EU Approval Research Articles

Changes to the regulatory system for sports funding through the corporate tax system and the concentration of subsidies

Support through the corporate tax system is a very specific form of funding to promote the functioning of team sports. The basic idea of the mechanism is that profit-oriented companies can donate a larger part of their corporate tax to sports organisations. The scheme has been in operation in Hungary since 2011. Its introduction and fine-tuning required several legislative changes and EU approval. Its importance is reflected in the increase in the number of sports organisations in the respective sports. While funding is available to many sports organisations, in some cases it is quite concentrated. In our empirical research we sought to find out how the degree of concentration has changed over time. The degree of concentration has an impact on how balanced the competition is. One of the key values for sports services is the requirement of an uncertain output. The data reveal that over time the distribution has become more evenly balanced across all sport operators. The amount of funding for sports organisations has started to converge. According to these figures, there are several sports organisations with equivalent subsidies participating in the competition system. However, the majority of clubs with the highest subsidies tend to be the same from year to year. The allocation of grants is determined by the sports federation of the given sport according to the submitted applications. Decision-makers should pay particular attention to maintaining the balance of competition over a long period of time. To this end, the list of sporting organisations with the highest subsidies should be continuously assessed and revised.

12275 Effect Of Osilodrostat On Cardiovascular And Metabolic Manifestations Of Hypercortisolism In Patients With Non-Pituitary Cushing’s Syndrome: Findings From A Retrospective Observational Study (LINC 7)

Abstract Disclosure: N. Scheyer: Other; Self; Recordati Rare Diseases. J. Bertherat: Consulting Fee; Self; Novartis, HRA Pharma, Recordati Rare Diseases. B. Decoudier: Consulting Fee; Self; Recordati Rare Diseases. H. Lasolle: Speaker; Self; Recordati Rare Diseases. H. Lefebvre: Speaker; Self; Recordati Rare Diseases. D. Drui: None. C. Vaillant: None. J. Morera: None. F. Castinetti: Consulting Fee; Self; HRA Pharma Rare Diseases, Recordati Rare Diseases. Grant Recipient; Self; HRA Pharma Rare Diseases, Recordati Rare Diseases. J. Cristante: Grant Recipient; Self; HRA Pharma, Pfizer, Inc.. N. Chevalier: None. S. Fodil-Cherif: None. A. Antonellini: Employee; Self; Recordati Rare Diseases. W. Agbotounou: Employee; Self; Recordati Rare Diseases. A. Mueller: Employee; Self; Recordati Rare Diseases. A. Tabarin: Consulting Fee; Self; H Lundbeck A/S, Crinetics Pharmaceuticals, HRA Pharma, Recordati Rare Diseases. Introduction: Endogenous Cushing’s syndrome (CS) is associated with increased cardiovascular morbidity and mortality because of hypercortisolism. Osilodrostat, a potent oral 11β-hydroxylase inhibitor, is approved for patients (pts) with endogenous CS (EMA) and Cushing’s disease (CD; for whom pituitary surgery is not an option or has not been curative; FDA). The long-term safety and efficacy of osilodrostat has been demonstrated in Phase II (LINC 2, NCT01331239) and Phase III (LINC 3, NCT02180217; LINC 4, NCT02697734) studies of CD pts. Here, we investigated the effect of osilodrostat on clinical manifestations of hypercortisolism in a real-world, retrospective, observational study conducted in a heterogeneous patient population with non-pituitary CS (LINC 7; NCT05633953). Methods: Adult pts with non-pituitary CS who initiated osilodrostat prior to EU approval under the French Autorisation Temporaire d’Utilisation scheme and/or, once approved, in routine clinical practice were followed up retrospectively for up to 36 months. The primary endpoint was proportion of pts with mean urinary free cortisol (mUFC) ≤upper limit of normal (ULN) at week (W) 12, based on the modified intention-to-treat (mITT) population (pts with any cortisol measurement at W12 or not collected because of safety reasons). Secondary endpoints included cardiovascular and metabolic parameters, recorded every 4 or 12W, depending on clinical practice. No formal statistical hypothesis testing was performed; all analyses are descriptive. Results: 103 pts were enrolled (mean [SD] age: 59.3 years [15.5]; female 61.2% [n=63]; adrenal adenoma [16.5%, n=17/103; mITT: 9.6%, n=5/52], adrenocortical carcinoma [18.4%, n=19/103; mITT: 11.5%, n=6/52], macronodular adrenal hyperplasia [13.6%, n=14/103; mITT: 17.3%, n=9/52], ectopic adrenocorticotropic hormone secretion [51.5%, n=53/103; mITT: 61.5%, n=32/52]). Median (min-max) osilodrostat exposure and dose at baseline was 164.0 days (1-1178) and 5.0 mg/day (1-60), respectively. Median (min-max) osilodrostat dose at W12 and W36 was 6.0 mg/day (0-60) and 10.0 mg/day (0-120), respectively. 23/52 pts (44.2%; 95% CI 30.5-58.7) had mUFC ≤ULN at W12. Mean (95% CI) changes in cardiovascular and metabolic-related parameters from baseline to W12 and W36, respectively, were: systolic blood pressure (−5.7 [−17.9, −6.6] mmHg, n=29 and −6.3 [−19.0, −6.5] mmHg, n=11); diastolic blood pressure (−4.7 [−10.6, −1.1] mmHg, n=29 and −8.2 [−20.7, −4.3] mmHg, n=11); weight (−2.3 [−4.2, −0.4] kg, n=27 and −3.6 [−9.6, −2.5] kg, n=12); body mass index (−0.8 [−1.5, −0.2] kg/m2, n=27 and −1.2 [−3.2, −0.8] kg/m2, n=12). No new safety signals were identified. Conclusions: Findings from this real-world setting show that osilodrostat provides cortisol control alongside improvements in clinical manifestations of hypercortisolism in non-pituitary CS pts, alleviating the disease burden. Presentation: 6/1/2024

