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Biosimilar insulin analogues are increasing market access for diabetic patients globally. Scientific establishment of biosimilarity is cornerstone of this key change in the medical landscape. BGL-ASP is a biosimilar insulin aspart developed by BioGenomics Limited, India. BioGenomics has considered a stepwise approach in generating the totality of evidence required to establish similarity with reference product. Insulin aspart is a recombinant rapid-acting human insulin analogue utilised in the treatment of type-1 and type-2 diabetes mellitus. The single amino acid substitution at position B28 where proline is replaced with aspartic acid results in a decreased propensity to form hexamers, thus increasing the absorption rate on subcutaneous administration compared to native insulin. In order to establish the safety and efficacy of BGL-ASP, the critical quality attributes (CQAs) of BGL-ASP are identified based on the impact created on biological activity, pharmacokinetic/pharmacodynamic (PK/PD), immunogenicity and safety. The CQAs of insulin aspart are related to product structure, purity and functionality and are characterised using a series of state-of-the-art orthogonal analytical tools. The primary protein sequence, the secondary, tertiary and quaternary structure are found to be highly similar for BGL-ASP and reference product. The product related impurities of insulin aspart and the assay content are determined using high performance liquid chromatography (HPLC) based analysis and is similar for BGL-ASP and reference insulin aspart sourced from United States of America (US), Europe Union (EU) and India. The safety, efficacy and immunogenicity of BGL-ASP is also found to be comparable with reference product and is confirmed through the clinical trials conducted as recommended by International Council for Harmonisation of Technical Requirements of Pharmaceuticals for Human Use (ICH) and European Medicines Agency (EMA) guidelines. The data encompassed in this study demonstrates that reference insulin aspart and BGL-ASP are highly similar in terms of structural, physicochemical, and biological properties, thus confirming its safety and efficacy for usage as potential alternative economical medicinal treatment for diabetes mellitus. [ABSTRACT FROM AUTHOR]

Background. Chimeric antigen receptor (CAR) T cell therapy, a "living drug" immunotherapy, harnesses the power of T-cells from a patient (autologous) or healthy donor (allogeneic) to target and kill cancer cells and has shown unprecedented outcomes in patients with relapsed and refractory malignancies. Treatment with CAR-T cells requires the application of unique skillsets in recognised specialist centres for successful outcomes and requires management by the multidisciplinary team incorporating the specialist pharmacist. Method. A multimodal research strategy was employed for this literature review whereby PubMed, Google Scholar, Embase, Stella Library Search, EMA website, and EBMT website were sources of information. The search was limited from 2020 onwards with key terms referring to CAR-T cell therapy. Results and Discussion. There are six CAR-T cell products currently approved by the European Medicines Agency (EMA) and Food and Drug Administration (FDA) which target haematological malignancies with abundant clinical trials underway exploring new and improved CAR designs and antigen targets. As CAR-T cell therapy is an advanced therapy medicinal product (ATMP), there is need for an extensive regulatory framework underpinning its safety and efficacy. The clinical pharmacist plays an integral role in the provision of safe and effective CAR-T cell therapy including governance, operational and clinical aspects of treatment. Pharmacists may also be involved through provision of "Qualified Person" (QP) expertise in clinical trials and for release within hospitals under certain circumstances. There is a need for harmonised and accessible guidance on the clinical delivery of ATMPs such as CAR-T cells, with fully delineated responsibilities of pharmacists involving the oversight and supervision of CAR-T cell treatment. Conclusion. There is an unmet need to provide suitable and applicable literature for clinical pharmacists who are involved in the delivery of CAR-T cells. We have provided an overview of T-cell biology and an explanation of CAR-T cell design and the biomanufacturing process. We reviewed the complex and multifaceted treatment cycle requiring considerable logistics, and described the involvement of the clinical pharmacist in each part of this cycle from patient selection to postinfusion care. Finally, we look to the challenges and future opportunities that will require the involvement of the clinical pharmacist. [ABSTRACT FROM AUTHOR]

Background: The nonclinical as well as clinical development of orphan drugs is difficult, owing to unknown pathophysiology and the absence of animal models. Both, the U.S. Food and Drug Administration (FDA) Guidance and European Medicines Agency (EMA) Guidelines, for orphan drug development describe non-clinical studies, but lack specific information, such as animal species and study design. Against this background, this study aimed to elucidate efficient methods for evaluating nonclinical efficacy based on a review report of orphan drugs approved in Japan. Results: A total of 184 orphan drugs, including 84 anticancer and 100 non-anticancer drugs, approved in Japan from January 2010 to December 2019 were investigated. Some anticancer drugs progressed to clinical development without distinct efficacy data in nonclinical studies. Patient-derived cells have been used for some drugs due to a lack of established cell lines. Cells used for non-clinical studies were devised for drugs indicated for cancers resistant to prior therapies, tumours with specific amino acid mutations in the target molecules, and solid tumours with specific biomarkers. For some non-anticancer drugs, similar disease animal models and normal animals were used for evaluation, since animal models did not exist. Biomarkers have been used specifically for evaluation in normal animals and as endpoints in some clinical trials. Conclusions: It was possible to evaluate drug efficacy by flexibly designing nonclinical studies according to disease characteristics for potentials orphan drugs. These approaches, which are not described in detail in the EMA Guideline or FDA Guidance, may thus lead to approval. [ABSTRACT FROM AUTHOR]

Roflumilast, a selective phosphodiesterase 4 inhibitor, was approved by the European Medicines Agency Committee for Medicinal Products for Human Use in 2010 for the treatment of severe chronic obstructive pulmonary disease. However, low solubility of Roflumilast is a question mark to design a suitable dosage form to get therapeutic objectives. The aim of this work was to enhance solubility of the drug to develop fast release oral tablet. Drug-polymer binary system was developed at 1:1 w/w ratio followed by development of immediate release tablet by direct compression method. Drug-polymer compatibility studies were assessed by Fourier-transform infrared spectroscopy, X-ray diffraction, thermogravimetric analysis, and scanning electron microscopic studies. Pre and Post- compression tests and in vitro dissolutions studies in acidic (pH 1.2) and PBS pH 6.8 were performed to evaluate in vitro performance of the developed formulations. In vitro kinetic models were applied and similarity and difference factors were computed in comparison with reference product (marketed brand). Drug content was found between 95.37 to 99.57 in the developed formulations. Drug-polymer compatibility results demonstrated good compatibility among drug, polymers and other excipients. The micromeretic parameters and post compression studies results were in acceptable limit for all the developed formulations. Fast drug release behavior was observed in acidic medium. The results suggested that similarity factor (f2) values of the developed formulations were within acceptable limit (50-100). The developed binary systems may apply to overcome solubility issues of biopharmaceutical classification system class II drugs. The developed formulations are easy to scale-up. [ABSTRACT FROM AUTHOR]

In the European Union, the Committee for Medicinal Products for Human Use of the European Medicines Agency (EMA) develop guidelines to guide drug development, supporting development of efficacious and safe medicines. A European Public Assessment Report (EPAR) is published for every medicine application that has been granted or refused marketing authorisation within the EU. In this work, we study the use of text embeddings and similarity metrics to investigate the semantic similarity between EPARs and EMA guidelines. All 1024 EPARs for initial marketing authorisations from 2008 to 2022 was compared to the 669 current EMA scientific guidelines. Documents were converted to plain text and split into overlapping chunks, generating 265,757 EPAR and 27,649 guideline text chunks. Using a Sentence BERT language model, the chunks were transformed into embeddings and fed into an in-house piecewise matching algorithm to estimate the full-document semantic distance. In an analysis of the document distance scores and product characteristics using a linear regression model, EPARs of anti-virals for systemic use (ATC code J05) and antihemorrhagic medicines (B02) present with statistically significant lower overall semantic distance to guidelines compared to other therapeutic areas, also when adjusting for product age and EPAR length. In conclusion, we believe our approach provides meaningful insight into the interplay between EMA scientific guidelines and the assessment made during regulatory review, and could potentially be used to answer more specific questions such as which therapeutic areas could benefit from additional regulatory guidance. [ABSTRACT FROM AUTHOR]

