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

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

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]

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]

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]

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]

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]

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]

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]

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]

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]

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 CLint (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]

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]

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]

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]

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]

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]

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]

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 IC50 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]

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]

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]

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]

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]

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]

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]

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]

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]

Background: In the Danish Veterinary Statistics Program, VetStat, sales data on medicinal products prescribed for veterinary consumption is collected. The Danish Food and Veterinary Administration (DVFA) manages the database and each purchase contains detailed product-specific information linked with a species-specific ID. National surveillance systems are also implemented or being developed in the other European Union Member States. By 2029, all Member States are required to report data on antimicrobial usage for companion animals to the European Medicines Agency. This study aimed to assess the challenges encountered when using the VetStat database to quantify antimicrobial use in Danish companion animals. Raw VetStat data were propagated by the DVFA and originated from veterinary practitioners and Danish pharmacies. Results: Comprehensive estimates of antimicrobial use in Danish companion animals were not readily available due to database construct. Antimicrobials sold for use in companion animals (linked to a companion animal ID) comprised a large number of products licensed solely for horses or livestock, while data assigned a replacement code encompassed both topical and peroral antimicrobials licensed for companion animals. Additionally, antimicrobials sold from pharmacies to veterinary practitioners presented the biggest challenge in data retrieval and validation. Treatment data are only transferred to VetStat through the billing systems when Danish veterinarians are treating livestock, but not companion animals. Information on products sold for in-house use in companion animals is only available from pharmacy records without a species-specific ID. As a result, parenteral antimicrobials with multi-species authorization utilized by small animal veterinary practitioners are not accounted for in the overall estimate for companion animals. Conclusions: Owing to the database structure and requirements for data entry, antimicrobial use in companion animals is an approximation. The actual consumption may be significantly higher than what is currently calculated from the database, as the majority of parenteral products are not included. Consumption data can be measured more accurately provided treatment data from veterinary practitioners in small or mixed practices are transferred to the database through the billing system. This would equal the legal requirements for Danish veterinary practitioners treating livestock. [ABSTRACT FROM AUTHOR]

Introduction: Although the European Medicines Agency (EMA) encourage coronavirus disease 2019 (COVID-19) vaccination in pregnant women, the scientific evidence supporting the use of COVID-19 vaccines during pregnancy is still limited. Aim: We aimed to investigate adverse events following immunization (AEFI) with COVID-19 vaccines during pregnancy. Methods: We retrieved Individual Case Safety Reports (ICSRs) related to the use of COVID-19 vaccines during pregnancy from the EudraVigilance database for the year 2021. We analyzed AEFI related to the mother and fetus/newborn. The reporting odds ratio (ROR) was computed to compare the reporting probability of spontaneous abortion between COVID-19 vaccines. Results: During the study period, among 1,315,315 ICSRs related to COVID-19 vaccines, we retrieved 3,252 (0.25%) reports related to the use in pregnancy. More than half (58.24%) of ICSRs were submitted by non-healthcare professionals. Although the majority (87.82%) of ICSRs concerned serious AEFI, their outcomes were mostly favorable. In this study, 85.0% of total ICSRs referred to pregnant women (n = 2,764), while 7.9% referred to fetuses/newborns (n = 258). We identified 16,569 AEFI. Moreover, 55.16% were AEFI not related to pregnancy (mostly headache, pyrexia, and fatigue), while 17.92% were pregnancy-, newborn-, or fetus-related AEFI. Among pregnancy-related AEFI, the most reported was spontaneous abortion. Messenger RNA (mRNA) vaccines had a lower reporting probability of spontaneous abortion than viral vector-based vaccines (ROR 0.80, 95% CI 0.69–0.93). Moderna and Oxford-AstraZeneca vaccines had a higher reporting probability of spontaneous abortion (ROR 1.2, 95% CI 1.05–1.38 and ROR 1.26, 95% CI 1.08–1.47, respectively), while a lower reporting probability was found for Pfizer-BioNTech vaccine compared with all other COVID-19 vaccines (ROR 0.73, 95% CI 0.64–0.84). In addition, 5.8% of ICSRs reported a fatal outcome. Conclusions: No strong insight of unknown AEFI associated with COVID-19 vaccination in pregnant women was observed. Considering the high risk associated with severe acute respiratory syndrome coronavirus 2 (SARSCoV- 2) infection, our analysis suggests that the benefits of COVID-19 vaccines during pregnancy outweigh the possible risks. However, it is important to continue monitoring the safety profile of COVID-19 vaccines in this subpopulation. [ABSTRACT FROM AUTHOR]

