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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]

Increased global longevity requires a re‐evaluation of current structures in society to adapt to the consequential demographic shift. As (very) old people are prone to impaired human organ and body functions resulting in, for example, multimorbidity, polypharmacy, hospitalisation and problems in medication management, it is increasingly acknowledged that re‐evaluations should include the suitability of pharmaceutical patient care as one of the cornerstones of public health. Following the 2011 European Medicines Agency (EMA) Geriatric Strategy, in 2017 the EMA published the draft "Reflection paper on the pharmaceutical development of medicines for use in the older population". The draft paper was opened for public consultation and specific attention and feedback (either supportive or with a proposal for revision) was asked on three design aspects: tablet breaking, drug administration through enteral feeding tubes and medication management. Following publication, the draft paper was presented at two public conferences attended by participants from different disciplines. This manuscript is intended to draw the attention of different stakeholder parties to the urgent need to collaborate on the emerging issues arising from increasing longevity and multimorbidity, and especially those associated with pharmaceutical patient care and drug product design, including the need for collaborative research into existing or emerging knowledge gaps. The manuscript focuses on the three aforementioned aspects of pharmaceutical development (tablet breaking, drug administration through enteral feeding tubes and medication management) as these highly relate to medication safety and efficacy and constitute persistent and typical challenges for older people, caregivers and healthcare professionals in daily clinical practice. [ABSTRACT FROM AUTHOR]

This position paper describes the view adopted by EUCAST on the role of daptomycin in the treatment of serious infections caused by Enterococcus species. High-dose daptomycin is considered effective in the treatment of enterococcal bloodstream infection (BSI) and endocarditis, although published clinical experience with the latter condition is limited. EUCAST reviewed the available published data on pharmacokinetics–pharmacodynamics (PK-PD), resistance selection, clinical efficacy and safety for the use of 10–12 mg/kg/day of daptomycin for these conditions, noting that the doses licensed by the European Medicines Agency are only 4–6 mg/kg/day, and only for infections caused by Staphylococcus aureus. The PK-PD evidence shows that, even with doses of 10–12 mg/kg/day, it is not possible to treat infections caused by isolates at the upper end of the wild-type distributions of Enterococcus faecalis (with MICs of 4 mg/L) and E. faecium (with MICs of 4 or 8 mg/L). For this reason, and because there are ongoing issues with the reliability of laboratory testing, EUCAST lists daptomycin breakpoints for Enterococcus species as "IE"—insufficient evidence. EUCAST advises increased vigilance in the use of high-dose of daptomycin to treat enterococcal BSI and endocarditis. Additional PK-PD studies and prospective efficacy and safety studies of serious Enterococcal infections treated with high-dose daptomycin may permit the setting of breakpoints in the future. [ABSTRACT FROM AUTHOR]

Adopted guidelines reflect a harmonised European approach to a specific scientific issue and should reflect the most recent scientific knowledge. However, whilst EU regulations are mandatory for all member states and EU directives must be followed by national laws in line with the directive, EMA guidelines do not have legal force and alternative approaches may be taken, but these obviously require more justification. This new series of the BJCP, developed in collaboration with the EMA, aims to address this issue by providing an annotated version of some relevant EMA guidelines and regulatory documents by experts. Hopefully, this will help in promoting their diffusion and in opening a forum for discussion with our readers. [ABSTRACT FROM AUTHOR]

Copyright of Néphrologie & Thérapeutique is the property of John Libbey Eurotext Ltd. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

The article discusses the benefits of the electronic patient reporting (ePRO) than the paper-based diaries for clinical research sponsors as accepted by Food and Drug Administration (FDA) and European Medicines Agency (EMA). The author says that the ePRO technology can cut costs through compliance rates and the function of the ePRO automates data management which includes reviewing, collating, and verifying. Moreover, he presents an overview regarding the research on paper vs. ePRO model.

