653 results
Search Results
152. Safety Monitoring of COVID‐19 Vaccines: Perspective from the European Medicines Agency.
- Author
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Durand, Julie, Dogné, Jean‐Michel, Cohet, Catherine, Browne, Kate, Gordillo‐Marañón, María, Piccolo, Loris, Zaccaria, Cosimo, and Genov, Georgy
- Subjects
VACCINE safety ,COVID-19 vaccines ,COVID-19 ,WEB-based user interfaces ,VACCINATION status ,MESSENGER RNA - Abstract
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]
- Published
- 2023
- Full Text
- View/download PDF
153. A Comparison of FDA and EMA Pregnancy and Lactation Labeling.
- Author
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Kappel, Dana, Sahin, Leyla, Yao, Lynne, Thor, Shannon, and Kweder, Sandra
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DRUG labeling ,PREGNANCY ,HUMAN body ,CLINICAL trials ,LACTATION ,LACTATION in cattle - Abstract
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]
- Published
- 2023
- Full Text
- View/download PDF
154. New harmonized considerations on the evaluation instruments for baseline characterization of frailty in the European Union.
- Author
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Cerreta, Francesca, Cherubini, A., Cruz‐Jentoft, A., Gudmundson, A., Haberkamp, M., Jansen, P., Marchionni, N., Morgan, S., Pilotto, A., Rosa, M‐M., Rönnemaa, E., and Wildiers, H.
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DRUG registration ,FRAIL elderly ,DRUG side effects ,OLDER people - Published
- 2020
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155. Physiologically Based Pharmacokinetics Is Impacting Drug Development and Regulatory Decision Making.
- Author
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Rowland, M, Lesko, LJ, and Rostami‐Hodjegan, A
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PHARMACOKINETICS ,DRUG development - Abstract
It is no coincidence that the reports of two meetings, one organized by the US Food and Drug Administration (FDA), in March 2014, and the other by the UK Medicines and Healthcare Products Regulatory (MHRA), in collaboration with ABPI (the Association of British Pharmaceutical Industry), in June 2014, have been published in tandem in CPT-PSP. Both reports deal with the same topic, namely, the impact of physiologically based pharmacokinetics (PBPK) in clinical drug development and the best practices for such applications. This reflects the transition of PBPK from academic curiosity to industrial norm, manifested by the regulatory agencies encouraging its use and receiving an increasing number of submissions containing PBPK models. The goal of both meetings was to help determine the need and facilitate the development of regulatory guidances on this subject within the conceptual framework of model informed drug development and regulatory decision-making. A further reflection of this intent is the publication by the European Medicines Agency of a Concept Paper on PBPK. One is reminded of a similar train of events surrounding the introduction of population PK/PD and nonlinear mixed effects modeling in the early-late 1990s, again with encouragement and receptivity of regulatory agencies leading to FDA guidance on the topic. Indeed, the intention of PBPK modeling and simulation is to complement other approaches, such as compartmental modeling, or, in some cases, replace them with a more mechanistic approach. PBPK models represent an important class of models that characterize absorption, distribution, metabolism, excretion (ADME) processes and their underlying biological and physiological drivers. An increased understanding of these drivers and their unique interactions with drug substance and formulation factors provides critical insights into how drugs will behave in healthy volunteers and patients with disease. [ABSTRACT FROM AUTHOR]
- Published
- 2015
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156. Transition From Clinical to Commercial Supply Chain--Regulatory Starting Materials.
- Author
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Jurkauskas, Valdas and Minzhang Chen
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DRUG laws ,DRUG development ,PHARMACOLOGY ,PHARMACEUTICAL industry - Abstract
The article discusses regulatory aspects transition from clinical to commercial supply chain in the pharmaceutical industry. It states that challenges faced in selection of drug substance regulatory starting materials (RSMs), and mentions the emphasis during pharmaceutical development on the portion downstream of the RSMs. It notes that the European Medicines Agency (EMA) published a reflection paper on the requirements for selection and justification of starting materials.
- Published
- 2018
157. European Medical Device Regulations.
- Author
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PRINEETHA M., TALLAPANENI, VYSHNAVI, BASKARAN, MAHENDRAN, and SATYANARAYANA REDDY KARRI, VEERA VENKATA
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MEDICAL equipment ,MEDICAL laws ,MANUFACTURED products - Abstract
Medical devices are equipment or products usually designed for medical use. They are controlled by national competent officials, but the European Medicines Agency (EMA) also participates in the evaluation of certain classifications of medical devices under European Union (EU) laws. EU has adopted new medical device regulation 2017/745, it has a transition period of 3 years and will be applied fully from 26 May 2020. During the transition period the manufacturer may place their device on the market in accordance with the latest regulations if they comply or in accordance with EU directives which are currently in force. Medical device regulations will be focusing on clinical evaluation and clinical investigation which ensure the device are safe and effective. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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158. Can source control of pharmaceuticals decrease the investment needs in urban wastewater infrastructure?
- Author
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Corominas, Lluís, Gimeno, Pau, Constantino, Carlos, Daldorph, Peter, and Comas, Joaquim
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SEWAGE , *DRUGS , *ENVIRONMENTAL quality , *ENVIRONMENTAL health , *WATERSHEDS , *MICROPOLLUTANTS , *ENVIRONMENTAL standards - Abstract
The source control of pharmaceuticals involves influencing the everyday consumption volume and compound choice. This paper evaluates how source control contributes to protecting the environmental health and decreasing the investment needs in urban wastewater infrastructure. Different levels of reduction in diclofenac consumption (as recommended by the European Medicines Agency) compensated by equivalent increases in naproxen consumption (a less environmentally harmful compound) are evaluated. The different loads of compounds are fed into a microcontaminant fate and transport model of the Llobregat river basin (Spain) to assess the investment needs in tertiary treatment to reach diclofenac and naproxen concentrations below environmental quality standards. The results show that, despite the implementation of source control measures, tertiary treatment upgrades are still required in every scenario evaluated. Even though source control of pharmaceuticals decreases the investment needs in urban wastewater infrastructure, apparent concentrations reductions (i.e. statistically significant differences relative to the reference situation) are only observed in drastic substitutions of diclofenac by naproxen (a reduction in the total diclofenac consumption by 73% and a corresponding increase in naproxen consumption). The results also show that Spain is on good track with regards to the substitution of diclofenac by naproxen (among the top 5 in Europe), and this paper shows how positive this substitution can be for the environment. ga1 • We assess the substitution of diclofenac by naproxen as a source-control measure. • Source control of pharmaceuticals has a positive effect on freshwater ecosystems. • Investment needs for tertiary treatment are reduced. • Substitution at the UK level would lead to significant savings. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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159. Orphan Designation and Cisplatin/Hyaluronan Complex in an Intracavitary Film for Malignant Mesothelioma.
- Author
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Banella, Sabrina, Quarta, Eride, Colombo, Paolo, Sonvico, Fabio, Pagnoni, Antonella, Bortolotti, Fabrizio, Colombo, Gaia, and Minghetti, Paola
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CISPLATIN ,ATOMIC absorption spectroscopy ,ASBESTOS ,GEL permeation chromatography ,HYALURONIC acid ,MESOTHELIOMA ,CHLORIDE ions - Abstract
Pleural mesothelioma is a lung diffuse tumor, whose complete resection is unlikely. Consequently, metastases reappear where the primary tumor was removed. This paper illustrates the orphan medicine designation procedure of an intracavitary cisplatin film and related pharmaceutical development aspects requested by the European Medicines Agency (EMA) in its Scientific Advice. Since cisplatin pharmacokinetics from the implanted film in sheep resulted substantially modified compared to intravenous administration, the formation of a cisplatin/hyaluronan complex had been hypothesized. Here, the interaction between sodium hyaluronate (NaHA) and cisplatin (CisPt) was demonstrated. Size exclusion chromatography qualitatively evidenced the complex in the film-forming mixture, only showing the NaHA peak. Atomic absorption spectroscopy of the corresponding fraction revealed platinum, confirming the interaction. Reverse phase HPLC quantified about 5% free cisplatin in the film-forming mixture, indirectly meaning that 95% was complexed. Finally, a study of CisPt release from the film assessed how CisPt/NaHA complex affected drug availability. In water, a medium without chloride ions, there was no release and the film remained intact for 48 h and longer, whereas the placebo film dissolved in 15 min. In 0.9% NaCl medium, the film became more soluble, dissolving within 3–4 h. However, cisplatin release was still controlled by the existing complex in solution until chloride ions displaced it. While the film modified its dissolution with aging, CisPt release remained unaffected (90% released in 48 h). [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
160. Medicines for older people: assessment and transparency at the European Medicines Agency regarding cardiovascular and antithrombotic medicinal products.