Oligometastatic non-small cell lung cancer: Impact of local and contemporary systemic treatment approaches on clinical outcome.

Oligometastatic (OMD) non-small cell lung cancer (NSCLC) is a distinct but heterogeneous entity. Current guidelines recommend systemic therapy and consolidation with local ablative therapy (LAT). However, evidence regarding the optimal choice of multimodal treatment approaches is lacking, in particular with respect to the integration of immunotherapy. This real-world study identified 218 patients with OMD NSCLC (2004-2023, prespecified criteria: ≤5 metastases in ≤2 organ systems) from three major German comprehensive cancer centers. Most patients had one (72.5%) or two (17.4%) metastatic lesions in a single (89.9%) organ system. Overall survival (OS) was significantly longer with a single metastatic lesion (HR 0.54, p = .003), and female gender (HR 0.4, p < .001). Median OS of the full cohort was 27.8 months, with 29% survival at 5 years. Patients who had completed LAT to all NSCLC sites, typically excluding patients with early progression, had a median OS of 34.4 months (37.7% 5-year OS rate) with a median recurrence-free survival (RFS) of 10.9 months (13.3% at 5 years). In those patients, systemic treatment as part of first-line therapy was associated with doubling of RFS (12.3 vs. 6.4 months, p < .001). Despite limited follow-up of patients receiving chemo-immunotherapy (EU approval 2018/2019), RFS was greatly improved by adding checkpoint inhibitors to chemotherapy (HR 0.44, p = .008, 2-year RFS 51.4% vs. 15.1%). In conclusion, patients with OMD NSCLC benefitted from multimodality approaches integrating systemic therapy and local ablation of all cancer sites. A substantial proportion of patients achieved extended OS, suggesting a potential for cure that can be further augmented with the addition of immunotherapy.

Insulin Icodec: First Approval.

Insulin icodec (AWIQLI®) is an ultra-long-acting basal insulin analogue that is being developed by Novo Nordisk for the treatment of diabetes mellitus. Administered once weekly as a subcutaneous injection, insulin icodec is designed to improve treatment adherence and glycaemic control relative to once-daily insulin analogues. On 7 March 2024, insulin icodec was approved in Switzerland for the treatment of diabetes mellitus in adults. Insulin icodec was approved in Canada on 12 March 2024 for the once-weekly treatment of adults with diabetes mellitus to improve glycaemic control and received EU approval in May 2024 for the treatment of diabetes mellitus in adults. This article summarizes the milestones in the development of insulin icodec leading to this first approval for diabetes mellitus.

Avelumab first-line maintenance (1LM) in patients (pts) with locally advanced or metastatic urothelial carcinoma (la/mUC) in the Czech Republic: Interim real-world results from a national reimbursement registry.

