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Older people are often affected by impaired organ and bodily functions resulting in multimorbidity and polypharmacy, turning them into the main user group of many medicines. Very often, medicines have not specifically been developed for older people, causing practical medication problems for them like limited availability of easy to swallow formulations, easy to open packaging and dosing instructions for enteral administration. In 2020, the European Medicines Agency (EMA) published a reflection paper 'Pharmaceutical development of medicines for use in the older population', which discusses how the emerging needs of an ageing European population can be addressed by medicines regulation. The paper intends to help industry to better consider the needs of older people during pharmaceutical/clinical medicines development by summarising data on the most relevant topics, providing early suggestions on how to move forward and prompting expert discussions and studies into knowledge gaps. Topics include patient acceptability, (dis)advantages of an administration route, formulation, dosage form, packaging, dosing device and user instruction. While the paper is directed at older people and the pharmaceutical industry, the reflections are also relevant to younger patients with similar disease‐related needs and of value to other stakeholders parties, e.g., healthcare professionals, academics, patients and caregivers, as the paper makes clear what can be expected from industry and where collaborative work is needed. This commentary provides an overview of the different steps in the development of the reflection paper, discusses points considered most controversial and/or subject to (multidisciplinary) expert discussions and indicates their value for real world clinical practice. [ABSTRACT FROM AUTHOR]

Liraglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist used for the management of type 2 diabetes and obesity. It was the first GLP-1 receptor agonist to be approved by the US Food and Drug Administration and the European Medicines Agency for the treatment of obesity. To date, numerous skin adverse reactions to liraglutide have been reported, but data regarding hypersensitivity reactions are scarce, raising concerns about its safety and clinical management. We present the case of a 56-year-old female patient with class 3 obesity who was started on subcutaneous liraglutide (Saxenda) by her endocrinologist. One month after starting the aforementioned treatment, the patient presented well-defined, round, erythematous pruriginous plaques surrounding the injection site, around 24 hours after the drug administration. A liraglutide-induced, delayed-type hypersensitivity reaction was suspected, which could be subsequently confirmed by allergy testing and histopathological study. This paper explores the clinical use of liraglutide, the occurrence of hypersensitivity reactions, diagnosis, management, and implications for future research. Understanding and managing liraglutide hypersensitivity is crucial to ensuring the safety and efficacy of this medication. [ABSTRACT FROM AUTHOR]

Analytical method validation is the process of verifying a method for its purpose of fit, whether it suffices its intended application or not. Analytical method validation is a mandatory requirement to be fulfilled for measuring critical quality attributes (CQA) during the manufacturing process to get a drug approval for human, and veterinary use. As the drug approval process differs from one country to another in a similar way method validation guidelines also differ from one country to another, these requirements will be added as your country of approval differs, In the present review an attempt was made to bring all method validation guidelines in a comparative manner by comparing country-specific requirements these countries/organizations hold the major pharma market and the Stringent regularity countries. The paper majorly focuses on the analytical method used in the Biosimilar manufacturing process and its validation approach by comparing the method validation guidelines from the International Council for Harmonisation of Technical Requirements of Pharmaceuticals for Human Use (ICH), USA, European Medicines Agency (EMA), Japan and India with the CQAs monitored during the biosimilar manufacturing process. [ABSTRACT FROM AUTHOR]

We have developed a method to determine the limit of detection (LoD) for quantitative measurement of exogenous analytes in the outer layer of the human skin by in vivo confocal Raman spectroscopy. The method is in accordance with the guidelines of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use that have been adopted by regulatory authorities such as the American Food and Drug Administration and the European Medicines Agency. The method can be applied in silico so that the limit of detection can be assessed before starting a skin penetration study, for example, in areas of pharmaceutical formulation, pharmacokinetics, or toxicokinetics. This can significantly reduce the need for expensive and time-consuming feasibility studies. This paper describes the method to calculate this LoD as well as the experimental and methodological factors that can influence the calculation of the LoD. [ABSTRACT FROM AUTHOR]