- Author
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Cerreta, Francesca, Padrão, Andreia, Skibicka-Stepien, Izabela, Strampelli, Anna, and de Orbe Izquierdo, Maria Silvia
- Abstract
Purpose: To describe whether for the cardiovascular and antithrombotic medicines approved in the period 2006-2016 (a) the pivotal trial was designed with an upper ageexclusion criterion, (b) the age distribution of the participants in the registration trials reflected expected use, (c) post-authorisation studies were planned, and d) the age distribution of participants was clearly presented in the approval documents.Methods: The data provided to EMA in support of centralized marketing authorisations of were analysed.Results: Two out of 19 protocols excluded patients over 80 and 85 years old. In the heart failure, atrial fibrillation and antithrombotic drug registration trials, the proportion of patients aged 65-74 years was 33-50%, and 13-20% over 75 years. For antithrombotic drugs, it was 25-35% for the 65-74 age, and around 15% for the 75+ age. For statins and antihypertensives, it was 20-40% for the 65-74 age and 3-6% for 75+ age. Post-authorisation studies were planned in two cases. An improvement on the transparency of public data is apparent, although information is not always presented clearly and uniformly.Conclusions: There is more publicly available information since 2006, but data on older patients with frailty and multimorbidity are generally scant. To address this, CHMP Geriatric Expert Group has currently published a Reflection paper on physical frailty to support subgroup categorisation of older patients beyond age with the aim of ensuring that clinical trial populations are representative of the users of the medicine. [ABSTRACT FROM AUTHOR]
- Published
- 2018
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161. A gold standard method for the evaluation of antibody-based materials functionality: Approach to forced degradation studies.
- Author
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Coussot, Gaëlle, Le Postollec, Aurélie, Faye, Clément, and Dobrijevic, Michel
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IMMUNOGLOBULINS , *BIOCOMPATIBILITY , *HORSERADISH peroxidase , *MEDICAL technology - Abstract
The scope of this paper is to present a gold standard method to evaluate functional activity of antibody (Ab)-based materials during the different phases of their development, after their exposure to forced degradations or even during routine quality control. Ab-based materials play a central role in the development of diagnostic devices, for example, for screening or therapeutic target characterization, in formulation development, and in novel micro(nano)technology approaches to develop immunosensors useful for the analysis of trace substances in pharmaceutical and food industries, clinical and environmental fields. A very important aspect in diagnostic device development is the construction of its biofunctional surfaces. These Ab surfaces require biocompatibility, homogeneity, stability, specificity and functionality. Thus, this work describes the validation and applications of a unique ligand binding assay to directly perform the quantitative measurement of functional Ab binding sites immobilized on the solid surfaces. The method called Antibody Anti-HorseRadish Peroxidase (A2HRP) method, uses a covalently coated anti-HRP antibody (anti-HRP Ab) and does not need for a secondary Ab during the detection step. The A2HRP method was validated and gave reliable results over a wide range of absorbance values. Analyzed validation criteria were fulfilled as requested by the food and drug administration (FDA) and European Medicines Agency (EMA) guidance for the validation of bioanalytical methods with 1) an accuracy mean value within +15% of the nominal value; 2) the within-assay precision less than 7.1%, and 3) the inter-day variability under 12.1%. With the A2HRP method, it is then possible to quantify from 0.04 × 10 12 to 2.98 × 10 12 functional Ab binding sites immobilized on the solid surfaces. A2HRP method was validated according to FDA and EMA guidance, allowing the creation of a gold standard method to evaluate Ab surfaces for their resistance under laboratory constraints. Stability testing was described through forced degradation studies after exposure of Ab-surfaces to storage, pH and aqueous-organic solvent mixture stresses. [ABSTRACT FROM AUTHOR]
- Published
- 2018
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162. Editorial comment.
- Author
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Savin, Peter
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HUMAN error ,MEDICAL equipment safety measures - Abstract
An introduction is presented in which the editor discusses various reports within the issue including human error as a citation among companies as a cause of deviation with a subsequent corrective and preventive action, a review of the new European Medicines Agency (EMA) Draft Guideline on Sterilisation of the Medicinal Product and anti-counterfeiting and sterilisation issue.
- Published
- 2016
163. REPLACING RCTS WITH REAL WORLD DATA FOR REGULATORY DECISION MAKING.
- Author
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Morales, Daniel R. and Arlett, Peter
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PROFESSIONAL standards ,DRUG efficacy ,RANDOMIZED controlled trials ,DECISION making in clinical medicine - Published
- 2023
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164. The therapeutic value of treatment for multiple sclerosis: analysis of health technology assessments of three European countries.
- Author
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Gozzo, Lucia, Romano, Giovanni Luca, Brancati, Serena, Longo, Laura, Vitale, Daniela Cristina, and Drago, Filippo
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TECHNOLOGY assessment ,MEDICAL technology ,MULTIPLE sclerosis ,NEURODEGENERATION ,AUTOIMMUNE diseases - Abstract
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]
- Published
- 2023
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165. Challenges in Assessing COVID-19 Vaccines Safety Signals—The Case of ChAdOx1 nCoV-19 Vaccine and Corneal Graft Rejection.
- Author
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Bizimungu, Christelle, Sabbe, Martine, Wuillaume, Françoise, Hamdani, Jamila, Koch, Philippe, and Dogné, Jean-Michel
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GRAFT rejection ,VACCINE safety ,COVID-19 vaccines ,CORNEA ,VACCINES ,COMMUNICATIVE disorders - Abstract
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]- Published
- 2023
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166. Real-world use of dimethyl fumarate in patients with plaque psoriasis: a Delphi-based expert consensus.
- Author
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Burlando, Martina, Campione, Elena, Cuccia, Aldo, Malara, Giovanna, Naldi, Luigi, Prignano, Francesca, and Zichichi, Leonardo
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DIMETHYL fumarate ,PSORIASIS ,LYMPHOPENIA ,DRUG interactions ,DRUG dosage ,PATIENT selection - Abstract
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]
- Published
- 2023
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- View/download PDF
167. Impact of European Union Label Changes for Fluoroquinolone-Containing Medicinal Products for Systemic and Inhalation Use: Post-Referral Prescribing Trends.
- Author
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Ly, Nelly F., Flach, Clare, Lysen, Thom S., Markov, Emanuil, van Ballegooijen, Hanne, Rijnbeek, Peter, Duarte-Salles, Talita, Reyes, Carlen, John, Luis H., Karimi, Leila, Reich, Christian, Salek, Sam, and Layton, Deborah
- Subjects
ELECTRONIC health records ,FOOD labeling ,INFECTION prevention ,NERVOUS system - Abstract
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]
- Published
- 2023
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168. Safety‐Related Drug Label Changes Following Large Post‐Marketing Cardiometabolic Trials: A Review of European Public Assessment Reports.
- Author
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Starokozhko, Viktoriia, Tarrahi, Fatima, Vrijlandt, Patrick J.W.S., and Mol, Peter G.M.
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DRUG labeling ,DRUG side effects ,FIBRINOLYTIC agents - Abstract
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]
- Published
- 2023
- Full Text
- View/download PDF
169. Impact of regulatory restrictions on the use of valproic acid in women of childbearing age: An Italian study.
- Author
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Di Vito, Lidia, Mazzoni, Stefania, Belotti, Laura Maria Beatrice, Poluzzi, Elisabetta, Baldin, Elisa, Zenesini, Corrado, Bisulli, Francesca, Tinuper, Paolo, and Mostacci, Barbara
- Subjects
CHILDBEARING age ,VALPROIC acid ,TIME series analysis ,MENTAL illness - Abstract
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]
- Published
- 2023
- Full Text
- View/download PDF
170. Reported hepatotoxicity and hepatotoxicity guidance in the product information of protein kinase inhibitors in oncology registered at the European Medicines Agency.
