Standardised and Reproducible Phenotyping Using Distributed Analytics and Tools in the Data Analysis and Real World Interrogation Network (DARWIN EU).

Purpose: The generation of representative disease phenotypes is important for ensuring the reliability of the findings of observational studies. The aim of this manuscript is to outline a reproducible framework for reliable and traceable phenotype generation based on real world data for use in the Data Analysis and Real-World Interrogation Network (DARWIN EU). We illustrate the use of this framework by generating phenotypes for two diseases: pancreatic cancer and systemic lupus erythematosus (SLE).

Real-World Evidence to Support EU Regulatory Decision Making-Results From a Pilot of Regulatory Use Cases.

Studies using real-world data (RWD) can complement evidence from clinical trials and fill evidence gaps during different stages of a medicine's lifecycle. This review presents the experience resulting from the European Medicines Agency (EMA) pilot to generate RWE to support evaluations by EU regulators and down-stream decision makers from September 2021 to February 2023. A total of 61 research topics were identified for RWE generation during this period, covering a wide range of research questions, primarily generating evidence on medicines safety (22, 36%), followed by questions on the design and feasibility of clinical trials (11, 18%), drug utilization (10, 16%), clinical management (10, 16%), and disease epidemiology.

Is There an Increased Risk of Hepatotoxicity with Metamizole? A Comparative Cohort Study in Incident Users.

Introduction: The analgesic metamizole, which has been withdrawn from the market in several countries due to the risk of agranulocytosis but is still available on the market in Germany and some other countries, has been associated with liver injury in published case reports; however, epidemiological studies on the risk of liver injury are limited.

Objective: The aim of this study was to compare the risk of liver injury up to 270 days after the first start of treatment with metamizole with the corresponding risk in patients starting treatment with paracetamol, using a retrospective cohort incident user design.

Methods: The first prescription for either metamizole or paracetamol in the Intercontinental Medical Statistics (IMS) Disease Analyzer Germany database during the study period (2009-2018) was identified in patients with at least 365 days of observation and no prior diagnosis of liver events, cancer or HIV, or treatment within the last 6 months with hepatotoxic drugs typically administered for chronic conditions.

Different Strategies to Execute Multi-Database Studies for Medicines Surveillance in Real-World Setting: A Reflection on the European Model.

Although postmarketing studies conducted in population-based databases often contain information on patients in the order of millions, they can still be underpowered if outcomes or exposure of interest is rare, or the interest is in subgroup effects. Combining several databases might provide the statistical power needed. A multi-database study (MDS) uses at least two healthcare databases, which are not linked with each other at an individual person level, with analyses carried out in parallel across each database applying a common study protocol.

Association between hydrochlorothiazide exposure and different incident skin, lip and oral cavity cancers: A series of population-based nested case-control studies.

Aims: Hydrochlorothiazide-induced photosensitivity may increase squamous cell carcinoma (SCC), basal cell carcinoma (BCC) and lip cancer risk. The aim was to quantify these risks.

Methods: Nested case-control studies using data from the UK THIN database from 01 January 1999 to 01 May 2016.

Ability of Primary Care Health Databases to Assess Medicinal Products Discussed by the European Union Pharmacovigilance Risk Assessment Committee.

This study measured the exposure to different categories of medicinal products discussed by the European Union (EU) Pharmacovigilance Risk Assessment Committee from September to November 2018 in four electronic primary care health databases: IQVIA Medical Research Data-UK, IQVIA Medical Research Data-France, IQVIA Medical Research Data-Germany, and Clinical Practice Research Datalink Aurum, in the entire lifespan of each database until August 31, 2018. The assessment of 83 centrally authorized products and 45 nationally authorized products showed that coverage was better for products marketed for longer duration and worse for orphan drugs. The ability to detect associations against hypothetical comparators was better for more common events and for larger effect sizes.

Exploratory Study of Signals for Asthma Drugs in Children, Using the EudraVigilance Database of Spontaneous Reports.

Introduction: As asthma medications are frequently prescribed for children, knowledge of the safety of these drugs in the paediatric population is important. Although spontaneous reports cannot be used to prove causality of adverse events, they are important in the detection of safety signals.

Objective: Our objective was to provide an overview of adverse drug events associated with asthma medications in children from a spontaneous reports database and to identify new signals.

Association Between Peripheral Neuropathy and Exposure to Oral Fluoroquinolone or Amoxicillin-Clavulanate Therapy.

Importance: Peripheral neuropathy has been associated with systemic fluoroquinolone exposure, but risk has been poorly quantified.

Objective: To calculate relative and absolute risk estimates for the association of fluoroquinolone exposure with peripheral neuropathy and to examine how risk may be affected by timing of fluoroquinolone exposure and by other risk factors.

Design, Setting, And Participants: This nested case-control study used anonymized data from all patients routinely registered with general practices in The Health Improvement Network database, a large primary care population database in the United Kingdom, from January 1, 1999, to December 31, 2015.

Correction to: Relative and Absolute Risk of Tendon Rupture with Fluoroquinolone and Concomitant Fluoroquinolone/Corticosteroid Therapy: Population-Based Nested Case-Control Study.

The article Relative and Absolute Risk of Tendon Rupture with Fluoroquinolone and Concomitant Fluoroquinolone/Corticosteroid Therapy: Population-Based Nested Case-Control Study, written by Morales DR, Slattery J, Pacurariu A, Pinheiro L, McGettigan P, Kurz X, was originally published Online First without open access.

Relative and Absolute Risk of Tendon Rupture with Fluoroquinolone and Concomitant Fluoroquinolone/Corticosteroid Therapy: Population-Based Nested Case-Control Study.

