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Hidradenitis suppurativa (HS), also known as acne inversa, is a chronic disabling and debilitating inflammatory disease with a high unmet medical need. The prevalence of HS reported in most studies is 1–2%, although it is likely to be under-reported and estimates vary globally owing to variance in data collection methods, ethnicity, geographical location and under-diagnosis. HS is characterized by persistent, painful cutaneous nodules, abscesses and draining tunnels commonly affecting the axillary, anogenital, inguinal and perianal/gluteal areas. Over time, chronic uncontrolled inflammation results in irreversible tissue destruction and scarring. Although the pathophysiology of HS has not been fully elucidated, the tumour necrosis factor (TNF)-α and interleukin (IL)-17 pathways have an important role, involving multiple cytokines. Currently, treatment options include topical medications; systemic therapies, including repeated and/or rotational courses of systemic antibiotics, retinoids and hormonal therapies; and various surgical procedures. The anti-TNF-α antibody adalimumab is currently the only biologic approved by both the US Food and Drug Administration and the European Medicines Agency for HS; however, its efficacy varies, with a clinical response reported in approximately 50% of patients in phase III trials. HS is a rapidly evolving field of discovery, with a diverse range of agents with distinct mechanisms of action currently being explored in clinical trials. Several other promising therapeutic targets have recently emerged, and agents targeting the IL-17 and Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathways are the most advanced in ongoing or completed phase III clinical trials. Alongside limited therapeutic options, significant challenges remain in terms of diagnosis and disease management, with a need for better treatment outcomes. Other unmet needs include significant diagnostic delays, thus missing the therapeutic 'window of opportunity'; the lack of standardized outcome measures in clinical trials; and the lack of established, well-defined disease phenotypes and biomarkers. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis (RA) is a systemic, chronic, immune-mediated inflammatory condition. Treatments options encompass conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), biologic disease-modifying antirheumatic drugs (bDMARDs) like tumor necrosis factor (TNF) inhibitors (TNFis) and targeted synthetic disease-modifying antirheumatic drugs (tsDMARDs) including Janus Kinase inhibitors (JAKinibs). Orally administered JAKinibs have demonstrated comparable or, in specific cases, superior efficacy compared to bDMARDs in inflammatory conditions. However, the escalating clinical utilization has been accompanied by the emergence of serious adverse effects, including major adverse cardiac events (MACE), malignancies and venous thrombotic episodes (VTE), leading to regulatory restrictions imposed by health authorities in both the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA). [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]

Introduction: Real-world evidence (RWE) in health technology assessment (HTA) holds significant potential for informing healthcare decision-making. A multistakeholder workshop was organised by the European Health Data and Evidence Network (EHDEN) and the GetReal Institute to explore the status, challenges, and opportunities in incorporating RWE into HTA, with a focus on learning from regulatory initiatives such as the European Medicines Agency (EMA) Data Analysis and Real World Interrogation Network (DARWIN EU®). Methods: The workshop gathered key stakeholders from regulatory agencies, HTA organizations, academia, and industry for three panel discussions on RWE and HTA integration. Insights and recommendations were collected through panel discussions and audience polls. The workshop outcomes were reviewed by authors to identify key themes, challenges, and recommendations. Results: The workshop discussions revealed several important findings relating to the use of RWE in HTA. Compared with regulatory processes, its adoption in HTA to date has been slow. Barriers include limited trust in RWE, data quality concerns, and uncertainty about best practices. Facilitators include multidisciplinary training, educational initiatives, and stakeholder collaboration, which could be facilitated by initiatives like EHDEN and the GetReal Institute. Demonstrating the impact of "driver projects" could promote RWE adoption in HTA. Conclusion: To enhance the integration of RWE in HTA, it is crucial to address known barriers through comprehensive training, stakeholder collaboration, and impactful exemplar research projects. By upskilling users and beneficiaries of RWE and those that generate it, promoting collaboration, and conducting "driver projects," can strengthen the HTA evidence base for more informed healthcare decisions. [ABSTRACT FROM AUTHOR]

Adrenocortical carcinoma (ACC) is an uncommon, aggressive endocrine malignancy with a high rate of recurrence, a poor prognosis, and a propensity for metastasis. Currently, only mitotane has received certification from both the US Food and Drug Administration (FDA) and the European Medicines Agency for the therapy of advanced ACC. However, treatment in the advanced periods of the disorders is ineffective and has serious adverse consequences. Completely surgical excision is the only cure but has failed to effectively improve the survival of advanced patients. The aberrantly activated Wnt/β-catenin pathway is one of the catalysts for adrenocortical carcinogenesis. Research has concentrated on identifying methods that can prevent the stimulation of the Wnt/β-catenin pathway and are safe and advantageous for patients in view of the absence of effective treatments and the frequent alteration of the Wnt/β-catenin pathway in ACC. Comprehending the complex connection between the development of ACC and Wnt/β-catenin signaling is essential for accurate pharmacological targets. In this review, we summarize the potential targets between adrenocortical carcinoma and the Wnt/β-catenin signaling pathway. We analyze the relevant targets of drugs or inhibitors that act on the Wnt pathway. Finally, we provide new insights into how drugs or inhibitors may improve the treatment of ACC. [ABSTRACT FROM AUTHOR]

Exotic companion animals have had an important role in our society since ancient times. Preserving animal health is necessary to do a responsible use of veterinary medicines. This study aimed to describe the prescription patterns of drugs in exotic pets and wildlife animals attending the Veterinary Teaching Hospital of the University of León (HVULE). A retrospective study was carried out between 2018 and 2022. Birds were the largest group of exotic animals attending the HVULE. Visits were related to emergency reasons and for musculoskeletal disorders. One-third of the animals were eventually euthanised. Regarding pharmacological treatments, the most frequently active ingredients used were pentobarbital, isoflurane, meloxicam, and within antibiotics, marbofloxacin (category B in the classification of European Medicines Agency). [ABSTRACT FROM AUTHOR]