- Author
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Maliepaard, Marc, Faber, Yoran S., and van Bussel, Mark T. J.
- Subjects
PROTEIN kinase inhibitors ,ASPARTATE aminotransferase ,HEPATOTOXICOLOGY ,ALANINE aminotransferase ,PRODUCT attributes - Abstract
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]
- Published
- 2023
- Full Text
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171. Physicochemical and Biological Stability Assessment of SB11 (Ranibizumab Biosimilar) Under Ambient and In-Use Storage for Intravitreal Administration.
- Author
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Kaiser, Peter K., Yun, Jihoon, Kim, Soyeon, Kim, Jihyun, and Park, Su Jin
- Subjects
MEDICAL personnel ,VASCULAR endothelial growth factors ,RANIBIZUMAB ,ISOELECTRIC focusing - Abstract
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 (A
280 ) 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]- Published
- 2023
- Full Text
- View/download PDF
172. Replacing RCTs with real world data for regulatory decision making: a self-fulfilling prophecy?
- Author
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Wieseler, Beate, Neyt, Mattias, Kaiser, Thomas, Hulstaert, Frank, and Windeler, Jürgen
- Subjects
DRUG approval ,HEALTH policy ,EXPERIMENTAL design ,SCIENTIFIC observation ,GOVERNMENT regulation ,INVESTIGATIONAL drugs ,RANDOMIZED controlled trials ,GROUP decision making ,DRUG development - Published
- 2023
- Full Text
- View/download PDF
173. Assessing Medicines for Use in the Geriatric Population.
- Author
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Cerreta, Francesca, Vučić, Katarina, and Laslop, Andrea
- Subjects
DRUG side effects ,GERIATRICS ,MEDICAL personnel ,EVIDENCE gaps ,INAPPROPRIATE prescribing (Medicine) - Abstract
The aging processes alter the body's response to a medicine's pharmacokinetics, pharmacodynamics, and susceptibility to adverse effects. In addition, older adults, especially the oldest age category (85+ years) or those with multiple chronic health conditions, polypharmacy, or frailty, are under‐represented in clinical trials of new medicines. Evidence‐based prescribing guidelines based on these trials might result in inappropriate prescription, increasing the risk of drug interactions and adverse drug reactions. Regulators face a conundrum between acquiring sufficient data and putting susceptible patients at risk in the early stages of a development program, when little is known about a medicine's effects. Healthcare professionals and patients deserve to have access to clear information on the knowledge and evidence gaps leading to the approval of a new medicinal product. This should also include proper consideration of the population of older patients. In the present article, we outline the approach taken by the European Medicines Agency (EMA) regulators in the assessment of a new medicine's dossier. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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174. Enhanced safety surveillance of GSK's quadrivalent seasonal influenza vaccine in Germany and Spain (2021/2022 season) using an electronic patient‐reported outcome system for vaccine safety remote monitoring.
- Author
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Dos Santos, Gaël, Eckermann, Tamara, Martínez‐Gómez, Xavier, Parra, Jose, Nwoji, Ugo, and Salamanca de la Cueva, Ignacio
- Subjects
SEASONAL influenza ,VACCINE safety ,INFLUENZA vaccines ,SYSTEM safety ,COVID-19 pandemic - Abstract
Background: Seasonal influenza epidemics are managed through vaccination each winter in the European Union, to prevent infections, complications, and deaths. As circulating virus strains vary unpredictably, vaccines are reformulated annually, and their safety monitored rapidly and continuously at the start of each season, following European Medicines Agency guidelines.Seasonal influenza epidemics are managed through vaccination each winter in the European Union, to prevent infections, complications, and deaths. As circulating virus strains vary unpredictably, vaccines are reformulated annually, and their safety monitored rapidly and continuously at the start of each season, following European Medicines Agency guidelines. Methods: This enhanced safety surveillance study assessed pre‐specified and other adverse events (AEs) occurring within 7 days of GSK's inactivated quadrivalent seasonal influenza vaccine (IIV4) in children and adults in Spain and Germany. As the study was conducted during the COVID‐19 pandemic (2021/2022 season), data were collected electronically, using a web portal or call center. Results: Safety was assessed in 737 participants (median age 49 and 9 years in Germany and Spain, respectively, 19.3% with a chronic medical condition). After Dose 1 and Dose 2, respectively, 332 (45.1%) and 5 (26.3%) participants reported at least one AE, primarily pre‐specified AEs. The most common AEs after Dose 1 (adults and children) were injection site pain, swelling or erythema, headache, and fatigue. After Dose 2 (in children), the most common AEs were injection site pain, rhinorrhea, fatigue, and decreased appetite. No new or unexpected safety issues were identified. Conclusion: This study supports and confirms the safety profile of GSK's IIV4 in all age groups with a vaccine indication. The new electronic safety reporting method (with response rates of 75.4% following Dose 1 and 100% following Dose 2) provides an alternative for future studies to reduce the burden on sites or in case site visits are not feasible. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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175. Quality Requirements for Medicinal Cannabis and Respective Products in the European Union – Status Quo#.
- Author
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Veit, Markus
- Subjects
DRUG approval ,MEDICAL marijuana ,QUALITY assurance ,QUALITY control ,PHARMACEUTICAL industry ,CANNABINOIDS ,DOSAGE forms of drugs - Abstract
Medicinal cannabis and respective products have been available in EU member states as single-patient prescriptions without regular marketing authorizations for a couple of years. The Netherlands was the first member state to realize this; in the meantime other member states have followed. Today, aside from the Netherlands, Germany is the most important market for such products. The regulatory framework for the approval of medicinal cannabis and its distribution to patients in the EU member states is, however, not harmonized at all, and there are distinct national regulations. Regarding the quality of such products, the general requirements for herbal medicinal products as defined in the European Pharmacopoeia, national pharmacopoeias, and the EMA guidance documents in place beside GMP requirements in the EU are applicable. However, for a couple of aspects, every EU member state follows its own interpretation of these requirements. To facilitate free distribution of such products between EU member states in future and to harmonize requirements for quality and GMP, an EU-wide approach is needed. As a first step, this should be realized by implementing monographs for cannabis medicinal products in the European Pharmacopoeia. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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- View/download PDF
176. Gilding the Pill.
- Author
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Boyer, Kelly
- Subjects
DRUG development ,DRUG tablets ,PHARMACEUTICAL industry ,DRUG delivery systems ,DOSAGE forms of drugs - Abstract
The article discusses the innovative approaches used by pharmaceutical companies to improve patient experience and patient outcomes in taking their medication. Guidance documents encouraging pharmaceutical companies to design products that promote patient compliance and reduce medication errors has been issued by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA).
- Published
- 2019
177. WHO OWNS THE INFORMATION HELD BY EU AGENCIES? WEED KILLERS, COMMERCIALLY SENSITIVE INFORMATION AND TRANSPARENT AND PARTICIPATORY GOVERNANCE.
- Author
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KORKEA-AHO, EMILIA and LEINO, PÄIVI
- Subjects
CHEMICALS ,DATA protection - Abstract
EU agencies have become key actors in the operationalization of the EU regime on public access to documents. A tension between confidentiality and transparency has become particularly evident in the framework of regulatory procedures concerning chemical substances, food, and medicinal products. Applicants must provide EU agencies with commercially sensitive information to trigger the scientific and technical evaluation needed for marketing authorization or approval. We analyse three EU agencies: European Chemicals Agency, European Food Safety Agency, and European Medicines Agency. They hold information that is both commercially sensitive and highly relevant for EU regulators and the public at large. Using decisions of the EU courts and the European Ombudsman, this article shows how a new "ownership" paradigm seems to have evolved, in conflict with EU public access legislation. New rulings on the Aarhus regime suggest that more information should in the future become disclosable, putting the agencies under increased pressure by companies trying to protect industry know-how. EU agencies are constantly arbitrating between conflicting public interests. As the exercise of political discretion is exactly what EU agencies are not expected to do, the situation calls for legislative intervention. [ABSTRACT FROM AUTHOR]
