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Patient registries offer a powerful and practical means of real-world data collection system for rare diseases. Many guidelines have been released to standardize patient registries, although most of them do not address issues specific to rare disease patient registries. In November 2018, the European Medicines Agency (EMA) released a draft discussion paper on methodological and operational aspects of disease registries and made proposals on good registry practice (henceforth referred to as EMA guidance). This guidance was highly anticipated by all stakeholders with a strong interest toward governance, operationalization, and study conduct in registries. With improved clarity toward conduct of patient registries, this guidance will encourage overall registry use in regulatory decision making. TuberOus SClerosis registry to increase disease Awareness (TOSCA) was an international, multicenter patient registry to assess the manifestations, interventions, and outcomes in patients with tuberous sclerosis complex (TSC). The planning of TOSCA was initiated in 2011, patient enrolment commenced in August 2012, and final analysis database was locked in August 2017, long before the EMA guidance was released. Moreover, initial publications of TOSCA, such as first interim analysis, had also been published before the release of the EMA guidance. Extensive feedback and lessons learned from the TOSCA registry have provided insights into rare disease registry planning and operations. In this paper, we tested the recommendations from the EMA guidance on a rare disease registry, that is, the TOSCA registry. We elaborated the compliance and deviations of the TOSCA registry from the EMA guidance on a point-by-point basis. A careful observation revealed that in most aspects, TOSCA was in compliance with EMA. However, there were several practical issues identified in TOSCA, which deviated from EMA guidance. These issues demonstrate that deviations from EMA guidance, particularly in rare disease registries, do not signify compromised registry quality and can be somewhat expected in small populations. Despite multiple deviations of TOSCA from the EMA guidance, TOSCA was able to meet its objectives to enhance our understanding of TSC and its manifestations. [ABSTRACT FROM AUTHOR]

Substance use disorders (SUDs) are an extremely challenging category of disorders because of the high rate of relapse, lower life expectancy, important rate of psychiatric and somatic co-morbidity, lack of patients' insight during most of the disease duration, healthcare costs, etc. One of the reasons to consider these disorders very difficult for physicians and the healthcare system is the lack of adequate pharmacological agents with long-term proven efficacy. So far, there are no Food and Drug Administration (FDA) or European Medicines Agency (EMA)-approved treatments for most of the SUDs, except for alcohol use disorder, nicotine use disorder, and opioid use disorder. Immunotherapy has been considered a possible solution to SUDs because it may selectively target a certain drug of abuse, it may have a long-lasting effect (several weeks or months), and it ensures an adequate therapeutic adherence. The objective of this paper was to establish the current stage of research in the field of SUDs vaccines, based on a brief literature review. Vaccines for cocaine and nicotine dependence have reached phase III trials, while other researchers are focusing on passive immunization therapy for methamphetamine use disorder. New generations of vaccines are currently explored, and they are based on superior technologies compared to the first generation of immune therapy (e.g., viral transfer genes, more immunogenic adjuvants, or higher specificity haptens). Therefore, finding immune therapies for substance use disorders SUDs remains a matter of interest, and this approach may be useful for the management of an extremely dangerous and versatile psychiatric pathology. [ABSTRACT FROM AUTHOR]

Medicines receiving a conditional marketing authorization through Medicines Adaptive Pathways to Patients (MAPPs) will be a challenge for payers. The "introduction" of MAPPs is already seen by the European Medicines Agency (EMA) as a fait accompli, with payers not consulted or involved. However, once medicines are approved through MAPPs, they will be evaluated for funding by payers through different activities. These include Health Technology Assessment (HTA) with often immature clinical data and high uncertainty, financial considerations, and negotiations through different types of agreements, which can require monitoring post launch. Payers have experience with new medicines approved through conditional approval, and the fact that MAPPs present additional challenges is a concern from their perspective. There may be some activities where payers can collaborate. The final decisions on whether to reimburse a new medicine via MAPPs will have more variation than for medicines licensed via conventional processes. This is due not only to increasing uncertainty associated with medicines authorized through MAPPs but also differences in legal frameworks between member states. Moreover, if the financial and side-effect burden from the period of conditional approval until granting full marketing authorization is shifted to the postauthorization phase, payers may have to bear such burdens. Collection of robust data during routine clinical use is challenging along with high prices for new medicines during data collection. This paper presents the concept of MAPPs and possible challenges. Concerns and potential ways forward are discussed and a number of recommendations are presented from the perspective of payers. [ABSTRACT FROM AUTHOR]

