a sovereign national state with clearly defined borders was able to adapt their concepts in a short period of time, after September 11, the EU is still hampered by institutional inconsistencies when they have to react to crisis situations. Unlike the concepts available in the U.S. in the field of security philosophy, organization and equipment of structures, Europe still looks like a cluster of states and administrative traditions . Neither the treaties provide the harmonization of public administration in Member States nor has the European Commission had the means to impose its laws, with some exceptions in terms of fair economic competition laws. [ABSTRACT FROM AUTHOR]

Purpose: When performing a life cycle assessment (LCA), the LCA practitioner faces the need to express the characterized results in a form suitable for the final interpretation. This can be done using normalization against some common reference impact-the normalization references-which require regular updates. The study presents updated sets of normalization inventories, normalization references for the EDIP97/EDIP2003 methodology and guidance on their consistent use in practice. Materials and methods: The base year of the inventory is 2004; the geographical scope for the non-global impacts is limited to Europe. The emission inventory was collected from different publicly available databases and monitoring bodies. Where necessary, gaps were filled using extrapolations. A new approach for inventorizing specific groups of substances-non-methane volatile organic compounds and pesticides-was also developed. The resulting inventory was combined with the most updated sets of characterization factors for each impact category in the EDIP methodologies. Results and discussion: Normalization references are provided for global and non-global impact categories for the year 2004, and causes of variations compared to previous versions are identified. For the non-toxic impact categories, they mainly reflect demographic evolution or change in emission intensities. For the toxic impact categories, they are strongly dependent on improvements in the characterization models as well as on the inventory analysis. Differentiation of substance groups into individual substance emissions is an important source, which leads to identification of inconsistencies in the current practice and guidance to ensure compatibility between LCI and LCIA. Uncertainties are not quantified but are mainly expected to lie in the toxic substance inventories, which are known not to encompass all potentially harmful chemicals released in Europe, e.g. omitting some toxic metals. Conclusions: The present study provides the most updated set of publicly available normalization references for the EDIP methodology and emission inventories for Europe that may also serve for the calculation of normalization references for other impact categories. It is believed to be the best estimate available for Europe and is thus recommended for use along with the guidance provided in this study. [ABSTRACT FROM AUTHOR]

In this article, the author discusses the environmental risk assessment of pesticides and the possibility of extrapolation among the climatic regions in Europe. He mentions the implementation of a new regulation on the setting of plant protection products at the market in North, Central and South Europe. He suggests the development of ecological settings for typical Mediterranean freshwater ecosystems when performing micro and mesocosm experiments in dealing with its various ecological features.

A new family of binomial trees as approximations to the Black–Scholes model is introduced. For this class of trees, the existence of complete asymptotic expansions for the prices of vanilla European options is demonstrated and the first three terms are explicitly computed. As special cases, a tree with third-order convergence is constructed and the conjecture of Leisen and Reimer that their tree has second-order convergence is proven. [ABSTRACT FROM AUTHOR]

Abstract: Technical change at the farm level or changes in input prices often have an impact on the firm''s supply function, which in turn affect their economic and environmental performance. These changes can take place in numerous ways. This paper presents a methodology that increases the consistency of supply responses across various sets of agricultural products and most representative farm typologies in Europe, with a market model based on a statistical response function approach. Since most farm simulation models are limited to a subset of regions and farm types, the linkage to an aggregated model requires a procedure for expanding these results to non-sample regions to achieve full regional coverage. This paper addresses theoretical aspects related to the consistency between micro and market level models. The proposed approach is applied using a consistent set of simulation results from farm models in seven European regions. Our results show a fairly stable behaviour of the farm models considered for the analysis and quite good fit of the estimated response surface. As results are still preliminary we critically reflect on the applicability of this method in addressing further needs on up-scaling of other economic as well as environmental indicators. [Copyright &y& Elsevier]