Background: The action of mesenchymal stem cells (MSCs) is the subject of intense research in the field of regenerative medicine, including their potential use in companion animals, such as dogs. To ensure the safety of canine MSC batches for their application in regenerative medicine, a quality control test must be conducted in accordance with Good Manufacturing Practices (GMP). Based on guidance provided by the European Medicines Agency, this study aimed to develop and validate a highly sensitive and robust, nucleic acid-based test panel for the detection of various canine pathogens. Analytical sensitivity, specificity, amplification efficiency, and linearity were evaluated to ensure robust assessment. Additionally, viable spike-in controls were used to control for optimal nucleic acid extraction. The conventional PCR-based and real-time PCR-based pathogen assays were evaluated in a real-life setting, by direct testing MSC batches. Results: The established nucleic acid-based assays displayed remarkable sensitivity, detecting 100–1 copies/reaction of template DNA. They also exhibited high specificity and efficiency. Moreover, highly effective nucleic acid isolation was confirmed by the sensitive detection of spike-in controls. The detection capacity of our optimized and validated methods was determined by direct pathogen testing of nine MSC batches that displayed unusual phenotypes, such as reduced cell division or other deviating characteristics. Among these MCS batches of uncertain purity, only one tested negative for all pathogens. The direct testing of these samples yielded positive results for important canine pathogens, including tick-borne disease-associated species and viral members of the canine infectious respiratory disease complex (CIRDC). Notably, samples positive for the etiological agents responsible for enteritis (CPV), leptospirosis (Leptospira interrogans), and neosporosis (Neospora caninum) were also identified. Furthermore, we conducted biosafety evaluation of 12 MSC batches intended for therapeutic application. Eleven MSC batches were found to be free of extraneous agents, and only one tested positive for a specific pathogen, namely, canine parvovirus. Conclusion: In this study, we established and validated reliable, highly sensitive, and accurate nucleic acid-based testing methods for a broad spectrum of canine pathogens. [ABSTRACT FROM AUTHOR]

Antisense oligonucleotides (ASOs) are short single stranded synthetic RNA or DNA molecules, whereas double-stranded RNA nucleotide sequences are called small interfering RNA (siRNA). ASOs bind to complementary nucleic acid sequences impacting the associated functions of the targeted nucleic acids. They represent an emerging class of drugs that, through a revolutionary mechanism of action, aim to directly regulate disease-causing genes and their variants, providing an alternative tool to traditional "protein-specific" therapies. The majority of the ASOs are designed to treat orphan genetic disorders that in most of the cases are seriously disabling and still lacking an adequate therapy. In order to translate ASOs into clinical success, constant technological advances have been instrumental in overcoming several pharmacological, toxicological and formulation limitations. Accordingly, chemical structures have been recently implemented and new bio-conjugation and nanocarriers formulation strategies explored. The aim of this work is to offer an overview of the antisense technology with a comparative analysis of the oligonucleotides approved by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA). [ABSTRACT FROM AUTHOR]

Introduction: Numerous investigations on herbal medicine that have been undertaken in the past several years demonstrate the general acceptance of its safety. The Saudi Food and Drug Authority (SFDA) established the Herb–Drug Interaction (HDI) project to detect and assess potential HDIs to ensure safety. The aim is to detect safety signals and assess them based on available evidence. Methods: First, SFDA-registered herbal products (n = 30) were selected and prioritized based on commonly used herbs. Second, reported potential HDIs were retrieved from the World Health Organization global database of individual case safety reports (VigiBase), AdisInsight®, and the Natural Medicines database. We excluded drugs non-registered by SFDA and labeled interactions in the product information of SFDA, the US Food and Drug Administration (FDA), and the European Medicines Agency (EMA). Finally, a comprehensive evaluation of potential HDIs was carried out using several evidence sources: literature, global cases, local cases, and other relevant documents. The Drug Interaction Probability Scale (DIPS) scale was used to assess the probability of a causal relationship between the interacting herb and drug and the event. Results: The search yielded 566 potential signals, and 41 had published evidence and were referred for assessment. The assessment results using DIPS were: 22 possible (53.6 %), 7 probable (17%), and 12 doubtful (29.2%) interactions. The recommendation was to include probable HDIs in the product information, including turmeric–tacrolimus, etoposide–Echinacea, Ginkgo biloba–ibuprofen, green tea–warfarin, and licorice–thiazides interactions. Conclusion: The HDI project assessed the screening and identification of potential HDIs. The action plan of this project can be used in post-marketing activities to identify potential drug interactions. [ABSTRACT FROM AUTHOR]

Background and Objectives: There is a lack of well-controlled US studies of intramuscular (IM) interferon beta (IFNβ)-1a use in pregnant women with multiple sclerosis; however, in the European Medicines Agency region, IFNβ formulations may be considered during pregnancy if clinically needed based on data from European Union cohort registries. The AVONEX Pregnancy Exposure Registry was established to prospectively study the effects of IM IFNβ-1a on the risk of birth defects and spontaneous pregnancy loss in a US population. Methods: Pregnant women with multiple sclerosis exposed to IM IFNβ-1a within ~ 1 week of conception or during the first trimester were included. Participants were followed until there was a pregnancy outcome, live-born infants were followed until age 8–12 weeks. Data were collected on IM IFNβ-1a exposure, demographics, patient characteristics, medical history, and pregnancy outcomes, including live births (with or without birth defect), spontaneous abortions/miscarriages and fetal death/stillbirth, elective abortions (with and without birth defect), and ectopic pregnancies. A population-based birth defect surveillance program, the Metropolitan Atlanta Congenital Defects Program (MACDP), served as the primary external control group for evaluating the risk of birth defects. Results: Three-hundred and two patients with a median (range) age of 31.0 (16–48) years and a median (range) gestational age at the time of enrollment of 10.1 (4–39) weeks were evaluable. Most patients (n = 278/302; 92%) reported IM IFNβ-1a exposure in the week before conception and most (n = 293/302; 97%) discontinued treatment before the end of the first trimester. Of 306 pregnancy outcomes, there were 272 live births, 28 spontaneous abortions of 266 pregnancies enrolled before 22 weeks' gestation (rate 10.5%; 95% confidence interval 7.2–15.0), five elective abortions, and one stillbirth. There were 17 adjudicator-confirmed major birth defects of 272 live births (rate 6.3%; 95% confidence interval 3.8–10.0); the pattern of birth defects observed was not suggestive of a relationship to prenatal IM IFNβ-1a exposure. Conclusions: This large US registry study suggests IM IFNβ-1a exposure during early pregnancy was not clinically associated with adverse pregnancy outcomes in women with multiple sclerosis. These findings help inform clinicians and patients in weighing the risks and benefits of IM IFNβ-1a use during pregnancy. Clinical Trial Registration: ClinicalTrials.gov: NCT00168714, 15 September, 2005. [ABSTRACT FROM AUTHOR]