Introduction: In 2021, the European Medicines Agency supported the "Covid Vaccine Monitor (CVM)," an active surveillance project spanning 13 European countries aimed at monitoring the safety of COVID-19 vaccines in general and special populations (i.e., pregnant/breastfeeding women, children/adolescents, immunocompromised people, and people with a history of allergies or previous SARS-CoV-2 infection). Italy participated in this project as a large multidisciplinary network called the "ilmiovaccinoCOVID19 collaborating group." Methods: The study aimed to describe the experience of the Italian network "ilmiovaccinoCOVID19 collaborating group" in the CVM context from June 2021 to February 2023. Comprising about 30 partners, the network aimed to facilitate vaccinee recruitment. Participants completed baseline and follow-up questionnaires within 48 h from vaccination over a 6-month period. Analyses focused on those who completed both the baseline and the first follow-up questionnaire (Q1), exploring temporal trends, vaccination campaign correlation, and loss to follow-up. Characteristics of recruited vaccinees and vaccineereported adverse drug reactions (ADRs) were compared with passive surveillance data in Italy. Results: From June 2021 to November 2022, 22,384,663 first doses and 38,207,452 booster doses of COVID-19 vaccines were administered in Italy. Simultaneously, the study enrolled 1,229 and 2,707 participants for the first and booster doses, respectively. Of these, 829 and 1,879 vaccinees, respectively, completed both baseline and at least Q1 and were included in the analyses, with a significant proportion of them (57.8%/34.3%) belonging to special cohorts. Most vaccinees included in the analyses were women. Comirnaty® (69%) and Spikevax® (29%) were the most frequently administered vaccines. ADR rates following Comirnaty® and Spikevax® were higher after the second dose, particularly following Spikevax®. Serious ADRs were infrequent. Differences were observed in ADR characteristics between CVM and Italian passive surveillance. Conclusion: This study confirmed the favorable safety profile of COVID-19 vaccines, with findings consistent with pivotal clinical trials of COVID-19 vaccines, although different proportions of serious ADRs compared to spontaneous reporting were observed. Continuous evaluation through cohort event monitoring studies provides real-time insights crucial for regulatory responses. Strengthening infrastructure and implementing early monitoring strategies are essential to enhance vaccine safety assessment and prepare for future pandemics. [ABSTRACT FROM AUTHOR]

The cardioprotective and anti-inflammatory effects of long chain omega-3 polyunsaturated fatty acids (n3 PUFA) are believed to be partly mediated by their oxygenated metabolites (oxylipins). In the last two decades interest in a novel group of autacoids termed specialized pro-resolving mediators (SPMs) increased. These are actively involved in the resolution of inflammation. SPMs are multiple hydroxylated fatty acids including resolvins, maresins, and protectins derived from the n3 PUFA eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) as well as lipoxins derived from arachidonic acid (ARA). In the present paper, we developed an LC-MS/MS method for a comprehensive set of 18 SPMs derived from ARA, EPA, and DHA and integrated it into our targeted metabolomics platform. Quantification was based on external calibration utilizing five deuterated internal standards in combination with a second internal standard for quality assessment of sample preparation in each sample. The tandem mass spectrometric parameters were carefully optimized for sensitive and specific detection. The influence of source parameters of the used AB Sciex 6500 QTRAP instrument as well as electronic parameters and the selection of transitions are discussed. The method was validated/characterized based on the criteria listed in the European Medicines Agency (EMA) guideline on bioanalytical method validation and method performance is demonstrated regarding recovery of internal standards (between 78 ± 4% and 87 ± 3% from 500 μL of human serum) as well as extraction efficacy of SPMs in spiked plasma (intra-day accuracy within ±20 and ±15% at 0.1 and 0.3 nM in plasma, respectively). Based on the lower limit of quantification of 0.02–0.2 nM, corresponding to 0.18–2.7 pg on column, SPMs were generally not detectable/quantifiable in plasma and serum supporting that circulating levels of SPMs are very low, i.e., <0.1 nM in healthy subjects. Following septic shock or peritonitis, SPMs could be quantified in the samples of several patients. However, in these studies with a small number of patients no clear correlation with severity of inflammation could be observed. [ABSTRACT FROM AUTHOR]

