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Time is of the essence in evaluating potential drugs and biologics for the treatment and prevention of COVID‐19. There are currently 876 randomized clinical trials (phase 2 and 3) of treatments for COVID‐19 registered on clinicaltrials.gov. Covariate adjustment is a statistical analysis method with potential to improve precision and reduce the required sample size for a substantial number of these trials. Though covariate adjustment is recommended by the U.S. Food and Drug Administration and the European Medicines Agency, it is underutilized, especially for the types of outcomes (binary, ordinal, and time‐to‐event) that are common in COVID‐19 trials. To demonstrate the potential value added by covariate adjustment in this context, we simulated two‐arm, randomized trials comparing a hypothetical COVID‐19 treatment versus standard of care, where the primary outcome is binary, ordinal, or time‐to‐event. Our simulated distributions are derived from two sources: longitudinal data on over 500 patients hospitalized at Weill Cornell Medicine New York Presbyterian Hospital and a Centers for Disease Control and Prevention preliminary description of 2449 cases. In simulated trials with sample sizes ranging from 100 to 1000 participants, we found substantial precision gains from using covariate adjustment–equivalent to 4–18% reductions in the required sample size to achieve a desired power. This was the case for a variety of estimands (targets of inference). From these simulations, we conclude that covariate adjustment is a low‐risk, high‐reward approach to streamlining COVID‐19 treatment trials. We provide an R package and practical recommendations for implementation. [ABSTRACT FROM AUTHOR]

Allergen exposure chambers (AECs) can be used for controlled exposure to allergenic and non‐allergenic airborne particles in an enclosed environment, in order to (i) characterize the pathological features of respiratory diseases and (ii) contribute to and accelerate the clinical development of pharmacological treatments and allergen immunotherapy for allergic disease of the respiratory tract (such as allergic rhinitis, allergic rhinoconjunctivitis, and allergic asthma). In the guidelines of the European Medicines Agency for the clinical development of products for allergen immunotherapy (AIT), the role of AECs in determining primary endpoints in dose‐finding Phase II trials is emphasized. Although methodologically insulated from the variability of natural pollen exposure, chamber models remain confined to supporting secondary, rather than primary, endpoints in Phase III registration trials. The need for further validation in comparison with field exposure is clearly mandated. On this basis, the European Academy of Allergy and Clinical Immunology (EAACI) initiated a Task Force in 2015 charged to gain a better understanding of how AECs can generate knowledge about respiratory allergies and can contribute to the clinical development of treatments. Researchers working with AECs worldwide were asked to provide technical information in eight sections: (i) dimensions and structure of the AEC, (ii) AEC staff, (iii) airflow, air processing, and operating conditions, (iv) particle dispersal, (v) pollen/particle counting, (vi) safety and non‐contamination measures, (vii) procedures for symptom assessments, (viii) tested allergens/substances and validation procedures. On this basis, a minimal set of technical requirements for AECs applied to the field of allergology is proposed. [ABSTRACT FROM AUTHOR]

Background: Veterinary medicinal products (VMPs) administered to livestock might affect the environment. Therefore, an environmental risk assessment (ERA) is conducted during the approval process of VMPs. In the European Union (EU), the ERA, which was established approximately 10 years ago, consists of two phases. In the present review, we examined the first phase. In this phase, VMPs are subjected to a decision-making process comprising 19 questions and several tables with default values published in the "Guideline on environmental impact assessment for veterinary medicinal products in support of the VICH guidelines GL6 and GL38 (European Medicines Agency 2016)." Since a proportion of livestock husbandry systems is currently shifting toward ecological husbandry and free-range production systems, there is a lower risk of VMP consumption in general, but livestock excretions possibly containing VMPs might be directly released into the environment instead of being stored and applied as manure. In the present study, the first phase of the current ERA of VMPs in the EU was critically discussed with respect to the changes in animal husbandry. The large number of default values used in the ERA were checked for topicality. In a three-step approach, firstly trends and changes in animal husbandry in Europe that might be relevant for the ERA were collected, secondly, the interactions between Phase I and animal husbandry were evaluated and thirdly, the default values used in Phase I were verified in order to identify research gaps. Results: Several default values used in the current ERA were identified as outdated. Together with the lack of valid data (e.g., on animal husbandry systems or VMP treatments), this may have an impact on the predicted environmental concentration (PEC) as the central decision threshold of the ERA. Conclusions: The results of the present study indicate that an update of the ERA of VMPs in the EU is required to consider the changes in animal husbandry. Several aspects related to this issue are critically discussed. [ABSTRACT FROM AUTHOR]

Background: Mitochondrial disorders are among the most common heritable diseases, with an overall lifetime risk of approximately one in 1500. Nonetheless, their diagnosis is often missed because of their extreme phenotypic and genotypic heterogeneity. Methods: This review is based on publications retrieved by a selective literature search on the clinical features, genetics, pathogenesis, diagnosis, and treatment of mitochondrial diseases. Results: Pathogenic defects of energy metabolism have been described to date in over 400 genes. Only a small number of these genes lie in the mitochondrial DNA; the corresponding diseases are either maternally inherited or of sporadic distribution. The remaining disease-associated genes are coded in nuclear DNA and cause diseases that are inherited according to Mendelian rules, mostly autosomal recessive. The most severely involved organs are generally those with the highest energy requirements, including the brain, the sensory epithelia, and the extraocular, cardiac, and skeletal musculature. Typical manifestations include epileptic seizures, stroke-like episodes, hearing loss, retinopathy, external ophthalmoparesis, exercise intolerance, and diabetes mellitus. More than two manifestations of these types should arouse suspicion of a disease of energy metabolism. The severity of mitochondrial disorders ranges from very severe disease, already evident in childhood, to relatively mild disease arising in late adulthood. The diagnosis is usually confirmed with molecular-genetic methods. Symptomatic treatment can improve patients' quality of life. The only disease-modifying treatment that has been approved to date is idebenone for the treatment of Leber hereditary optic neuropathy. Intravitreal gene therapy has also been developed for the treatment of this disease; its approval by the European Medicines Agency is pending. Conclusion: Patients with mitochondrial diseases have highly varied manifestations and can thus present to physicians in practically any branch of medicine. A correct diagnosis is the prerequisite for genetic counseling and for the initiation of personalized treatment. [ABSTRACT FROM AUTHOR]

