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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]

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]

In 2014, the European Medicines Agency (EMA) released for comment a draft reflection paper on the use of patient-reported outcome (PRO) measures in oncology studies. A twelve-member International Society for Quality of Life Research (ISOQOL) taskforce was convened to coordinate the ISOQOL response. Twenty-one ISOQOL members provided detailed comments and suggestions on the paper: 81 % from academia and 19 % from industry. Taskforce members consolidated and further refined these comments and shared the recommendations with the wider ISOQOL membership. A final response was submitted to the EMA in November 2014. The impending publication of the EMA reflection paper presents a valuable opportunity for ISOQOL to comment on the current direction of EMA PRO guidance and strategy. The EMA paper, although focused on cancer, could serve as a model for using PROs in other conditions, as it provides a useful update surrounding some of the design issues common to all trial research including PRO endpoints. However, we believe there are a number of additional areas in need of greater consideration. The purpose of this commentary is therefore to highlight the strengths of this timely and potentially useful document, but also to outline areas that may warrant further discussion. [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 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]

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]

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]

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]

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]

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]

Introduction: According to current understanding of the role of excipient in medicines, they could not be considered as completely pharmacologically inert substances. Although excipients do not have the potential to cause adverse drug reactions (ADRs) in most patients, some of their negative effects have been established. Special caution regarding excipients intake is advised, especially in vulnerable populations such as pediatric one. Aim: The aim of this paper was to investigate the exposure of children on antibiotic therapy to excipients with known effects (EKE). Methods: During a one-month period antibiotic prescriptions data were taken from community pharmacies in Novi Sad, Serbia. Age, diagnosis and prescribed therapy were observed. Data about qualitative content of prescribed medicines were taken from Summaries of Product Characteristics (SmPC) available at the official website of Medicines and medical devices agency of Serbia (ALIMS). Excipients were considered to be potentially harmful if they were listed in European Medicines Agency (EMA) guidelines. Results: The most commonly observed diagnosis was a respiratory infection, which affected more than 88% of children prescribed with an antibiotic. Only 5 out of 33 prescribed antibiotic formulations did not contain at least one EKE. Prescribed medicines mostly contained sodium compounds (77.78%), sucrose (34.07%) and sodium benzoate (31.11%). In addition, the following EKE were detected: propylene glycol, aspartame, sorbitol, lactose, potassium, mannitol, benzalkonium chloride, azorubine, parabens, sodium metabisulfite and sunset yellow. Around 75% of prescribed antibiotic formulations contained inappropriately labeled EKE (sodium and potassium compounds, sodium benzoate and propylene glycol). Additionally, inappropriately labeled information leaflets did not include possible adverse effects caused by the EKE. Conclusions: This paper indicates high exposure of patients to EKE, where almost all children treated with antibiotics (96.3%) were simultaneously administered at least one EKE. We confirmed that approved medicines cannot meet the treatment needs of all patients, and that inappropriately labeled medicines carry a risk of ADRs, especially in newborns. Personalized treatment is especially important in children, as the appropriate dosage forms and diversity in formulation ingredients is lacking. Knowing the type and roles of each ingredient of the medicines it is possible to formulate a preparation that will meet all the individual children’s needs. [ABSTRACT FROM AUTHOR]

• Europe needs a sustainable system for timely, high-quality evidence on vaccine benefits and risks. • European vaccine stakeholders have different perspectives but similar information needs. • The ADVANCE project (now VAC4EU) has developed and tested a system to generate the necessary evidence. The influenza A/H1N1 pandemic in 2009 taught us that the monitoring of vaccine benefits and risks in Europe had potential for improvement if different public and private stakeholders would collaborate better (public health institutes (PHIs), regulatory authorities, research institutes, vaccine manufacturers). The Innovative Medicines Initiative (IMI) subsequently issued a competitive call to establish a public-private partnership to build and test a novel system for monitoring vaccine benefits and risks in Europe. The ADVANCE project (Accelerated Development of Vaccine benefit-risk Collaboration in Europe) was created as a result. The objective of this paper is to describe the perspectives of key stakeholder groups of the ADVANCE consortium for vaccine benefit-risk monitoring and their views on how to build a European system addressing the needs and challenges of such monitoring. These perspectives and needs were assessed at the start of the ADVANCE project by the European Medicines Agency together with representatives of the main stakeholders in the field of vaccines within and outside the ADVANCE consortium (i.e. research institutes, public health institutes, medicines regulatory authorities, vaccine manufacturers, patient associations). Although all stakeholder representatives stated they conduct vaccine benefit-risk monitoring according to their own remit, needs and obligations, they are faced with similar challenges and needs for improved collaboration. A robust, rapid system yielding high-quality information on the benefits and risks of vaccines would therefore support their decision making. ADVANCE has developed such a system and has tested its performance in a series of proof of concept (POC) studies. The system, how it was used and the results from the POC studies are described in the papers in this supplementary issue. [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]