557 Background: Avelumab 1LM treatment is recommended by international guidelines as the standard of care for pts with la/mUC that has not progressed with 1L platinum-based chemotherapy (PBC) and has been approved in the EU since Jan 2021. In the Czech Republic, following EU approval, there is a requirement to provide real-world data for “highly innovative medicinal products” such as avelumab 1LM when reimbursement decisions are temporary. Obtaining reimbursement therefore requires the creation of a registry to collect real-world data. We report interim results from a retrospective analysis of a national reimbursement registry for avelumab 1LM in the Czech Republic. Methods: Registry data were collected by the Office of Health Insurance (KZP) for pts with la/mUC receiving avelumab 1LM in the Czech Republic between Oct 2021 and Jan 2023. The primary endpoint was overall survival (OS) from the start of avelumab 1LM (index date); secondary endpoints included progression-free survival (PFS) from the start of avelumab 1LM and safety. Descriptive statistics were used to analyze the data. OS and PFS were estimated using the Kaplan-Meier method. Results: 59 eligible pts with la/mUC were treated and documented. At data cutoff (Jan 3, 2023), median follow-up was 6.1 mo (range, 0-16.5). All pts were White; 43 were male and 16 were female. At the start of avelumab 1LM, median age was 71 y (range, 49-84) and 22 pts (37.3%) had visceral metastases. 1L PBC was cisplatin-based in 30 pts (50.8%), carboplatin-based in 24 (40.7%), and both (switched from cisplatin to carboplatin) in 5 (8.5%). Best response to 1L PBC was complete response in 5 pts (8.5%), partial response in 30 (50.8%), and stable disease in 24 (40.7%). Median time from the end of PBC to the start of avelumab was 4.1 wk (range, 1.0-44.0). Effectiveness data for avelumab 1LM are shown in the Table. OS and PFS data are immature, with only 14 pts (23.7%) having died or had disease progression at the time of analysis. 10 adverse events were reported in 9 pts (15.3%), including grade 3 infusion-related reaction (1 pt), grade 2 diarrhea (2 pts), and grade 2 nephritis, pneumonitis, and Addison disease (1 pt each). At last evaluation, 53 pts were alive, of whom 5 pts had started subsequent treatment. Conclusions: This is the first study of pts with la/mUC treated with avelumab 1LM in a real-world setting in the Czech Republic. These preliminary data agree with the results of the phase 3 JAVELIN Bladder 100 trial and other real-world studies, confirming the effectiveness and manageable safety profile of avelumab 1LM in la/mUC. Follow-up for OS is ongoing. [Table: see text]

An Investigation in the Comparability of the Exposure and Recommended Dose of Selected Pfizer Drugs in East Asian Countries: Is Mutual Usage of Clinical Data Among East Asian Countries Feasible?

The current regulatory path for new drug registration in East Asian countries has led to significant delay of the new medicines in these countries. A unified regulatory path and allowance of mutual usage of clinical data in East Asian countries would lead to cost saving in drug development and expedite the new drug registration in these countries. The objectives of the present analysis are to compare the approval dates of a selection of products developed by Pfizer in the United States and East Asian countries (China, Japan, Korea) and compare the pharmacokinetics and recommended doses of these products in East Asian countries. Eighteen products (20 drugs, 2 products with 2 combination drugs) with exposure data available in at least 2 of the 3 East Asian countries across different therapeutic areas were included in the analyses. The results showed that most products had delayed approval in East Asian countries (up to 8 years) after US or EU approval. No distinct differences were observed in the drug exposure and recommended doses for the selected products in East Asian countries. These results together with literature data of genetic similarity of the East Asian populations support the mutual usage of the clinical data in the East Asian countries for expedited regulatory submission and approval.

Results of health technology assessments of orphan drugs in Germany-lack of added benefit, evidence gaps, and persisting unmet medical needs.

The number of orphan drug (OD) approvals has increased sharply in Europe. In Germany, all ODs are initially subject to a limited assessment after market access. Their added benefit over the standard of care is accepted as established upon EU approval; a regular health technology assessment (HTA) is performed only in certain cases. We assessed whether the increase in OD approvals has led to improvements in patient-relevant outcomes as supported by the evidence submitted by market authorization holders (MAHs) for HTA in Germany. We also examined the extent to which these ODs address unmet medical needs. The results of limited assessments and regular HTAs of ODs in Germany (January 2011-September 2021, plus January-December 2023) were analyzed to determine their added benefit based on MAH-submitted dossiers. Added benefit was reported separately for each research question generated from the EU-approved therapeutic indications and any sub-indications (e.g., different subpopulations or control interventions) specified for HTA in Germany. Eighty-nine ODs (limited assessments: sixty-nine; regular HTAs: twenty) were evaluated in 175 research questions (limited assessments: ninety-seven; regular HTAs: seventy-eight). The added benefit granted in limited assessments was non-quantifiable in nearly eighty percent of the ninety-seven questions. In regular HTAs, no proof of added benefit was shown in fifty-four percent of the seventy-eight questions, mainly due to insufficient comparative data with the standard of care. Established treatments were available for fifty-eight percent of the seventy-eight questions; more than half of which addressed oncology indications (although these account for only eight percent of rare diseases). Due to evidence gaps in post-approval HTA, many ODs approved in the EU lack proof of added benefit in terms of improving patient-relevant outcomes. Moreover, most approved ODs are indicated for diseases with established treatments and oncology indications, while many unmet medical needs remain. Incentives are required to encourage research in areas of unmet medical need and to generate comparative data with the standard of care.

