European Regulatory Authorities Research Articles

Development of Monoclonal Antibody Therapeutics for Alzheimer's Disease

Background: In a previous review article in the Taiwanese Journal of Psychiatry (Takeda and Tagami: Taiwanese J. Psychiatry 2020; 34: 152-61), we gave the development status of drugs for Alzheimer's disease, presented a relatively pessimistic view, and highlighted the difficulties in their development. Methods: Since I have witnessed some encouraging development of monoclonal antibody therapeutics against Alzheimer's disease, I have decided to contribute this article. I reviewed new data from published journals and from internal reports of pharmaceutical companies. I have also offered some explanations and comments. Results: In 2021, I saw promising clinical trial results reporting the use of aducanumab, a monoclonal antibody treatment against amyloid β protein, and the U.S. Food and Drug Administration (FDA) announced a decision for expedited approval of aducanumab. But the results of aducanumab's phase III clinical trials were considered by some to be insufficient for the approval, and the FDA's decision was controversial. The European and Japanese regulatory authorities did not approve aducanumab. In September 2022, however, more promising results were announced from Phase III clinical trials of another monoclonal antibody, lecanemab. Conclusion: In this review, I have recounted the state of the arts of drugs for treating dementia and highlighted remarkable recent progress in the development of monoclonal antibody therapeutics for Alzheimer's disease.

Personalised Therapies for Metastatic Triple-Negative Breast Cancer: When Target Is Not Everything.

Simple SummaryThe purpose of the present review is to shed light on new molecular biomarkers in triple-negative breast cancer (TNBC), showing emerging therapeutic approaches related to specific molecular signatures and their mechanisms of action. A general overview of ongoing clinical trials, future perspectives and differences in approval by American and European regulatory authorities is provided.Triple-negative breast cancer—defined by the absence of oestrogen/progesterone receptors and human epidermal growth factor receptor 2 expression—is a complex and heterogeneous type of tumour characterised by poor prognosis, aggressive behaviour and lack of effective therapeutic strategies. The identification of new biomarkers and molecular signatures is leading to development of new therapeutic strategies including immunotherapy, targeted therapy and antibody-drug conjugates (ADCs). Against a background where chemotherapy has always been considered the standard of care, evolution towards a precision medicine approach could improve TNBC clinical practice in a complex scenario, with many therapeutic options and new drugs. The aim of this review was to focus on emerging therapeutic targets and their related specific therapy, discussing available and emerging drugs, underlining differences in approval by American and European regulatory authorities and showing the future perspective in the large number of ongoing clinical trials.

The role of statistical significance testing in public law and health risk assessment.

SummaryFollowing a fundamental statement made in 2016 by the American Statistical Associations and broad and consistent changes in data analysis and interpretation methodology in public health and other sciences, statistical significance/null hypothesis testing is being increasingly criticized and abandoned in the reporting and interpretation of the results of biomedical research. This shift in favor of a more comprehensive and non-dichotomous approach in the assessment of causal relationships may have a major impact on human health risk assessment. It is interesting to see, however, that authoritative opinions by the Supreme Court of the United States and European regulatory agencies have somehow anticipated this tide of criticism of statistical significance testing, thus providing additional support to its demise. Current methodological evidence further warrants abandoning this approach in both the biomedical and public law contexts, in favor of a more comprehensive and flexible method of assessing the effects of toxicological exposure on human and environmental health.

