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Abaloparatide is associated with transient increases in heart rate. These transient increases in heart rate were not associated with an increased number of major adverse CV events (MACE) or arrhythmias, neither in the clinical developmental program, nor in the retrospective observational cohort study (BA058-05-028), nor from the five and half years of post-marketing experience in the United States.
The transient increase in heart rate associated with abaloparatide, CV events of MI, stroke and arrhythmia are identified as potential safety risks in the European Union (EU)-Risk Management Plan (RMP) for abaloparatide. Therefore, to further evaluate these potential safety risks for abaloparatide, this EU-based post authorisation safety study (PASS) has been planned as an additional pharmacovigilance activity.
Research question and objectives
Research Question: Is the risk of major cardiovascular events (MACE-1 and MACE-2), arrhythmia, and all-cause mortality (including CV death) associated with abaloparatide use in routine clinical practice in Europe not different relative to teriparatide?
The primary objective of this study is to evaluate the risk of CV events of MACE-1 (defined as events of myocardial infarction (MI), stroke, or CV death), potentially associated with the use of abaloparatide, in comparison with the use of teriparatide in routine clinical practice in Europe.
The secondary objectives of this study are to evaluate the risk of MACE-2 (defined as events of MI, stroke, or all-cause mortality including CV death), MI, stroke, CV death, all-cause mortality including CV death, and arrythmia potentially associated with the use of abaloparatide in comparison with the use of teriparatide in routine clinical practice in Europe
Study design
We will perform a European international network cohort study using data mapped to the Observational
Medical Outcomes Partnership (OMOP) Common Data Model (CDM). The study will use a “new users” design and compare new users of abaloparatide to new users of teriparatide. The index date will be defined as the date on which the patient has a first prescription for either abaloparatide or teriparatide during the data identification period.
MODEL DE SOL·LICITUD
2 IMP-126-CT Versió 08
Study population
The study population comprises all women from the 4 participating databases with osteoporosis (OP) who are prescribed abaloparatide or teriparatide medication for the first time (new user) during the data identification period, have been continuously registered in the data source for at least 12 months prior to the index date, and are at least 50 years of age on the date of the first prescription of abaloparatide or teriparatide.
Variables
The medications of interest include abaloparatide (target therapy) and teriparatide (active comparator).
Primary outcome is MACE-1 (first occurrence of MI, stroke, or death due to CV causes). Secondary outcomes are MI, stroke, death due to CV causes, all-cause mortality, MACE-2 (first occurrence of MI, stroke, or death (all-cause including CV death)), and arrhythmia. Other key covariates and potential confounding factors will be identified at index date based on the patients’ records prior to index date, and will include general patient characteristics, CV risk factors, markers of OP severity, use of other medications, and any other predictors of treatment with abaloparatide as described in detail in the study protocol.
Data sources
This study will be conducted using routinely collected data from different data sources. Data from 4 European countries (France, Spain, Italy, and Germany) will provide heterogeneous and representative data on the safety of abaloparatide in Europe. Data from primary care records (Spain and Italy), outpatient records (Germany), and national claims (France) will be used.
Data Analysis
The data identification period will cover from the second quarter (Q2) of 2024 (when abaloparatide is projected to be launched in the first of the participating countries) until the latest data release available in each of the contributing databases. The IRs of CV events of interest for abaloparatide or teriparatide will be calculated. IR and 95% confidence intervals (CIs) of CV events of interest will be calculated for both study drug users using a Poisson model. The CV event rates for each study drug will also be provided stratified by age groups and key CV risk factors. In addition, large-scale propensity scores (PS) will be estimated using Lasso logistic regression, and the resulting PS will be used to match comparable participants. Then, Cox regression models stratified by matched sets will be used to calculate hazard ratio and 95% confidence interval (CI) for each of the study outcomes according to exposure status.
Post-authorization study: ahttps://www.ema.europa.eu/en/medicines/human/EPAR/eladynos

Rationale and background
Depression, self-harm, suicidal ideation, attempt, and suicide are prevalent health conditions causing significant healthcare utilisation, morbidity, and mortality. Safety concerns on the use of medicines in these populations or as causes of these conditions are common. A better understanding on how well data on these areas are captured will be important to inform the feasibility of conducting RWD studies on these populations or their use as outcomes in DARWIN EU® studies, including the potential validity of phenotypes.
Objectives
1. What is the proportion of individuals with the following types of recording in the DARWIN EU® network: suicide (completed), suicide attempt, suicidal ideation, self-harm, depression, symptom measurement data (PHQ9 depression scales), procedures (psychotherapy and electrotherapy), and depression remission
2. To characterise reporting of suicide, suicide attempt, suicidal ideation, self-harm, and depression within the Darwin EU® network in terms of:
a) Median number (and IQR) of suicides, suicide attempts, suicidal ideation, self-harm, depression, symptom measurement, and resolution reporting per individual within the study period.
b) Rates of suicide, suicide attempt, suicidal ideation, self-harm, and depression, symptom measurement, and resolution reporting within the study period and per calendar year.
c) Explore the values of the symptom measurement data
3. What are the characteristics of individuals with records of suicide, suicide attempt, suicidal ideation, self-harm, and depression in terms of demography, use of concomitant medications (antidepressants, antipsychotics, benzodiazepines, antipsychotics, stimulants, hypnotics), comorbidities (schizophrenia, anxiety disorder, substance use disorder, personality disorders), procedures, and lifestyle factors.
Note: SIDIAP can support the achievement of most of the study’s objectives; however, objectives deemed unfeasible due to data limitations will not be executed (for instance, SIDIAP does not capture cause of mortality)
Methods
Study design
• A population-level descriptive epidemiology study will be conducted to address objectives 1, 2b, and 2c.
• An individual-level characterisation study will be conducted to address objectives 2a and 3.
Population
For objective 1, 2b, and 3c, the study population will include all individuals present in the data source during the study period 01/01/2015 to 31/12/2024 (or to the end of available data) and with at least 365 days of data source history prior to index date. For objective 2a and 3, the study population will include individuals with a first occurrence of suicide (completed), suicide attempt, suicide ideation, self-harm, or depression in the study period with at least 365 days of prior observation.
Variables
Outcome:
Suicide (completed), composite suicide-related events (suicide, suicide attempt, suicide ideation, self-harm), composite fatal suicide-related events, composite non-fatal suicide-related events, suicide attempt, suicidal ideation, self-harm, depression, measurement occurrence of Patient Health Questionnaire-9 (PHQ9) depression scale, healthcare referral and hospital admission, electrotherapy, and psychotherapy.
Relevant covariates:
Demographic characteristics, drug prescriptions (antidepressants, antipsychotics, benzodiazepines, stimulants, hypnotics), conditions (schizophrenia, anxiety disorder, substance use disorder, personality disorders), procedures (psychotherapy, electrotherapy), and observation occurrences (smoking, obesity)
Relevant covariates will be considered at any time prior to the index date.
Statistical analysis
Characteristics will be described by means of pre-specified characterisation. Covariates of interest will be reported as counts and proportions. Yearly incidence rates per 100,000 person-years and period prevalence (proportion) of the outcomes will be estimated in the general population, overall and stratified by age categories and sex. Incidence rates will be given together with 95% Poisson confidence intervals. The statistical analyses will be performed based on OMOP CDM mapped data using IncidencePrevalence and CohortCharacteristics R packages.

Eating disorders (ED) are serious mental illnesses that affect millions of people around the world and entail considerable personal, family, and social costs. It is a hidden public health problem with a great population impact, of which the magnitude in our environment and its characteristics are unknown.
This project aims to characterize and determine the magnitude of eating disorders (ED) in Catalonia, and to describe the social inequalities of people diagnosed with ED in primary care or admitted to hospital.
Specific objectives:
1. To estimate the incidence and prevalence of ED in Catalonia among the individuals diagnosed in primary care or admitted to hospital between 2010 and 2024.
2. To examine, sex, age, nationality, rural/urban setting, and socioeconomic inequalities of ED diagnosis in Catalonia among the individuals who visited primary care or were admitted to the hospital between 2010 and 2024.
3. To identify comorbidities and lifestyle factors associated with ED diagnosed in primary care or admitted to the hospital between 2010 and 2024 in Catalonia.
Study design:
We will conduct a population-based cohort study using individual-level routinely collected Electronic Health Records (EHR) obtained from SIDIAP database.
The study will compromise two consecutive parts:
• Population-level cohort study: This part will estimate the incidence and prevalence of ED in the whole cohort and by specific subgroups (objective 1 and 2)
• Patient-level characterisation: This part aims to estimate comorbidities and associated factors among individuals diagnosed with ED (Obejctive 3).
Study period:
The study period will be from 1st of January 2010 until the end of data availability.
Statistical analyses:
We will estimate monthly incidence and prevalence rates with 95% CI of eating disorders over the study period (2010-2023) in the overall population. Incidence and prevalence will be calculated for the overall of ED and separately for each outcome (anorexia nervosa, bulimia nervosa, binge eating disorder, avoidant/restrictive eating disorder and unspecified eating disorders).
We will stratify our analyses on incidence and prevalence by age, sex, nationality, socioeconomic status (MEDEA), residence type (urban / rural) and other somatic comorbidities. Incidence rate ratios (IRR) with 95%CI will be calculated for each subgroup to compare the differences in the incidence of each strata using negative binomial regression models.
We will explore the effects of explanatory variables such other mental conditions diagnosis (neurodevelopmental disorder, alcohol and substance use disorders, mood and anxiety disorders, personality disorders, obsessive compulsive disorder, impulsivity disorders),, obesity, diabetes and lifestyle factors such as smoking and alcohol risk for each ED.
Finally, we will also conduct a large-scale characterization of the ED cohort to identify the medical conditions in the individuals’ history and compared them to a random subsample of individuals in SIDIAP.

Rationale and background
Atogepant is an oral calcitonin gene-related peptide (CGRP) receptor antagonist indicated for the prophylaxis of migraine in adults who have at least 4 migraine days per month. The safety of atogepant in patients with significant cardiovascular (CV) or cerebrovascular (CeV) disease has not been evaluated in clinical trials. The implications of the use of atogepant in this population are unknown, therefore further characterisation in a real-world population is needed.
Research question and objectives
This study aims to evaluate the utilisation and safety of atogepant among patients diagnosed with migraine and significant CV or CeV disease.
The first phase of the study is descriptive and will evaluate the following objectives:
Objective 1: Among patients with migraine and significant CV or CeV disease who initiate atogepant, the first objective is to:
– Describe utilisation of atogepant;
– Describe patient characteristics (including demographics, comorbidities, comedications) at the time of atogepant initiation; and
– Estimate the incidence rate of CV and CeV events after initiating atogepant.
Objective 2: The second objective of this study is to determine the feasibility of a comparative safety study among patients with migraine and significant CV or CeV disease who initiate atogepant compared to a suitable comparator population, including:
– Evaluate proposed comparator population to inform feasibility of a comparative safety study; and – Examine accuracy and completeness of information on potential confounders.
The second phase of the study is comparative and will be conducted if deemed according to the Phase 1 results. The following objective will be investigated:
Objective 3: If feasible, a comparative safety analysis will be conducted to compare the incidence of CV and CeV events among patients with migraine and significant CV or CeV disease who are exposed to atogepant with users of a suitable comparator.
The scope and design of the comparative analysis will be determined as part of the interim report based on the results of the Phase 1 analyses.
Study design
This will be an observational, non-interventional study using data from population-based healthcare databases in four European countries.
Population
The study will include a cohort of all patients diagnosed with migraine with at least one dispensing of atogepant in population-based healthcare databases from four proposed countries in Europe, including Denmark, The Netherlands, Spain, and Sweden. Patients with migraine who initiate treatment with a comparator migraine preventive product during the study period will also be evaluated. The study period will start at the launch date of atogepant in each country (estimated by end of 2024 in all countries). The study population will include patients with migraine and a history of significant CV or CeV disease.
Variables
Exposure
The primary exposure of interest will include treatment with atogepant, defined as at least one dispensing or prescription for atogepant. Exposure to comparator migraine preventive products will be evaluated similarly and defined as at least one dispensing (or prescription) of the comparator. Dispensing data will be prioritised over prescription data, and the latter will be used only if dispensing data is not available or incomplete
Outcomes
The primary outcome is a composite of all CV and CeV events of interest (i.e., nonfatal myocardial infarction [MI], ischaemic heart disease, unstable angina, nonfatal ischaemic stroke, transient ischaemic attack [TIA], coronary revascularisation [percutaneous coronary intervention, coronary artery bypass grafting], and CV or CeV death [includes fatal MI, fatal ischaemic stroke, etc.]). The secondary outcomes are: nonfatal CV events (i.e., nonfatal MI, ischaemic heart disease, unstable angina, or coronary revascularisation), nonfatal CeV events (i.e., nonfatal ischaemic stroke or TIA event), and CV or CeV death (i.e., cardiovascular or CeV death). As cause of death is not available, a proxy will be used.
Covariates
Demographic and clinical characteristics will be included to describe the main cohort of patients diagnosed with migraine and significant CV or CeV disease and as confounders in the potential comparative study. All available data prior to treatment will be used, with a minimum of 12 months, to assess baseline and clinical covariates.
Data sources
Data will be obtained from the following proposed European databases: Danish Health Registers (DHR; Denmark), PHARMO Data Network (The Netherlands), Sistema d’Informació per al Desenvolupament de la Investigació en Atenció Primària (SIDIAP; Spain), and Swedish Health Registers (SHR; Sweden). The suitability of these databases for the comparative analysis will be evaluated as part of the feasibility assessment (Phase 1, Objective 2). Each database will be evaluated individually and included in the comparative analysis (Phase 2) if deemed suitable.
Study size
The number of atogepant-exposed patients included in this study will depend on the uptake of atogepant in the countries of interest. The descriptive outcomes will be presented in the final report regardless of the size of the study population (note: results for population sizes with N < 5 will not be presented due to privacy restrictions) and incidence rates for the primary and secondary outcomes will also be presented. Full comparative analyses will only be performed if the results of the interim study report confirm the ability to produce a valid analysis. One criterion for the feasibility of the comparative analyses (see other criteria outlined in Section 9.7.6. Comparative safety analyses) is to determine adequate sample size, specifically to have a sample size that will allow detection of at least a 2-fold difference in the primary outcome of composite CV and CeV events. Assuming a power of 80%, a 2-sided significance level of 0.05, propensity score matching, and a matching ratio of 1:1 of atogepant vs. comparator users is used, at least 10,388 person-years of follow-up in atogepant-exposed patients will be required in each database. Data analysis Descriptive statistics will be used for demographic and clinical characteristics at baseline. The incidence rate for the primary outcome will be presented for atogepant users, as well as the incidence rates for the secondary outcomes. The interim study report results will inform the design of the final study report and will determine if each database is suitable for the comparative analysis including (but not limited to): if the proposed data source has adequate atogepant uptake, whether confounding can be adequately addressed, whether the number of observed events during the follow-up is sufficient, final inclusion/exclusion criteria, comparator drug, study design (e.g., new user or prevalent new user study design), and analysis approach (e.g., matching or inverse probability of treatment weighting [IPTW], inclusion of a negative control, sensitivity analyses). Assuming atogepant uptake and number of events are adequate, appropriate adjustment for confounding and matching/IPTW feasible, and a suitable comparator identified, a comparative analysis will be conducted to compare the incidence of CV and CeV events among patients with migraine and significant CV or CeV disease that are atogepant-exposed with users of a comparator. Relative risks for the outcomes of interest will be estimated as hazard ratios (HRs). A sensitivity analysis will be performed to examine the association between atogepant use and the safety outcomes of interest while excluding those with epilepsy.

Rationale and Background
Cluster headache (CH) is a primary headache disorder characterized by episodes of severe, strictly unilateral pain accompanied by ipsilateral conjunctival injection, lacrimation, nasal congestion, rhinorrhoea, forehead and facial sweating, miosis, ptosis and/or eyelid oedema, and/or with restlessness or agitation, that lasts 15- 180 minutes and occurs from once every other day to eight times a day. CH affects 0.1% of the population and its clinical management is broadly divided into acute treatment and prophylactic treatments.

The EHDEN (European Health Data & Evidence Network) Foundation Research Programmes aim to foster non-competitive research collaborations with Data Partners, Academia, and Industry across various therapeutic areas. To obtain a better understanding of the characteristics of patients with CH as well as other headache disorders in a real-world setting, a pilot study within the Neuroscience Research Program of the EHDEN Foundation will be conducted. The pilot comprises a database feasibility assessment for selection of data partners, protocol development, and final analysis.

Research question and Objectives

The aim of this study is to obtain a better understanding of the characteristics of patients with cluster headache (CH) as well as other headache disorders in a real-world clinical setting. The primary objective of the study is to describe the sex and age of patients in each of the cohorts derived from the study population (see Population below).

The secondary objectives of this study are:
• To assess patterns of pharmacological treatment, procedures, and emergency room (ER) visits among CH patients and differences from the other cohorts.
• To describe common morbidities among CH patients and differences from the other cohorts as well as the risk of new morbidities after initiating the most frequent treatments.
• Understanding major subgroups of patients by morbidity and treatment.

Research Methods
Study design
The study design comprises a multinational, retrospective cohort study on patients with CH and other headache disorders using routinely collected health data. Data are sourced from selected EHDEN data partners, chosen based on database and cohort feasibility assessments.

Population
The study cohorts will comprise all individuals in the selected EHDEN data partners’ databases during the study period from 2015 to 2024 or latest data coverage with at least 730 days of data (365 days prior to index date and 365 days after index date).

• The CH cohort will comprise all individuals of the study population with a first CH diagnosis, and an observation period starting at least 365 days before and ending the at earliest 365 days after the first CH diagnosis recorded in the database.
• The episodic CH cohort will comprise all individuals of the study population with a first episodic CH diagnosis, and an observation period starting at least 365 days before and ending the at earliest 365 days after the first CH diagnosis recorded in the database.
• The chronic CH cohort will comprise all individuals of the study population with a first chronic CH diagnosis, and an observation period starting at least 365 days before and ending the at earliest 365 days after the first CH diagnosis recorded in the database.
• The PTH cohort will comprise all individuals of the study population with a first PTH diagnosis, and an observation period starting at least 365 days before and ending the at earliest 365 days after the first PTH diagnosis recorded in the database.
• The concussion cohort will comprise all individuals of the study population with a first concussion diagnosis, and an observation period starting at least 365 days before and ending the at earliest 365 days after the first concussion diagnosis recorded in the database.
• The migraine cohort will comprise all individuals of the study population with a migraine diagnosis, and an observation period starting at least 365 days before and ending the at earliest 365 days after the first migraine diagnosis recorded in the database.
• The chronic migraine cohort will comprise all individuals of the study population with a migraine diagnosis, and an observation period starting at least 365 days before and ending the at earliest 365 days after the first chronic migraine diagnosis recorded in the database.
• The headache cohort will comprise all individuals of the study population with any kind of headache diagnosis, and an observation period starting at least 365 days before and ending the at earliest 365 days after the first headache diagnosis recorded in the database.
• The random sample cohort will be a sample of all individuals with at least one visit and 365 days of observation before that visit and 365 days after.
Variables
The following variables are planned to be collected from the databases to meet the study objectives, depending on availability:
• Sociodemographic characteristics (age, sex, and country).
• Comorbidities
• Treatment and medical interventions.
Data sources
This study will be conducted using routinely collected data from primary care and/or secondary care as available in the EHDEN data partners’ Information System for Research in Primary Care (Sistema d’Informació per al Desenvolupament de la Investigació en Atenció Primària [SIDIAP]) and Integrated Primary Care Information (IPCI) databases. SIDIAP is a database comprising primary care records of more than 8 million individuals in the Catalonia region in Spain since 2006, with 5.8 million active individuals in June 2021 (75% of the population in the region). IPCI is a database containing routinely collected electronic health records (EHR) of approximately 2.5 million patients registered with a selected group of GPs in the Netherlands.
Sample size
No sample size has been calculated.
Data analyses
The data analysis methods aim to characterize and compare the defined cohorts in a summarized manner, using descriptive statistics, statistical comparisons and descriptive clustering methods.