The development of specific drug therapy for children was a paradigm‐changing event that transformed paediatric medical practice. However, a series of tragedies involving drug treatment for children resulted in a gap developing between drug regulation and practice, with the majority of drugs used in child healthcare being used off‐label, rendering children therapeutic orphans. Over the past two decades changes in drug regulation led by the US Food and Drug Administration and followed by the European Union's European Medicines Agency have led to substantial changes in how new drugs with potential use in children are studied and labelled. While these changes have substantially improved labelling for new drugs, there has been much less progress with older drugs. Although the unique challenges of conducting clinical research in children have been addressed by novel clinical trial designs, many of these innovations have not been translated into approaches accepted for the drug approval process. The regulations applying to the need for paediatric studies currently are only applicable in the United States and the European Union, and there is less impetus for paediatric labelling in other jurisdictions. This impacts on a number of issues beyond labelling, including the availability of child‐friendly formulations. Finally, the impact of Brexit on paediatric drug studies in the UK remains unclear and is subject to ongoing negotiations between the UK government and the European Union. [ABSTRACT FROM AUTHOR]

The disposition of a drug is driven by various processes, such as drug metabolism, drug transport, glomerular filtration and body composition. These processes are subject to developmental changes reflecting growth and maturation along the paediatric continuum. However, knowledge gaps exist on these changes and their clinical impact. Filling these gaps may aid better prediction of drug disposition and creation of age‐appropriate dosing guidelines. We present innovative approaches to study these developmental changes in relation to drug metabolism and transport. First, analytical methods such as including liquid chromatography–mass spectrometry for proteomic analyses allow quantitation of the expressions of a wide variety of proteins, e.g. membrane transporters, in a small piece of organ tissue. The latter is specifically important for paediatric research, where tissues are scarcely available. Second, innovative study designs using radioactive labelled microtracers allowed study—without risk for the child—of the oral bioavailability of compounds used as markers for certain drug metabolism pathways. Third, the use of modelling and simulation to support dosing recommendations for children is supported by both the European Medicines Agency and the US Food and Drug Administration. This may even do away with the need for a paediatric trial. Physiologically based pharmacokinetics models, which include age‐specific physiological information are, therefore, increasingly being used, not only to aid paediatric drug development but also to improve existing drug therapies. [ABSTRACT FROM AUTHOR]

BNT162b2 (BioNTech/Pfizer) was the first SARS-CoV-2 mRNA vaccine approved by the European Medicines Agency. We monitored the long-term humoral responses of healthcare workers (HCWs) who received three vaccine doses. A total of 59 healthcare workers were studied: 47 were never SARS-CoV-2-infected (naïve-HCWs), and 12 (infected-HCWs) recovered from COVID-19 before the first vaccine. Serum and saliva were collected at baseline (before the first dose), just before the second dose, 1, 3, 6, and 9 months after the second dose, and 10 days after the third vaccine. SARS-CoV-2-specific IgG and IgA were evaluated in serum and saliva, respectively, and the presence of neutralizing antibodies (NAb) was analyzed in serum. SARS-CoV-2-specific IgG peaked one month after the second vaccine in naïve-HCWs but right before this timepoint in infected-HCWs. IgG titers significantly decreased during follow-up and at month 9 were still detectable in 50% of naïve-HCWs and 90% of infected-HCWs. NAb were significantly decreased 6 months after the second vaccine in naïve-HCWs and 9 months after this dose in infected-HCWs. Salivary SARS-CoV-2-specific IgA titers were significantly higher in infected-HCWs and were undetectable 9 months after the second vaccine in 43% of the naïve-HCWs alone. The third vaccine greatly increased humoral IgG and mucosal IgA in both groups. Two BNT162b2 doses induced strong systemic and humoral immune responses; to note, these responses weakened over time, although they are more prolonged in individuals who had recovered from COVID-19. The third vaccine dose quickly boosts systemic and mucosal humoral responses. [ABSTRACT FROM AUTHOR]