Background: The new European Medicines Agency (EMA) Clinical Trials Information System (CTIS), based on the Clinical Trials Regulation (CTR EU 536/2014), came into full effect on 31 January 2022 and was intended to provide an easier, more streamlined approach to the registration of clinical trials taking place in Europe. Using the experience gained on the new regulatory framework from three multi-national European clinical research studies of outbreak-prone infectious diseases, this article describes the advantages and shortcomings of the new clinical trial submission procedure. Methods: We report the time to approval, size of the application dossier, and number of requests for information (RFIs) for each study. We also explore the experience of each study within the regulatory framework and its use of CTIS to document the real-world, practical consequences of the system on individual studies. The study assesses the experience of three multi-country studies conducted in Europe working within the EU and non-EU regulatory environments. Results: While the time to regulatory and ethical approval has improved since the implementation of the new regulation, the timelines for approvals are still unacceptably slow, particularly for studies being conducted in the context of an evolving outbreak. Within the new regulatory approval procedure, there is evidence of conflicting application requirements, increased document burden, barriers to submitting important modifications, and debilitating technical hurdles. Conclusions: CTIS promised to lower the administrative bar, but unfortunately this has not been achieved. There are challenges that need to be urgently confronted and addressed for international research collaborators to effectively manage health crises in the future. While the value of multi-national outbreak research is clear, the limitations and delays imposed by the system, which raise challenging ethical questions about the regulation, are prejudicial to all clinical research, especially publicly funded academic studies. This report is relevant to both regulators and clinical researchers. It is hoped that these findings can help improve pan-European clinical trials, especially for the purpose of epidemic preparedness and response. Trial registration: This paper references experiences gained during management of three pan-European trials: EU-SolidAct's Bari-SolidAct (CT No. 2022-500385-99-00 - 15 March 2022) and AXL-SolidAct (CT No. 2022-500363-12-00 - 19 April 2022), and MOSAIC (CT No. 2022-501132-42-00 - 22 June 2022). [ABSTRACT FROM AUTHOR]

Background: CT-P43 is a candidate ustekinumab biosimilar in clinical development. Objectives: This paper aims to demonstrate equivalent efficacy of CT-P43 to originator ustekinumab in adults with moderate to severe plaque psoriasis. Methods: This double-blind, phase III trial randomised patients (1:1) to receive subcutaneous CT-P43 or originator ustekinumab (45/90 mg for patients with baseline body weight ≤ 100 kg/> 100 kg) at week 0 and week 4 in Treatment Period I. Prior to week 16 dosing in Treatment Period II, patients receiving originator ustekinumab were re-randomised (1:1) to continue originator ustekinumab or switch to CT-P43; patients initially randomised to CT-P43 continued receiving CT-P43 (at weeks 16, 28 and 40). The primary endpoint of the trial was mean per cent improvement from baseline in Psoriasis Area Severity Index (PASI) score at week 12. Equivalence was concluded if confidence intervals (CIs) for the estimate of treatment difference were within pre-defined equivalence margins: ± 10% [90% CI; modified intent-to-treat set; Food and Drug Administration (FDA) approach] or ± 15% [95% CI; full analysis set for patients only receiving 45 mg doses in Treatment Period I; European Medicines Agency (EMA) approach]. Additional efficacy, pharmacokinetic, safety and immunogenicity endpoints were evaluated through week 52. Results to week 28 are reported here. Results: In Treatment Period I, 509 patients were randomised (CT-P43: N = 256; originator ustekinumab: N = 253). The mean per cent improvement in PASI score at week12 was 77.93% and 75.89% for CT-P43 and originator ustekinumab, respectively (FDA approach); per the EMA approach, corresponding values were 78.26% and 77.33%. Estimated treatment differences were 2.05 (90% CI −0.23, 4.32) and 0.94 (95% CI −2.29, 4.16); equivalence was achieved for both sets of assumptions. Further efficacy parameters and pharmacokinetic, safety and immunogenicity outcomes were comparable between treatment groups, including after switching from originator ustekinumab to CT-P43. Conclusions: CT-P43 demonstrated equivalent efficacy to originator ustekinumab in patients with moderate to severe plaque psoriasis, with comparable pharmacokinetic, safety and immunogenicity profiles. Clinical Trial Registration: ClinicalTrials.gov Identifier: NCT04673786; date of registration: 17 December, 2020 [ABSTRACT FROM AUTHOR]