- Published
- 2017
178. New medicinal products for chronic heart failure: advances in clinical trial design and efficacy assessment.
- Author
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Cowie, Martin R., Filippatos, Gerasimos S., de los Angeles Alonso Garcia, Maria, Anker, Stefan D., Baczynska, Anna, Bloomfield, Daniel M., Borentain, Maria, Slot, Karsten Bruins, Cronin, Maureen, Doevendans, Pieter A., El-Gazayerly, Amany, Gimpelewicz, Claudio, Honarpour, Narimon, Janmohamed, Salim, Janssen, Heidi, Kim, Albert M., Lautsch, Dominik, Laws, Ian, Lefkowitz, Martin, and Lopez-Sendon, Jose
- Subjects
- *
CLINICAL trials , *HEART failure treatment , *HEART failure patients ,DESIGN & construction - Abstract
Despite the availability of a number of different classes of therapeutic agents with proven efficacy in heart failure, the clinical course of heart failure patients is characterized by a reduction in life expectancy, a progressive decline in health-related quality of life and functional status, as well as a high risk of hospitalization. New approaches are needed to address the unmet medical needs of this patient population. The European Medicines Agency (EMA) is undertaking a revision of its Guideline on Clinical Investigation of Medicinal Products for the Treatment of Chronic Heart Failure. The draft version of the Guideline was released for public consultation in January 2016. The Cardiovascular Round Table of the European Society of Cardiology (ESC), in partnership with the Heart Failure Association of the ESC, convened a dedicated two-day workshop to discuss three main topic areas of major interest in the field and addressed in this draft EMA guideline: (i) assessment of efficacy (i.e. endpoint selection and statistical analysis); (ii) clinical trial design (i.e. issues pertaining to patient population, optimal medical therapy, run-in period); and (iii) research approaches for testing novel therapeutic principles (i.e. cell therapy). This paper summarizes the key outputs from the workshop, reviews areas of expert consensus, and identifies gaps that require further research or discussion. Collaboration between regulators, industry, clinical trialists, cardiologists, health technology assessment bodies, payers, and patient organizations is critical to address the ongoing challenge of heart failure and to ensure the development and market access of new therapeutics in a scientifically robust, practical and safe way. [ABSTRACT FROM AUTHOR]
- Published
- 2017
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179. Stretching and Challenging the Boundaries of Law: Varieties of Knowledge in Biotechnologies Regulation.
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Faulkner, Alex and Poort, Lonneke
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- *
ANIMAL biotechnology , *MEDICAL equipment laws , *PHARMACEUTICAL industry , *BIOMATERIALS , *LAW - Abstract
The paper addresses the question of adaptation of existing regulatory frameworks in the face of innovation in biotechnologies, and specifically the roles played in this by various expert knowledge practices. We identify two overlapping ideal types of adaptation: first, the stretching and maintenance of a pre-existing legal framework, and second, a breaking of existing classifications and establishment of a novel regime. We approach this issue by focusing on varieties of regulatory knowledge which, contributing to and parting of political legitimacy, in principle enable the making of legally binding decisions about risks and benefits of technologies. We base the discussion around two case studies, one of animal biotechnology ethical regulation, the other of 'advanced therapy' medicinal product regulation, both in the context of European Union frameworks. Specifically, we explore the knowledge configurations constituting expert committees and other institutional formations of expert regulatory knowledge in their political context. We show that where sectoral and moral boundaries are challenged, different modes of regulatory knowledge beyond scientific forms - legal, procedural, moral, economic and industrial - can shape regulatory innovations either by maintenance of regimes through commensuration and stretching, or through differentiation and separation creating new frameworks. We conclude that establishing an essential techno-scientific difference between pre-existing and novel technologies does not in itself require new regulatory structures, and that the regulatory strategy that is followed will be determined by a combination of different forms of knowledge. [ABSTRACT FROM AUTHOR]
- Published
- 2017
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180. Noninferiority studies with multiple reference treatments.
- Author
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Huang Li-Ching, Wen Miin-Jye, Cheung Siu Hung, and Kwong Koon Shing
- Subjects
- *
CLINICAL trials , *STATISTICS , *CANCER research - Abstract
The increasing popularity of noninferiority trials reflects the ongoing efforts to replace existing treatments (reference treatments) with new treatments (experimental treatments) that retain a substantial fraction of the effect of the reference treatments. The adoption of any new treatment has to be vindicated by a demonstration of benefits that outweigh a possible clinically insignificant reduction in the reference treatment efficacy. Statistical methods have been developed to analyze data collected from noninferiority trials. However, these methods focus on cases with only one reference treatment. In this paper, we provide the statistical inferential procedures for situations with multiple reference treatments. The computation of the corresponding critical values for simultaneous testings of noninferiority of several new treatments to multiple reference treatments in the presence of a placebo is provided. Furthermore, for a prespecified level of test power, a technique to determine the optimal sample size before the onset of a noninferiority trial is derived. A clinical example is given to illustrate our proposed procedure. [ABSTRACT FROM AUTHOR]
- Published
- 2017
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181. Rapid LC-MS/MS Bosutinib Quantification with Applications in Metabolic Stability Estimation.
- Author
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Attwa, Mohamed W. and Alanazi, Mohammed M.
- Subjects
LIQUID chromatography-mass spectrometry ,CHRONIC myeloid leukemia ,LIVER microsomes ,FORMIC acid ,MASS spectrometers - Abstract
Bosutinib (BOS) is FDA approved drug for the treatment of chronic phase (CP) Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML). We report a fast, sensitive, and simple LC-MS/MS method, validated for the determination of BOS in human liver microsomes, utilizing tofacitinib (TOF) as the internal standard. The separation of BOS and TOF was done using a 1.8 μm C18 column (2.1 × 50 mm) at room temperature using the isocratic elution system of acetonitrile–water (30:70, v/v) containing 0.1 M formic acid at a flow rate of 0.15 mL/min, and a triple-quadrupole tandem mass spectrometer (TQD-MS) with an electrospray ionization (ESI) source that was operated in the positive ion mode. The method was validated according to the European Medicines Agency, and the rapid and specific quantification of BOS in human liver microsomes was achieved in the range of 5–200 ng/mL, with a determination coefficient of 0.999. Intra- and inter-day accuracy and precision values were <4% in all cases. The procedure is rapid, specific, reliable, and can be applied in metabolic stability evaluations since it is the first LC-MS/MS method specific to BOS quantification. The metabolic stability assessment of BOS showed high CL
int (34.3 µL/min/mg) and short in vitro t1/2 values of 20.21 min, indicating that BOS may be rapidly eliminated from the blood by the liver. [ABSTRACT FROM AUTHOR]- Published
- 2023
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182. The pharmacogenetics of the new-generation antipsychotics - A scoping review focused on patients with severe psychiatric disorders.
- Author
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Vasiliu, Octavian
- Subjects
PEOPLE with mental illness ,PHARMACOGENOMICS ,ANTIPSYCHOTIC agents ,DRUG interactions ,INDIVIDUALIZED medicine ,SEROTONIN syndrome ,NEUROLEPTIC malignant syndrome - Abstract
Exploring the possible correlations between gene variations and the clinical effects of the new-generation antipsychotics is considered essential in the framework of personalized medicine. It is expected that pharmacogenetic data will be useful for increasing the treatment efficacy, tolerability, therapeutic adherence, functional recovery, and quality of life in patients with severe psychiatric disorders (SPD). This scoping review investigated the available evidence about the pharmacokinetics, pharmacodynamics, and pharmacogenetics of five new-generation antipsychotics, i.e., cariprazine, brexpiprazole, aripiprazole, lumateperone, and pimavanserin. Based on the analysis of 25 primary and secondary sources and the review of these agents' summaries of product characteristics, aripiprazole benefits from the most relevant data about the impact of gene variability on its pharmacokinetics and pharmacodynamics, with significant consequences on this antipsychotic's efficacy and tolerability. The determination of the CYP2D6 metabolizer status is important when administering aripiprazole, either as monotherapy or associated with other pharmacological agents. Allelic variability in genes encoding dopamine D2, D3, and serotonin, 5HT2A, 5HT2C receptors, COMT, BDNF, and dopamine transporter DAT1 was also associated with different adverse events or variations in the clinical efficacy of aripiprazole. Brexpiprazole also benefits from specific recommendations regarding the CYP2D6 metabolizer status and the risks of associating this antipsychotic with strong/moderate CYP2D6 or CYP3A4 inhibitors. US Food and Drug Administration (FDA) and European Medicines Agency (EMA) recommendations about cariprazine refer to possible pharmacokinetic interactions with strong CYP3A4 inhibitors or inducers. Pharmacogenetic data about cariprazine is sparse, and relevant information regarding gene-drug interactions for lumateperone and pimavanserin is yet lacking. In conclusion, more studies are needed to detect the influence of gene variations on the pharmacokinetics and pharmacodynamics of new-generation antipsychotics. This type of research could increase the ability of clinicians to predict favorable responses to specific antipsychotics and to improve the tolerability of the treatment regimen in patients with SPD. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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183. Effects of Cannabidiol on Innate Immunity: Experimental Evidence and Clinical Relevance.