Introduction: SB12 is a biosimilar to eculizumab reference product [SolirisTM (Soliris is a trademark of Alexion Pharmaceuticals, Inc.)] that acts as a C5 complement protein inhibitor. The infusion stability of in-use (diluted) SB12 outside the conditions stated in the reference product's label is unknown. Objective: The objective of this study was to assess the stability of SB12 after extended storage in conditions not claimed in the originator label. Methods: Infusion stability was assessed in SB12 samples (diluted in 0.9% NaCl, 0.45% NaCl, and 5% dextrose, final concentration of 5 mg/mL per clinical trial protocol and the reference product's label) kept at 5 ± 3 °C for up to 3 months, then 30 ± 2 °C/65 ± 5% relative humidity (RH) for 72 h. The product was stored in different containers [polyolefin (PO) bags, glass bottles and syringes], and the protocol followed International Conference on Harmonisation (ICH) and European Medicines Agency (EMA) requirements for stability evaluation of biological products. Stability was evaluated using complementary assays, including pH, protein concentration (A280), purity (size exclusion-high-performance liquid chromatography, capillary electrophoresis-sodium dodecyl sulfate, and imaged capillary isoelectric focusing), biological activity (C5 binding and inhibition), and safety (subvisible particles). Results: Except for charge variants in SB12 diluted in 5% dextrose, all results met the stability acceptance criteria. There were no major changes in terms of physicochemical stability, biological activity, and subvisible particles. Conclusions: The infusion stability of SB12 after extended storage (5 ± 3 °C for up to 3 months, then 30 ± 2 °C/65 ± 5% RH for 72 h) was demonstrated for longer periods and at higher temperatures than what is stated in the EU and US labels of the reference product. The physicochemical properties, biological activity, and subvisible particles of in-use SB12 diluted in 0.9% NaCl and 0.45% NaCl were maintained under the described conditions and for all tested containers. However, instability was observed for the diluted SB12 in 5% dextrose. These results may reduce the workload of clinical staff and minimize drug waste from treatment delays without any loss in product quality and biological activity. [ABSTRACT FROM AUTHOR]

(1) Background: In 2022, monkeypox (Mpox) was declared a public health emergency. The European Medicines Agency has authorized the use of Imvanex/Jynneos, a smallpox vaccine, for coverage against pox. Healthcare workers (HCWs) are all considered by the European Centre for Disease Prevention and Control to be at risk, but in Italy, vaccination was offered only to laboratory personnel. The present study aims to investigate smallpox vaccination coverage (VC) that provides protection against Mpox among HCWs in an Italian university hospital and to assess HCWs' attitudes towards the possibility of getting vaccinated against Mpox. (2) Methods: We conducted a cross-sectional survey. 336 HCWs from selected wards were asked to fill out a self-declaration to collect their sex, profession, ward, vaccination status, and attitude toward Mpox vaccination. (3) Results: 60.71% of HCWs involved provided the requested data; 38.7% of them were previously vaccinated against smallpox, which corresponds to 23.5% of the total HCWs in the wards considered. Considering those born before 1979 as vaccinated, VC increases from 23.5% to 41.7%; the percentage of HCWs who adhered to vaccination is 23%; laboratory technicians showed a lower willingness to be vaccinated. The ward with the highest willingness to vaccinate is proctological surgery. (4) Conclusions: Based on our experience, a variability in smallpox VC and in willingness to vaccination has emerged both among different job titles and age categories and across the wards analyzed. Additionally, our survey reveals that vaccination attitudes are higher among HCWs from wards that currently do not have free access to such vaccinations. [ABSTRACT FROM AUTHOR]

Spinal muscular atrophy (SMA) is a lower motor neuron disease due to biallelic mutations in the SMN1 gene on chromosome 5. It is characterized by progressive muscle weakness of limbs, bulbar and respiratory muscles. The disease is usually classified in four different phenotypes (1–4) according to age at symptoms onset and maximal motor milestones achieved. Recently, three disease modifying treatments have received approval from the Food and Drug Administration (FDA) and the European Medicines Agency (EMA), while several other innovative drugs are under study. New therapies have been game changing, improving survival and life quality for SMA patients. However, they have also intensified the need for accurate biomarkers to monitor disease progression and treatment efficacy. While clinical and neurophysiological biomarkers are well established and helpful in describing disease progression, there is a great need to develop more robust and sensitive circulating biomarkers, such as proteins, nucleic acids, and other small molecules. Used alone or in combination with clinical biomarkers, they will play a critical role in enhancing patients’ stratification for clinical trials and access to approved treatments, as well as in tracking response to therapy, paving the way to the development of individualized therapeutic approaches. In this comprehensive review, we describe the foremost circulating biomarkers of current significance, analyzing existing literature on non-treated and treated patients with a special focus on neurofilaments and circulating miRNA, aiming to identify and examine their role in the follow-up of patients treated with innovative treatments, including gene therapy. [ABSTRACT FROM AUTHOR]

B-cell acute lymphoblastic leukemia (B-ALL) is the most common subtype of acute leukemia in the pediatric population. The prognosis and treatment of B-ALL have dramatically improved over the past decade with the adoption of intensive and prolonged combination chemotherapy regimens. The advent of novel immunologic agents such as blinatumomab and inotuzumab has changed the treatment landscape of B-ALL. However, patients have continued to relapse, raising the need for novel therapies. Chimeric antigen receptor (CAR) T-cells have achieved a milestone in the treatment of B-ALL. Two CD19-targeting CAR T-cells were approved by the Food and Drug Administration and the European Medicines Agency for the treatment of relapsed and/or refractory B-ALL. In this review, we review the available data regarding CD19-targeting CAR T-cells with their safety profile as well as the mechanism of resistance to these agents and the way to overcome this resistance. [ABSTRACT FROM AUTHOR]

The prices of oncology drugs have been rising progressively in recent years. Despite accounting for only a small share of prescriptions, oncology drugs are the most expensive drugs on the market. However, the association between drug price and clinical benefit often remains questionable. Therefore, we set out to analyze the development of prescription and benefit assessment of protein kinase inhibitors. We identified 20 protein kinase inhibitors with oncological indications that were newly approved by the European Medicines Agency (EMA) between 2015 and 2019, based on the Arzneiverordnungsreport (AVR, Drug Prescription Report). For these 20 drugs, the number of prescriptions, sales, defined daily dose (DDD), and DDD costs were identified for the year of approval and for 2020, respectively, based on data from the Wissenschaftliches Institut der Ortskrankenkassen (WIdO, Scientific Institute of the General Local Health Insurance Fund, AOK). Moreover, the additional benefit assessments by the Gemeinsamer Bundesausschuss (GBA, Federal Joint Committee) were considered for each drug. It is shown that the share of a drug in prescriptions, sales, and DDD does not correlate with the clinical benefit of the drug as measured by the additional benefit assessment by the GBA. Lastly, the advertisement pattern of protein kinase inhibitors in a representative oncology journal does not correlate with drug benefit. In conclusion, the immense costs of oncology drugs are therefore largely caused by drugs for which no additional benefit has been proven by the GBA. In order to ensure the long-term stability of health care systems, price-regulation measures are urgently needed, especially for drugs whose additional benefit has not been proven. [ABSTRACT FROM AUTHOR]

Primula veris (cowslip) is an important medicinal–aromatic plant used traditionally for its expectorant and anti-inflammatory properties, as well as a valuable horticultural plant with ornamental value and agroalimentary interest (edible flowers and leaves). With extensive illegal harvesting across northern Greece to date, the long-term survival of Greek cowslip wild-growing populations seems compromised. With the aim to characterize the phytochemical content of locally adapted native genotypes of P. veris subsp. veris, we examined samples from 13 wild-growing populations sourced from 8 mountain areas along a longitudinal gradient of northern Greece. Flowers, leaves, and roots were separately evaluated with HPLC-PDA-MS for their chemical content to select the genotypes associated with the best phytochemical traits. The flowers were found to contain mainly flavonoids, isorhamnetin, quercetin, and kaempferol triglycosides, with varied population contents, generally higher in northwestern population samples with a colder and more humid climate; however, all in line with the European Medicines Agency's (EMA) reports. The leaves were characterized by the prevalence of kaempferol and quercetin triglycosides, being generally higher than that of the flowers. In the roots, saponins were detected in relatively low percentages, and the phenolic glycosides were found up to nearly 2%. The results of this study suggest a potential specificity of the marginal Greek genotypes being at the edge of the species' native distribution range in Europe and Asia. The phytochemical characterization herein supports the domestication process of Greek native cowslip genotypes. In turn, this may alleviate the overharvesting pressure in wild populations, thus contributing to species conservation and offering an incentive for farmers to sustainably cultivate at local scales well-adapted indigenous genotypes of high value. [ABSTRACT FROM AUTHOR]