This paper presents the theoretical calculations of the inclusion complex formation between native ceftobiprole, a promising antibiotic from the cephalosporin group, and selected cyclodextrins (CDs) approved by the European Medicines Agency. Ceftobiprole was studied in three protonation states predicted from pKa calculations, along with three selected CDs in a stoichiometric ratio of 1:1. It was introduced into the CD cavity in two opposite directions, resulting in 18 possible combinations. Docking studies determined the initial structures of the complexes, which then served as starting structures for molecular dynamics simulations. The analysis of the obtained trajectories included the spatial arrangement of ceftobiprole and CD, the hydrogen bonds forming between them, and the Gibbs free energy (ΔG) of the complex formation, which was calculated using the Generalised Born Surface Area (GBSA) equation. Among them, a complex of sulfobutyl ether- (SBE-) β-CD with protonated ceftobiprole turned out to be the most stable (ΔG = −12.62 kcal/mol = −52.80 kJ/mol). Then, experimental studies showed changes in the physiochemical properties of the ceftobiprole in the presence of the CDs, thus confirming the validity of the theoretical results. High-performance liquid chromatography analysis showed that the addition of 10 mM SBE-β-CD to a 1 mg/mL solution of ceftobiprole in 0.1 M of HCl increased the solubility 1.5-fold and decreased the degradation rate constant 2.5-fold. [ABSTRACT FROM AUTHOR]

The regulatory standards of the United States Food and Drug Administration (FDA) require substantial evidence of effectiveness from adequate and well-controlled trials, for drugs developed in both adults and children. However, when scientifically justified, relying on extrapolation may be acceptable. Historically, the FDA's extrapolation approach was based on draft guidance published in 2014, which introduced the categories of full, partial, and no extrapolation. The European Medicines Agency (EMA) took a different view on pediatric extrapolation. To better understand the use of extrapolation to support pediatric drug development and approval, we reviewed the pediatric labeling changes published by the FDA, focusing on the labeling updates between 1/1/2015 and 7/31/2021, the period where the extrapolation approach is in transition to harmonize with the EMA. Within this time window, among the 265 drugs and biological products with pediatric labeling changes, 169 (63.8%) were identified where extrapolation was used. This includes 64 (24.2%) labeling changes, where full extrapolation was used, and 105 (39.6%) labeling changes, where partial extrapolation was used. The major disease areas that extrapolation was used include neuroscience (40/53, 75.5%) and infectious disease (20/28, 71.4%). The extrapolation approach was identified in terms of source population beyond the use of adult as well as extrapolation from clinical trials conducted in the same drug class. The use of extrapolation increased the rates of new and expanded pediatric indication in the period. This review gives the most recent landscape of pediatric labeling changes using extrapolation. With the released ICH (International Council for Harmonization) E11A guidance in April 2022, the paper also provides insights for future pediatric drug development programs. [ABSTRACT FROM AUTHOR]

Background: There is an increasing body of evidence supporting a more flexible approach in clinical data requirements for the approval of more complex biosimilar substances such as monoclonal antibodies (mAbs). Objective: The aim of this paper is to further analyse the role of quality/chemistry, manufacturing and controls (CMC) and clinical data for the conclusion on biosimilarity and the decision on marketing authorisation (MA). Methods: In the present study, we analysed the MA applications (MAAs) of all 33 mAbs and three fusion proteins evaluated by the European Medicines Agency (EMA) between July 2012 and November 2022 with special emphasis on all submitted rituximab (four products) and trastuzumab (seven products) biosimilar candidates, including withdrawn applications. For the two withdrawn applications, the comparative efficacy trials suggested biosimilarity, but the quality/CMC package was not accepted by EMA. We therefore investigated whether a negative MAA outcome could have been predicted based on the evidence generated in the quality/CMC packages, regardless of clinical trial data. For this purpose, we reviewed the respective European Public Assessment Reports (EPARs) or withdrawal assessment reports, and the first regulatory assessments for all these 36 MAAs (i.e. day 120 of the centralized procedure), which are not publicly available. During EMA review, where significant issues are identified which would preclude a marketing authorisation, these issues are raised as questions to the applicant and are classified as major objections (MO). Results: In 67% of cases, the outcome of the quality and clinical assessment was the same, i.e. both the quality and clinical assessments either supported approval or did not support approval. In 11% of cases, MO were identified in the quality part of the submission but not in the clinical data. In 22% of cases, MO were raised on the clinical data package but not on the quality data. However, we found no instance where seemingly negative clinical data, including failed efficacy trials, led to a negative overall decision. In each instance, the failure to confirm similar clinical performance in all investigated aspects was eventually viewed as not being related to the biosimilar per se but as being due to imbalances in the trial arms, immaturity of secondary endpoint results, change in the reference product, or even chance findings. Furthermore, when performing an in-depth analysis of the quality and clinical packages of trastuzumab and rituximab biosimilars, we found that in no case were clinical trial data necessary to resolve residual uncertainties regarding the quality part. Conclusion: The results further support the argument that sufficient evidence for biosimilarity can be obtained from a combination of analytical and functional testing and pharmacokinetic studies which may also generate immunogenicity data. This calls into question the usefulness of comparative efficacy studies for the purposes of regulatory decision-making when approving biosimilar mAbs and fusion proteins. [ABSTRACT FROM AUTHOR]