Abstract: Aims: Patient-reported outcomes (PROs) have recently gained greater credibility with regulatory bodies aiming to standardise their use and interpretation in RCTs, thereby supporting medicinal product submissions. For this reason, the United States (US) Food and Drug Administration (FDA) and the European Medicines Agency (EMEA) have released guidelines. This review paper provides an overview of the current perspectives and views on these guidelines. Method: To evaluate the FDA and EMEA PRO guidelines, 47 expert responses to the FDA guidance were qualitatively reviewed. Two reviewers independently extracted data from these letters and checked these responses to warrant consistency and agreement in the evaluation process. A PubMed literature review was systematically examined to obtain supporting evidence or related articles for both the guidance documents. Results: Generally, there is agreement between regulatory authorities and the research community on the contents of the FDA and EMEA PRO draft guidance. However, disagreements exist on significant philosophical topics (e.g. the FDA focuses more on conceptual models and symptoms than the EMEA) and design topics (e.g. the FDA is more restrictive on issues of recall bias, blinding of oncology trials and degrees of psychometric validation than researchers and the EMEA). This could influence the approval of PRO claims. Conclusion: PRO guidance from the EMEA and FDA has been valuable, and has raised the profile and active debate of PROs in oncology. However, our review of the current opinion shows that there are controversial aspects of the guidance. Consequently, greater latitude should be given to how the guidance is interpreted and applied. [Copyright &y& Elsevier]

During the last 10 years the European Medicines Agency (EMA) organized a number of workshops on modeling and simulation, working towards greater integration of modeling and simulation (M&S) in the development and regulatory assessment of medicines. In the 2011 EMA - European Federation of Pharmaceutical Industries and Associations (EFPIA) Workshop on Modelling and Simulation, European regulators agreed to the necessity to build expertise to be able to review M&S data provided by companies in their dossier. This led to the establishment of the EMA Modelling and Simulation Working Group (MSWG). Also, there was agreement reached on the need for harmonization on good M&S practices and for continuing dialog across all parties. The MSWG acknowledges the initiative of the EFPIA Model-Informed Drug Discovery and Development (MID3) group in promoting greater consistency in practice, application, and documentation of M&S and considers the paper is an important contribution towards achieving this objective. [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]

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]

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: 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]

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]

Background: In line with the European Paediatric Regulation, the European Medicines Agency (EMA) asks for investigation of a medicine's acceptability in paediatric medicines development. A standardised acceptability testing method combining the outcome of "swallowability" and "palatability" assessments to a "composite endpoint on acceptability" was recently developed. Before this method's suitability for selection of the most acceptable drug formulation of a new medicine for children can be broadly recommended, the acceptance and relevance of such established acceptability needs the critical review and input from young patients with understanding of the medicines development methodology. The benefit of involving patients in drug product development, clinical research and innovation is well established. Methods: During a focus group meeting with the KIDS Barcelona (young people advisory group, age 16–23 years) the suitability of the "composite endpoint on acceptability" methodology was assessed. Via electronic questionnaires the importance of involving patients in the medicines development and in the acceptability method development was investigated. Questions on how best to determine palatability and swallowability were asked. The relevance of all EMA-listed acceptability elements was assessed via coloured and numbered stickers and questionnaires. Results: The results showed that the involvement of young people in the medicines and acceptability method development was rated high. The group worked out that a 5-point smiley Likert Scale is preferred for assessing acceptability by 6–11 year old patients, while a Visual Analogue Scale is preferred for collecting adolescents' opinion. The ranking of the EMA-listed acceptability elements showed that palatability and swallowability are the most relevant parameters, while colour of the medicine was rated as least relevant. These results, established face-to-face, were confirmed in a repeat of the ranking through an electronic questionnaire, completed by the participants individually and remotely, 5 weeks later. Conclusion: This work reinforced the need and value to involve young people in the medicines lifecycle, and specifically in this acceptability method development. As next step other focus group meetings with more young people from different European countries are planned. Plain English Summary: Before a new medicine is authorized, its acceptability by children must be investigated according to law. An acceptability testing method combining the outcomes of "swallowability" and "palatability" assessments was recently developed. During a focus group meeting with KIDS Barcelona (young people advisory group, age 16–23 years) their opinion on the suitability of the method and the relevance of patient engagement in the medicines development process were assessed with paper-based and electronic questionnaires. Questions on how best to determine palatability and swallowability were asked. The importance of different elements that typically affect acceptability was rated. The order of relevance of those listed acceptability elements was assessed using coloured and numbered stickers and questionnaires. The results showed that the involvement of young people in the medicines and acceptability method development was rated high. The group worked out that a 5-point smiley Likert Scale that allows for marking a choice between total agreement and total disagreement is preferred for assessing acceptability by 6–11 year old patients. A Visual Analogue Scale (scale consisting of a 10 cm long line on which a mark has to be placed at the desired position, between total agreement and total rejection) is preferred for collecting adolescents' (12–18 years) opinion. The ranking of acceptability elements showed that palatability and swallowability of a new medicine are the most relevant parameters, and colour the least. The clarity of the outcome reinforced the benefit of involving young people in the development of medicines relevant for children. [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]