Introduction: Over the preceding decade, an increasing number of drugs have been approved by the European Medicines Agency (EMA) with limited knowledge of their relative efficacy. This is due to the utilization of non-randomized, singlearm studies, surrogate endpoints, and shorter follow-up time. The impact of this trend on the accessibility and affordability of newly approved drugs in Europe remains uncertain. The primary objective of this study is to provide insights into the issues of accessibility and affordability of new drugs in the Norwegian healthcare system. Method: The presented study entails an analysis of all reimbursement decisions for hospital drugs in Norway spanning 2021–2022. The included drugs were approved by the EMA between 2014 and 2022, with the majority (91%) receiving approval between 2018 and 2022. The drugs were categorized based on the level of documentation of relative efficacy. Approval rates and costs (confidential netprices) were compared. Results: A total of 35% (70/199) of the reimbursement decisions were characterized by limited certainty regarding relative efficacy and as a consequence the Norwegian Health Technology Assessment (HTA) body did not present an incremental cost-effectiveness ratio (ICER) in the HTA report. Within this category, a lower percentage of drugs (47%) gained reimbursement approval compared to those with a higher certainty level, which were presented with an ICER (58%). On average, drugs with an established relative efficacy were accepted with a 4.4-fold higher cost (confidential net-prices). These trends persisted when specifically examining oncology drugs. Conclusion: Our study underscores that a substantial number of recently introduced drugs receive reimbursement regardless of the level of certainty concerning relative efficacy. However, the results suggest that payers prioritize documented over potential efficacy. Given that updated information on relative efficacy may emerge post-market access, a potential solution to address challenges related to accessibility and affordability in Europe could involve an increased adoption of market entry agreements. These agreements could allow for price adjustments after the presentation of new knowledge regarding relative efficacy, potentially resolving some of the current challenges. [ABSTRACT FROM AUTHOR]

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

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

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

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]

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]

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]

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]

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]

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]

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]

The implementation of pharmacogenetic testing into clinical practice has been a slow process so far. Here, we review the implementation of pre-treatment testing of dihydropyrimidine dehydrogenase gene (DPYD) risk variants to prevent early-onset fluoropyrimidine (FP)-related toxicity in cancer patients in Switzerland based on data of a large Swiss diagnostic center. In January 2017, the Swiss Federal Office of Public Health introduced the reimbursement of DPYD testing by the compulsory health insurance in Switzerland based on evidence for the clinical relevance of DPYD -risk variants and the cost-effectiveness of pre-treatment testing, and on the availability of international guidelines. However, we did not observe a strong increase in DPYD testing at our diagnostic center from 2017 to 2019. Only a low number of DPYD -testing requests (28–42 per year), concerning mostly retrospective investigations of suspected FP-toxicity, were received. In contrast, we observed a 14-fold increase in DPYD testing together with a strong shift from retrospective to pre-treatment test requests upon the release of recommendations for DPYD testing prior to FP-treatment in April 2020 by the European Medicines Agency. This increase was mainly driven by three geographic regions of Switzerland, where partner institutions of previous research collaborations regarding FP-related toxicity are located and who acted as early-adopting institutions of DPYD testing. Our data suggest the important role of early adopters as accelerators of clinical implementation of pharmacogenetic testing by introducing these policies to their working environment and educating health workers from their own and nearby institutions. [ABSTRACT FROM AUTHOR]

The European Society for Organ Transplantation (ESOT) submitted a Broad Scientific Advice request to the European Medicines Agency (EMA) in 2018, to explore whether updating guidelines on clinical trial endpoints would encourage innovations in kidney transplantation research, thereby improving long-term outcomes for allograft recipients. The request was refined collaboratively by the EMA and ESOT, with the EMA issuing a final response in December 2020. This Transplant International special issue explores the topics that were the focus of these interactions between the EMA and ESOT. Articles explore the current issues and dilemmas in kidney transplantation, primarily relating to unclear or outdated risk stratification and markers of transplantation success, although several potential improvements for outcomes assessment are also suggested. Discussions between the EMA and ESOT and recommendations are summarized, in the hope that this project will generate further discussion eventually generating a consensus on clinical trial endpoints and risk stratification, increase the quality of research in transplantation medicine, and improve long-term outcomes for kidney transplant recipients. [ABSTRACT FROM AUTHOR]