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]

The recent benefit–risk framework (BRF) developed by the Food and Drug Administration (FDA) is intended to improve the clarity and consistency in communicating the reasoning behind the FDA's decisions, acting as an important advancement in US drug regulation. In the PDUFA VI implementation plan, the FDA states that it will continue to explore more structured or quantitative decision analysis approaches; however, it restricts their use within the current BRF that is purely qualitative. By contrast, European regulators and researchers have been long exploring the use of quantitative decision analysis approaches for evaluating drug benefit–risk balance. In this paper, we show how quantitative modelling, backed by decision theory, could complement and extend the FDA's BRF to better support the appraisal of evidence and improve decision outcomes. After providing relevant scientific definitions for benefit–risk assessment and describing the FDA and European Medicines Agency (EMA) frameworks, we explain the components of and differences between qualitative and quantitative approaches. We present lessons learned from the EMA experience with the use of quantitative modelling and we provide evidence of its benefits, illustrated by a real case study that helped to resolve differences of judgements among EMA regulators. [ABSTRACT FROM AUTHOR]

GW Research Ltd. provided two separate, but similar, submissions to the National Institute for Health and Care Excellence (NICE) on the clinical and cost-effectiveness of cannabidiol (CBD) 10 mg/kg/day, trade name Epidyolex®, for the adjunctive treatment of seizures associated with Lennox-Gastaut syndrome (LGS) and Dravet syndrome (DS). This paper highlights important methodological issues related to the company submissions, the Evidence Review Group (ERG) reports, and the subsequent development of the NICE guidance by the Appraisal Committee (AC) for the use of CBD. The company identified four randomised controlled trials (RCTs) of CBD (GWPCARE1 and GWPCARE2 for DS, and GWPCARE3 and GWPCARE4 for LGS) and an ongoing open-label extension study (GWPCARE5) as relevant to both submissions. In these RCTs, CBD in addition to current clinical management (CCM) was compared to CCM without CBD (i.e. CCM plus placebo). GWPCARE2 and GWPCARE3 were three-arm studies and compared two dosages of CBD (10 mg/kg/day and 20 mg/kg/day) in addition to CCM and CCM plus placebo. GWPCARE1 and GWPCARE4 compared CBD (20 mg/kg/day) in addition to CCM and CCM plus placebo. Both DS patients in GWPCARE2 and LGS patients in GWPCARE3 who received 10 mg/kg/day CBD in addition to CCM achieved better seizure frequency outcomes than those who received CCM plus placebo. In the company's base case, use of CBD for LGS patients resulted in an incremental cost-effectiveness ratio (ICER) of £31,107 per quality-adjusted life year (QALY) gained and, for DS patients, £36,046 per QALY gained versus CCM. The ERG considered that these ICERs were extremely uncertain and suffered from validity issues concerning model structure (e.g. patients receiving CCM moved back to baseline drop seizure frequency), input (e.g. inclusion of caregivers' QALYs), and transparency issues (e.g. hidden worksheets and coding in Visual Basic for Applications), and hence incorporated adjustments to the original base case which increased the ICERs. During the process, the European Medicines Agency (EMA) licence granted marketing authorisation for CBD only in conjunction with clobazam. Hence, the company provided evidence from this subgroup in an additional submission, which resulted in an ICER of £33,721 per QALY gained for LGS and an ICER of £32,471 per QALY gained for DS. In this submission and clarifications, the ERG was able to verify and validate most of the company's responses to the ERG's concerns. However, some issues remained regarding the face validity of model assumptions on patient pathways after treatment discontinuation. Finally, the AC recommended CBD with clobazam as an option for treating seizures associated with LGS and DS in patients aged 2 years and older only if (1) the frequency of drop seizures is checked every 6 months and CBD is stopped if the frequency has not fallen by at least 30% compared with 6 months before starting treatment and (2) the company provides CBD according to the commercial arrangement. [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]