Background: Biosimilars have been used for 15 years in the European Union (EU), and have been shown to reduce costs and increase access to important biological medicines. In spite of their considerable exposure and excellent safety record, many prescribers still have doubts on the safety and interchangeability of biosimilars, especially monoclonal antibodies (mAbs) and fusion proteins. Objectives: The aim of this study was to analyse the short- and long-term safety and interchangeability data of biosimilar mAbs and fusion proteins to provide unbiased information to prescribers and policy makers. Methods: Data on the safety, immunogenicity and interchangeability of EU-licensed mAbs and fusion proteins were examined using European Public Assessment Reports (EPARs) and postmarketing safety surveillance reports from the European Medicines Agency (EMA). As recent biosimilar approvals allow self-administration by patients by the subcutaneous route, the administration devices were also analyzed. Results: Prelicensing data of EPARs (six different biosimilar adalimumabs, three infliximabs, three etanercepts, three rituximabs, two bevacizumabs, and six trastuzumabs) revealed that the frequency of fatal treatment-emergent adverse events (TEAEs), TEAEs leading to discontinuation of treatment, serious adverse events (SAEs), and main immune-mediated adverse events (AEs) were comparable between the biosimilars and their reference products. The availability of new biosimilar presentations and administration devices may add to patient choice and be an emerging factor in the decision to switch patients. Analysis of postmarketing surveillance data covering up to 7 years of follow-up did not reveal any biosimilar-specific adverse effects. No product was withdrawn for safety reasons. This is in spite of considerable exposure to biosimilars in treatment-naïve patients and in patients switched from the reference medicinal product to the biosimilar. Analysis of data from switching studies provided in regulatory submissions showed that single or multiple switches between the originator and its biosimilar versions had no negative impact on efficacy, safety or immunogenicity. Conclusions: In line with previous reports of prelicensing studies of biosimilar mAbs and etanercepts, this study demonstrated comparable efficacy, safety, and immunogenicity compared with the reference products. This is the first study to comprehensively analyze postmarketing surveillance data of the biosimilar mAbs and etanercept. An analysis of more than 1 million patient-treatment years of safety data raised no safety concerns. Based on these data, we argue that biosimilars approved in the EU are highly similar to and interchangeable with their reference products. Thus, additional systematic switch studies are not required to support the switching of patients. [ABSTRACT FROM AUTHOR]

Copyright of Arab Journal of Psychiatry is the property of Arab Federation of Psychiatrists 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.)

Introduction: Input from patients and healthcare professionals to regulatory assessments is essential for benefit–risk management of medicines. How to best obtain input in different risk scenarios is uncertain. Objectives: The objective of this study was to investigate whether the International Risk Governance Council (IRGC) Framework is applicable to pharmacovigilance and can guide selecting engagement mechanisms for optimising stakeholder input. Methods: For proof-of-concept, classify 'iconic' cases of pharmacovigilance engagement at the European Medicines Agency (EMA) by IRGC risk scenario types and compare the engagement that happened with the engagement discourse recommended by the IRGC Framework for different risk scenarios. If the concept is proven, derive proposals for strengthening engagement. Results: Six iconic cases were classified by risk scenario type at the respective time points when deciding on engagement: venous thromboembolism with combined hormonal contraceptives (complex risk); lipodystrophy with highly active antiretroviral therapy medicines, carcinogenicity with contaminated nelfinavir products (uncertain risks); teratogenicity with thalidomide, progressive multifocal leukoencephalopathy with natalizumab, teratogenicity and developmental disorders with valproate (ambiguous risks). The comparison of the engagement events with IRGC recommendations showed correspondence between the scope/outcomes of the events and the features of the recommended discourse. Conclusions: The IRGC Framework appears applicable to pharmacovigilance. Proposals derived from the IRGC recommendations may be valuable for guiding regulators when selecting mechanisms for engagement with patients and healthcare professionals in given risk scenarios. The proposed decision guide aims at ensuring systematic and consistent engagement across regulatory assessments and providing for the most purposeful discourse, to effectively obtain real-world input for regulatory risk assessment, evaluation of risk minimisation measures and decision making. [ABSTRACT FROM AUTHOR]

Copyright of Revista Română de Drept European is the property of Wolters Kluwer Romania 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 uncertainty of agreement between Great Britain and the European Union (EU) on the future location of the European Medicines Agency (EMA) when the country takes its leave from the EU. It notes the position paper presented by drugs industry urging heads of states to make some firm decisions, including Pfizer, GlaxoSmithKine, and Sanofi. Also noted is the number of EU member states vying to accommodate the agency, citing its annual budget and number of staff.

Pteridophytes, represented by ferns and allies, are an important phytogenetic bridge between lower and higher plants. Ferns have evolved independently of any other species in the plant kingdom being its secondary metabolism a reservoir of phytochemicals characteristic of this taxon. The study of the potential uses of Polypodium vulgare L. (Polypodiaceae) as medicinal plant has increased in recent years particularly when in 2008 the European Medicines Agency published a monograph about the rhizome of this species. Our objective is to provide scientific knowledge on the polar constituents extracted from the fronds of P. vulgare , one of the main ferns of European distribution, to contribute to the validation of certain traditional uses. Specifically, we have characterized the methanolic extract of P. vulgare fronds (PVM) by HPLC-DAD and investigated its potential cytotoxicity, phototoxicity, ROS production and protective effects against oxidative stress by using in vitro methods. The 3T3, HaCaT, HeLa, HepG2, MCF-7 and A549 were the cell lines used to evaluate the possible cytotoxic behaviour of the PVM. HPLC-DAD was utilized to validate the polyphenolic profile of the extract. H2O2 and UVA were the prooxidant agents to induce oxidative stress by different conditions in 3T3 and HaCaT cell lines. Antioxidant activity of in vitro PVM in 3T3 and HaCaT cell lines was evaluated by ROS assay. Our results demonstrate that PVM contains significant amounts of shikimic acid together with caffeoylquinic acid derivatives and flavonoids such as epicatechin and catechin; PVM is not cytotoxic at physiological concentrations against the different cell lines, showing cytoprotective and cellular repair activity in 3T3 fibroblast cells. This biological activity could be attributed to the high content of polyphenolic compounds. The fronds of the P. vulgare are a source of polyphenolic compounds, which can be responsible for certain traditional uses like wound healing properties. In the present work, fronds of the common polypody are positioned as a candidate for pharmaceutical applications based on traditional medicine uses but also as potential food ingredients due to lack of toxicity at physiological concentrations. [ABSTRACT FROM AUTHOR]

Background Roxadustat is an orally active hypoxia-inducible factor prolyl hydroxylase inhibitor for the treatment of chronic kidney disease (CKD) anemia. Methods This Phase 3, multicenter, randomized, double-blind, placebo-controlled study examined patients with Stages 3–5 CKD, not on dialysis (NCT01887600). Patients were randomized (2:1) to oral roxadustat or placebo three times weekly for 52–104 weeks. This study examined two primary efficacy endpoints: European Union (European Medicines Agency)—hemoglobin (Hb) response, defined as Hb ≥11.0 g/dL that increased from baseline (BL) by ≥1.0 g/dL in patients with Hb >8.0 g/dL or ≥2.0 g/dL in patients with BL Hb ≤8.0 g/dL, without rescue therapy, during the first 24 weeks of treatment; US Food and Drug Administration—change in Hb from BL to the average Hb level during Weeks 28–52, regardless of rescue therapy. Secondary efficacy endpoints and safety were examined. Results A total of 594 patients were analyzed (roxadustat: 391; placebo: 203). Superiority of roxadustat versus placebo was demonstrated for both primary efficacy endpoints: Hb response [odds ratio = 34.74, 95% confidence interval (CI) 20.48–58.93] and change in Hb from BL [roxadustat – placebo: +1.692 (95% CI 1.52–1.86); both P < 0.001]. Superiority of roxadustat was demonstrated for low-density lipoprotein cholesterol change from BL, and time to first use of rescue medication (both P < 0.001). The incidences of treatment-emergent adverse events were comparable between groups (roxadustat: 87.7%, placebo: 86.7%). Conclusions Roxadustat demonstrated superior efficacy versus placebo in terms of both Hb response rate and change in Hb from BL. The safety profiles of roxadustat and placebo were comparable. [ABSTRACT FROM AUTHOR]