Tolerability of duloxetine in elderly and in non-elderly adults: a protocol of a systematic review and individual participant data meta-analysis of randomized placebo-controlled trials

BackgroundDuloxetine is an antidepressant that benefits from a wide range of approval in the elderly population, while its safety for use compared to non-elderly is not clearly assessed. This protocol outlines a systematic review and individual participant data meta-analysis comparing the tolerability of duloxetine between elderly and non-elderly.MethodsSearches will be conducted in PubMed, ClinicalTrials.gov, Clinicaltrialsregister.eu, data sharing platforms, FDA drug approval packages, European public assessment reports and withdrawn applications from the EMA website. The review will be performed on studies available in electronic databases from their date of inception to the 31 March 2022. Only randomized controlled clinical trials, comparing duloxetine to placebo, will be included in this meta-analysis. The studies will be selected if they comprise both elderly and non-elderly adults, in conditions of use of duloxetine approved by the European Medical Agency (EMA) and the Food and Drug Administration (FDA). The primary outcome will be the rate ratio of serious adverse events under duloxetine compared to placebo, between participants at least 65 years old and non-elderly. Second, the number of any adverse events, clinical efficacy and quality of life will be compared between elderly and non-elderly under both interventions. The quality of evidence in the tolerability of duloxetine will be assessed using the GRADE system. A one or two-stage individual participant data random effect meta-analysis will be conducted depending on the availability of the data.DiscussionThis meta-analysis will investigate the tolerability safety of duloxetine in the elderly population across all conditions approved by European and American regulatory authorities. The results from this meta-analysis are intended to help prescribers to provide better care for the elderly population.Systematic review registrationThe protocol has been registered at the International Prospective Register of Systematic Reviews (PROSPERO; registration number: CRD42019130488).

Drospirenone 4 mg in a 24/4 regimen maintains inhibition of ovulation even after a 24-h delay pill intake - Pharmacological aspects and comparison to other progestin-only pills.

This review focuses on the pharmacological and inhibition of the ovulation of progestin-only, estrogen-free contraceptive containing drospirenone in a dosage of 4 mg in a regimen 24/4. The USA and European regulatory authorities have approved it. The molecule has anti-gonadotropic, anti-mineralocorticoid, anti-estrogenic, and antiandrogenic properties. This regime improves the bleeding profile, maintains the plasma E2 levels comparable to the menstrual cycle's early follicular phase, avoids hypoestrogenism, and preserves efficacy despite forgetting the tablet intake as drospirenone has a half lifetime of 30-34 hours. Clinical studies have shown good efficacy, very low cardiovascular side effects, and high acceptability and maintenance of ovulation inhibition after scheduled 24-h delays in pill intake. The molecule is compared to other POP like levonorgestrel or desogestrel.

The SQ HDM SLIT-Tablet is safe and well tolerated in patients with House Dust Mite allergic rhinitis with or without asthma: A "real-life" French study.

BackgroundThe SQ House Dust Mite (HDM) SubLingual ImmunoTherapy (SLIT)‐Tablet (Acarizax) is the only allergen immunotherapy authorized by European regulatory authorities to treat HDM‐induced allergic asthma (AA) that is not well‐controlled by inhaled corticosteroids and associated with mild‐to‐severe HDM allergic rhinitis (AR). The aim of this study was to add evidence on the safety of the SQ HDM SLIT‐Tablet in patients with AR, alone or with AA, under real‐life conditions.MethodsThis was a French “real‐life”, multicenter, non‐comparative, longitudinal, prospective study. It included patients initiating the SQ HDM SLIT‐Tablet for either persistent moderate‐to‐severe HDM AR or AA not well‐controlled by inhaled corticosteroids and associated with mild‐to‐severe HDM AR. Adverse Events (AEs) were collected at the first intake and throughout the study. Logistic regression was used to compare safety according to asthma control before treatment initiation.ResultsBetween May 09, 2018 and May 29, 2019, 1526 patients were enrolled at 185 sites and 1483 were included in the safety population (SAF). Of them, 33.6% had suspected clinical manifestations of AA. Asthma was uncontrolled for 18.2% of the patients, partially controlled for 27.9% and well‐controlled for 53.8%. Overall, 31.9% of the SAF patients experienced at least one AE. The percentage of patients with AEs was 29.9% among patients with AR alone and 35.9% among those with AA (p = 0.0193). No significant difference was observed in the rate of AE or SAE depending on asthma control at inclusion (2.2% of SAEs reported for patients with uncontrolled asthma, 1.4% for partly controlled and 1.1% for well‐controlled).ConclusionsThe overall results indicate a good SQ HDM SLIT‐Tablet safety profile consistent with that reported in previous studies, regardless of asthma control.