Antibody–drug conjugates (ADCs) are complex chemical structures composed of a monoclonal antibody, serving as a link to target cells, which is conjugated with a potent cytotoxic drug (i.e., payload) through a chemical linker. Inspired by Paul Ehrlich's concept of the ideal anticancer drug as a "magic bullet", ADCs are also highly specific anticancer agents, as they have been demonstrated to recognize, bind, and neutralize cancer cells, limiting injuries to normal cells. ADCs are among the newest pharmacologic breakthroughs in treating solid and hematologic malignancies. Indeed, in recent years, various ADCs have been approved by the Food and Drug Administration and European Medicines Agency for the treatment of several cancers, resulting in a "practice-changing" approach. However, despite these successes, no ADC is approved for treating patients affected by renal cell carcinoma (RCC). In the present paper, we thoroughly reviewed the current literature and summarized preclinical studies and clinical trials that evaluated the activity and toxicity profile of ADCs in RCC patients. Moreover, we scrutinized the potential causes that, until now, hampered the therapeutical success of ADCs in those patients. Finally, we discussed novel strategies that would improve the development of ADCs and their efficacy in treating RCC patients. [ABSTRACT FROM AUTHOR]

The Multiple Comparison Procedures with Modeling Techniques (MCP‐Mod) framework has been recently approved by the U.S. Food, Administration, and European Medicines Agency as fit‐for‐purpose for phase II studies. Nonetheless, this approach relies on the asymptotic properties of Maximum Likelihood (ML) estimators, which might not be reasonable for small sample sizes. In this paper, we derived improved ML estimators and correction for their covariance matrices in the censored Weibull regression model based on the corrective and preventive approaches. We performed two simulation studies to evaluate ML and improved ML estimators with their covariance matrices in (i) a regression framework (ii) the Multiple Comparison Procedures with Modeling Techniques framework. We have shown that improved ML estimators are less biased than ML estimators yielding Wald‐type statistics that controls type I error without loss of power in both frameworks. Therefore, we recommend the use of improved ML estimators in the MCP‐Mod approach to control type I error at nominal value for sample sizes ranging from 5 to 25 subjects per dose. [ABSTRACT FROM AUTHOR]

Cannabinoids are active substances present in plants of the Cannabis genus. Both the Food and Drug Administration (FDA) and European Medicines Agency (EMA) have approved several medicinal products containing natural cannabinoids or their synthetic derivatives for the treatment of drug-resistant epilepsy, nausea and vomiting associated with cancer chemotherapy, anorexia in AIDS patients, and the alleviation of symptoms in patients with multiple sclerosis. In fact, cannabinoids constitute a broad group of molecules with a possible therapeutic potential that could be used in the management of much more diseases than mentioned above; therefore, multiple preclinical and clinical studies on cannabinoids have been carried out in recent years. Danio rerio (zebrafish) is an animal model that has gained more attention lately due to its numerous advantages, including easy and fast reproduction, the significant similarity of the zebrafish genome to the human one, simplicity of genetic modifications, and body transparency during the early stages of development. A number of studies have confirmed the usefulness of this model in toxicological research, experiments related to the impact of early life exposure to xenobiotics, modeling various diseases, and screening tests to detect active substances with promising biological activity. The present paper focuses on the current knowledge of the endocannabinoid system in the zebrafish model, and it summarizes the results and observations from studies investigating the pharmacological effects of natural and synthetic cannabinoids that were carried out in Danio rerio. The presented data support the notion that the zebrafish model is a suitable animal model for use in cannabinoid research. [ABSTRACT FROM AUTHOR]