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

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

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

Background: The use of quinolones has been associated with the development of serious and persistent adverse drug reaction (ADR) mainly affecting muscles, joints and the nervous system. This risk has led the European Medicines Agency (EMA) to endorse some restrictions on the use of this class of antibiotic. Therefore, we performed a study to primary estimate the reporting probability of musculoskeletal, neurological, and psychiatric ADRs among quinolone generations using national data. Methods: We retrieved Individual Case Safety Reports (ICSRs) with a quinolone as suspected drug among those reported through the Campania spontaneous reporting system from January 1st, 2001 to April 30th 2019. Moreover, we retrieved national aggregated safety data from the online public report system (RAM system) for the period from January 1st, 2002 to March 31st, 2019. Risk factors were classified as "age greater than 60 years," "therapeutic indication," "renal failure," "organ transplantation," "use of corticosteroid," and "history of side effects". Reporting odds ratio (ROR) was computed to evaluate the reporting probability of musculoskeletal, neurological, or psychiatric events among quinolones generations. Results: A total of 87 ICSRs with a quinolone as suspected drug that reported at least one musculoskeletal, neurological, and psychiatric adverse event were identified in the Campania spontaneous reporting system. Forty-nine (56.3%) ICSRs reported risk factors (total risk factors 59). The most reported risk factor was "age greater than 60 years" (69.5%), followed by "therapeutic indication" (16.9%), "renal failure" (5.1%), "organ transplantation" (3.4%), "use of corticosteroid" (3.4%), and "history of side effects" (1.7%). Second-generation quinolones were associated with a lower reporting probability of musculoskeletal (ROR 0.70; 95% CI 0.63–0.79), neurological (ROR 0.81; 95% CI 0.73–0.90), and psychiatric (ROR 0.55; 95% CI 0.44–0.63) ADRs compared to the third generation of quinolones. Conclusions: Our findings showed that third-generation quinolones were always associated with a higher reporting probability of musculoskeletal, neurological, and psychiatric ADRs compared to the second generation ones. Moreover, we described risk factors in more than half of our cases suggesting that the inappropriate use of quinolones is a phenomenon that may frequently predispose patients to the occurrence of these ADRs. [ABSTRACT FROM AUTHOR]

Recently, breakthroughs have been made in the use of mesenchymal stem cells (MSCs) to treat various diseases. Several stem cell types have been authorized as drugs by the European Medicines Agency and the U.S. Food and Drug Administration. The Chinese official document "Notification of the management of stem cell clinical research (trial)" was also published in August 2015. Currently, China has approved 106 official stem cell clinical research filing agencies and 62 clinical research projects, which are mostly focused on MSC therapy. Hence, the optimization and development of stem cell drugs is imperative. During this process, maximizing MSC expansion, minimizing cell loss during MSC transplantation, improving the homing rate, precisely regulating the differentiation of MSCs, and reducing MSC senescence and apoptosis are major issues in MSC preclinical research. Similar to artemisinin extracted from the stems and leaves of Artemisia annua , ginsenoside Rg1 (Rg1) is purified from the root or stem of ginseng. In the human body, Rg1 regulates organ function, which is inseparable from its regulation of adult stem cells. Rg1 treatment may effectively regulate the proliferation, differentiation, senescence, and apoptosis of MSCs in different microenvironments in vitro or in vivo. In this review, we discuss recent advances in understanding the effect of Rg1 on MSCs and describe the issues that must be addressed and prospects regarding Rg1 regulation of MSCs in preclinical or clinical studies. [ABSTRACT FROM AUTHOR]