The COVID-19 pandemic posed challenges to communicating accurate information about vaccines because of the spread of misinformation. The European Medicines Agency (EMA) tried to reassure the public by communicating early on about the development and approval of COVID-19 vaccines. The EMA surveyed patients/consumers, healthcare professional organizations, and individual stakeholders, both at the EU level and in an Italian regional context. The objectives of the study were to see if the EMA's core information materials were informative and well-understood and which communication channels were preferred by the public. The main findings showed that individual patients/consumers generally prefer to obtain information about COVID-19 vaccines from the internet or mass media, while organizations and individual healthcare professionals prefer to obtain information from national and international health authorities. Both at EU and local levels, participants had a good understanding of the key messages from regulators and found the materials useful and relevant. However, some improvements were recommended to the visual, text, and dissemination formats, including publishing more information on safety and using a more public-friendly language. Also, it was recommended to maintain the EMA's approach of using media, stakeholder engagement, and web-based formats to communicate about COVID-19 vaccines. In conclusion, user-testing of proactive communication materials aimed to prebunk misinformation during a public health crisis helps to ensure that users understand the development and safety of novel vaccine technologies. This information can then be used as a basis for further evidence-based communication activities by regulators and public health bodies in an emergency context. [ABSTRACT FROM AUTHOR]

The recruitment of therapeutics and most importantly COVID-19 vaccines has seen a measurable reduction in transmission, re-infection, severity, hospitalization and mortality associated with the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The development and approval of some vaccines and therapeutics undoubtedly signaled renewed hope for public health personnel, the government, the World Health Organization (WHO) and the entire world population. At present, most countries have progressed beyond administering first and second doses to administering COVID-19 vaccine updated boosters to prevent transmission and provide protection. Notably, a bivalent COVID-19 vaccine from Pfizer-BioNTech and Moderna, also called an "updated" COVID-19 vaccine booster dose, is a formulation that houses the original virus strain and omicron BA.1, which provides broad immunity against COVID-19 including the omicron variant (BA.1) and the Paxlovid drug (Nirmatrelvir-ritonavir) authorized for use by the Food and Drug Administration (FDA) and the European Medicines Agency. This current review outlines the variant of concern (VOC), viral cell entry and pathogenesis, host immunity and viral immune evasion. In addition, we discuss the therapeutic and vaccine treatment approach, WHO and FDA authorization, vaccine storage and vaccine efficacy. In conclusion, bearing in mind the trend of continued mutations as observed on the spike (S) glycoprotein and receptor binding domain (RBD) of SARS-CoV-2, which lead to more immune-evasive strains such as BQ.1, BQ.1.1, BF.7, XBB and XBB.1, researcher and clinician attention should be tailored toward the design and development of variant-specific vaccines for future interventions. [ABSTRACT FROM AUTHOR]

Abstract Aims We have previously described the European Medicines Agency’s (EMA) and the US Food and Drug Administration’s guidelines, each for a specific psychiatric indication, on how to design pivotal drug trials used in new drug applications. Here, we report on our efforts over 3 years to retrieve conflicts of interest declarations from EMA. We wanted to assess potential internal industry influence judged as the proportion of guideline committee members with industry conflicts of interest. Methods We submitted Freedom of Information requests in February 2020 to access EMA’s lists of committee members (and their declared conflicts of interest) involved in drafting the 13 ‘Clinical efficacy and safety’ guidelines available on EMA’s website pertaining to psychiatric indications. In our request, we did not specify the exact EMA committees. Here, we describe the received documents and report the proportion of members with industry interests (i.e. defined as any financial industry relationship). It is a follow-up paper to our first report (http://doi.org/10.1017/S2045796021000147). Results After 2 years and 9 months (November 2022), the EMA sent us member lists and corresponding conflicts of interest declarations from the Committee for Medicinal Products for Human use (CHMP) from 2012, 2013 and 2017. These member lists pertained to 3 of the 13 requested guidelines (schizophrenia, depression and autism spectrum disorder). The 10 remaining guidelines were published before 2011 and EMA stated that they needed to require permission from their expert members (with unknown retrieval rate) and foresaw excessive workload and long wait. Therefore, we withdrew our request. The CHMPs from 2012, 2013 and 2017 had from 34 to 36 members; 39%–44% declared any interests and we judged 14%–18% as having industry interests. For the schizophrenia guideline, we identified two members with industry interests to companies who submitted feedback on the guideline. We did not receive declarations from the Central Nervous System (CNS) Working Party, the CHMP appointed expert group responsible for drafting and incorporating feedback into the guidelines. Conclusions After almost 3 years, we received information, which only partly addressed our request. We recommend EMA to improve transparency by publishing the author names and their corresponding conflicts of interest declarations directly in the ‘Clinical efficacy and safety’ guidelines and to not remove conflicts of interest declarations after 1 year from their website to reduce the risk of stealth corporate influence during the development of these influential guidelines.

Despite the available therapies for treatment-resistant depression (TRD), there are a limited number that are evidence-based and effective in this hard-totreat population. The European Group for the Study of Resistant Depression (GSRD) investigated in the last two decades the illness characteristics, genetic underpinnings, as well as psychopharmacotherapy of TRD. The GSRD staging model characterizing response, nonresponse and resistance to antidepressant (AD) treatment was applied to 2762 patients in eight European countries. The retrospective and prospective studies of the GSRD reporting that switching antidepressants according to different classes was not associated with better response or remission rates influenced the European Medicines Agency (EMA) that subsequently revised its definition for TRD. Accordingly, the EMA defines TRD as non-response to at least two courses of antidepressants of the same or a different substance class administered in adequate doses and duration in adherent patients (EMA, 2013). A prediction model reaching accuracy of above 0.7 highlighted symptom severity, suicidality, comorbid anxiety and lifetime MDEs as the most informative predictors for TRD. Novel associations of single nucleoid polymorphisms (SNPs) within the PPP3CC, ST8SIA2, CHL1, GAP43 and ITGB3 genes and gene pathways associated with neuroplasticity, intracellular signaling and chromatin silencing have also been found to be associated with TRD. Applying machine learning algorithms, a signature of three SNPs of the BDNF, PPP3CC and HTR2A genes and lacking melancholia predicted treatment response. Taken together, the plethora of findings substantiated by the GSRD over two decades of research offers a unique and balanced perspective on TRD. On this foundation, further research will elaborate on specific clinical and genetic hypotheses, as well as treatment strategies within appropriate study-designs, especially interaction-based models for studying treatment outcome predictors and RCTs for investigating efficacy of particular psychopharmacotherapeutic strategies and prediction models. [ABSTRACT FROM AUTHOR]

This study aims to investigate the barriers that exist when implementing continuous improvement methodologies, such as Lean Six Sigma (LSS), within the Irish Pharma industry. The main finding of this study is that 45% of participants perceived that a highly regulated environment could be a barrier to continuous improvement implementation, while 97% of respondents utilised Continuous improvement (CI) methods, such as Lean, Six Sigma, and LSS, within their organisations. While the International Conference of Harmonisation integrates CI into its Pharmaceutical Quality Systems (PQS) regulations, the highest motivation for CI implementation amongst the Irish Pharma industry is to improve Productivity and Quality. The main obstacles highlighted for CI implementation in Pharma attributed to stringent regulatory regimes were fear of extra validation activity, a compliance versus quality culture, and a regulatory culture of being "safe". Another relevant finding presented in this paper is that participants CI LSS tools are very strongly integrated into the pharma industries corrective and preventative action system, deviations, and internal audit systems. Limitations of the research are that all the data collected in the survey came from professionals working for multinational Pharmaceutical companies based in Ireland. The authors understand that this is the first research focused on the barriers and status of CI initiatives in the pharmaceutical industry. The results of this study represent an important step towards understanding the enablers and obstacles for the use of continuous improvement methodologies in pharmaceutical manufacturing industries on a global scale. [ABSTRACT FROM AUTHOR]

The European Medicines Agency (EMA) has released a new guideline on the clinical investigation of antidepressants. The guideline aims to improve the efficacy, safety, and personalization of these medications. It provides information on depressive disorders, clinical trial methodology, statistical analysis, and requirements for trials in difficult-to-treat populations. The guideline also discusses the use of psychedelics in depression treatment and highlights the need for randomized, double-blind, placebo-controlled trials. The ongoing consultation process will address remaining challenges in the field. [Extracted from the article]