Rationale and background
Portal vein thrombosis (PVT) stands as a significant and frequent complication among patients with cirrhosis, marking a critical event in their natural history. There is no approved treatment to prevent PVT in cirrhosis. Simvastatin is a statin with a lipophilic nature with a safety profile in cirrhosis. In vitro, treatment with simvastatin demonstrated a potential preventive role in endothelial-to-mesenchymal transition (EndMT) initiation and progression. We hypothesize that statins may offer a novel approach to preventing PVT development in individuals with cirrhosis.
Research questions
1.Are people with cirrhosis receiving statins different to individuals with cirrhosis not receiving statins?
2.In people with cirrhosis, initiating a treatment with statins reduces the risk of having PVT compared to not initiating a treatment with statins?
3.Does this effect differ according to the NASH and decompensation status of the cirrhosis?
Objectives
Main objective: Investigate whether statins can prevent PVT development in patients with cirrhosis in a large population in Catalonia from 2010 to 2023.
Specific objectives:
1.To describe and compare the characteristics of patients with cirrhosis with and without initiation of statin treatment in terms of age, sex, lifestyle factors, socioeconomic status, comorbidities, cirrhosis etiology, and stage of liver disease.
2.To investigate whether patients with cirrhosis initiating statins treatment have a lower risk of venous thrombosis and PVT compared to cirrhotic patients without statins treatment.
3 .To explore how statin initiation affects the risk of venous thrombosis and PVT in cirrhotic patients, comparing outcomes between those with NASH-related versus non-NASH cirrhosis, and between patients with compensated versus decompensated cirrhosis.
Research methods
Study design
A new-user matched cohort study, using individual-level routinely collected Electronic Health Records (EHR) from the SIDIAP database, from January 2010-December 2023.
Population
We will include all patients diagnosed with cirrhosis defined by ICD-10-CM diagnosis codes.
Variables
Drug of interest
The primary exposure of interest will be treatment with statins in patients with cirrhosis.
Condition of interest
The primary outcome of the study will be the incidence of venous thrombosis or PVT.
Analytical methods
In a new-user cohort design, we will perform propensity-score matching of cirrhotic individuals initiating a treatment with statins to cirrhotic individuals non-initiating a treatment with statins. Cox-proportional hazards regression will estimate hazards ratios to assess the association of statins with venous thrombosis and PVT. We will further explore whether this association is modified by cirrhosis etiology (NASH versus non-NASH) and stage of liver disease (compensated versus decompensated).

Rationale and background
Globally, sexually transmitted infections (STIs) constitute a major public health concern, with more than one million acquired every day. In Catalonia, as also seen in Spain and Europe more broadly, rates of STIs have been increasing in recent years. In addition, the COVID-19 pandemic led to significant disruptions in sexual health services, which may have exacerbated existing barriers to health service access, particularly for those who were less engaged with the health service prior to COVID-19. Given the higher rates of STIs reported as well as the barriers migrants may face in accessing sexual health services, migrants comprise an important population for STI prevention and response. However, there is significant diversity among migrants as a group. In order to target interventions, it is crucial to better understand the characteristics of migrants most at risk of STIs as well as the impact of COVID-19 disruptions on access to and uptake of sexual health services.
Objectives
The aim of this study is to estimate time trends in the incidence and prevalence of sexually transmitted infections, including Chlamydia, Gonorrhoea, Syphilis, Trichomoniasis, Genital herpes, Mpox and HPV, in Spanish and non-Spanish primary care users in Catalonia and identify changes in key population groups at risk over time.
This aim will be addressed through three objectives:
1.Characterise Spanish and non-Spanish primary care users in Catalonia in terms of sex, age, socioeconomic status, geographic location, and country of origin.
2.Investigate the incidence and prevalence of STIs in Spanish and non-Spanish individuals by sex, age, socioeconomic status, geographic location and country of origin.
3.Explore the impact of COVID-19-related disruptions on access to sexual health services and STI positivity among migrants and non-migrants.
Methods
Study design
This study is a population-based observational cohort study using individual-level routinely collected Electronic Health Records from the SIDIAP database
Population
The study population will include all patients registered with primary care in Catalonia, with a recorded nationality, diagnosed with any of the following STIs, including chlamydia, syphilis, gonorrhoea, trichomoniasis, HPV, genital herpes, and mpox, from 1st January 2006 to end of data availability. Patients will need to have at least 365 days of data visibility prior to index date.
Variables
Primary outcome: diagnosis of STI including chlamydia, syphilis, gonorrhoea, trichomoniasis, human papillomavirus (HPV), genital herpes, and mpox.
Secondary outcomes: visits to sexual health services and uptake of HPV vaccination.
Relevant covariates: sex, age, socioeconomic deprivation, geographic location and region of origin.
Data Source
The Information System for Research on Primary Care (SIDIAP), Spain
Statistical analysis
We will firstly characterise participants in terms of nationality (Spanish vs. non-Spanish), sex, age, socioeconomic status, geographic area, and region of origin (in the case of non-Spanish individuals) at their index date. Then we will summarise incidence and prevalence rates by infection and overall by nationality (Spanish vs. non-Spanish) and calculate relative risks adjusted by sex, age and socioeconomic status. Lastly, we will conduct an interrupted time series analysis of the impact of COVID-19-related health service disruptions on access to STI services and diagnosis for migrants and non-migrants.
The statistical analyses will be performed based on OMOP-CDM mapped data using OHDSI R packages. A minimum cell counts of 5 will be used when reporting results, with any smaller count reported as <5.

Rationale and background
Hypertrophic cardiomyopathy (HCM) is an inherited heart disease characterised by an increased wall thickness or mass of the left ventricular wall, with a broad clinical spectrum. The diagnosis of HCM requires the presence of hypertrophy of the left ventricle (LV) in the absence of any other cardiac, metabolic, or systemic disease (e.g., systemic hypertension) that could explain the observed hypertrophy. HCM is classified into two types based on the presence or absence of left ventricular outflow tract (LVOT) obstruction, a distinction that influences patient management. The obstructive form of HCM (oHCM) is observed in approximately 66% of patients.
The prevalence of HCM in the general population was initially estimated to be approximately 1 in 500 individuals (0.2%) in a study conducted in the United States (U.S). However, discrepancies in the literature including findings from several studies in U.S. and Europe, suggest a much lower prevalence of clinically diagnosed HCM, indicating that many individuals with HCM may experience a normal lifespan without significant symptoms or the need for major interventions.
Estimating the prevalence of HCM is challenging due to several factors, including the relative rarity of the condition, the high proportion of asymptomatic patients, and diagnostic difficulties. Furthermore, fragmentation across healthcare databases can hinder accurate estimation, as patient histories may be incomplete or unavailable. As a result, large-scale epidemiological studies on the demographics and morbidity burden of HCM in Europe are scarce, with many existing studies relying solely on inpatient records that do not capture the full extent of the disease burden.
This study aims to address these gaps by estimating the prevalence of HCM and oHCM on a large scale across several European countries. In addition, it will provide valuable insights into the characteristics of patients with HCM. This approach will contribute to a more accurate understanding of the true population-level prevalence of HCM in Europe, which is essential for improving diagnosis and management across diverse populations.
Research question and objectives
The general objective of this study is to characterise hypertrophic cardiomyopathy (HCM) and obstructive HCM (oHCM) in Europe in terms of prevalence, demographics, clinical measurements, comorbidities, and treatment.
MODEL DE SOL·LICITUD
2 IMP-126-CT Versió 07
The specific objectives of this study are:
1. To estimate the annual prevalence of clinically apparent HCM and oHCM in Europe, overall and stratified by age and sex.
2. To characterise patients newly diagnosed with HCM and oHCM in terms of demographics, selected HCM-related clinical measurements, and comorbidities existing before, at the time of, and after a first HCM diagnosis.
3. To describe the frequency of selected HCM-related treatments, including medications, medical devices, and procedures before, at the time of, and after a first HCM diagnosis.
Methods
Study design
The study will consist of a retrospective cohort design including patients with a first diagnosis of HCM or oHCM. We will perform a population-level descriptive epidemiology, and a patient-level characterisation study classified as “off-the-shelf” (C1) and as described in the DARWIN EU® Complete Catalogue of Standard Data Analyses. A retrospective cohort study of all HCM or oHCM cases will be conducted.
Population
The study population will include all individuals with a first diagnosis of HCM or oHCM identified in the database during the patient selection period, which is between 01/01/2010, or from when accurate data becomes available in each database (InGef 2015, NAJS 2017), and end of available data in each database.
Variables
For objective 1, diagnosis of HCM and oHCM will be identified through the diagnosis codes defined by SNOMED.
For objective 2, selected clinical measurements and comorbidities will be identified using SNOMED and LOINC codes. These include:
– Comorbidities: cardiac arrhythmias (atrial fibrillation, ventricular fibrillation, (sustained) ventricular arrythmia, premature atrial, nodal or ventricular complexes, sick sinus syndrome, atrioventricular block), sudden cardiac arrest, ischaemic stroke, , heart failure, ischaemic heart disease, sudden cardiac death, valvular heart disease, essential hypertension, disorders of lipoprotein metabolism and other lipidaemia, type 2 diabetes mellitus, obesity chronic kidney disease, chronic obstructive pulmonary disease.
– Measurements: echocardiogram (left ventricular outflow tract and left ventricular ejection fraction measurements, maximum left ventricular thickness), cardiac magnetic resonance imaging, genetic test, Holter electrocardiogram, exercise test.
For objective 3, selected HCM treatments will be identified using RxNorm and SNOMED codes. These include:
Pharmacological treatments: beta blocking agents, non-dihydropyridine calcium channel blockers (diltiazem or verapamil), dysopiramide, myosin inhibitors (mavacamten), oral diuretics, oral anticoagulants (warfarin, phenprocoumon, dabigatran, rivaroxaban, apixaban, and edoxaban), angiotensin converting enzyme inhibitors, angiotensin II receptor blockers, mineralocorticoid receptor antagonists, antiplatelets, digoxin, amiodarone.
Procedures: implantation of cardioverter defibrillator, implantation of pacemaker, septal reduction therapy (surgical septal myectomy, alcohol septal ablation), heart transplantation.
Data sources
1. Clinical Practice Research Datalink (CPRD) GOLD, United Kingdom (UK)
2. Danish Data Health Registries (DK-DHR), Denmark
3. InGef Research Database (InGef), Germany
4. Sistema d’Informació per al Desenvolupament de la Investigació en Atenció Primària (SIDIAP), Spain
5. Croatian National Public Health Information System (NAJS), Croatia
6. Norwegian Linked Health Registry data (NLHR), Norway
Sample size
No sample size has been calculated as this is a descriptive disease epidemiology study. Based on a preliminary feasibility assessment the expected number of HCM records in the included databases for this study will be approximately 80,500. For oHCM, the expected number of records is approximately 21,400.
Statistical analysis
For objective 1, we will estimate the period prevalence on an annual basis, defined as the period from January 1st to December 31st for each year. It will be calculated as the number of individuals diagnosed with HCM and oHCM divided by the total active population, with complete persistence. All estimates will be provided overall and stratified by age and sex, along with 95% confidence intervals calculated using the Wilson method.
Patient-level characterisation will be conducted for objectives 2 and 3, both overall and by grouping patients diagnosed before 2020 and those diagnosed in 2020 or later. The index date will correspond to the date of the first HCM or oHCM diagnosis for each patient.
Age and sex at time of first HCM or oHCM diagnosis will be described. The absolute number and percentage of patients receiving pre-specified list of clinical measurements and experiencing selected comorbidities will be assessed across the following non-overlapping time intervals: >5 years, 5-3 years, 3-1 years, 364-181 days, 180-91 days, 90-1 days before the index date, and during the periods 1-90 days, 91-180 days, 181-364 days, 1-3 years, 3-5 years, >5 years after the index date, with the denominator being the patients still observed at each time point.
For objective 3, the number and percentage of patients receiving each treatment from the pre-specified list of HCM treatments will be assessed across the same non-overlapping time intervals defined for objective 2.
Additionally, the number and percentage of patients receiving each measurement, experiencing each comorbidity, and taking each treatment prior to the index date will be assessed for the entire available observation period, without considering specific time intervals, in order to describe the presence of the covariates at any time before the HCM or oHCM diagnosis.
For all continuous variables, mean with standard deviation and median with interquartile range will be reported. For all categorical analyses, number and percentages will be reported. A minimum cell count of 5 will be used when reporting results, with any smaller counts reported as “<5”. All analyses will be reported by country/database, overall and stratified by age and sex when possible. FI

Rationale and background The Marketing Authorisation Holders (MAHs) that hold Marketing Authorisations (MAs) for acitretin in Canada and the US have included purpura in their label. The Pharmacovigilance Risk Assessment Committee (PRAC) requested additional real-world evidence (RWE) to assess the causal association between certain purpura and related conditions and acitretin before deciding whether to include selected purpura and related conditions in section 4.4 (or 4.8) of the Summary of product characteristics (SmPC) of acitretin.
Acitretin (D05BB02) is a synthetic aromatic analogue of retinoic acid. Retinol (a derivative of Vitamin A) is known to be essential for normal epithelial growth and differentiation. Acitretin is a Nationally Authorised Product (NAP) with approved indications including severe forms of psoriasis (erythrodermic psoriasis and local or generalized pustular psoriasis); severe disorders of keratinization such as congenital ichthyosis, pityriasis rubra pilaris, and Darier’s disease. And other disorders of keratinization which may be resistant to other therapies. It is authorised in the majority of European Union (EU) countries (not in Bulgaria, Cyprus, Greece, Malta, Romania).
This study aims to characterise patients treated with acitretin, estimate the incidence rate of purpura and related conditions in patients with treatment indications for acitretin and to assess the association between acitretin use and purpura and related conditions.
Research question and objectives
1. To characterise patients initiating treatment of acitretin in terms of:
a. Demographics
b. Treatment indications
c. Risk factors for purpura and related conditions
d. Comorbidities
2. To describe patient-level acitretin utilisation in a cohort of new users including:
a. Duration of treatment
b. Concomitant medications prescribed at/before/after index date
3. To estimate crude and age-sex standardised incidence rates of purpura and related conditions in patients with common indications for acitretin and/or treatment groups, and stratified by:
a. Treatment: methotrexate, cyclosporine, azathioprine-containing immunosuppressants; acitretin; TNF alfa blockers; interleukin inhibitors
b. Indication (psoriasis vs other)
c. Thrombocytopenic purpura vs non-thrombocytopenic purpura
Methods
Study design
• New drug user cohort (Objectives 1-2)
• Population-level descriptive epidemiology (Objective 3)
Population
Patient-level characterisations (Objectives 1-2): New users of acitretin in the study period between 01/01/2010 and 31/12/2023 (or the latest date of data availability of the respective databases), with at least 365 days of visibility prior to the date of their first prescription and no prior use of acitretin.
Population-level descriptive epidemiology (Objective 3): New users of acitretin, alternative treatments, and/or diagnosis of a condition of interest in the study period between 01/01/2010 and 31/12/2023 (or the latest date of data availability of the respective databases), with at least 365 days of visibility prior to the date of their first prescription and no prior use of the respective drug/s, will comprise the denominator population based on the respective treatment and indication groups.
Variables
Condition of interest
Indications of interest are psoriasis and severe disorders of keratinization such as congenital ichthyosis, pityriasis rubra pilaris, and Darier’s disease.
Exposure of interest is acitretin.
Outcomes of interest for the new-user cohort study are purpura and related conditions.
Co-variates for Objective 3
Treatment groups: methotrexate, cyclosporine, azathioprine-containing immunosuppressants; acitretin; TNF alfa blockers; interleukin inhibitors
All co-morbidities and co-medications will be used for large-scale patient characterisation during cohort diagnostics, identified as concept/code and descendants. A separate list of pre-specified co-morbidities and co-medications of interest for acitretin new users will also be described.
Data source
1. SIDIAP (Spain, Primary Care Database) [Objective 1 to 3]
2. IPCI (Netherlands, Primary Care Database) [Objective 1 to 3]
3. DK-DHR (Denmark, National Registry) [Objective 1 to 3]
4. CPRD GOLD (United Kingdom [UK], Primary Care Database) [Objective 1 to 3]
Statistical analysis
Analytical methods:
Patient level characterisation will be conducted any time before or on index date (date of first prescription of acitretin), including patient demographics, treatment indications, risk factors for purpura and related conditions. For drug utilisation duration of treatment and concomitant medications at index date, 90 days before and after index date will be reported.
Incidence rates (IRs) will be calculated for purpura and related conditions in acitretin users, those of other major treatment groups and those indicated for treatment with acitretin. Incidence rates per 100,000 person years will be estimated crude and age-sex standardised. Results will be reported for overall purpura and related conditions, and for thrombocytopenic purpura vs non-thrombocytopenic purpura.
For all analyses a minimum cell counts of 5 will be used when reporting results, with any smaller counts will be noted as