ПРОГАЛИНИ У РЕГУЛЯЦІЇ ПРОВЕДЕННЯ КЛІНІЧНИХ ДОСЛІДЖЕНЬ МЕДИЧНИХ ВИРОБІВ ТА МЕДИЧНИХ ВИРОБІВ ДЛЯ IN VITRO ДІАГНОСТИКИ В УКРАЇНІ

The article summarizes the arguments and counterarguments within the scientific debate on the issue of gaps in the regulation of clinical research of medical devices and medical devices for in vitro diagnostics in Ukraine. The main goal of the conducted research is to identify an exhaustive list of such gaps and develop recommendations for improving the mentioned regulations. The systematization of literary sources and approaches to solving the problem of gaps in the regulation of clinical research of medical devices and medical devices for in vitro diagnostics in Ukraine proved that the scientific discussion on this topic is not conducted in Ukraine, despite the presence of WHO recommendations on the revision of relevant legal acts . The urgency of solving this scientific problem lies in the fact that filling the gaps in the relevant regulations and harmonizing the regulations with the relevant regulations of the European Union is an integral part of the recognition of clinical evidence on the effectiveness and safety of medical devices obtained during research in Ukraine by European regulatory authorities. Filling these gaps could potentially lead to increased demand for clinical trials of medical devices and medical devices for in vitro diagnostics in Ukraine. The results of the empirical analysis of the market of clinical research of medical products in Ukraine, in comparison with clinical research of medicinal products in Ukraine, proved that Ukraine is more attractive for conducting clinical research of medicinal products. This trend is explained, in particular, by the presence of specialized regulation of clinical trials of medicinal products in Ukraine, the presence of a body responsible for supervision, audit, and evaluation of the results of such clinical trials. The study empirically confirms and theoretically proves that the regulation of this area is insufficient, which leads to the need for additional examination of research materials abroad, and therefore to lower interest in conducting clinical research of medical devices in Ukraine. The results of the conducted research may be useful to regulatory bodies for the development of a regulatory framework for conducting clinical trials of medical devices and products for in vitro diagnostics in Ukraine, sponsors of such trials and contractor companies performing such trials in Ukraine

Advancing African Medicines Agency through Global Health Diplomacy for an Equitable Pan-African Universal Health Coverage: A Scoping Review.

The African continent is home to 15% of the world’s population and suffers from a disease burden of more than 25% globally. In this COVID-19 era, the high burden and mortality are further worsened due to inequities, inequalities such as inadequate health systems, scarce financial and human resources, as well as unavailability of inexpensive medicines of good quality, safety, and efficacy. The Universal Health Coverage ensures that people have access to high-quality essential health services, secure, reliable, and affordable essential medicines and vaccines, as well as financial security. This paper aimed at addressing the critical need for a continental African Medicines Agency (AMA) in addressing the inequities and the role of global health diplomacy in building consensus to support the ratification of the Treaty of AMA. A literature review was done in Scopus, Web of Science, MEDLINE/PubMed, and Google Scholar search engine to identify the critical literature in the context of study objectives. All the articles published after 2015 till 2021 in the context of AMA were included. African Health Strategy 2016–2030 highlighted the importance of an African regulatory mechanism for medicines and medical products. Through global health diplomacy (GHD), the African Union and its partners can negotiate and cooperate in providing infrastructural, administrative, and regulatory support for establishing the AMA. The paper emphasizes the South–South cooperation and highlights the contributions of India and China in the supply of medicines and vaccines to Africa. A strong AMA created through GHD can be a vital instrument in utilizing Trade-Related Aspects of Intellectual Property Rights (TRIPS) flexibilities extension and an ideal partner for European and other regional regulatory authorities seeking to stem the tide of counterfeit, sub-standard, or fake products.