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

The European Medicines Agency (EMA) fosters access to innovative medicines through accelerated procedures and flexibility in the authorization requirements for diseases with unmet medical needs, such as many rare diseases as well as oncological diseases. However, the resulting increase of medicines being marketed with conditional authorizations and in exceptional circumstances has lead to higher clinical uncertainty about their efficacy and safety than when the standard authorizations are applied. This uncertainty has significant implications for clinical practice and the negotiation of pricing and reimbursement, particularly as high prices are based on assumptions of high value, supported by regulatory prioritization. The burden of clinical development is often shifted towards public healthcare systems, resulting in increased spending budgets and opportunity costs. Effective management of uncertainty, through appropriate testing and evaluation, and fair reflection of costs and risks in prices, is crucial. However, it is important not to sacrifice essential elements of evidence-based healthcare for the sake of access to new treatments. Balancing sensitive and rational access to new treatments, ensuring their safety, efficacy, and affordability to healthcare systems requires thoughtful decision-making. Ultimately, a responsible approach to timely access to innovative medicines that balances the needs of patients with healthcare systems' concerns is necessary. This approach emphasizes the importance of evidence-based decision-making and fair pricing and reimbursement. [ABSTRACT FROM AUTHOR]

Background: Rare diseases negatively impact patients' quality of life, but the estimation of health state utility values (HSUVs) in research studies and cost–utility models for health technology assessment is challenging. Objectives: This study compared the methods for estimating the HSUVs included in manufacturers' submissions of orphan drugs to the National Institute for Health and Care Excellence (NICE) with those of published studies addressing the same rare diseases to understand whether manufacturers fully exploited the existing literature in developing their economic models. Methods: All NICE Technology Appraisal (TA) and Highly Specialized Technologies (HST) guidance documents of non-cancer European Medicines Agency (EMA) orphan medicinal products were reviewed and compared with any published primary studies, retrieved via PubMed until November 2020, and estimating HSUVs for the same conditions addressed in manufacturers' submissions. Results: We identified 22 NICE TA/HST appraisal reports addressing 19 different rare diseases. Sixteen reports presented original HSUVs estimated using EQ-5D or Health Utility Index (n = 12), direct methods (n = 2) or mapping (n = 2), while the other six included values obtained from the literature only. In parallel, we identified 111 published studies: 86.6% used preference-based measures (mainly EQ-5D, 60.7%), 12.5% direct techniques, and 2.7% mapping. The collection of values from non-patient populations (using 'vignettes') was more frequent in manufacturers' submissions than in the literature (22.7% vs. 8.0%). Conclusions: The agreement on methodological choices between manufacturers' submissions and published literature was only partial. More efforts should be made by manufacturers to accurately reflect the academic literature and its methodological recommendations in orphan drugs submissions. [ABSTRACT FROM AUTHOR]

The European Food Safety Authority (EFSA) has revised their estimate of the toxicity of bisphenol A (BPA) and, as a result, have recommended reducing the tolerable daily intake (TDI) by 20 000-fold. This would essentially ban the use of BPA in food packaging such as can liners, plastic food containers, and in consumer products. To come to this conclusion, EFSA used a systematic approach according to a pre-established protocol and included all guideline and nonguideline studies in their analysis. They found that Th-17 immune cells increased with very low exposure to BPA and used this endpoint to revise the TDI to be human health protective. A number of regulatory agencies including the European Medicines Agency (EMA) have written formal disagreements with several elements of EFSA's proposal. The European Commission will now decide whether to accept EFSA's recommendation over the objections of EMA. If the Commission accepts EFSA's recommendation, it will be a landmark action using knowledge acquired through independent scientific studies focused on biomarkers of chronic disease to protect human health. The goal of this Perspective is to clearly articulate the monumental nature of this debate and decision and to explain what is at stake. Our perspective is that the weight of evidence clearly supports EFSA's proposal to reduce the TDI by 20 000-fold. [ABSTRACT FROM AUTHOR]

Consensus of regulatory decisions on the same Marketing Authorization Application (MAA) are critical for stakeholders. In this context, regulatory decision patterns from the Swissmedic (SMC), the US Food and Drug Administration (FDA), and the European Medicines Agency (EMA) were analyzed for hemato‐oncology products (OP) and non‐oncology products (NOP). We compared 336 SMC regulatory decisions between 2009 and 2018 on new active substances with the EMA and the FDA for OP (n = 77) and NOP (n = 259) regarding approval rates, consensus, and divergent decisions. For OP MAA, we analyzed the underlying reasons for divergent decisions; for consensus decisions, the similarity and strictness of labeling. For OP, the approval rate for the SMC was 88.4%, the EMA 91.3%, and the FDA 95.7%. For NOP, the SMC had an approval rate of 86.2%, the EMA of 93.8%, and the FDA of 88.8%. The consensus decision rate among agencies was 88.4% for OP and 84.4% for NOP. The main clinical driver for divergent decisions for OP was nonrandomized trial design and low patient numbers. Comparing the approved indication wordings, the highest similarity was between the SMC and the EMA, and lowest for the FDA and the EMA. Investigating label strictness, the FDA numerically had the highest but not‐statistically significant number of strict labels. The approval rate stratified by disease area (OP and NOP) differed among the SMC, the EMA, and the FDA. High concordance in regulatory decisions was observed between agencies for OP as well as NOP. Reasons for divergent decisions regarding OP were mainly due to scientific uncertainties. Comparing strictness of indications, numerical but no statistically significant differences were observed between agencies. [ABSTRACT FROM AUTHOR]

Veterinary antibiotics have become a major concern due to potential environmental effects. This study presents an investigation of the exposure and environmental effects of the veterinary medicinal product in powder form, administered in the drinking water of piglets, chickens and turkeys, containing 250 mg/g penicillin G (benzylpenicillin potassium), performed according to the European Medicines Agency (EMEA) guideline and the results obtained by an analytical method based on online solid-phase extraction, ultra-high performance liquid chromatography coupled to a triple quadrupole mass spectrometer (SPE-online-UHPLC-MS/MS). The study presents the determination of the environmental risk and through an original, interactive, fast software method, created on the basis of a proprietary calculation algorithm that goes through all the prescriptions and recommendations of the EMEA guide. The results demonstrated that the concentration value for penicillin G determined in surface water by SPE-online-UHPLC-MS/MS is much lower than that predicted by calculation (predictable concentration in surface water, PECsurface water = 37.66 µg/L and the concentration SPE-online-UHPLC-MS/MS = 0.032 µg/L). Both results lead to a sub-unit risk quotient (R) indicating that the treatment carried out with the considered veterinary product does not present any risk to the environment. [ABSTRACT FROM AUTHOR]

Niels Kaj Jerne has proposed the "immune network theory" of interactions among anti‐idiotypic antibodies, able to interfere with humoral responses to certain antigens. After the occurrence of the primary generation of antibodies, against an antigenic epitope, idiotypes of these antibodies induce anti‐idiotypic antibodies that modulate the intensity of the first response, and so on. Adverse effects following SARS‐COV‐2 COVID‐19 vaccines are occasionally similar to the symptoms of COVID‐19 infection. Rare events linked to SARS‐CoV‐2 vaccines also resemble some rarely reported COVID‐19 complications. Safety data from product information by European Medicines Agency suggest that spectra do overlap for four main vaccines. The proposition is that vaccine events and COVID‐19 complications are related to anti‐idiotypic antibodies whose spatial shape can lead to interactions with ACE2 molecules, in individuals with a prolonged Spike protein synthesis. The vaccines target cells by their affinity to the vaccine vector, or to engulf lipid nanoparticles. Anti‐idiotypic antibodies shaped similarly to the Spike protein possibly interact with ACE2 molecules and cause diverse signs and symptoms. [ABSTRACT FROM AUTHOR]