Background. The initial approval of the Pfizer/BioNTech and Moderna vaccines by the European Medicines Agency (EMA) and Food and Drug Administration (FDA) marked a milestone in the fight against the COVID-19 pandemic. The increased public debate about the vaccine development process and vaccine side effects has activated the anti-vaccine community, which has begun to spread conspiracy theories about vaccine safety. Objectives. Our study is the first to investigate the awareness of Polish patients suffering from various chronic diseases, mainly cancer, about vaccination against SARS-CoV-2. Materials and methods. An anonymous survey was made available from November 2020 to February 2021 to representatives of patient organizations through social media (Facebook) and to patients in the Chemotherapy Department of the Clinical Hospital in Poznań. The survey was completed by 836 patients. The majority of the survey respondents had cancer (77%, n = 644), and almost 1/5 of the respondents indicated hypertension (15.7%, n = 131) as well as depression and/or anxiety disorders (11.1%, n = 93). Results. Less than half of the respondents (43.5%, n = 364) believed that SARS-CoV-2 vaccines were safe (40.4%, n = 260, among cancer patients; 53.9%, n = 104, among patients with other medical conditions). More than half of the respondents (60.5%, n = 506) intended to be vaccinated against SARS-CoV-2 (58.8%, n = 378, among cancer patients; 66.3%, n = 128, among patients with other medical conditions). Fear of vaccine complications and lack of belief in vaccine effectiveness were prevalent among both cancer patients and patients with other medical conditions. Conclusions. The vast majority of cancer and medical patients wanted to be vaccinated against COVID-19. More than half of the respondents did not believe that the COVID-19 vaccine would be safe for them. Education of cancer and medical patients on the safety and effectiveness of the vaccine, as well as the use of additional protective measures against infection, is an extremely important element of prevention during the COVID-19 pandemic. [ABSTRACT FROM AUTHOR]

Rationale, aims and objectives: New therapies are increasingly approved by regulatory agencies such as the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) based on testing in non‐randomized clinical trials. These treatments have typically displayed "dramatic effects" (ie, effects that are considered large enough to obviate the combined effects of biases and random errors that may affect the study results). The agencies, however, have not identified how large these effects should be to avoid the need for further testing in randomized controlled trials (RCTs). We investigated the effect size that would circumvent the need for further RCTs testing by the regulatory agencies. We hypothesized that the approval of therapeutic interventions by regulators is based on heuristic decision making whose accuracy can be best characterized by the application of signal detection theory (SDT). Methods: We merged the EMA and FDA database of approvals based on non‐RCT comparisons. We excluded duplicate entries between the two databases. We included a total of 134 approvals of drugs and devices based on non‐RCTs. We integrated Weber‐Fechner law of psychophysics and recognition heuristics within SDT to provide descriptive explanations of the decisions made by the FDA and EMA to approve new treatments based on non‐randomized studies without requiring further testing in RCTs. Results: Our findings suggest that when the difference between novel treatments and the historical control is at least one logarithm (base 10) of magnitude, the veracity of testing in non‐RCTs seems to be established. Conclusion: Drug developers and practitioners alike can use the change in one logarithm of effect size as a benchmark to decide if further testing in RCTs should be pursued, or as a guide to interpreting the results reported in non‐randomized studies. However, further research would be useful to better characterize the threshold of effect size above which testing in RCTs is not needed. [ABSTRACT FROM AUTHOR]

Summary: Allogeneic islet transplantation is a standard of care treatment for patients with labile type 1 diabetes in many countries around the world, including Japan, the United Kingdom, Australia, much of continental Europe, and parts of Canada. The United States is now endorsing islet cell treatment for type 1 diabetes, but the FDA has chosen to consider islets as a biologic that requires licensure, making the universal implementation of the procedure in the clinic very challenging and opening the manufacture of islet grafts to private companies. The commercialization of human tissues raises significant legal and ethical issues and ironically leads to a situation where treatments developed as a result of the scientific and economic efforts of academia over several decades become exploited exclusively by for‐profit entities. [ABSTRACT FROM AUTHOR]

Purpose: Various incentives are provided by the European Medicines Agency (EMA) to facilitate the development and marketing of orphan drugs. A 10-year period of market exclusivity is reserved to an orphan medicinal product. Sometimes, the sponsor renounces the designation before the expiration of that standard period. Our aim was to focus on these premature withdrawals. Methods: We retrieved all the molecules included in the Community Register of Orphan Medicinal Products for Human Use from 2000 to November 2020. We considered the active substance, therapeutic indication, sponsor, year of designation, year of approval of the corresponding medicinal product, and that of the withdrawal of the orphan designation, if occurred. Results: Overall, 2350 orphan designations were approved from 2000 to November 2020. Of these, 141 have been marketed. Premature withdrawal of orphan designation concerned 23 drugs (20 being antineoplastic agents), corresponding to 16 medicinal products. These withdrawals occurred after almost 2 years (range <1–7 years). Conclusions: A not negligible fraction of marketed orphan medicinal products underwent premature removal of their orphan designation. No motivation is requested by the EMA for this renouncement, although the peculiarity of the orphan medicinal products would need a greater transparency. We can only speculate about possible compensations in support of this decision, for instance in terms of commercial agreements between pharmaceutical companies, giving way to alternative products, as a couple of examples suggest. An open debate on this topic among members of academia, regulatory bodies, price and reimbursements committees, and pharmaceutical industry representatives will be welcome. [ABSTRACT FROM AUTHOR]

As per the ICH Q3A(R2) and Q3B(R2) regulatory guidelines, safety studies may be needed when an impurity in new drug substances or products is above the qualification threshold, and such qualification studies should be conducted in one nonclinical species for a duration of 14–90 days. However, the guidelines do not specify details about species selection, recommended study design, and the exact study duration that would support clinical use of a specific duration. This lack of guidance leads to ambiguity and sponsors have used various study designs to qualify impurities. In 2018, the European Medicines Agency provided a draft reflection paper encouraging the incorporation of 3Rs (Replacement, Reduction, and Refinement) principles for animal use into impurity qualification. As a response, the IQ DruSafe Impurity Working Group (WG) surveyed the IQ member companies to capture the current practices for impurity qualification, and evaluate study designs for a potential reduction in animal testing. This article summarizes the results and learnings from the survey. Additionally, the WG leveraged the survey learnings and provided harmonized study design considerations aimed towards achieving the study objectives, while supporting the 3Rs initiative in reducing the total number of animals used (up to 90%) for impurity qualification. • An IQ DruSafe survey demonstrated variations in impurity qualification designs amongst pharmaceutical companies. • No toxicity from impurities has been observed in the surveyed impurity qualification studies. • Harmonized study designs have been developed in accordance with the regulatory guidance. • The study designs will continue to ensure patient safety, while emphasizing the 3Rs, specifically reduction and refinement. • Variations from the study design are included which may be considered on a case-by-case basis. [ABSTRACT FROM AUTHOR]

