European Regulatory Authorities Research Articles

Efficiency of working coveralls and chemical resistant gloves in reducing operator exposure to pesticides

AbstractPersonal Protective Equipment (PPE) is used to reduce exposure when working with chemicals. For pesticides, exposure scenarios comprise mixing and loading (M&L) and application. The exposure prediction model recommended by European regulatory agencies for operator risk assessments—the Agricultural Operator Exposure Model (AOEM) – is based on 48 operator exposure studies involving over 500 professional operators from 10 European countries in typical working situations to assess exposure under realistic field conditions. We used the AOEM data to assess the efficiency of exposure reduction resulting from wearing chemical-resistant nitrile gloves and non-certified working coveralls during M&L (tank and backpack sprayer), applications using groundboom and airblast spraying, and outdoor and indoor (greenhouse) applications using handheld sprayers. All studies indicated consistent and high exposure reduction > 90% for gloves and non-certified coveralls across all investigated scenarios. Exceptions were almost exclusively observed when an operator incorrectly used the PPE. The mean exposure reduction from all operators, including those that used PPE incorrectly, was 95.0% for gloves and 96.4% for polyester/cotton working coveralls during M&L, and 91.1% for gloves and 94.9% for non-certified coveralls during all application scenarios. This analysis confirms the essential role of PPE and non-certified working coveralls in reducing operator exposure to pesticides. Outliers indicate that operators need to be properly trained and adhere to label instructions to apply pesticides according to good agricultural practices.

Real-World Experience of Ceftobiprole for Community- and Hospital-Acquired Pneumonia from a Stewardship Perspective.

Ceftobiprole is a fifth-generation cephalosporin approved by European and American regulatory agencies for the treatment of community-acquired pneumonia (CAP) and hospital-acquired pneumonia (HAP). Ceftobiprole administration is useful in severe CAP as well as HAP where the potential is to save other β-lactams including carbapenems or linezolid/vancomycin in clinical practice. The aim of this study was to report the real-world evidence of ceftobiprole in patients with CAP and HAP in a single center. In this retrospective study, we included 159 patients with CAP or HAP: 105 (66%) had CAP and 54 (34%) had HAP. The median age was 70 years (IQR 60-77), the median Charlson Comorbidity Index was 5 (IQR 3-7.5) and baseline INCREMENT ESBL score was 8 (IQR 6-11). Ceftobiprole was mostly given as a combination treatment (77%) or as a carbapenem-sparing strategy (44%). There were no differences in mortality between shorter and longer duration of treatment (<7 days compared with ≥7 days (HR 1.02, C.I. 0.58-1.77, p = 0.93) or between first-line (HR 1.00, C.I. 0.46-2.17, p = 0.989) and second-line therapy. Ceftobiprole use in CAP or HAP in the real world is effective as a first- and second-line treatment as well as a carbapenem-sparing strategy. Further studies are needed to explore the full potential of ceftobiprole, including its real-world use in antimicrobial stewardship programs.

Neurologijos srityje vartojamų vaistinių preparatų klinikinių tyrimų tendencijos Lietuvoje ir Europoje

Background. As the global burden of neurological diseases has been increasing, clinical trials have become more important. Yet, no systematic analysis of clinical trials of neurological medicinal products has been done in Europe and, specifically, in Lithuania. The aim of this study is to evaluate the tendencies of characteristics and registration dynamics of clinical trials of neurological medicines in Europe and Lithuania.Materials and methods. Analysis of data from the clinical trials register of the European Union drug regulatory authorities (EudraCT) has been performed. Applications of clinical trials of neurological medicines included in the register during the period between 2012–2021 have been reviewed. The following aspects have been evaluated: the phase of the trial, the sponsor status, the neurological condition (indication), the expected sample size of the trial, the trial design, and the number of member countries.Results. 2,242 clinical trials of neurological medicines have been registered in Europe during the period of 2012–2021, and they comprised 6.49% of all clinical trials registered in Europe. The annual registration rates did not change significantly during the period of 2012–2021 (R² = 0.039; p = 0.606). The majority of the trials (72.18%) were sponsored by commercial pharmaceutical companies. Most trials (31.73%) were registered as phase I trials. The majority of the trials (363 (17.20%)) were clinical trials for Alzheimer’s disease and other dementias. During the period of 2012–2021, there was a significant decrease in the annual registration rate of clinical trials for Alzheimer’s disease and other dementias (R² = 0.751, p = 0.001) and an increase of clinical trials for myoneural junction and muscle diseases and motor neuron disease (R² = 0.582, p = 0.010 and R² = 0.635, p = 0.006, accordingly). Commercial trials had a higher planned number of subjects (p = 0.014). Multiple member states participated in commercial trials more frequently (p &lt; 0.001). Fifty-five clinical trials of neurological medicines were registered in Lithuania during the period of 2012–2021, and they comprised 8.08% of all clinical trials registered in Lithuania. The annual registration rate has decreased significantly (R² = 0.401, p = 0.049). Almost all trials in Lithuania (53 out of 55) were sponsored by commercial companies. The majority of trials (23 (42%)) were trials for demyelinating diseases of the CNS.Conclusions. The annual registration rates of trials of neurological medicines remain stable in Europe while decreasing in Lithuania. Commercial clinical trials have more participants, and are more commonly conducted in multiple member states.

