Published and unpublished evidence in coverage decision-making for pharmaceuticals in Europe: existing approaches and way forward

List of regulatory documents organized per country and list of publications. (PDF 274 kb

From market access to patient access: overview of evidence-based approaches for the reimbursement and pricing of pharmaceuticals in 36 European countries

Sources per country. (DOCX 34 kb

Spatial distribution of Dechlorane Plus and dechlorane related compounds in European background air

The highly chlorinated chemical Dechlorane Plus (DP) was introduced as a replacement flame retardant for Mirex, which is banned through the Stockholm Convention (SC) for its toxicity (T), environmental persistence (P), potential for bioaccumulation (B) and long-range environmental transport potential (LRETP). Currently, Dechlorane Plus is under consideration for listing under the Stockholm Convention and by the European Chemical Agency as it is suspected to also have potential for P, B, T and LRET. Knowledge of atmospheric concentrations of chemicals in background regions is vital to understand their persistence and long-range atmospheric transport but such knowledge is still limited for Dechlorane Plus. Also, knowledge on environmental occurrence of the less described Dechlorane Related Compounds (DRCs), with similar properties and uses as Dechlorane Plus, is limited. Hence, the main objective of this study was to carry out a spatial mapping of atmospheric concentrations of Dechlorane Plus and Dechlorane Related Compounds at background sites in Europe. Polyurethane foam passive air samplers were deployed at 99 sites across 33 European countries for 3 months in summer 2016 and analyzed for dechloranes. The study showed that synand anti-DP are present across the European continent (3 and 3 , respectively), including parts of the Arctic. This supports that these compounds have potential for long-range atmospheric transport to remote regions. The highest concentrations of Dechlorane Plus were observed in central continental Europe, with anti-DP fractions close to the commercial mixture of Dechlorane Plus. The only detected Dechlorane Related Compounds was Dechlorane-602, which was found in 27% of the samples (3 ). The measured concentrations and spatial patterns of Dechlorane Plus and Dechlorane-602 in air across Europe indicate the influence of primary sources of these compounds on background concentrations in European air. Future air monitoring efforts targeting dechloranes is needed in both background and source areas, including consistent temporal trends

Spatial variability and temporal changes of POPs in European background air

Concentration data on POPs in air is necessary to assess the effectiveness of international regulations aiming to reduce the emissions of persistent organic pollutants (POPs) into the environment. POPs in European background air are continuously monitored using active- and passive air sampling techniques at a limited number of atmospheric monitoring stations. As a result of the low spatial resolution of such continuous monitoring, there is limited understanding of the main sources controlling the atmospheric burdens of POPs across Europe. The key objectives of this study were to measure the spatial and temporal variability of concentrations of POPs in background air with a high spatial resolution (n = 101) across 33 countries within Europe, and to use observations and models in concert to assess if the measured concentrations are mainly governed by secondary emissions or continuing primary emissions. Hexachlorobenzene (HCB) was not only the POP detected in highest concentrations (median: 67 pg/m3), but also the only POP that had significantly increased over the last decade. HCB was also the only POP that was positively correlated to latitude. For the other targeted POPs, the highest concentrations were observed in the southern part of Europe, and a declining temporal trend was observed. Spatial differences in temporal changes were observed. For example, γ-HCH (hexachlorocyclohexane) had the largest decrease in the south of Europe, while α-HCH had declined the most in central-east Europe. High occurrence of degradation products of the organochlorine pesticides and isomeric ratios indicated past usage. Model predictions of PCB-153 (2,2’,4,4’,5,5’-hexachlorobiphenyl) by the Global EMEP Multi-media Modelling System suggest that secondary emissions are more important than primary emissions in controlling atmospheric burdens, and that the relative importance of primary emissions are more influential in southern Europe compared to northern Europe. Our study highlights the major advantages of combining high spatial resolution observations with mechanistic modelling approaches to provide insights on the relative importance of primary- and secondary emission sources in Europe. Such knowledge is considered vital for policy makers aiming to assess the potential for further emission reduction strategies of legacy POPs

Attributes of children and adolescents with avoidant/restrictive food intake disorder.