- Author
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Martini, Stefano, Gemma, Alessandra, Ferrari, Marco, Cosentino, Marco, and Marino, Franca
- Subjects
CANNABIDIOL ,NATURAL immunity ,CANNABIS (Genus) ,LENNOX-Gastaut syndrome ,CANNABACEAE ,GUINEA pigs - Abstract
Cannabidiol (CBD) is the main non-psychotropic cannabinoid derived from cannabis (Cannabis sativa L., fam. Cannabaceae). CBD has received approval by the Food and Drug Administration (FDA) and European Medicines Agency (EMA) for the treatment of seizures associated with Lennox–Gastaut syndrome or Dravet syndrome. However, CBD also has prominent anti-inflammatory and immunomodulatory effects; evidence exists that it could be beneficial in chronic inflammation, and even in acute inflammatory conditions, such as those due to SARS-CoV-2 infection. In this work, we review available evidence concerning CBD's effects on the modulation of innate immunity. Despite the lack so far of clinical studies, extensive preclinical evidence in different models, including mice, rats, guinea pigs, and even ex vivo experiments on cells from human healthy subjects, shows that CBD exerts a wide range of inhibitory effects by decreasing cytokine production and tissue infiltration, and acting on a variety of other inflammation-related functions in several innate immune cells. Clinical studies are now warranted to establish the therapeutic role of CBD in diseases with a strong inflammatory component, such as multiple sclerosis and other autoimmune diseases, cancer, asthma, and cardiovascular diseases. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
184. Fast and Sensitive Analysis of Cefiderocol in Human Plasma Microsamples by Liquid Chromatography-Isotope Dilution Tandem Mass Spectrometry for Therapeutic Drug Monitoring.
- Author
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Barone, Rossella, Conti, Matteo, Cojutti, Pier Giorgio, Gatti, Milo, Viale, Pierluigi, and Pea, Federico
- Subjects
TANDEM mass spectrometry ,DRUG monitoring ,GRAM-negative bacterial diseases ,MATRIX effect ,DILUTION - Abstract
Cefiderocol (C) is a parenteral siderophore cephalosporin with relevant inter-individual pharmacokinetic variability among critically ill patients, which may potentially affect effective drug exposure. Therapeutic drug monitoring (TDM) may concur in improving the real-time management of C therapy in clinics. In this study, we developed and validated a fast and sensitive Liquid Chromatography-Isotope Dilution Tandem Mass Spectrometry (LC-ITD-MS/MS) method for measuring C in human plasma microsamples, as small as 3 microliters. Analysis was preceded by a user-friendly pre-analytical single-step and was performed by means of a very fast chromatographic run of 4 min, followed by positive electrospray ionization and detection on a high sensitivity triple quadrupole tandem mass spectrometer operated in multiple reaction monitoring mode. The straightforward analytical procedure was successfully validated, based on the European Medicines Agency (EMA) guidelines, in terms of specificity, sensitivity, linearity, precision, accuracy, matrix effect, extraction recovery, limit of quantification, and stability. The novel method was successfully applied to TDM of C in more than 50 cases of critically carbapenem-resistant Gram-negative bacterial infections and enabled us to optimize antibiotic therapy. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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185. Fast and Simple Liquid Chromatography-Isotope Dilution Tandem Mass Spectrometry Method for Therapeutic Drug Monitoring of Dalbavancin in Long-Term Treatment of Subacute and/or Chronic Infections.
- Author
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Barone, Rossella, Conti, Matteo, Cojutti, Pier Giorgio, Gatti, Milo, Viale, Pierluigi, and Pea, Federico
- Subjects
TANDEM mass spectrometry ,DRUG monitoring ,DILUTION ,MATRIX effect ,LIQUIDS - Abstract
Dalbavancin (DBV) is a long-acting antistaphylococcal lypoglycopeptide that is being increasingly used for long-term treatment of a wide range of subacute and/or chronic infections, mainly osteo-articular infections (OAI). Population pharmacokinetic studies showed that two 1500 mg doses 1 week apart can ensure effective treatment for several weeks. In this scenario, therapeutic drug monitoring (TDM) can be a helpful tool for providing clinicians with real-time feedback on the duration of optimal treatment by measuring drug concentrations over time in each single patient. The aim of this study was to develop and validate a fast and simple analytical method based on the Liquid Chromatography-Isotope Dilution Tandem Mass Spectrometry (ITD LC-MS/MS) technique for measuring DBV concentrations in human plasma microsamples. It will allow an innovative, very convenient and minimally invasive way of sampling. Analysis was performed by simple single-step sample preparation and very short instrumental run time (4 min). Analytical performance met all criteria in terms of specificity, sensitivity, linearity, precision, accuracy, matrix effect, extraction recovery, limit of quantification, dilution integrity and stability under different conditions set by the European Medicines Agency (EMA) for drug quantification by means of bioanalytical methods. The method was successfully applied for measuring DBV concentrations (range = 2.0–77.0 mg/L) in a cohort of patients receiving long-term DBV treatment of subacute and/or chronic infections. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
186. Risk factors for herpes zoster: should people with asthma or COPD be vaccinated?
- Author
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Safonova, Ekaterina, Yawn, Barbara P., Welte, Tobias, and Wang, Chengbin
- Subjects
HERPES zoster ,ASTHMATICS ,VARICELLA-zoster virus ,CHRONIC obstructive pulmonary disease ,HERPES zoster vaccines ,VACCINE effectiveness - Abstract
Without vaccination, an estimated 1 in 3 individuals will develop herpes zoster (HZ) in their lifetime. Increased risk of HZ is attributed to impaired cell-mediated immunity, as observed in age-related immunosenescence or in individuals immunocompromised due to disease or immunosuppressive treatments. Most vaccination guidelines recommend HZ vaccination in all adults ≥ 50 years of age, although Shingrix
® was recently approved by the U.S. Food and Drug Administration for use in individuals aged ≥ 18 years who are or will be at increased risk of HZ due to immunodeficiency or immunosuppression caused by known disease or therapy, followed by approval by the European Medicines Agency for use in immunocompromised individuals aged ≥ 18 years. Chronic respiratory diseases are also risk factors for HZ. A new meta-analysis reported 24% and 41% increased risks of HZ in those with asthma and chronic obstructive pulmonary disorder (COPD), respectively, compared with healthy controls. Asthma and COPD increase a person's risk of HZ and associated complications at any age and may be further elevated in those receiving inhaled corticosteroids. Despite the increased risks, there is evidence that HZ vaccination uptake in those aged ≥ 50 years with COPD may be lower compared with the age-matched general population, potentially indicating a lack of awareness of HZ risk factors among clinicians and patients. The 2022 Global Initiative for Chronic Lung Disease report recognizes that Centers for Disease Control and Prevention recommended to vaccinate those aged ≥ 50 years against HZ, although health systems should consider the inclusion of all adults with asthma or COPD into their HZ vaccination programs. Further research into HZ vaccine efficacy/effectiveness and safety in younger populations is needed to inform vaccination guidelines. Highlights: Re-activation of the latent varicella zoster virus manifests as herpes zoster (HZ), which is associated with burdensome symptoms and can lead to complications Risk factors for HZ are often associated with a decline in cell-mediated immunity, as observed with ageing, immunocompromised conditions, immunosuppressive therapy and chronic conditions that compromise the immune system Several chronic conditions, including chronic respiratory conditions such as asthma and chronic obstructive pulmonary disorder (COPD), increase an individual's risk of HZ and the associated complications HZ vaccination is effective at reducing HZ occurrence, with guidelines generally recommending their use in those ≥ 50 years of age and in at-risk adult populations There is some evidence that use of inhaled corticosteroids, which is often used to manage asthma or COPD, can independently increase a person's risk of developing HZ The increased risk of HZ and its complications in those with asthma and COPD suggests that these populations may benefit from HZ vaccination, although cost–benefit analyses in those < 50 years of age are lacking Plain Language Summary: What is the context? After experiencing chickenpox, the varicella-zoster virus remains in the body and can be reactivated years later in a form called herpes zoster, more commonly known as shingles. Although shingles is more common in people aged ≥ 50 years, it is also more likely to occur in people with immune systems that do not work normally, which may include those with respiratory conditions such as asthma and chronic obstructive pulmonary disorder (COPD). This disease can be prevented by vaccination. Therefore, it is important for doctors to know which patients are at increased risk of shingles and who could be considered for vaccination. What is new? This review is the first to summarize the risk of shingles in people with asthma or COPD, drawing together evidence from across the world. It also evaluates the recommended use of different shingles vaccines in these patients, with a focus on two widely used vaccines: Zostavax® (ZVL) and Shingrix® (RZV). Asthma or COPD can make people more likely to develop shingles and related medical complications, even in younger people. Most guidelines recommend vaccination against this disease for those aged 50 years and above, with some also recommending vaccination in people aged 18–49 years who may be at higher risk of shingles. There is limited information on the benefit of shingles vaccination in those aged ≤ 50 years with asthma or COPD, but their increased risk of developing shingles suggests they may also benefit from inclusion in vaccination programs. What is the impact? The data presented in the review suggest that people with asthma or COPD aged 18–49 years could benefit from shingles vaccination. This group is not currently included in most vaccination guidelines, despite the evidence of increased risk of shingles and its complications. More information is needed on the risks and benefits of vaccinating this group to determine if it would be cost-effective. [ABSTRACT FROM AUTHOR]- Published
- 2023
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- View/download PDF
187. Commentary on the European Medicines Agency's extended mandate: Protecting public health in times of crisis and improving availability of medicines and medical devices.