Recent advances and current challenges of new approach methodologies in developmental and adult neurotoxicity testing.

Adult neurotoxicity (ANT) and developmental neurotoxicity (DNT) assessments aim to understand the adverse effects and underlying mechanisms of toxicants on the human nervous system. In recent years, there has been an increasing focus on the so-called new approach methodologies (NAMs). The Organization for Economic Co-operation and Development (OECD), together with European and American regulatory agencies, promote the use of validated alternative test systems, but to date, guidelines for regulatory DNT and ANT assessment rely primarily on classical animal testing. Alternative methods include both non-animal approaches and test systems on non-vertebrates (e.g., nematodes) or non-mammals (e.g., fish). Therefore, this review summarizes the recent advances of NAMs focusing on ANT and DNT and highlights the potential and current critical issues for the full implementation of these methods in the future. The status of the DNT in vitro battery (DNT IVB) is also reviewed as a first step of NAMs for the assessment of neurotoxicity in the regulatory context. Critical issues such as (i) the need for test batteries and method integration (from in silico and in vitro to in vivo alternatives, e.g., zebrafish, C. elegans) requiring interdisciplinarity to manage complexity, (ii) interlaboratory transferability, and (iii) the urgent need for method validation are discussed.

Effect of Peg-IFN on the viral kinetics of patients with HDV infection treated with bulevirtide

Background & AimsBulevirtide is a first-in-class entry inhibitor antiviral treatment for chronic hepatitis D. The viral kinetics during bulevirtide therapy and the effect of combining bulevirtide with pegylated-interferon (Peg-IFN) are unknown. MethodsWe used mathematical modelling to analyze the viral kinetics in two French observational cohorts of 183 patients receiving bulevirtide with or without Peg-IFN for 48 weeks. ResultsThe efficacy of bulevirtide in blocking cell infection was estimated to 90.3%, whereas Peg-IFN blocked viral production with an efficacy of 92.4%, albeit with large inter-individual variabilities. The addition of Peg-IFN to bulevirtide was associated with a more rapid virological decline, with a rate of virological response (>2 log of decline or undetectability) at week 48 of 86.9% (95% prediction interval [PI] = [79.7–95.0]), compared with 56.1% (95% PI = [46.4–66.7]) with bulevirtide only. The model was also used to predict the probability to achieve a cure of viral infection, with a rate of 8.8% (95% PI = [3.5–13.2]) with bulevirtide compared with 18.8% (95% PI = [11.6–29.0]) with bulevirtide + Peg-IFN. Mathematical modelling suggests that after 144 weeks of treatment, the rates of viral cure could be 42.1% (95% PI = [33.3–52.6]) with bulevirtide and 66.7% (95% PI = [56.5–76.8]) with bulevirtide + Peg-IFN. ConclusionsIn this analysis of real-world data, Peg-IFN strongly enhanced the kinetics of viral decline in patients treated with bulevirtide. Randomized clinical trials are warranted to assess the virological and clinical benefit of this combination, and to identify predictors of poor response to treatment. Impact and implicationsBulevirtide has been approved for chronic HDV infection by regulatory agencies in Europe based on its good safety profile and rapid virological response after treatment initiation, but the optimal duration of treatment and the chance to achieve a sustained virological response remain unknown. The results presented in this study have a high impact for clinicians and investigators as they provide important knowledge on the long-term virological benefits of a combination of Peg-IFN and bulevirtide in patients with CHD. Clinical trials are now warranted to confirm those predictions.