PURPOSE: Electronic health record (EHR)–based real-world data (RWD) are integral to oncology research, and understanding fitness for use is critical for data users. Complexity of data sources and curation methods necessitate transparency into how quality is approached. We describe the application of data quality dimensions in curating EHR-derived oncology RWD. METHODS: A targeted review was conducted to summarize data quality dimensions in frameworks published by the European Medicines Agency, The National Institute for Healthcare and Excellence, US Food and Drug Administration, Duke-Margolis Center for Health Policy, and Patient-Centered Outcomes Research Institute. We then characterized quality processes applied to curation of Flatiron Health RWD, which originate from EHRs of a nationwide network of academic and community cancer clinics, across the summarized quality dimensions. RESULTS: The primary quality dimensions across frameworks were relevance (including subdimensions of availability, sufficiency, and representativeness) and reliability (including subdimensions of accuracy, completeness, provenance, and timeliness). Flatiron Health RWD quality processes were aligned to each dimension. Relevancy to broad or specific use cases is optimized through data set size and variable breadth and depth. Accuracy is addressed using validation approaches, such as comparison with external or internal reference standards or indirect benchmarking, and verification checks for conformance, consistency, and plausibility, selected on the basis of feasibility and criticality of the variable to the intended use case. Completeness is assessed against expected source documentation; provenance by recording data transformation, management procedures, and auditable metadata; and timeliness by setting refresh frequency to minimize data lags. CONCLUSION: Development of high-quality, scaled, EHR-based RWD requires integration of systematic processes across the data lifecycle. Approaches to quality are optimized through knowledge of data sources, curation processes, and use case needs. By addressing quality dimensions from published frameworks, Flatiron Health RWD enable transparency in determining fitness for real-world evidence generation. [ABSTRACT FROM AUTHOR]

Background: Topical chlormethine (CL) is recommended as a first-line treatment for early-stage mycosis fungoides (MF) and in 2017, the European Medicines Agency approved the CL gel formulation to treat adult patients. More recently, to increase patient compliance and adherence, clinicians have developed flexible protocols that allow the concomitant use of CL gel with topical corticosteroids in daily practice regimens. Therefore, sharing real-life data on CL gel use and side effects management may help improve the use of this agent. Objectives: To expand knowledge about the actual use of CL gel in patients with MF, the present study assessed the improvement of MF skin lesions after CL gel treatment and provided information on the management of cutaneous adverse events (AEs) in a real-life setting. Methods: This was an Italian retrospective study conducted among six dermatology referral centers. Patients ≥18 years affected by MF and in treatment with CL gel (160 µ/g), alone or in combination according to routine clinical practice, between December 2019 and December 2021 were considered. The study's primary aim was to evaluate the effectiveness of CL gel in terms of overall response rate (ORR) after 3 months of treatment. Results: A total of 79 patients (61% male) with different stages of MF (84% early stage) were included. CL gel was prescribed mainly in association with topical corticosteroids (66% of patients). ORR after 3 months of treatment was 42%, with no differences between early- and advanced-stage MF. Response rates improved over time up to 97% after 18 months of treatment. Overall, 66 AEs were reported in 67% of patients; most were hyperpigmentation (45%) and irritant contact dermatitis (37%). Six AEs led to treatment discontinuation, and five out of six (83%) patients who reported these events resumed treatment after interruption. No AEs were classified as severe. Conclusions: Our observations support the use of CL gel in patients with early- and advanced-stage MF, making it a valuable treatment option. [ABSTRACT FROM AUTHOR]

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

Background: 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]

PredictONCO 1.0 is a unique web server that analyzes effects of mutations on proteins frequently altered in various cancer types. The server can assess the impact of mutations on the protein sequential and structural properties and apply a virtual screening to identify potential inhibitors that could be used as a highly individualized therapeutic approach, possibly based on the drug repurposing. PredictONCO integrates predictive algorithms and state-of-the-art computational tools combined with information from established databases. The user interface was carefully designed for the target specialists in precision oncology, molecular pathology, clinical genetics and clinical sciences. The tool summarizes the effect of the mutation on protein stability and function and currently covers 44 common oncological targets. The binding affinities of Food and Drug Administration/ European Medicines Agency -approved drugs with the wild-type and mutant proteins are calculated to facilitate treatment decisions. The reliability of predictions was confirmed against 108 clinically validated mutations. The server provides a fast and compact output, ideal for the often time-sensitive decision-making process in oncology. Three use cases of missense mutations, (i) K22A in cyclin-dependent kinase 4 identified in melanoma, (ii) E1197K mutation in anaplastic lymphoma kinase 4 identified in lung carcinoma and (iii) V765A mutation in epidermal growth factor receptor in a patient with congenital mismatch repair deficiency highlight how the tool can increase levels of confidence regarding the pathogenicity of the variants and identify the most effective inhibitors. The server is available at https://loschmidt.chemi.muni.cz/predictonco. [ABSTRACT FROM AUTHOR]

Aims: To describe characteristics of applicant, tool, outcomes, regulatory responses and general learnings from European Medicines Agency (EMA) Qualification Procedures on patient‐reported outcomes (PROs), observer‐reported outcomes (ObsROs) and performance outcomes (PerfOs) finalized between January 2013 and December 2018. Methods: Descriptive analysis, and qualitative review of the regulatory outcomes of the study procedures. Results: Seventeen qualification programmes for PROs, 6 for ObsRO tools and 11 for PerfO tools were submitted by consortia, large and small/medium companies. Gastroenterology and neurology were the most frequent therapeutic areas. There was a high level of regulators' partial agreement (above 70%) with applicant's approaches with constructive input; EMA published Letters of Support for PRO (6), ObsRO (2) and PerfO (4) tools, and Qualification Opinions on PROs (2) and PerfOs (1). General issues related to Qualification Procedures on PROs raised by EU regulatorsincluded: population, appropriate studies to demonstrate ability to detect change, tool validation in interventional trials, anchoring, identification of the minimally important difference, item selection, weighting, and multiple domains. In addition, specific issues for ObsROs and PerfO tools validation are identified. Conclusions: Regulators discussed principles and challenges of validation tailored to specific setting in tool development, providing constructive feedback. Regulatory outputs supportive of further development were published in over one‐third of programs. We encourage applicants intending to use or develop novel PRO, ObsRO and PerfO tools that will generate evidence for regulatory submissions on medicines to consider Qualification procedures for novel methods to seek feedback on the development and validation of these tools. [ABSTRACT FROM AUTHOR]

Objective We evaluated the uptake of medicines licensed as orphan drugs by the United States Food and Drug Administration (FDA) or European Medicines Agency (EMA) into the WHO Model list of essential medicines and the WHO Model list of essential medicines for children from 1977 to 2021. Methods We collated and analysed data on drug characteristics, reasons for adding or rejecting medicines, and time between regulatory approval and inclusion in the lists. We compared trends in listing orphan drugs before and after revisions to the inclusion criteria of the essential medicines lists in 2001, as well as differences in trends for listing orphan and non-orphan drugs, respectively. Findings The proportion of orphan drugs in the essential medicines lists increased from 1.9% (4/208) in 1977 to 14.6% (70/478) in 2021. While orphan drugs for communicable diseases have remained stable over time, we observed a considerable shift towards more orphan drugs for noncommunicable diseases, particularly for cancer. The median period for inclusion in the essential medicines lists after either FDA or EMA first approval was 13.5 years (range: 1-28 years). Limited clinical evidence base and uncertainty about the magnitude of net benefit were the most frequent reasons to reject proposals to add new orphan drugs to the essential medicines lists. Conclusion Despite lack of a global definition of rare diseases, the essential medicines lists have broadened their scope to include medicines for rare conditions. However, the high costs of many listed orphan drugs pose accessibility and reimbursement challenges in resourceconstrained settings. [ABSTRACT FROM AUTHOR]

