Metadata for Data dIscoverability aNd Study rEplicability in obseRVAtional Studies (MINERVA): Development and Pilot of a Metadata List and Catalogue in Europe.

Purpose: Metadata for data dIscoverability aNd study rEplicability in obseRVAtional studies (MINERVA), a European Medicines Agency-funded project (EUPAS39322), defined a set of metadata to describe real-world data sources (RWDSs) and piloted metadata collection in a prototype catalogue to assist investigators from data source discoverability through study conduct.

Methods: A list of metadata was created from a review of existing metadata catalogues and recommendations, structured interviews, a stakeholder survey, and a technical workshop. The prototype was designed to comply with the FAIR principles (findable, accessible, interoperable, reusable), using MOLGENIS software.

Lessons learned from a multi-data source research collaboration: The mirabegron post-authorization safety study program.

Background: Many factors contribute to developing and conducting a successful multi-data source, non-interventional, post-authorization safety study (NI-PASS) for submission to multiple health authorities. Such studies are often large undertakings; evaluating and sharing lessons learned can provide useful insights to others considering similar studies.

Objectives: We discuss challenges and key methodological and organizational factors that led to the delivery of a successful post-marketing requirement (PMR)/PASS program investigating the risk of cardiovascular and cancer events among users of mirabegron, an oral medication for the treatment of overactive bladder.

Liver, renal, genitourinary and diabetic ketoacidosis risks among new users of empagliflozin versus dipeptidyl peptidase-4 inhibitors in patients with type 2 diabetes: Post-authorization safety study based on multinational cohorts.

Aim: To estimate risks of diabetic ketoacidosis (DKA), acute liver injury (ALI), acute kidney injury (AKI), chronic kidney disease (CKD), severe complications of urinary tract infection (UTI) and genital infection (GI) among patients with type 2 diabetes initiating empagliflozin versus those initiating a dipeptidyl peptidase-4 (DPP-4) inhibitor.

Materials And Methods: In this large multinational, observational, new-user cohort study in UK, Danish and US healthcare data sources, patients initiated empagliflozin or a DPP-4 inhibitor between August 2014 and August 2019, were aged ≥18 years, and had ≥12 months' continuous health plan enrolment. Incidence rates by exposure and incidence rate ratios, adjusted for propensity-score deciles, were calculated.

HARmonized Protocol Template to Enhance Reproducibility of Hypothesis Evaluating Real-World Evidence Studies on Treatment Effects: A Good Practices Report of a Joint ISPE/ISPOR Task Force.

Objectives: Ambiguity in communication of key study parameters limits the utility of real-world evidence (RWE) studies in healthcare decision-making. Clear communication about data provenance, design, analysis, and implementation is needed. This would facilitate reproducibility, replication in independent data, and assessment of potential sources of bias.

HARmonized Protocol Template to Enhance Reproducibility of hypothesis evaluating real-world evidence studies on treatment effects: A good practices report of a joint ISPE/ISPOR task force.

Problem: Ambiguity in communication of key study parameters limits the utility of real-world evidence (RWE) studies in healthcare decision-making. Clear communication about data provenance, design, analysis, and implementation is needed. This would facilitate reproducibility, replication in independent data, and assessment of potential sources of bias.

Risk Assessment of Acute Myocardial Infarction and Stroke Associated with Long-Acting Muscarinic Antagonists, Alone or in Combination, versus Long-Acting beta2-Agonists.

Background: The long-acting muscarinic antagonist (LAMA) aclidinium was approved in Europe in 2012 to relieve symptoms in adult patients with chronic obstructive pulmonary disease (COPD). A post-authorization safety study was initiated to assess potential cardiovascular risks associated with LAMAs versus long-acting beta2-agonists.

Purpose: To estimate incidence rates and adjusted incidence rate ratios (IRRs) for acute myocardial infarction (AMI), stroke, and major adverse cardiac events (MACE) in new users of aclidinium, aclidinium/formoterol, tiotropium, other LAMA, long-acting beta-agonists/inhaled corticosteroids (LABA/ICS), and LAMA/LABA compared with initiators of LABA.

Incidence of Acute Renal Failure in Patients Using Levetiracetam Versus Other Antiseizure Medications: A Voluntary Post-Authorization Safety Study.

Introduction: Acute kidney injury is an expected adverse drug reaction listed in the European Union (EU) Summary of Product Characteristics (SmPC) for levetiracetam, one of the most widely used modern antiseizure medications (ASMs).

Objective: We conducted a voluntary post-authorization safety study to characterize the rate of acute renal failure (ARF) in patients exposed to levetiracetam versus other ASMs.

Methods: New users of ASMs without prior renal dysfunction were identified and followed for 30 days in the IBM MarketScan database (USA, January 2008-December 2017).