Commentary on Hey, Hunter, Muller et al. A Never-ending Story: Evaluating Evidence in Medicinal Product Decision Making

Decision making in medicinal product development and regulatory approval for marketing authorization are intended to be evidence based. While decision making based on evidence is documented to be a millennial old process, particularly for making legal and economic determinations, the nature and use of evidence continues to evolve, particularly when new technologies need to be factored in. The formal use of evidence for medicinal product evaluation has been in practice for less than 75 years and remains a dynamic process among all stakeholders. The nature of decision making for marketing authorization is particularly complex as it occurs on at least five levels: Causative, Generalizability, Clinical Significance, Risk to Benefit, and Value. Consequently, all stakeholders including product developers and regulatory authorities must communicate and coordinate to ensure functionality, as all are constantly learning to integrate new technologies, ever increasing knowledge of biology and disease, and improved understanding of the decision making process and its consequences. Structured interactions in the form of Scientific Advice with the European regulatory authorities were developed to facilitate knowledge sharing. The Scientific Advice process itself is dynamic and benefits from structured input on how it can better serve the needs and expectations of stakeholders. To that end, Hey, Hunter, Muller, et al provide suggestions in a manuscript following an initial consultative phase and then a peer review phase. The manuscript is an example of the type of engagement and good citizenship that can facilitate the efficient generation and use of evidence to support the complex decision making to which the evidence is applied.

Oromucosal spray products – Viscosity impact on spray performance evaluation

In recent years, the development of oromucosal drug delivery products has garnered significant attention as an opportunity for improved drug delivery and patient acceptance. Effective oromucosal drug delivery can be achieved through the combination of formulations with spray devices to tailor the administration.According to United States and European regulatory authorities, a drug product delivered and packed in a spray device is considered a combination product. This fact compels a full characterization of both the formulation and the spray device before submission. Herein, two formulations were tested using different spray designs, and the results showed low variability in the in-use actuations between formulations. The presence of Carbopol® increased the viscosity and density, requiring more priming and force to actuate, especially for device A with an actuator extension. Overall, the delivered doses were uniform and met acceptance criteria. The spray pattern of formulation 1 assembled with device A was a uniform circular plume at 30 mm, with a spray angle of 25.1° and a droplet size distribution (D90) between 591.3 and 650.5 μm.This study expects to support scientists on upcoming developments of oromucosal spray products, reinforcing the importance of investigating its quality attributes and their impact on spray performance since the early stages of development.

Evidence evaluated by European Food Safety Authority does not support lowering the temporary tolerable daily intake for bisphenol A.

The European Food Safety Authority (EFSA) recently derived a tolerable daily intake (TDI) for bisphenol A (BPA) of 0.2 ng/kg bw/day. There are several issues with EFSA's hazard assessment review process, including that it was based on a limited subset of relevant studies. Multiple public commenters on EFSA's draft evaluation of BPA, including several European regulatory agencies, noted these issues, yet they were not adequately addressed by EFSA in the final evaluation. The TDI for BPA was based on an intermediate immunotoxicity endpoint in mice that has not been observed in other species; there is no evidence that it is a precursor event to any downstream pathological outcome. The TDI is several orders of magnitude lower than estimates of safe doses of BPA established by agencies worldwide, including EFSA's temporary TDI (t-TDI) for BPA established in 2015. Overall, the EFSA hazard assessment review process has led to a conclusion that there are low-dose effects of BPA based on very few, lower quality experimental animal studies. This conclusion is not supported by the totality of the available evidence, which includes multiple high-quality studies not considered by EFSA and indicates that the t-TDI established in 2015 is protective of human health.

Off-Label Immunosuppressant Drugs in Solid Organ Transplantation.