Need for harmonisation of extremity dose monitoring in nuclear medicine: results of a survey amongst national dose registries in Europe

Staff handling radiopharmaceuticals in nuclear medicine (NM) may receive significant extremity doses. Over the last decade in particular there has been an increase in NM procedures and new radiopharmaceuticals have been introduced. However, literature provides limited recent data on the exposure of the extremities. In addition, proper assessment of the equivalent dose to the skin can be difficult when applied to the fingertips. In order to gain insight in the actual exposure and to find out how European countries are dealing with monitoring of the extremities, a survey was performed amongst European regulatory authorities. The questions covered general aspects of the national dose registries (NDRs), the measured extremity doses and the practice of the monitoring of workers. The survey shows that extremity dosimetry is performed for about 25%–50% of the monitored workers in NM. Also, the recorded extremity doses in the NDRs are low (mean values 5–29 mSv yr−1) compared to the dose limit. Despite the recommendations that have been published in the last 10 years, few countries provide guidance on the wearing position of extremity dosemeters and the correction factor to estimate the maximum equivalent skin dose from the measured dose. This may lead to an underestimation of the maximum skin dose. Thermoluminescence ring dosemeters are widely used, but wrist dosemeters are also very common, even though the correlation of the measurement with the maximum skin dose is worse than for ring dosemeters. Furthermore, not all countries had a central registration of the extremity dose at the time the survey was performed.

Nusinersen for Spinal Muscular Atrophy in the United States: Findings From a Retrospective Claims Database Analysis.

IntroductionSpinal muscular atrophy (SMA) is a rare, genetic neuromuscular disorder caused by deletion/mutation of the survival motor neuron 1 gene, characterized by progressive loss of motor neurons, resulting in increasing muscular weakness, deteriorating motor function, and, in its most severe form, death before 2 years. Nusinersen, an antisense oligonucleotide that increases expression of the functional SMN protein, was approved for SMA by US and European regulatory agencies in 2016 and 2017, respectively. The indicated regimen requires intrathecal injections every 4 months, following the first four injections during the loading phase. Adherence is integral to treatment success. Adherence to nusinersen may pose particular challenges as most patients with SMA are young children who require complex multidisciplinary care (including ongoing intrathecal treatment administration and potential specialized anesthetic and surgical procedures) at specialized centers. However, real-world data on adherence to nusinersen are limited.MethodsWe conducted a retrospective claims database analysis from December 23, 2016, to November 20, 2019, to study nusinersen adherence and discontinuation/persistence in US patients with SMA types 1–3 who completed the loading phase, and to determine the impact of non-adherence or treatment discontinuation on SMA-related comorbidities, health care resource utilization (HCRU), and costs.ResultsWe identified 23 patients with SMA type 1, 41 patients with SMA type 2, and 260 patients with SMA type 3 who had completed the loading phase. Deviations from the indicated nusinersen treatment schedule were frequent in real-world usage, with most patients receiving ≥1 dose outside the scheduled interval. Across SMA types, non-adherent patients were more likely to have had SMA-related comorbidities (e.g., feeding difficulties, dyspnea and respiratory anomalies, and muscle weakness) and greater HCRU. Persistence rates 12 months after treatment initiation for patients with SMA types 1, 2, and 3 were 55.2%, 42.4%, and 54.6%, respectively. Patients who discontinued nusinersen and those who did not had generally similar comorbidity profiles. Discontinuation was associated with greater health care costs across SMA types.ConclusionOur analysis of claims data indicated that discontinuation and non-adherence to nusinersen treatment were prevalent, and associated with greater frequency of comorbidities, greater HCRU, and increased costs for patients.Supplementary InformationThe online version contains supplementary material available at 10.1007/s12325-021-01938-w.