Aims: There is a trend for more flexibility in timing of evidence generation in relation to marketing authorization, including the option to complete phase III trials after authorization or not at all. This paper investigated the relation between phase II and III clinical trial efficacy in oncology. Methods: All oncology drugs approved by the European Medicines Agency (2007–2016) were included. Phase II and phase III trials were matched based on indication and treatment and patient characteristics. Reported objective response rates (ORR), median progression‐free survival (PFS) and median overall survival (OS) were analysed through weighted mixed‐effects regression with previous treatment, treatment regimen, blinding, randomization, marketing authorization type and cancer type as covariates. Results: A total of 81 phase II‐III matches were identified including 252 trials. Mean (standard deviation) weighted difference (phase III minus II) was −4.2% (17.4) for ORR, 2.1 (6.7) months for PFS and −0.3 (5.1) months for OS, indicating very small average differences between phases. Differences varied substantially between individual indications: from −46.6% to 47.3% for ORR, from −5.3 to 35.9 months for PFS and from −13.3 to 10.8 months for OS. All covariates except blinding were associated with differences in effect sizes for at least 1 outcome. Conclusions: The lack of marked average differences between phases may encourage decision‐makers to regard the quality of design and total body of evidence instead of differentiating between phases of clinical development. The large variability emphasizes that replication of study findings remains essential to confirm efficacy of oncology drugs and discern variables associated with demonstrated effects. [ABSTRACT FROM AUTHOR]

Average bioequivalence tests are used in clinical trials to determine whether a generic drug has the same effect as an original drug in the population. For highly variable drugs whose intra-subject variances of direct drug effects are high, extra criteria are needed in bioequivalence studies. Currently used average bioequivalence tests for highly variable drugs recommended by the European Medicines Agency and the US Food and Drug Administration use sample estimators in the null hypotheses of interest. They cannot control the empirical type I error rate, so the consumer's risk is higher than the predetermined level. In this paper, we propose two new statistically sound methods that can control the empirical type I error rate without involving any sample estimators in the null hypotheses. In the proposed methods, we consider the average level of direct drug effects and the intra-subject variance of the direct drug effects. The first proposed method tests the latter parameter first to determine whether a product should be regarded as a highly variable drug, and then tests the former using corresponding bioequivalence limits. The second proposed method tests these two parameters simultaneously to capture the bioequivalence region. Extensive simulations are done to compare these methods. The simulation results show that the proposed methods have good performance on controlling the empirical type I error rate. The proposed methods are useful for pharmaceutical manufacturers and regulators. [ABSTRACT FROM AUTHOR]

Developing a novel drug, including discovery, nonclinical toxicology studies, initial clinical trials, and thorough pivotal studies, may take many years. Once an applicant has generated this comprehensive body of data, the final step prior to regulatory approval is Health Authority review of the marketing authorization application. Review by regulatory authorities to evaluate whether the data support a positive benefit/risk profile takes many months, adding additional time before patients may access therapy. In this paper, we discuss the various opportunities the US Food and Drug Administration and the European Medicines Agency offer to expedite the drug development and regulatory approval timelines for drugs intended to treat serious diseases and unmet medical needs. [ABSTRACT FROM AUTHOR]

Background: Regulatory agencies, such as the European Medicines Agency and Health Canada, are requiring the public sharing of clinical trial reports that are used to make drug approval decisions. Both agencies have provided guidance for the quantitative anonymization of these clinical reports before they are shared. There is limited empirical information on the effectiveness of this approach in protecting patient privacy for clinical trial data.Methods: In this paper we empirically test the hypothesis that when these guidelines are implemented in practice, they provide adequate privacy protection to patients. An anonymized clinical study report for a trial on a non-steroidal anti-inflammatory drug that is sold as a prescription eye drop was subjected to re-identification. The target was 500 patients in the USA. Only suspected matches to real identities were reported.Results: Six suspected matches with low confidence scores were identified. Each suspected match took 24.2 h of effort. Social media and death records provided the most useful information for getting the suspected matches.Conclusions: These results suggest that the anonymization guidance from these agencies can provide adequate privacy protection for patients, and the modes of attack can inform further refinements of the methodologies they recommend in their guidance for manufacturers. [ABSTRACT FROM AUTHOR]