Once a solid organ transplantation (SOT) has been performed, it is necessary to prescribe immunosuppressant medication to prevent graft rejection. This task has the peculiarity that many of these drugs do not have specific indications for transplant use in the technical data sheets. We performed a review of different immunosuppressive drugs' information available at European and American regulatory agencies in order to analyze the approved indications by the type of SOT. In our work, besides showing these differences between different indication approvals in different SOT modalities, we also attempted to reflect other differences under the approved indications according to age group, formulation type, geographical area, etc. Although consensus documents on the subject have been published, the access to immunosuppressants depends on each country's regulation and healthcare system, and off-label prescription is a reality that healthcare professionals need to be familiar with.

Association of semaglutide with risk of suicidal ideation in a real-world cohort.

Concerns over reports of suicidal ideation associated with semaglutide treatment, a glucagon-like peptide 1 receptor (GLP1R) agonist medication for type 2 diabetes (T2DM) and obesity, has led to investigations by European regulatory agencies. In this retrospective cohort study of electronic health records from the TriNetX Analytics Network, we aimed to assess the associations of semaglutide with suicidal ideation compared to non-GLP1R agonist anti-obesity or anti-diabetes medications. The hazard ratios (HRs) and 95% confidence intervals (CIs) of incident and recurrent suicidal ideation were calculated for the 6-month follow-up by comparing propensity score-matched patient groups. The study population included 240,618 patients with overweight or obesity who were prescribed semaglutide or non-GLP1R agonist anti-obesity medications, with the findings replicated in 1,589,855 patients with T2DM. In patients with overweight or obesity (mean age 50.1 years, 72.6% female), semaglutide compared with non-GLP1R agonist anti-obesity medications was associated with lower risk for incident (HR = 0.27, 95% CI = 0.200.32-0.600.36) and recurrent (HR = 0.44, 95% CI = 0.32-0.60) suicidal ideation, consistent across sex, age and ethnicity stratification. Similar findings were replicated in patients with T2DM (mean age 57.5 years, 49.2% female). Our findings do not support higher risks of suicidal ideation with semaglutide compared with non-GLP1R agonist anti-obesity or anti-diabetes medications.

Percutaneous Strategies in Structural Heart Diseases: Focus on Chronic Heart Failure.

Central Illustration : Percutaneous Strategies in Structural Heart Diseases: Focus on Chronic Heart Failure Transcatheter devices for monitoring and treating advanced chronic heart failure patients. PA: pulmonary artery; LA: left atrium; AFR: atrial flow regulator; TASS: Transcatheter Atrial Shunt System; VNS: vagus nerve stimulation; BAT: baroreceptor activation therapy; RDN: renal sympathetic denervation; F: approval by the American regulatory agency (FDA); E: approval by the European regulatory agency (CE Mark). Innovations in devices during the last decade contributed to enhanced diagnosis and treatment of patients with cardiac insufficiency. These tools progressively adapted to minimally invasive strategies with rapid, widespread use. The present article focuses on actual and future directions of device-related diagnosis and treatment of chronic heart failure.

The Impact of Transitory Climate Risk on Firm Valuation and Financial Institutions: A Stress Test Approach

Addressing recent calls by European regulatory and supervisory authorities, we develop a new bottom-up climate risk assessment method to examine the resilience of the European banking industry regarding transitory climate risks. We illustrate our approach by estimating the impact of a 50–100 EUR carbon tax per tCO2\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\ extit{tCO}_{2}$$\\end{document} equivalent on the valuation and default risk of STOXX Europe 600 firms. For about 5% of the sample firms, we find asset devaluation shocks larger than 30% and for about 16% of the firms probabilities of default (PDs) dropping below investment-grade level of 3%. At the sector level, our results yield asset devaluations shocks of 15–36% and new PDs of 5–34% for the six most affected sectors. Running a stress test on credit risk based on these results, we find a decrease in capital ratios between -1.2\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$-1.2$$\\end{document} and -1.6\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$-1.6$$\\end{document} percentage points for key regulatory capital ratios in the most adverse scenario while only addressing 36% of the bank’s total risk-weighted assets. Our analysis sheds light on the substantial transitory climate risk for asset portfolios of banks and contributes to the pressing question how to integrate climate risk into risk management and regulation of financial institutions.