Rationale and background
Multiple studies have showed that oral combined hormonal contraception is associated with an increased risk of venous thromboembolism (VTE), especially for high dose combined oral contraception.
Recently, a nationwide study from Denmark reported that NSAIDs use was associated with increased VTE risk in women 15-49 years old, especially among those with concomitant use of high/medium risk hormonal contraception. More data on theassociation of venous thromboembolism with NSAIDs in women of reproductive age has been requested by medicines regulators to see if such associations are seen in other databases , including data on women using hormonal contraception.
Research question and objectives
The study aims to answer the question of: Is there an association with VTE during concomitant use of NSAIDs prescribed to women taking hormonal contraceptive users aged 15-49 years old?
Specific objectives:
1. To characterise the use of oral NSAIDs among women aged 15-49 using hormonal contraceptives.
2. To measure the association of any oral NSAID use and the incidence of VTE among 15-49 years old women on high, medium, and low risk hormonal contraceptives.
3. To measure the association of ibuprofen, diclofenac and naproxen use on the incidence of VTE among 15-49 years old women on high, medium, and low risk hormonal contraceptives.
Methods
Study design
Objective 1 will be a drug utilisation study where new users of oral NSAIDs during the use of hormonal contraceptives will be characterised.
Objectives 2 and 3 will use a self-controlled case series (SCCS) design, nested within a cohort of hormonal contraceptive users.
Data source
This study will be conducted using routinely collected health data (also known as ‘real world data’) from 4 databases in 4 European countries. All databases were previously mapped to the OMOP CDM.
1. Clinical Practice Research Datalink (CPRD GOLD), United Kingdom
2. Danish Data Health Registries (DK-DHR), Denmark
3. Sistema d’Informació per al Desenvolupament de la Investigació en Atenció Primària (SIDIAP), Spain
4. Norwegian Linked Health Registry data (NLHR), Norway
Population
In Objective 1, the study population will be women aged 15-49 who initiate oraloral NSAIDs (ibuprofen, diclofenac and naproxen) during the use of hormonal contraceptives, defined using a 90-day washout window.
In objective 2, study population will include women aged 15-49, included when they start treatment with hormonal contraceptives, and with no history of venous or arterial thromboembolism, cancer (except non-melanoma skin cancer), thrombophilia, hysterectomy, bilateral oophorectomy, sterilisation or infertility treatment. For the SCCS analysis, only women who used NSAIDs as well as having VTE events during the hormonal contraceptive use will be included.
Variables
Hormonal contraceptives will be classified into three groups based on the risk of VTE.
The exposures will be any NSAIDs, and Ibuprofen, diclofenac, and naproxen separately. Ibuprofen, diclofenac, naproxen are most used NSAIDs in Europe. The primary outcome of interest is incident VTE, deep vein thrombosis and pulmonary embolism will be assessed combined and individually.
Other variables include the risk factors of VTE and indications of NSAIDs: recent surgery, trauma/ fracture, cancer, and hospitalisation.
Statistical analysis
Objective 1: Drug utilisation of oral NSAIDs (ibuprofen, diclofenac and naproxen) among women aged 15-49 using hormonal contraceptives.
Among women using hormonal contraceptives who initiate concomitant oral ibuprofen, diclofenac and naproxen, the initial dose and cumulative dose will be assessed at ingredient level for the initial medication. A grace period of 30 days will be used to define the treatment episode. For each drug exposure record in the database, the start date is the dispensing or prescription date, and the end date is defined either by duration or days’ supply, or quantity divided by daily dose. A 90-days washout window will be used to define NSAIDs initiation.
Duration of the treatment episode will be summarised providing the minimum, p25, median, p75, and maximum treatment duration. Number of prescriptions within the treatment episode will be reported. We will also assess the potential indication of NSAIDs during the 7- and 30- days before initiation. Analysis will be conducted for ibuprofen, diclofenac, and naproxen separately.
Objectives 2 and 3: Incidence rate ratio of VTE
For the descriptive analysis, we will conduct large-scale characterisation as well as pre-specified patient-level characteristics of the study population at: i.cohort entry for each contraceptive group (start of hormonal contraceptive); ii.start of NSAIDs exposure (First treatment episode) during hormonal contraceptive use; and iii.time of VTE diagnosis. We will report number and percentage of people who developed conditions that might increase the risk of VTE during each follow-up period.
We will then conduct the self-controlled case series analysis, which compares the incidence rate of events during time exposed to NSAIDs with the rate during all other observed time periods using hormonal contraceptives within individual. We will allocate person-time exposed to hormonal contraceptive into four intervals: Baseline period, defined as on treatment with hormonal contraceptive but not exposed to a NSAIDs; NSAIDs exposure risk period, defined by concomitant use of hormonal contraceptives and NSAIDs; Pre-exposure period: 2-week period before starting NSAIDs (while on hormonal contraceptives); and post-exposure period: 30-day period after stopping using NSAIDs (while still on hormonal contraceptives).
Firstly, we will perform diagnostics to test the assumptions of SCCS analysis, including event-dependent exposures, and event-dependent observation periods.
The SCCS model will be fitted using conditional Poisson regression with an offset of the length of risk
periods. Incidence rate ratios (IRR) and 95% confidence intervals of events will be estimated for the pre-exposure period and the risk periods. Age, and development of health conditions that are risk factors of VTE will be adjusted for as they are time-varying confounders.
All analyses will be conducted for each hormonal contraceptive groups (high, medium, low). In objective 2, we will define the exposure as any NSAIDs. In objective 3, ibuprofen, diclofenac and naproxen will be analysed separately. We will use paracetamol both with or without codeine as a negative control exposure.
Three sensitivity analyses will be performed. In SCCS analysis, if an event increases the probability of death, the assumption of “occurrence of the outcome event does not affect an individual’s time observed” might be violated. Therefore, we will conduct a sensitivity analysis by excluding cases who died within 90 days of VTE outcome. To assess the impact of confounding by indication, that NSAIDs were prescribed to treat conditions which are also risk factors of VTE, we will exclude VTE recorded recorded in the 6 months after cancer, trauma, cancer, or hospitalisation records. We will also conduct a sensitivity analysis by restricting to the first hormonal contraceptives use episode of individuals.

Title
DARWIN EU® – Drug Utilisation Study of prescription opioids.
Rationale and Background
Prescription opioids, while effective for managing severe pain, have led to a public health crisis due to misuse, addiction, and overdose, particularly in the US. Recently, concerns have been growing in Europe due to increasing opioid use and related mortality. Factors such as chronic pain, mental health disorders, and advanced age can exacerbate misuse and the development of dependence. Given the potential for global spread of this issue, enhanced surveillance and in-depth research into opioid utilisation patterns are imperative. A drug utilisation study using a Common Data Model (CDM) is a promising approach to supplement European opioid monitoring systems, providing more granular data to inform evidence-based decisions on this complex topic.
Research question and Objectives
The objectives of this study are
i To investigate the annual incidence and annual period prevalence of use of opioids (overall, active drug substance, strength (weak/strong opioids) and route (oral, transdermal or parenteral), stratified by history of cancer/no history of cancer and for calendar year, age, sex and country/database during the study period. (ii) To determine duration of prescription opioid use, as well as characteristics of new users and indication for opioid prescribing/dispensing overall and in people with history of cancer/no history of cancer, all stratified by calendar year and country/database.
Research Methods
Study design
• Population level cohort study (Objective 1, Population-level drug utilisation study on opioids)
• New drug user cohort study (Objective 2, Patient-level drug utilisation analyses regarding summary characterisation, duration, and indication of opioid use)
Population
Population-level utilisation of opioids: All people registered in the respective databases on 1st of January of each year in the period 2012-2024 (or the latest available, whatever comes first), with at least 1 year of prior data availability, will participate in the population-level analysis (period prevalence calculation in Objective
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1). Therefore, children aged <1 year will be excluded. New users of opioids in the period between 1/1/2012 and 31/12/2024 (or latest date available, whatever comes first), with at least 1 year of data availability, and no use of the respective opioid in the previous 12 months, will be included for incidence rate calculations in Objective 1. Patient-level drug utilisation: New users of opioids in the period between 1/1/2012 and 31/12/2024 (or latest date available, whatever comes first), with at least 1 year of data availability, and no use of the respective opioid in the previous 12 months, will be included for patient-level drug utilisation analyses. Variables Drug of interest: Opioids (substances listed in ATC classes N01AH, N02A and R05DA); naloxone; and fixed naloxone-opioid combinations. Data sources 1. Estonian Biobank (EBB), Estonia 2. IQVIA LBD Belgium, Belgium 3. Integrated Primary Care Information Project (IPCI), The Netherlands 4. The Information System for Research in Primary Care (SIDIAP), Spain 5. Clinical Data Warehouse for Bordeaux University Hospital (CDWBORDEAUX), France 6. Danish Data Health Registries (DK-DHR), Denmark 7. Institut Municipal Assistència Sanitària Information System (IMASIS), Spain 8. Norwegian Linked Health Registry (NLHR), Norway Sample size No sample size has been calculated. Data analyses Population-level drug utilisation will be conducted in all databases. Patient-level DUS analyses will be conducted in all databases. No duration will be calculated for EBB. Population-level opioid use: Annual period prevalence of opioid use and annual incidence rates per 100,000 person years will be estimated. Patient-level opioid use: Summary patient-level characterisation by list of pre-defined conditions/medications of interest will be conducted at index date, including patient demographics, and history of comorbidities and comedication. Frequency of indication at index date, and in the immediate time before will be calculated. Cumulative treatment duration will be estimated for the first treatment era and the minimum, p25, median, p75, and maximum will be provided. For all analyses a minimum cell count of 5 will be used when reporting results, with any smaller counts will be noted as <5.

El problema al que queremos dar solución es el ictus. Los ictus más graves son los producidos por la fibrilación auricular (FA). La FA es un proceso complejo de abordar, lo que pone en relevancia la necesidad de una solución integral para reducir el ictus, las hemorragias y la mortalidad. El objetivo de este estudio es validar una solución tipo software, accesible des de la historia clínica electrónica, actualizable según las directrices vigentes, con buena usabilidad para el profesional, abordando los principales puntos clave de mejora del proceso de la FA.
Se ha desarrollado la fase de prueba de concepto y se ha obtenido un software que es el mínimo producto viable.
La metodología de validación tendrá tres fases:
1. Validación prueba de viabilidad con Stakeholders.
2. Validación en entorno relevante con base de datos poblacional de pacientes con FA. Estudio de fiabilidad y validez del software versus patrón oro, validación de resultados, validación por expertos.
3. Validación en entorno real. Prueba Piloto con implementación del software en historia clínica informatizada en equipos de atención primaria (rural y urbano).
Durante las tres fases se desarrollarán las acciones de innovación para acelerar la llegada al mercado, consistentes en: mercado, negocio, regulatoria y protección industrial. La participación ciudadana y de los profesionales y la perspectiva de género son aspectos transversales que se tendrán especialmente en cuenta durante el proyecto, que se desarrollará durante los 3 años y permitirá realizar la transición de TRL4 a TRL6. El equipo tiene relevante trayectoria en la temática, es multidisciplinar y adecuado para alcanzar los objetivos

Background
Climate change leading to extreme events represent pressing challenges for humanity. Short- term exposure
to ambient air pollution and temperature has been associated with exacerbations of chronic respiratory
diseases, yet significant knowledge gaps remain regarding specific diseases, such as interstitial lung diseases
and bronchiectasis, and potential adaptation strategies to decrease the risk of exacerbations.
Objectives
To investigate the short-term effects of air pollution and temperature, including their co- occurrence, on
chronic respiratory diseases exacerbations and sick leaves in Catalonia; to evaluate potential adaptation
strategies, including the role of inhaled corticosteroids, statins, SGLT-2 inhibitors, and vaccines in modifying
these effects; to incorporate patient perspectives to understand coping mechanisms against climate change
stressors and disease burden.
Methods
Using a well-characterised cohort with detailed environmental exposure data, we will analyze associations
between air pollution and temperature, and chronic respiratory diseases exacerbations, accounting for
hospitalisations, mortality, and sick leaves. We will apply advanced statistical modelling to disentangle
exposure-outcome relationships, assess effect modification, and integrate a qualitative research approach
to capture patient experiences.
Expected results
Identification of environmental triggers of chronic respiratory disease exacerbations, evaluation of
protective effects of pharmacological and behavioural adaptation measures, and generation of evidence to
inform public health policies and clinical guidelines.

Background: Non-communicable diseases (NCDs) are a major global health challenge, contributing to significant morbidity, mortality, and healthcare burden worldwide. Monitoring NCDs is essential for tracking disease prevalence, evaluating trends, and assessing the impact of preventive and control measures. In response to this need, the World Health Organization (WHO) developed the NCD Facility-Based Monitoring Guidance, which provides a framework and a set of core and optional indicators to assess patient care and health programs at the primary care level. Leveraging electronic health records (EHRs) can facilitate reliable and timely monitoring, enabling data-driven policy and healthcare decisions.
Objective: We aim to demonstrate how primary care EHR data can be used to monitor NCDs in Europe using the WHO-proposed indicators.
Methods: A population-based descriptive epidemiological study will be conducted using routinely collected data from multiple European databases willing to participate. Databases that have already committed to participate include SIDIAP (Spain) and IPCI (Netherlands). The study will cover the period from January 1, 2010, to the most recent data available. Specifically, the study will (1) assess the feasibility of estimating the WHO-defined indicators using European databases mapped to the Observational Medical Outcomes Partnership Common Data Model (OMOP CDM), (2) develop phenotypes for selected indicators, and (3) estimate prevalence rates of these indicators over time, stratified by age, sex, socioeconomic status, nationality, and Charlson Comorbidity Index.
Expected results: This study will demonstrate the feasibility of using EHR data to systematically track NCD indicators across Europe. The findings will support data-driven decision-making for policymakers and healthcare providers, contributing to improved NCD prevention and management strategies.

Rationale and background
Benzodiazepines are commonly prescribed for their anxiolytic, hypnotic, and sedative effects. Despite the use of benzodiazepines during pregnancy, there is limited evidence to support their use during this period or to favour their use over alternative treatments that may provide similar symptom relief with differing safety profiles. Understanding the patterns of benzodiazepine use during pregnancy in Europe, together with the rates of pregnancy losses, is essential for evaluating safety and effectiveness. Despite detailed pregnancy information in many data sources, pregnancy episodes in electronic health record (EHR) data are often inconsistently coded across sources.
As part of the upcoming benzodiazepines periodic safety update report single assessment (PSUSA), the Pharmacovigilance Risk Assessment Committee (PRAC) has requested real-world evidence (RWE) on the utilisation of commonly used benzodiazepines during pregnancy. Additionally, the background rates of pregnancy losses will be described to help contextualise the assessment of treatment safety during pregnancy. To date, two data partners within the DARWIN EU® Data Network have pre-processed pregnancy episodes and developed a Pregnancy Extension Table (PET). While the table has been successfully employed in other contexts, this study marks the first application of this table within the DARWIN EU® Data Network.
Research question and objectives
Research Question: This study is meant to inform on the use of benzodiazepine among pregnant individuals and the feasibility of a risk-assessment study that investigates benzodiazepine use during pregnancy.
The specific study objectives are the following:
1. To characterise users of benzodiazepine and alternative treatments (SSRIs, SNRIs, Z-hypnotics, and Melatonin) during pregnancy in terms of demographics, prior medications, history of mental illness and other comorbidities.
2. To characterise treatments with benzodiazepine and alternative treatments during pregnancy in terms of duration, posology, and indication of prescription during pregnancy.
3. To describe the prevalence of benzodiazepine and alternative treatments’ use during pregnancy
4. To describe trajectories of prescriptions fills for benzodiazepine and alternative treatments throughout the year before pregnancy, pregnancy period, and one month following pregnancy end date.
5. To estimate the incidence of pregnancy loss among all pregnancies and in benzodiazepines and alternative treatment users during pregnancy (when numbers allow).
6. To characterise individuals with pregnancy loss in terms of demographics, comorbidities, and prior medications.
Objectives 1, 2, 5, and 6 will also include stratification by age categories and pregnancy periods. When counts allow, objectives 2, 3, 4, and 5 will be stratified by each benzodiazepine active ingredient, grouped by
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benzodiazepines’ half-life (short and long-acting). When referring to alternative treatments, each alternative treatment will be reported separately (except for objective 4).
Exploratory objectives (to assess their suitability for subsequent analyses)
7.To estimate the incidence rates of potential negative control outcomes (e.g., musculoskeletal injuries, skin conditions, urinary tract infection) in benzodiazepine and alternative treatment users.
Methods
Study design:
Cohort study design.
Study Period:
From 01/01/2010 until 31/12/2023 or the first and last date of data availability in each database.
Population:
Individuals of female sex (at birth) and at least one year of prior database history, with a pregnancy episode during the study period (2010-2023) and a pregnancy start date on or before December 31, 2022. For specific objectives, the following nested cohorts will be defined as follows:
Objectives 1, 2, and 3: Individuals exposed to drugs of interest during pregnancy. For objectives 1 and 2, only the first exposure episode will be considered.
Objective 4: Individuals exposed to drugs of interest at any point during the year preceding pregnancy, pregnancy, or within 1 month following pregnancy end date.
Objective 5: No subset will be required. The main analysis will not impose any exclusion for a prior history of pregnancy, while additional analysis will: 1. exclude anyone with a pregnancy history in the year before the pregnancy start date. 2. exclude anyone with an unknown pregnancy outcome.
Variables
Indications: Indications will be derived from data by the presence of at least one diagnostic code for the following conditions (assessed using different time windows relative to index date): anxiety disorders, sleep disorders, including insomnia, and history of mental illness (a more general group of » mental illnesses» [including depression, bipolar disorder, schizophrenia and psychotic disorders, excluding anxiety and insomnia/sleep disorders]).
Exposures of interest:
– Benzodiazepines (at the active ingredient level). Prescription of any benzodiazepine, defined as the presence of any RxNorm codes.
Alternative treatments:
– Selective serotonin reuptake inhibitors (SSRI) (at the active ingredient level). Prescription of any SSRI, defined as the presence of any RxNorm codes.
– Selective noradrenaline reuptake inhibitors (at the active ingredient level). Prescription of any SNRI, defined as the presence of any RxNorm codes.
– Z-hypnotics (at the active ingredient level). Prescription of any Z-hypnotic, defined as the presence of any RxNorm codes.
– Melatonin (at the active ingredient level). Prescription of Melatonin, defined as the presence of any RxNorm codes.
Outcomes of interest
This study will describe the characteristics of benzodiazepine and alternative treatment users, treatment patterns (including first treatment era duration and dose), and indications. The prevalence of benzodiazepine and alternative treatment use will be estimated. Prescription trajectories categorised as restarting, switching, restarting with switching to another, or discontinuation will be assessed. The incidence of pregnancy loss (miscarriage and stillbirth combined, and separately) will be estimated, and individuals
who experience these events will be characterised. Additionally, the study will estimate the incidence of potential negative control outcomes, such as musculoskeletal injuries, skin conditions, and urinary tract infections, among benzodiazepine and alternative treatment users.
Relevant covariates
Pregnancy start and end date, gestational week, pregnancy year (pregnancy start date), age groups (=24, 25-29, 30-34, =35), selected conditions and medications, number of healthcare visits, prior pregnancies, and pregnancy period (<20, >20 weeks).
Follow up
The index dates and follow-up will be different for the cohorts of interest and objectives and will consist of:
For the general population cohort, individuals will be followed from the first date of eligibility criteria fulfilment (pregnancy start date), whereas for the benzodiazepine and alternative treatment nested cohorts, follow-up will start at the date of first treatment initiation during pregnancy (index date). Follow-up will end with pregnancy end date (irrespective of the outcome), or censoring (due to loss to follow-up, death), whichever occurs first.
For objective 4, follow-up will begin at the first initiation of the treatment of interest (index date) within the period contained within the year prior to pregnancy start, pregnancy, and one month following pregnancy end date, or censoring (due to loss to follow-up, death), whichever occurs first.
Data sources
The following data sources, which have already implemented the PET, will be used for this study.
1. Sistema d’Informació per al Desenvolupament de la Investigació en Atenció Primària (SIDIAP), Spain.
2. The Norwegian Linked Health Registry data (NLHR), Norway.
Statistical analysis
Characterisation of users of benzodiazepines and alternative treatments during pregnancy and individuals experiencing pregnancy losses will be done using PatientProfiles and CohortCharacteristics R package. For objectives 2 and 4, we will use the DrugUtilisation and TreatmentPatterns R packages to characterise benzodiazepines and alternative treatments during pregnancy, including counts (%) for each class, duration of treatment, prior medication use, and trajectories of prescription fill. For the calculation of the prevalence of benzodiazepines and alternative treatments during pregnancy, and the incidence rates of the outcomes of interest, the IncidencePrevalence R package will be used. Rates will be reported with the 95% Poisson confidence intervals. A minimum cell counts of 5 will be used when reporting results, with any smaller count reported as “<5”. All analyses will be reported by country/database, overall and stratified by age groups and pregnancy period, when possible (minimum cell count reached). No meta-analysis will be performed.

