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Therapeutical monoclonal antibodies are structurally and functionally complex, whereas the innovator's manufacturing processes are proprietary. With respect to the similarity assessment, a proposed biosimilar product needs to demonstrate a side-by-side comparison between the reference product (RP) and candidate product in terms of physicochemical properties and biological activities, as well as nonclinical and clinical outcomes. Here, a comprehensive analytical similarity assessment was performed for in-depth comparison of HLX04, China-sourced Avastin ® (CN-Avastin ® ), and Europe-sourced Avastin ® (EU-Avastin ® ) following a tier-based quality attribute (QA) evaluation. A series of orthogonal and state-of-the-art analytical techniques were developed for the assessment. Ten lots of HLX04 were compared with 29 lots bevacizumab RP. Referred to the characterization results, HLX04 is highly similar to the RPs with respect to physicochemical properties and biological functions. In addition, HLX04 was found with similar stability and degradation behaviors upon multiple stressed conditions to bevacizumab. Minor differences were observed in glycosylation, aggregates, FcγRIIIa(F), and FcγRIIIa(V) binding activities; nevertheless, they were evaluated and demonstrated not to impact clinical outcomes. According to the reported clinical results, the totality of evidence, including the pharmacokinetic, efficacy, safety, and immunogenicity, further shows that HLX04 is similar to CN-/EU-Avastin ® ., (© 2023. Springer-Verlag GmbH Germany, part of Springer Nature.)

The GM content in a food or feed product produced from or containing genetically modified organisms (GMO) has to be expressed in Europe in the form of a GM mass fraction. However, the most widely used quantification methods, based on PCR, are basically counting PCR-amplifiable DNA fragments in a sample extract. This paper outlines the requirements for obtaining comparable measurement results which are fit for regulatory decision-making. It introduces the concept of a reference measurement system which enables GMO analysis laboratories to relate their results to a universally accessible reference, thus establishing metrological traceability to a unique reference point. The conversion factors required for transforming data from one measurement unit into the other have to carry a minimum uncertainty and are anchored to specified certified reference materials. The establishment of such conversion factors and related calibration approaches to achieve comparable GM quantification results are sketched. Graphical abstract ᅟ.

Standardized and transparent priority setting in medicine, desirable as it is, will generally exacerbate inter-temporal equity problems arising from changes in treatment priorities: when can it be fair that the treatment of already waiting patients who would have had priority under an established system should be postponed (withheld) for an extended period of time to advance the treatment of others under a reformed system? The reform of the Eurotransplant system of priority setting in kidney allocation (ETKAS), which is in many respects ideal, is a case in point. To give due weight to new medical knowledge, waiting time after the onset of end state renal failure should change from a priority-enhancing to a priority-reducing factor. Since those who have gained in priority by waiting under the present system would be set back under the new, severe problems of transitional justice must be overcome when responding to advances in medical knowledge. The paper explores conceptually some possible ways of rule change and indicates their general relevance from an ethical and a practical point of view for future problems of medical resource allocation under transparent, standardized priority-setting rules.

Bioaccumulation of PFAS in aquatic organisms is an environmental problem of growing concern around the world. This problem has been tackled by regulatory bodies by proposing EQS for biota in EU water bodies and tolerable daily intake for food. The introduction of regulatory limits requires the availability of harmonised and validated analytical methods of sufficient sensitivity. This paper reviews recent advances in analytical methods for analysis of PFAS in aquatic organisms. The methods available for biota analysis are mostly based on three extraction procedures: ion-pair extraction, solvent liquid extraction, and alkaline digestion. The resulting extracts are then subjected to different clean-up or enrichment steps on solid adsorbents, for example graphitized carbon black, C(18), and WAX phases. All methods reviewed in this work give reliable results but are partially validated only, because of the lack of certified reference materials and regular interlaboratory exercises. The few interlaboratory exercises performed on real unspiked samples did not afford satisfactory results for PFAS other than PFOS, especially for matrices with high lipid content, for example mussels. The reasons for those partially negative results have been identified, and can mainly be attributed to calibration procedures and availability and purity of standards. The urgent need for certified reference materials for this type of analysis is emphasized.

Recently, several checklists systematically assessed factors that affect the transferability of cost-effectiveness (CE) studies between jurisdictions. The role of the threshold value for a QALY has been given little consideration in these checklists, even though the importance of a factor as a cause of between country differences in CE depends on this threshold. In this paper, we study the impact of the willingness-to-pay (WTP) per QALY on the importance of transferability factors in the case of smoking cessation support (SCS). We investigated, for several values of the WTP, how differences between six countries affect the incremental net monetary benefit (INMB) of SCS. The investigated factors were demography, smoking prevalence, mortality, epidemiology and costs of smoking-related diseases, resource use and unit costs of SCS, utility weights and discount rates. We found that when the WTP decreased, factors that mainly affect health outcomes became less important and factors that mainly effect costs became more important. With a WTP below 1,000, the factors most responsible for between country differences in INMB were resource use and unit costs of SCS and the costs of smoking-related diseases. Utility values had little impact. At a threshold above 10,000, between country differences were primarily due to different discount rates, utility weights and epidemiology of smoking-related diseases. Costs of smoking-related diseases had little impact. At all thresholds, demography had little impact. We concluded that, when judging the transferability of a CE study, we should consider the between country differences in WTP threshold values.