Impact of TBT on Marine Products Exports from Kerala in a Benefits and Foibles Settings Based on Primary Data Inferences

Seafood trade is a major item in the global trade of all products. The GATT has been replaced with the WTO for minimizing trade restrictions, but the irony is that in the ambit of WTO newer trade rules have been introduced in the form of TBT and other quality standards. Though it is possible for the Codex committee to introduce new guidelines and rules connected with trade. But the developed countries might change these stipulation as per their self-interest. The study is based on primary data collected from 30 processing-cum-export firms in the three districts of Kerala by using appropriate statistical techniques to endorse the benefits and foibles of the study. The EU approval has helped the firms to minimize rejections citing the implementation of the TBT standards by the importers. There were several factors that had led to these changes, apart from simple demand-supply dynamics and competitiveness. The impact of TBT on seafood exports of Kerala pointed towards strongness of its influence, particularly generating market diversification as its primary consequence of TBT stipulations. Market diversification, though is seemed a temporary solution, value addition and high unit value realisation are inevitable coping up mechanisms with a view to reducing the present high TBT impact index.

A Snapshot of the Management of Chronic Lymphocytic Leukemia in Italy. Preliminary Analysis on over 3000 Patients Enrolled in the Gimema CLL2121 Trial

In recent years the management of patients (pts) with chronic lymphocytic leukemia (CLL) has benefited from a deeper knowledge of the mechanisms underlying the disease and from the development of novel therapeutic approaches. That notwithstanding, local and national accessibility to drugs and tests may lead to distinct “real-world” practices in terms of management of pts that are worth of being recorded and compared to understand the degree of reproducibility and applicability of international guidelines. This could also be relevant for the design of future clinical trials, more tailored to the true patient's needs. To this end, within the GIMEMA cooperative study group the observational retrospective and prospective CLL2121 study (NCT04867915) has been designed with the objective of evaluating the diagnosis and management of CLL in all hematological centers in Italy through the assessment of: 1) the methods and the actual diagnostic/prognostic work-up capacity; 2) the algorithms applied to define disease progression and treatment requirements with respect to national and international guidelines; 3) the clinical and biological variables not strictly associated with CLL, but capable of influencing the clinical course and overall survival; 4) the true incidence of some rarer complications associated with CLL. The study consists of a collection of clinico-biological data from all pts with newly diagnosed CLL, small lymphocytic lymphoma (SLL) or CLL-like monoclonal B-cell lymphocytosis (MBL), according to the iwCLL 2018 criteria in Italy. The retrospective part aims at including all cases followed at the participating centers with a diagnosis between January 2010 and September 2021, while the prospective part will include all pts with a documented diagnosis of CLL, SLL or MBL between September 2021 and September 2025. In this pilot analysis of the study, we examined pts' demographics, diagnosis, treatment line and type. Data were collected using the REDCap electronic data capture platform, analyzed using the SAS software v.9.4 and reported as numbers and frequencies. Between 2 November 2021 and 28 June 2023, 3294 eligible pts were enrolled in 75 hematology centers (out of the total of 110 centers who will be activated during the study) across the entire Italian territory. At the time of the present report, 3033 pts had clinical data available for our preliminary analysis. The vast majority of pts registered (N=2599, 85.7%) belonged to the retrospective cohort while only a minority (N=434, 14.3%) to the prospective cohort. Pts had a median age of 68 years ranging from 29 to 97; 60% of pts were males. 2630 pts (86.8%) had a diagnosis of CLL, 187 (6.2%) of SLL and 214 (7.0%) of MBL (2 missing information). Among those with available results 112 pts (12.6%) were TP53 mutated, 526 (45.6%) del(13q) positive, 174 (14.9%) del(11q) positive, 142 (11.9%) del(17p) positive and 226 (20.4%) presented a trisomy 12. The majority of pts (57.6%) were untreated, while 42.4% have been treated. Within the latter subset, 67.3% of pts have received one line of therapy, 21.4% 2 lines of therapy, 11.3% ≥3 lines of therapy. The most common therapeutic regimens were the combination of chemotherapy with an anti-CD20 antibody (39.3%), mainly rituximab, and those based on BTK inhibitors (33.3%), mainly ibrutinib. Chemotherapy alone was used in 12% of pts. Only 5% of pts was treated with the BCL2 inhibitor venetoclax. In the remaining 10% of pts, other approaches were used. This is the initial report of a nation-based real-world data collection aimed at describing the biological and clinical features of pts diagnosed with CLL in virtually all Italian hematology centers starting from 2010. The pattern of treatments highlighted in our preliminary analysis, with a wide use of the watch &amp; wait policy and of chemoimmunotherapy, will help understand how the introduction of novel therapies impacted treatment habits also in light of the timing of the local reimbursement policy. The different time of drug access in Italy, typically delayed after the EU approval, may also have affected the limited use of venetoclax-based treatment. The continuous accrual of pts in this study will allow to obtain a close-to-registry vision of CLL management in Italy over time, in terms of coverage of the entire country but enriched with the granularity of the data and flexibility of the collection typical of a real-world study.