Rationale and background
Clozapine is an effective treatment for treatment-resistant schizophrenia and Parkinson’s disease psychosis, but it carries a risk of severe haematological complications, including neutropenia and agranulocytosis. Emerging evidence suggests that the risk is highest in the initial months of treatment, yet stringent haematological monitoring requirements remain in place throughout long-term use. These requirements may hinder clinical practice, leading to underuse, early treatment discontinuation, or reluctance to initiate therapy. This study aims to provide epidemiological evidence on the incidence and timing of clozapine-associated neutropenia and agranulocytosis across Europe.
Research question and objectives
Research question
What is the incidence of agranulocytosis and neutropenia over time in new users of clozapine?
Study objectives
1. To estimate the incidence rates of agranulocytosis and neutropenia in consecutive weekly and monthly intervals following the new initiation of clozapine treatment, overall and stratified by age, sex and country/database.
2. To estimate the Kaplan-Meier curves for the time to onset of agranulocytosis and neutropenia in individuals initiating clozapine treatment, overall and stratified by age, sex and country/database.
3. To characterise individuals initiating clozapine treatment in terms of demographics and pre-specified conditions related to the indication for clozapine use. Results will be stratified by country/database.
4. To determine the treatment duration for clozapine use. Results will be stratified by country/database.
Methods
Study design
• Population-level cohort study (Objective 1, Population-level descriptive epidemiology of agranulocytosis and neutropenia in new users of clozapine).
• Cohort analysis (Objective 2, Patient-level characterisation to the time of onset of agranulocytosis and neutropenia in individuals initiating clozapine treatment).
• New drug user cohort (Objective 3 and 4, Patient-level drug utilisation regarding demographics, pre-specified conditions related to clozapine initiation and treatment duration).
Study period
1st of January 2010 to 31st of December 2024 (or latest available data
Population
Population-level descriptive epidemiology: Population-level descriptive epidemiology will include all new users of clozapine registered in the respective databases between 1st of January 2010 and 31st of December 2024. Eligible individuals must have at least 1 year of data visibility prior to becoming eligible for study inclusion and no history of clozapine use. Children <1 year of age will be excluded. Patient-level characterisation: Patient-level characterisation will include all new users of clozapine registered in the respective databases between 1st of January 2010 and 31st of December 2024. Eligible individuals must have at least 1 year of data visibility prior to becoming eligible for study inclusion and no history of clozapine use. Additionally, to ensure sufficient follow-up, only individuals who initiated clozapine treatment at least 1 year before the end of the available data will be included. Children <1 year of age will be excluded. Patient-level utilisation of clozapine: Patient-level drug utilisation analysis will include all new users of clozapine in the period between 1st of January 2010 and 31st of December 2024, with at least 1 year of data visibility prior to becoming eligible for study inclusion and no history of clozapine use prior to the index date. For treatment duration analysis, to ensure sufficient follow-up, only individuals who initiated clozapine treatment at least one year before the end of the available data will be included. Variables Drug of interest: Clozapine. Outcomes of interest: Agranulocytosis and neutropenia following the initiation of clozapine treatment. Agranulocytosis and neutropenia will be defined separately (narrow definition) and additionally as a combined outcome (broad definition). To ensure that only incident cases are captured, individuals with a prior history of agranulocytosis or neutropenia will be excluded. Data source 1. Finnish Care Register for Health Care (FinOMOP-HILMO), Finland 2. Croatian National Public Health Information System (NAJS), Croatia 3. IQVIA Disease Analyzer Germany (IQVIA DA Germany), Germany 4. The Information System for Research in Primary Care (SIDIAP), Spain Sample size No sample size has been calculated a this is a descriptive study. Statistical analysis Population-level descriptive epidemiology: Incidence rates of newly diagnosed agranulocytosis and neutropenia will be estimated following clozapine treatment initiation (objective 1). These rates will be expressed as the number of individuals with the newly diagnosed outcome of interest following clozapine initiation per 1,000 person-years. Incidence rates will be calculated for consecutive weekly (0-7 days, 8-14 days, 15-21 days etc.) and monthly intervals (0-30 days, 31-60 days, 61-90 days etc.) since the initiation of clozapine treatment (index date), with a maximum follow-up period of 24 months for reporting both weekly and monthly estimates. The statistical analysis will be performed based on OMOP-CDM mapped data using “IncidencePrevalence” R package. The results will be reported overall and stratified by age, sex and country/database. Patient-level characterisation: Kaplan-Meier curves for the time of onset of agranulocytosis and neutropenia will be estimated in individuals initiating clozapine treatment (objective 2). This analysis will be conducted using “CohortSurvival” R package based on OMOP-CDM mapped data. The results will be stratified by age, sex and country/database. Patient-level utilisation of clozapine: Characterisation including age and sex will be assessed at the date of new (incident) prescription of clozapine (index date) (objective 3). The frequency of pre-specified conditions related to clozapine initiation will be assessed at any time prior to 1 day before index date, 365 days prior to 1 day before index date and at the index date. Duration of treatment will be calculated and summarised providing the minimum, quartiles and maximum, where available (objective 4). Statistical analyses will be conducted using the “CohortCharacteristics” and “DrugUtilisation” R package based on OMOP-CDM mapped data. The results will be stratified by country/database. For all analyses a minimum cell counts of 5 will be used when reporting results, with any smaller counts obscured.

Rationale and background
The WHO 2023 AWaRe classification (who.int) of antibiotics for evaluation and monitoring of use classifies 258 antibiotics into 3 categories (Access/Watch/Reserve) according to their impact on antimicrobial resistance.
The ‘Access’ category includes antibiotics that are recommended as first- or second-line treatments for a wide range of common infectious diseases. These antibiotics are generally active against a broad spectrum of commonly encountered, susceptible pathogens and have a relatively lower risk of promoting antimicrobial resistance compared to agents in other categories. The WHO emphasizes that ‘Access’ antibiotics should be widely available, affordable, and of assured quality across all healthcare settings to ensure equitable treatment, especially in low- and middle-income countries. As of the 2023 update, the ‘Access’ group includes 84 antibiotics, such as amoxicillin and doxycycline, which are used to treat high-burden infections like pneumonia and urinary tract infections.(1, 2) Promoting the use of ‘Access’ antibiotics for appropriate indications is a key component of global antimicrobial stewardship strategies aimed at reducing the need for broader-spectrum agents and mitigating the spread of resistance.
The DARWIN EU®_ P1-C1-003 study focused on the Watch category but there is now interest in including also the other category (‘Access’) to characterise the use of most antibiotics, and increased focus on the indication for use.
This study will improve the understanding of the use of antibiotics in routine health care delivery, including indication, treatment duration and trends over time. The results will contribute to the EU efforts to monitor use of antibiotics as part of the global fight against antimicrobial resistance.
Research question and objectives
Research question
What is the incidence of prescription of the antibiotics in the ‘Access’ category, including indication and treatment duration, from 2012 to 2024, stratified by demographic characteristics, calendar year/month, and country?
Objectives
1. To investigate the incidence of use of antibiotics (from the WHO AWaRe ‘Access’ category) stratified by age, sex, calendar year/month, and country/database during the study period 2012-2024.
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2. To characterise antibiotic (WHO AWaRe ‘Access’ category 2023) use by duration of use over the study period 2012 to 2024.
3. To characterise antibiotic use (WHO AWaRe ‘Access’ list 2023) by indication of use over the period 2012 to 2024 stratified by calendar year.
Methods
Study design
• Population level cohort study (Objective 1, Population-level drug utilisation study on ‘Access’ category antibiotics)
• New drug user cohort study (Objectives 2 and 3, Patient-level drug utilisation analysis with regard to duration and indication of antibiotic use)
Population
Population-level utilisation of antibiotics (objective 1): All individuals present in the database in the period between 01/01/2012 and 31/12/2024 will be included in the analysis after 365 days of database history.
Patient-level antibiotic utilisation (Objectives 2 and 3): All new users of antibiotics (i.e. no use of the antibiotic of interest in the preceding 30 days) in the period between 01/01/2012 and 31/12/2024, with at least 365 days of visibility prior to the date of their first antibiotic prescription.
Study period
Study period will start from 2012 until the end of available data. In the NAJS data source, accurate data will be available from 2017 on.
Variables
Exposures
All antibiotics from the WHO AWaRe ‘Access’ category.
Outcome
n/a
Relevant covariates
Age groups, sex, calendar year/month, predefined conditions of interest.
Data source
1. Danish Data Health Registries (DK-DHR), Denmark
2. Finnish Care Register for Health Care (FinOMOP-HILMO), Finland
3. The Integrated Primary Care Information (IPCI), the Netherlands
4. IQVIA Disease Analyser (DA) Germany, Germany
5. National Public Health Information System (NAJS), Croatia
6. Information System for Research in Primary Care (SIDIAP), Spain
Sample size
No sample size has been calculated as this is an exploratory study which will not test a specific hypothesis.
Statistical analysis
Population-level antibiotic use: Yearly and monthly incidence rates of antibiotic prescriptions per 100,000 person-months (PMs) will be estimated. Overall incidence rates will be reported as well as stratified by age, sex, calendar year/month, and country/database. Incidence rates will be reported together with 95% Poisson confidence intervals.
Patient-level antibiotic use: Proportions of indication of use at index date will be assessed. Index date will be the date of each prescription of the specific antibiotic for each person. Cumulative treatment duration will be estimated and the minimum, p25, median, p75, and maximum will be provided.
The statistical analyses will be performed based on OMOP-CDM mapped data using “IncidencePrevalence” and “DrugUtilizationCharacteristics” R packages. A minimum cell counts of 5 will be used when reporting results, with any smaller count reported as “<5”.

Rationale and background
Antipsychotic drugs are indicated for the management of schizophrenia and bipolar disorder. They are also used in adults to manage behavioural and psychological symptoms of dementia (BPSD) with the recommendation to be discontinued after BPSD symptoms resolve. Antipsychotic drugs can be classified into typical and atypical antipsychotics with different recommendations for their use. For example, guidelines recommend the preferential use of atypical antipsychotics when required for the management of BPSD.[1, 2]
Safety concerns in adults have previously led to regulatory warnings and risk communications over their use.[3, 4] Antipsychotic drugs have been associated with several adverse drug reactions, particularly in the elderly. Somnolence, hypotension, extrapyramidal side effects and gait abnormalities are well-recognized side effects that may in turn contribute to the risk of falls and fracture in elderly persons.[1] Similarly, cardiovascular adverse effects, falls and injuries may increase mortality.
Antipsychotics are sometimes used in children and adolescents; however, not all antipsychotics have been approved for use in children and adolescents and if prescribed their use would be considered off-label. A prior study reported an increased use of antipsychotics between 2008 and 2017 in the paediatric populations of Catalonia (35.7%), Norway (45.1%) and Sweeden (57.6%).[5] Likewise, in England, the use of antipsychotics in patients between 3 and 18 years doubled between 2000 and 2019.[6]
This study aims to provide an overview of antipsychotic prescribing in the children in databases from Europe, and to describe the characteristics of children initiating antipsychotics. This will provide a benchmark to understand current clinical practice over their use in children and adolescents and help to understand whether off-label use may occur.
Research question and objectives
1. To characterise children with a first prescription of an antipsychotic in each database in terms of age, sex, comorbidities and indication of use.
2. To measure trends in the incidence/prevalence of antipsychotic prescribing in children overall, by typical/atypical grouping and separately for 11 drug substances in each database. Results would be stratified by calendar year, age and sex.
3. To characterise first use of antipsychotic initiation in children (overall, by typical/atypical use, and by the 11 prespecified drug substances) in terms of dose and duration in each database. Results will be
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stratified by age and sex.
Methods
Study design
1. A new user cohort study will be used to describe patient-level characterisation of antipsychotic users.
2. A population-level cohort study will be used to assess incidence rates of antipsychotic use.
3. A new user cohort study will be conducted to describe patient-level antipsychotic utilisation.
Population
The study cohort will comprise all paediatric individuals between 1- and 18-years old present in the database during the study period (i.e., 2013-2023).
Additional eligibility criteria for patient-level antipsychotic characterisation and drug utilisation, and for the calculation of incidence rates will be applied, where a minimum follow-up of 365 days of data availability
will be required to exclude individuals with a prior use of the respective drug of interest (i.e., when overall, no prior use of any of the common antipsychotics will be required; when stratified by specific antipsychotic drug, no prior use of the specific antipsychotic will be required).
Variables
Exposure of interest: all antipsychotics under the ATC code N05A (overall, and by typical/atypical grouping); and eleven prespecified drug substances that cover most antipsychotics prescribed in the paediatric population (selected based upon feasibility in the data sources of interest): risperidone, aripiprazole, olanzapine, quetiapine, paliperidone, chlorprothixene, clozapine, methotrimeprazine (levomepromazine), pipamperone, sulpiride and promazine.
Data sources
• BIFAP (Spain, Primary Care Database)
• DK-DHR (Denmark, National Registry)
• InGef RDB (Germany, Claims Database)
• IPCI (Netherlands, Primary Care Database)
• NAJS (Croatia, National Claims Registry) [Only Objectives 1 and 2]
• NLHR (Norway, National Registry)
• SIDIAP (Spain, Primary Care Database)
Statistical analysis
1. Patient-level characterisation study: characterisation of patient-level features for new users of antipsychotics will be calculated overall, by typical/atypical, and by the 11 pre-specified drug substances for each database, including description of age (mean [SD] and median [IQR]), age groups [N,%] and sex [N,%] at index date (date of first prescription of the antipsychotic of interest),comorbidities [N,%] recorded -7 days, -30 days or any time before (index date), and indications of use [N,%] recorded -30 days or any time before (index date).
2. Population-level drug utilisation study: annual incidence and annual period prevalence estimates will be calculated for antipsychotic treatment overall, by typical/atypical and by the 11 pre-specified drug substances for each database.
3. Patient-level drug utilisation study: patient-level characterisation of new antipsychotic users will be conducted at index date (date of first prescription of the antipsychotic of interest) for overall, by typical/atypical and by the 11 pre-specified drug substances for each database, including median [IQR] prescribed or dispensed initial and cumulative dose of antipsychotics, and median [IQR] treatment duration.
For all analyses a minimum cell counts of 5 will be used when reporting results, with any smaller counts will be noted as <5.

Rationale and background
Asthma affects 3-8% of pregnant women and often changes in severity during pregnancy. Uncontrolled asthma poses risks such as pregnancy loss, low birth weight, and perinatal mortality, making continued treatment crucial. Studies have shown inconsistent adherence to asthma treatments among pregnant women and variations in prescribing patterns.
Research question and objectives
Research questions
This study aims to explore the trends in use of asthma medication in the year before, during and year after pregnancy from 2010 until 2023, in order to update our knowledge on the current trend of asthma medication use among pregnant women.
Objectives
The specific objectives of this study are:
1. To estimate the prevalence of use of asthma medication in the year before, during and the year after pregnancy
2. To estimate the proportion of women discontinuing the asthma treatment before or during pregnancy, and among those who discontinued the proportion restarting the treatment
3. To characterise pregnant women with prior asthma diagnosis
Methods
Study design
• Patient-level DUS
• Population-level DUS
Population
The study population will include all pregnant women present in the Netherlands and Spain primary care databases during the study period 01/01/2010 to 31/12/2023 or to the end of available data, with prior asthma diagnosis and with at least 365 days of database history prior to the index date (i.e., start date of pregnancy).
Variables
Exposure(s): Asthma medication
Outcome(s): Prevalence rate of asthma medication use the year before, during and after pregnancy
Proportion of women discontinuing and restarting use of asthma drugs Characteristics of pregnant women with asthma
Relevant covariate(s):
• Age
• Smoking status
• History of respiratory conditions (assessed at index date)
o Chronic rhinosinusitis (+/- nasal polyposis)
o Allergic rhinitis
o Respiratory infections
• Metabolic and cardiovascular
o Obesity: Body mass index: body mass index may be stratified in groups (such as <27, 27-39, =40) o Gastroesophageal reflux disease o Diabetes mellitus o Thyroid dysfunction • Mental health o Depression o Anxiety • Inflammatory conditions o Atopic dermatitis Data source 1. Integrated Primary Care Information (IPCI), Netherlands 2. The Information System for Research on Primary Care (SIDIAP), Spain Sample size. No sample size has been calculated Statistical analysis Prevalence of use of asthma medication and the proportion of pregnant women discontinuing and restarting treatment with asthma drugs will be estimated one year before and one year after end of pregnancy and per trimester during pregnancy. Characteristics of pregnant women with asthma will be described using mean (+ ± SD), median (+ range) or number of person (N, %). In addition, covariates of interest will also be reported as counts and proportions. The statistical analyses will be performed based on OMOP-CDM mapped data using Darwin R packages.