Evaluation of Radon Action Plans: Searching for a Systematic and Standardised Method

Radon, a carcinogenic radioactive gas, is a leading cause of lung cancer according to the World Health Organization. European Member States are required to develop and implement National Radon Action Plans (RAPs) to address its dangerous health effects. However, assessing the effectiveness of these RAPs presents challenges for authorities. This study aims to explore the possibility of a systematic and standardised assessment method to evaluate the effectiveness of RAP strategies and its implementation. The method involved analysing the strategies of 27 EU Member States and the UK, conducting legal document analysis and group interviews with responsible authorities. Additionally, four regional workshops and one final European workshop were held. The research took place from March 2021 to May 2023. Findings indicate that evaluating RAP effectiveness is challenging due to limited existing common criteria or indicators. To address this, the study proposes guiding questions for each element required by the EU Directive, as well as additional questions related to education and training. This contribution benefits RAP owners and European regulatory authorities, supporting the development of effectiveness indicators for RAPs. By improving assessment methods, we can enhance the effectiveness of strategies in mitigating the risks associated with radon exposure.

Approval Delay in Drugs from Non-Global Company in Europe and Japan: Analysis of Novel Drugs for Hematologic Malignancies

Background: Since most therapeutic agents for hematologic malignancies are developed and first approved in the US, it is important for each country to review and approve these agents without delay. Recently, the number of drugs developed by non-global companies including biotech start-ups has increased. Most of these non-global companies are located in the US, and typically do not have offices outside of the US. Thus, it is possible that drugs developed by non-global companies are likely to be approved later in countries other than the US, including the EU. However, their characteristics have not been fully evaluated. Study Design and Methods: Using the public database of the Food and Drug Administration (FDA) from January 2011 to December 2020, new molecular entity (NME) drugs for hematological malignancies that were approved in the US during the relevant period were identified. Cellular products, including chimeric antigen receptor (CAR)-T cells, were excluded from this analysis. NMEs for hematological malignancies were divided into two categories according to the applicant company: NMEs from non-global companies (non-Global group) and NMEs from global companies (Global group). Global companies were defined as those with branches or headquarters in all following regions: the US, the EU, and Japan. The others were classified as non-global companies. Based on the public databases of Japanese regulatory agency (PMDA) and European regulatory agency (EMA), we estimated the rate at which these drugs remained unapproved (unapproved rate) using the Kaplan-Meier method. The unapproved rate of NMEs was compared between the non-Global and Global groups. Results: A total of 39 NMEs for hematologic malignancies approved in the US during the study period were identified. Of these, 13 (33%) NMEs were from non-global companies (non-Global group) and 26 (67%) NMEs were from global companies (Global group). The proportion of orphan drug (13/13 vs. 26/26, p=1.000) and priority review designation (12/13 [92%] vs. 22/26 [85%], p=0.648) were not significantly different between the non-Global and Global groups. In the non-Global group, 12 (92%) NMEs were from the companies headquartered in the US, while 10 (39%) NMEs were from the US companies in the Global group. The proportion of pivotal phase Ⅰ/Ⅱ trial used for marketing authorization in the US was significantly higher in the non-Global group (11/13 [85%] vs. 13/26 [50%], p=0.045). The proportion of pivotal trials enrolling Japanese participants was lower in the non-Global group (0/13) than in the Global group (6/26 [23%]), while the proportion was similar in the EU (9/13 [69%] in the non-Global group and 16/26 [62%] in the Global group). In the EU, the unapproved rate 2 years after the US approval was higher in the non-Global group (54% vs. 22%), but the 5-year unapproved rate was rather lower than that in the Global group (15% vs. 22%) (Figure 1a). Similarly, in Japan, the unapproved rate of NMEs in the non-Global group was higher at 2 years (92% vs. 65%), but rather slightly lower than that in the Global group at 5 years (20% vs. 35%) (Figure 1b). After the US approval, 9 (69%) of the 13 NMEs filed by non-global companies had subsequently partnered with or been acquired by the global companies. Discussion and Conclusion: In both the EU and Japan, drugs in the non-Global group had a higher unapproved rate at 2 years. Notably, 54% of the drugs in the non-Global group were not approved in the EU, even though the participation rate in the pivotal trial used for US approval was similar between the non-Global and Global groups in the EU. However, at 5 years, the unapproved rate had decreased to approximately 20% in both the EU and Japan, presumably due to the fact that lots of the non-global companies were subsequently partnered with or acquired by the global companies.