Abstract: Within the European fusion programme, the helium cooled lithium lead (HCLL) breeding blanket is one of the concepts to be pursued as possible candidates for the European DEMO reactor. A HCLL-DEMO reactor has been assessed in 2007, a near term fusion power plant based on limited technologies and plasma extrapolation from ITER. In this frame, this paper presents the results of the activities carried out by CEA teams, including both in vessel and ex vessel components. The high interdependency between the several technological components is highlighted. A careful integrated assessment to further account for the integration of all the components of the machine towards a final robust and consistent version of HCLL-DEMO is also recommended as future activity. [Copyright &y& Elsevier]

We propose a new computational method for the valuation of options in jump-diffusion models. The option value function for European and barrier options satisfies a partial integrodifferential equation (PIDE). This PIDE is commonly integrated in time by implicit-explicit (IMEX) time discretization schemes, where the differential (diffusion) term is treated implicitly, while the integral (jump) term is treated explicitly. In particular, the popular IMEX Euler scheme is first-order accurate in time. Second-order accuracy in time can be achieved by using the IMEX midpoint scheme. In contrast to the above approaches, we propose a new high-order time discretization scheme for the PIDE based on the extrapolation approach to the solution of ODEs that also treats the diffusion term implicitly and the jump term explicitly. The scheme is simple to implement, can be added to any PIDE solver based on the IMEX Euler scheme, and is remarkably fast and accurate. We demonstrate our approach on the examples of Merton's and Kou's jump-diffusion models, the diffusion-extended variance gamma model, as well as the two-dimensional Duffie-Pan-Singleton model with correlated and contemporaneous jumps in the stock price and its volatility. By way of example, pricing a one-year double-barrier option in Kou's jump-diffusion model, our scheme attains accuracy of 10-5 in 72 time steps (in 0.05 seconds). In contrast, it takes the first-order IMEX Euler scheme more than 1.3 million time steps (in 873 seconds) and the second-order IMEX midpoint scheme 768 time steps (in 0.49 seconds) to attain the same accuracy. Our scheme is also well suited for Bermudan options. Combining simplicity of implementation and remarkable gains in computational efficiency, we expect this method to be very attractive to financial engineering modelers. [ABSTRACT FROM AUTHOR]

A long-term joint UK–Swedish–German project has been undertaken on the measurement and analysis of HF spectral occupancy over northern Europe. This has resulted in an extensive database of spectral occupancy measurements made at four sites over a complete sunspot cycle, and mathematical models for spectral occupancy have been developed. The procedures for measuring and modelling spectral occupancy are briefly presented, with final stable-day and stable-night models for northern Europe, when using calibrated monopole antennas. Accuracy of fit and examples of extrapolation in time and in space are presented. [ABSTRACT FROM AUTHOR]

An N–PLS regression technique was tested as an empirical downscaling method. Average monthly near-ground air temperature ( t), specific humidity ( q), and sea-level pressure ( p) fields across Central and Western Europe were used as predictors for average monthly air temperature ( T), dew temperature ( D), and precipitation amount ( P) at 4 locations in Slovenia. The empirical downscaling models (EM) were developed by means of available predictand data from the ARSO archive and predictor data from the NCEP/NCAR reanalysis project, for the period 1951–2002, separately for single months. Using the combination of t and p as predictors, the EM for T explained from 73% to 95% of predictand variability, for D from 74% to 97% of predictand variability, and for P from 31% to 76% of predictand variability. The use of q as an additional predictor did not improve the quality of the EM considerably. Developed EM using p and t as predictors were applied to the results of 5 general circulation models (GCM): CSIRO/Mk2, CCC/CGCM2, UKMO/HadCM3, DOE-NCAR/PCM, and MPI-DMI/ECHAM4-OPYC3. Only the simulations based on SRES A2 and B2 emission scenarios were considered in our calculations. Available mean monthly values of predictors for the period 1951–2100 were used. All the projections of GCM results indicate an increase in T and D and decrease in P in the 21st century at all 4 locations. The expected range of changes in T, D, and P is wide due to the different response of GCM to identical changes in the atmospheric composition, and represents a source of uncertainty in empirical downscaling results. Another important source of uncertainty in empirical downscaling studies, especially when temperature dependent predictors are used, is the problem of extrapolation. By using the proper mathematical approach for EM development we only reduce a part of the uncertainty related to the quality of empirical models that also strongly depend on the quality of input data and predictor selection. The N–PLS regression seems to be a suitable choice of mathematical method, as the feature selection from a large number of predictor time series is not predictand independent. Finally, any climate change and impact studies for the future are affected by many other uncertainties that we have to be fully aware of, while interpreting their results. [ABSTRACT FROM AUTHOR]