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]

Regulators and Health Technology Assessment (HTA) bodies are increasingly familiar with, and publishing guidance on, external controls derived from real‐world data (RWD) to generate real‐world evidence (RWE). We recently conducted a systematic literature review (SLR) evaluating publicly available information on the use of RWD‐derived external controls to contextualize outcomes from uncontrolled trials submitted to the European Medicines Agency (EMA), the US Food and Drug Administration (FDA), and/or select HTA bodies. The review identified several key operational and methodological aspects for which more detailed guidance and alignment within and between regulatory agencies and HTA bodies is necessary. This paper builds on the SLR findings by delineating a set of key takeaways for the responsible generation of fit‐for‐purpose RWE. Practical methodological and operational guidelines for designing, conducting, and reporting RWD‐derived external control studies are explored and discussed. These considerations include: (i) early engagement with regulators and HTA bodies during the study planning phase; (ii) consideration of the appropriateness and comparability of external controls across multiple dimensions, including eligibility criteria, temporality, population representation, and clinical evaluation; (iii) ensuring adequate sample sizes, including hypothesis testing considerations; (iv) implementation of a clear and transparent strategy for assessing and addressing data quality, including data missingness across trials and RWD; (v) selection of comparable and meaningful endpoints that are operationalized and analyzed using appropriate analytic methods; and (vi) conduct of sensitivity analyses to assess the robustness of findings in the context of uncertainty and sources of potential bias. [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]

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]

Copyright of Journal of Laboratory Medicine / Laboratoriums Medizin is the property of De Gruyter and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Patient registries offer a powerful and practical means of real-world data collection system for rare diseases. Many guidelines have been released to standardize patient registries, although most of them do not address issues specific to rare disease patient registries. In November 2018, the European Medicines Agency (EMA) released a draft discussion paper on methodological and operational aspects of disease registries and made proposals on good registry practice (henceforth referred to as EMA guidance). This guidance was highly anticipated by all stakeholders with a strong interest toward governance, operationalization, and study conduct in registries. With improved clarity toward conduct of patient registries, this guidance will encourage overall registry use in regulatory decision making. TuberOus SClerosis registry to increase disease Awareness (TOSCA) was an international, multicenter patient registry to assess the manifestations, interventions, and outcomes in patients with tuberous sclerosis complex (TSC). The planning of TOSCA was initiated in 2011, patient enrolment commenced in August 2012, and final analysis database was locked in August 2017, long before the EMA guidance was released. Moreover, initial publications of TOSCA, such as first interim analysis, had also been published before the release of the EMA guidance. Extensive feedback and lessons learned from the TOSCA registry have provided insights into rare disease registry planning and operations. In this paper, we tested the recommendations from the EMA guidance on a rare disease registry, that is, the TOSCA registry. We elaborated the compliance and deviations of the TOSCA registry from the EMA guidance on a point-by-point basis. A careful observation revealed that in most aspects, TOSCA was in compliance with EMA. However, there were several practical issues identified in TOSCA, which deviated from EMA guidance. These issues demonstrate that deviations from EMA guidance, particularly in rare disease registries, do not signify compromised registry quality and can be somewhat expected in small populations. Despite multiple deviations of TOSCA from the EMA guidance, TOSCA was able to meet its objectives to enhance our understanding of TSC and its manifestations. [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]

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]

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]

Copyright of Journal of Chinese Pharmaceutical Sciences is the property of Journal of Chinese Pharmaceutical Sciences and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Aims: Guidelines establish a framework for how therapeutics and vaccines are developed, assessed and approved. They influence which innovations are likely to be approved in the European Union (EU), and thus, they have an impact on the pipeline decisions taken by research‐based industry. This study analyses the level of acceptance for changes suggested by stakeholders within the authoring groups at the European Medicines Agency (EMA). Methods: We looked at 87 guidelines from EMA Working Parties (WPs) launched for consultation between 2013 and 2017. Acceptance of stakeholder proposals and the time between the end of consultation and guideline adoption were studied as well as the openness of different WPs to accept changes. Results: Adoption of a guideline after the close of public consultation took at least 4 months, with an average of 12–16 months. The number of accepted and rejected comments were nearly equal across the stakeholders, with government having slightly higher chance for acceptance. Academia and nongovernmental organizations (NGOs) had generally higher chances to have their comments accepted for general and indication‐level guidelines. Government and individual companies had highest acceptance for molecule‐level guidelines and trade associations for indication‐level guidelines. Only a third of the comments related to scientific content of the guideline. Conclusion: This pattern of progress in regulatory science at EMA demonstrates the essential and interrelated role of academia, industry, government and civil society—described as the quadruple helix model—to promote establishment of a strong innovation ecosystem in Europe. [ABSTRACT FROM AUTHOR]