- Author
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Abed, Inga, Gonzalez‐Quevedo, Rosa, Mura, Manuela, Dias, Monica, da Rocha Dias, Silvy, and García Burgos, Juan
- Subjects
MEDICAL equipment ,MEDICAL communication ,PUBLIC health ,COVID-19 ,DRUGS ,ARTIFICIAL joints ,INVISCID flow - Abstract
IMPROVING AVAILABILITY OF MEDICINES AND MEDICAL DEVICES Shortages of medicines have been a problem in the EU and globally long before the pandemic. Moreover, EMA and ETF members have contributed to scientific and regulatory initiatives by EU bodies such as the directorate-general of the European Commission, the HERA and the EU member states to purchase and use available medicines. With the emergence of COVID-19 in early 2019, the European Union (EU) was confronted with unexpected challenges on many fronts. Finally, the high number of medicines developed and assessed for COVID-19 as opposed to previous emergencies, as well as the duration of the COVID-19 pandemic, have clearly highlighted the need for the EU network to become more agile and to better use available resources in Europe. [Extracted from the article]
- Published
- 2023
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- View/download PDF
188. A Data Driven Approach to Support Tailored Clinical Programs for Biosimilar Monoclonal Antibodies.
- Author
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Guillen, Elena, Ekman, Niklas, Barry, Sean, Weise, Martina, and Wolff‐Holz, Elena
- Subjects
CHIMERIC proteins ,MONOCLONAL antibodies ,BEVACIZUMAB ,BIOSIMILARS ,FUNCTIONAL analysis ,MEDICAL care costs - Abstract
Biosimilar monoclonal antibodies (mAbs) have been approved in the European Union since 2013 and have been demonstrated to reduce healthcare costs and to expand patient access. Biosimilarity is mainly established on the basis of demonstrated similarity of relevant quality attributes (QAs), determined by comprehensive physiochemical and functional analyses, and demonstration of bioequivalence. In addition, comparative efficacy/safety studies have been requested for all approved biosimilar mAbs so far, although the European Medicines Agency (EMA) Guidelines state that such confirmatory clinical trials may not be necessary in specific circumstances. In order to evaluate the degree of analytical similarity, how residual uncertainty regarding biosimilarity was resolved, and the value of clinical data, we analyzed the quality and clinical data packages for authorized adalimumab (7 products) and bevacizumab (5 products) biosimilars. The percentage of biosimilar batches meeting the similarity range for QAs, as defined by the biosimilar manufacturer based on a comprehensive characterization of the EU reference product (RP), was determined and clinical data were reviewed. Our analyses show that QAs of approved adalimumab and bevacizumab biosimilars have varying concordance with the EU‐RP similarity range. In this study, we found that clinical efficacy data played a limited role in addressing quality concerns. Therefore, we encourage a regulatory review of the standards for clinical data requirements for mAb and fusion protein biosimilars. This study outlines a quality data driven approach for facilitating tailored clinical programs for biosimilars. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
189. Contribution of Real‐World Evidence in European Medicines Agency's Regulatory Decision Making.
- Author
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Bakker, Elisabeth, Plueschke, Kelly, Jonker, Carla J., Kurz, Xavier, Starokozhko, Viktoriia, and Mol, Peter G. M.
- Subjects
DECISION making ,GOVERNMENT agencies ,CLINICAL medicine ,DRUGS ,MARKETING ,RISK perception - Abstract
Real‐world data/evidence (RWD/RWE) may provide insightful information on medicines' clinical effects to guide regulatory decisions. While its contribution has been recognized for safety monitoring and disease epidemiology across medicines' life cycles, using RWD/RWE to demonstrate efficacy requires further evaluation. This study aimed to (i) characterize RWD/RWE presented by applicants to support claims on medicines' efficacy within initial marketing authorization applications (MAAs) and extension of indication applications (EoIs), and (ii) analyze the contribution of RWD/RWE to regulatory decisions on medicines' benefit–risk profile. RWD/RWE was included to support efficacy in 32 MAAs and 14 EoIs submitted 2018–2019. Of these, RWD/RWE was part of the preauthorization package of 16 MAAs and 10 EoIs, and was (i) considered supporting the regulatory decision in 10 applications (five MAAs, five EoIs), (ii) considered not supporting the regulatory decision in 11 (seven MAAs, four EoIs), and (iii) not addressed at all in the evaluation of 5 applications (four MAAs, one EoI). Common limitations of submitted RWD/RWE included missing data, lack of representativeness of populations, small sample size, absence of an adequate or prespecified analysis plan, and risk of several types of bias. The suitability of RWD/RWE in a given application still requires a case‐by‐case analysis considering its purpose of use, implying reflection on the data source, together with its assets and limitations, study objectives and designs, and the overall data package issued. Early interactions and continuous dialogues with regulators and relevant stakeholders is key to optimize fit‐for‐purpose RWE generation, enabling its broader use in medicines development. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
190. Fexinidazole for Human African Trypanosomiasis, the Fruit of a Successful Public-Private Partnership.
- Author
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Bernhard, Sonja, Kaiser, Marcel, Burri, Christian, and Mäser, Pascal
- Subjects
AFRICAN trypanosomiasis ,PUBLIC-private sector cooperation ,DRUG discovery ,TRYPANOSOMA brucei ,TRANSMISSION zeros - Abstract
After 100 years of chemotherapy with impractical and toxic drugs, an oral cure for human African trypanosomiasis (HAT) is available: Fexinidazole. In this case, we review the history of drug discovery for HAT with special emphasis on the discovery, pre-clinical development, and operational challenges of the clinical trials of fexinidazole. The screening of the Drugs for Neglected Diseases initiative (DNDi) HAT-library by the Swiss TPH had singled out fexinidazole, originally developed by Hoechst (now Sanofi), as the most promising of a series of over 800 nitroimidazoles and related molecules. In cell culture, fexinidazole has an IC
50 of around 1 µM against Trypanosoma brucei and is more than 100-fold less toxic to mammalian cells. In the mouse model, fexinidazole cures both the first, haemolymphatic, and the second, meningoencephalitic stage of the infection, the latter at 100 mg/kg twice daily for 5 days. In patients, the clinical trials managed by DNDi and supported by Swiss TPH mainly conducted in the Democratic Republic of the Congo demonstrated that oral fexinidazole is safe and effective for use against first- and early second-stage sleeping sickness. Based on the positive opinion issued by the European Medicines Agency in 2018, the WHO has released new interim guidelines for the treatment of HAT including fexinidazole as the new therapy for first-stage and non-severe second-stage sleeping sickness caused by Trypanosoma brucei gambiense (gHAT). This greatly facilitates the diagnosis and treatment algorithm for gHAT, increasing the attainable coverage and paving the way towards the envisaged goal of zero transmission by 2030. [ABSTRACT FROM AUTHOR]- Published
- 2022
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- View/download PDF
191. Luspatercept: A New Tool for the Treatment of Anemia Related to β-Thalassemia, Myelodysplastic Syndromes and Primary Myelofibrosis.