The main aim of this paper is to answer the research question, "Is the Gompertz model suitable for studying the diffusion of the ISO 22000 standard in Europe?" Forecasting models adopting the Gompertz model were developed to estimate to which extent the Food Safety Management Systems (FSMS) based on the ISO 22000 standard are expected to be implemented and certified in the European continent. To provide a forecast for the next few years, data from the diffusion of renowned ISO standards, namely, ISO 9001 and ISO 14001, were extrapolated in order to overcome the shortcoming since data concerning ISO 22000 certification was only available for the period 2007 to 2018. The results provide a cross-sectional portrayal of the European diffusion of ISO 22000 certification and suggest an interval of the estimated number of certificates issued in Europe. This research paper presents the first attempt to empirically analyze the dynamic of diffusion of the European ISO 22000 certification. A more accurate fitting with real results may be expected with further information available in the forthcoming years. [ABSTRACT FROM AUTHOR]

The article discusses the useful parameters in achieving a better understanding of the inflated prison population phenomenon in many European countries in December 1994. It says that the growing discrepancy between the rising number of prisoners and the capacity of prisons is extrapolated for the future. It says that many European countries were faced with a significant increment in their prison population during the 1980s. According to the author, the nature of the offenses in an essential factor in the consequences of the increasing length of detention and the declining number of committals. The increasing number of inmates in Portugal, Spain and Greece is also discussed.

• Fatal train accidents per train-kilometre in Europe fell at the rate of 6% per year from 1990 until 2019. • There were 0.85 fatal accidents per billion train-kilometres in 2019. • There was a mean of 4.2 fatalities per fatal accident in 1990–2019. • the proportion of accidents caused by signals passed at danger fell from 40 % in the 1990s to 21 % in the 2010s. This may be due to the increasing deployment of train protection systems. This paper presents an analysis of fatal train accident rates and trends on Europe's main line railways from 1990–2019. It is a sequel to the paper Fatal train accidents on Europe's railways: 1980–2009 (Evans (2011), which covers the three decades 1980–2009. The present paper discards the data for the 1980s, but adds the data for 2010−2019. The data cover the 28 countries of the European Union as in 2019, together with Norway and Switzerland. The source of the recent data is largely the European Union Agency for Railways. The estimated overall trend in the number of fatal train collisions and derailments per train-kilometre was –5.6 % per year from 1990–2019, with a 95 % confidence interval of –7.1 % to -4.2 %. The estimated accident rate in 2019 was 0.85 fatal collisions or derailments per billion train-kilometres, which represents a fall of 78 % since 1990. This gives an estimated mean number of fatal accidents in Europe in 2019 of 3.89. The data and results for 2010−2019 closely match the extrapolation of the results for 1990−2009, so that in 2009 extrapolation would have given a good forward projection for 2019. By the same argument this paper gives a forward projection of the mean number of accidents in 2029 of 2.12, assuming no change in train-kilometres, or pro-rata changes with changes in train-kilometres. The paper investigates the causes of accidents. A notable finding is that the proportion of accidents caused by signals passed at danger (SPADs) fell from 40 % in 1990−1999 to 21 % in 2010−2019. This is probably due to the increasing deployment of train protection systems. The number of fatalities in individual accidents has a skew distribution: most accidents have a small number of fatalities, but a few have a large number. The overall observed number of fatalities per accident is 4.23, and there is no indication that this mean changes with time. This implies that the mean number of fatalities per year has the same downward trend of 5.6 % per year as the mean number of accidents per year. [ABSTRACT FROM AUTHOR]