An HPLC method with UV detection was developed for the determination of carnosic acid in human plasma and applied to a pharmacokinetic study after oral administration of Rosemary extract to a healthy volunteer. Sample preparation depends on liquid–liquid extraction with hexane. Chromatographic separation was achieved with C18 column (150 mm × 4.6 mm × 5 μm), at 25°C with isocratic elution, mobile phase composed of solution A (methanol), and solution B (2% o-phosphoric acid in water) (90:10, v/v) at flow rate of 1.0 mL/min. The analyte was detected at 230 nm. The retention time is 4.20 ± 0.03 min. The method was validated in terms of accuracy, precision, specificity, robustness and detection and quantification limits, in accordance with European Medicines Agency guidelines. LOD and LOQ were found to be 0.075 and 0.25 ng/mL, respectively. The method was applied to the analysis of carnosic acid in human plasma with good recovery as 91.7%. The plasma concentration-time profile and pharmacokinetic parameters: AUC0– t , AUC0–∞, C max, t max, t 1/2 were calculated according to the assays. The method can certainly be used for routine analysis of carnosic acid in human plasma after oral administration of Rosemary extract, and for phase I clinical studies and bioavailability-bioequivalance studies as well. [ABSTRACT FROM AUTHOR]

Chronic prurigo (CPG) is a neuroinflammatory, fibrotic dermatosis that is defined by the presence of chronic pruritus (itch lasting longer than 6 weeks), scratch-associated pruriginous skin lesions and history of repeated scratching. Patients with CPG experience a significant psychological burden and a notable impairment in their quality of life. Chronic prurigo of nodular type (CNPG; synonym: prurigo nodularis) represents the most common subtype of CPG. As CNPG is representative for all CPG subtypes, we refer in this review to both CNPG and CPG. We provide an overview of the clinical characteristics and assessment of CPG, the burden of disease and the underlying pathophysiology including associated therapeutic targets. The information provided results from a PubMed search for the latest publications and a database search for current clinical trials (ClinicalTrials.gov, EU Clinical Trials Register [European Medicines Agency]; using the following terms or combinations of terms: 'chronic prurigo', 'prurigo', 'prurigo nodularis', 'pathophysiology', 'therapy', 'biologics', 'treatment'). Dupilumab is the first authorized systemic therapy by the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA) for CNPG to date. Topical and systemic agents that are currently under investigation in clinical randomized, placebo-controlled phase II and III trials such as biologics (e.g., nemolizumab, vixarelimab/KPL-716, barzolvolimab/CDX-0159), small molecules (ruxolitinib cream, povorcitinib/INCB054707, abrocitinib) and the opioid modulator nalbuphine are highlighted. In the last past 15 years, several milestones have been reached regarding the disease understanding of CPG such as first transcriptomic analysis, first terminology, first guideline, and first therapy approval in 2022, which contributed to improved medical care of affected patients. The broad range of identified targets, current case observations and initiated trials offers the possibility of more drug approvals in the near future. [ABSTRACT FROM AUTHOR]

Relapsed and refractory B‐cell acute lymphoblastic leukemia (B‐ALL) is an aggressive B‐cell neoplasm associated with poor outcomes. Conventional multiagent chemotherapy and bispecific antibody therapy may induce remission; however, relapse rates remain high and overall survival is poor. Chimeric antigen receptor T‐cell (CAR‐T) therapy provides durable, deep complete remission, and long‐term cures in relapsed and refractory B‐ALL. However, with this new treatment modality, 10%–30% of patients do not achieve remission, and over 50% experience relapse after therapy. Currently, there are two approved CD19‐specific CAR‐T cell constructs in B‐ALL, Tisagenlecleucel and Brexucabtagene Autoleucel by the United States Food and Drug Administration, and the European Medicines Agency (EMA). In this review, we discuss patients, disease, and CAR‐T predictors of outcomes in B‐ALL. We describe the two approved CD19‐directed CAR‐T cell products, review the current literature, and discuss factors associated with high risks of therapy failure and future direction in CAR‐T cell therapy for B‐ALL. [ABSTRACT FROM AUTHOR]

Futibatinib is a selective fibroblast growth factor receptor (FGFR) inhibitor under investigation for use in cholangiocarcinoma (CCA), which is a rare but aggressive tumour of the bile ducts. There are limited treatment options for CCA, particularly in metastatic disease where outcomes are especially poor. This means that futibatinib could potentially be an important treatment option, particularly as it has good efficacy in patients resistant to treatment with other FGFR inhibitors. This article covers the history and status of futibatinib in the treatment of metastatic intrahepatic cholangiocarcinoma (iCCA) with FGFR2 fusions and other rearrangements. The positive results from phase I and II clinical trials (including FOENIX-CCA2) have led to US Food and Drug Administration (FDA) approval of futibatinib for the treatment of adult patients with previously treated, unresectable, locally advanced or metastatic iCCA with FGFR2 gene fusions or other rearrangements. Futibatinib has also been recommended for approval by the European Medicines Agency (EMA) and is being considered by the UK National Institute for Health and Care Excellence (NICE). However, primary and acquired resistance to futibatinib is still common, and a new generation of FGFR inhibitors may help to alleviate this issue. Phase III clinical trials in the first line (FOENIX-CCA3 and SAFIR-ABC-10) are either underway or due to start shortly, which will help to further clarify the position of futibatinib in the treatment paradigm of metastatic iCCA. [ABSTRACT FROM AUTHOR]