Recently approved by the FDA and European Medicines Agency, CAR-T cell therapy is a new treatment option for B-cell malignancies. Currently, CAR-T cells are manufactured in centralized facilities and face bottlenecks like complex scaling up, high costs, and logistic operations. These difficulties are mainly related to the use of viral vectors and the requirement to expand CAR-T cells to reach the therapeutic dose. In this paper, by using Sleeping Beauty-mediated genetic modification delivered by electroporation, we show that CAR-T cells can be generated and used without the need for ex vivo activation and expansion, consistent with a point-of-care (POC) approach. Our results show that minimally manipulated CAR-T cells are effective in vivo against RS4;11 leukemia cells engrafted in NSG mice even when inoculated after only 4 h of gene transfer. In an effort to better characterize the infused CAR-T cells, we show that 19BBz T lymphocytes infused after 24 h of electroporation (where CAR expression is already detectable) can improve the overall survival and reduce tumor burden in organs of mice engrafted with RS4;11 or Nalm-6 B cell leukemia. A side-by-side comparison of POC approach with a conventional 8-day expansion protocol using Transact beads demonstrated that both approaches have equivalent antitumor activity in vivo. Our data suggest that POC approach is a viable alternative for the generation and use of CAR-T cells, overcoming the limitations of current manufacturing protocols. Its use has the potential to expand CAR immunotherapy to a higher number of patients, especially in the context of low-income countries. [ABSTRACT FROM AUTHOR]

The last two decades witnessed significant advances in the treatment of acquired demyelinating disorders: thirteen new agents have been approved for the treatment of multiple sclerosis in adults by the European Medicines Agency and US Food and Drug Administration in the last twenty years. Although the long-term efficacy and safety profiles of some new drugs are still being assessed in paediatric MS, clinicians may have to use them in the management of paediatric onset MS resistant to first-line medications, based on results obtained in adult-onset disease. This review summarizes the current approach to treatment in children with demyelinating syndromes. WHAT THIS PAPER ADDS: Serological markers affect management in paediatric demyelinating diseases. Antibodies against aquaporin-4 and myelin oligodendrocyte glycoprotein should be tested in children with acute demyelinating disease. New therapeutic agents currently in trial for pediatric disease should be used with close follow-up. [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]

This paper reviews the main tools for communicating benefit-risk medicines information to patients that are used, or could be used, by pharmaceutical regulators. One highly successful tool from the food safety sector (front-of-package traffic-light labelling) and the mental models approach (which provides a framework for developing new tools) are also reviewed as they show great promise for being usefully adapted to the pharmaceutical context. The evolution of benefit-risk medicines communication is first contextualised within the broader risk communication literature. Three distinct goals are then made explicit before critically examining the evidence for and against tools developed in the US (e.g. at the Food and Drug Administration [FDA]) and Europe (e.g. at the European Medicines Agency [EMA]). These goals are (i) sharing information (e.g. publishing clinical trial and adverse event data online); (ii) changing patients' beliefs by conveying factual knowledge (e.g. patient information leaflets and the drugs facts box); and (iii) changing behaviour (e.g. patient alert cards and warning labels). The mental models approach and traffic-light labelling, developed outside the pharmaceutical context, are then examined. Ultimately, the paper provides a helicopter view of the variety of benefit-risk communication tools that are used, or could be used, by pharmaceutical regulators in the US and Europe. [ABSTRACT FROM AUTHOR]

In 2016, the European Medicines Agency published the conclusions of its pilot on adaptive pathways, with products in early stages of development still building up to their marketing authorisation. Adaptive pathways rests on three principles: iterative development; gathering evidence through real‐life use to supplement clinical trial data; and early engagement of patients, payers and health technology assessment bodies in discussions on a medicine's development. While the pilot has now finished, the practical system‐wide implications of employing the adaptive pathways approach are not known and further consideration of these three principles is required. In this paper we used the three principles that underpin adaptive pathways to discuss main scientific and European policy developments likely to determine progress on further implementing adaptive pathways in the European setting. [ABSTRACT FROM AUTHOR]

The Critical Path for Parkinson's (CPP) Imaging Biomarker and Modeling and Simulation working groups aimed to achieve qualification opinion by the European Medicines Agency (EMA) Committee for Medical Products for Human Use (CHMP) for the use of baseline dopamine transporter neuroimaging for patient selection in early Parkinson's disease clinical trials. This paper describes the regulatory science strategy to achieve this goal. CPP is an international consortium of three Parkinson's charities and nine pharmaceutical partners, coordinated by the Critical Path Institute. [ABSTRACT FROM AUTHOR]