The 'totality-of-the-evidence' biosimilarity concept requires that sufficient structural, functional, nonclinical, and clinical data are acquired in a stepwise manner, to demonstrate that no clinically meaningful differences in quality, safety, or efficacy are observed compared with the reference product. We describe the totality of the evidence for PF-06438179/GP1111 (PF-SZ-IFX; IXIFI™ [infliximab-qbtx]/Zessly®) that supported its approval as an infliximab (IFX) biosimilar for all eligible indications of reference IFX (ref-IFX; Remicade®) in Europe and in the US. Analytical similarity involving in vitro assays capable of distinguishing structural or functional differences between PF-SZ-IFX and ref-IFX formed a foundation for the biosimilarity exercise. Differences identified in N-glycosylation and charge heterogeneity were found not to impact the results in in vitro biological assays reflective of the pharmacology underlying the mechanisms of action (tumor necrosis factor binding, reverse signaling, antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity) of IFX across disease indications. Similarity was assessed in a comparative clinical pharmacokinetic study and in a clinical efficacy and safety study in patients with rheumatoid arthritis, where therapeutic equivalence between PF-SZ-IFX and ref-IFX provided confirmatory evidence of biosimilarity, and, when coupled with the analytical similarity already established, supported extrapolation to all eligible disease indications of ref-IFX. [ABSTRACT FROM AUTHOR]

Single-particle energies of the Λc charmed baryon are obtained in several nuclei from the relevant self-energy constructed within the framework of a perturbative many-body approach. Results are presented for a charmed baryon-nucleon (YcN) potential based on a SU(4) extension of the meson-exchange hyperon-nucleon potential ˜A of the Jülich group. Three different models (A, B, and C) of this interaction, which differ only on the values of the couplings of the scalar σ meson with the charmed baryons, are considered. Phase shifts, scattering lengths, and effective ranges are computed for the three models and compared with those predicted by the YcN interaction derived by Haidenbauer and Krein [Eur. Phys. A 54, 199 (2018)] from the extrapolation to the physical pion mass of recent results of the HAL QCD Collaboration. Qualitative agreement is found for two of the models (B and C) considered. Our results for Λc nuclei are compatible with those obtained by other authors based on different models and methods. We find a small spin-orbit splitting of the p-, d-, and f-wave states as in the case of single Λ hypernuclei. The level spacing of Λc single-particle energies is found to be smaller than that of the corresponding one for hypernuclei. The role of the Coulomb potential and the effect of the coupling of the ΛcN and ΣcN channels on the single-particle properties of Λc nuclei are also analyzed. Our results show that, despite the Coulomb repulsion between the Λc and the protons, even the less attractive one of our YcN models (model C) is able to bind the Λc in all the nuclei considered. The effect of the ΛcN-ΣcN coupling is found to be almost negligible due to the large mass difference of the Λc and Σc baryons. [ABSTRACT FROM AUTHOR]

Introduction : The approval of rituximab, a monoclonal antibody targeting CD20, revolutionized the treatment of B-cell non-Hodgkin lymphomas and became an undisputed standard of care. However, as with all biologic medicines, the complex development and manufacturing process for rituximab have meant that the medicine attracts high treatment costs. Approved rituximab biosimilars have been comprehensively demonstrated to match the reference medicine. With the potential to increase access to biologic therapy, they have a key role in helping to improve patient outcomes in lymphoma care. Areas covered : In this review, we discuss the role of rituximab in the treatment of lymphoma. We explore development and regulatory requirements for biosimilar development and the potential impact of these medicines on access and sustainability. Focusing on biosimilars of rituximab, we examine in detail the evidence for biosimilarity for the two rituximab biosimilars that are approved in Europe and provide an overview of rituximab biosimilars currently in development. Expert opinion : We foresee a wider uptake of biosimilar medicines for lymphoma treatment over the next 5 years. The associated cost savings should be invested in broadening patient access to biological therapies, enabling wider use of more expensive treatment strategies and driving innovation in cancer care.