Characteristics of New Users of Aclidinium Bromide, Aclidinium/Formoterol, and Other COPD Medications in the United Kingdom, Denmark, and Germany.

Background And Objectives: Aclidinium bromide was approved in the European Union for the treatment of chronic obstructive pulmonary disease (COPD) in adult patients in 2012 and in a fixed-dose combination with formoterol in 2014. We characterised new users of aclidinium, aclidinium/formoterol and other COPD medications and evaluated off-label prescribing of these medications in three European populations.

Methods: We described demographic characteristics, comorbidities, comedications, COPD severity and off-label prescribing of new users of aclidinium, aclidinium/formoterol and other COPD medications in patients with COPD aged ≥ 40 years in the Clinical Practice Research Datalink (CPRD, UK), Danish National Health Databases, and German Pharmacoepidemiological Research Database (GePaRD) between 2015 and 2017.

Long-Term Risk of Skin Cancer and Lymphoma in Users of Topical Tacrolimus and Pimecrolimus: Final Results from the Extension of the Cohort Study Protopic Joint European Longitudinal Lymphoma and Skin Cancer Evaluation (JOELLE).

Purpose: Evidence is insufficient to infer whether topical calcineurin inhibitors (TCIs; tacrolimus and pimecrolimus) cause malignancy. The study objective was to estimate the long-term risk of skin cancer and lymphoma associated with topical TCI use in adults and children, separately.

Patients And Methods: A cohort study in Denmark, Sweden, UK, and the Netherlands was conducted.

Cardiovascular Risk in Users of Mirabegron Compared with Users of Antimuscarinic Treatments for Overactive Bladder: Findings from a Non-Interventional, Multinational, Cohort Study.

Introduction: During clinical trials, mirabegron, a β3-adrenoreceptor agonist, was associated with increased vital signs vs placebo in patients with overactive bladder.

Objective: The purpose of this study was to compare incidence rates of adverse cardiovascular (CV) outcomes following mirabegron or antimuscarinic use.

Methods: We conducted an observational post-marketing safety study utilising real-world data.

Use of intravenous iron and risk of anaphylaxis: A multinational observational post-authorisation safety study in Europe.

Purpose: This post-authorisation safety study estimated the risk of anaphylaxis in patients receiving intravenous (IV) iron in Europe, with interest in iron dextran and iron non-dextrans. Studies conducted in the United States have reported risk of anaphylaxis to IV iron ranging from 2.0 to 6.

A Cohort Study to Evaluate the Risk of Hospitalisation for Congestive Heart Failure Associated with the Use of Aclidinium and Other Chronic Obstructive Pulmonary Disease Medications in the UK Clinical Practice Research Datalink.

Background: The long-acting anticholinergic (LAMA) aclidinium was approved in Europe in 2012 to relieve symptoms in adults with chronic obstructive pulmonary disease (COPD). A Post-Authorisation Safety Study (PASS) was initiated to assess potential cardiovascular safety concerns for aclidinium.

Objective: To estimate the adjusted incidence rate ratio (IRR) for hospitalisation for heart failure in patients with COPD who were new users of aclidinium, tiotropium, other LAMA, long-acting beta-agonists/inhaled corticosteroids (LABA/ICS), and LAMA/LABA were compared with initiators of LABA.

A study of cancer occurrence in users of mirabegron and antimuscarinic treatments for overactive bladder.

Objective: This post-authorization safety study (EU PAS Register Number: EUPAS16088) was designed to compare the incidence of cancer outcomes in patients treated with mirabegron versus antimuscarinic medications.

Methods: Cohorts of mirabegron initiators during 2012-2018 were propensity-score matched to antimuscarinic medication initiators within real-world data sources (Danish National Registers, Swedish National Registers, Clinical Practice Research Datalink [UK], Optum [US], and Humana [US]). Incident cancer cases were identified during follow-up from direct linkage to cancer registers or validated through medical record review or through physician questionnaires.

Validation of cardiovascular outcomes and risk factors in the Clinical Practice Research Datalink in the United Kingdom.

Purpose: Strategies to identify and validate acute myocardial infarction (AMI) and stroke in primary-care electronic records may impact effect measures, but to an unknown extent. Additionally, the validity of cardiovascular risk factors that could act as confounders in studies on those endpoints has not been thoroughly assessed in the United Kingdom Clinical Practice Research Datalink's (CPRD's) GOLD database. We explored the validity of algorithms to identify cardiovascular outcomes and risk factors and evaluated different outcome-identification strategies using these algorithms for estimation of adjusted incidence rate ratios (IRRs).

Agomelatine Drug Utilisation Study in Selected European Countries: A Multinational, Observational Study to Assess Effectiveness of Risk-Minimisation Measures.