Whereas islet autoantibodies (AAs) are well‐established risk factors for developing type 1 diabetes (T1D), there is a lack of biomarkers endorsed by regulators to enrich clinical trial populations for those at risk of developing T1D. As such, the development of therapies that delay or prevent the onset of T1D remains challenging. To address this drug development need, the Critical Path Institute's T1D Consortium (T1DC) acquired patient‐level data from multiple observational studies and used a model‐based approach to evaluate the utility of islet AAs as enrichment biomarkers in clinical trials. An accelerated failure time model was developed, discussed in our previous publication, which provided the underlying evidence required to receive a qualification opinion for islet AAs as enrichment biomarkers from the European Medicines Agency (EMA) in March 2022. To further democratize the use of the model for scientists and clinicians, we developed a Clinical Trial Enrichment Graphical User Interface. The interactive tool allows users to specify trial participant characteristics, including the percentage of participants with a specific AA combination. Users can specify ranges for participant baseline age, sex, blood glucose measurement from the 120‐minute timepoints of an oral glucose tolerance test, and HbA1c. The tool then applies the model to predict the mean probability of a T1D diagnosis for that trial population and renders the results to the user. To ensure adequate data privacy and to make the tool open‐source, a deep learning‐based generative model was used to generate a cohort of synthetic subjects that underpins the tool. [ABSTRACT FROM AUTHOR]

Cell and gene therapy (CGT) describes a broad category of medicinal products with potential applications to prevent and treat human disease in multiple therapeutic areas. These therapies leverage the use of modified nucleic acids, altered cells or tissue, or both. The modality, mechanism, route of administration, and therapeutic indication for a CGT product will influence the challenges and opportunities for early clinical development, some of which may be highly specific to the product under consideration. Both the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA) encourage early interaction between sponsor and health authority to align on key elements of the CGT development program. [ABSTRACT FROM AUTHOR]

Cenobamate (CNB), ([(R)-1-(2-chlorophenyl)-2-(2H-tetrazol-2-yl)ethyl], is a novel tetrazole alkyl carbamate derivative. In November 2019, the Food and Drug Administration approved Xcopri®, marketed by SK Life Science Inc., (Paramus, NJ, USA) for adult focal seizures. The European Medicines Agency approved Ontozry® by Arvelle Therapeutics Netherlands B.V.(Amsterdam, The Neatherlands) in March 2021. Cenobamate is a medication that could potentially change the perspectives regarding the management and prognosis of refractory epilepsy. In this way, this study aims to review the literature on CNB's pharmacological properties, pharmacokinetics, efficacy, and safety. CNB is a highly effective drug in managing focal onset seizures, with more than twenty percent of individuals with drug-resistant epilepsy achieving seizure freedom. This finding is remarkable in the antiseizure medication literature. The mechanism of action of CNB is still poorly understood, but it is associated with transient and persistent sodium currents and GABAergic neurotransmission. In animal studies, CNB showed sustained efficacy and potency in the 6 Hz test regardless of the stimulus intensity. CNB was revealed to be the most cost-effective drug among different third-generation antiseizure medications. Also, CNB could have neuroprotective effects. However, there are still concerns regarding its potential for abuse and suicidality risk, which future studies should clearly assess, after which protocols should be changed. The major drawback of CNB therapy is the slow and complex titration and maintenance phases preventing the wide use of this new agent in clinical practice. [ABSTRACT FROM AUTHOR]

Background: The evaluation of clinical evidence takes account of health benefit (efficacy and safety) and the degree of certainty in the estimate of benefit. In orphan indications practical and ethical challenges in conducting clinical trials, particularly in paediatric patients, often limit the available evidence, rendering structured evaluation challenging. While acknowledging the paucity of evidence, regulators and reimbursement authorities compare the efficacy and safety of alternative treatments for a given indication, often in the context of the benefits of other treatments for similar or different conditions. This study explores the feasibility of using the Institute for Clinical and Economic Review (ICER) Evidence Rating Matrix for Comparative Clinical Effectiveness in structured assessment of both the magnitude of clinical benefit (net health benefit, NHB) and the certainty of the effect estimate in a sample of orphan therapies for paediatric indications. Results: Eleven systemic therapies with European Medicines Agency (EMA) orphan medicinal product designation, licensed for 16 paediatric indications between January 2017 and March 2020 were identified using OrphaNet and EMA databases and were selected for evaluation with the ICER Evidence Rating Matrix: burosumab; cannabidiol; cerliponase alfa; chenodeoxycholic acid (CDCA); dinutuximab beta; glibenclamide; metreleptin; nusinersen; tisagenlecleucel; velmanase alfa; and vestronidase alfa. EMA European Public Assessment Reports, PubMed, EMBASE, the Cochrane Library, Clinical Key, and conference presentations from January 2016 to April 2021 were searched for evidence on efficacy and safety. Two of the identified therapies were graded as "substantial" NHB: dinutuximab beta (neuroblastoma maintenance) and nusinersen (Type I SMA), and one as "comparable" NHB (CDCA). The NHB grade of the remaining therapies fell between "comparable" and "substantial". No therapies were graded as having negative NHB. The certainty of the estimate ranged from "high" (dinutuximab beta in neuroblastoma maintenance) to "low" (CDCA, metreleptin and vestronidase alfa). The certainty of the other therapies was graded between "low" and "high". The ICER Evidence Rating Matrix overall rating "A" (the highest) was given to two therapies, "B+" to 6 therapies, "C+" to five therapies, and "I" (the lowest) to three therapies. The scores varied between rating authors with mean agreement over all indications of 71.9% for NHB, 56.3% for certainty and 68.8% for the overall rating. Conclusions: Using the ICER Matrix to grade orphan therapies according to their treatment benefit and certainty is feasible. However, the assessment involves subjective judgements based on heterogenous evidence. Tools such as the ICER Matrix might aid decision makers to evaluate treatment benefit and its certainty when comparing therapies across indications. [ABSTRACT FROM AUTHOR]

An economical & eco-friendly spectrofluorometric method has been developed for the determination of prucalopride succinate (PRU) in human urine on the basis of the drug's native fluorescence. The type of solvent and the wavelengths of excitation and emission have been carefully selected for optimal experimental conditions. In deionized water, the fluorescence intensity was measured at λ emission 362 nm upon excitation at 310 nm. This bio-validated method was carried out using 30uL urine without any preliminary steps. The calibration curve for prucalopride succinate shows a linear relationship in a concentration range of 0.75–5.5 µg/mL. Accuracy and precision were obtained using 4 quality control samples which are: 0.75 μg/ mL (LLOQ), 2.25 μg/mL (QCL), 2.5 μg/mL (QCM) & 4.125 µg/mL (QCH). The validation of this proposed technique obeys European Medicines Agency (EMA) Guidelines for validating bioanalytical methods and the greenness assessment was evaluated according to the Analytical GAPI approach. [ABSTRACT FROM AUTHOR]

Background: Four vaccines have been authorized by the European Medicines Agency (EMA): viral vector-based vaccines (AstraZeneca; AZD1222 and Johnson & Johnson; Ad26.COV2. and 2 mRNA-based vaccines (Pfizer/BioNTech; BNT162b2 and Moderna; mRNA-1273). Adverse events (AEs) related to vaccination have been described in the literature. The main aim of the dermatological practice was to avoid the diffusion of COVID-19, allowing the continuity of care for patients. Objective: The aim of this review article is to investigate current literature regarding cutaneous reactions following COVID-19 vaccination, mainly inflammatory dermatological diseases. Materials and methods: Investigated manuscripts included metanalyses, reviews, letters to the editor, real-life studies, case series, and reports. Results: We selected a total of 234 articles involving more than 550 patients. We have divided the results section into various sub-sections to ensure greater understanding for readers. Conclusions: Clinicians should keep in mind the possibility of new onsets or the worsening of several dermatoses following vaccination in order to promptly recognize and treat these AEs. Certainly, vaccination should not be discouraged. [ABSTRACT FROM AUTHOR]