Public policies and regulations strongly influence research and manufacturing in pharmaceutical sector. Therefore, it is of critical importance that these policies and regulations are of high quality as well as appropriately balanced between general rules and detailed solutions. The process of public consultations prolongs adoption of novel documents. On the other hand, comments from different stakeholders like academia, industry, public administration and patients allow 360-degree critical evaluation of the document and a better understanding of the topic. This mini-review summarizes the contributions of numerous members of ORBIS project team in open consultations of draft regulatory documents published by European Medicines Agency (EMA) and the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). ORBIS project feedback on the Pharmaceutical Strategy for Europe is also presented. ORBIS project members contributed to open consultations of two ICH draft guidelines, and three EMA draft documents. ORBIS project was also active during the European Commission's efforts to develop Pharmaceutical Strategy for Europe. The interaction between representatives of academic and industrial sectors allowed to form balanced comments. We hope that this paper will inspire more researchers to participate in future open consultations on public policies. [ABSTRACT FROM AUTHOR]

The Quality by Design (QbD) concept has been appreciated and expected by the regulatory agencies, especially the "United States Food and Drug Administration" (USFDA), the "European Medicines Agency" (EMA), and other agencies that have adopted the "International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use" (ICH) around the globe. This paper describes the application of QbD principles in the pharmaceutical development of Oral Solid Dosage forms (OSDs). It encourages the implementation of risk-based approaches when designing pharmaceutical products. It provides a thorough understanding of formulation variables, Critical Material Attributes (CMAs), process variables, and Critical Process Parameters (CPPs) based on industrial experience that can be considered for risk assessment during the development of OSDs. It provides handy guidance to academics, research scholars, and industry scientists for implementing QbD in developing the OSDs. [ABSTRACT FROM AUTHOR]

Background: The U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) have published guidelines on the use of cancer treatments in young people of reproductive potential. However, no such guideline is available in Japan. Therefore, this project aimed to gather relevant data and draft a respective guidance paper. Methods: From April 2019 to March 2021, the Study Group for Providing Information on the Proper Use of Pharmaceuticals in Patients with Reproductive Potential at the Japan Agency for Medical Research and Development gathered opinions from experts in reproductive medicine, toxicology, and drug safety measures. The group considered these opinions, the FDA and EMA guidelines, and relevant Japanese guidelines and prepared a guidance paper, which they sent to 19 related organizations for comment. Results: By November 2020, the draft guidance paper was completed and sent to the related organizations, 17 of which provided a total of 156 comments. The study group finalized the guidance paper in March 2021. Conclusions: The "Guidance on the Need for Contraception Related to Use of Pharmaceuticals" (The report of the Study Group for Providing Information on the Proper Use of Pharmaceuticals in Patients with Reproductive Potential, Research on Regulatory Science of Pharmaceuticals and Medical Devices, Japan Agency for Medical Research and Development: JP20mk0101139) is expected to help Japanese healthcare professionals provide fertility-related care and advice to adolescents, and young adults with cancer and their families. [ABSTRACT FROM AUTHOR]

Several nanomedicine based medicinal products recently reached the market thanks to the drive of the COVID-19 pandemic. These products are characterized by criticality in scalability and reproducibility of the batches, and the manufacturing processes are now being pushed towards continuous production to face these challenges. Although the pharmaceutical industry, because of its deep regulation, is characterized by slow adoption of new technologies, recently, the European Medicines Agency (EMA) took the lead in pushing for process improvements using technologies already established in other manufacturing sectors. Foremost among these technologies, robotics is a technological driver, and its implementation in the pharma field should cause a big change, probably within the next 5 years. This paper aims at describing the regulation changes mainly in aseptic manufacturing and the use of robotics in the pharmaceutical environment to fulfill GMP (good manufacturing practice). Special attention is therefore paid at first to the regulatory aspect, explaining the reasons behind the current changes, and then to the use of robotics that will characterize the future of manufacturing especially in aseptic environments, moving from a clear overview of robotics to the use of automated systems to design more efficient processes, with reduced risk of contamination. This review should clarify the regulation and technological scenario and provide pharmaceutical technologists with basic knowledge in robotics and automation, as well as engineers with regulatory knowledge to define a common background and language, and enable the cultural shift of the pharmaceutical industry. [ABSTRACT FROM AUTHOR]