The European Medicines Agency (EMA) Committee for Medicinal Products for Human Use (CHMP) has publicly endorsed the World Federation of Hemophilia (WFH) Gene Therapy Registry as the global standard for consolidating international data on individuals with hemophilia who receive gene therapy. This endorsement highlights the importance of the registry in ensuring patient safety and uniting all stakeholders involved in hemophilia treatment. The registry collects comprehensive, long-term data on individuals with hemophilia who undergo gene therapy and aims to assess the safety, efficacy, and quality of life of patient recipients. The registry follows strict international regulations and standards of data privacy and has a multi-stakeholder governance structure to ensure wide representation. The funding for the registry comes from the manufacturers of gene therapy products, and industry representatives are included in the governance committees but are not involved in decision-making regarding data analysis or reporting. The endorsement by the CHMP is significant as gene therapy products for hemophilia are being approved for use in multiple countries, and the registry provides a centralized repository of standardized global data for robust analyses and identification of safety events. The registry benefits patients, hemophilia treatment centers, national registries, industry partners, regulatory agencies, and Health Technology Assessment organizations. Overall, the endorsement emphasizes the importance of collaboration among all stakeholders in ensuring the safety of individuals with hemophilia who receive gene therapy. [Extracted from the article]

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

The level of vitamin B group in human serum is an important index of human health. Among B vitamins, cyanocobalamin in serum is unstable and its content is extremely low. Rapid and simultaneous detection of multiple B vitamins including cyanocobalamin is a challenge. Herein, we have developed a rapid and stable method that can realize the determination of thiamine, riboflavin, nicotinamide, pantothenic acid, pyridoxic acid, biotin, 5‐methyltetrahydrofolate, and cyanocobalamin simultaneously in 6 min. The method was established based on protein precipitation with methanol and then chromatographic separation was achieved using Waters acquity ultra‐high‐performance liquid chromatography high strength silica T3 column, which was stable and sensitive especially for cyanocobalamin. Limit of quantification, precision, trueness, and matrix effect were validated according to the European Medicines Agency and United States Food and Drug guidelines and Clinical and Laboratory Standards Institute guidelines on bioanalytical method. The limit of quantification for thiamine, riboflavin, nicotinamide, pantothenic acid, pyridoxic acid, biotin, 5‐methyltetrahydrofolate, and cyanocobalamin was 0.4, 0.4, 0.8, 2.0, 0.4, 0.1, 0.4, and 0.04 ng/mL separately, respectively. Intra‐ and interday precisions were 1.1%–12.4% and 2.0%–13.5%, respectively. The relative errors were between 0.3% and 13.3%, and the matrix effects were between 2.6% and 10.4%. [ABSTRACT FROM AUTHOR]

Introduction: New combinations of old β-lactam drugs with novel β-lactamase inhibitors, approved in recent years by the US Food and Drug Administration and the European Medicines Agency, are a promising alternative for the treatment of infections caused by multidrug-resistant strains. Due to limited availability and increasing resistance to antibacterial drugs, they should be used with caution, especially in patients with limited treatment options. It should be noted that both diazobicycloctane and boron inhibitors are inactive against metallo-β-lactamase (MBL) producing strains. The aim of this study was to evaluate the in vitro susceptibility of carbapenemase-producing Gram-negative bacilli to meropenem/vaborbactam, imipenem/relebactam and ceftazidime/avibactam in clinical samples from hospitalized patients. Materials and methods: The analysis included 102 clinical strains of carbapenemase-producing Enterobacterales and nonfermenters from hospital centers in Łódź, Poland. A minimum inhibitory concentration test strip method was used to determine antimicrobial susceptibility. Results: Seventy-one percent of Escherichia coli, 40% of Klebsiella pneumoniae, and 67% of Pseudomonas aeruginosa were resistant to meropenem/vaborbactam, 57%, 66%, and 60% to imipenem/relebactam, and 71%, 74%, and 60% to ceftazidime/avibactam, respectively. Considering carbapenemase resistance mechanisms, the highest efficacy was observed in Klebsiella pneumoniae carbapenemases (KPC) strains for each drug combination tested. Conclusions: The results of our study confirm the conclusions of the studies evaluating the susceptibility of Gram-negative, fermenting, and non-fermenting bacilli to ceftazidime/avibactam, meropenem/vaborbactam and imipenem/relebactam and indicate that there are reasonable grounds for using these antibiotics in the treatment of patients hospitalized with serious infections. However, limitations in their use against MBL-producing strains are highlighted. [ABSTRACT FROM AUTHOR]

Context: Warfarin is extensively used for venous thromboembolism and other coagulopathies. In clinicalsettings, warfarin is administered as a mixture of S‑warfarin and R‑warfarin, and both enantiomers are metabolized by multiple cytochrome P450 enzymes into many hydroxylation metabolites. Validation of analysis method and estimation of warfarin plasma levels are important, especially in narrow‑index drugs such as warfarin. Aims: This study aimed to obtain a validated method for analyzing warfarin in patient plasma according to the European Medicines Agency (EMA) guidelines. Materials and Methods: A total of 77 patients were enrolled in this study. Five millimeters of venous blood was collected using sodium ethylenediaminetetraacetic acid (EDTA) tubes for pharmacokinetic analysis. Samples were prepared by the protein precipitation technique using acetonitrile. The optimum conditions for the analysis of warfarin in human plasma were tested using fluorescence detector (FLD) high‑performance liquid chromatography (HPLC) with Chiralcel OD‑RH column (4.6 × 150 mm i.d., 5 μm), Chiralcel OD‑RH guard column (4.0 × 10 mm, 5 μm), and a column temperature of 45°C. The mobile phase used was acetonitrile: phosphate buffer pH 2 (40:60), with an isocratic flow rate of 1 ml/min and an injection volume of 20 μl. Excitation and emission wavelengths were 310 and 350 nm (warfarin) and 300 and 400 nm (griseofulvin). The retention time of griseofulvin was 6–7.5 minutes; R‑warfarin was 10–11.5 minutes; and S‑warfarin was 14–16 minutes. Results: The result of this validation obtained the optimum conditions. This method yielded the limit of detection (LOD) values of 0.0674 ppm (R‑warfarin) and 0.0897 ppm (S‑warfarin). The limit of quantification (LOQ) values were 0.225 ppm (R‑warfarin) and 0.298 ppm (S‑warfarin). Linearity existed at concentrations of 0.2–3 ppm with the line equation y = 0.0705x + 0.0704 with R² = 0.978 for R‑warfarin and y = 0.0513x + 0.0297 with R² = 0.9924 for S‑warfarin. At least 75% of the seven concentrations met the reverse concentration requirements, which were below ± 15%. This method met the requirements of accuracy and precision within and between runs, selectivity, and carryover where the %RSD and %diff values were below ± 15%. The mean plasma concentrations of R‑warfarin and S‑warfarin were found to be 0.76 ± 1.87 (SD) μg/ml and 0.59 ± 0.81 (SD) μg/ml, respectively. The mean standard dose group plasma concentration from the analysis of 77 samples was 0.68 ± 0.61 μg/mL for R‑warfarin and 0.52 ± 0.42 μg/mL for S‑warfarin. Conclusions: Based on these results, this analytical method can be declared valid and can be used for sample measurement in warfarin pharmacokinetic studies. [ABSTRACT FROM AUTHOR]