Pesticide residues with hazard classifications relevant to non-target species including humans are omnipresent in the environment and farmer residences

Intensive and widespread use of pesticides raises serious environmental and human health concerns. The presence and levels of 209 pesticide residues (active substances and transformation products) in 625 environmental samples (201 soil, 193 crop, 20 outdoor air, 115 indoor dust, 58 surface water, and 38 sediment samples) have been studied. The samples were collected during the 2021 growing season, across 10 study sites, covering the main European crops, and conventional and organic farming systems. We profiled the pesticide residues found in the different matrices using existing hazard classifications towards non-target organisms and humans. Combining monitoring data and hazard information, we developed an indicator for the prioritization of pesticides, which can support policy decisions and sustainable pesticide use transitions. Eighty-six percent of the samples had at least one residue above the respective limit of detection. One hundred residues were found in soil, 112 in water, 99 in sediments, 78 in crops, 76 in outdoor air, and 197 in indoor dust. The number, levels, and profile of residues varied between farming systems. Our results show that non-approved compounds still represent a significant part of environmental cocktails and should be accounted for in monitoring programs and risk assessments. The hazard profiles analysis confirms the dominance of compounds of low-moderate hazard and underscores the high hazard of some approved compounds and recurring “no data available” situations. Overall, our results support the idea that risk should be assessed in a mixture context, taking environmentally relevant mixtures into consideration. We have uncovered uncertainties and data gaps that should be addressed, as well as the policy implications at the EU approval status level. Our newly introduced indicator can help identify research priority areas, and act as a reference for targeted scenarios set forth in the Farm to Fork pesticide reduction goals.

The Changing Landscape for Human Absorption, Metabolism, and Excretion: Practical Experiences From a Data Analysis of 500 Studies.

Coincidental with the intensified regulatory and industry focus on the design and conduct of human absorption, metabolism, and excretion (hAME) studies in the past 12 months, we have recently completed our 500th cohort involving radiolabeled test item administration to humans. Here, we build upon a recent industry white paper in this journal1 and share some of our own experiences as a Contract Research Organization based upon collaborations with numerous pharma companies and their differing approaches to design and timing, to add further context to the discussion regarding hAME studies and the pivotal role that drug metabolism and pharmacokinetics plays. In this article, we explore how both changing relationships within the industry and shifting regulatory guidelines are impacting strategies, and compare EU and US pre-study approval requirements, before evaluating the trends from over 500 studies conducted at our global facilities conducted over more than 30 years. We conclude with a review of how improved technical capabilities and strategies are influencing the design and conduct of hAME studies, before speculating on some of the driving factors which may shape the direction they take in the future.