Background And Objective: Tendon rupture can result from fluoroquinolone exposure. The objective of this study was to quantify relative and absolute risk and determine how risk is affected by timing of exposure.

Methods: The UK Health Improvement Network primary care database was used to perform a nested case-control study measuring the association between fluoroquinolone exposure and tendon rupture.

Electronic healthcare databases in Europe: descriptive analysis of characteristics and potential for use in medicines regulation.

Objective: Electronic healthcare databases (EHDs) are useful tools for drug development and safety evaluation but their heterogeneity of structure, validity and access across Europe complicates the conduct of multidatabase studies. In this paper, we provide insight into available EHDs to support regulatory decisions on medicines.

Methods: EHDs were identified from publicly available information from the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance resources database, textbooks and web-based searches.

Masking by vaccines in pediatric drug safety signal detection in the EudraVigilance database.

Purpose: Postmarketing drug safety surveillance relies upon measures of disproportionate reporting in spontaneous reporting systems. It has been hypothesized that products or events reported frequently may "mask" signals.

Methods: We analyzed the masking effect of vaccines in pediatrics in the EudraVigilance database by conducting disproportionality analysis in the full database (containing vaccine exposures) and in a restricted set (excluding vaccine exposures).

EU-funded initiatives for real world evidence: descriptive analysis of their characteristics and relevance for regulatory decision-making.

Introduction: A review of European Union (EU)-funded initiatives linked to 'Real World Evidence' (RWE) was performed to determine whether their outputs could be used for the generation of real-world data able to support the European Medicines Agency (EMA)'s regulatory decision-making on medicines.

Method: The initiatives were identified from publicly available websites. Their topics were categorised into five areas: 'Data source', 'Methodology', 'Governance model', 'Analytical model' and 'Infrastructure'.

Characteristics of drugs safety signals that predict safety related product information update.

Purpose: Investigation of drug safety signals is one of the major tasks in pharmacovigilance. Among many potential signals identified, only a few reflect adverse drug reactions requiring regulatory actions, such as product information (PI) update. Limited information is available regarding the signal characteristics that might predict PI update following signal evaluation.

Impact of different assumptions on estimates of childhood diseases obtained from health care data: A retrospective cohort study.

Purpose: Accurate estimates of disease incidence in children are required to support pediatric drug development. Analysis of electronic health care records (EHR) may yield such estimates but pediatric-specific methods are lacking. We aimed to understand the impact of assumptions regarding duration of disease episode and length of run-in period on incidence estimates from EHRs.

Is patient exposure preapproval and postapproval a determinant of the timing and frequency of occurrence of safety issues?

Background: The amount of drug exposure, pre and post approval, is considered to be a direct determinant of knowledge about the safety of a drug. A larger pre-approval exposed population is supposed to reduce the risk of unanticipated safety issues post-approval. The amount of use in the postapproval population is also expected to influence the occurrence and timing of safety issues.

Measuring the impact of medicines regulatory interventions - Systematic review and methodological considerations.

Aims: Evaluating the public health impact of regulatory interventions is important but there is currently no common methodological approach to guide this evaluation. This systematic review provides a descriptive overview of the analytical methods for impact research.

Methods: We searched MEDLINE and EMBASE for articles with an empirical analysis evaluating the impact of European Union or non-European Union regulatory actions to safeguard public health published until March 2017.

Decision making in drug safety-a literature review of criteria used to prioritize newly detected safety issues.

Purpose: In drug safety, there is a lack of guidance on how prioritization of safety issues should be performed. The aim of this literature review is to provide an overview of criteria used for signal prioritization and of the associated decision support frameworks.

Methods: A search strategy was constructed to identify relevant articles in Medline/Embase databases from the period from 1 January 1995 to 31 August 2015.

Patterns of spontaneous reports on narcolepsy following administration of pandemic influenza vaccine; a case series of individual case safety reports in Eudravigilance.

Objective: This study aims to describe the frequency and quality of spontaneous narcolepsy case reports following administration of pandemic influenza vaccine as captured in the Eudravigilance database.

Methods: We conducted a retrospective descriptive study of spontaneous Individual Case Safety Reports (ICSRs), reporting narcolepsy following administration of pandemic influenza vaccine as received by Eudravigilance until July 2014. De-duplication was carried out by Eudravigilance.

Pharmacoepidemiological safety studies in children: a systematic review.

Purpose: In order to identify challenges in pediatric pharmacoepidemiological safety studies, we assessed the characteristics of such (published) studies.

Methods: Relevant articles from inception to 2013 were retrieved from Embase and Medline. We sequentially screened titles, abstracts and full texts with independent validation.

Drug Safety Monitoring in Children: Performance of Signal Detection Algorithms and Impact of Age Stratification.

Introduction: Spontaneous reports of suspected adverse drug reactions (ADRs) can be analyzed to yield additional drug safety evidence for the pediatric population. Signal detection algorithms (SDAs) are required for these analyses; however, the performance of SDAs in the pediatric population specifically is unknown. We tested the performance of two SDAs on pediatric data from the US FDA Adverse Event Reporting System (FAERS) and investigated the impact of age stratification and age adjustment on the performance of SDAs.

Useful Interplay Between Spontaneous ADR Reports and Electronic Healthcare Records in Signal Detection.

Background And Objective: Spontaneous reporting systems (SRSs) remain the cornerstone of post-marketing drug safety surveillance despite their well-known limitations. Judicious use of other available data sources is essential to enable better detection, strengthening and validation of signals. In this study, we investigated the potential of electronic healthcare records (EHRs) to be used alongside an SRS as an independent system, with the aim of improving signal detection.