Rationale and background
Art.31 CHMP referral in 2016 on metformin and use in patients with reduced kidney function led to PI updates including introduction of a warning and interaction with concomitant use with iodinated agents for patients undergoing imaging procedures.
Based on the evidence reviewed in the PSUSA, it was considered premature to delete the warning and interaction in the metformin PIs, at this stage. PRAC suggested the possibility to conduct a RWD study to gather more data on this specific issue and understand better if further regulatory action would be deemed necessary Research question and objectives
1. To phenotype and characterise ICA in patients with type 2 diabetes initiating metformin
2. To phenotype AKI and CKD stage using diagnosis codes and eGFR measurements among patients
with type 2 diabetes initiating metformin
3. To characterise patients with type 2 iabetes initiating treatment of metformin in terms of:
a. Demographics (age, sex)
b. Recorded comorbidities
c. Recorded duration from first diabetes diagnosis
d. Previous procedures with ICA
e. CKD stage (most recent in past year)
4. To characterise patients with type 2 diabetes with a first procedure requiring ICA with ongoing
metformin use in terms of previous history of:
a. Demographics (age, sex)
b. Comorbidities
c. Recorded duration from first diabetes diagnosis
d. CKD stage
e. ICA type
f. Time from metformin initiation to first procedure requiring ICA
5. To quantify the occurrence of renal dysfunction and of acute diabetes decompensation among
patients with type 2 diabetes with a first procedure requiring ICA during metformin use specifically:
a. AKI
b. Lactic acidosis
c. Diabetic ketoacidosis
Methods
Study design
New user cohort study
Population
Two cohorts:
1) Metformin new users: new users of metformin between 01/01/2014 and 31/12/2024 (or latest date
available), with a diagnosis of diabetes and at least 365 days of history prior to the date of their first
metformin prescription and no prior use of metformin.
2) ICA new use: first procedure requiring an ICA between 01/01/2014 and 31/12/2024 (or latest date available), with metformin initiation during the study period, ongoing metformin use, previous diagnosis of diabetes and 365 days of prior history before metformin initiation. ICA new use population (Cohort 2) is a subset of the metformin new users (Cohort 1).
We will exclude patients with a record of AKI, ketoacidosis or diabetic acidosis within a year of index date.
Variables
Exposures: ICA, metformin
Outcomes:
• AKI
• Lactic acidosis
• Diabetic ketoacidosis
Covariates for characterisation:
• Demographics (age, sex)
• Comorbidities: Anxiety, asthma, CKD, chronic liver disease, chronic obstructive pulmonary disorder (COPD), dementia, gastroesophageal reflux disease (GERD), heart failure, human immunodeficiency virus (HIV), hypertension, hypothyroidism, inflammatory bowel disease, malignant neoplastic disease, myocardial infarction, osteoporosis, pneumonia, rheumatoid
arthritis, stroke, venous thromboembolism
• Duration of diabetes (days from initial diagnosis of type 2 diabetes to index date)
• Previous use of ICA
• CKD stage
• ICA type
• Time from metformin initiation to first procedure requiring ICA
Objective 5: Survival analyses will be stratified by
• ICA indication/type
• CKD stage (1-5)
Data source
1. SIDIAP (Spain, Primary Care Database)
2. FinOMOP-HILMO (Finland, National Registry)
3. DK-DHR (Denmark, National Registry)
4. CPRD GOLD (United Kingdom [UK], Primary Care Database)
Statistical analysis
Phenotyping and characterisation of ICA, and AKI/CKD using diagnosis codes and eGFR measurements, will be done for patients with type 2 diabetes initiating metformin.
Patient-level characterisation will be conducted in databases based on data availability.
Patient-level characterisation of new metformin users will be conducted at index date (date of first prescription), including patient demographics, comorbidities, time since diabetes diagnosis, previous use of ICA, and CKD stage.
Patient-level characterisation of first procedure requiring ICA during ongoing metformin use will be conducted at index date (date of first procedure), including patient demographics, comorbidities, time since diabetes diagnosis, CKD stage, ICA type and time from metformin initiation to first procedure requiring ICA.
We will estimate Kaplan Meier survival functions to describe the probability of outcome occurrence and median survival to outcomes of interests, specially, AKI, lactic acidosis, diabetic ketoacidosis among patients with type 2 diabetes with a first procedure requiring ICA during metformin use stratified by CKD stage, and ICA type.
For all analyses a minimum cell counts of 5 will be used when reporting results, with any smaller counts will be noted as <5.

Rationale and background
Meningococcal vaccines are recommended in the immunisation schedule in targeted children and
adolescent population to preventing Invasive Meningococcal Disease (IMD). Various Meningococcal vaccines
have been developed to target distinct serogroups of the bacteria Neisseria Meningitidis including groups A,
B, C, W and Y responsible for IMD. The current vaccination schedule in countries within the Europe have
recommended the uptake of three doses Meningococcal group B (MenB) vaccines for children at age 2, 4
and 12 months, single dose of MenC or Haemophilus influenzae type b/Meningococcal group C (Hib/MenC)
vaccines at age 12 months and quadrivalent Meningococcal groups ACWY (MCV4) vaccines as a single dose
schedule in adolescent between 14 and 18 years of age as the main vaccination schedule for the prevention
of severe meningococcal infection. This study aims to generate comprehensive evidence on the coverage of
these separate types of meningococcal vaccines within the target population across six countries within
Europe.
Research question and objectives
The general objective of this study is to examine the coverage of meningococcal vaccines routinely
administered in countries across Europe for preventing IMD in eligible individuals.
The specific objectives of this study are:
1. To examine the coverage of MenB vaccine in children at age one and two years by dose received (1
dose, 2 doses and 3 doses)
2. To examine the coverage of MenC or Hib/MenC conjugate vaccines in children at age two years
3. To examine the coverage of MCV4 vaccines in individuals at age 18 years
4. To estimate the coverage of specific brand of MenB vaccines (Bexsero® and Trumemba®) in
individuals aged two years and MCV4 vaccines (Menveo® and Nimenrix®) in individuals aged 18 years
Methods
Study design
Population-level drug utilisation study (DUS)
Population
The study population will include all individuals aged one year and two years at the index date of separate
observation windows for assessing the coverage of MenB vaccines and individuals aged 18 for assessing the
coverage of MCV4 vaccines.
Variables
Data source
1. Base de Datos para la Investigación Farmacoepidemiológica en el Ámbito Público (BIFAP), Spain
2. Clinical Practice Research Datalink (CPRD) GOLD, United Kingdom (UK)
3. Danish Data Health Registries (DK-DHR), Denmark
4. Finnish Care Register for Health Care (FinOMOP-HILMO), Finland
5. InGef Research Database (InGef), Germany
6. Croatian National Public Health Information System (NAJS), Croatia
7. Sistema d’Informació per al Desenvolupament de la Investigació en Atenció Primària (SIDIAP), Spain
Statistical analysis
Objective one of this study examines the point prevalence of individuals who have received different
number of doses of MenB vaccines (1 dose, 2 doses and 3 doses) in separate age groups (age 1 years and 2
years of age). Objective 2 examines the point prevalence of eligible individuals aged two who have received
at least one dose of MenC or Hib/MenC vaccines. Objective three examines the point prevalence of MCV4
recipient in individuals at 18 years of age. Objective four of this study examines the point prevalence of
MenB and MCV4 vaccines by brand (MenB: Bexsero®, Trumemba®; MCV4: Menveo®, Nimenrix®). The
analyses stated above will be conducted in separate quarterly and yearly observation windows.

To date, asthma prevalence has been mainly assessed from self or parental-reported questionnaires in cross-sectional studies, implying recall bias. Despite its noteworthy prevalence, its age-specific evolving incidence among children and adolescents remains unclear and region-specific data from Catalonia is scarce.
In this context, comprehensive, population-based data sources such as routinely collected electronic health records (EHR) that capture real-time healthcare information and minimise recall bias, can offer a valuable alternative.
The objective of this study is to investigate time trends in the prevalence and incidence of asthma, among individuals from 0 to 18 years in Catalonia, Spain. We will conduct a population-based open cohort with individual level data from the Information System for Research in Primary Care (SIDIAP) mapped to the OMOP-CDM from 2008 to 2024. We will estimate overall and annual incidence and prevalence of asthma among children and adolescents overall and stratified by sex, age, nationality and socioeconomic status. We will estimate crude and age-standardised rates of asthma. We will also investigate changes in time trends over the study period.
Our study will enable to identify temporal trends in asthma in Catalonia and will inform preventive strategies targeted to specific groups that are more vulnerable, helping to address asthma disparities across different demographics.

Title
DARWIN EU® – Trends in utilisation of Attention-Deficit Hyperactivity Disorder (ADHD) Medications
Rationale and background
A first off-the-shelf study has been performed in 2024 at the request of the SPOC Working Party (responsible for monitoring and reporting events that could affect the supply of medicines in the EU) that has been monitoring shortages of different medicines to treat Attention-Deficit Hyperactivity Disorder (ADHD), mainly due to an increased demand in multiple markets, production constraints related to raw material availability, new regulatory approvals for some medicines, and changes in the competitive
landscape. The main products under monitoring are lisdexamfetamine and methylphenidate, but three more have the indication in Europe (atomoxetine, dexamfetamine and guanfacine). Currently, the situation has improved slightly in the EU and there are no critical shortages. However, it is anticipated that constraints in the supply will continue throughout 2024. The initial study was conducted to better anticipate potential shortages and its impact on appropriate patient management, as it is important to assess the evolution of prescriptions over time and get an overview of how these ADHD medicines are used across Europe. The Spanish Regulatory Authority (AEMPS) after having seen the results of the initial study has asked the EMA if we could repeat the study with additional data partners, especially Spanish ones as the network expanded in this country since the first FA request.
Research question and objectives
The overall aim of this study is to characterise the use of ADHD medications in the period of 2010 to 2023.
The specific objectives are:
1. To estimate the monthly and yearly period prevalence of use of each ADHD medicine, overall and stratified by age and sex in each database.
2. To estimate the monthly and yearly incidence of use of each ADHD medicine, overall and stratified by age and sex in each database.
3. Among new users of each ADHD medicine, to identify the indication at the time of the initial of the prescribing/dispensing, overall and stratified by age and sex.
4. Among new users of each ADHD medicine, to estimate the initial dose, cumulative dose, and time on treatment of the initial medication, overall and stratified by age and sex.
5. Among new users of any ADHD medicine, to estimate the total treatment duration, number of prescriptions overall and by medicine, stratified by initial medicine, age, and sex.
6. To identify the treatment pathway of each individual who initiated an ADHD medicine, including treatment add-on, switch, and concurrent medication/co-prescribing, stratify by calendar time of initiation, age, and sex.
Methods
Study design
Population-level drug utilisation study (Objectives 1 and 2)
Patient-level utilisation study (Objectives 3 – 6, new user cohort study)
Population
In the population-level utilisation of ADHD medications (prevalence, incidence), all people aged 3 years and older, registered in the respective databases since 1st of January of 2010 to the latest available data, with at least 365 days of prior data availability, will be included.
In the patient-level utilization of ADHD medications, new users will be identified using the first record of any of the ADHD medications of interest within the study period, having no previous records for the study medication during the 12 months before cohort entry.
Variables
Drugs of interest: Five approved medications for the treatment of ADHD in Europe: methylphenidate, dexamphetamine, lisdexamfetamine, atomoxetine and guanfacine.
Data source
• SIDIAP, covering primary care and linked hospital data from Catalonia, Spain
• BIFAP, covering Spanish primary care
• DK-DHR, linked national registries from Danmark
• NLHR, linked national registries from Norway
• InGef RDB, national wide claims data with primary and secondary care from Germany
• SMPA-GU, linked national registries from Sweden
Statistical analysis
Objectives 1 to 2 are population-level drug utilisation study, monthly and yearly period prevalence and incidence use of each ADHD medications will be estimated, overall and stratified by age group and sex.
Objectives 3 to 6 are patient-level drug utilisation study. In Objectives 3 and 4, new user cohorts will be constructed for each ADHD medicine with pre-defined washout period, characteristics of user will be described, indication for the initial prescribing/dispensing will be estimated, overall and stratified by age and sex. Initial dose, cumulative dose, and length of the treatment will be calculated. In Objectives 5 and 6, we will construct new user cohorts of any ADHD medicine, estimate the total treatment duration and number
of prescriptions. Treatment pathways will be defined and proportion of individuals in each path and the length of each treatment stage will be reported.
For all analyses, a minimum cell counts of 5 will be used when reporting results, with any smaller counts will be noted as “<5”.

Rationale and background
Cystic fibrosis (CF) is a progressive genetic disorder associated with significant morbidity and premature mortality, primarily affecting the respiratory and gastrointestinal systems. It leads to chronic lung infections, pancreatic insufficiency, and other complications requiring comprehensive, lifelong management. This study aims to generate epidemiological evidence on the clinical haracteristics and monitoring of individuals diagnosed with CF across Europe between 2015 and 2024.
Research question and objectives
Research question:
What are the demographic and clinical characteristics of individuals diagnosed with cystic fibrosis (CF) in Europe between 2015 and 2024?
Study objectives:
1. To characterise individuals newly diagnosed with CF in terms of demographics, pre-specified comorbidities, Pseudomonas aeruginosa colonisation, CF screening, genotyping test and CFTR modulator treatment use, overall and stratified by paediatric and adult populations.
2. To characterise timing and availability of key clinical measurements including Forced Expiratory Volume (FEV), height, weight, Body Mass Index (BMI) measurements, sweat chloride levels and genotyping tests in
individuals who initiated any CFTR modulator treatment after CF diagnosis, overall and stratified by paediatric and adult populations.
3. To estimate the background incidence rates of pre-specified events of special interest: susceptibility for influenza virus infections, cataract, depression, anxiety and hepatotoxicity by treatment, in the CF population, overall and stratified by paediatric and adult populations and by calendar year.
4. To measure the incidence of pulmonary exacerbation among individuals newly diagnosed with CF overall and stratified by country/database, paediatric and adult populations, sex and time since diagnosis (one and two years post-diagnosis).
Methods
Study design
This retrospective cohort study aims to characterise individuals newly diagnosed with CF in terms of demographics, Pseudomonas aeruginosa colonisation, pre-specified comorbidities, CF screening test and genotyping test and CFTR modulator treatment use (objective 1), clinical characteristics including key clinical measurements (FEV, height, weight, BMI), sweat chloride levels and genotyping tests (objective 2) and to estimate the incidence of selected events of special interest and pulmonary exacerbation (objective 3 and 4).
Study period
1st January 2015 to 31st December 2024 (or latest available).
Study population
New CF diagnosis cohort (objective 1, 3 and 4): The study population will include all individuals with a first recorded diagnosis of CF in the period between 1st January 2015 and 31st December 2024 (or latest available). To ensure sufficient follow-up, only individuals diagnosed no later than 180 days prior to the end of data availability in each database will be included. Eligible individuals must have at least one year of data visibility prior to the date of CF diagnosis. The requirement of one year prior data availability will not hold or children below 1 year of age.
New CFTR modulator user cohort (objective 2): The study population will include individuals with a first diagnosis of CF in the period between 1st January 2015 and 31st December 2024 (or latest available) who initiated any CFTR modulator therapy after CF diagnosis. To ensure sufficient follow-up, only individuals diagnosed with CF at least 180 days before the end of data availability in each data source will be included.
Eligible individuals must have at least one year of prior data visibility prior to the date of CF diagnosis and no use of CFTR modulator therapy in one year preceding treatment initiation. This requirement will not hold for children < 1 year of age. Condition of interest: cystic fibrosis Variables Medication of interest: CFTR modulator therapy CFTR modulator therapy WHO ATC classification code · Ivacaftor R07AX02 · Ivacaftor and lumacaftor R07AX30 · Ivacaftor and tezacaftor R07AX31 · Ivacaftor, tezacaftor and elexacaftor R07AX32 · Deutivacaftor, tezacaftor and vanzacaftor R07AX33 Pre-specified comorbidities: depression, anxiety, sleeping disorders, pregnancy, congenital adverse events, diabetes, liver morbidity or mortality (if not feasible overall mortality), bone content (or measurements of bone content), gastro-intestinal complaints including constipation, acid reflux and abdominal pain. Events of special interest: susceptibility for influenza virus infections, cataract, depression, anxiety, hepatotoxicity by treatment, pulmonary exacerbations. Data sources 1. Assistance Publique – Hôpitaux de Marseille (APHM), France 2. Hospital Universitario 12 de Octubre (H12O), Spain 3. Norwegian Linked Health Registry data (NLHR), Norway 4. Research Repository @Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (POLIMI), Italy 5. The Information System for Research in Primary Care (SIDIAP), Spain 6. Semmelweis University Clinical Data (SUCD), Hungary Statistical analysis Descriptive characterisation will be performed at the patient level (objective 1). Age and sex at the time of the first recorded diagnosis of CF will be reported. The index date is defined as the date of the first recorded CF diagnosis for each individual. The number and percentage of individuals with a record of the prespecified condition of interest, colonisation with Pseudomonas aeruginosa, CF screening, genotyping test or CFTR modulator use will be assessed during pre-defined time windows. The statistical analysis will be conducted using “CohortCharacteristics” R package based on OMOP-CDM mapped data. Clinical characterisation (objective 2) will include age and sex at the date of incident CFTR modulator initiation. Additionally, the number and proportion of individuals initiating CFTR modulator treatment with available record of clinical measurements (FEV, height, weight, BMI) at index date and during pre-defined time windows, will be reported overall and stratified age. If available, clinical measurements (FEV, height, weight, BMI) will be summarised using minimum, quartiles and maximum values at index date and during pre-defined time windows, overall and stratified age groups. Similarly, number and proportion of individuals initiating CFTR modulators with a record of sweat chloride and genotyping tests will be reported at the index date and during the pre-defined time windows, overall and stratified by age. Results of sweat chloride levels and genotyping tests (if available) will also be reported, overall and stratified by age. The statistical analysis will be conducted using “CohortCharacteristics” R package based on OMOP-CDM mapped data. Incidence rates of pre-specified events of special interest (objective 3) will be estimated following CF diagnosis. The pre-specified events of interest are susceptibility for influenza virus infections, cataract, depression, anxiety and hepatotoxicity by treatment. These incidence rates will be expressed as the number of individuals with the event of interest following new CF diagnosis per 1,000 person-years of the individuals fulfilling the inclusion and exclusion criteria. Incidence rates will be reported overall and stratified by paediatric and adult populations and calendar year. The statistical analyses will be performed based on OMOP-CDM mapped data using the “IncidencePrevalence” R package. Incidence rates of newly diagnosed pulmonary exacerbation (objective 4) will be estimated following CF diagnosis. The results will be expressed as the number of individuals with the pulmonary exacerbation per 1,000 person-years of the individuals fulfilling the inclusion and exclusion criteria. Incidence rates will be calculated for consecutive yearly intervals since the CF diagnosis (index date), with a maximum follow-up period of 24 months. Incidence rates will be stratified by paediatric and adult populations and sex. These statistical analyses will be performed based on OMOP-CDM mapped data using the “IncidencePrevalence” R package. For all analyses a minimum cell counts of 5 will be used when reporting results, with any smaller counts obscured.