This study seeks to investigate the impact of strengthened requirements for clinical evaluation for medical device manufacturers in Europe due to the new Medical Device Regulations. Qualitative interviews were conducted with eight clinical evaluation consultants from eight different European countries who review and approve clinical evaluation reports for manufacturers prior to their submission to notified bodies. The study describes the sources of device clinical evaluation evidence and describes the consultants' recommendations and challenges encountered when reviewing Clinical Evaluation Reports. The findings from the study demonstrate that understanding what constitutes sufficient clinical evidence poses the biggest challenge to the generation of an MDR-compliant Clinical Evaluation Report. Additionally, the study identified a knowledge and skills gap in the generation and assessment of acceptable regulatory and clinical data. Further, there is heterogeneity in the reviews of Clinical Evaluation Reports received by consultants and inadequate guidance to enable compliance by manufacturers. This study found that some manufacturers of certain CE-marked medical devices are planning to remove them from the EU market upon expiration of their certificate, and in the case of new innovative devices, some manufacturers may launch in other non-EU markets. [ABSTRACT FROM AUTHOR]

Conditional (European Medicines Agency) or accelerated (U.S. Food and Drug Administration) approval of drugs allows earlier access to promising new treatments that address unmet medical needs. Certain post‐marketing requirements must typically be met in order to obtain full approval, such as conducting a new post‐market clinical trial. We study the applicability of the recently developed harmonic mean χ2‐test to this conditional or accelerated approval framework. The proposed approach can be used both to support the design of the post‐market trial and the analysis of the combined evidence provided by both trials. Other methods considered are the two‐trials rule, Fisher's criterion and Stouffer's method. In contrast to some of the traditional methods, the harmonic mean χ2‐test always requires a post‐market clinical trial. If the p‐value from the pre‐market clinical trial is ≪0.025, a smaller sample size for the post‐market clinical trial is needed than with the two‐trials rule. For illustration, we apply the harmonic mean χ2‐test to a drug which received conditional (and later full) market licensing by the EMA. A simulation study is conducted to study the operating characteristics of the harmonic mean χ2‐test and two‐trials rule in more detail. We finally investigate the applicability of these two methods to compute the power at interim of an ongoing post‐market trial. These results are expected to aid in the design and assessment of the required post‐market studies in terms of the level of evidence required for full approval. [ABSTRACT FROM AUTHOR]

The US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have robust collaboration and dialogue around the need for data and the inclusion of pregnant and lactating individuals in clinical trials. Despite this collaboration, the two agencies have their own standards for the format and content of labeling for these populations. To understand these differences, the pregnancy and lactation labeling sections for 31 approved drugs were compared, and trends were assessed for use of language concordance and discordance related to use during pregnancy and lactation between the 2 agencies. Further analysis evaluated the presence of human data included in the labeling. The EMA and the FDA had high discordance between pregnancy and lactation labeling language, in 68% and 71% of labeling, respectively, and only 10% of pregnancy labeling and 16% of lactation labeling include human data. Concordance in labeling language is not the norm but occurs when there is a sizeable body of human data, animal data suggesting a particular safety issue, drug mechanism of action information, or disease‐specific considerations. This study highlights the need for more human data to inform prescribing decisions in these populations. The results also suggest that there is an opportunity for alignment in labeling across regions. [ABSTRACT FROM AUTHOR]

Prior to deployment of coronavirus disease 2019 (COVID‐19) vaccines in the European Union in 2021, a high vaccine uptake leading to an unprecedented volume of safety data from spontaneous reports and real‐world evidence, was anticipated. The European Medicines Agency (EMA) implemented specific activities to ensure enhanced monitoring of emerging vaccine safety information, including intensive monitoring of reports of adverse events of special interest and the use of observed‐to‐expected analyses. The EMA also commissioned several independent observational studies using a large network of electronic healthcare databases and primary data collection via mobile and web‐based applications. This preparedness was key for two high‐profile safety signals: thrombosis with thrombocytopenia syndrome (TTS), a new clinical entity associated with adenovirus‐vectored vaccines, and myocarditis/pericarditis with messenger RNA vaccines. With no existing case definition nor background rates, the signal of TTS posed particular challenges. Nevertheless, it was rapidly identified, evaluated, contextualized and the risk minimized thanks to close surveillance and an efficient use of available evidence, clinical expertise and flexible regulatory tools. The two signals illustrated the complementarity between spontaneous and real‐world data, the former enabling rapid risk identification and communication, the latter enabling further characterization. The COVID‐19 pandemic has tremendously enhanced the development of tools and methods to harness the unprecedented volume of safety data generated for the vaccines. Areas for further improvement include the need for better and harmonized data collection across Member States (e.g., stratified vaccine exposure) to support signal evaluation in all population groups, risk contextualization, and safety communication. [ABSTRACT FROM AUTHOR]

In accordance with European regulation, medicines containing a new active substance to treat neurodegenerative diseases as well as autoimmune and other immune dysfunctions must be approved by the European Medicines Agency (EMA) through the centralized procedure before they can be marketed. However, after EMA approval, each country is responsible for national market access, following the assessment performed by health technology assessment (HTA) bodies with regard to the therapeutic value. This study aims to provide a comparative analysis of HTA recommendations issued by three EU countries (France, Germany, and Italy) for new drugs for multiple sclerosis (MS) following EMA approval. In the reference period, we identified 11 medicines authorized in Europe for MS, including relapsing forms of MS (RMS; n = 4), relapsing–remitting MS (RRMS; n = 6), secondary progressive MS (SPMS; n = 1), and the primary progressive form (PPMS; n = 1). We found no agreement on the therapeutic value (in particular, the “added value” compared to the standard of care) of the selected drugs. Most evaluations resulted in the lowest score (“additional benefit not proven/no clinical improvement”), underlining the need for new molecules with better efficacy and safety profiles for MS, especially for some forms and clinical settings. [ABSTRACT FROM AUTHOR]

Dimethyl fumarate (DMF) was recently approved by the European Medicines Agency for systemic treatment of moderateto-severe chronic plaque psoriasis. Appropriate management of DMF treatment is required to achieve optimal clinical benefits. 7 dermatology experts gathered online for 3 meetings to identify consensus on the use of DMF in patient selection, drug dosage/titration, side effects management, and follow-up, with the aim to provide guidance on the use of DMF for psoriasis in clinical dermatological practice based on literature data and expert opinion. 20 statements were discussed and voted on using a facilitator-mediated modified Delphi methodology. Strong consensus was reached for all statements (agreement level of 100%). DMF treatment is characterized by dosage flexibility, sustained efficacy, high rates of drug survival, and low potential for drug-drug interactions. It can be used in a broad range of patients, including the elderly or those with comorbidities. Side effects (mainly gastrointestinal disorders, flushing, and lymphopenia) are frequently reported but are generally mild and transient and can be minimized by dosage adjustments and a slow titration schedule. Hematologic monitoring throughout the treatment course is required to reduce the risk of lymphopenia. This consensus document provides clinical dermatologists with answers on the optimal use of DMF to treat psoriasis. [ABSTRACT FROM AUTHOR]

The rapid and large-scale roll-out of new COVID-19 vaccines has led to unprecedented challenges in assessing vaccine safety. In 2021, the European Medicines Agency (EMA) processed about 1.7 million safety reports related to COVID-19 vaccines in the EudraVigilance (EV) database and identified more than 900 potential signals. Beyond the large amount of information to be processed, the evaluation of safety signals has faced several difficulties and limitations, both in the assessment of case reports and in the investigation of databases. The evaluation of a signal of corneal graft rejection (CGR) with Vaxzevria® was no exception to this. In this commentary, we present the challenges encountered in making regulatory decisions in the context of evolving evidence and knowledge. The pandemic crisis emphasised the importance of quick and proactive communication to address the many questions and, above all, to ensure the transparency of safety data. [ABSTRACT FROM AUTHOR]