Budesonide delayed-release capsules to reduce proteinuria in adults with primary immunoglobulin A nephropathy

ABSTRACT Introduction Immunoglobulin A nephropathy (IgAN) is characterized by mesangial deposition of immune complexes containing galactose-deficient IgA1 (Gd-IgA1). This Gd-IgA1 is believed to originate from mucosally sited B cells, which are abundant in the Peyer’s patches-rich distal ileum. Nefecon is a targeted-release form of budesonide developed to act in the distal ileum, thereby exerting a direct action on the mucosal tissue implicated in the pathogenesis of the disease. Areas covered This review discusses IgAN pathophysiology and provides an overview of the current therapeutic landscape, focusing on Nefecon, the first drug to receive accelerated US approval and conditional EU approval for the treatment of patients with IgAN at risk of rapid disease progression. Expert opinion Nefecon trial data thus far have demonstrated a promising efficacy profile, with a predictable pattern of adverse events. Treatment with Nefecon for 9 months reduces proteinuria substantially (Part A of the Phase 3 trial and the Phase 2b trial). A nearly complete prevention of deterioration of renal function has been observed at 12 months in patients at greatest risk of rapid disease progression. Long-term data from Part B of the Phase 3 study will provide 24-month data, furthering understanding of the durability of the 9-month treatment course.

Experimental comparison of herbicide-free methods for weed management on railway tracks

Weed management on railway tracks is important to maintain function and operational safety, especially with regard to track stability and drainage. As the EU approval of the herbicide glyphosate expires in 2022, there is an urgent need for alternative weed management. Here, we investigated the potential of two thermal (hot water and freezing) and two mechanical approaches (manual weeding and mowing) for plant removal on tracks. Application of hot water at 10 L/m² resulted in a plant-damaging temperature of 55°C at up to 15 cm depth in the ballast. Freezing with dry ice did not go deep and only damaged aerial parts of plant when applied at up to 10 kg/m². Mechanical measures that uprooted the plants (force of 40 - 160 N) were more effective than those removing aerial plant parts only. In sum, mechanical approaches seem most promising for herbicide-free weed management on railway tracks.

CO60 Mortality Impact Following the EU Approval of Numerous Novel Non-Small Cell Lung Cancer (NSCLC) Therapies Between 2010-2020

CO60 Mortality Impact Following the EU Approval of Numerous Novel Non-Small Cell Lung Cancer (NSCLC) Therapies Between 2010-2020

Non-Road Mobile Machinery Emissions and Regulations: A Review

Non-Road Mobile Machinery (NRMM) incorporate a wide range of machinery, with or without bodywork and wheels, and are installed with a combustion engine and not intended for carrying passengers or goods on the road. These are used in many different sectors including construction, agriculture, forestry, mining, local authorities, airport and port ground operations, railways, inland waterways and within the household and gardening sector. This article presents a review of the state of knowledge with regard to non-road mobile machinery, particularly focusing on their regulation and the atmospheric emissions associated with them. This was undertaken as there is currently a lack of this information available in the literature, which is an oversight due to the potential for Non-Road Mobile Machinery to form a greater part of atmospheric emissions in the future, as other areas of emissions are tackled by regulations, as is outlined in the article. Emissions such as particulate matter (PM), carbon oxide (CO), carbon dioxide (CO2), hydrocarbons (HC), nitrogen oxides (NOx) and sulphur oxides (SOx) from NRMM contribute considerably to total emissions released into the air. NRMM are diverse in application, engine type and fuel use, and are therefore difficult to categorise. This leads to numerous issues when it comes to the control and regulation of their emissions. The most recent European and international regulations are outlined in this article. Due to the divergent nature of NRMM, their emissions profiles are highly varied, and in-use emissions monitoring is challenging. This has led to a lack of data and inaccuracies in the estimation of total emissions and emission inventories. It was assumed in the past that emissions from non-road sources did not contribute as significantly to total emissions as those from on-road sources. This assumption was partly due to the difficulty in gathering relevant data, and it was disproven in the 1990s by studies in The Netherlands, Finland and Sweden. It is now understood that NRMM will eventually surpass on-road vehicles as the leading source of mobile pollution due to the continuing efforts to reduce emissions from other sources. Many states worldwide gather emissions data from NRMM, and EU member states are required to report their emissions. As of January 2017, a new European regulation establishing limits for gaseous and particulate pollutants from NRMM applies, and this regulation also defines administrative and technical requirements for EU approval. The exact number of NRMM and the total amount of fuel they use is currently not known. In Ireland, for example, their fuel use has been reported under stationary boilers and engines. However, this results in the underestimation of emissions of some pollutants (NOx in particular) because emissions of air pollutants tend to be higher in mobile than in stationary machinery.