This study aimed to evaluate the pharmacokinetics of acipimox in rats under simulated high altitude hypoxia conditions. A sensitive and reliable LC–MS/MS method has been established for the quantitation of acipimox in rat plasma and tissue homogenate and validated according to the guidelines of the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA). Western blotting and enzyme linked immunosorbent assay (ELISA) were used to investigate the expression of lipid metabolism-related proteins and free fatty acid (FFA) levels, respectively. Cell viability was detected using a Cell Counting kit-8 assay (CCK-8). The method was then successfully applied in a pharmacokinetic comparison between normoxic and hypoxic rats. The results indicated that there were significant differences in the main pharmacokinetics parameters of acipimox between normoxic and hypoxic rats. HCAR2 expression in the hypoxia group was upregulated compared to that in the normoxia group and the levels of FFA decreased more in the hypoxia group. Under the hypoxia condition, the proliferation of HK2 cells was inhibited with increasing concentrations of acipimox. The results provide important and valuable information for the safety and efficacy of acipimox, which indicated that the dosage of acipimox might be adjusted appropriately during clinical medication in hypoxia. [ABSTRACT FROM AUTHOR]

Networks of national authorities are often mandated to help enforce EU policies, but receive less scholarly attention than EU agencies. This article examines two networks in the policy areas of medical devices and aviation incident investigation. These are puzzling cases, as two EU agencies already existed in similar policy areas: the European Medicines Agency (EMA) and the European Aviation Safety Authority (EASA). Why did EU legislators mandate new networks of national authorities, and not existing EU agencies? The article argues that national authorities' experts held a central position in the decision-making process and have considerably influenced the decision not to mandate the EMA and the EASA. The article also refines a common assumption about the Commission, and argues that it seems less keen to establish new EU agencies if these already exist in largely similar policy areas. The article's case studies rely on 24 interviews and an analysis of primary and secondary documentation. [ABSTRACT FROM AUTHOR]

Biosimilars are defined as biological products that are highly similar to a reference product, notwithstanding minor differences in clinically inactive components. Biosimilars show no clinically meaningful differences in safety, purity, and potency of the product in comparison to the reference product. With the ever looming patent expiry of some major high cost biologics, biosimilar production is becoming ever more lucrative to companies. Europe (EU) set the precedent, followed by the United States (US) in early 2012, for the approval process for biosimilars. Therefore, the purpose of this paper is to explore the nature of the regulatory processes in the US and EU and to determine the requirements of each in the approval process of a biosimilar. The current Food and Drug Administration (FDA) and European Medicines Agency's (EMA) guidance documents for biosimilars were reviewed revealing a need for further clarifications, as well as specifically addressing Celltrion's and Sandoz's application for approval for the biosimilars infliximab and filgrastim, respectively. Currently, the FDA and EMA focus on comparability in terms of the clinical, pharmacokinetic (PK)/pharmacodynamic (PD), preclinical, biological activity, and physiochemical characterization results, as well as requiring a robust and consistent manufacturing process. Both the EU and US have prepared guidance documents for biosimilars that will result in biotherapeutics that are as safe and efficacious as the innovator product but the necessity exists to globally harmonize international nonproprietary naming nomenclature and clarify how the concept of pharmacovigilance, extrapolation, and interchangeability will be handled and regulated in the future. [ABSTRACT FROM AUTHOR]

Purpose This paper examines conditional approvals that allow the marketing of medicines with unsettled benefit–risk profiles in the European Union. Methods We identified medicines that had received conditional approval from the European Medicines Agency in the period January 2006–June 2015. We searched the reasons and bases for approvals, the median time to address the specific obligations imposed in order to cover the information gap and allow regular authorisations, and their extent of fulfilment. Results Of the 26 products conditionally authorised two were withdrawn for commercial reasons, ten were switched to regular approval, and 14 are still under conditional approval. Conditional approval was granted mainly to medicinal products intended for seriously debilitating disease or life-threatening disease. The median time to address the specific obligations was four years (range 0.2 to 7.7). There were delays or discrepancies in the fulfilment of these obligations in more than one third of the authorisation procedures. Conclusions In most cases there was limited evidence supporting the positive benefit–risk balance at the time of approval. Delays or discrepancies in the fulfilment of obligations allow medicinal products with unsettled benefit–risk profiles onto the market for several years. This should be taken into account when further early or step-wise licensing strategies are considered. [ABSTRACT FROM AUTHOR]