Protein kinase inhibitors (PKIs) used in oncology can induce severe and even fatal hepatotoxicity. Several PKIs are registered within a certain class to target a specific kinase. No systematic comparison of the reported hepatotoxicity and clinical guidance for monitoring and management of hepatotoxic events between the various PKI summaries of product characteristics (SmPC) is yet available. A systematic analysis of data on 21 hepatotoxicity parameters obtained from the SmPCs and European public assessment reports (EPARs) of European Medicines Agency‐approved antineoplastic PKIs (n = 55) has been conducted. The median reported incidence (range) of all grades of aspartate aminotransferase (AST) elevations was 16.9% (2.0%–86.4%) for PKI monotherapy, with 2.1% (0.0%–10.3%) being grade 3/4 and for all grades alanine aminotransferase (ALT) elevations 17.6% (2.0%–85.5%), with 3.0% (0.0%–25.0%) being grade 3/4. Fatalities due to hepatotoxicity were reported for 22 out of 47 PKIs (monotherapy) and for 5 out of 8 PKIs (combination therapy). A maximum grade of grade 4 and grade 3 hepatotoxicity was reported for 45% (n = 25) and 6% (n = 3), respectively. Liver parameter monitoring recommendations were present in 47 of the 55 SmPCs. Dose reductions were recommended for 18 PKIs. Discontinuation was recommended for patients meeting Hy's law criteria (16 out of 55 SmPCs). Severe hepatotoxic events are reported in approximately 50% of the analyzed SmPCs and EPARs. Differences in the degree of hepatotoxicity are apparent. Although liver parameter monitoring recommendations are present in the vast majority of the analyzed PKI SmPCs, the clinical guidance for hepatotoxicity was not standardized. [ABSTRACT FROM AUTHOR]

Introduction: Concerns of the persistence and severity of the adverse effects of fluoroquinolones, mainly involving the nervous system, muscles and joints, resulted in the 2018 referral procedure led by the European Medicines Agency (EMA). They advised to stop prescribing fluoroquinolones for infections of mild severity or of a presumed self-limiting course and for prevention of infections, plus to restrict prescriptions in cases of milder infections where other treatment options are available, and restrict in at-risk populations. We aimed to examine whether the impact of EMA regulatory interventions implemented throughout 2018–2019 had an impact on fluoroquinolone prescribing rates. Methods: A retrospective population-based cohort study was conducted using electronic health care records from six European countries between 2016 and 2021. We analysed monthly incident fluoroquinolone use rates overall and for each fluoroquinolone active substance through flexible modelling via segmented regression to detect time points of trend changes, in monthly percentage change (MPC). Results: The incidence of fluoroquinolone use ranged from 0.7 to 8.0/1000 persons per month over all calendar years. While changes in fluoroquinolone prescriptions were observed over time across countries, these were inconsistent and did not seem to be temporally related to EMA interventions (e.g., Belgium: February/May 2018, MPC − 33.3%, 95% confidence interval [CI] − 35.9 to − 30.7; Germany: February/May 2019, MPC − 12.6%, 95% CI − 13.7 to − 11.6]; UK: January/April 2016, MPC − 4.9%, 95% CI − 6.2 to − 3.6). Conclusion: The regulatory action associated with the 2018 referral did not seem to have relevant effects on fluoroquinolone prescribing in primary care. [ABSTRACT FROM AUTHOR]

Introduction: SB11 (Byooviz™) is a ranibizumab biosimilar that acts as a vascular endothelial growth factor (VEGF)-A inhibitor. Stability data for unopened SB11 vials at room temperature are limited and no data are available for SB11 withdrawn into syringes (in-use) for intravitreal administration. Methods: SB11 stability was assessed in two different settings: unopened vials stored at 30 ± 2 °C/65 ± 5% relative humidity (RH) for 2 months, and in-use SB11 withdrawn into syringes stored at 5 ± 3 °C for 98 days and then 25 ± 2 °C/60 ± 5% RH for 24 h. The product was stored in the absence of light, and the experimental design followed International Conference on Harmonization and European Medicines Agency requirements for stability evaluation of biological products. Analysis included visual appearance (color, clarity, and presence of visible particles), pH, protein concentration (A280) and purity (size-exclusion high-pressure liquid chromatography, capillary electrophoresis–sodium dodecyl sulfate, imaged capillary isoelectric focusing), biological activity (VEGF binding and neutralization), and safety (sub-visible particulates). Results: Except for charge variants in unopened vials at room temperature after 1 month by US standards, all results met the stability acceptance criteria (US and EU) for both unopened vials and for in-use SB11. There were no major changes in terms of physicochemical stability, biological activity and sub-visible particulates. Conclusion: SB11 was stable for longer periods and at higher temperatures than what is stated in the labels of the reference product (Lucentis) and SB11. The physicochemical properties, biological activity, and sub-visible particulates of SB11 in both tested settings (unopened vials at room temperature and in-use product withdrawn into syringes) were maintained under the described storage periods. This information can help to avoid unnecessary delays in patient treatment without any loss in quality and biological activity, lower the workload of health care providers and reduce costs associated with drug waste. [ABSTRACT FROM AUTHOR]

Selective safety data collection may simplify late‐stage clinical trials and improve their feasibility. However, the impact on increasing overall drug safety knowledge is unknown. The aim of this study is to evaluate how much safety information is added to the drug label based on large trials after initial authorization. Changes made to the "undesirable effects" section of the drug label of cardiometabolic agents approved between 2000 and 2020 based on the results of large (> 1,000 patient) clinical trials submitted to the European Medicines Agency (EMA) were evaluated. The study focused on glucose lowering, antithrombotic, and lipid‐modifying agents. The primary outcome was the number of changes in adverse drug reactions in the drug label. The EMA reviewed 55 large trials concerning 25 cardiometabolic agents after the initial marketing authorization, which included 402,444 patients. Ultimately, 38 trials (69%) resulted in a safety section update, whereas 17 trials (31%) did not. Changes in listed adverse drug reactions were made following 19 trials (35%) for 12 agents: 77 adverse drug reactions were added, 11 were deleted, and the frequencies of 43 were changed. Most changes in adverse drug reactions arose from trials with antithrombotic agents (88%) and trials performed in a new population (92%). Large trials for cardiometabolic agents reported after authorization add limited new safety information on adverse drug reactions, especially when performed in the population studied prior to approval. This suggests that selective safety data collection does not reduce learnings from late stage cardiometabolic trials in populations comprehensively studied before. [ABSTRACT FROM AUTHOR]

Objective: Due to significant risks to the offspring after intrauterine exposure, the European Medicines Agency issued recommendations in 2014 and 2018 restricting the use of valproate (VPA) in women of childbearing age (WOCA). We aimed to evaluate their impact in the Emilia‐Romagna region (ERR) of Northern Italy. Methods: Using administrative databases, we identified all the ERR residents who received antiseizure medication (ASM) prescriptions from 2010 to 2020. Time series of incidence rates by sex and age group were evaluated for all ASMs. Focusing on VPA, an interrupted time series analysis was applied to assess the impact of the restrictions in WOCA with epilepsy (WOCA‐E) and WOCA with psychiatric disorders (WOCA‐P). We then evaluated the chronological order of ASM prescriptions with regard to the position of VPA. Results: Incidence rates of VPA prescriptions overall decreased over time. A significant decrease was observed only for females. The effect was stronger for WOCA, after both the first (incidence rate ratio [IRR] =.85, 95% confidence interval [CI] =.75–.96) and the second restriction (IRR =.67, 95% CI =.55–.82). The decrease was significant after the second restriction both for WOCA‐E (IRR =.43, 95% CI =.27–.68) and for WOCA‐P (IRR =.49, 95% CI =.35–.70), as well as VPA as a first prescription in both populations. VPA prescriptions as further choice did not show the same trend. Significance: After the regulatory restrictions, an overall significant decline in the use of VPA in WOCA was observed in ERR. The second restriction has been effective in consolidating the prescription trend. However, VPA appears still to be a commonly used drug in WOCA when other ASMs have failed. [ABSTRACT FROM AUTHOR]