1543P A retrospective cross-sectional study of treatment patterns in small cell lung cancer (SCLC) in Europe 2018–2021

SCLC is an aggressive neuroendocrine malignancy with poor prognosis. Development of new effective treatments was limited until the emergence of immune checkpoint inhibitors. The anti-PD-L1 therapies, atezolizumab and durvalumab, received EU approval for 1st-line (1L) treatment of extensive stage SCLC (ES-SCLC) in 2019 and 2020, respectively. To better characterise the emerging treatment landscape, we investigated SCLC treatment patterns in France, Germany, Spain, Italy and the UK. The study included all adults aged ≥18 years who were diagnosed with ES-SCLC and received any systemic treatments between Q1 2018 and Q4 2021 from a representative, retrospective oncology database. Baseline characteristics and treatment regimens by year, line of therapy, and platinum-sensitivity status were described. Of 5832 eligible patients (1L=4898, 2L=804, 3L+=130), 3843 were male (65.9%), with a median age of 66 years. Most patients were diagnosed with stage IV disease (88.4%). The most common 1L regimens over 2018–2021 were platinum + etoposide combination chemotherapies (91.8%, 86.0%, 62.9%, 42.3%, respectively; Table). Use of a platinum-based regimen + atezolizumab increased from 2019 to 2021 (5.6%, 27.3%, 40.0%, respectively). In 2021, platinum + atezolizumab was the most common 1L regimen in Germany (54.8%), France (46.2%) and the UK (43.7%). In France, platinum + durvalumab was the second most common therapy in 2021, accounting for 30.3% of 1L regimens, but this combination was uncommon in Germany (2.7%), Spain (2.0%), the UK (0.4%) and Italy (0.3%). Uptake of immune checkpoint inhibitor use was also observed in 2L treatment between 2019–2021 (3.8%, 4.9%, 11.0%, respectively), equally distributed for both platinum-resistant and platinum-sensitive patients.Table: 1543PRegimens by year in 1L ES-SCLC in EuropeRegimen2018 (n=1176)2019 (n=1190)2020 (n=1329)2021 (n=1203)Platinum1 + etoposide1079 (91.7)1023 (86.0)835 (62.8)509 (42.3)Platinum mono30 (2.6)49 (4.1)43 (3.2)49 (4.1)Platinum1 + atezolizumab067 (5.6)363 (27.3)481 (40.0)Platinum1 + durvalumab006 (0.5)53 (4.4)Anti-PD-(L)1/anti-CTLA-4 mono or combo22 (0.2)8 (0.7)32 (2.4)63 (5.2)Etoposide mono18 (1.5)11 (0.9)9 (0.7)8 (0.7)Other347 (4.0)32 (2.7)41 (3.1)40 (3.3)Data are n (%). 1Platinum-based chemo. 2Includes atezolizumab, durvalumab, nivolumab, pembrolizumab, tremelimumab, ipilimumab. 3Includes platinum combos, non-platinum-based chemo, and other non-chemo treatments Open table in a new tab Data are n (%). 1Platinum-based chemo. 2Includes atezolizumab, durvalumab, nivolumab, pembrolizumab, tremelimumab, ipilimumab. 3Includes platinum combos, non-platinum-based chemo, and other non-chemo treatments Since approval, use of anti-PD-L1 inhibitor combination therapy as a 1L treatment of ES-SCLC in Europe increased, although the speed of uptake varied between countries.

ТРЕНДИ ЗАКОНОДАВЧОГО, НОРМАТИВНО-ПРАВОВОГО РЕГУЛЮВАННЯ ЄС СТОСОВНО ДОПУСКУ НА РИНОК СІЛЬСЬКОГОСПОДАРСЬКИХ ТРАНСПОРТНИХ ЗАСОБІВ