Antimicrobial peptides (AMPs) are one of the elements of innate immunity that have a crucial role in fighting infections. These molecules are produced by all kinds of cells and can display a wide spectrum of action against bacterial or fungal infections. Bacterial resistance toward broad‐spectrum antibiotics has become a major concern in recent years. In this context, AMPs have emerged as promising alternative therapy in response to this increasing problem because of their ability to inhibit growth and biofilm formation, even in drug‐resistant microorganisms. However, despite the myriad of patents filed related to AMPs, only a small proportion of AMPs have already received certification, either by the Food and Drug Administration (FDA) or European Medicines Agency (EMA). In order to pave the way of AMPs to certification, a comprehensive knowledge of the mechanism of action of these peptides is essential. Several models have been proposed to explain it and the permeabilization of the bacterial envelope seems to play a key role in most of them. In this review, we describe the different techniques that are generally used to assess the permeabilization induced by AMPs in either in vivo or in vitro systems. Additionally, a comprehensive analysis of the cooperation during the process of binding and permeabilization is included. [ABSTRACT FROM AUTHOR]

Real‐world data (RWD) and real‐world evidence (RWE) are increasingly used to support regulatory decision making, but regulatory agencies and stakeholders may apply different definitions for RWD and use different criteria to determine when analysis of such data are considered RWE in decisions on drug approvals. To explore this issue, we reviewed two prominent publications that operationalized the definitions of RWD and RWE when describing the use of RWE in drug approvals by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA). Both publications considered noninterventional (observational) studies, RWD as a comparator arm for a single‐arm trial, product‐related literature reviews, and RWD to support clinical trial implementation (e.g., to identify potential participants) as generating RWE. In contrast, inconsistencies were identified regarding types of data sources and study designs that were considered as not generating RWE. For example, a lack of agreement existed regarding whether RWE is generated when RWD describe therapeutic contexts or are used in phase I/II interventional trials, open‐label extension studies, or pharmacovigilance activities. These discrepancies highlight opportunities to develop a consistent understanding of the role of RWE in regulatory decision making for drug approvals among regulatory agencies and stakeholders. [ABSTRACT FROM AUTHOR]

Upadacitinib is a selective Janus kinase (JAK) inhibitor which is approved by the US Food and Drug Administration, the European Medicines Agency, as well as other agencies around the world for the treatment of several chronic inflammatory diseases, including rheumatic, dermatologic, and gastrointestinal diseases. Through inhibition of JAK, upadacitinib inhibits phosphorylation of downstream effector proteins, which consequently inhibits cytokine signaling for key pathways involved in inflammatory diseases. Upadacitinib more potently inhibits JAK1 than other JAK isoforms. The pharmacokinetics, pharmacodynamics, efficacy, and safety of upadacitinib were characterized in many clinical trials, which demonstrated the superiority of upadacitinib treatment over placebo or an active comparator in rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, non‐radiographic axial spondyloarthritis, atopic dermatitis, Crohn's disease, and ulcerative colitis. The safety profile of upadacitinib supported a favorable benefit–risk profile across all the approved indications. In this article, we review the mechanism of action of upadacitinib and describe how the JAK–STAT (Janus kinase–signal transducers and activators of transcription) pathway is involved in the pathogenesis of several chronic and progressive immune‐mediated inflammatory diseases. In addition, this review also provides an overview of key clinical trials that were conducted as well as relevant data which supported the clinical development of upadacitinib and informed the recommended dose(s) in each of the approved indications. [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]

The accelerated approval (AA) program in the USA has succeeded in expediting the regulatory approval of new cancer drugs based on surrogate endpoint data. It is unclear whether the AA program promotes overall drug development, including verification of the clinical benefit, as the verification of drugs granted AA often takes long time. To determine the impact of the AA program on overall drug development, the time required for verification of clinical benefits was compared between anticancer drugs that initially received AA and those that received regular approval (RA). It was found that anticancer drugs that were approved under the AA program took longer time for verification, suggesting that the program may delay the start of a confirmatory study, and there may be room for speeding up the process. In addition, discordance was found in the pivotal study between the USA and the EU and the USA and Japan for obtaining the indication for which AA was granted in the USA and a delay in the start of the confirmatory study for the AA indication was considered to lead to a delay in approval in the EU and Japan. Early initiation of confirmatory studies for AA indications is recommended to reduce the time that patients receive drugs with unproven benefit in the USA, as well as to deliver innovative new drugs to patients earlier in the EU and Japan. [ABSTRACT FROM AUTHOR]

Background: Prompted by the Covid-19 pandemic and the need to ensure timely and safe access to medicines during a pandemic, the aim of this study was to compare and contrast the EU and US regulations, processes, and outcomes pertaining to the granting of accelerated Marketing Authorizations (MAs) for COVID-19 vaccines and treatments with a view to determining how effective these regulations were in delivering safe medicines in a timely manner. Methods: MAs for medicines approved for Covid-related indications in the first two pandemic years (March 2020–February 2022) were identified using the European Medicines Agency (EMA) and US Food and Drug Administration (FDA) websites. Authorization reports and utilized regulations were reviewed to determine and compare approval timelines, facilitated pathways, accepted clinical evidence, and effectiveness of the regulations by assessing them against time and safety standards. Results: By the end of February 2022, the EMA and FDA had granted 12 and 14 MAs, respectively. Two EU and two US approvals were issued in relation to new indications for already-approved treatments; the remaining ones were first-time approvals of novel vaccines and treatments. The median time to approval was 24 days for the EMA's conditional MAs and 36 days for the USFDA's Emergency Use Authorizations (EUA) for all Covid-19 medicines. This is compared with 23 and 28 days, respectively, specifically for first-time novel vaccines and treatments authorized by both USFDA and EMA. The USFDA and EMA differed markedly in terms of the time taken to approve new indications of already-approved treatment; the USFDA took 65 days for such approval, compared with 133 days for the EMA. Where MAs were issued by both authorities, USFDA approvals were issued before EMA approvals; applications for approval were submitted to the FDA before submission to the EMA. Three EU and two US MAs were based on data from two or more phase 3 clinical trials; the remaining ones were based on single trial data. Only six EU and four US trials had been completed by the time of authorization. This was in line with regulations. While the applicable regulations shared many similarities, there were marked differences. For instance, the EU's conditional MA regulation pertains only to first approvals of new treatments. It does not cover new indications of already-approved treatments. This contrasts with the US, where the EUA regulation applies to both types of applications, something that may have impacted approval timelines. Overall, both EU and US utilized regulations were considered to be effective. For most cases, utilizing such regulations for Covid-19 MAs resulted in faster approval timelines compared to standard MAs. They were flexible enough to manage the process of granting emergency approvals while maintaining strict requirements and allowing comprehensive reviews of the supporting evidence. Conclusion: US and EU regulations were effective in ensuring timely accelerated market access to Covid-19 medicines during the pandemic without compromising the approval standards related to safety or efficacy. The population in both regions will receive comparable access to medicines during a pandemic if sponsors submit their applications to both authorities in parallel. [ABSTRACT FROM AUTHOR]