Rationale and background
Childhood hypertension (CHT), defined as elevated blood pressure in children and adolescents, is a significant health concern with implications for both short- and long-term health outcomes. CHT can be classified into two main categories. Primary hypertension refers to cases without an identifiable underlying cause, while hypertension that results from a specific underlying, potentially reversible cause, is classified as secondary hypertension. Among the pharmacological options available for managing CHT, angiotensin receptor blockers, commonly referred to as sartans, are among the recommend first-line antihypertensive treatments. However, real-world data on prevalence of CHT and the prescribing patterns of sartans and other antihypertensive medications in paediatric populations remain limited. This study aims to generate real-world evidence on the prevalence of CHT and the prescribing patterns of sartans and other antihypertensive medication among individuals with CHT across Europe to support regulatory decision-making and inform clinical practice.
Research question and objectives
Research question
What is the real-world prevalence of childhood hypertension and antihypertensive medication prescribing among patients with childhood hypertension over time across Europe?
Study objectives
1. To estimate the annual prevalence of childhood hypertension. Results will be stratified by age group (children vs. adolescents), sex, and type of hypertension (primary vs. secondary). 2. To estimate the annual prevalence of prescribing of sartans and other antihypertensive medications in patients with childhood hypertension. Results will be stratified by drug class, age group (children vs. adolescents), sex, and type of hypertension (primary vs. secondary).
Methods
Study design
• Descriptive disease epidemiology study employing a retrospective cohort study at population level to describe the prevalence of childhood hypertension (objective 1)
Drug utilisation study employing a retrospective cohort study at patient level to describe the prevalence of prescribing of sartans and other antihypertensive medication (objective 2) Index date
(objective 1): Date of childhood hypertension diagnosis
Index date (objective 2): Date of prescription of pre-specified antihypertensive medication in individuals with childhood hypertension.
The study period for recruitment is from 1st of January 2015 to 31st of December 2024.
Individuals are followed up until 1) end of study period (31st of December 2024), 2) end of data availability, 3) loss to follow up, 4) age = 19 years, or 5) death, whichever came first.
Population
The study population includes all children who meet the eligibility criteria at study entry and are present in the database during the recruitment period (from 01/01/2015 to 31/12/2024). Eligibility criteria are as follows:
• Individuals aged 18 years or younger at the time of study entry.
• Diagnosis of childhood hypertension (relevant for objective 2).
Variables
Outcomes
Condition of interest: childhood hypertension (CHT)
Drugs of interest: sartans and other antihypertensive medication drug classes (reported at WHO ATC level 3)
Relevant covariates: age group (children aged >0 to <13 years vs. adolescents aged =13 to <19 years), sex, and type of hypertension (primary vs. secondary) Data source 1. Finland: Hospital District of Helsinki and Uusimaa (FinOMOP - HUS) 2. Finland: Tampere University Hospital patient cohort (FinOMOP - TaUH Pirha) 3. Germany: InGef Research Database (InGef RDB) 4. Hungary: Semmelweis University Clinical Data (SUCD) 5. Norway: Norwegian Linked Health Registry data (NLHR) 6. Spain: Base de Datos para la Investigación Farmacoepidemiológica en el Ámbito Público (BIFAP) 7. Spain: The Information System for Research on Primary Care (SIDIAP) Study size No sample size has been calculated, as this is an exploratory study which will not test a specific hypothesis. Based on a preliminary feasibility assessment, the estimated number of record counts for CHT in the databases included in this study ranges from 5,800 (FinOMOP - TaUH Pirha) to 30,400 (SUCD). The estimated number of record counts for sartans in children in the databases included in this study ranges from 1,100 (SUCD) to 63,600 (BIFAP). Statistical analysis Yearly period prevalence (expressed as proportion) of 1) CHT and 2) pre-specified antihypertensive medication among individuals with CHT will be estimated. Prevalence will be calculated for children aged =18 years old, both overall and stratified by age categories, sex, and type of hypertension. The statistical analyses will be conducted on OMOP-CDM mapped data using the “IncidencePrevalence” R package. A minimum cell counts of 5 will be used when reporting results, with any smaller count reported as “<5”.

Rationale and background
During the revision of the European Medicines Agency (EMA) Guideline on Influenza Vaccines, it was agreed that the optimal way to monitor the performance of influenza vaccines was to generate high-quality vaccine effectiveness data. However, there are identified challenges to generating annual brand-specific influenza vaccine effectiveness (IVE) evidence from previous European initiatives. With the need for real-world evidence on influenza vaccines, the current study will contribute to informing EMA on the opportunities and challenges of conducting brand-specific IVE studies within the DARWIN EU® network. Such IVE studies aim to provide robust evidence to support decision-making by EMA.
Research question and objectives
Objectives
The aim of this study is to assess the availability, quality, and completeness of fit-for-purpose data sources that record seasonal influenza vaccine exposure, including brand where available, as well as influenza-related clinical outcomes and covariates relevant for influenza vaccine effectiveness (IVE) studies.
The specific objectives of this study are:
1. To estimate the period prevalence of influenza vaccination in the general population for each influenza season from 2015/16 to 2023/24, overall and stratified by age group and sex.
2. To characterise influenza vaccine use within each influenza season by vaccine brand and route of administration, stratified by age group.
3. To describe the baseline characteristics of individuals receiving any influenza vaccine in each influenza season, including demographics, comorbidities, and receipt of other vaccinations.
4. To estimate the incidence rates of influenza-related clinical outcomes, hospitalisations, and deaths in each influenza season, both in the general and vaccinated populations, overall and stratified by age group.
Methods
Study design
. Population-level drug utilisation study (Objective 1)
. Patient-level characterisation (Objective 2 and 3)
. Population-level descriptive epidemiology study (Objective 4)
Objective 1: Population-level drug utilisation on influenza vaccine
Population
The study population will include all individuals present in the database during the study period 01/08/2015 to 31/07/2024, or to the end of available data. Individuals with missing information on sex and age will be excluded.
Variables
Exposure:
Not applicable
Outcome:
Influenza vaccine
Covariates:
The following covariates will be used for stratification:
• Age group (<6 years, 6-17 years, 18-64 years, =65 years) • Sex Statistical analysis Period prevalence of influenza vaccines will be estimated in the general population for each influenza season from August to July, overall and stratified by age group and sex. The statistical analyses will be performed based on OMOP CDM mapped data using “IncidencePrevalence” R package. A minimum cell counts of 5 will be used when reporting results, with any smaller count reported as “<5”. Objective 2: Patient-level characterisation on type of influenza vaccine Population The study population will include individuals who were present in the database and received an influenza vaccine during the study period 01/08/2015 to 31/07/2024, or to the end of available data. Individuals with missing information on sex and age will be excluded. Variables Exposure: Influenza vaccine Outcome: Not applicable Covariates: The following covariates will be used to characterise type of influenza vaccine: • Vaccine brand, route of administration The following covariates will be used for stratification: • Age group (<6 years, 6-17 years, 18-64 years, =65 years) Statistical analysis Patient level characteristics on type of influenza vaccine in each influenza season on predefined covariates of interest will be reported as counts and proportions. The statistical analyses will be performed based on OMOP CDM mapped data using “CohortCharacteristics” R package. A minimum cell counts of 5 will be used when reporting results, with any smaller count reported as “<5”.

Rationale and background
Acute myeloid leukaemia (AML) is an aggressive haematological malignancy characterised by the uncontrolled proliferation of myeloid precursors. It primarily affects older adults but is also diagnosed in children. Despite advances in diagnostics and treatment, survival remains poor, especially among elderly patients. Diagnosis relies on blast counts and genetic markers, with evolving classifications emphasising molecular features. Standard treatment includes induction chemotherapy and, in eligible patients, haematopoietic stem cell transplantation. Although novel targeted therapies show promise, further evidence is needed to support their safety. This study aims to generate real-world evidence on AML incidence, patient characteristics, treatment patterns, and survival, utilising routinely collected healthcare data, to inform both clinical and regulatory decision-making.
Research question and objectives
Research questions
What real-world data and evidence is currently available to contextualise treatment choices and outcomes in AML patients?
Objectives
This study aims to estimate the incidence of AML and characterise patients with AML in terms of comorbidities, diagnostic tests, treatments, and survival.
Specific objectives are:
1. To estimate the annual incidence of AML in children (<18 years old) and adults (=18). 2. To characterise AML patients in terms of the comorbid conditions, medications, procedures, and diagnostic measurements. 3. To describe treatment patterns (including hematopoietic stem-cell transplantation) in AML patients. 4. To estimate overall survival 1, 3, and 5 years for patients with AML. Methods Study design Retrospective cohort studies will be conducted using routinely collected health data from five databases across four European countries. A population-level descriptive epidemiology study will address annual AML incidence (objective 1), and a patient-level characterisation study will address the remaining objectives (objectives 2 to 4). Population Objective 1: All individuals present in the respective databases during the study period (January 1, 2015, to MODEL DE SOL·LICITUD 2 IMP-126-CT Versió 07 December 31, 2024, or until the end of available data). Objectives 2–4: All patients diagnosed with AML within the same period. Variables Sex (female/male), age (continuous and age groups 0 to 17; =18; 18 to 39; 40 to 59; 60 to 79; =80 years), calendar year, study period (2015–2020, 2021–2024), medications, comorbidities, procedures, and diagnostic measurements. Outcomes Diagnosis of AML (objective 1), death from any cause (objective 4) Data sources 1. Croatia: Croatian National Public Health Information System (NAJS) 2. Germany: InGef Research Database (InGef RDB) 3. Netherlands: Netherlands Cancer Registry (NCR) 4. Spain: The Information System for Research on Primary Care (SIDIAP) 5. Multiple countries: HARMONY - Acute Myeloid Leukaemia (HARMONY-AML) Study size No sample size has been calculated, as this is an exploratory study that will not test a specific hypothesis. Statistical analysis Population-level descriptive epidemiology: Annual incidence rates per 100,000 person-years will be estimated overall and stratified by sex and age. The statistical analyses will be performed based on OMOP CDM mapped data using the “IncidencePrevalence” package. Only NAJS, InGef, and SIDIAP databases will be used in this objective. Patient-level characterisation: Demographics (age and sex) will be described at the time of AML diagnosis. Large-scale patient-level characterisation will be conducted at any time before, at the date of AML diagnosis, and two years after, and describe demographics, comorbidities, medications, and procedures, using the “CohortCharacteristics” package. All treatments at the ingredient level and combinations of pre-specified medicines of interest initiated in patients with AML will also be described using the “TreatmentPatterns” package. Overall survival probabilities and restricted mean survival time (RMST) at 1, 3, and 5 years, as well as median survival, will be calculated using the “CohortSurvival” package. Results will be presented with 95% confidence intervals. A minimum cell count of 5 will be applied to all reporting results, with any smaller count reported as “<5”.

Rationale and background
Existing evidence from case reports and preclinical data raised concerns regarding the proarrhythmic potential of aliskiren, especially with underlying risk of atrial fibrillation. However, little is known about the usage of aliskiren, in particular characteristics of aliskiren users.
This study aims to characterise new aliskiren users to inform the planning and feasibility of a potential future safety study investigating risk of cardiac events.
Research question and objectives
Objectives
The objective of this study is to characterise new aliskiren users to inform the planning of potential future safety studies on aliskiren. The specific objectives are as follows:
1.
To characterise new aliskiren users in terms of demographics, comorbidities, and potential indications for aliskiren use, overall and stratified by age and by sex, during the study period of 2007–2024.
2.
To assess the use of medication, both prior to and after new aliskiren treatment initiation, overall and stratified by age and by sex, during the study period of 2007–2024.
3.
To estimate the number of people with both at least one aliskiren prescription/dispensation record(s) and a record of pre-specified cardiac events anytime during the study period (cross-cohort counts), overall and stratified by age and by sex.
Methods
Study design
Patient-level characterisation
Objective 1 and 2: Patient-level characterisation of new aliskiren users (new drug user cohort)
Population
The study population will include all individuals who received a new aliskiren prescription during the study period 01/01/2007 to 31/12/2024 (or the end of available data), with at least 365 days of database history available prior to the first aliskiren prescription, and with no aliskiren use in the 365 days prior to the “new” aliskiren prescription.
Variables
Exposure: •
Aliskiren
Covariates for characterisation:
•
Demographics: age, sex (Objective 1)
•
Comorbidities: cardiac arrhythmia, cardiomyopathy, heart failure, ischemic heart disease, myocardial infarction, stroke, venous thromboembolism, anxiety, chronic kidney disease, chronic liver disease, dementia, depressive disorder, diabetes, hyperthyroidism, hypothyroidism, malignant neoplastic disease (Objective 1)
•
Indication: hypertension (Objective 1)
•
Medication: agents acting on the renin-angiotensin system (excluding aliskiren), beta blocking agents (systemic), calcium channel blockers, diuretics, other antihypertensive agents, antiarrhythmic agents, antithrombotic agents, digoxin, ivabradine, acetylcholinesterase inhibitor, antibacterials for systemic use, antifungals for systemic use, antidepressants, antiemetics, antimalarial agents, antineoplastic agents, opioids, psycholeptics, psychostimulants (Objective 2)
Covariates for stratification:
•
Age groups
•
Below 18 years
•
18–64 years
•
65 years and above
•
Sex
Statistical analysis
Patient level characteristics of new aliskiren users, including demographics, comorbidities, medication, and potential indication for aliskiren treatment will be reported as counts and proportions. The statistical analyses will be performed based on OMOP CDM mapped data using CohortCharacteristics. A minimum cell counts of 5 will be used when reporting results, with any smaller count reported as “<5”. Objective 3: Patient-level characterisation of first-time aliskiren users (new drug user cohort, first-time user) Population The study population will include all individuals, who received a new aliskiren prescription during the study period 01/01/2007 to 31/12/2024 (or the end of available data), with at least 365 days of database history available prior to the first aliskiren prescription, and without any prior exposure of aliskiren. Variables Exposure: • Aliskiren Covariate for characterisation: • Cardiac events, as a composite of Atrial fibrillation Atrial arrhythmia other than atrial fibrillation Ventricular arrhythmias Sudden cardiac death • Cardiac arrhythmia • Atrial fibrillation • Atrial arrhythmia other than atrial fibrillation • Ventricular arrhythmias • Sudden cardiac death Covariates for stratification: • Age groups • Below 18 years • 18–64 years • 65 years and above • Sex Statistical analysis The number of persons with both first-time aliskiren use and with cardiac events any time before/after aliskiren treatment will be reported (person counts). The statistical analyses will be performed based on OMOP CDM mapped data using CohortCharacteristics. A minimum cell counts of 5 will be used when reporting results, with any smaller count reported as “<5”. Data sources 1. Denmark: Danish Data Health Registries (DK-DHR) 2. Spain: The Information System for Research on Primary Care (SIDIAP) 3. United Kingdom: Clinical Practice Research Datalink GOLD (CPRD GOLD) Study size No sample size has been calculated, as this is an exploratory study which will not test a specific hypothesis. Based on a preliminary feasibility assessment, the expected number of persons counts for aliskiren in the databases included in this study range from 2,300 (CPRD GOLD) to 11,000 (SIDIAP).

Rationale and background
Few studies on obesity and weight management have used anthropometric measurements, largely due to methodological challenges. This study aims to assess the availability and completeness of data on obesity, weight, and obesity-related variables across the network of DARWIN EU® data partners. These findings will inform the viability of conducting further Real-World Data (RWD) studies on obesity and related comorbidities.
Research question and objectives
1. What proportion of individuals within the DARWIN EU® network have records of obesity-related conditions, measurements, observations, and procedures?
2. What are the median number and values of anthropometric measurements and lifestyle factors recorded in the DARWIN EU® network?
3. How do the demographic and obesity-related conditions, medications, procedures, and lifestyle factors of individuals with a high body mass index (BMI) compare to those of individuals with a recorded condition of obesity within the DARWIN EU® network?
Objectives
1. To assess the proportion of individuals with records of obesity-related conditions, measurements, lifestyle factors, and procedures within the DARWIN EU® network
2. To characterise reporting of anthropometric measurements and lifestyle factors within the DARWIN EU network in terms of Median number (IQR) of BMI, weight, cholesterol, waist circumference, diet, and physical activity records per individual within the study period
3. To summarise the median value (min-max, Q1, and Q3) of BMI and weight measurements
4. To assess changes in the rate of BMI and weight measurements over time
5. To compare the characteristics of individuals with obesity based on disease codes versus those with obesity defined by BMI cutoff value in terms of demography, comorbidity, use of concomitant medications, procedures, and lifestyle factors
Methods
Study design
We will perform a retrospective cohort study with three components: (i) to assess the proportion of individuals with obesity-related variables (objective 1); (ii) to perform a patient-level characterisation to describe the characteristics of individuals with anthropometric, lab, and lifestyle measurements (objective 2); and (iii) a patient-level characterisation to describe the characteristics of individuals with obesity (objective 3).
Population
The study population will include all individuals present in the database during the study period 01/01/2010 to 31/12/2024 (or to the end of available data) and with at least 365 days of database history prior to index date (except for individuals in hospital data sources).
Variables
Outcome:
For prevalence estimation, outcomes will include condition records of obesity and measurements of BMI, weight, height, cholesterol, and waist circumference.
Relevant covariates:
This study will characterise by the following: occurrences of BMI, weight, height, cholesterol, and waist circumference measurements; the value of the measurements of BMI and weight; condition records of obesity, diabetes mellitus type 2, hypertension, ischemic heart disease, and chronic kidney disease; drug records of Glucagon-like peptide-1 (GLP-1) receptor agonists, Orlistat, Metformin, and Naltrexone-bupropion; procedure record of bariatric surgery; and observations of diet, exercise, and smoking status.
Data sources
1. Estonia: Estonian Biobank (EBB)
2. Italy: Research Repository @Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico (POLIMI)
3. Spain: Hospital Universitario 12 de Octubre (H12O)
4. Spain: Platafoma de Recerca en Informació Sanitària de les Illes Balears (PRISIB)
5. Spain: The Information System for Research on Primary Care (SIDIAP)
6. United Kingdom: Clinical Practice Research Datalink GOLD (CPRD GOLD)
7. United Kingdom: UK BioBank (UKBB)
Study size
No sample size has been calculated, as this is an exploratory study which will not test a specific hypothesis; instead, the study specifically aims to estimate the number of and describe the variables under study.
Statistical analysis
The period prevalence of obesity and obesity-related measurements will be estimated in all individuals in the data sources, overall and stratified by sex and age categories. Characteristics will be described by means of median age, sex, and the covariates of interest, which will be reported as counts and proportions. The statistical analyses will be performed based on OMOP common data model mapped data using the IncidencePrevalence and CohortCharacterisation R packages. A minimum cell counts of 5 will be used when reporting results.