The purpose of the research is to summarize the trends of legislative, regulatory and legal regulation of the EU regarding the admission to the market of agricultural vehicles. Research methods - used methods of systematization and analysis of regulatory and legislative documents of the European Union on the admission to the market of agricultural and forestry vehicles. Research results. EU countries are taking a number of measures to increase the safety of cars at the legislative level. Such conditions are updated as the requirements for the development and manufacture of new models of agricultural and forestry vehicles, new technical and technological solutions of safety requirements are updated and the number of components, systems, technical units to which the requirements are established is expanded. For agricultural vehicles, the result was a new Regulation 167/2013 which applies to EU approval of agricultural and forestry tractors, their trailers and trailers, systems, components and individual technical units. In 2019, the EU countries submitted reports to the EU Commission on the operation of the regulation, which in turn must submit a report by 31.12.2022 with proposals for changes and updates of legislation, if necessary. Other agricultural machinery falls within the scope of Directive 2006/42 / EC of the European Parliament and of the Council on machinery, which also applies to mobile machinery and covers safety aspects of agricultural vehicles not covered by Regulation 167/2013. From 2019, the Machinery Directive is under revision. A draft regulation on mechanical engineering products was published in Brussels on 21.04.2021 (After the draft regulation of the European Commission was issued, discussions were held in parallel in the European Council and the European Parliament. Compromise amendments to the revision of the Machinery Directive 2006/42 / EU were voted and approved on 02.05.2022. The next step will be to start discussions and deliberations between the Commission, the Parliament and the Council of the EU to reach an agreement on the differences in mid-June 2022. Harmonization of road safety requirements for off-road mobile vehicles (NRMM) in the EU has been an important topic among politicians and other stakeholders for decades. A number of activities were carried out, in particular: A study commissioned by the Executive Agency for Small and Medium Business (EASME) in 2016 and published a report of the European Commission "EU study on harmonization of mobile traffic requirements" prepared by EASME consultant in 2019. In October 2021 A bilateral meeting was organized between the Industrial Working Group on Off-Road Mobile Technology (ITF NRMM) and representatives of the Commission of the Directorate General for Internal Market, Industry, Entrepreneurship and Small and Medium Business (DG GROW) to clarify some aspects of drafting proposals for establishment road requirements for NRMM. In the second quarter of 2022, the DG GROW Commission plans to prepare draft proposals for further discussion. Conclusions. EU countries are taking a number of measures to increase the safety of cars at the legislative level. This gives both producers and consumers of agricultural and forestry machinery a number of advantages: - no need for duplication / additional tests and / or documentation for placing machines on the market in several EU countries; - reduction of costs of manufacturers due to reduction of tests and terms of administration; - reduction of technical barriers to access to other EU markets with a small number of machines; - providing buyers with a wider range of goods to choose from; - reduction of supply chain costs, for example, in the absence of the need to add special kits for lighting and signaling, turning them into a burden for end users; - introduction of modern technical requirements in countries where this is not the case. Key words: safety requirements, EU directive, legislative acts, normative legal acts, EU regulations, agricultural and forestry vehicles, trends.

Opinion on the Safety of BioProtein® by the Scientific Panel on Animal Feed of the Norwegian Scientific Committee for Food Safety

Opinion on the Safety of BioProtein® by the Scientific Panel on Animal Feed of the Norwegian Scientific Committee for Food Safety

Phenotypic and Gene Expression Profiles of Embryo Development of the Ascidian Ciona robusta Exposed to Dispersants

Within EU approval policies, most dispersant ecotoxicity testing considers lethal concentrations for marine adult species, overlooking the embryotoxicological effects. Here we studied the ecotoxicity of two commercial dispersant formulations (dispersant A and B) on the embryogenesis of the ascidian Ciona robusta. Embryotoxicity and phenotypic alterations stated that dispersant B resulted more toxic than A (EC50 value of 44.30 and 160 μg mL−1, respectively) and induced severe larvae malformations at lower concentrations. Furthermore, the analysis of genes involved in different cellular response pathways indicated that those belonging to biotransformation were upregulated by dispersant A treatment, likely related to the presence of hydrocarbons. Instead, dispersant B induced cas8 gene downregulation, probably as a result of the prolonged exposure to mixture components. Our preliminary findings support the use of the C. robusta embryotoxicity test as a valuable tool for dispersant approval procedures, by providing sub-lethal responses on marine invertebrates closely related to vertebrates.

Accuracy of Two CE-Marked Blood Glucose Monitoring System Based on EN ISO 15197:2015

Blood glucose monitoring systems (BGMS) are essential for the management of diabetic patients. Although International Organization for Standardization (ISO) 15197:2015 criteria require rigorous monitoring of BGMS devices before commercialization, manufacturing quality standards may decline after FDA or EU approval. This work aimed to demonstrate the accuracy and precision of two BGMS devices currently available on the market. A laboratory study was conducted from June to August 2021 using two BGMS devices. One hundred samples were collected and evaluated according to ISO 15197:2015 guidelines. Over 95% accuracy was achieved by both devices using stricter ISO criteria (at least 95% of values within ±10 mg/dL or ±10% of the results of the reference measurement procedure). Analysis of the error grid showed that 99.5% of the results were in zone A. Surveillance of the accuracy and precision of BGMS devices after FDA and EU approval is an essential procedure to help patients and physicians manage glycemia and determine an appropriate outcome and personalized approach to diabetes treatment.