Objectives: To discuss considerations regarding the selection, prescribing, and monitoring of biosimilars in the clinical management of patients with inflammatory disorders., Methods: A search of the Internet as well as PubMed was conducted through August 2014 for information related to the clinical use of biosimilars in chronic inflammatory disorders using the keywords biosimilar, rheumatoid arthritis, juvenile idiopathic arthritis, psoriasis, psoriatic arthritis, Crohn׳s disease, ulcerative colitis, and ankylosing spondylitis. The European Medicines Agency (EMA) and US Food and Drug Administration (FDA) websites were searched for biosimilar guidelines., Results: Articles and guidelines relating to integrating biosimilars into the clinical management of patients with inflammatory disorders have been published by regulatory agencies, professional associations, healthcare providers, and others., Conclusions: The recent approval of the biosimilar infliximab in some countries makes biosimilars a reality for rheumatologists and others involved in the care of patients with inflammatory disorders. To successfully and confidently integrate biosimilars into clinical practice, physicians must understand factors such as variation in innovator/reference products, extrapolation of data, naming and labeling, interchangeability and automatic substitution, and pharmacovigilance., (Copyright © 2015 Elsevier Inc. All rights reserved.)

The regulation of biosimilars is a process that is still developing. In Europe, guidance regarding the approval and use of biosimilars has evolved with the products under consideration. It is now more than 3 years since the first biosimilar agents in oncology support, erythropoiesis-stimulating agents, were approved in the EU. More recently, biosimilar granulocyte colony-stimulating factors have received marketing approval in Europe. This review considers general issues surrounding the introduction of biosimilars and highlights current specific issues pertinent to their use in clinical practice in oncology. Information on marketing approval, extrapolation, labelling, substitution, immunogenicity and traceability of each biosimilar product is important, especially in oncology where patients are treated in repeated therapy courses, often with complicated protocols, and where biosimilars are not used as a unique therapy for replacement of e.g. growth hormone or insulin. While future developments in the regulation of biosimilars will need to address multiple issues, in the interim physicians should remain aware of the inherent differences between biosimilar and innovator products. [ABSTRACT FROM AUTHOR]

A biosimilar is intended to be highly similar to a reference biologic such that any differences in quality attributes (i.e., molecular characteristics) do not affect safety or efficacy. Achieving this benchmark for biologics, especially large glycoproteins such as monoclonal antibodies, is challenging given their complex structure and manufacturing. Regulatory guidance on biosimilars issued by the U.S. Food and Drug Administration, Health Canada and European Medicines Agency indicates that, in addition to a demonstration of a high degree of similarity in quality attributes, a reduced number of nonclinical and clinical comparative studies can be sufficient for approval. Following a tiered approach, clinical studies are required to address concerns about possible clinically significant differences that remain after laboratory and nonclinical evaluations. Consequently, a critical question arises: can clinical studies that satisfy concerns regarding safety and efficacy in one condition support "indication extrapolation" to other conditions? This question will be addressed by reviewing the case of a biosimilar to infliximab that was approved recently in South Korea, Europe, and Canada for multiple indications through extrapolation. The principles discussed should also apply to biosimilars of other monoclonal antibodies that are approved to treat multiple distinct conditions., (Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Biosimilars have the potential to lead to enormous cost savings in healthcare without reducing the level of care for patients. In Europe, biosimilars have to demonstrate comparability in an extensive biosimilarity exercise including analytical, preclinical and comparative clinical studies. By successfully completing the biosimilarity exercise, the biosimilar shows that all aspects that are considered relevant for the clinical activity of the product fall within the same range as observed for the innovator. It should be carefully considered whether the benefit of additional information from more comparative clinical studies weighs up to the additional barriers such studies create for biosimilars to enter clinical practice., (Copyright © 2014 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved.)