Dosimetric optimization of nuclear medicine therapy based on the Council Directive 2013/59/EURATOM and the Italian law N. 101/2020. Position paper and recommendations by the Italian National Associations of Medical Physics (AIFM) and Nuclear Medicine (AIMN).

This recommendation by the Italian Associations of Nuclear Medicine (AIMN) and Medical Physics (AIFM) focuses on the dosimetric optimization of Nuclear Medicine Therapy (NMT) as clearly requested by the article 56 of the EURATOM Directive 2013/59 and its consequent implementation in article 158 in the Italian Law n. 101/2020. However, this statement must deal with scientific and methodological limits that still exist and, above all, with the currently available limited resources. This paper addresses these specific issues. It distinguishes among many possible kinds of NMT. For each type, dosimetric optimization is recommended or considered optional, according to the general criteria adopted in any human choice, i.e. a check of technical feasibility first, followed by a cost/benefit argument. The classification of therapies as standardized or non-standardized is presented. This is based on the complexity of the type of pathology, on the variability of the treatment outcome, and on the risks involved. According to the present document, which was officially delivered to Italian Health Ministry as necessary interpretation of the law, a therapeutic team can, in science and consciousness, overcome the indications of posology, to optimize and tailoring a treatment with dosimetry, on the basis of published national or international data or guidelines, without need of an Ethics Committee approval. Data collected in this way will provide additional evidence about optimal dosimetric reference values. As conclusion, a formal appeal is made to the European and National regulatory agencies for pharmaceuticals to obtain the official acknowledgment of this principle.

ATENA-A Novel Rapidly Manufactured Medical Invasive Ventilator Designed as a Response to the COVID-19 Pandemic: Testing Protocol, Safety, and Performance Validation.

Background: The urgent need for mechanical ventilators to support respiratory insufficiency due to SARS-CoV-2 led to a worldwide effort to develop low-cost, easily assembled, and locally manufactured ventilators. The ATENA ventilator project was developed in a community-based approach targeting the development, prototyping, testing, and decentralized manufacturing of a new mechanical ventilator.Objective: This article aims to demonstrate ATENA's adequate performance and safety for clinical use.Material: ATENA is a low-cost ventilator that can be rapidly manufactured, easily assembled, and locally produced anywhere in the world. It was developed following the guidelines and requirements provided by European and International Regulatory Authorities (MHRA, ISO 86201) and National Authorities (INFARMED). The device was thoroughly tested using laboratory lung simulators and animal models.Results: The device meets all the regulatory requirements for pandemic ventilators. Additionally, the pre-clinical experiences demonstrated security and adequate ventilation and oxygenation, in vivo.Conclusion: The ATENA ventilator had a good performance in required tests in laboratory scenarios and pre-clinical studies. In a pandemic context, ATENA is perfectly suited for safely treating patients in need of mechanical ventilation.

Clinical Trials Inspections In The European Union

Introduction : The development and authorization of medicinal products are based on an approach, of which an essential part is clinical trials. Clinical trials prove the safety and efficacy of new health technologies and add benefit to real clinical practice. It is crucial in this development to adhere to high ethical and regulatory standards – that clinical trials generate high quality data sufficient to authorize the investigated medicinal product for use. Verification of adherence to these requirements is carried out through audits and inspections, an exclusive right of the regulatory authorities. The aim of this publication is to outline the requirements for clinical trial inspections in the European Union (EU), to study and compare inspection practices of some European regulatory agencies. Materials and methods : This paper is based on the study of specific practices of EU regulatory agencies in conducting inspections to establish compliance with Good Clinical Practice (GCP). The annual reports of the European Medicines Agency (EMA), which summarize the inspections of GCP-inspectors over the last three years, have been examined. As well as guidelines for the preparation and conduct of GCP-inspections issued by EMA and the UK regulator. Results : The decrease in the number of critical non-compliances detected during the GCP-inspections for the period 2016-2018, on the background of increased large and small non-compliances, shows an increase in the level of compliance with the requirements while maintaing depth of inspections. A comparison with the inspections carried out remotely in 2020, due to the COVID-19 pandemic, would reveal whether there are changes in the way inspections are carried out and how any changes affect the discrepancies found. Conclusion : Performing GCP-inspections is one of the most important tools for monitoring the conduct of clinical trials. Following the good practices is essential to ensure that human dignity, patient well-being and data integrity are preserved.