Nitrosamine impurities being reported to potentially present in medicinal products are the new hot issues in the pharmaceutical field during recent years. Five classes of medicinal products are being reported due to the possible presence of nitrosamine impurities: Sartan medicines, Metformin-containing medicines, Ranitidine medicines, Rifampicin medicines, and Champix. In this paper, we introduced the source and potential root causes of nitrosamine formation, potential or founded nitrosamine impurities in API and medicinal products, and acceptable intake limits recommended for those impurities. Moreover, we also summarized the current nitrosamine impurities concerned with medicinal products and corresponding control strategies adopted by the FDA and EMA, and it is expected to give reference for the Chinese or foreign pharmaceutical enterprises, as well as the regulatory authority, to get the comprehensive understanding of the nitrosamine impurities in the medicinal products. [ABSTRACT FROM AUTHOR]

Background: Electronic informed consent (eIC) may offer various advantages compared to paper-based informed consent. However, the regulatory and legal landscape related to eIC provides a diffuse image. By drawing from the perspectives of key stakeholders in the field, this study aims to inform the creation of a European guidance framework on eIC in clinical research. Methods: Focus group discussions and semi-structured interviews were conducted with 20 participants from six stakeholder groups. The stakeholder groups included representatives of ethics committees, data infrastructure organizations, patient organizations, and the pharmaceutical industry as well as investigators and regulators. All were involved in or knowledgeable about clinical research and were active in one of the European Union Member States or at a pan-European or global level. The framework method was used for data analysis. Results: Stakeholders underwrote the need for a multi-stakeholder guidance framework addressing practical elements related to eIC. According to the stakeholders, a European guidance framework should describe consistent requirements and procedures for implementing eIC on a pan-European level. Generally, stakeholders agreed with the definitions of eIC issued by the European Medicines Agency and the US Food and Drug Administration. Nevertheless, it was raised that, in a European guidance framework, it should be emphasized that eIC aims to support rather than replace the personal interaction between research participants and the research team. In addition, it was believed that a European guidance framework should include details on the legality of eIC across European Union Member States and the responsibilities of an ethics committee in the eIC assessment process. Although stakeholders supported the idea to include detailed information on the type of eIC-related materials to be submitted to an ethics committee, opinions varied on this regard. Conclusion: The creation of a European guidance framework is a much needed factor to advance eIC implementation in clinical research. By collecting the views of multiple stakeholder groups, this study advances recommendations that may facilitate the development of such a framework. Particular consideration should go to harmonizing requirements and providing practical details related to eIC implementation on a European Union-wide level. [ABSTRACT FROM AUTHOR]

• Enhanced Safety Surveillance for seasonal influenza vaccines is mandatory in EU since 2014/15. • Data from Enhanced Passive Safety Surveillance for Influvac® and Influvac® Tetra are presented. • Passive surveillance implemented for Influvac® & Influvac® Tetra complies with EU requirements. • Results confirm the favourable safety profiles of Influvac® and Influvac® Tetra. In 2014, the European Medicines Agency (EMA) set out requirements for an enhanced safety surveillance for seasonal influenza vaccines. This paper presents data from the yearly Enhanced Passive Safety Surveillance (EPSS) implemented for Influvac® since season 2014/15 and continued for Influvac® Tetra from season 2018/19 onwards. In seven consecutive seasons, an EPSS, aiming for at least 1,000 vaccinees (additional target of 100 vaccinees per five predefined age groups), was conducted in Germany, where market characteristics were expected to allow for a quick generation of representative data. Reactogenicity data in terms of reporting rates, severity and duration of pre-specified local and systemic adverse events of interest (AEI) were collected using response cards, which were completed by vaccinees and returned seven days after vaccination via regular mail. In addition, response cards contained a call center number to enhance reporting of other than pre-specified adverse events. The primary target of at least 1,000 vaccinees was surpassed in all seasons, as was the additional target of 100 adults and elderly. Reactogenicity data were in line with known safety profile of Influvac® and Influvac® Tetra. In children, the target was mostly met in seasons when the EPSS was conducted for Influvac®, but not in seasons when it was conducted for Influvac® Tetra. Although the data for Influvac® Tetra are based on a low number of paediatric vaccinees, they do not indicate a different reactogenicity profile of Influvac® Tetra compared with Influvac®. No signals were identified. The EPSS set up for Influvac® and Influvac® Tetra proved a robust and effective methodology to comply with the objectives of EMÁ's guidance on enhanced safety surveillance of seasonal influenza vaccines. Safety data from seven consecutive seasons confirmed the favourable safety profile of both vaccines. [ABSTRACT FROM AUTHOR]