N-Nitrosamines have recently been the subject of intense regulatory scrutiny, including the setting of low exposure limits (18 ng/day) (European Medicines Agency (EMA), 2020). This paper evaluates different methodologies to determine statistically robust bounds on the carcinogenic potency of chemical classes, using historic TD 50 data (Peto et al., 1984; Thresher et al., 2019) and exemplified for N-nitrosamines. Initially, the distribution of TD 50 values (TD 50 s) for N-nitrosamines of known potency was characterised. From this, it is possible to compare parametric and non-parametric methods to obtain percentiles of interest from the distribution of TD 50 s, which are shown to be robust to uncertainty in the initial TD 50 estimates. These methods may then be applied to different chemical subclasses. The values obtained may be of use in refining acceptable intakes for N-nitrosamines and their subclasses. • The distribution of N-nitrosamine carcinogenic potencies is log-normal. • Parametric methods allow for increased statistical power when estimating features of interest. • Structure based subclasses of N-nitrosamines show different potencies. [ABSTRACT FROM AUTHOR]

Few studies have empirically examined the relationship between trust and its consequences in the pharmaceutical context (e.g. the consequences of trust in medicines advice for patient behaviour). This study empirically examined the European public's perceived trustworthiness of medical, societal, and industry sources of medicines advice, and its consequences for their behavioural intentions including their medicine-taking and information-seeking behaviour. A representative survey (N = 6,001) was conducted with adults from six European countries: Great Britain, France, Germany, Denmark, Italy, and Poland. As expected, respondents consistently rated advice from medical sources (GPs, pharmacists, local hospitals, emergency services) as significantly more trustworthy than advice from societal sources (the Internet, friends/relatives, and the mass media) and, especially, industry (pharmaceutical companies and brand specific websites). A structural equation model then revealed strong associations between the public's perceived trustworthiness of these medical, societal, and industry sources and their medicine-taking and information seeking intentions. Important national variations were found including in the public's opinions on when authorities should convey new safety information. Implications for communicating benefit-risk information in a more transparent regulatory environment are discussed, including the importance of maintaining and strengthening trust in medical actors and committing more resources to supporting national risk communication. [ABSTRACT FROM AUTHOR]

Getting the right dose regimen for children and adolescents is important but poses great scientific, practical, and ethical challenges. At the same time, the availability of data in adults is a huge advantage and needs to be used optimally when designing studies in children and analyzing pediatric data. Furthermore, the processes of maturation and growth are always key when selecting doses for children. All the above make study adaptations and model‐informed approaches imperative for dose exposure‐response characterization and dose selection in children. This article summarizes the experience gained in the European Medicines Agency on this topic and proposes some general guiding principles for defining objectives, study designs, and methodology tools for pediatric dose selection. [ABSTRACT FROM AUTHOR]

Gene therapy medicinal products have the potential to provide curative treatment for many diseases with current limited therapeutic options. As advanced therapy medicinal products (ATMPs), these therapies undergo a centralised, single European Union authorisation by the European Medicines Agency (EMA), but the risks and potential harm to the environment and population at large are weighted in each application, and different interpretations at national level exist. A streamlined procedure is now in place to facilitate a consistent approach for the assessment of the environmental risks of medicines containing genetically modified organisms for both clinical trial applications and marketing authorisation applications. This article provides an overview of basic requirements across the EU, an overview of the new streamlined process and discusses available guidance for developers with particular emphasis on marketing authorisation applications. All these initiatives are aimed to remove hurdles for ATMP developers and facilitate faster access to patients. [ABSTRACT FROM AUTHOR]

Scientific advice (SA) is an important tool offered by regulators to help developers generate robust evidence on a medicine's benefits and risks. Drawing on accumulated experience and looking at the SA provided by the European Medicines Agency in 2018 to advanced therapy medicinal products originally developed by public bodies, we discuss most commonly raised issues and the complexity and timings of the questions posed. Earlier and more frequent SA could help advanced therapy medicinal product developers to pre‐empt delays at the marketing authorisation stage. Carefully addressing quality and nonclinical issues before entering the pivotal phase of development will clear the path for a smooth clinical development and successful marketing authorisation. [ABSTRACT FROM AUTHOR]

Aim: To retrospectively analyse hospital outpatient treatment (HOT) withdrawal due to unacceptable toxicity at our hospital. Information regarding unacceptable toxicity leading to treatment withdrawal was recorded. Methods: HOT interruptions because of unacceptable toxicity were identified from the Register of Patients and Treatments (RPT) (January 2014 to December 2017). Information regarding the demographic and clinical characteristics of patients, adverse drug reactions (ADRs) and drug treatments was retrieved from electronic health records. Causality and previous knowledge of ADRs were assessed according to the Spanish Pharmacovigilance System algorithm. Information regarding HOT risk management plans (RMPs) and their classification as inverted black triangle medicines was obtained from the European Medicines Agency (EMA). Results: HOTs were withdrawn due to unacceptable toxicity in 136 (1.5%) registries corresponding to 135 (1.7%) patients. Fifty‐one different HOTs (38.6% of those registered) were involved in 240 ADR/HOT pairs: 24 (47%) were additional monitoring medicines and 37 (72.5%) were EMA RMPs. The most frequent medicines involved in ADRs were lenalidomide (30, 12.5%) (mainly neutropenia, thrombocytopenia and bicytopenia), bevacizumab (19, 7.9%) (mainly venous and pulmonary thromboembolism) and sunitinib (13, 5.4%) (mainly thromboembolic events, diarrhoea and worsening of chronic renal failure). Cytopenia (40, 17.3%), diarrhoea (15, 6.5%), asthenia (9, 3.9%) and neuropathy (6, 2.6%) were the most frequent ADRs. All ADRs were severe, 10 (6 patients) had been poorly described or were unknown and only 9 (5 patients) had been reported by spontaneous notification. Conclusions: Valuable information regarding severe and unknown ADRs was obtained from the RPT. Such registers are useful tools to complement spontaneous ADR notifications. [ABSTRACT FROM AUTHOR]

Mono- and bis-pyridinium quaternary aldoximes (K-oximes) have long been employed as cholinesterase reactivator components of antidotes against lethal cholinesterase-inhibiting organophosphorous chemicals. Their positive charge poses difficulties in their chromatographic analysis, resulting in the publication of different approaches for each K-oxime. A multiplexed method is presented for the rapid quantitation of 10 K-oximes in blood with its utility demonstrated in vivo. Liquid chromatography with absorbance detection was employed. Reversed-phase separation was achieved on a highly nonpolar stationary phase. Method validation was based on the respective guideline of the European Medicines Agency. Times to peak concentrations and 120-min areas under the time–concentration curves were determined in rats following intraperitoneal administration. Adequate retention and separation of K-oximes with acceptable peak shapes in short isocratic runs was achieved by adjusting ionic strength, organic content and the concentration of the ion-pairing agent of the mobile phase. Chromatographic properties were governed by optimizing the concentration of dissolved ions. Accurate adjustment of the organic content was indispensable for avoiding peak drifting and splitting. Dose-adjusted exposure to K-347 and K-868 was exceptionally low, while exposure to K-48 was the highest. The method is suitable for screening systemic exposure to various K-oximes and can be extended. [ABSTRACT FROM AUTHOR]

