Challenges in the Implementation of EU Risk Minimisation Measures for Medicinal Products in Clinical Practice Guidelines: Mixed Methods Multi-Case Study.

Introduction: Risk minimisation measures (RMMs) aim to ensure safe use of medicines, but their implementation in clinical practice is complicated by the diversity of stakeholders whose clinical decision making they seek to inform. Clinical practice guidelines (CPGs) are considered integral in clinical decision making.

Objectives: To determine the extent to which RMMs are included in the relevant CPGs and to describe factors that determine RMM inclusion.

Analytical Methods for Comparing Uncontrolled Trials With External Controls From Real-World Data: A Systematic Literature Review and Comparison With European Regulatory and Health Technology Assessment Practice.

Objectives: This study aimed to provide an overview of analytical methods in scientific literature for comparing uncontrolled medicine trials with external controls from individual patient data real-world data (IPD-RWD) and to compare these methods with recommendations made in guidelines from European regulatory and health technology assessment (HTA) organizations and with their evaluations described in assessment reports.

Methods: A systematic literature review (until March 1, 2023) in PubMed and Connected Papers was performed to identify analytical methods for comparing uncontrolled trials with external controls from IPD-RWD. These methods were compared descriptively with methods recommended in method guidelines and encountered in assessment reports of the European Medicines Agency (2015-2020) and 4 European HTA organizations (2015-2023).

Use of antibiotics in the early COVID-19 pandemic in Poland, the Netherlands and Spain, from erraticism to (more) logic.

Introduction: In the Spring of 2020, the world was hit with unparalleled impact by the coronavirus pandemic. Antibiotics were widely used, even without good rationale. The aim of our study was to compare the use of antibiotics in patients with confirmed COVID-19 from three hospitals across Europe (Poland, the Netherlands and Spain) between two subsequent periods in the early days of the pandemic.

Limitations Reported in Evaluating Effectiveness of Risk Minimization Measures in the EU during 2018-2021: A Qualitative Analysis of Industry-Sponsored Post-Authorization Safety Studies.

Marketing-authorization holders evaluate the effectiveness of risk minimization measures (RMM) for medicines through the conduct of post-authorization safety studies (PASS). Earlier studies show that concluding on RMM effectiveness is challenging. The aim of this study was to describe reported limitations associated with RMM effectiveness assessments of industry-sponsored PASS that did not render a conclusion.

[Risk minimalisation measures for medications; are they incorporated in Dutch clinical guidelines?].

Objective: Risk minimisation measures (RMM) are put in place to ensure safe and effective use of medicines. This study assessed whether RMM for five medicines are implemented in Dutch clinical guidelines.

Design: Descriptive study.

Real-World Evidence to Inform Regulatory Decision Making: A Scoping Review.

Real-world evidence (RWE) is increasingly considered in regulatory decision making. When, and to which extent, RWE is considered relevant by regulators likely depends on many factors. This review aimed to identify factors that make RWE necessary or desirable to inform regulatory decision making.

Which Benefits Can Justify Risks in Research?

Research ethics committees (RECs) evaluate whether the risk-benefit ratio of a study is acceptable. Decentralized clinical trials (DCTs) are a novel approach for conducting clinical trials that potentially bring important benefits for research, including several collateral benefits. The position of collateral benefits in risk-benefit assessments is currently unclear.

Opportunities and Challenges for Decentralized Clinical Trial Approaches: European Health Technology Assessment Perspective.

Objectives: Decentralized clinical trial (DCT) approaches are clinical trials in which some or all trial activities take place closer to participants' proximities instead of a traditional investigative site. Data from DCTs may be used for clinical and economic evaluations by health technology assessment (HTA) bodies to support reimbursement decision making. This study aimed to explore the opportunities and challenges for DCT approaches from an HTA perspective by interviewing representatives from European HTA bodies.

Discontinuation of infliximab treatment in patients with inflammatory bowel disease who retransitioned to originator and those who remained on biosimilar.

Background: Many patients with inflammatory bowel disease (IBD) have transitioned from an infliximab originator to a biosimilar. However, some patients retransition to the originator (i.e.

Duration of Effectiveness Evaluation of Additional Risk Minimisation Measures for Centrally Authorised Medicinal Products in the EU Between 2012 and 2021.

Introduction: In studies evaluating the effectiveness of additional risk minimisation measures (aRMMs), the need for speed must be properly balanced with the quality of the study. We assessed the duration of aRMM effectiveness evaluations, using additional pharmacovigilance activities, for centrally authorised medicinal products in the European Union.

Methods: We established a cohort of medicinal products with aRMMs at marketing authorisation (MA) that were centrally authorised from July 2012-December 2021 using the European Public Assessment Reports.

Review of Studies Evaluating Effectiveness of Risk Minimization Measures Assessed by the European Medicines Agency Between 2016 and 2021.

The European Medicines Agency (EMA) supervises medicines' safe and effective use throughout the product's life cycle by, for example, monitoring the implementation of risk minimization measures (RMMs). Limited information is available on factors associated with effectiveness of RMMs. This study reviews post-authorization safety studies (PASS) evaluating the effectiveness of RMMs assessed by the Pharmacovigilance Risk Assessment Committee (PRAC) between 2016 and 2021.

Impact of a Treatment Guide on Intravenous Fluids in Minimising the Risk of Hospital-Acquired Hyponatraemia in Denmark.