Rationale and background
Terbinafine is a well-established antifungal agent indicated for the treatment of superficial mycoses, with widespread use across Europe in both oral and topical formulations. Monitoring its utilisation is essential to informing regulatory decision-making, particularly in relation to emerging safety concerns, such as antifungal resistance. This study aims to characterise the incidence and patterns of terbinafine use, describe the clinical profiles of treated patients, and examine treatment pathways.
Research question and objectives What are the patterns of use of terbinafine-containing products in Europe, 2015–2024?
1. To calculate the monthly and annual incidence of terbinafine use, overall and stratified by age and sex.
2. To characterise patients at the time of each terbinafine treatment initiation in terms of i) demographics, ii) indication for use, iii) comorbidities and co-administered medicines, iv) other antifungal and antibiotic treatments (6, 3, and 1 month prior to and 6 months following treatment initiation), and v) disease code for resistance (6 months before and 6 months after treatment initiation).
3. To report the number of treatment initiations, dose (initial, cumulative), and duration of terbinafine use, overall and stratified by indication of use.
4. To explore the treatment pattern following new terbinafine treatment initiation, overall and by type of dermatophytosis, including transitions between topical to systemic and combination therapies.
Note: SIDIAP can support the achievement of most of the study’s objectives; however, objectives deemed unfeasible due to data limitations will not be executed.
Methods
Study design
This retrospective cohort study aims to estimate population-level drug utilisation of terbinafine-containing products (objective 1), characterise individuals being treated with terbinafine (objective 2), evaluate treatment utilisation at the patient-level by assessing dose and treatment duration (objective 3), and describe patient-level treatment patterns (objective 4).Population
Population-level cohort (objective 1): The study population will include all individuals present in the data source during the study period between 1 January 2015 and 31 December 2024 (or latest date available), and with at least 1 year of data visibility prior to the index date. Children <1 year of age will be excluded. New terbinafine user cohort (objectives 2, 3, and 4): All individuals with a new record of a terbinafine containing product in the period between 1 January 2015 and 31 December 2024 (or latest date available). Eligible individuals must have at least 1 year of data visibility prior to becoming eligible and no use of the terbinafine products in the previous 1 year. To ensure sufficient follow-up, only individual who initiate terbinafine treatment at least 1 year prior the end of data availability in each data source will be included. Children <1 year of age will be excluded. For objectives 2 and 3, the cohort will include all new terbinafine treatment episodes meeting the washout criteria. Individuals may contribute multiple treatment episodes, provided each is preceded by 1 year washout period. For objective 4, only the first recorded terbinafine prescription per individual during the study period will be considered. Statistical analysis Population-level utilisation of terbinafine-containing products (objective 1): Monthly and annual incidence rates of terbinafine use will be estimated and expressed as the number of terbinafine treatment initiations per 1,000 person-years among individuals fulfilling the inclusion and exclusion criteria. Incidence rates will be calculated overall and stratified by age group (=18 years and >18 years) and sex. Estimates will be given together with 95% Poisson confidence intervals. The statistical analyses will be performed based on OMOP CDM mapped data using the IncidencePrevalence R package. Patient-level utilisation of terbinafine-containing products (objectives 2 and 3): Patient demographics (age, sex) will be assessed at the date of terbinafine prescription for each new treatment episode (after one year washout). Indication of use will be estimated at treatment initiation (index date), and across predefined time windows at 6, 3, and 1 month prior to terbinafine treatment initiation. Comorbidities and co-administered medication will be evaluated at the start of each treatment episode (index date) and within one year prior to the terbinafine treatment episode. Comorbidities and comedication will also be evaluated any time prior to the treatment initiation. Pre-specified antifungal and antibiotic treatments will be evaluated 6, 3, and 1 month prior to and 6 months following treatment initiation. The proportion of patients with a disease code for resistance will be evaluated 6 months before and 6 months after. Number of treatment initiations will be reported. Initial and cumulative dose, as well as treatment duration, will be estimated, and the minimum, p25, median, p75, and maximum will be provided. These analyses will be conducted using CohortCharacteristics and DrugUtilisation R packages based on OMOP CDM mapped data. Patient-level characterisation (objective 4): The treatment pattern following the first recorded terbinafine prescription during the study period will be presented by Sunburst and Sankey diagrams, which will provide information on sequences of terbinafine-containing products and other antifungal products over time. These analyses will be stratified by indication. The statistical analysis will be performed based on OMOP CDM mapped data using the TreatmentPatterns R package. A minimum cell counts of 5 will be used when reporting results, with any smaller count reported as “<5”.

Varilrix and Varivax are authorised for prevention of varicella infection (chickenpox) in adults and children aged 9 – 12 months and older. Both vaccines contain live-attenuated varicella virus (OKA strain) The EMA Pharmacovigilance Risk Assessment Committee (PRAC) is reviewing the risk of encephalitis associated with these vaccines following a report of a fatal case in a paediatric recipient of Varilrix (PRAC meeting highlights June 2025). These vaccines are widely used across the EU, and encephalitis is already listed as an adverse reaction in their product information based on rare reports during post-marketing surveillance. At its July 2025 meeting, PRAC recommended updating the product information of Varilrix and Varivax to provide further details on the severity of encephalitis risk (PRAC meeting highlights July 2025). Considering the seriousness of encephalitis and the regulatory context, further investigation is needed. In particular, timely real-world evidence (RWE) is needed to evaluate the association between varicella vaccination and risk of encephalitis in the paediatric population.
Research question and objectives
This study aims to evaluate the association between varicella vaccines (V)/varicella-containing Measles-Mumps-Rubella vaccines (MMRV)/varicella-containing Measles-Rubella vaccines (MVR) and the occurrence of encephalitis in paediatric populations.
Objectives
The specific objectives of this study are:
1.To describe vaccine uptake of V/MMRV/MVR, by vaccine type, brand, dose, country, and age groups, and to describe the characteristics of vaccine recipients.
2.To describe the background rates of encephalitis in the general paediatric population, and to estimate crude incidence rates of encephalitis following varicella infection (chickenpox).
3.To assess the association between V/MMRV/MVR vaccines and varicella infection (chickenpox) with encephalitis among children and adolescents aged 9 months to 18 years. Methods
Study design
Objectives 1 and 2: Population-level descriptive epidemiology and drug utilisation studies (descriptive studies on vaccine uptake, patient characterisations, crude incidence rates of encephalitis after varicella infection (chickenpox), and background rates for encephalitis)
Objective 3: Self-controlled risk intervals (SCRI) analyses
Note: SIDIAP can support the achievement of most of the study’s objectives; however, objectives deemed unfeasible due to data limitations (e.g., vaccines brand) will not be executed.
Population
The study population will include all individuals aged between 9 months and 18 years who are present in the data source during the study period from 1st January 2015 until the latest date of data availability, with at least 365 days of data availability before (reduced to 90 days for children =1 years) index date.
Variables
Exposure:
Primary exposure: varicella vaccines (V) and varicella-containing vaccines (MMRV/MVR). The primary exposure of V will be further categorised into V only, and V+MMR recorded on the same date, as well as by the number of doses received [first or second dose].
Secondary exposures: varicella infection (chickenpox) (overall and severe (defined as requiring hospitalisation) only).
Outcome:
Objective 1: Vaccine uptake and vaccination coverage.
Objective 2 and 3: Encephalitis, defined according to a previous DARWIN EU® study (DARWIN EU® – Background incidence rates of selected vaccine adverse events of special interest (AESIs) ). A 90-day washout period will be used to define incident encephalitis.
Relevant covariates: Age groups, sex, calendar year, season.
Statistical analysis
All analyses will be conducted separately for each data source, and will be carried out in a federated manner, allowing analyses to be run locally without sharing patient-level data. To comply with data privacy regulation, cell counts <5 will be suppressed. Results from all analyses will be presented separately for each data source. Additionally, for SCRI, we will pool the effect estimates for the main analysis (V1) across data sources using random effect meta-analyses, if all data sources have event counts =5 for the respective analyses. We will estimate the vaccine uptake and coverage of children vaccinated in the relevant age group for each vaccine type and dose. Vaccine uptake will be estimated as the absolute number of children and adolescents who received a specified vaccine dose(s) among eligible children. Vaccination coverage will be estimated as the proportion of eligible children who received the specified number of vaccine doses in the relevant age group/at the relevant age milestone. We will report the vaccine uptake and coverage by year. We will then describe the characteristics of vaccine recipients, including age at vaccination, sex, history of other live-attenuated vaccines, and history of encephalitis. Crude incidence rates of encephalitis will also be estimated among a cohort of children and adolescents with a recorded varicella infection (chickenpox) (event rates per 100,000 patient years, with 95% CI), restricted to the first 42 days post diagnosis. Background rates of encephalitis will be estimated for the study period, stratified by age groups. Incidence rate ratios (IRRs) will be estimated using a self-controlled risk intervals (SCRI) design comparing rates of encephalitis in the immediate time after vaccination/varicella infection

Rationale and background
Vasomotor symptoms (VMS), including hot flashes and night sweats, affect up to 80% of menopausal women and significantly impair quality of life. Hormone replacement therapy (HRT) remains the primary treatment for VMS, with various formulations and regimens available depending on clinical factors. Despite its widespread use, there are risks associated with HRT, which vary by age, timing, and treatment type. However, contemporary data on HRT utilisation patterns in Europe are limited, highlighting the need for real-world evidence to inform regulatory decisions.
Research question and objectives
Research question
What are the patterns and trends in hormone replacement therapy (HRT) utilisation among postmenopausal women in European countries over the past three decades?
Objectives
The specific objectives of this study are:
To describe the demographic and clinical characteristics of postmenopausal women, including: age,body mass index (BMI),
smoking status, and: concomitant conditions. HRT type (natural or synthetic) (if feasible). To estimate annual prevalence of HRT use and treatment characteristics among postmenopausal women, overall and stratified by: HRT formulation. route of administration (systemic or local). HRT type (natural or synthetic) (if feasible).
Estimates will additionally be stratified by age group at treatment initiation.
1. To estimate the duration of HRT use among postmenopausal women initiating HRT, overall, and by age group.
2. To describe HRT treatment patterns among postmenopausal women over ten years following HRT initiation, overall, and by age group.
Methods
Study design
A descriptive retrospective cohort study will be conducted using routinely collected health data from 5 data sources from 4 countries across Europe.
Population
The study population will include postmenopausal women defined as i) women aged 50 to 65 years, and ii) women aged <50 years with a prior history of conditions indicating premature or early menopause. This definition will be applied consistently across study objectives. Patient-level characterisation (objective 1): The study population will include postmenopausal women stratified into two cohorts: new HRT users and non-HRT users. Population-level drug utilisation (objective 2): The study population will include all postmenopausal women who meet the criteria defined above during the study period. Patient-level drug utilisation (objectives 3 and 4): The study population will include postmenopausal women initiating HRT during the study period. Variables Exposure: HRT treatment including oestrogen only, progestogen only, oestrogen + progestogen, oestrogen + testosterone, oestrogen + progestogen + testosterone, or other available formulations. Indication: Postmenopausal symptoms/disorders Data source 1. Denmark: Danish Data Health Registries (DK-DHR) 2. Germany: IQVIA Disease Analyzer Germany (IQVIA DA Germany) 3. Spain: Base de Datos para la Investigación Farmacoepidemiológica en el Ámbito Público (BIFAP) 4. Spain: The Information System for Research on Primary Care (SIDIAP) 5. United Kingdom: Clinical Practice Research Datalink GOLD (CPRD GOLD) Statistical analysis Patient-level characterisation (objective 1): Clinical characteristics of interest will be reported as counts and proportions for categorial variables, and as medians with interquartile ranges (IQR) for continuous variables. Population-level drug utilisation (objective 2): Annual prevalence of HRT use will be estimated and expressed as proportion of women using HRT among postmenopausal women. The annual prevalence estimates will also be estimated for HRT formulation (e.g., oestrogen only, progestogen only, oestrogen + progestogen, oestrogen + testosterone, oestrogen + progestogen + testosterone, or other available formulations), route of administration (systemic or local), and HRT type (natural or synthetic) (if feasible). All prevalence estimates will be reported overall and stratified by age group at treatment initiation (<50 years, 50–60 years, and >60 years). Patient-level drug utilisation (objectives 3 and 4): Treatment duration will be estimated and the minimum, q25, median, q75, and maximum will be provided. The treatment pattern will be described based on the sequence of HRT treatment over time. These analyses will be performed overall, and stratified by age group (<50 years, 50–60 years, and >60 years). Potential limiations and considerations Menopausal status is not directly recorded in the database, though it will be inferred based on the age of the women included. Additionally, we do not have information on the type of HRT, such as whether it is natural or synthetic and, therefore, SIDIAP will not contribute to that specific sub-objective, but it will contribute to the rest of study objectives.

Rationale and background
Thromboembolic events are a common complication for individuals with cancer, with risk varying according to the cancer site, suggesting cancer-specific mechanisms playing a role in the occurrence of these events. Haematological malignancies and lung, pancreas, stomach, bowel, and brain cancers are generally associated with a high risk of clot formation, whilst prostate and breast cancers are associated with low risk of thrombosis.
When a safety signal of a thromboembolic event appears in cancer populations, it can be challenging to assess a potential association with the oncologic treatment without reliable information on the background risk. This study is intended to address this knowledge gap by generating evidence on the time to onset of different venous thromboembolic events among adults with selected cancer types.
Research question and objectives
Research question
What was the time to onset of venous thromboembolic events in adults newly diagnosed with each type of selected cancer during the period 2016–2022?
Objectives
The aim of this study is to estimate time to onset of venous thromboembolic events in adults with each type of selected cancer.
The specific objectives of the study are:
1. To estimate the probability of not having thromboembolic events at 6-month intervals within 5 years in adults with each type of selected cancer, overall and stratified by age group, sex, and study subperiod.
2. To estimate median time to onset of venous thromboembolic events in a cohort of adults with thromboembolic events with each type of selected cancer, overall and stratified by age group, sex, and study subperiod.
Methods
Study design
Population-based cohort study. The index date, i.e., date of cohort entry, will be the date of the first cancer diagnosis. Individuals are followed up until the earliest of occurrence of the outcome, loss to follow-up, end of data availability, end of the study period, or death.
Population
The study population will be the population that was included in the study EUPAS1000000440, of which this is a routinely repeated study. This study population will include all individuals aged 18 years and above with a primary diagnosis of one of the selected cancers (bone, brain, breast, colorectal, corpus uteri, kidney, leukaemia and lymphoma, liver, lung, melanoma, oesophageal, ovary, pancreas, prostate, stomach) during the inclusion period (from 01/01/2016 to 31/12/2022). Only individuals with an incident cancer diagnosis (excluding non-melanoma skin cancer), defined as a first cancer diagnosis after =365 days cancer-free history, will be included. Cancer cases and thromboembolic events will be identified based on appropriate computable phenotyping algorithms. Conditions in the OMOP CDM use the Systematised Nomenclature of Medicine (SNOMED) as the standard vocabulary for diagnosis codes. The International Classification of Diseases for Oncology, 3rd Edition (ICD-O-3) will also be considered for cancer diagnoses.
Other eligibility criteria will include at least 365 days of database history prior to index date and at least 365 days between index date and end of data availability in the data source.
Variables
Exposure:
Not applicable.
Outcome:
The outcomes will include thromboembolic events, specifically: deep vein thrombosis (DVT), pulmonary embolism (PE), venous thromboembolism (VTE, composite of DVT and PE), pelvic venous thrombosis (PVT), splanchnic vein thrombosis (SVT, including hepatic and extra-hepatic vein thrombosis), retinal vein thrombosis (RVT, including retinal central vein thrombosis), and disseminated intravascular coagulation (DIC).
Relevant covariates:
The following covariates will be assessed at index date: age group in years (18–34, 35–44, 45–54, 55–64, 65–74, 75–84, and =85), sex, and study subperiod (2016–2019 and 2020–2022). These variables will be used to stratify the results.
Data sources
1. Belgium: IQVIA Longitudinal Patient Database Belgium (IQVIA LPD Belgium)
2. Denmark: Danish Data Health Registries (DK-DHR)
3. Estonia: Estonian Biobank (EBB)
4. Finland: Finnish Care Register for Health Care (FinOMOP-THL)
5. Germany: IQVIA Disease Analyzer Germany (IQVIA DA Germany)
6. Netherlands: Integrated Primary Care Information (IPCI)
7. Spain: The Information System for Research on Primary Care (SIDIAP)
8. United Kingdom: Clinical Practice Research Datalink GOLD (CPRD GOLD) 9. United Kingdom: UK BioBank (UKBB)
Study size
No sample size will be calculated, as this is an exploratory study which will not test a specific hypothesis. Based on the results of the study EUPAS1000000440, the expected number of person counts will be the lowest for DIC (during 1-year follow-up: 5 in FinOMOP-THL – 171 in SIDIAP, with 0 counts in CPRD GOLD, EBB, IPCI, IQVIA DA Germany, and IQVIA LPD Belgium) and highest for VTE (during 1-year follow-up: 27 in IQVIA LPD Belgium – 4,597 in FinOMOP-THL).
Statistical analysis
Analyses will be conducted separately for each data source and carried out in a federated manner, allowing analyses to be run locally without sharing individual-level data.
Objective 1
The probabilities of not having thromboembolic events at 6-month intervals within 5 years in adults with each type of selected cancer will be assessed using the R package CohortSurvival, accounting for a competing risk of death.
Objective 2
The median time to onset of venous thromboembolic events in a cohort of adults with thromboembolic events with each type of selected cancer will be assessed using the R package CohortSurvival.
The R package CohortSurvival is designed to work with data in the OMOP CDM format to extract and summarise survival data applying the Kaplan-Meier method. The analyses will be conducted for the overall cohorts as well as by strata of age group, sex, and study subperiod.
Absence of diagnosis codes will be interpreted as a lack of the conditions themselves. A minimum cell count of 5 will be used when reporting results, with any smaller count reported as “<5” and zero counts as “0”.

Objetivos: 1. Estimar la exposición a la adiposidad a lo largo de la vida, incluyendo la edad de inicio y los años vividos con sobrepeso/obesidad, usando una base de datos poblacional longitudinal; 2. Investigar la asociación entre la exposición a la adiposidad a lo largo de la vida y el riesgo y la mortalidad por cáncer; 3. Investigar el papel de las comorbilidades y las intervenciones de pérdida de peso (cirugía bariátrica) en la asociación entre la exposición a la adiposidad a lo largo de la vida y el riesgo de cáncer. Fuente de información y métodos: utilizaremos datos de una base de datos prospectiva poblacional de España (SIDIAP). SIDIAP incluye registros electrónicos de atención primaria de salud pseudoanonimizados para >5,8 millones de personas. Los datos son recogidos por los profesionales de la salud durante visitas médicas desde 2006. Incluiremos personas de =2 años durante al menos un año. Implementaremos un enfoque de imputación múltiple de series temporales para tener información completa sobre el IMC para todos los participantes a diferentes edades. La adiposidad a lo largo de la vida se estimará utilizando valores de IMC repetidos a lo largo del tiempo. Los cocientes de riesgos se calcularán utilizando modelos de Cox y la no linealidad se estudiará utilizando splines cúbicos restringidos. Para el objetivo 3, el riesgo/mortalidad por cáncer estará relacionado en presencia/ausencia de comorbilidad o cirugía bariátrica. Impacto: Este proyecto mejorará sustancialmente nuestra comprensión del impacto de la adiposidad a lo largo del curso de la vida sobre el cáncer. Ayudará a identificar períodos críticos de la vida en los que se deben implementar estrategias de prevención y, por lo tanto, ayudará a mitigar los efectos del cáncer por sobrepeso/obesidad en la salud pública.

Objectives
The main aim of the project is to study the associations between urban environmental indicators and development and survival of 20 specific cancer sites using data from prospectively collected primary care records from 6 million people living in Catalonia. The specific objectives of the project are:
1. To investigate associations between urban environment indicators including air and noise pollution, access to green spaces, and unhealthy food availability, with the risk of development and survival to 20 specific cancer sites.
2. To investigate whether the possible associations between urban environment indicators and cancer development are mediated by obesity, physical activity, smoking, or alcohol exposures, as well as psychological well-being indicators (anxiety and depression).
3. To explore and understand the general population and cancer patient perspectives on the urban environment in relation to cancer development and survival.
4. To develop a health impact assessment to estimate the impact of potential urban environment interventions aimed at cancer.