Purpose: The off-label (OL) use of antineoplastic drugs for the treatment of various types of tumors in patients of different disease stages is becoming a common occurrence. The objective of this study was to analyze these patterns by quantification and characterization of the OL use of antineoplastic drugs and their level of scientific evidence in a medium/high-complexity Spanish general university hospital. Method: All oncology patients who underwent OL treatment with one or several antineoplastics during the 10 years from 2002 to 2012 were retrospectively selected. The use of these drugs was considered OL if they were used for indications, stages, lines of treatment, or chemotherapy schemes not reflected in the summary of product characteristics published by the European Medicines Agency at the time of prescription. To calculate the prevalence of patients who received one or more OL treatments during the study period, all patients whose primary or secondary diagnosis had been coded with the diagnoses included in the study were selected through the minimum basic data set (MBDS). This database was cross-referenced with that of the Farmatools® program (Dominion®), which collects information on all patients receiving chemotherapy to obtain the total number of patients who received chemotherapy in the hospital during this period. Results: In total, 684 patients and 866 OL treatments were included. The prevalence of patients undergoing OL treatment with antineoplastics was 6%. OL treatments were used mainly for breast, gynecological, lung, and gastric tumors. The most often-used antineoplastic was paclitaxel, followed by gemcitabine, carboplatin, vinorelbine, and capecitabine, which were used mainly in monotherapy and with palliative intent. A total of 56.1% of the OL schemes used had a level of evidence of 2A according to the National Comprehensive Cancer Network, and 55.3% had a level of evidence of 2B according to Micromedex®. Conclusion: The OL use of antineoplastics in oncology patients is limited; their use is mainly focused in a small group of tumors and at advanced stages of disease. OL use of antineoplastics occurs under palliative therapeutic strategies with a limited number of drugs, preferably off-patent drugs. In addition, these OL treatments have high levels of clinical evidence. [ABSTRACT FROM AUTHOR]

The development of novel regulatory tools such as adaptive clinical trial design and utilization of real-world evidence are topics of high interest. Recently, the European Medicines Agency (EMA) introduced the Adaptive Pathways (AP) that represents an innovative tool in healthcare systems allowing the early dialogue with multiple stakeholders on promising and innovative medicinal products in areas with an high unmet medical need. The innovative aspect in the AP is the early involvement of several stakeholders such as pharmaceutical industry, the Academia, Health Technology Assessment (HTA) bodies, and patient representatives bringing their real experience with the disease and their expectations about the treatment. AP is not a new licensing tool but an opportunity for a very early discussions, before starting the phase II studies, among all stakeholders, including regulators, companies, HTA bodies, and patient representatives on a new potential medicine in areas of high unmet medical need. The aim of this paper is to describe the evolution of the AP approach from the beginning of the pilot project to date, highlighting major advances, and achievement at European level.

Nalmefene is approved for as-needed pharmacological treatment in alcohol use disorder (AUD) by the European Medicines Agency. While the cellular effects of nalmefene have been thoroughly investigated, data are very limited on how this agent influences neural signals associated with inhibitory control and the visual analysis of environmental cues. This double-blind crossover study assessed the behavioral and neural effects of acute nalmefene administration in patients diagnosed with AUD. In experiment 1, we validated our experimental paradigm (electroencephalography combined with a modified Go/NoGo task using images of alcoholic and nonalcoholic drinks as prime stimuli) in 20 healthy adults to ensure that our protocol is suitable for assessing the behavioral and neural aspects of executive control. In experiment 2, we recruited 19 patients with AUD, and in a double-blind crossover design, we investigated the effects of nalmefene versus placebo on task performance (response accuracy, the sensitivity index, and reaction times), visual responses to appetitive cues (occipital P1, N1, and P2 components), and electrophysiological markers of conflict detection and response inhibition (frontal N2 and P3 waveforms). Under placebo, patients produced faster reaction times to alcohol-primed Go stimuli, an effect that was weak despite being statistically significant. However, the effect of alcoholic cues on the speed of response initiation disappeared after receiving nalmefene. We found no placebo versus nalmefene difference regarding our patients' ability to accurately inhibit responses to NoGo stimuli or for occipital and frontal event-related potentials. Our results suggest that nalmefene might be potent in reducing the vigor to act upon alcoholic cues in AUD patients, but this effect is most probably mediated via subcortical (rather than cortical) neural circuits. [ABSTRACT FROM AUTHOR]