Background: Promethazine is a medicinal product, available on its own or in combination with other ingredients including dextromethorphan, paracetamol and/or expectorants. Anecdotal reports have however indicated that promethazine may have a misuse potential, especially in adolescents. Objective: We here aimed at studying how this phenomenon has been reported to the European Monitoring Agency Adverse Drug Reactions database. Methods: After a formal request to the European Monitoring Agency, the promethazine-specific dataset has been studied, performing a descriptive analysis of misuse/abuse/dependence-related adverse drug reaction reports. The study was approved by the University of Hertfordshire (LMS/PGR/UH/03234). Results: The analysis of promethazine data showed increasing levels of misuse/abuse/ dependence issues over time (2003–2019). Out of a total number of 1543 cases of adverse drug reactions, the abuse/misuse/dependence-related cases reported were 557, with 'drug abuse' (300/557: 53.8%) and 'intentional product misuse' (117/557: 21.0%). being the most represented adverse drug reactions. A high number of fatalities were described (310/557: 55.6%), mostly recorded as 'drug toxicity/drug abuse' cases, with opiates/opioids having been the most commonly reported concomitant drugs used. Conclusion: Anecdotal promethazine misuse/abuse reports have been confirmed by European Monitoring Agency data. Promethazine misuse/abuse appears to be an alarming issue, being associated with drug-related fatalities. Thus, healthcare professionals should be warned about a possible misuse of promethazine and be vigilant, as in some countries medicinal products containing promethazine can be purchased over the counter. Since promethazine is often available in association with opioids, its abuse may be considered a public health issue, with huge implications for clinical practice. [ABSTRACT FROM AUTHOR]

Since March 2020, the world has been fighting a global pandemic caused by a new coronavirus SARS-CoV-2 (COVID-19). SARS-CoV-2 is responsible for severe acute respiratory syndrome, an airway disease that can be severe and fatal in a percentage of cases. Patients with severe COVID-19 can develop extrapulmonary lesions, with renal, hepatic, cardiac, neurological, and tissue involvement that can cause further severe complications. On December 21, 2021, the European Medicines Agency (EMA) authorized the marketing of the first COVID-19 vaccine. However, several randomized trials are ongoing to find effective, safe, and widely available treatments. The most severe stages of COVID-19 infection are characterized by a multi-system inflammatory state induced by a cytokine storm causing multi-organ injury. Epidemiologic evidence has shown that glucocorticoids (GCs), particularly dexamethasone, are used in severe, hospitalized patients with COVID-19 with good therapeutic benefit. COVID-19 can also damage the endothelial system, causing microcirculatory disturbances and consequently leading to functional organ disorders. The combination of endothelial dysfunction with a generalized inflammatory state may contribute to the general pro-coagulative state described in patients with COVID-19 with increased risk of venous and arterial occlusions. The aim of this article is to describe the therapeutic utility of GCs in stabilizing the vascular endothelial barrier in COVID-19 infection. Indeed, we believe that the stabilization of the endothelial barrier and the anti-inflammatory effect of GCs could be the main effect underlying the therapeutic efficacy in COVID-19 patients. [ABSTRACT FROM AUTHOR]

Gene therapy has entered a new era after decades-long efforts, where the recombinant adeno-associated virus (AAV) has stood out as the most potent vector for in vivo gene transfer and demonstrated excellent efficacy and safety profiles in numerous preclinical and clinical studies. Since the first AAV-derived therapeutics Glybera was approved by the European Medicines Agency (EMA) in 2012, there is an increasing number of AAV-based gene augmentation therapies that have been developed and tested for treating incurable genetic diseases. In the subsequent years, the United States Food and Drug Administration (FDA) approved two additional AAV gene therapy products, Luxturna and Zolgensma, to be launched into the market. Recent breakthroughs in genome editing tools and the combined use with AAV vectors have introduced new therapeutic modalities using somatic gene editing strategies. The promising outcomes from preclinical studies have prompted the continuous evolution of AAV-delivered therapeutics and broadened the scope of treatment options for untreatable diseases. Here, we describe the clinical updates of AAV gene therapies and the latest development using AAV to deliver the CRISPR components as gene editing therapeutics. We also discuss the major challenges and safety concerns associated with AAV delivery and CRISPR therapeutics, and highlight the recent achievement and toxicity issues reported from clinical applications. [ABSTRACT FROM AUTHOR]

Monitoring of antimicrobial use is essential in the management of the development and selection of antimicrobial resistance. A variety of indicators has become available to monitor antimicrobial use in human and animal medicine. One of them is an indicator based on defined daily dose (DDD). By using the number of DDDs administered and normalising it by the population at risk of being treated over a defined period, one can estimate the number of treatment days with antimicrobial agents in a population. For veterinary medicine, the European Medicines Agency (EMA) has published the European values of DDD (DDDvet) for food-producing animals. In this study, we defined Japanese defined daily doses for antimicrobial agents (DDDjp) using DDD values that we previously assigned for antimicrobial products approved for use in pigs, cattle and poultry in Japan and compared them with DDDvet values. For the comparison, the quotient of Japanese and European values (QDDD) was calculated and the effect of the administration route and the number of active substances contained in the preparation was investigated. A total of 59 DDDjp values were defined for 43 antimicrobial agents using the data of 276 products approved for use in pigs. Likewise, a total of 55 DDDjp values were defined for 32 antimicrobial agents using the data of 196 products for use in cattle, and a total of 27 DDDjps values were defined for 25 antimicrobial agents using the data of 131 products approved for use in poultry. A comparison was made for 42, 28 and 17 pairs of DDDjp and DDDvet values for antimicrobial agents used for pigs, cattle and poultry respectively. The comparison showed median QDDD value of 0.61 and 0.66 for antimicrobial agents used for pigs and cattle respectively (p<0.01), indicating that the Japanese daily doses are significantly lower than the corresponding EMA values in these species. For the antimicrobial agents used for poultry, no significant difference was observed between DDDjp and DDDvet values with a median QDDD value of 1.15. The difference between DDDvet and DDDjp values and absence of DDDvet values for some antimicrobial agents marketed in Japan indicate that DDDjp rather than DDDvet should be used as the basis for the calculation of antimicrobial use monitoring in farm animals in Japan. [ABSTRACT FROM AUTHOR]

The summary of product characteristics from the European Medicines Agency is a reference document on medicines in the EU. It contains textual information for clinical experts on how to safely use medicines, including adverse drug reactions. Using natural language processing (NLP) techniques to automatically extract adverse drug reactions from such unstructured textual information helps clinical experts to effectively and efficiently use them in daily practices. Such techniques have been developed for Structured Product Labels from the Food and Drug Administration (FDA), but there is no research focusing on extracting from the Summary of Product Characteristics. In this work, we built a natural language processing pipeline that automatically scrapes the summary of product characteristics online and then extracts adverse drug reactions from them. Besides, we have made the method and its output publicly available so that it can be reused and further evaluated in clinical practices. In total, we extracted 32,797 common adverse drug reactions for 647 common medicines scraped from the Electronic Medicines Compendium. A manual review of 37 commonly used medicines has indicated a good performance, with a recall and precision of 0.99 and 0.934, respectively. [ABSTRACT FROM AUTHOR]