- Author
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Hatzimichael, Eleftheria, Timotheatou, Despoina, Koumpis, Epameinondas, Benetatos, Leonidas, and Makis, Alexandros
- Subjects
MYELODYSPLASTIC syndromes ,BLOOD diseases ,ANEMIA treatment ,HEMATOPOIESIS ,MYELOFIBROSIS ,EXTRAMEDULLARY hematopoiesis ,FC receptors ,THROMBOPOIETIN receptors - Abstract
Anemia is a common feature of both benign and malignant hematologic diseases. Beta-thalassemia (β-thalassemia) syndromes are a group of hereditary disorders characterized by ineffective erythropoiesis, due to a genetic deficiency in the synthesis of the beta chains of hemoglobin, often accompanied by severe anemia and the need for red blood cell (RBC) transfusions. Myelodysplastic syndromes (MDS) are characterized by cytopenia(s) and ineffective hematopoiesis, despite a hypercellular bone marrow. Primary myelofibrosis (PMF) is a clonal myeloproliferative neoplasm characterized by reactive fibrosis of the bone marrow, accompanied by extramedullary hematopoiesis. Luspatercept, previously known as ACE-536, is a fusion protein that combines a modified activin receptor IIB (ActRIIB), a member of the transforming growth factor-β (TGF-β) superfamily, with the Fc domain of human immunoglobulin G (IgG1). It has shown efficacy in the treatment of anemia due to beta β-thalassemia, MDS and PMF and recently gained approval by the Federal Drug Agency (FDA) and the European Medicines Agency (EMA) for transfusion-dependent (TD) patients with β-thalassemia and very low to intermediate-risk patients with MDS with ringed sideroblasts who have failed to respond to, or are ineligible for, an erythropoiesis-stimulating agent. In this review, we describe the key pathways involved in normal hematopoiesis and the possible mechanism of action of luspatercept, present its development and data from the most recent clinical trials in β-thalassemia, MDS and PMF, and discuss its potential use in the treatment of these hematological disorders. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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192. High performance liquid chromatography coupled with mass spectrometry for simultaneous determination of rivastigmine and its metabolite in rat plasma.
- Author
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Sato, Yuhki, Michihara, Ayana, Nagatsuka, Yuka, Yamamoto, Kouichi, Shirakawa, Makoto, and Katayama, Hirokazu
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LIQUID chromatography-mass spectrometry ,HIGH performance liquid chromatography ,RIVASTIGMINE ,PRECIPITATION (Chemistry) - Abstract
Several studies on the pharmacokinetic parameters of antidementia drugs have reported that plasma concentration is linked to the drugs' efficacy and adverse effects. At present, there is no quantitation method that is highly sensitive and can be applied to simultaneous monitoring of the pharmacokinetics of rivastigmine and its metabolites (NAP 226-90) in rat plasma. No methods fulfilling the assay validation requirements of the US Food and Drug Administration and the European Medicines Agency was also established. Therefore, this study developed a quantitative method for measuring rivastigmine and NAP 226-90 concentrations using high-performance liquid chromatography and tandem mass spectrometry, examining plasma samples after rivastigmine administration. Rat plasma samples were prepared via the protein precipitation method. The methods for measuring rivastigmine and NAP 226-90 concentrations showed good fit over wide ranges of 1–100 ng mL
−1 and 0.5–50 ng mL−1 , with lower limits of quantification at 1 ng mL−1 and 0.5 ng mL−1 , respectively. The plasma concentrations of rivastigmine and NAP 226-90 in six healthy rats were successfully determined, demonstrating the feasibility of applying the developed method. Thus, this research has successfully developed a sensitive, selective method, to simultaneously quantify rivastigmine and NAP 226-90 concentrations in rat plasma and be applicable to a pharmacokinetic study. [ABSTRACT FROM AUTHOR]- Published
- 2022
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193. European Medicines Agency Viewpoint.
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Spivey, Chris
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DRUG approval ,INSTITUTIONAL cooperation ,INVESTMENTS ,VACCINES ,INVENTORY shortages ,HEALTH services administration ,SOCIAL support ,GOVERNMENT regulation ,NEGOTIATION ,CELLULAR therapy ,MANUFACTURING industries ,MEDICAL supplies ,DRUG packaging ,ORGANIZATIONAL goals ,BUSINESS networks ,HEALTH insurance reimbursement ,SUPPLY chains ,PATENTS ,INTELLECTUAL property ,DRUGS ,INTERPROFESSIONAL relations ,QUALITY assurance ,GENE therapy ,DRUG labeling ,COMMUNICATION ,PHARMACEUTICAL industry ,COVID-19 pandemic ,PUBLIC opinion ,PSYCHOLOGICAL resilience ,MEDICAL research - Abstract
The article focuses on insights provided by Steffen Thirstrup, the chief medical officer at the European Medicines Agency, regarding regulatory challenges and successes in Europe's pharmaceutical landscape. Topics discussed include the impact of the COVID-19 pandemic on regulatory agility, challenges and collaborations in drug pricing and reimbursement, and efforts to enhance supply chain resilience and proximity to manufacturing infrastructure.
- Published
- 2024
194. European banks could see boost in portfolio financing from EBA plans.
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Sanderson, Owen
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ASSET backed financing ,FIXED-income securities ,INVESTMENTS ,HEDGE funds - Abstract
European-regulated banks might see a boost to their business from an obscure tweak to securitization rules, rolled out in a European Banking Authority paper published on Tuesday. The proposals could see them better able to compete with US firms in the increasingly lucrative business of portfolio financing through securitization. [ABSTRACT FROM AUTHOR]
- Published
- 2018
195. Can a supranational medicines agency restore trust after vaccine suspensions? The case of Vaxzevria.
- Author
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Albanese, Andrea, Fallucchi, Francesco, and Verheyden, Bertrand
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REGRESSION discontinuity design ,TRUST ,THROMBOSIS ,VACCINES - Abstract
Over the first half of March 2021, the majority of European governments suspended Astrazeneca's Vaxzevria vaccine as a precaution following media reports of rare blood clots. We analyse the impact of the European Medicines Agency's (EMA) March 18th statement assuring the public of the safety of Vaxzevria and the immediate reinstatement of the vaccine by most countries on respondents' intention to get vaccinated. By relying on survey data collected in Luxembourg and neighbouring areas between early March and mid-April, we observe that the willingness to be vaccinated was severely declining in the days preceding the EMA statement. We implement a regression discontinuity design exploiting the time at which respondents completed the survey and find that the vaccine reinstatement substantially restored vaccination intentions. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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196. Safety profile of tyrosine kinase inhibitors used in non-small-cell lung cancer: An analysis from the Italian pharmacovigilance database.