Background: Hepatotoxic reactions are an important identified risk listed in the agomelatine risk management plan. This post-authorisation safety study evaluated the effectiveness of additional risk-minimisation measures (aRMMs) for agomelatine.

Objective: The objective of this study was to evaluate, among physicians prescribing agomelatine and their patients, liver function monitoring adherence, compliance with contraindications and patients' reasons for non-compliance with liver monitoring.

Validity of hospital ICD-10-GM codes to identify acute liver injury in Germany.

Purpose: Acute liver injury (ALI) is an important adverse drug reaction. We estimated the positive predictive values (PPVs) of ICD-10-GM codes of ALI used in an international postauthorisation safety study (PASS).

Methods: Analyses used routine data (2007 to 2016, adults) from a German academic hospital in a cross-sectional design.

Validity of ICD-9 and ICD-10 codes used to identify acute liver injury: A study in three European data sources.

Purpose: Validating cases of acute liver injury (ALI) in health care data sources is challenging. Previous validation studies reported low positive predictive values (PPVs).

Methods: Case validation was undertaken in a study conducted from 2009 to 2014 assessing the risk of ALI in antidepressants users in databases in Spain (EpiChron and SIDIAP) and the Danish National Health Registers.

Use of aclidinium did not increase the risk of death in a noninterventional cohort study in the Clinical Practice Research Datalink (CPRD), United Kingdom.

Background: Aclidinium bromide is an inhaled long-acting muscarinic antagonist (LAMA). Although the initial potential increased cardiovascular and mortality risk among users of tiotropium has been ruled out by several observational studies, and clinical trials, there are still concerns related to the use of newer LAMA medications. The current study aimed to evaluate the risk of death among users of aclidinium and other LAMAs.

Risk of Acute Liver Injury in Agomelatine and Other Antidepressant Users in Four European Countries: A Cohort and Nested Case-Control Study Using Automated Health Data Sources.

Background: Agomelatine is a melatonin receptor agonist and serotonin 5-HT receptor antagonist indicated for depression in adults. Hepatotoxic reactions like acute liver injury (ALI) are an identified risk in the European risk management plan for agomelatine. Hepatotoxic reactions have been reported for other antidepressants, but population studies quantifying these risks are scarce.

Antidepressant use in Denmark, Germany, Spain, and Sweden between 2009 and 2014: Incidence and comorbidities of antidepressant initiators.

Background: We aimed to describe patterns of use and characteristics of 10 commonly used antidepressants for the period 2009-2014 in Denmark, Germany, Spain, and Sweden.

Methods: Adult initiators from 2009 to 2014 of each study antidepressant were identified in four countries using five data sources: the Danish National registers, GePaRD (Germany), EpiChron (Aragon, Spain), SIDIAP (Catalonia, Spain), and the Swedish National Registers. The study included 10 study antidepressants: citalopram, escitalopram, fluoxetine, paroxetine, sertraline, duloxetine, venlafaxine, amitriptyline, mirtazapine, and agomelatine.

Risk of acute myocardial infarction during use of individual NSAIDs: A nested case-control study from the SOS project.

Background: Use of selective COX-2 non-steroidal anti-inflammatory drugs (NSAIDs) (coxibs) has been associated with an increased risk of acute myocardial infarction (AMI). However, the risk of AMI has only been studied for very few NSAIDs that are frequently used.

Objectives: To estimate the risk of AMI for individual NSAIDs.

Patterns of use of antimuscarinic drugs to treat overactive bladder in Denmark, Sweden, and the United Kingdom.

Purpose: To describe the use of antimuscarinic drugs to treat overactive bladder (OAB) in Denmark, Sweden, and the United Kingdom (UK).

Methods: We identified new users of darifenacin, fesoterodine, oxybutynin, solifenacin, tolterodine, and trospium aged 18 years or older from the Danish National Registers (2004-2012), the Swedish National Registers (2006-2012), and UK Clinical Practice Research Datalink (2004-2012). Users were followed until disenrollment, cancer diagnosis, death, or study end.

Effectiveness of risk minimization measures for the use of cilostazol in United Kingdom, Spain, Sweden, and Germany.

Purpose: The purpose of the study is to evaluate the effectiveness of risk minimization measures-labeling changes and communication to health care professionals-recommended by the European Medicines Agency for use of cilostazol for the treatment of intermittent claudication in Europe.

Methods: Observational study of cilostazol in The Health Improvement Network (United Kingdom), EpiChron Cohort (Spain), SIDIAP (Spain), Swedish National Databases, and GePaRD (Germany). Among new users of cilostazol, we compared the prevalence of conditions targeted by the risk minimization measures in the periods before (2002-2012) and after (2014) implementation.