Use of gadolinium-based contrast agents in multiple sclerosis: a review by the ESMRMB-GREC and ESNR Multiple Sclerosis Working Group.

Magnetic resonance imaging (MRI) is the most sensitive technique for detecting inflammatory demyelinating lesions in multiple sclerosis (MS) and plays a crucial role in diagnosis and monitoring treatment effectiveness, and for predicting the disease course. In clinical practice, detection of MS lesions is mainly based on T2-weighted and contrast-enhanced T1-weighted sequences. Contrast-enhancing lesions (CEL) on T1-weighted sequences are related to (sub)acute inflammation, while new or enlarging T2 lesions reflect the permanent footprint from a previous acute inflammatory demyelinating event. These two types of MRI features provide redundant information, at least in regular monitoring of the disease. Due to the concern of gadolinium deposition after repetitive injections of gadolinium-based contrast agents (GBCAs), scientific organizations and regulatory agencies in Europe and North America have proposed that these contrast agents should be administered only if clinically necessary. In this article, we provide data on the mode of action of GBCAs in MS, the indications of the use of these agents in clinical practice, their value in MS for diagnostic, prognostic, and monitoring purposes, and their use in specific populations (children, pregnant women, and breast-feeders). We discuss imaging strategies that achieve the highest sensitivity for detecting CELs in compliance with the safety regulations established by different regulatory agencies. Finally, we will briefly discuss some alternatives to the use of GBCA for detecting blood-brain barrier disruption in MS lesions. CLINICAL RELEVANCE STATEMENT: Although use of GBCA at diagnostic workup of suspected MS is highly valuable for diagnostic and prognostic purposes, their use in routine monitoring is not mandatory and must be reduced, as detection of disease activity can be based on the identification of new or enlarging lesions on T2-weighted images. KEY POINTS: • Both the EMA and the FDA state that the use of GBCA in medicine should be restricted to clinical scenarios in which the additional information offered by the contrast agent is required. • The use of GBCA is generally recommended in the diagnostic workup in subjects with suspected MS and is generally not necessary for routine monitoring in clinical practice. • Alternative MRI-based approaches for detecting acute focal inflammatory MS lesions are not yet ready to be used in clinical practice.

WITHDRAWN: Letter to editor: Evidence evaluated by EFSA does not support lowering the temporary tolerable daily intake for bisphenol A

The European Food Safety Authority (EFSA) recently derived a tolerable daily intake (TDI) for bisphenol A (BPA) of 0.2 ng/kg bw/day. There are several issues with EFSA's hazard assessment review process, including that it was based on a limited subset of relevant studies. Multiple public commenters on EFSA's draft evaluation of BPA, including several European regulatory agencies, noted these issues, yet they were not adequately addressed by EFSA in the final evaluation. The TDI for BPA was based on an intermediate immunotoxicity endpoint in mice that has not been observed in other species; there is no evidence that it is a precursor event to any downstream pathological outcome. The TDI is several orders of magnitude lower than estimates of safe doses of BPA established by agencies worldwide, including EFSA's temporary TDI (t-TDI) for BPA established in 2015. Overall, the EFSA hazard assessment review process has led to a conclusion that there are low-dose effects of BPA based on very few, lower quality experimental animal studies. This conclusion is not supported by the totality of the available evidence, which includes multiple high quality studies not considered by EFSA and indicates that the t-TDI established in 2015 is protective of human health.

Regulatory measures when implementing a new medical device into the cosmetic surgery industry. A case example: Macrolane