BackgroundAvoidant/Restrictive Food Intake Disorder (ARFID) is a comparatively new DSM-5 diagnosis. In an effort to better understand this heterogeneous patient group, this study aimed to describe the physical and psychological attributes of children and adolescents with ARFID, and to compare them to patients with full-threshold or atypical anorexia nervosa (AN).MethodsChildren and adolescents aged 7-to-19 years (N = 193) were examined upon presenting at a pediatric eating disorder center between July 2015 and December 2017. Data included diagnosis assessed via the semi-structured Eating Disorder Examination interview along with measures of anthropometrics, depression, anxiety, self-esteem, perfectionism and clinical impairment.ResultsCompared to AN and atypical AN (n = 87), patients with ARFID (n = 106) were significantly younger (12.4 vs. 15.1 years, p < .0001), male (41% vs. 15%, p < .0002), and were more likely to be diagnosed with at least one co-morbid DSM-5 diagnosis (75% vs. 61%, p = .04). Patients with ARFID were less likely to be bradycardic (4.7% vs. 24.1%, p < .0001), amenorrheic (11.1 and 34.7%, p = .001), admitted to the hospital (14.2% vs. 27.6%, p = .02), and have a diagnosis of depression (18.9% vs. 48.3%, p < .0001). Patients with ARFID were significantly less likely to experience acute weight loss vs. chronic weight loss as compared with those with AN or atypical AN (p = .0001). On self-report measures, patients with ARFID reported significantly fewer symptoms of depression, anxiety, perfectionism, clinical impairment, concerns about weight and shape, and higher self-esteem than patients with AN or atypical AN (all ps < .0001). No differences were observed by race, anxiety disorder, orthostatic instability, suicidal ideation, and history of eating disorder treatment.ConclusionsStudy results highlight the clinical significance of ARFID as a distinct DSM-5 diagnosis and the physical and psychological differences between ARFID and AN/atypical AN. The novel finding that ARFID patients are more likely than those diagnosed with AN to experience chronic, rather than acute, weight loss suggests important related treatment considerations

Reimbursement Status and Recommendations Related to Orphan Drugs in European Countries

Objective: To review the reimbursement recommendations issued by selected European health technology assessment agencies for orphan drugs and the reimbursement status of these drugs; to assess the relationship between the type of recommendation and reimbursement status. Methods: The list of orphan drugs to be included in the analysis was obtained from the European Medicines Agency and Orphanet. Seven European states were included in the analysis: Belgium, England, France, Germany, Poland, Scotland, and Spain. For all identified orphan drugs, relevant data on the reimbursement status and type of recommendation were collected for each country. The relationship between the type of recommendation and reimbursement status was evaluated separately for each considered country, using Cohen’s kappa coefficient for the measurement of agreement; sub-analyses for oncology and metabolic drugs were performed. Results: Most reimbursement recommendations for orphan drugs were positive (71%), while approximately 17% were negative and almost 13% were conditional. The highest percentage of positive reimbursement recommendations was observed in Spain (97%) and France (95%) and the highest percentage of negative reimbursement recommendations was revealed for Poland (49%). On average, 65% of the 163 analyzed orphan drugs were reimbursed from public funds. The highest number of reimbursed orphan drugs was observed in Germany (n = 148), while the lowest, in Poland (n = 41). Considering all analyzed drugs, the highest agreement between recommendations and reimbursement status was observed for Spain (value of 1), and the lowest, for Germany (κ = -0.03). Conclusions: On average, more than 60% of identified orphan drugs were reimbursed from public funds in the included countries, and the majority of reimbursement recommendations were found to be positive. The agreement between reimbursement recommendations and reimbursement status differed between the countries, but overall, it did not show any patterns, as it ranged from -0.03 to 1 (κ coefficient)

A proximity proteomics pipeline with improved reproducibility and throughput.

Proximity labeling (PL) via biotinylation coupled with mass spectrometry (MS) captures spatial proteomes in cells. Large-scale processing requires a workflow minimizing hands-on time and enhancing quantitative reproducibility. We introduced a scalable PL pipeline integrating automated enrichment of biotinylated proteins in a 96-well plate format. Combining this with optimized quantitative MS based on data-independent acquisition (DIA), we increased sample throughput and improved protein identification and quantification reproducibility. We applied this pipeline to delineate subcellular proteomes across various compartments. Using the 5HT2A serotonin receptor as a model, we studied temporal changes of proximal interaction networks induced by receptor activation. In addition, we modified the pipeline for reduced sample input to accommodate CRISPR-based gene knockout, assessing dynamics of the 5HT2A network in response to perturbation of selected interactors. This PL approach is universally applicable to PL proteomics using biotinylation-based PL enzymes, enhancing throughput and reproducibility of standard protocols