Copyright of Hospital Pharmacology: International Multidisciplinary Journal is the property of Serbian Medical Society, Section for Clinical Pharmacology and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

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]

Study sponsors and market authorization holders are required by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) to enroll patients administered a gene therapy product, whether in a trial setting or post‐licensure, in a long term follow‐up safety study to continue the safety assessments of their product. These follow‐up studies range between 5 and 15 years after dosing. This unprecedented duration of engagement with patients and caregivers raises logistical challenges that will require innovation and collaboration across sponsors and regulators. In this paper we delineate some of the key considerations for designing long term follow‐up protocols in the gene therapy setting, with an eye toward platform and master protocol approaches, and offer guidance for innovative operational and statistical methods that can help assess the safety profile and durability of response for these novel therapeutics. [ABSTRACT FROM AUTHOR]

Dried blood spot as biosampling method offers a less invasive and easier procedure. This study aimed to develop the validated analytical method of doxorubicin hydrochloride and doxorubicinol simultaneously in dried blood spot with hexamethylphosphoramide as the internal standard. A total of 30 µL blood was spotted on DBS paper and dried for 3 hours before it was extracted by protein precipitation method using water and methanol. The separation was performed on column Acquity UHPLC BEH C-18 (2.1 × 100 mm; 1.7 µm), with 0.15 mL/min flow rate and using 0.1% acetic acid and acetonitrile as mobile phase in gradient elution for 7 min. Quantification analysis was performed by a triple quadrupole mass spectrometry with electrospray ionization (ESI) in positive ion mode. The multiple reaction monitoring (MRM) was set at m/z 544.22 > 397.06 for doxorubicin hydrochloride; m/z 546.22 > 361.05 for doxorubicinol; and m/z 180.03 > 135.16 for hexamethylphosphoramide. The lower limit of quantitation was 10 ng/mL for doxorubicin and 4 ng/mL for doxorubicinol. Concentration range acquired was 10-200 ng/mL for doxorubicin and 4-100 ng/mL for doxorubicinol. The precision and accuracy were within acceptable criteria of <15%. Dried blood spot samples acquired was stable for at least 30 days before analysis. This method fulfilled the validation requirement refers to Bioanalytical Method Validation Guideline of European Medicines Agency 2011 and US Food and Drug Administration 2018. [ABSTRACT FROM AUTHOR]

The article offers suggestions for meeting regulatory concerns regarding Electronic Data Capture (EDC) data integrity and site control over the source of data in clinical trials. Topics include the consensus across the pharmaceutical industry regarding the maintenance of clinical data by writing results on papers; the guidelines of the U.S. Food and Drug Administration regarding use of electronic data in clinical trials; and guidelines of European Medicines Agency regarding electronic data.

The diagnosis of idiopathic short stature (ISS) refers to children who are considerably shorter than average without any identified medical reason. The US Food and Drug Administration (FDA) authorised marketing of recombinant human growth hormone (hGH) for ISS in 2003, while the European Medicines Agency (EMA) refused it in 2007. This paper examines the arguments for these decisions as detailed in selected FDA and EMA documents. It combines argumentative analysis with an approach to policy analysis called 'What's the problem represented to be'. It argues that the FDA presents its approval as an argument for equity of access to the treatment (given that hGH was already authorised for other indications), describing short stature as a potential disadvantage, and assuming that height normalisation is a clinically meaningful result. The EMA, instead, refuses marketing authorisation with an argument that there is an imbalance of risks and benefits, describing ISS as a healthy condition, and arguing that hGH should provide some psychosocial and/or quality of life benefits to children with ISS other than height gain. This paper then discusses how these arguments could be read through different models of disability, particularly through the medical model of disability and the relational, experiential, and cultural understandings of disability. [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]