Over the past two decades, the cosmetic surgery industry has experienced significant global growth. This expansion has piqued the interest of healthcare professionals and product manufacturers, both aiming to enhance accessibility to surgery for a broader demographic. This manuscript presents the case example of “macrolane” hyaluronic acid. This product was introduced into the cosmetic surgery industry in 2007 and then removed from the market in 2012 by the manufacturer. The manuscript also presents and discusses the regulatory measures that were enacted following the introduction of macrolane into the European market. Specifically, these regulatory measures involved: insurance, professional qualifications and training, clinician representatives, sanitation, safety, cooling-off periods, informed consent, and advertising. Within the manuscript, it is also highlighted that interests from different stakeholders can create tension in the cosmetic industry, specifically: 1. clients might ask for a product, and they need to be protected; 2. healthcare providers are seeking a profit, and are subject to liability; 3. product’s manufacturers, who are seeking to expand their market, need to pass through regulatory processes. In conclusion, we wish to raise awareness of the ethical issues related to the regulatory measures implemented by European regulatory agencies responsible for public health, especially during the launch of a new product. These ethical considerations encompass several aspects: establishing accountability for validating research authenticity, delineating the functions of compensatory systems, overseeing educational processes, and supervising advertising and marketing practices. It should be noted that the comprehensive exploration of these ethical matters falls outside the scope of this manuscript, as they pertain more to public affairs rather than the realm of cosmetic surgery itself. Therefore, the discourse on these matters is better suited for engagement by experts in political and social ethics. Level of Evidence: Level V, analysis of current regulatory practices.

Innovative tools and methods for toxicity testing within PARC work package 5 on hazard assessment.

New approach methodologies (NAMs) have the potential to become a major component of regulatory risk assessment, however, their actual implementation is challenging. The European Partnership for the Assessment of Risks from Chemicals (PARC) was designed to address many of the challenges that exist for the development and implementation of NAMs in modern chemical risk assessment. PARC's proximity to national and European regulatory agencies is envisioned to ensure that all the research and innovation projects that are initiated within PARC agree with actual regulatory needs. One of the main aims of PARC is to develop innovative methodologies that will directly aid chemical hazard identification, risk assessment, and regulation/policy. This will facilitate the development of NAMs for use in risk assessment, as well as the transition from an endpoint-based animal testing strategy to a more mechanistic-based NAMs testing strategy, as foreseen by the Tox21 and the EU Chemical's Strategy for Sustainability. This work falls under work package 5 (WP5) of the PARC initiative. There are three different tasks within WP5, and this paper is a general overview of the five main projects in the Task 5.2 'Innovative Tools and methods for Toxicity Testing,' with a focus on Human Health. This task will bridge essential regulatory data gaps pertaining to the assessment of toxicological prioritized endpoints such as non-genotoxic carcinogenicity, immunotoxicity, endocrine disruption (mainly thyroid), metabolic disruption, and (developmental and adult) neurotoxicity, thereby leveraging OECD's and PARC's AOP frameworks. This is intended to provide regulatory risk assessors and industry stakeholders with relevant, affordable and reliable assessment tools that will ultimately contribute to the application of next-generation risk assessment (NGRA) in Europe and worldwide.

ANMCO Position paper: Inclisiran: an innovative therapeutic approach for the clinical management of hypercholesterolemia

Research focused on lipid-lowering treatments has led to the development of new therapeutic options aimed at cardiovascular risk reduction. Gene silencing represents one of the most innovative approaches to reduce low-density lipoprotein cholesterol (LDL-C). Inclisiran is a small interfering RNA that inhibits proprotein convertase subtilisin/kexin type 9 synthesis and promotes LDL-C clearance by enhancing LDL-C receptor expression on hepatocyte cell surface. Several clinical studies have demonstrated inclisiran efficacy in terms of LDL-C reduction (~50%) with a dosage regimen of 300 mg administered twice a year after the first two doses administered at time 0 and after 90 days. Inclisiran use has recently been approved by the European and American drug regulatory agencies as a therapeutic option in addition to the maximum tolerated statin therapy in adults with primary hypercholesterolemia or mixed dyslipidemia who need further LDL-C reduction.

A regulatory robust conditional approach to measuring the efficiency of wholesale water supply and wastewater treatment services

A benchmarking evaluation instrument was designed with a European Union country regulatory authority for water supply and wastewater treatment services to determine the efficient operating cost of its service providers that operated in the wholesale market segment in the 2017–2021 period. To this end, the non-parametric Data Envelopment Analysis technique was adapted to a robust and conditional approach. The results point to similar mean efficiency scores between water supply and wastewater services in the five-year period, despite the greater heterogeneity in the latter. Furthermore, the estimated potential cost savings for both services ranged from about 2% to 3%.