Introduction: The public health threat of substandard and falsified medicines has been well known in the last two decades, and several studies focusing on the identification of products affected and preventing consumption have been published. However, the number of these products reaching patients and causing health consequences and adverse drug reactions is not a wellresearched area. Objectives: Our aim was to identify and describe the characteristics of cases that are related to adverse drug reactions potentially originating from counterfeit medication using publicly available pharmacovigilance data. Methods: A descriptive study was performed based on pharmacovigilance data retrieved from Individual Case Safety Reports (ICSRs) identified in the European Medicines Agency's EudraVigilance and FDA Adverse Event Reporting System (FAERS) databases in April 2022 using selected MedDRA preferred terms: counterfeit product administered, product counterfeit, product label counterfeit, product packaging counterfeit, suspected counterfeit product, adulterated product, product tampering, and suspected product tampering. ICSRs were analyzed by age and gender, by year of reporting, region of origin, reporter's profession, and severity of the outcome. The disproportionality method was used to calculate pharmacovigilance signal measures. Results: A total of 5,253 cases in the FAERS and 1,049 cases in the EudraVigilance database were identified, generally affecting middle-aged men with a mean age of 51.055 (±19.62) in the FAERS and 64.18% of the cases between 18 and 65 years, while the male to female ratios were 1.18 and 1.5. In the FAERS database, we identified 138 signals with 95% confidence interval including sildenafil (n = 314; PRR, 12.99; ROR, 13.04; RRR, 11.97), tadalafil (n = 200; PRR, 11.51; ROR, 11.55; RRR, 10.94), and oxycodone (n = 190; PRR, 2.47; ROR, 2.14; RRR, 2.47). While in the EV data 31, led by vardenafil (n = 16, PRR = 167.19; 101.71-274.84; 95% CI, RRR = 164.66; 100.17-270.66; 95% CI, ROR = 169.47; 103.09-278.60; 95% CI, p < 0.001), entecavir (n = 46, PRR = 161.26, RRR = 154.24, ROR = 163.32, p < 0.001), and tenofovir (n = 20, PRR = 142.10, RRR = 139.42, ROR = 143.74, p < 0.001). Conclusion: The application of pharmacovigilance datasets to identify potential counterfeit medicine ADRs can be a valuable tool in recognition of potential risk groups of consumers and the affected active pharmaceutical ingredients and products. However, the further development and standardization of ADR reporting, pharmacovigilance database analysis, and prospective and realtime collection of potential patients with health consequences are warranted in the future. [ABSTRACT FROM AUTHOR]

Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are effective and safe lipid-lowering treatments (LLT). The primary endpoint of the study was to assess the prevalence of patients eligible for treatment with PCSK9 inhibitors in a real-life clinical setting in Italy before and after the recent enlargement of reimbursement criteria. For this study, we consecutively considered the clinical record forms of 6231 outpatients consecutively admitted at the Lipid Clinic of the University Hospital of Bologna (Italy). Patients were stratified according to whether they were allowed or not allowed to access to treatment with PCSK9 inhibitors based on national prescription criteria and reimbursement rules issued by the Italian Medicines Agency (AIFA). According to the indications of the European Medicines Agency (EMA), 986 patients were candidates to treatment with PCSK9 inhibitors. However, following the prescription criteria issued by AIFA, only 180 patients were allowed to access to PCSK9 inhibitors before reimbursement criteria enlargement while 322 (+14.4%) with the current ones. Based on our observations, low-cost tailored therapeutic interventions for individual patients can significantly reduce the number of patients potentially needing treatment with PCSK9 inhibitors among those who are not allowed to access to the treatment. The application of enlarged reimbursement criteria for PCSK9 inhibitors could mildly improve possibility to adequately manage high-risk hypercholesterolemic subjects in the setting of an outpatient lipid clinic. [ABSTRACT FROM AUTHOR]

Between 2000 and 2021, the European Medicines Agency (EMA) assigned the orphan designation to over 1,900 medicines. Due to their small target populations, leading to challenges regarding clinical trial recruitment, study design and little knowledge on the natural history of the disease, the overall clinical evidence submitted at the time of marketing authorisation application for these medicines is often limited. Patient registries have been recognised as important sources of data on healthcare practices, drug utilisation and clinical outcomes. They may help address these challenges by providing information on epidemiology, standards of care and treatment patterns of rare diseases. In this review, we illustrate the utility of patient registries across the different stages of development of medicinal products, including orphans, to provide evidence in the context of clinical studies and to generate post-authorisation long term data on their effectiveness and safety profiles. We present important initiatives leveraging the role of registries for orphan medicinal products' development and monitoring to ultimately improve patients' lives. [ABSTRACT FROM AUTHOR]