The US Food and Drug Administration (FDA), European Medicines Agency (EMA), and Pharmaceuticals and Medical Devices Agency (PMDA) guidances on small‐molecule drug–drug interactions (DDIs), with input from the International Transporter Consortium (ITC), recommend the evaluation of nine drug transporters. Although other clinically relevant drug uptake and efflux transporters have been discussed in ITC white papers, they have been excluded from further recommendation by the ITC and are not included in current regulatory guidances. These include the ubiquitously expressed equilibrative nucleoside transporters (ENT) 1 and ENT2, which have been recognized by the ITC for their potential role in clinically relevant nucleoside analog drug interactions for patients with cancer. Although there is comparatively limited clinical evidence supporting their role in DDI risk or other adverse drug reactions (ADRs) compared with the nine highlighted transporters, several in vitro and in vivo studies have identified ENT interactions with non‐nucleoside/non‐nucleotide drugs, in addition to nucleoside/nucleotide analogs. Some noteworthy examples of compounds that interact with ENTs include cannabidiol and selected protein kinase inhibitors, as well as the nucleoside analogs remdesivir, EIDD‐1931, gemcitabine, and fialuridine. Consequently, DDIs involving the ENTs may be responsible for therapeutic inefficacy or off‐target toxicity. Evidence suggests that ENT1 and ENT2 should be considered as transporters potentially involved in clinically relevant DDIs and ADRs, thereby warranting further investigation and regulatory consideration. [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]

Substance use disorders (SUDs) are an extremely challenging category of disorders because of the high rate of relapse, lower life expectancy, important rate of psychiatric and somatic co-morbidity, lack of patients' insight during most of the disease duration, healthcare costs, etc. One of the reasons to consider these disorders very difficult for physicians and the healthcare system is the lack of adequate pharmacological agents with long-term proven efficacy. So far, there are no Food and Drug Administration (FDA) or European Medicines Agency (EMA)-approved treatments for most of the SUDs, except for alcohol use disorder, nicotine use disorder, and opioid use disorder. Immunotherapy has been considered a possible solution to SUDs because it may selectively target a certain drug of abuse, it may have a long-lasting effect (several weeks or months), and it ensures an adequate therapeutic adherence. The objective of this paper was to establish the current stage of research in the field of SUDs vaccines, based on a brief literature review. Vaccines for cocaine and nicotine dependence have reached phase III trials, while other researchers are focusing on passive immunization therapy for methamphetamine use disorder. New generations of vaccines are currently explored, and they are based on superior technologies compared to the first generation of immune therapy (e.g., viral transfer genes, more immunogenic adjuvants, or higher specificity haptens). Therefore, finding immune therapies for substance use disorders SUDs remains a matter of interest, and this approach may be useful for the management of an extremely dangerous and versatile psychiatric pathology. [ABSTRACT FROM AUTHOR]

The paper applies a functional approach to the analysis of an emerging technology within an innovation system (IS) in a developing country. By doing so, the paper identifies the advantages and drawbacks of the approach through a dynamic analysis and highlights the life cycle of an IS within which a new technology is emerging. This is done empirically by analysing the emergence of biosimilars within the infant Turkish biotechnology system mainly from the perspective of firms. Our analysis of the Turkish case illustrates how the tool of functional approach could be valuable in understanding the dynamics of a technology in a developing country context. Policy suggestions and implications of the study are presented as concluding remarks. [ABSTRACT FROM PUBLISHER]

Diclofenac is a nonsteroidal anti-inflammatory human and veterinary medicine widely detected in European surface waters, especially downstream from Wastewater Treatment Plants. With some notable exceptions, veterinary uses of diclofenac in Europe are greatly restricted, so wastewater is the key Europe-wide exposure route for wildlife that may be exposed via the aquatic environment. Proposed Environmental Quality Standards (EQS) which include an assessment of avian exposure from secondary poisoning are under consideration by the European Commission (EC) to support the aims of the Water Framework Directive (WFD). In this paper we summarise information on avian toxicity plus laboratory and field evidence on diclofenac bioaccumulation and bioconcentration in avian food items. A safe diclofenac threshold value for birds of 3 μg kg−1 wet weight in food was previously derived by the European Medicines Agency and should be adopted as an EQS under the WFD to maintain consistency across European regulations. This value is also consistent with values of 1.16–3.99 µg kg−1diet proposed by the EC under the WFD. Water-based EQS of 5.4 or 230 ng L−1 in freshwater are derived from these dietary standards, respectively, by the EC and by us, with the large difference caused primarily by use of different values for bioaccumulation. A simple assessment of potential water-based EQS compliance is performed for both of these latter values against reported diclofenac concentrations in samples collected from European freshwaters. This shows that exceedances of the EC-derived EQS would be very widespread across Europe while exceedances of the EQS derived by us are confined to a relatively small number of sites in only some Member States. Since there is no evidence for any declines in European waterbird populations associated with diclofenac exposure we recommend use of conservative EQS of 3 µg kg−1diet or 230 ng L−1 in water to protect birds from diclofenac secondary poisoning through the food chain. [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]