Background: Cannabidiol (CBD), which is one major constituent of the Cannabis sativa plant, has anti-seizure properties and does not produce euphoric or intrusive side effects. A plant-derived, highly purified CBD formulation with a known and constant composition has been approved by the US Food and Drug Administration for the treatment of seizures associated with Dravet syndrome, Lennox-Gastaut syndrome, and tuberous sclerosis complex. In the European Union, the drug has been authorized by the European Medicines Agency for the treatment of seizures associated with Dravet syndrome and Lennox-Gastaut syndrome, in conjunction with clobazam, and is under regulatory review for the treatment of seizures in patients with tuberous sclerosis complex.Objectives: This systematic review aimed to summarize the currently available body of knowledge about the use of this US Food and Drug Administration/European Medicines Agency-approved oral formulation of pharmaceutical-grade CBD in patients with epileptic conditions, especially developmental and epileptic encephalopathies other than Dravet syndrome and Lennox-Gastaut syndrome.Methods: The relevant studies were identified through MEDLINE and the US National Institutes of Health Clinical Trials Registry in October 2020. There were no date limitations or language restrictions. The following types of studies were included: clinical trials, cohorts, case-control, cross-sectional, clinical series, and case reports. Participants had to meet the following criteria: any sex, any ethnicity, any age, diagnosis of epilepsy, receiving plant-derived, highly purified (> 98% w/w) CBD in a sesame oil-based oral solution for the treatment of seizures. Data extracted from selected records included efficacy, tolerability, and safety outcomes.Results: Five hundred and seventy records were identified by database and trial register searching. Fifty-seven studies were retrieved for detailed assessment, of which 42 were eventually included for the review. The participants of the studies included patients of both pediatric and adult age. Across the trials, purified CBD was administered at dosages up to 50 mg/kg/day. In a randomized double-blind controlled trial in patients with tuberous sclerosis complex, CBD was associated with a significantly greater percent reduction in seizure frequency than placebo over the treatment period. Open-label studies suggested the effectiveness of CBD in the treatment of children and adults presenting with other epilepsy syndromes than those addressed by regulatory trials, including CDKL5 deficiency disorder and Aicardi, Dup15q, and Doose syndromes, SYNGAP1 encephalopathy, and epilepsy with myoclonic absences. The most common adverse events observed during treatment with CBD included somnolence, decreased appetite, diarrhea, and increased serum aminotransferases.Conclusions: The currently available data suggest that response to treatment with a highly purified, plant-derived CBD oil-based solution can be seen in patients across a broad range of epilepsy disorders and etiologies. The existing evidence can provide preliminary support for additional research. [ABSTRACT FROM AUTHOR]

Aims: Dose adjustment for drugs eliminated by the kidneys generally assume a linear relationship between renal drug clearance (CLR) and glomerular filtration rate (GFR). This assumption may not hold for drugs that undergo extensive tubular secretion where nonlinearity in drug handling is expected. The aim of this study is to determine if renal drug study designs recommended by the European Medicines Agency (EMA) and Food and Drug Administration (FDA) could distinguish linear from nonlinear renal drug handling. Methods: In this simulation and estimation study, the study designs based on the EMA and FDA guidelines for Phase I renal drug studies were evaluated for their ability to discriminate a linear from a nonlinear relationship between CLR and GFR. The number of subjects for each simulated study ranged from 4 to 960. Power, relative standard error and bias were calculated. Results: Study designs under the EMA and FDA guidelines required ≥8 and ≥48 subjects, respectively, to achieve ≥80% power to discriminate a linear from nonlinear relationship between CLR and GFR. The relative standard error of estimated parameters were 13–37 and 17–44% for the designs with 24 subjects under the EMA and FDA guidelines, respectively. The bias in parameter estimates under the EMA designs were not evident, however, they were biased (13–21%) under the FDA designs. Conclusion: The EMA design was found to require fewer subjects (n = 8) compared to the FDA (n = 48) to discriminate linear from nonlinear drug renal handling at ≥80% study power while both the designs perform poorly for the parameter precision. [ABSTRACT FROM AUTHOR]

Background and Aims: The Enhanced Passive Safety Surveillance is a requirement of the European Medicines Agency (EMA) for seasonal influenza vaccines, aiming to rapidly detect any significant change in frequency or severity of expected reactogenicity or allergic events prior to widespread use of a vaccine in any particular year. The aim of this surveillance was to assess the quadrivalent inactivated split-virion influenza vaccine (IIV4) during routine immunization in Finland, as per the national immunization program for 2019/20. The primary objective was to investigate the suspected adverse drug reactions (ADR) occurring within 7 days following vaccination.Methods: Passive surveillance of individuals vaccinated with IIV4 was conducted within the first 4 to 6 weeks of the influenza season in Finland. Potential ADRs were reported via phone or posted adverse event forms. The vaccinee reporting rate and ADR reporting rate were calculated and compared with the known or expected safety data in order to identify any change which was clinically significant.Results: Data were collected from 939 individuals, with 56 reports received for 163 suspected ADRs. Of these, 38 individuals reported 117 suspected ADRs within 7 days following vaccination, corresponding to an ADR reporting rate of 12.46% (95% CI: 10.41, 14.74%); vaccination-site pain, vaccination-site reaction, and pyrexia were the most frequently reported ADRs. The 18-to-65 years of age category had an ADR reporting rate of 12.56%, the over-65 years of age category had an ADR reporting rate of 16.22%, and no ADRs were reported for individuals aged 6 months to 18 years. No serious suspected ADRs were reported at any time post-vaccination, and the ADR rates were comparable to those reported for IIV4 in the 2018/19 seasonal assessment. The frequency of suspected ADRs was generally aligned with those reported in the Summary of Product Characteristics (SmPC), with the exception of asthenia, somnolence, and erythema, which were slightly higher. No reporting pattern by type, frequency, or severity was identified for the suspected ADRs.Conclusions: No clinically significant changes in what is known or expected for IIV4 was reported for the 2019/20 season, which supports the overall safety profile. [ABSTRACT FROM AUTHOR]

5-fluorouracil (5-FU) and its pro-drug capecitabine are widely used anticancer agents. Most 5-FU catabolism is dependent on dihydropyrimidine dehydrogenase (DPD) encoded by the DPYD gene, and DPYD variants that reduce DPD function increase 5-FU toxicity. Most DPD deficient patients are heterozygous and can be treated with reduced 5-FU dosing. We describe a patient with a genotype associated with near complete absence of DPD function, and severe and likely fatal toxicity with 5-FU treatment. The patient was treated effectively with alternative systemic therapy. Routine pretreatment DPYD genotyping is recommended by the European Medicines Agency, and guidelines for use of 5-FU in DPD deficient patients are available. However, outside the province of Quebec, routine pretreatment screening for DPD deficiency remains unavailable in Canada. It is likely our patient would have died from 5-FU toxicity under the current standard of care, but instead provides an example of the potential benefit of DPYD screening on patient outcomes. [ABSTRACT FROM AUTHOR]