Background: Chikungunya (CHIKV) is a reemerging arboviral disease and represents a global health threat because of the unprecedented magnitude of its spread. Diagnostics strategies rely heavily on reverse transcriptase-polymerase chain reaction (RT-PCR) and antibody detection by enzyme-linked Immunosorbent assay (ELISA). Rapid diagnostic tests (RDTs) are available and promise to decentralize testing and increase availability at lower healthcare system levels. Objectives: We aim to identify the extent of research on CHIKV RDTs, map the global availability of CHIKV RDTs, and evaluate the accuracy of CHIKV RDTs for the diagnosis of CHIKV. Eligibility criteria: We included studies reporting symptomatic individuals suspected of CHIKV, tested with CHIKV RDTs, against the comparator being a validated laboratory-based RT-PCR or ELISA assay. The primary outcome was the accuracy of the CHIKV RDT when compared with reference assays. Sources of evidence: Medline, EMBASE, and Scopus were searched from inception to 13 October 2021. National regulatory agencies (European Medicines Agency, US Food and Drug Administration, and the Brazilian National Health Surveillance Agency) were also searched for registered CHIKV RDTs. Results: Seventeen studies were included and corresponded to 3,222 samples tested with RDTs between 2005 and 2018. The most development stage of CHIKV RDTs studies was Phase I (7/17 studies) and II (7/17 studies). No studies were in Phase IV. The countries that manufacturer the most CHIKV RDTs were Brazil (n = 17), followed by the United States of America (n = 7), and India (n = 6). Neither at EMA nor FDA-registered products were found. Conversely, the ANVISA has approved 23 CHIKV RDTs. Antibody RDTs (n = 43) predominated and demonstrated sensitivity between 20% and 100%. The sensitivity of the antigen RDTs ranged from 33.3% to 100%. Conclusions: The landscape of CHIKV RDTs is fragmented and needs coordinated efforts to ensure that patients in CHIKV-endemic areas have access to appropriate RDTs. Further research is crucial to determine the impact of such tests on integrated fever case management and prescription practices for acute febrile patients. [ABSTRACT FROM AUTHOR]

Rare diseases remain a challenge for many of the countries in the world. The millions of people collectively suffering from rare diseases, in the context of raging COVID-19 pandemics globally, require an innovative and recent solution from different stakeholders. Regulatory bodies such as the Food and Drug Administration and the European Medicines Agency have come up with many different approaches including financial assistance to prompt drug development and approval. Novel approaches pertinent to clinical trials of such drugs such as patient centricity, early interaction with regulatory bodies, and establishing clinical outcome of interest have been experimented. Various international organizations including cross-country collaborators have initiated various projects or consortiums to bridge the gap between knowledge and practice. The challenges remain more pivotal in developing countries such as India, which has adopted few noteworthy initiatives by involving relevant stakeholders in the presence of limited resources, infrastructures, and a nascent regulatory framework. Therefore, it is imperative to revisit the key aspects of orphan drug development to fulfill the unmet needs of such patients suffering from various rare diseases. [ABSTRACT FROM AUTHOR]

The amount and type of data in regulatory submissions increases dramatically from the first-in-human clinical trials application through to the extensive dossier that is required for marketing authorization. The Pharmaceuticals and Biotechnology industries are very familiar with the requirements and expectations of Health Authorities for small molecule and biologics, but have limited experience for cell-based therapies. Fortunately, the United States Food and Drug Administration (FDA) and European Medicines agency (EMA) Committee for Advanced Therapies (CAT) have considerable experience in regulating cell therapies and have provided extensive Guidance documents for developers. The Agencies offers advice to Sponsors through a variety of meetings. However, it is incumbent on the Sponsor to understand the regulations, interpret the Guidance documents and formulate clear company positions to enable the Agency to provide clear feedback. It is important for Sponsors to understand the factors that are critical for the safety and efficacy of their product and to demonstrate to the Health Authorities that they have a control strategy that ensures safety and efficacy during all stages of development. The focus of this paper is to describe some of the challenges for the chemistry manufacturing and controls (CMC) for cell therapies being development internationally. [ABSTRACT FROM AUTHOR]

This paper presents 10 recommendations for improving the European Medicines Agency's guidance for environmental risk assessment of human pharmaceutical products. The recommendations are based on up-to-date, available science in combination with experiences from other chemical frameworks such as the REACH-legislation for industrial chemicals. The recommendations concern: expanding the scope of the current guideline; requirements to assess the risk for development of antibiotic resistance; jointly performed assessments; refinement of the test proposal; mixture toxicity assessments on active pharmaceutical ingredients with similar modes of action; use of all available ecotoxicity studies; mandatory reviews; increased transparency; inclusion of emission data from production; and a risk management option. We believe that implementation of our recommendations would strengthen the protection of the environment and be beneficial to society. Legislation and guidance documents need to be updated at regular intervals in order to incorporate new knowledge from the scientific community. This is particularly important for regulatory documents concerning pharmaceuticals in the environment since this is a research field that has been growing substantially in the last decades. [ABSTRACT FROM AUTHOR]