Eminent societies of clinicians worldwide advise the implementation of therapeutic monitoring of meropenem. Our aim was to validate the new high-performance liquid chromatography (HPLC) technique for the measurement of meropenem in plasma that we developed. The validation of the method was performed in accordance with the official European Medicines Agency (EMA) guideline for bioanalytical method validation through the assessment of the following validation parameters: linearity and limit of detection/quantification, trueness and precision, recovery, selectivity, matrix-effect assessment, dilution integrity, carry-over assessment, and stability. Our calibration curve was found to be linear over the concentration ranges of 1.25--100 μg/mL, which covers the therapeutic range of meropenem in patients. From the calibration curve, the limits of detection and quantification were calculated to be 0.4 μg/mL and 1.2 μg/mL, respectively. Recovery ranged from 81.7% to 95.9%. Intra-day trueness ranged from -1.9% to 2.6% and inter-day trueness ranged from -4.7% to 3.8%. Intra-day precision was less than 4%, while inter-day precision was less than 7%. Meropenem remained stable in the patient plasma sample for one week at -20°C. Our HPLC technique can be applied in clinical practice for the therapeutic monitoring of meropenem in critically ill and other vulnerable patients since it is simple, rapid, and reliable. [ABSTRACT FROM AUTHOR]

Based on pharmacokinetic studies carried out according to the methodologies defined by the European Medicines Agency (EMA) using mass spectrometry analysis, a new formulation of a veterinary drug for the treatment of broiler chickens is proposed. Currently, the traditional trimethoprim–sulfamethoxazole drug used for broilers is applied in a 1:5 ratio, and the recommended dose is 45 mg kg−1 of live weight administered at 24 h intervals for 3 to 5 days. In this study, we propose a novel combination containing similar active substances in a newly established ratio of 1:4, with a recommended dosage of 20 mg kg−1 of live weight administered at 24 h intervals for 3 to 5 days. With this method, the currently recommended dose of the traditional trimethoprim–sulfamethoxazole drug used for broilers can be reduced by more than half. The efficacy of the newly designed formulation and dosage of the drug was verified in a bioassay for the treatment of broilers experimentally infected with an avian pathogenic strain of Escherichia coli. In the experiment, we compared the newly designed dosage with the traditional dosage in terms of efficacy and dosage. There were no statistically significant differences between the two drugs in efficacy regarding the survival of chickens after experimental infection or changes in their health status. The experimental results suggest that a significant reduction in the recommended daily dose of drugs containing trimethoprim and sulfamethoxazole for the treatment of bacterial infections in broilers is possible and can support the prudent use of antimicrobials, including the limitation of their overuse. [ABSTRACT FROM AUTHOR]

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

The article shows that the input given by healthcare professionals (HCPs) adds value to the regulatory processes surrounding the development, authorisation, and monitoring of a medicine, but is also an instrument for accountability, trust, mutual exchange as well as an insight into the public health issues that matter most to one of the key stakeholder groups the Agency works with. We highlight the role of HCPs in the EU regulatory process and take stock of the first 10 years of the Framework for Interaction with HCPs to describe how practises have evolved over this time to meet the goals of informing, consulting and improving trust in the EU regulatory system. We will analyse what led European Medicines Agency (EMA) to develop this framework through to the next steps and where the interaction might lead in the future.

This article analyzes the most common findings of the European Medicines Agency (EMA) and regulatory agencies regarding the quality of essential documents that led to delays in study approvals and major observations by EMA inspectors. The authors analyzed the content and length of informed consent forms used within clinical trials within the last 10 years and revealed a tendency toward increased length and complexity of the documents. Criteria for developing patient informed consent forms are suggested to implement in medical writing practice to make informed consent forms short and simple to read and understand by a layperson. [ABSTRACT FROM AUTHOR]

Because there is little clinical experience with apixaban in patients with severe renal impairment and non-valvular atrial fibrillation, the European Medicines Agency does not advise using it to prevent strokes in these patients. However, only a small number of pharmacokinetic and pharmacodynamic investigations showed how crucially different elimination pathways contribute to the clearance of apixaban. A 74-year-old male patient who was receiving apixaban treatment for stroke prevention in atrial fibrillation was referred to our hospital because of acute severe renal failure brought on by dehydration and abnormally elevated apixaban plasma levels. The patient was treated only with intravenous fluid therapy; serum creatinine recovered slowly over the course of six days, but plasma apixaban levels recovered quickly. No bleeding events have been recorded. Our experience demonstrates the safety profile of apixaban in cases of severe renal failure, but it also emphasizes the need for more research to confirm this evidence. [ABSTRACT FROM AUTHOR]

IntroductionThe European Medicines Agency (EMA) offers scientific advice to support the qualification procedure of novel methodologies, such as preclinical and in vitro models, biomarkers, and pharmacometric methods, thereby endorsing their acceptability in medicine research and development (R&D). This aspect is particularly relevant to overcome the scarcity of data and the lack of validated endpoints and biomarkers in research fields characterized by small samples, such as pediatrics.AimThis study aimed to analyze the potential pediatric interest in methodologies qualified as “novel methodologies for medicine development” by the EMA.MethodsThe positive qualification opinions of novel methodologies for medicine development published on the EMA website between 2008 and 2023 were identified. Multi-level analyses were conducted to investigate data with a hierarchical structure and the effects of cluster-level variables and cluster-level variances and to evaluate their potential pediatric interest, defined as the possibility of using the novel methodology in pediatric R&D and the availability of pediatric data. The duration of the procedure, the type of methodology, the specific disease or disease area addressed, the type of applicant, and the availability of pediatric data at the time of the opinion release were also investigated.ResultsMost of the 27 qualifications for novel methodologies issued by the EMA (70%) were potentially of interest to pediatric patients, but only six of them reported pediatric data. The overall duration of qualification procedures with pediatric interest was longer than that of procedures without any pediatric interest (median time: 7 months vs. 3.5 months, respectively; p = 0.082). In parallel, qualification procedures that included pediatric data lasted for a longer period (median time: 8 months vs. 6 months, respectively; p = 0.150). Nephrology and neurology represented the main disease areas (21% and 16%, respectively), while endpoints, biomarkers, and registries represented the main types of innovative methodologies (32%, 26%, and 16%, respectively).DiscussionOur results underscore the importance of implementing innovative methodologies in regulatory-compliant pediatric research activities. Pediatric-dedicated research infrastructures providing regulatory support and strategic advice during research activities could be crucial to the design of ad hoc pediatric methodologies or to extend and validate them for pediatrics.