Medicines receiving a conditional marketing authorization through Medicines Adaptive Pathways to Patients (MAPPs) will be a challenge for payers. The “introduction” of MAPPs is already seen by the European Medicines Agency (EMA) as a fait accompli, with payers not consulted or involved. However, once medicines are approved through MAPPs, they will be evaluated for funding by payers through different activities. These include Health Technology Assessment (HTA) with often immature clinical data and high uncertainty, financial considerations, and negotiations through different types of agreements, which can require monitoring post launch. Payers have experience with new medicines approved through conditional approval, and the fact that MAPPs present additional challenges is a concern from their perspective. There may be some activities where payers can collaborate. The final decisions on whether to reimburse a new medicine via MAPPs will have more variation than for medicines licensed via conventional processes. This is due not only to increasing uncertainty associated with medicines authorized through MAPPs but also differences in legal frameworks between member states. Moreover, if the financial and side-effect burden from the period of conditional approval until granting full marketing authorization is shifted to the post-authorization phase, payers may have to bear such burdens. Collection of robust data during routine clinical use is challenging along with high prices for new medicines during data collection. This paper presents the concept of MAPPs and possible challenges. Concerns and potential ways forward are discussed and a number of recommendations are presented from the perspective of payers.

The use of generic formulations of immunosuppressive drugs in renal transplantation has been and still is a controversial subject. The lack of clinical studies about safety and efficacy in transplant patients is one of the factors restricting the diffusion of generic drugs in the renal transplant field. Since March 2013, our transplant unit has incorporated generic tacrolimus (Adoport®; Sandoz), replacing the one we were currently using (Prograf®; Astellas). When carrying out our retrospective analysis comparing the two different formulations, we evaluated several clinical results: tacrolimus trough concentrations ( C0) at 5-7 days; 1, 3, and 6 months post-transplantation; concentration/dose ratio at 6 months; acute rejection incidence; delayed graft function ( DGF); renal function (as CKD- EPI); and proteinuria at 6 months in 120 patients (1:1 ratio of Prograf® versus Adoport®), noticing no important differences. We also evaluated the results of protocol biopsies at 6 months in a subgroup of patients, thus verifying the safety and efficacy of this particular generic drug versus the reference product on a histological basis as well. No difference in the development of dn DSA ( de novo donor-specific antibody) was found between the two groups. [ABSTRACT FROM AUTHOR]

The assessment report formats of four major regulatory reference agencies, US Food and Drug Administration, European Medicines Agency, Health Canada, and Australia's Therapeutic Goods Administration were compared to a benefit-risk (BR) documentation template developed by the Centre for Innovation in Regulatory Science and a four-member Consortium on Benefit-Risk Assessment. A case study was also conducted using a US FDA Medical Review, the European Public Assessment Report and Australia's Public Assessment Report for the same product. Compared with the BR Template, existing regulatory report formats are inadequate regarding the listing of benefits and risks, the assigning of relative importance and values, visualization and the utilization of a detailed, systematic, standardized structure. The BR Template is based on the principles of BR assessment common to major regulatory agencies. Given that there are minimal differences among the existing regulatory report formats, it is timely to consider the feasibility of a universal template. [ABSTRACT FROM AUTHOR]

Aims: Cardiovascular outcome trials with anti-diabetic drugs suggest that additional cardiovascular benefit can be achieved independent of improving glycaemic control. Nonetheless, dose selection of anti-diabetic drugs is typically based solely on glycaemic effects. We evaluated whether off-target drug effects are currently considered for dose justification to regulatory agencies. Methods: In the European Union, anti-diabetic drugs are registered by the European Medicines Agency. We extracted available information regarding dose selection from public assessment reports and marketing application dossiers. Descriptive statistics were used to summarise the extracted information. Results: In total, 14 drugs of three drug classes were included; sodium-glucose co-transporter-2 inhibitors (n = 4), dipeptidyl peptidase-4 inhibitors (n = 4) and glucagon-like peptide-1 receptor agonists (n = 6). For these drugs, 21 dose-finding trials were submitted including results of multiple off-target effects, of which body weight (n = 18) and low-density lipoprotein cholesterol (n = 14) were most frequently reported. Dose-response curves for off-target effects appeared to be different compared to the glycaemic dose-response curve. Glycated hemoglobin (100%) and fasting plasma glucose (42.9%), were used most frequently for the dose justification, but generally off-target effects (<25%) were not. Conclusions: Dose justification to regulatory authorities was mainly based on glycaemic effects. The dose-response relationship for the off-target effects did not necessarily follow the dose-response relationship of the on-target effects suggesting that selection of the optimal anti-diabetic dose could benefit from including off-target effects in the dose selection process as well. [ABSTRACT FROM AUTHOR]