Purpose: Patient-reported outcomes (PROs) are increasingly used in clinical trials to provide patients' perspectives regarding symptoms, health-related quality of life, and satisfaction with treatments. A range of guidance documents exist for the selection of patient-reported outcome measures (PROMs) in clinical trials, and it is unclear to what extent these documents present consistent recommendations. Methods: We conducted a targeted review of publications and regulatory guidance documents that advise on the selection of PROMs for use in clinical trials. A total of seven guidance documents from the US Food and Drug Administration, European Medicines Agency, and scientific consortia from professional societies were included in the final review. Guidance documents were analyzed using a content analysis approach comparing them with minimum standards recommended by the International Society for Quality of Life Research. Results: Overall there was substantial agreement between guidance regarding the appropriate considerations for PROM selection within a clinical trial. Variations among the guidance primarily related to differences in their format and differences in the perspectives and mandates of their respective organizations. Whereas scientific consortia tended to produce checklist or rating-type guidance, regulatory groups tended to use more narrative-based approaches sometimes supplemented with lists of criteria. Conclusion: The consistency in recommendations suggests an emerging consensus in the field and supports use of any of the major guidance documents available to guide PROM selection for clinical trials without concern of conflicting recommendations. This work represents an important first step in the international PROTEUS Consortium's ongoing efforts to optimize the use of PROs in clinical trials. [ABSTRACT FROM AUTHOR]

Metabolomics is a dynamically evolving field, with a major application in identifying biomarkers for drug development and personalized medicine. Numerous metabolomic studies have identified endogenous metabolites that, in principle, are eligible for translation to clinical practice. However, few metabolomic‐derived biomarker candidates have been qualified by regulatory bodies for clinical applications. Such interruption in the biomarker qualification process can be largely attributed to various reasons including inappropriate study design and inadequate data to support the clinical utility of the biomarkers. In addition, the lack of robust assays for the routine quantification of candidate biomarkers has been suggested as a potential bottleneck in the biomarker qualification process. In fact, the nature of the endogenous metabolites precludes the application of the current validation guidelines for bioanalytical methods. As a result, there have been individual efforts in modifying existing guidelines and/or developing alternative approaches to facilitate method validation. In this review, three main challenges for method development and validation for endogenous metabolites are discussed, namely matrix effects evaluation, alternative analyte‐free matrices, and the choice of internal standards (ISs). Some studies have modified the equations described by the European Medicines Agency for the evaluation of matrix effects. However, alternative strategies were also described; for instance, calibration curves can be generated in solvents and in biological samples and the slopes can be compared through ratios, relative standard deviation, or a modified Stufour suggested approaches while quantifying mainly endogenous metabolitesdent t‐test. ISs, on the contrary, are diverse; in which seven different possible types, used in metabolomics‐based studies, were identified in the literature. Each type has its advantages and limitations; however, isotope‐labeled ISs and ISs created through isotope derivatization show superior performance. Finally, alternative matrices have been described and tested during method development and validation for the quantification of endogenous entities. These alternatives are discussed in detail, highlighting their advantages and shortcomings. The goal of this review is to compare, apprise, and debate current knowledge and practices in order to aid researchers and clinical scientists in developing robust assays needed during the qualification process of candidate metabolite biomarkers. © 2019 John Wiley & Sons Ltd. Mass Spec Rev [ABSTRACT FROM AUTHOR]

Drug development includes imaging agents, contrast agents and radiopharmaceuticals; these materials differ from therapeutic drugs in that they are largely used to diagnose and/or monitor diseases and not treat them. Consequently, nonclinical safety testing needs are different. An examination of testing packages supporting clinical entry and/or marketing of these materials has shown a common approach to some study types (eg, imaging, biodistribution and toxicity testing). Recent regulatory guidelines to support development are the United States Food and Drug Administration (FDA)'s "Guidance for Industry Microdose Radiopharmaceutical Diagnostic Drugs: Nonclinical Study Recommendations" and the European Medicines Agency (EMA)'s "Guideline on the Non‐Clinical Requirements for Radiopharmaceuticals" (currently draft). It is hoped that these documents will allow developers to only perform nonclinical studies that are necessary to support functionality, follow distribution of the material and examine general safety/toxicity. However, as they are mainly focused on radiopharmaceuticals, companies are likely to apply knowledge of established testing packages to other new imaging agents and/or follow principles given in older regulatory guidelines, namely FDA's "Guidance for Industry Developing Medical Imaging Drug and Biological Products Part I Conducting Safety Assessments". Thus, in some cases, the need for regulatory agency interaction is still vital to avoid development surprises and delays due to an incomplete or badly performed testing package. Nonclinical safety testing is a vital part of the development of imaging agents, contrast agents and radiopharmaceuticals. Available regulatory guidelines allow developers to only perform nonclinical studies that are necessary to support functionality, follow distribution of the material and to examine general safety/toxicity. However, in some cases, the need for regulatory agency interaction is important to avoid development surprises and delays. [ABSTRACT FROM AUTHOR]

Introduction: Additional risk minimisation measures (aRMMs) may be required to minimise important risks of medicines. aRMMs may be required at the time of authorisation, but may also be introduced or discontinued during the product life cycle as new safety information arises. The aim of this study is to describe post-authorisation introductions of new aRMMs and discontinuations of existing aRMMs for medicines authorised in the European Union (EU). Methods: We performed a retrospective cohort study that included all new active substances authorised through the EU centralised procedure between January 1st 2006 and December 31st 2017. Data was extracted from European Public Assessment Reports available on the website of the European Medicines Agency (ema.europa.eu). Medicines were followed up from the date of marketing authorisation (MA) until first introduction or discontinuation of aRMMs, excluding Direct Healthcare Professional Communications (DHPCs), withdrawal/suspension/revocation of the MA, or July 1st 2018, when data extraction took place. Descriptive statistics were used to analyse frequency data, and survival analysis was used to calculate 5- and 10-year probability of introduction or discontinuation of aRMMs. Results: A total of 476 medicines were authorised during the study period. The probability of getting aRMMs after authorisation for products authorised without aRMMs was 3.5% [95% confidence interval (CI) 1.2–5.7] within 5 years after authorisation and 6.9% (95% CI 2.6–11) within 10 years after authorisation. For products authorised with aRMMs, the probability of discontinuation of aRMMs was 0.9% (95% CI 0–2.6) within 5 years and 8.3% (95% CI 0–16.1) within 10 years after authorisation. Conclusions: We found low probabilities of introduction and discontinuation of aRMMs (excluding DHPCs) during the product life cycle for medicines authorised between 2006 and 2017. The low rate of discontinuation may potentially be due to a lack of robust data on effectiveness of aRMMs. Further research is needed to get more insight into the dynamics of aRMMs during the medicine life cycle. [ABSTRACT FROM AUTHOR]