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.

In this latest update we highlight: a publication from the US FDA regarding the definitions of real-world data (RWD) and real-world evidence (RWE); a publication from academic researchers on a demonstration project for target trial emulation; a publication from the National Institute of Health and Care Excellence (NICE) on the 1 year anniversary of their RWE framework; and a publication from NICE and Flatiron Health on the utility of US RWD for initial UK health technology assessment decision making.

Rationale: Alcohol use disorder affects 4% to 5% of the world's population. Analysis methods are available for various biological fluids to detect this disorder. Determination of ethyl glucuronide in urine by the liquid chromatography–tandem mass spectrometry (LC/MS/MS) method is frequently used in forensic toxicology. These analyses are known to cause matrix effects. Methods: The presented study describes the elimination of matrix effects for ethyl glucuronide. This study used two different LC/MS/MS systems containing orthogonal and z‐spray ion sources. Ethyl glucuronide was analyzed in negative polarity in electrospray ionization. A different dilution method was chosen for each study. The methods were developed and validated according to the European Medicines Agency bioanalytical method validation parameters. Results: The lower limit of quantitation of the developed methods was 0.025 μg/mL for ethyl glucuronide. The calibration curve of ethyl glucuronide was between 0.025 and 100 μg/mL with a correlation coefficient of >0.99 for the two methods. Conclusions: It was determined that the analyses using the z‐spray ion source were more affected by the matrix effect. The two validated methods involve rapid analysis time and simple sample preparation. Also, the methods were applied to real patients' urine. [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]

Background: Temozolomide (TMZ) oral suspension (Ped-TMZ, KIZFIZO®) is being developed for the treatment of relapsed or refractory neuroblastoma, a rare cancer affecting infants and young children. The study assessed the safety and the bioequivalence of this novel pediatric formulation with existing TMZ oral capsules. Methods: In vitro dissolution profiles and the bioequivalence were evaluated following the European Medicines Agency "Guidelines on the investigation of Bioequivalence". The phase I, multicenter, randomized, open-label, crossover, single-dose bioequivalence study enrolled 36 adult patients with glioblastoma multiforme or lower-grade glioma. Each patient received 200 mg/m2 Ped-TMZ suspension and TMZ capsules (Temodal®) on 2 consecutive days, with the order being randomly assigned. Fourteen blood samples were collected up to 10 h post-dosing. Bioequivalence was assessed by comparing the 90% confidence interval for the ratio of the geometric means of maximum TMZ plasma concentration (Cmax) and the area under the curve (AUCt). Other endpoints included further pharmacokinetic parameters and safety. Results: Both formulations exhibited a fast in vitro dissolution profile with more than 85% of TMZ dissolved within 15 min. For the bioequivalence study, thirty patients completed the trial as per the protocol. The ratio of Ped-TMZ/TMZ capsule geometric means (90% CI) for AUCt and Cmax were 97.18% (95.05–99.35%) and 107.62% (98.07–118.09%), respectively, i.e., within the 80–125% bioequivalence limits. No buccal toxicity was associated with Ped-TMZ liquid formulation. Conclusions: This study showed that Ped-TMZ oral suspension and TMZ oral capsule treatment are immediate release and bioequivalent medicines. There were also no unexpected safety signals or local toxicity (funded by ORPHELIA Pharma; ClinicalTrials.gov number, NCT04467346). [ABSTRACT FROM AUTHOR]

This document explores the use of treatment response endpoints (TREs) in the early benefit assessment (EBA) of hemato-oncological drugs in Germany. The study found that survival was often considered the most important endpoint, but it had limitations due to longer clinical trial duration and a focus on early-stage diseases. The European Medicines Agency also frequently chose endpoints other than survival for hemato-oncology drugs. The document discusses the acceptance of TREs by the decision-making body and compares it with their relevance in clinical practice. It highlights the discrepancy between the conclusions of EBAs and clinical guidelines regarding the value of endpoints, suggesting that the narrow definition of patient relevance in EBAs may overlook the value of TREs in clinical practice. [Extracted from the article]

Objectives: The treatment of relapsed/refractory (R/R) diffuse large B‐cell lymphoma (DLBCL) changed remarkably since the European Medicines Agency‐approved chimeric antigen receptor T‐cell (CAR‐T) therapies (axicabtagene ciloleucel [axi‐cel], lisocabtagene maraleucel [liso‐cel], tisagenlecleucel [tisa‐cel]) for the third‐line onwards (3+L), and targeted therapies (polatuzumab vedotin–bendamustine–rituximab [pola‐BR], tafasitamab–lenalidomide [Tafa‐L]) for the second‐line (2L) onwards. As associated rising treatment costs represent an economic burden, the cost‐effectiveness of transplant‐ineligible R/R DLBCL interventions was assessed from a German healthcare payer's perspective, using the efficiency frontier (EF) approach. Methods: A systematic literature review was performed to determine the clinical benefit concerning median overall survival (OS) of bendamustine–rituximab (BR), rituximab–gemcitabine–oxaliplatin (R‐GemOx), axi‐cel, liso‐cel, tisa‐cel, pola‐BR, and Tafa‐L. First‐year treatment costs (drug and medical services costs) were calculated. Results were merged on two‐dimensional graphs illustrating 2L and 3+L EFs. Results: Second‐line EF is formed by BR (median OS 11.49 months, €23 958) and Tafa‐L (45.7, €104 541), 3+L EF is formed by R‐GemOx (12.0, €29 080), Tafa‐L (15.5, €104 541), and axi‐cel (18.69, €308 516). These interventions build the respective cost‐effectiveness thresholds for novel interventions. Conclusions: Using the EF approach, the currently most cost‐effective interventions (based on cost‐effectiveness ratios) in the indication of R/R DLBCL were identified to guide international reimbursement decisions. [ABSTRACT FROM AUTHOR]