- Author
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Barbieri, Maria Antonietta, Sorbara, Emanuela Elisa, Cicala, Giuseppe, Santoro, Vincenza, Cutroneo, Paola Maria, Franchina, Tindara, Santarpia, Tindara, Silvestris, Nicola, and Spina, Edoardo
- Subjects
PROTEIN-tyrosine kinase inhibitors ,NON-small-cell lung carcinoma ,DRUG side effects ,RESPIRATORY diseases ,RESPIRATORY insufficiency ,INTERSTITIAL lung diseases ,CARDIOGENIC shock - Abstract
Introduction: Non-small cell lung cancer (NSCLC) is often caused by molecular alterations that can be detected by predictive biomarkers including mutations or amplifications of several genes. Several tyrosine kinase inhibitors (TKIs) have been approved in Europe by the European Medicines Agency (EMA) for NSCLC. The aim of this study was to analyze the onset of adverse drug reactions (ADRs) related to TKIs in NSCLC through a spontaneous reporting system (SRS) database. Methods: All ADR reports having as suspected drug afatinib (AFT), alectinib (ALEC), brigatinib (BRG), ceritinib (CER), crizotinib (CRIZ), erlotinib (ERL), gefitinib (GEF), lorlatinib (LORL), nintedanib (NTB), and osimertinib (OSI) recorded into the Report Reazioni Avverse dei Medicinali (RAM) system database for national data and into the Italian SRS database for Sicilian data and collected from 2006 to 2021 have been evaluated. A descriptive analysis of basal demographic and drug-related characteristics was performed. A case-by- case methodology was conducted paying particular attention to all serious ADR reports collected in Sicily, focusing on type of seriousness, age, sex, concomitant drugs, and comorbidities. Results: Of the 3,048 Italian reports, most of ADRs were related to ERL (n=1,448), followed by AFT (n = 435) and GEF (n = 366). ADR reports were slightly more frequent in females (52.2%) and in the age group >65 years (53.0%). A higher number of cases were related to skin disorders (n = 1,766; 57.9%), followed by gastrointestinal disorders (n = 1,024; 33.6%), general disorders and administration site conditions (n= 536; 17.6%), and infections (n = 483; 15.8%). The case-by-case assessment of Sicilian ADRs showed that 33 cases were serious (12.5%) and mainly involved ERL (n = 17; 51.5%), occurring in males with a higher onset of respiratory diseases (30.3%) such as respiratory failure, interstitial lung disease and dyspnea. Discussion: The analysis of spontaneous ADR reports of TKIs confirmed, in general, well-known risks, which often include skin, gastrointestinal, general, liver, and respiratory diseases as well as infections. However, more attention should be paid to the occurrence of serious life-threatening ADRs including respiratory failure, interstitial lung disease, and cardiogenic shock, especially in young patients. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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197. Can independent regulatory agencies mend Europe's democracy? The case of the European Medicines Agency's public hearing on Valproate.
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Wood, Matthew
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INDEPENDENT regulatory commissions ,VALPROIC acid ,PUBLIC meetings ,DELIBERATION ,PUBLIC value ,DEMOCRACY - Abstract
In 2017, the European Medicines Agency staged the first effort at democratic innovation within transnational European Union institutions directly influencing the transnational regulation of medicines. Alongside its public consultation on epilepsy drug Valproate, European Medicines Agency included a public hearing involving representatives of patients and testimony from those directly affected by the medicines. Using this critical case study, the article argues from a deliberative democratic perspective that although the hearing in many ways exhibited the traditional shortcomings of elite-driven deliberation, it also demonstrated unexpected and surprising deliberative qualities. Based on new quantitative analysis of the hearing using the Discourse Quality Index, and qualitative observation of over 4 hours of footage, the article argues European Medicines Agency's hearing facilitated equitable access and influence of patients and members of the public who had previously been excluded from decision making on drug distribution. These findings provide important new evidence of the deliberative democratic value of public hearings. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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198. Avelumab use in Merkel cell carcinoma treatment.
- Author
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Dudzisz-Śledź, Monika, Zwierzchowska, Martyna, Bylina, Elżbieta, Rutkowski, Piotr, and Czarnecka, Anna M.
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MERKEL cell carcinoma ,PROGRAMMED death-ligand 1 ,CHILD patients ,TREATMENT effectiveness ,PEDIATRIC therapy - Abstract
Avelumab is a programmed death-ligand 1 (PD-L1) blocking human IgG1 lambda monoclonal antibody. It was the first immunotherapy to be approved for the treatment of MCC. In March 2017, the FDA granted accelerated approval to avelumab for the treatment of adults and pediatric patients 12 years and older with metastatic Merkel cell carcinoma (MCC) –irrespective of prior therapy. In July 2017, the European Medicines Agency (EMA) recommended the approval of avelumab as a monotherapy for the treatment of adult patients with metastatic Merkel cell carcinoma (mMCC). Approvals were based on the efficacy and safety demonstrated in JAVELIN Merkel 200 (NCT02155647), a multi-center, open-label, single-arm, phase II clinical trial [1]. Part A of the study consisted of patients treated in the second line with metastatic, chemotherapy-refractory MCC. Part B consisted of systemic treatment-naive patients who received avelumab as a first-line treatment for metastatic or distally recurrent MCC. In the first line the ORR is 39.7%. Durable responses lasting at least 6 months were observed and the majority of responses are observed early with the median time to response of 6.1 week. PFS rate at 6 and 12 months are 41% and 31%, respectively. Median OS is 20.3 months. The OS rate at 1 year is 60%. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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199. DPYD genotyping and dihydropyrimidine dehydrogenase (DPD) phenotyping in clinical oncology. A clinically focused minireview.
- Author
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Paulsen, Niels Herluf, Vojdeman, Fie, Andersen, Stig Ejdrup, Bergmann, Troels K., Ewertz, Marianne, Plomgaard, Peter, Hansen, Morten Rix, Esbech, Peter Skov, Pfeiffer, Per, Qvortrup, Camilla, and Damkier, Per
- Subjects
DIHYDROPYRIMIDINE dehydrogenase ,ENZYME deficiency ,ONCOLOGY ,CANCER chemotherapy ,MEDICAL personnel - Abstract
Background: In clinical oncology, systemic 5‐fluorouracil (5‐FU) and its oral pro‐drugs are used to treat a broad group of solid tumours. Patients with dihydropyrimidine dehydrogenase (DPD) enzyme deficiency are at elevated risk of toxicity if treated with standard doses of 5‐FU. DPYD genotyping and measurements of plasma uracil concentration (DPD phenotyping) can be applied as tests for DPD deficiency. In April 2020, the European Medicines Agency recommended pre‐treatment DPD testing to reduce the risk of 5‐FU‐related toxicity. Objectives: The objective of this study is to present the current evidence for DPD testing in routine oncological practice. Methods: Two systematic literature searches were performed following the PRISMA guidelines. We identified studies examining the possible benefit of DPYD genotyping or DPD phenotyping on the toxicity risk. Findings: Nine and 12 studies met the criteria for using DPYD genotyping and DPD phenotyping, respectively. Conclusions: The evidence supporting either DPYD genotyping or DPD phenotyping as pre‐treatment tests to reduce 5‐FU toxicity is poor. Further evidence is still needed to fully understand and guide clinicians to dose by DPD activity. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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200. Patient-reported outcomes labeling for oncology drugs: Multidisciplinary perspectives on current status and future directions.
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Cella, David, Chieh-I Chen, Quek, Ruben G. W., Uribarren, Ainhoa, Reaney, Matthew, Mastey, Vera, Collyar, Deborah, and Chassany, Olivier
- Subjects
DRUG labeling ,ANTINEOPLASTIC agents ,GOVERNMENT agencies ,TECHNOLOGY assessment ,MEDICAL technology ,DRUG development - Abstract
Introduction: Regulatory agencies encourage the incorporation of the patient voices throughout clinical drug development. Patient-Reported Outcomes (PROs) offer one way of doing this and their use has markedly increased in many therapeutic areas, particularly oncology, in recent years. However, few oncology drug labels include PRO data and those which do, offer little consistency. Objective: To provide multidisciplinary perspectives (patient, pharmaceutical industry, PRO researcher, regulatory expert) on PRO data in oncology drug labels. Methods: PRO data in the labels of drugs approved by the Food and Drug Administration (FDA) and European Medicines Agency (EMA) for oncology indications between 2010 and 2020 were critically reviewed by authors who provided their insights on the advantages and disadvantages/gaps. Results: Forty-six oncology drugs included PRO data in their labels. Differences were observed between FDA and EMA PRO labeling (e.g., PRO concept, use of tables and graphs to display PROs or reference to clinical meaningfulness). In providing their perspectives on the number and nature of PROs in labels, authors noted limitations including: the low proportion of oncology drugs with PRO labeling, limited PRO information in labels, lack of patient-friendly language, and potential bias towards positive outcomes. Lack of consistency within- and between-agencies was noted. Conclusion: Despite regulatory agencies' commitment to incorporate patient voices in regulatory decisions, availability of PRO information is limited in oncology drug labels. While several PRO guidance documents are available from regulatory and Health Technology Assessment agencies, harmonization of PRO guidance for labeling inclusion around the world is needed to better inform prescribers and consequently their patients in the process of shared medical decisions. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
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