Implementation of Innovative Medical Technologies in German Inpatient Care: Patterns of Utilization and Evidence Development

A Correction to this article was published on 24 January 2022 https://doi.org/10.1186/s13012-022-01187-7Background: Innovative medical technologies are commonly associated with positive expectations. At the time of their introduction into care, there is often little evidence available regarding their benefits and harms. Accordingly, some innovative medical technologies with a lack of evidence are used widely until or even though findings of adverse events emerge, while others with study results supporting their safety and effectiveness remain underused. This study aims at examining the diffusion patterns of innovative medical technologies in German inpatient care between 2005 and 2017 while simultaneously considering evidence development. Methods: Based on a qualitatively derived typology and a quantitative clustering of the adoption curves, a representative sample of 21 technologies was selected for further evaluation. Published scientific evidence on efficacy/effectiveness and safety of the technologies was identified and extracted in a systematic approach. Derived from a two-dimensional classification according to the degree of utilization and availability of supportive evidence, the diffusion patterns were then assigned to the categories “Success” (widespread/positive), “Hazard” (widespread/negative), “Overadoption” (widespread/limited or none), “Underadoption” (cautious/positive), “Vigilance” (cautious/negative), and “Prudence” (cautious/limited or none). Results: Overall, we found limited evidence on the examined technologies regarding both the quantity and quality of published randomized controlled trials. Thus, the categories “Prudence” and “Overadoption” together account for nearly three-quarters of the years evaluated, followed by “Success” with 17%. Even when evidence is available, the transfer of knowledge into practice appears to be inhibited. Conclusions: The successful implementation of safe and effective innovative medical technologies into practice requires substantial further efforts by policymakers to strengthen systematic knowledge generation and translation. Creating an environment that encourages the conduct of rigorous studies, promotes knowledge translation, and rewards innovative medical technologies according to their added value is a prerequisite for the diffusion of valuable health care.TU Berlin, Open-Access-Mittel – 202

Pharmaceutical regulation in 15 European countries: review

In the context of pharmaceutical care, policy-makers repeatedly face the challenge of balancing patient access to effective medicines with affordability and rising costs. With the aim of guiding the health policy discourse towards questions that are important to actual and potential patients, this study investigates a broad range of regulatory measures, spanning marketing authorization to generic substitution and resulting price levels in a sample of 16 European health systems (Austria, Belgium, Denmark, England, Finland, France, Germany, Greece, Ireland, Italy, the Netherlands, Poland, Portugal, Scotland, Spain and Sweden). All countries employ a mix of regulatory mechanisms to contain pharmaceutical expenditure and ensure quality and efficiency in pharmaceutical care, albeit with varying configurations and rigour. This variation also influences the extent of publicly financed pharmaceutical costs. Overall, observed differences in pharmaceutical expenditure should be interpreted in conjunction with the differing volume and composition of consumption and price levels, as well as dispensation practices and their impact on measurement of pharmaceutical costs. No definitive evidence has yet been produced on the effects of different cost-containment measures on patient outcomes. Depending on the foremost policy concerns in each country, different levers will have to be used to enable the delivery of appropriate care at affordable prices

SARS-CoV-2 variants evolve convergent strategies to remodel the host response

SARS-CoV-2 variants of concern (VOCs) emerged during the COVID-19 pandemic. Here, we used unbiased systems approaches to study the host-selective forces driving VOC evolution. We discovered that VOCs evolved convergent strategies to remodel the host by modulating viral RNA and protein levels, altering viral and host protein phosphorylation, and rewiring virus-host protein-protein interactions. Integrative computational analyses revealed that although Alpha, Beta, Gamma, and Delta ultimately converged to suppress interferon-stimulated genes (ISGs), Omicron BA.1 did not. ISG suppression correlated with the expression of viral innate immune antagonist proteins, including Orf6, N, and Orf9b, which we mapped to specific mutations. Later Omicron subvariants BA.4 and BA.5 more potently suppressed innate immunity than early subvariant BA.1, which correlated with Orf6 levels, although muted in BA.4 by a mutation that disrupts the Orf6-nuclear pore interaction. Our findings suggest that SARS-CoV-2 convergent evolution overcame human adaptive and innate immune barriers, laying the groundwork to tackle future pandemics