Background and purpose: The COVID‐19 pandemic, caused by severe acute respiratory syndrome coronavirus type 2 (SARS‐CoV‐2), rapidly spread across the globe. Tremendous efforts have been mobilized to create effective antiviral treatment options to reduce the burden of the disease. This article summarizes the available knowledge about the antiviral drugs against SARS‐CoV‐2 from a neurologist's perspective. Methods: We summarize neurological aspects of antiviral compounds against SARS‐CoV‐2 with full, conditional, or previous marketing authorization by the European Medicines Agency (EMA). Results: Nirmatrelvir/ritonavir targets the SARS‐CoV‐2 3c‐like protease using combinatorial chemistry. Nirmatrelvir/ritonavir levels are affected by medications metabolized by or inducing CYP3A4, including those used in neurological diseases. Dysgeusia with a bitter or metallic taste is a common side effect of nirmatrelvir/ritonavir. Molnupiravir is a nucleotide analog developed to inhibit the replication of viruses. No clinically significant interactions with other drugs have been identified, and no specific considerations for people with neurological comorbidity are required. In the meantime, inconsistent results from clinical trials regarding efficacy have led to the withdrawal of marketing authorization by the EMA. Remdesivir is a viral RNA polymerase inhibitor and interferes with the production of viral RNA. The most common side effect in patients with COVID‐19 is nausea. Remdesivir is a substrate for CYP3A4. Conclusions: Neurological side effects and drug interactions must be considered for antiviral compounds against SARS‐CoV‐2. Further studies are required to better evaluate their efficacy and adverse events in patients with concomitant neurological diseases. Moreover, evidence from real‐world studies will complement the current knowledge. [ABSTRACT FROM AUTHOR]

Background: Biosimilars are additional treatment options that are approved based on robust analytical and clinical comparisons with their reference biologic. At the time of initial approval, the full safety profile of a biosimilar is inferred from the reference biologic. Nonetheless, there are still lingering concerns related to the long-term safety of biosimilars. Therefore, we reviewed the post-approval pharmacovigilance data for eight marketed biosimilars from one Marketing Authorization Holder (MAH) to summarize their safety experience in a real-world setting for up to 18 years since their first biosimilar launch. Methods: Post-approval cumulative patient exposure and safety experience for eight Sandoz biosimilars [adalimumab (Hyrimoz®), epoetin alfa (Binocrit®), etanercept (Erelzi®), filgrastim (Zarzio®), infliximab (Zessly®), pegfilgrastim (Ziextenzo®), rituximab (Rixathon®), and somatropin (Omnitrope®)] was summarized based on the available pharmacovigilance data from Periodic Safety Update Reports (PSURs) and the corresponding health authority-authored PSUR assessment reports, where available, as of 31 January 2023. Exposure to all biosimilars was calculated in patient treatment days (PTD) except for rituximab, which was expressed in number of patient doses (PD). Results: The combined post-approval cumulative exposure to seven out of the eight marketed Sandoz biosimilars was more than 1.3 billion PTD and for rituximab more than 1.8 million PD. Overall, a critical analysis of the cumulative safety data of all eight Sandoz biosimilar PSURs concluded that the overall benefit–risk profile of each remains favorable and is consistent with the respective reference biologics. Conclusions: This is one of the largest reviews of post-approval biosimilar pharmacovigilance data to date by one MAH. The real-world experience of all eight marketed Sandoz biosimilars for up to 18 years demonstrates that Sandoz biosimilars can be used as safely as their respective reference biologics. Therefore, patients and healthcare providers can be confident in the clinical benefit and safety of Sandoz biosimilars. It is reasonable to believe that similar conclusions about safety may be reached for other biosimilars developed and approved to the high standards as are already in place by major health authorities such as the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA). The long-term safety of biosimilars demonstrated here provides strong support for the concept of biosimilarity. [ABSTRACT FROM AUTHOR]

Introduction: Ranitidine, a histamine H2-receptor antagonist (H2RA), is indicated in the management of gastric acid-related disorders. In 2020, the European Medicines Agency (EMA) recommended suspension of all ranitidine-containing medicines in the European Union (EU) due to the presence of N-nitrosodimethylamine (NDMA) impurities, which were considered to be carcinogenic. The aim of this study was to investigate the impact of regulatory intervention on use patterns of ranitidine-containing medicines and their therapeutic alternatives. Objectives: The aim was to study drug utilisation patterns of ranitidine and report discernible trends in treatment discontinuation and switching to alternative medications. Methods: This retrospective, population-based cohort study was conducted using primary care records from six European countries between 2017 and 2023. To explore drug utilisation patterns, we calculated (1) incident use of ranitidine, other H2RAs, and other alternative drugs for the treatment of gastric ulcer and/or gastric bleeding; (2) ranitidine discontinuation; and (3) switching from ranitidine to alternative drugs (H2RAs, proton-pump inhibitors [PPIs], and other medicinal products for acid-related disorders). Results: During the study period, 385,273 new ranitidine users were observed, with most users being female and aged 18–74 years. Ranitidine was the most commonly prescribed H2RA in the pre-referral period (September 2017–August 2019), with incidence rates between 0.8 and 9.0/1000 person years (PY). A steep decline to 0.3–3.8/1000 PY was observed in the referral period (September 2019–March 2020), eventually dropping to 0.0–0.4/1000 PY in the post-referral period (April 2020–March 2022). Switching from ranitidine to alternative drugs increased in the post-referral period, with the majority of patients switching to PPIs. Discontinuation of ranitidine use ranged from 270 to 380/1000 users in 2017 and decreased over time. Conclusions: Ranitidine was commonly used prior to referral, but it was subsequently discontinued and replaced primarily with PPIs. [ABSTRACT FROM AUTHOR]

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

Multiple sclerosis (MS) is a chronic neurodegenerative disease that affects the central nervous system (CNS). Currently, MS treatment is limited to several Food and Drug Administration (FDA)- and European Medicines Agency (EMA)-approved medications that slow disease progression by immunomodulatory action. Fingolimod and siponimod have similar mechanisms of action, and consequently, their therapeutic effects may be comparable. However, while fingolimod is mainly used for relapsing–remitting MS (RRMS), siponimod, according to EMA label, is recommended for active secondary progressive MS (SPMS). Clinicians and scientists are analysing whether patients can switch from fingolimod to siponimod and identifying the advantages or disadvantages of such a switch from a therapeutic point of view. In this review, we aim to discuss the therapeutic effects of these two drugs and the advantages/disadvantages of switching treatment from fingolimod to siponimod in patients with the most common forms of MS, RRMS and SPMS. [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]