A new LC-MS/MS method for the quantification of lenvatinib (LENVA) in venous Dried Blood Spot (DBS) samples has been presented. This method is characterized by a short run time (4 min), requires a volumetric sampling of 10 µL and extraction of the entire spot to avoid hematocrit (Hct) and spot volume effects. The quantification method was successfully validated in the range of 5.00–2000 ng/mL on two different DBS filter papers (Whatman 31 ET CHR and Whatman 903) according to European Medicines Agency (EMA) and Food and Drug Administration (FDA) guidelines, European Bioanalysis Forum (EBF), and International Association of Therapeutic Drug Monitoring and Clinical Toxicology (IATDMCT) recommendations. During the validation process, the following parameters were evaluated: recovery (≥ 77% for both filter papers), absence of matrix effect, process efficiency (close to 72% for Whatman 31 ET CHR and close to 77% for Whatman 903), Hct effect (CV ≤ 6.3% and accuracy within 96–112%), linearity (r ≥ 0.998 for Whatman 31 ET CHR and r ≥ 0.999 for Whatman 903), intra- and inter-day precision (CV ≤ 8.8%) and accuracy (92.8–108%), selectivity and sensitivity, reproducibility with incurred samples reanalysis (ISR), and stability. This method was applied to quantify venous DBS samples from patients with hepatocellular carcinoma treated with LENVA enrolled in a cross-validation study (CRO-2018–83). A good correlation between LENVA plasma concentration determined by standard procedure and the new developed DBS LENVA method (R2 ≥ 0.996) has been observed. • The first LC-MS method for the quantification of lenvatinib in DBS matrix has been developed. • The method has been fully validated according to FDA, EMA, and IATDMCT guidelines. • DBS is a non-invasive sampling method that may improve TDM application in a cost-effective manner. • A preliminary clinical validation was performed and showed very promising results. [ABSTRACT FROM AUTHOR]

Ulipristal acetate (UPA) is a medical treatment for uterine fibroids and was authorized for surgical pre-treatment in 2012 after the conduct of the PEARL I and II randomized controlled trials and for intermittent treatment after the observational PEARL III and IV trials. However, UPA came into disrepute due to its temporary suspension in 2017 and 2020 because of an apparent association with liver injury. This clinical opinion paper aims to review the process of marketing authorization and implementation of UPA, in order to provide all involved stakeholders with recommendations for the introduction of future drugs. Before marketing authorization, the European Medicines Agency (EMA) states that Phase III registration trials should evaluate relevant outcomes in a representative population, while comparing to gold-standard treatment. This review shows that the representativeness of the study populations in all PEARL trials was limited, surgical outcomes were not evaluated and intermittent treatment was assessed without comparative groups. Implementation into clinical practice was extensive, with 900 000 prescribed treatment cycles in 5 years in Europe and Canada combined. Extremely high costs are involved in developing and evaluating pre-marketing studies in new drugs, influencing trial design and relevance of chosen outcomes, thereby impeding clinical applicability. It is vitally important that the marketing implementation after authorization is regulated in such way that necessary evidence is generated before widespread prescription of a new drug. All stakeholders, from pharmaceutical companies to authorizing bodies, governmental funding bodies and medical professionals should be aware of their role and take responsibility for their part in this process. [ABSTRACT FROM AUTHOR]

Between December 2020 and March 2021, the US Food and Drug Administration and the European Medicines Agency issued Emergency Use Authorizations and Conditional Marketing Authorizations for the distribution of the first COVID-19 vaccines. Although these vaccines were thoroughly assessed before their approval, regulators required companies to continue ongoing placebo-controlled clinical trials in order to gather further reliable scientific information on their safety and efficacy, as well as to start new studies to evaluate additional candidates. The aim of this paper is to present and discuss the ethical issues raised by the tension between the need to continue these types of clinical trials and the obligations related to the protection of the rights and well-being of research participants. Specifically, we question whether—how, and to what extent—fundamental principles governing research involving human beings can be applied to the current pandemic situation. We argue that continuing ongoing placebo-controlled clinical trials can be considered ethically justifiable only if all participants are adequately informed of any developments that may affect their willingness to remain enrolled, including the current situation of resource scarcity and the prioritization criteria established for vaccination. However, we also argue that currently approved vaccines, which are considered safe and effective enough to be administered to millions of people as part of the vaccination campaign, necessarily represent the "best proven intervention" currently available and, therefore, should be used as comparators in future studies instead of placebo. [ABSTRACT FROM AUTHOR]