This paper analyses the effect of absolute deductibles on the cost of insurance for outpatient services. Moreover, cost savings on retained losses are estimated. Sharing risks between the insured and the insurer reduces total expenditure for outpatient benefits by up to 35%. In particular, optimal deductibles are determined in their utilitarian sense: the maximum possible savings on medical expenses are computed from the ground up. As part of the study, the effect of age and gender on these savings is analysed. The analysis is based on data taken from the private medical insurance industry in Germany. Similarities and discrepancies with respect to results obtained in the RAND Health Insurance Experiment conducted in the United States from 1971 to 1982 are highlighted.

This analysis aims to get a step further in the understanding of the determining factors of social health inequalities, and to explore particularly the role played by parents' social status and their vital status or age at death on the social health inequalities in adulthood among European older adults. The wealth-related health inequalities are measured using the popular concentration index. We then implement the decomposition method of the indices and evaluate the contribution of the various determinants of health introduced in interval regression models. Health is measured using self-assessed health and country-specific cut-points that correct observed differences in self-report due to cross-cultural differences in reporting styles. This paper uses data for ten European countries from the first wave of the 2004 SHARE. The study highlights significantly higher wealth-related health inequalities in the Netherlands, Denmark and Germany. These social inequalities of health in Europe are explained largely by individuals' current social conditions, particularly wealth. Nevertheless, our analysis attests the existence of a long-term influence of initial conditions in childhood on health in middle-aged and beyond, independently of current social characteristics, which contribute to differences in health status across social groups. This article contributes to the identification of social determinants, which are important determinants of health and follows recommendations suggested to help 'close the gap' in various health inequities.

The structure and methods to complete and derive a quality score from the European Network of Health Economic Evaluation Databases (EURONHEED) transferability information checklists for published economic evaluations were reported and discussed in a previous paper (Boulenger et al. in Eur J Health Econ 6, 334-346, 2005). Within the same paper, the use of the checklists was illustrated through their application to a sample of economic evaluations conducted in France and UK. The transferability information subchecklist, consisting of 16 items from the original 42-point checklist, and methods used to derive it, were validated among 16 health economists across Europe participating in the EURONHEED project. Recent correspondence with other researchers, however, indicates that the checklists are now being utilised in empirical work and the methodology of assessing transferability and generalisability. This supplementary paper provides full details of the guidelines that have been developed and recently updated by the authors, such that the overall and subchecklists can be more widely and consistently completed and utilised. We also briefly discuss associated issues such as weighting of items in the checklists and give further clarifications regarding what we consider the most appropriate applications of the checklists to be.

This paper is an introduction to the study "The Burden of Rheumatoid Arthritis and Patient Access to Treatment". The objective of the study is to compare patient access to new drugs in Europe, North America and a selection of other countries, and to analyse the determinants of differences between countries, as basis for a discussion on how patients' access to new and effective treatments can be improved. There were few treatments available that could affect the progression of the disease prior to the introduction of the first TNF inhibitors in the late 1990s. Since the cost per patient treated with these biological drugs is high compared to previously available treatments, reimbursement through private and public insurance is an important determinant for access to treatment.

The aim of this methodological paper is to summarize evidence on how to implement cost-benefit assessment according to the new German legislative framework (Competition Enhancement Act). Given the complexity of existing health policy frameworks within industrialised countries in adapting health economics in their respective regulatory scheme, no clear international scientific consensus on which health economic methods should be chosen for assessment can be determined. Nevertheless, a broad consensus on the internal properties of methods itself can be found. Based on these common international standards in methodology, this work provides a minimum catalogue of methods and criteria that meet legal and local German requirements with regard to specific factors of its health care system. Aside from categorising clearly defined standards (e.g., study forms, cost and benefit categories) the suggested catalogue specifies some intensively debated areas in Germany (e.g., the QALY, modelling, the perspective used in the assessment). After the proposition of certain methods the paper leads to a first recommendation of a detailed assessment-process itself specific for the German way in implementing cost-benefit ratios within regulatory decision making in Germany.

The objective of this study was to determine the prevalence of neck pain (NP) in the world population and to identify areas of methodological variation between studies. A systematic search was conducted in five databases (MEDLINE, EMBASE, CINAHL, OSH-ROM, and PsycINFO), followed by a screening of reference lists of relevant papers. Included papers were extracted for information and each paper was given a quality score. Mean prevalence estimates were calculated for six prevalence periods (point, week, month, 6 months, year, and lifetime), and considered separately for age, gender, quality score, response rate, sample size, anatomical definition, geography, and publication year. Fifty-six papers were included. The six most commonly reported types of prevalence were point, week, month, 6 months, year, and lifetime. Except for lifetime prevalence, women reported more NP than men. For 1-year prevalence, Scandinavian countries reported more NP than the rest of Europe and Asia. Prevalence estimates were not affected by age, quality score, sample size, response rate, and different anatomical definitions of NP. NP is a common symptom in the population. As expected, the prevalence increases with longer prevalence periods and generally women have more NP than men. At least for 1-year prevalence Scandinavian countries report higher mean estimates than the rest of Europe and Asia. The quality of studies varies greatly but is not correlated with the prevalence estimates. Design varies considerably and standardisation is needed in future studies.