Radiopharmaceutical preparations: what are the legislative differences across Europe?

AbstractObjectivesRadiopharmaceuticals, since the discovery of the first medical application of radioactive isotope, have been essential therapeutics for the diagnosis and treatment of numerous diseases. Since the Directive 2001/83/EC entered in force, European regulatory authorities have established a harmonised framework to set quality requirements for the industrial production of radiopharmaceuticals. However, little is known about the harmonisation of extemporaneous preparation of radiopharmaceutical preparations (EPRPs) among European countries. In this context, this study aims to provide an overview of the national regulatory framework on the production of EPRPs of five European countries (i.e. UK, Spain, France, Germany and Italy).MethodsFive different national regulatory frameworks were compared based on the results of a literature search on electronic databases (i.e. PubMed, Google scholar).Key findingsUnlike industrially produced radiopharmaceuticals, the results highlighted that the regulatory framework on EPRPs is still not fully harmonised at the European level and many provisions are regulated by local national laws. Similarities and differences exist among the European countries, both regarding quality standards and educational courses the operators involved in the preparation of EPRPs have to attend.ConclusionsThe regulatory framework on the EPRPs is still not harmonised at the European level affecting the access to therapies of European citizens who are not equally guaranteed when an extemporaneous radiopharmaceutical has to be prepared to meet their needs.

Pharmacists\u2019 involvement in COVID-19 vaccination across Europe: a situational analysis of current practice and policy

One year since the emergence of the COVID-19 pandemic, rapid response measures have been implemented internationally to mitigate the spread of the virus. Following rapid and successful pre-clinical and human trials, several vaccines have been authorised for use across Europe through the European Medicines Agency and national regulatory authorities. Clinical trials have shown promising results including important reductions in disease severity, hospitalisation and mortality. In order to maximise the public health benefit of available vaccines, there is a pressing need to vaccinate a large proportion of the population. Internationally, this has prompted coordination of existing services at enormous scale, and development and implementation of novel vaccination strategies to ensure maximum inoculation over the shortest possible timeframe. Pharmacists are being promoted as healthcare professionals that enhance roll-out of COVID-19 vaccination programmes. This paper aims to summarise current policy and practice in relation to pharmacists’ involvement in COVID-19 vaccination in 13 countries across Europe.

DIGITALIZATION OF FINANCIAL SERVICES AND CHALLENGES OF ADAPTATION OF CONTROL

Abstract. Recently, we heard much more about digitalization and related processes around the world. In other words, digitalization is already an important part of modern trends. The main aspects of digitalization, digital transformation and its impact on the financial services of the banks have been discussed and analyzed in this article. Along with the effect of digitalization on everyone’s life, the influence on financial services of the banks and on their businesses are also important. It is noted that banks need to make changes in their approaches to financial services, business models and strategies in accordance with the new requirements. The paper also focuses on the start of a new digital age in financial markets and the need for the regulator to adopt a new approach over the course of its existence. Formation of the reality of regulators working with wider companies and areas, the need to analyze the larger databases, the importance of extensive use of digital opportunities for more effective run of their functions have been examined. It is stated that the supervisors should be interested in technological development, take the leadership in its application, have to consider possible development trends, new regulations with financial institutions, as well as large bigtech companies. In this regard, the measures taken by the European regulatory authorities, innovations have been analyzed, as well. Emphasizing the importance of defining a common framework approach by the ECB, aspects of the policy set by national regulators within that framework are examined. The obvious positive advantages of new technological solutions application are also discussed. Thus, possibility of modern technological development to create a fertile ground for concealing a number of criminal acts, such as money laundering, terrorism, fraud and tax evasion is noted.
 Keywords: digitalization, digital transformation, financial supervision, digital finance, financial stability, financial services, risk management.
 JEL Classification G21, O14, K20
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In and out of revolving doors in European Union financial regulatory authorities