Copyright of Revista de Lengua para Fines Específicos is the property of Revista de Lengua para Fines Especificos and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Polish Journal of Allergology / Alergologia Polska is the property of Termedia Publishing House and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

As the first biologics produced by recombinant deoxyribonucleic acid (DNA) technology were approved in the late 1980s and consequently the exclusive marketing rights of most of these biological medicinal products have expired or will expire very shortly, it is quite evident that biosimilars are being developed and marketed in developed as well as developing countries in line with these expiries. Hence, there is an explosion of published papers and scientific programs on biological medicinal products and biosimilar insulins in the last decade or so. Each of these papers or scientific programs generated more questions than providing clinically useful answers. The specific aim of the medical literature or scientific programs were blurred due to lot of attention (created by the innovators) directed towards confusing terminologies, past mishaps with biosimilars (in the era with the absence of regulatory guidelines for biosimilars) diverting our attention from the matters relevant to clinicians and patients. One of the principle reason behind this phenomenon has been our poor understanding of the manufacturing process, regulatory pathways, and study endpoints involved in developing a biosimilar in the present era. This drawback resulted in a nonsystematic approach in analyzing the biosimilars and apparently resulting in confusion. This review attempts at demystifying certain facets of frequently encountered information on biosimilars and acquire a personal understanding on the same, rather than depending on conflicting versions floated at different continuing medical educations (CMEs) and Diabetes Congresses. [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]

The new In Vitro Diagnostic Regulation (EU) 2017/746 (IVDR) introduces important changes in the EU legal framework for companion diagnostics (CDx), including a new risk‐based classification system for in vitro diagnostic tests (IVDs), a first legal definition for CDx and enhanced involvement of notified bodies in the conformity assessment and certification process of CDx. The IVDR also establishes an important link between the assessment of a CDx and the corresponding medicinal product by requiring the notified body to seek a scientific opinion from the medicines regulator on the suitability of the CDx for use with the concerned medicinal product(s) before issuing an IVD certificate. Whereas the IVDR aims at establishing a robust regulatory framework for IVDs, it is also associated with several challenges, such as insufficient capacity of notified bodies and readiness of manufacturers. To ensure timely access for patients to essential IVDs, a progressive roll‐out for this new legislation has been introduced. In addition, the new consultation process for CDx requires increased collaboration and alignment of assessments performed by the different stakeholders involved in this process. The European Medicines Agency (EMA) and notified bodies are currently building experience based on the first CDx consultation procedures that have been submitted from January 2022 onward. In the current article, we describe the new European regulatory framework for certification of CDx and highlight several challenges for medicine and CDx co‐development. In addition, we briefly touch upon the interplay between the Clinical Trial Regulation (EU) No. 536/2014 (CTR) and the IVDR. [ABSTRACT FROM AUTHOR]

One year since the emergence of the COVID-19 pandemic, rapid response measures have been implemented internationally to mitigate the spread of the virus. Following rapid and successful pre-clinical and human trials, several vaccines have been authorised for use across Europe through the European Medicines Agency and national regulatory authorities. Clinical trials have shown promising results including important reductions in disease severity, hospitalisation and mortality. In order to maximise the public health benefit of available vaccines, there is a pressing need to vaccinate a large proportion of the population. Internationally, this has prompted coordination of existing services at enormous scale, and development and implementation of novel vaccination strategies to ensure maximum inoculation over the shortest possible timeframe. Pharmacists are being promoted as healthcare professionals that enhance roll-out of COVID-19 vaccination programmes. This paper aims to summarise current policy and practice in relation to pharmacists' involvement in COVID-19 vaccination in 13 countries across Europe. [ABSTRACT FROM AUTHOR]