Background and purpose: High mortality rates have been reported in patients with cerebral venous sinus thrombosis (CVST) due to vaccine‐induced immune thrombotic thrombocytopenia (VITT) after vaccination with adenoviral vector SARS‐CoV‐2 vaccines. The aim of this study was to evaluate whether the mortality of patients with CVST‐VITT has decreased over time. Methods: The EudraVigilance database of the European Medicines Agency was used to identify cases of CVST with concomitant thrombocytopenia occurring within 28 days of SARS‐CoV‐2 vaccination. Vaccines were grouped based on vaccine type (adenoviral or mRNA). Cases with CVST onset until 28 March were compared to cases after 28 March 2021, which was the day when the first scientific paper on VITT was published. Results: In total, 270 cases of CVST with thrombocytopenia were identified, of which 266 (99%) occurred after adenoviral vector SARS‐CoV‐2 vaccination (ChAdOx1 nCoV‐19, n = 243; Ad26.COV2.S, n = 23). The reported mortality amongst adenoviral cases with onset up to 28 March 2021 was 47/99 (47%, 95% confidence interval 37%–58%) compared to 36/167 (22%, 95% confidence interval 16%–29%) in cases with onset after 28 March (p < 0.001). None of the four cases of CVST with thrombocytopenia occurring after mRNA vaccination died. Conclusion: The reported mortality of CVST with thrombocytopenia after vaccination with adenoviral vector‐based SARS‐CoV‐2 vaccines has significantly decreased over time, which may indicate a beneficial effect of earlier recognition and/or improved treatment on outcome after VITT. [ABSTRACT FROM AUTHOR]

Predictive toxicology plays an integral role in determining the toxicological profiles of chemicals for safety assessment. Vitamin D is an essential vitamin for the regulation of calcium absorption and homeostasis, as well as the treatment and prevention of several diseases such as rickets and osteomalacia. According to European Medicines Agency (EMA) Guideline on setting health-based exposure limits for use in risk identification in the manufacturing of different medicinal products in shared facilities, permitted daily exposure (PDE) calculation for active pharmaceutical ingredients (APIs) should be done by the medicinal product producers. PDE calculation is mainly based on critical toxicological endpoints such as repeated dose toxicity, genotoxicity, carcinogenicity, developmental and reproductive toxicity, and hypersensitivity potential. During this procedure, critical toxicological endpoints data of an API can be used to predict the PDE of another API that has a similar chemical structure. In the present paper, human toxicological endpoints of vitamin D2, D3, and their metabolites were evaluated and afterwards the data gaps in the toxicological endpoints were filled by forming a category. The read-across was justified by the structural and metabolic similarities. Molecular similarity and mechanistic relevance were found to be substantial, resulting in low uncertainty. The untested vitamin D analogs within the category can be read across with confidence to complete the data gaps related to the human health endpoints. [ABSTRACT FROM AUTHOR]

Simple Summary: Considering the high incidence and mortality of breast cancer, a lot of trials evaluating new drugs for the treatment of this disease are currently ongoing. However, few drugs show a statistically and clinically significant improvement in the outcomes leading to the Competent Authority approval. In this review we analyzed the European Medicines Agency breast cancer drug indications issued between January 2015 and June 2021 and we evaluated the clinical trials results leading to the approval and their update. Breast cancer represents the first cause of cancer worldwide and the leading cause of cancer mortality for women. Therefore, new therapies are needed to improve the prognosis of women diagnosed with this disease. In this review, we summarize the new drug indications for the treatment of breast cancer approved by European Medicines Agency between January 2015 and June 2021. In particular, we analyzed the clinical trials results leading to approvals and their update (when available), according to setting (localized and locally advanced or metastatic) and clinical features (hormone receptor positive, HER2 positive, triple negative, BRCA 1/2 mutation). The aim of this paper is to describe the clinical benefit obtained with the new indications. [ABSTRACT FROM AUTHOR]