AbstractAlthough the idea of revolving doors evokes the dynamic image of moving in and out of public and private sector jobs, most scholars take a static view of the revolving door phenomenon, looking mainly at entrances, sometimes at exits, but almost never at both. This is a serious oversight given that normative concerns about revolving doors turn mainly on assumptions about how individuals become socialized through their multiple interactions working on both sides of the revolving door. Our study seeks to revive a bidirectional picture of revolving doors. To this end, we use financial regulatory politics in the European Union (EU) as our case and a unique dataset of nearly 200 regulators from three EU financial regulatory bodies as of 2018. We first describe the extent to which these multiple movements are happening and, second, we explain differences between those who make zero revolving door movements and those who make multiple movements. Our central argument is that previous job experience in the regulated industry (finance) generates valuable expertise and network ties that in turn lead to more movements. Experience in industries outside of finance, however, diminishes this expertise and loosens network ties and hence leads to fewer movements. Our results support these arguments. We also find those making multiple movements are not in the business of finance (traders or those leading sales or marketing teams) but instead have careers on both sides of the revolving doors focused on law, policy, and government affairs.

Mesenchymal Stromal Cells: Microenvironmental Modulators Become Cell Therapy

An exceptional safety profile has been shown in a large number of clinical trials based on the use of mesenchymal stromal cells (MSCs) that have been performed worldwide. Consequently, MSCs are now approved by regulatory agencies in Europe, Japan, and US as treatment for pediatric Graft-versus-Host Disease and Crohn’s fistular disease. Nevertheless, reliable potency assays to predict MSC immunosuppressive efficacy in the clinical setting are still lacking. We discuss potential mechanisms of action for therapeutic effects of MSC transplantation, discuss experiemental models used to dissect tissue modulating function of MSCs, and propose approaches for identifying MSC functional effects in vivo.

Dianas terapéuticas en el tratamiento de las dislipemias: de las estatinas a los inhibidores de PCSK9. Necesidades no cubiertas

The use of low-density lipoprotein cholesterol (LDLc)-lowering medications has led to a significant reduction of cardiovascular risk in both primary and secondary prevention. Statins represent the cornerstone of lipid-lowering treatment and substantially decreases cardiovascular morbidity and mortality. However, there are still unmet clinical needs in the management of dyslipidaemia. Indeed, it is difficult to achieve LDLc targets in many patients, particularly in those at high/very high cardiovascular risk and in those with very high baseline LDLc concentrations. Moreover, a considerable proportion of patients are unable to tolerate maximum statin doses, mostly due to muscle-related adverse effects. In the present narrative review, a summary is presented on the current knowledge on the effects of the different cholesterol-lowering drugs, including those recently approved by European and American regulatory agencies, on lipid profile, and on cardiovascular risk. Since difficult-to-treat patients may benefit from new combination therapies as a result of the emergence of new drugs with clinical evidence, updates of the clinical guidelines would be recommended.

Excipients in the Paediatric Population: A Review.

This theoretical study seeks to critically review the use of excipients in the paediatric population. This study is based on the rules and recommendations of European and American drug regulatory agencies. On the one hand, this review describes the most frequent excipients used in paediatric medicine formulations, identifying the compounds that scientific literature has marked as potentially harmful regarding the side effects generated after exposure. On the other hand, this review also highlights the importance of carrying out safety -checks on the excipients, which, in most cases, are linked to toxicity studies. An excipient in the compilation of paediatric population databases is expected to target safety and toxicity, as in the STEP database. Finally, a promising pharmaceutical form for child population, ODT (Orally Disintegrating Tablets), will be studied.