Hypotonic intravenous (IV) fluids are associated with an increased risk of hospital-acquired hyponatraemia, eventually leading to brain injury and death. We evaluated the effectiveness of a treatment guide to improve prescribing practices of IV fluids. We conducted a before-and-after cross-sectional survey among physicians working at Danish emergency departments.

Unintended impact of pharmacovigilance regulatory interventions: A systematic review.

Aims: Studies assessing the impact of pharmacovigilance regulatory interventions often focus on the expected (or intended) outcomes, while any possible unintended impact may be overlooked. The update of the Good Pharmacovigilance Practice guideline in 2017 elaborated on impact assessment, emphasizing the need also to assess possible unintended impact. This systematic literature review investigated how often the unintended impact of regulatory interventions was considered in publications of studies investigating pharmacovigilance regulatory interventions in Europe.

Post-approval quality-related regulatory actions for biopharmaceuticals approved in the European Union and the United States between 1995 and 2019.

The quality of biopharmaceuticals is carefully monitored by manufacturers and regulators to ensure safety and efficacy throughout the entire product life cycle. Quality defects can lead to post-approval regulatory actions (RAs) to inform healthcare professionals (HCPs). The present study identified quality-related RAs for biopharmaceuticals approved in the European Union and United States between 1995 and 2019.

Direct-to-participant investigational medicinal product supply in clinical trials in Europe: Exploring the experiences of sponsors, site staff and couriers.

Aims: Insights into the current practice of direct-to-participant (DtP) supply of investigational medicinal product (IMP) in the context of clinical trials conducted in Europe are needed, as regulations are unharmonized. This study is set out to explore how DtP IMP supply has been employed in Europe and what the advantages and disadvantages and barriers and facilitators of its implementation are.

Methods: We conducted semi-structured interviews with representatives from sponsor companies, courier services and site study staff involved in the IMP dispensing and delivery process in Europe.

Impact of 2018 EU Risk Minimisation Measures and Revised Pregnancy Prevention Programme on Utilisation and Prescribing Trends of Medicinal Products Containing Valproate: An Interrupted Time Series Study.

Introduction: Due to established teratogenicity of valproates, the EU risk minimisation measures (RMMs) with a pregnancy prevention programme (PPP) for valproate were updated in March 2018.

Objectives: To investigate the effectiveness of the 2018 EU RMMs on valproate utilisation in five European countries/regions.

Methods: A multi-database, times series study of females of childbearing potential (12-55 years) was conducted using electronic medical records from five countries/regions (01.

The role of Real-World Data and evidence in oncology medicines approved in EU in 2018-2019.

Use of Real-World Data (RWD) has gained the interest of different stakeholders in cancer care. The aim of this study was to identify and describe the use of RWD/RWE during the pre-authorization phase of products authorized by the EMA in 2018 and 2019 (n = 111), with the focus on oncology medicines (n = 24). Information was extracted from the European Public Assessment Report (EPAR) summaries and recorded for 5 stages (11 categories) of the drug development lifecycle (discovery, early development, clinical development, registration/market launch, lifecycle management).

Bias in observational studies on the effectiveness of in hospital use of hydroxychloroquine in COVID-19.

Purpose: During the first waves of the coronavirus pandemic, evidence on potential effective treatments was urgently needed. Results from observational studies on the effectiveness of hydroxychloroquine (HCQ) were conflicting, potentially due to biases. We aimed to assess the quality of observational studies on HCQ and its relation to effect sizes.

Suspected adverse reactions reported for blood, blood components, and blood products in VigiBase.

Introduction: Since being designated as medicines by World Health Organization (WHO), blood components are subject to pharmacovigilance reporting. Using VigiBase, the WHO global database of individual case safety reports (ICSRs), we characterized reports of adverse reactions for all blood products.

Study Design And Methods: ICSRs involving blood products as the suspected medicine in VigiBase between 1968 and 2021 were extracted.

Recommendations on TNFα inhibitor biosimilar use in clinical practice: a comparison of European gastroenterology IBD guidance.

Background: Professional associations publish guidance advising gastroenterologists on prescribing biosimilars; however, guidelines differ between countries and change over time. This study aimed to map the presence and content of guidance from European gastroenterology associations on TNFα inhibitor biosimilar use and its development over time.

Research Design And Methods: Guidelines on biosimilar prescribing from national gastroenterology associations in the European Economic Area (EEA) partnered with the European Crohn's and Colitis Organization (ECCO) were collected.

Tell me what you want, what you really really want: Estimands in observational pharmacoepidemiologic comparative effectiveness and safety studies.

Purpose: Ideally, the objectives of a pharmacoepidemiologic comparative effectiveness or safety study should dictate its design and data analysis. This paper discusses how defining an estimand is instrumental to this process.

Methods: We applied the ICH-E9 (Statistical Principles for Clinical Trials) R1 addendum on estimands - which originally focused on randomized trials - to three examples of observational pharmacoepidemiologic comparative effectiveness and safety studies.

Prescribing of low-dose rivaroxaban in patients with atherosclerotic cardiovascular disease in the United Kingdom and the Netherlands.

Aims: Low-dose rivaroxaban has been indicated for the management of atherosclerotic cardiovascular disease (ASCVD) after recent (2019-2020) updates to European guidelines. We aimed to describe prescription trends of low-dose rivaroxaban in ASCVD patients over the period 2015-2022 in two European countries, to compare the trends before and after guideline changes, and to determine the characteristics of users.

Methods: In a cross-sectional interrupted time series analysis, utilization of low-dose rivaroxaban (2.