On August 25, 2020, a marketing authorization valid through the European Union was issued for belantamab mafodotin monotherapy for the treatment of multiple myeloma (MM) in adult patients who have received at least four prior therapies, whose disease is refractory to at least one proteasome inhibitor (PI), one immunomodulatory agent (IMiD), and an anti‐CD38 monoclonal antibody (mAb), and who have demonstrated disease progression on the last therapy. Belantamab mafodotin is an antibody‐drug conjugate that combines a mAb, which binds specifically to B‐cell maturation antigen, with maleimidocaproyl monomethyl auristatin F, which is a cytotoxic agent. It was evaluated in Study 205678 (DREAMM‐2), an open‐label, two arm, phase II, multicenter study in patients with MM who had relapsed following treatment with at least three prior therapies, who were refractory to an IMiD, a PI, and an anti‐CD38 mAb alone or in combination. Patients were randomized to receive 2.5 mg/kg (n = 97) or 3.4 mg/kg (n = 99) belantamab mafodotin by intravenous infusion every 3 weeks until disease progression or unacceptable toxicity. Belantamab mafodotin achieved an overall response rate (ORR) of 32% (97.5% confidence interval [CI]: 22–44) with a median duration of response (DoR) of 11 months (95% CI: 4.2 to not reached). The most frequently (≥20%) reported adverse reactions grades 3–4 with belantamab mafodotin were keratopathy (31%), thrombocytopenia (22%), and anemia (21%). With regard to the corneal risks associated with belantamab mafodotin, patients would need to undergo specific ophthalmic examinations so that any findings can be promptly and adequately managed. The scientific review concluded that a 32% ORR and a median DoR of 11 months observed with belantamab mafodotin was considered clinically meaningful. Given the manageable toxicity profile and considering that belantamab mafodotin has a mechanism of action that is different from that of authorized treatments in this group of highly pretreated patients whose disease is refractory to three classes of agents, the benefit risk for belantamab mafodotin monotherapy was considered positive, although the efficacy and safety evidence were not as comprehensive as normally required. Implications for Practice: Belantamab mafodotin (Blenrep, GlaxoSmithKline, St. Louis, MO, U.S.A) was approved in the European Union as monotherapy for the treatment of adult patients with refractory/relapsed multiple myeloma. Belantamab mafodotin resulted in durable response in highly pretreated patients whose disease is refractory to three classes of agents. Belantamab mafodotin is a monoclonal antibody against B‐cell maturation antigen conjugated with the potent antimitotic agent maleimidocaproyl monomethyl auristatin. This is the first monoclonal antibody to target this antigen in multiple myeloma, which represents a true novelty from a pharmacological point of view. This article summarizes the scientific review of the application leading to regulatory approval of belantamab mafodotin in the EU. [ABSTRACT FROM AUTHOR]

Background: Domperidone is used to treat gastrointestinal symptoms in patients with Parkinson's disease. Because of an increased risk of cardiac adverse events, the European Medicines Agency has issued recommendations restricting its use mainly in terms of age, dose, and treatment duration. Objective: The aim of this study was to investigate current prescription practices of domperidone in Parkinson's disease among French neurologists. Methods: A cross-sectional study based on a questionnaire was conducted among French neurologists from Parkinson's disease expert centers from the French NS-Park/FCRIN network, general hospitals, and private practice. Results: Among the 253 neurologists who completed the questionnaire, 86 (34%) were physicians from expert centers and 167 (66%) were from other healthcare settings; 209 (83%) were aware of recommendations restricting domperidone use. The majority of neurologists (92%) declared prescribing domperidone regardless of the age of the patients. Sixty-one percent of neurologists prescribed domperidone beyond 7 days in newly diagnosed patients, 33% in patients with orthostatic hypotension, and 79% in patients receiving continuous apomorphine treatment. They did not follow the recommendation on posology in newly diagnosed patients (7% of neurologists), patients with orthostatic hypotension (10%), and patients receiving continuous apomorphine therapy (25%). Finally, only 58% of neurologists declared taking specific precautions before prescribing domperidone. Conclusions: These findings show most French neurologists who responded to our questionnaire do not fully follow the restrictions on domperidone use, particularly in terms of treatment duration, and in patients receiving continuous apomorphine treatment. This may reflect the unmet need to prevent nausea in patients with Parkinson's disease treated with dopaminergic drugs, particularly continuous apomorphine therapy. [ABSTRACT FROM AUTHOR]

Regulatory science underpins the objective evaluation of medicinal products. It is therefore imperative that regulatory science and expertise remain at the cutting edge so that innovations of ever‐increasing complexity are translated safely and swiftly into effective, high‐quality therapies. We undertook a comprehensive examination of the evolution of science and technology impacting on medicinal product evaluation over the next 5–10 years and this horizon‐scanning activity was complemented by extensive stakeholder interviews, resulting in a number of significant recommendations. Highlighted in particular was the need for expertise and regulatory science research to fill knowledge gaps in both more fundamental, longer‐term research, with respect to technological and product‐specific challenges. A model is proposed to realise these objectives in Europe, comprising a synergistic relationship between the European Medicines Agency, the European Medicines Regulatory Network and academic research centres to establish a novel regulatory science and innovation platform. [ABSTRACT FROM AUTHOR]

Growing concerns over the related problems of speedily bringing innovative pharmaceuticals (especially so-called precision medicines) to market, and addressing areas of unmet medical need, have engendered critical scrutiny of the existing process for the licensing of pharmaceutical products. The objective is to enable these products to receive approval sooner, but on the basis of the provision of less complete evidence, than was previously the case. This article examines the attempts made to tackle this issue at European Union level, through a pilot programme exploring 'adaptive' approaches to licensing operated by the European Medicines Agency. Responses to this initiative indicate significant difficulty in securing regulatory legitimacy in this context. This suggests that innovative pharmaceutical technologies are disruptive of existing regulatory frameworks, such that future attempts to accommodate them within these may be susceptible to failure. [ABSTRACT FROM AUTHOR]

Infections due to multidrug-resistant Gram-negative bacteria (MDR-GNB), especially when carbapenem resistant, have been very difficult to manage in the last fifteen years, owing to the paucity of dependable therapeutic options. Cefiderocol is a siderophore cephalosporin recently approved by the Food and Drug Administration (FDA) and European Medicines Agency (EMA) that may have the potential to fill some of the remaining gaps in the treatment of MDR-GNB infections. Among others, cefiderocol demonstrated in vitro activity against carbapenem-resistant Acinetobacter baumannii and metallo-β-lactamases producers. Clinical data from both registrative studies and post-marketing experiences are essential to confirm whether these promises from in vitro studies could readily translate into clinical practice, as well as to delineate the precise place in therapy for cefiderocol for the treatment of MDR-GNB in the near future. Because of its unique potential, it is essential to provide both randomized controlled trials (RCT) and real-life data to improve the ability of clinicians to exploit its benefit in both empirical and targeted treatment of MDR-GNB infections. In this narrative review, we discuss the emerging data from pivotal RCT and initial real-life experiences on the use of cefiderocol for the treatment of MDR-GNB infections. [ABSTRACT FROM AUTHOR]

Basal cell carcinoma (BCC) accounts for almost 80% of skin cancers, and its healthcare workload burden is substantial within dermatology departments. Although most BCCs are small, well-defined tumors amenable of surgery or conservative procedures, in a small proportion of patients, BCCs can progress to an advanced stage including locally advanced BCC. The goal of the clinician in the treatment of BCC should be the right therapeutic approach at diagnosis, and different guidelines propose treatment strategies in order to prevent relapses or disease progression. In case of unresectable and untreatable BCC with radiotherapy, the first-choice medical therapy is Hedgehog-GLI (HH) pathway inhibitors. Sonidegib was approved by the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) as a first-line treatment for adult patients with locally advanced BCC, becoming the second HH pathway inhibitor receiving approval after vismodegib. In this review, data on pharmacology, safety, tolerability, and efficacy of sonidegib are summarized and compared to those of vismodegib. Lastly, indications on the management of advanced basal cell carcinoma based on author's clinical experience are provided. [ABSTRACT FROM AUTHOR]