Abstract The health benefits of the antimicrobial's use is inherently associated to the risk of antimicrobial resistance (AMR), an ever-increasing multifactorial problem, closely related with injudicious use of antimicrobials, and the lack of new antimicrobial medicines on the market, particularly for veterinary use. Currently, an increasing number of regulatory "One Health" action plans on AMR are running worldwide, already based on monitoring and surveillance systems for resistance and antimicrobials consumption. Such plans are still not mandatory in the European Union member States (EU-MS), but post marketing annual programmes for quality controls of medicines are, to verify and ensure full compliance with the marketing authorizations. The European "risk level" sampling is not based on the conventional risk-ranking process of severity factors vs the probability of occurrence, but instead, on the conviction that in the European Union (EU) all medicines are produced under good manufacturer practices (GMP) and rigorously controlled for quality by the marketing authorization holders (MAH). The present paper links poor-quality antimicrobials and AMR, highlighting examples of regulatory initiatives on this subject outside the EU, particularly those resulting from the World Health Organization (WHO) recommendations. It also intends to trigger a discussion on the role of such quality control programmes, particularly for antimicrobials, beyond the control at any stage of the quality parameters of a marketed medicine, to reflect whether or not it might be relevant to other regulatory coordinated actions against AMR. Highlights • Importance of antibiotic premixes, as oral forms, for antimicrobial resistance. • Good practices for medicine manufacturing and distribution should cover medicated feed. • European monitoring programmes of AMR must include quality of VAMs. [ABSTRACT FROM AUTHOR]

In June 2015, European Medicines Agency/Committee for Advanced Therapies (CAT) released the new version of the reflection paper on classification of advanced therapy medicinal products (ATMPs) established to address questions of borderline cases in which classification of a product based on genes, cells or tissues is unclear. The paper shows CAT's understanding of substantial manipulation and essential function(s) criteria that define the legal scope of cell-based medicinal products. This article aims to define the authors' viewpoint on the reflection paper. ATMP classification has intrinsic weaknesses derived from the lack of clarity of the evolving concepts of substantial manipulation and essential function(s) as stated in the EU Regulation, leading to the risk of differing interpretations and misclassification. This might result in the broadening of ATMP scope at the expense of other products such as cell/tissue transplants and blood products, or even putting some present and future clinical practice at risk of being classified as ATMP. Because of the major organizational, economic and regulatory implications of product classification, we advocate for increased interaction between CAT and competent authorities (CAs) for medicines, blood and blood components and tissues and cells or for the creation of working groups including representatives of all parties as recently suggested by several CAs. [ABSTRACT FROM AUTHOR]

A biosimilar is a high quality biological medicine shown to be in essence the same as an original product. The European Medicines Agency (EMA) paved the way in the regulatory arena by creating a safeguarding framework for the development of biosimilars. Biosimilar is thus a regulatory term that alludes to the evidence-based studies required to demonstrate such very high similarity. They are therefore not innovative products but the pathway laid down by the EMA for their approval represented a new paradigm. This has brought some confusion and has cast doubts among healthcare professionals about the scientific evidence behind their authorization. Many papers have been published to clarify the concept, and to reassure those professionals, but misconceptions frequently still arise. Unfortunately, this prevents biosimilars from deploying their full therapeutic added value. This paper is intended to approach those misconceptions from a new angle, by explaining what a biosimilar is not...and why. A biosimilar is neither a generic, nor an original product. It is not a biobetter or a 'stand-alone'. Therefore, it should not be managed as such therapeutically, commercially or from a healthcare policy viewpoint. The EMA's criteria were acknowledged by other agencies, but a significant regulatory gap with a vast majority of regulatory bodies still remains. This leaves room for the so-called non-original biologics (NOB), i.e. non-biosimilar biologics, to be launched in many regions. Raising awareness of what a biosimilar is and what it is not, will generate trust in biosimilars among healthcare professionals and will ultimately benefit patients [ABSTRACT FROM AUTHOR]

Registries will enable cohort studies to be performed, which are usually considered to be the best quality of observational studies. The quality of data of registries can be increased if is it possible to merge results ('crosstalk') between registries. A prerequisite for that is an agreed uniform core set of data to be collected and uniform definitions on the items to be collected. This paper discusses problems and barriers with existing registries and provides recommendations from an EMA workshop (European Medicines Agency), for core common data sets and how to secure the quality of data collected. The PedNet registry including >2200 children with haemophilia is presented as an example of a registry/cohort study. [ABSTRACT FROM AUTHOR]