Objectives: The main aim of this project is to estimate time trends in prevalence and incidence rates, and short- and long-term survival of site-specific cancers in the OHDSI network.
Design: This study will be a multinational observational cohort study and will be conducted using a network of large real world data sources that have been mapped to the Observational Medical Outcomes Partnership (OMOP) Common Data Model (CDM).
Setting: Population-based, electronic health records, claims and registry data from primary and secondary care.
Participants: Individuals with no prior history of cancer (for incidence and survival analyses only), and who have been on the database for at least 1 year before study entry.
Outcomes: Prevalent and incident cancer diagnoses and overall as well as 1-, 5-, and 10-year survival of site-specific cancers.
Data analyses: The OHDSI Cohort Diagnostics package will be used to assess the fitness of use of cancer data on each database. We will calculate prevalence (PR) and incidence rates (IR) with 95% confidence intervals (95%CI) for each year and study period by dividing the number of ever and first recorded cases of cancer, respectively, by 1,000 person-years of follow-up, overall and stratified by demographics and relevant comorbidities. The overall and 1-, 5-, and -10-year survival rates will be calculated as the percentage of people who have been diagnosed with cancer and are still alive during the study period as well as one or five years after diagnosis, respectively, per year and stratified by pre-defined subgroups. To assess the incidence trend over time, we will calculate the IRs in 5 year periods and then calculate the incidence rate ratios (IRRs) and their corresponding 95%CI to analyze the differences in incidence between the defined time periods.

Rationale and Background
The research agenda of the Vaccine Monitoring Platform jointly coordinated by EMA and the European Centre for Disease Prevention and Control (ECDC) includes the continuous assessment of COVID-19 vaccine effectiveness.
COVID-19 vaccines were authorised for use in the European Union. These vaccines, and any (future) adapted vaccines, would therefore benefit from post-authorisation studies to provide real-world evidence to guide regulatory and vaccination policies. A recent post-authorisation study performed in the Nordic countries, where near real-time data is available, showed that receipt of a bivalent BA4/5 mRNA booster as a fourth dose provides 67.8% protection against COVID-19 related hospitalisation. There is also evidence that effectiveness starts to wane after a few months. For regulatory purposes, such data are especially useful for the most recent variants, including XBB and later.
There is mounting evidence on post-acute outcomes of SARS-CoV-2 infection. This can include very specific outcomes such as cardiovascular events or the incidence of new-onset diabetes, or broader definitions such as the WHO clinical case definition for post COVID-19 condition. Data are needed regarding the COVID-19 vaccines effectiveness at preventing these outcomes. This is pertinent for the most recent variants, but equally important for older variants.

Objective(s)
To generate additional evidence on the effectiveness of COVID-19 vaccines at preventing severe COVID-19 and post-acute outcomes of SARS-CoV-2 infection.

Specifically, this study has 6 objectives:
1. To assess the effectiveness of COVID-19 vaccination for the prevention of severe COVID-19 related outcomes (COVID-19 related hospitalisation or COVID-19 related death)
2. To assess waning of the effectiveness of COVID-19 vaccination for the prevention of severe COVID-19 related outcomes (COVID-19 related hospitalisation or COVID-19 related death)
3. To assess the effectiveness of COVID-19 vaccination for the prevention of all-cause mortality in the 3- and 6-months following discharge for COVID-19 related hospitalisation
4. To assess the effectiveness of COVID-19 vaccination for the prevention of new-onset type 1 Diabetes Mellitus in the 12 months after a SARS-CoV-2 infection
5. To assess the effectiveness of COVID-19 vaccination for the prevention of new-onset type 2 Diabetes Mellitus in the 12 months after a SARS-CoV-2 infection
6. To assess the effectiveness of COVID-19 vaccination for the prevention of cardiovascular events in the 12 months after a SARS-CoV-2 infection

Research Methods
Study design: Population-level cohort studies

Data sources:
• Clinical practice Research Datalink (CPRD) GOLD, United Kingdom
• Integrated Primary Care Information Project (IPCI), The Netherlands
• The Information System for Research in Primary Care (SIDIAP), Spain

Additional databases can be added as part of a routine repetition of this study once they are successfully onboarded for DARWIN EU and meet feasibility requirements for this study.

Exposure:
Covid-19 vaccines BNT162b2 (Comirnaty) and mRNA-1273 (Spikevax), particularly the number of received vaccine doses per brand.
For those databases where this information is available, the 4th dose (2nd booster) will be stratified for monovalent (original strain) or adapted, bivalent (original strain + omicron ba1 or original strain + omicron ba4/5).
Analyses will be conducted separately for each vaccine brand.

Primary outcomes of interest:
1) Outcomes assessed from start of rollout of 4th vaccine dose/ 2nd booster dose program onwards:
1. COVID-19 related hospitalisation
2. COVID-19 related death
2) Outcome/s during periods with dominance of any SARS-CoV-2 variants:
3. All-cause mortality in the 3 months after discharge from a COVID-19 hospitalisation
4. All-cause mortality in the 6 months after discharge from a COVID-19 hospitalisation
5. Incidence of new-onset type 1 Diabetes Mellitus beyond the first 30d after SARS-CoV-2 infection
6. Incidence of new-onset type 2 Diabetes Mellitus beyond the first 30d after SARS-CoV-2 infection
7. Incidence of cardiovascular events (cerebrovascular disorders, dysrhythmias, ischemic and non-ischemic heart disease, pericarditis, myocarditis, heart failure and thromboembolic disease) in the 12 months after a SARS-CoV-2 infection
COVID-19 related hospitalisation (outcome 1, part of outcomes 3 and 4) is not available for IPCI and CPRD but will only be assessed in SIDIAP.

Study population:
All subjects aged 12 years and older, with at least 365 days of data availability before index date (ID) [ID defined as the date of the latest vaccine dose administered] AND data availability from 12/2020 onwards (i.e. the time when the roll-out of the vaccination campaign started) in the respective database will be included.

All studies will be carried out comparing 8 cohorts, which we defined based on varying degrees of vaccine exposure and period of predominant SARS-CoV-2 variant.

Outcomes 1-2 will be assessed in cohorts 1-2 (and 3-4 where available), outcomes 3-7 will be assessed in cohorts 5-8.
Unvaccinated groups will not be used as a comparator in our study for vaccine effectiveness research because they may be very different from vaccinated individuals regarding their risk of infection with SARS-Cov-2. This study therefore focusses on the association of varying degrees of vaccine exposure and COVID-19 related outcomes.

Study period:
Period of “start of roll-out 4th dose/2nd booster dose onwards”: from 01/08/2022 – last available data for each database.
Period of “XBB variant or later dominant”: 01/03/2023 – last available data for each database. Note: This period is not covered by any of the data cuts onboarded for DARWIN EU at the time of protocol submission.
Period of “any variant dominant”: 01/01/2021 (when the wider roll-out of the vaccination campaign started) – last available data for each database.

Statistical analyses:
All analyses will be conducted separately for each database, and will be carried out in a federated manner, allowing analyses to be run locally without sharing patient-level data. For each analysis, we will subsequently pool effect estimates across databases using random effect meta-analyses, I^2 for heterogeneity will be reported.
Cell counts <5 will be suppressed to comply with the database’s privacy protection regulations.

Rationale and Background:

Severe acute respiratory infection (SARI) caused by respiratory syncytial virus (RSV) has gained recognition as a global health problem with a high burden of disease. In children under 5 years, it is estimated that 3.6 million hospital admissions, and 101,400 deaths were attributable to RSV worldwide in 2019. RSV infection also represents a substantial health burden in older adults. It is estimated that 470,000 hospitalisations, and 33,000 in-hospital deaths in =60-year-old adults were attributable to RSV-related disease in high-income countries.
There have been substantial advances in the development of RSV vaccines, with several prophylactic candidates in late-phase clinical development. As of July 2023, the European Medicines Agency (EMA) has recommended granting a marketing authorisation for Arexvy and Abrysvo vaccines for use in the European Union. Arexvy is indicated for active immunisation for the prevention of lower respiratory tract disease caused by RSV virus in adults = 60 years. Abrysvo is indicated for the prevention of lower respiratory tract disease caused by RSV through: (a) passive protection in infants from birth through 6 months of age following maternal immunisation during pregnancy, (b) active immunisation of adults = 60 years. It is expected that more of these vaccines, using different platforms, will be approved by EMA in the coming year(s). Therefore, accurate information about RSV burden in high-risk groups is essential for decision-making to support the continuous assessment of their benefit/risk profile.
This study is expected to generate evidence that is complementary to the work carried out by European initiatives such as RESCEU; and PROMISE More importantly, the objective is to explore the feasibility of capturing adequate RSV-specific endpoints in the DARWIN EU® data sources (for example, availability of laboratory testing data) that may pave the way for effectiveness studies once the vaccines are being deployed and along their lifecycle, as part of the research agenda of the EU Vaccine Monitoring platform, a collaboration between EMA and the ECDC.

Research question and Objectives:

Research question
What are the age-specific disease frequencies, hospitalization rates, and mortality rates of Respiratory Syncytial Virus (RSV) infection in European countries over the past decade?

Study objectives
Objective 1: To estimate the incidence of RSV-related hospitalisation in the general population, stratified by year and age groups, during the period from January 1, 2013, to December 31, 2022.
Objective 2: To estimate the duration of RSV-related hospitalisation among patients diagnosed with RSV infection, stratified by year and age groups, between January 1, 2013, and December 31, 2022.
Objective 3: To estimate the prevalence of RSV-related intensive care unit (ICU) admissions among patients diagnosed with RSV infection, stratified by year and age groups, between January 1, 2013, and December 31, 2022.
Objective 4: To estimate the prevalence of RSV co-infections with other respiratory pathogens, specifically Influenza Viruses, Rhinoviruses, SARS-CoV-2, Parainfluenza Viruses, Adenoviruses, Metapneumovirus, and Enteroviruses, in the general population, stratified by year and age groups, during the period from January 1, 2013, to December 31, 2022.
Objective 5: To estimate RSV-related mortality rates among patients diagnosed with RSV infection, stratified by year and age groups, between January 1, 2013, and December 31, 2022.

Research Methods:

Study design:
Retrospective cohort study.
•Population-level cohort: Population-level descriptive epidemiology of the incidence of RSV-related hospitalisation (Objective 1), and prevalence of RSV co-infections with other respiratory pathogens (Objective 4) in the general population.
•Patient-level cohort: Patient-level characterisation to estimate duration of RSV-related hospitalisation (Objective 2), prevalence of RSV-related ICU admissions (Objective 3), and RSV-related mortality rates (Objective 5) in patients with diagnosed with RSV infection.

Population:
Population-level descriptive epidemiology: This analysis will include all individuals in the respective databases from 2013 to 2022 (or the latest available date if earlier), with a minimum of 1 year of data visibility prior to study entry date. However, this additional requirement will not be applicable to children aged <1 year. Patient-level characterization: This analysis will include all patients diagnosed with RSV infection between 2013 and 2022 (or the latest available date if earlier), with at least 1 year of data availability prior to their diagnosis. However, this additional requirement will not be applicable to children aged <1 year. Variables Drug of interest: None Condition of interest: RSV infection identified through SNOMED disease codes and LOINC laboratory test codes. Outcomes of interest: Study outcomes will include RSV-related hospitalisation, ICU admission, mortality rate, and co-infection with other respiratory pathogens (Influenza Viruses, Rhinoviruses, SARS-CoV-2, Parainfluenza Viruses, Adenoviruses, Metapneumovirus, and Enteroviruses). Data sources: 1. Clinical Data Warehouse of Bordeaux University Hospital (CHUBX), France 2. Clinical Practice Research Datalink GOLD (CPRD GOLD), United Kingdom 3. Estonian Biobank (EBB), Estonia 4. IQVIA Disease Analyzer Germany (IQVIA DA Germany), Germany 5. Institut Municipal Assistencia Sanitaria Information System (IMASIS), Spain 6. Sistema d’Informació per al Desenvolupament de la Investigació en Atenció Primària (SIDIAP), Spain Sample size: No sample size was calculated for this study as our primary objective is to describe the age-specific incidence rates of RSV-related disease outcomes in Europe, irrespective of the sample size. Based on a preliminary feasibility assessment, the estimated number of individuals with RSV infection in the included databases varied, ranging from 1,000 (CPRD GOLD) to 16,400 (SIDIAP). Additionally, specific counts for other databases are as follows: 6,100 (EBB), 6,700 (CHUBX), 9,100 (IQVIA DA Germany), and 9,800 (IMASIS). Data analysis: Data analysis will be conducted to estimate the number and rates of hospitalisation due to RSV infection (Objective 1) and the number and percentage of individuals with RSV co-infection with other respiratory pathogens (Objective 4) within the general population. Furthermore, the number and percentage of ICU admissions will be estimated among patients hospitalised due to with RSV infection (Objective 3). The statistical analyses will be performed on OMOP-CDM mapped data using the IncidencePrevalence R package, and stratified by age, calendar year and database. RSV-related mortality rates (Objective 5) will be calculated using the Kaplan-Meier (KM) method and data on time at risk of RSV-related death, defined as within 30 days of RSV infection. Results will be reported as plots of the estimated survival curves as well as the estimated probability of survival at 30 days. The statistical analysis will be performed on OMOP-CDM mapped data using the CohortSurvival R package, and stratified by age, calendar year and database. The duration of hospitalization will be calculated in patients with RSV infection. This will include key metrics such as the median, interquartile range (p25 and p75), maximum, and minimum days of hospitalization. Results will be provided stratified by age, calendar year and database. For all analyses a minimum cell counts of 5 will be used when reporting results, with any smaller counts obscured.

Rationale and Background
Shortage of essential medicines has a harmful impact on patient’s health by increasing mortality, adverse events, and therapy errors.
Since 2016, the European Medicines Agency (EMA) has published a public catalogue of medicines under surveillance due to shortage in more than one European country. The list includes information such as the reason for the shortage, and recommendations for patients, healthcare professionals and other stakeholders. The work of the task force that publish the catalogue of drug shortages was temporarily suspended between March 2020 and December 2021 due to the COVID-19 pandemic.
This study shall improve our understanding of drug shortages in routine health care delivery by showing trends over time as well as patient characteristics, including indication, treatment duration, and dose. The results will contribute to the European efforts to monitor use of critical medicines as part of the global fight against medicine shortage.
Research question and Objectives
The objectives of this study are:
i To investigate the incidence and prevalence of use of medicines with (suggested) shortage, including those listed as ongoing in the EMA shortages catalogue for =1 year and their alternatives by calendar year, stratified by healthcare setting for each database during the study period 2010-2023.

i To describe the incident and prevalent patients (including but not limited to duration of usage of the medicines of interest, the potential indication for prescribing/dispensing it, and dosage) stratified by calendar year), in order to observe changes in patient’s profiles

Research Methods
Study design
• Population level cohort study (Objective 1, Population-level drug utilisation study on medicines with [suggested] shortages and their alternatives)
• Patient level cohort study (Objective 2, Patient-level drug utilisation analysis describing patient characteristics, including duration of treatment, potential indication of the medicines of interest, and dose)

Population
Population-level drug utilisation study: All individuals present in the database in the period between 2010 and 2023 will be included. For this population, incidence and prevalence of use of medicines with (suggested) shortages and their alternatives will be explored.
Patient-level drug utilisation study: All new and prevalent users of medicines with (suggested) shortages and their alternatives in the period between 2010 and 2023. Patients can be eligible more than once during the study period.
Variables
Drug of interest: Drugs with (suggested) shortage, including ongoing shortages listed in the EMA shortages catalogue for =1 year, and their alternatives between 2010 and 2023 (see also section 9.3.1 – exposure)
Data sources
Open to any database from EHDEN data partners who finished their mapping to the OMOP CDM, this includes EHDEN consortium members (i.e. EFPIA).
Sample size
No sample size has been calculated.
Data analyses
Population-level drug utilisation study: annual period prevalence of the medicine use and annual incidence proportion, as described in section 9.7.5.1 – Population-level drug utilisation study.
Patient-level drug utilisation study: Large-scale patient-level characterisation will be conducted in incident and in prevalent users, defined as follows: I) in incident users, the index date will be the date of a prescription qualifying as a “new prescription” (i.e. after at least 30 days of non-use) of the specific medicine of interest for each person; II) the index date in prevalent users will be the earliest date of a prescription in the calendar year. Frequency of potential indication at index date will be assessed. Treatment duration will be estimated and the minimum, p25, median, p75, and maximum will be provided. Furthermore, daily dosage will be estimated and the minimum, p25, median, p75, and maximum will be provided. See for further description section 9.7.3 and 9.7.5.2 – Patient level drug utilisation study.
For all analyses a minimum cell count of 5 will be used when reporting results, with any smaller counts being masked.

Objective
To assess the incidence, prevalence, and characteristics of macrolide users within individuals diagnosed with asthma, chronic obstructive pulmonary disease (COPD), and asthma-COPD overlap syndrome (ACOS).

Methodology
Design
On one hand, it is a retrospective cohort study based on the purpose of assessing incidence of macrolide use. On the other hand, the cross-sectional study design is applicable as also period prevalence will be assessed.
Reference population
The entire SIDIAP population meeting the inclusion criteria (as seen in Figure 1).
Study population, and inclusion criteria
Individuals will be considered from the moment of database enrollment up to 31st of December 2023 (as seen in Figure 1).
First, individuals will be selected for the “general population” cohort, which serves as a reference cohort. An individual will enroll based on 3 requirements:
– Individual must have a database history of at least 365 days.
– After previous requirement, the individual will enroll in the cohort at the moment whichever disease is diagnosed first (i.e. index date, alias “start of observation” date)
– Lastly; a follow-up time is required of at least 90 days after index date. An individual exits the cohort (“end of observation” date) for whichever reason comes first (e.g. geographical movement, death).
Also, 3 target cohorts will be created based on the 3 previous criteria, but instead of “any disease”, the focus diagnosis per cohort is:
i) a COPD diagnosis (with no history of asthma. In case of a following asthma diagnosis, cohort exit applies)
ii) an asthma diagnosis (with no history of COPD. In case of a following COPD diagnosis, cohort exit applies) and
iii) a diagnosis of both asthma and COPD, i.e. the “Asthma & COPD overlap syndrome” (ACOS). Start of observation is at the moment whichever of the asthma and COPD diagnosis comes second.
Selection of these cohorts will be done by selecting the appropriate SNOMED codes (or other standard codes within OMOP-CDM) and their descendants related to asthma and COPD. In Annex 1, code details are provided.

Variables, most important
Demographics: age, sex
Life style factors: smoking, alcohol use
Measurements: spirometry data, blood eosinophilia
Procedures: electrocardiogram
History of underlying chronic comorbidities; e.g. pneumonia, cardiovascular conditions, cerebrovascular conditions, atopy, gastro-esophageal reflux disease, diabetes mellitus, obesity
Concomitant medication; respiratory agents, systemic steroids

Statistical data analysis
Baseline characteristics
Pearson’s chi-square test will be used to assess statistical difference between drug (macrolide) users and non-drug users for each cohort for the categorical variables. A t-test will be performed to determine statistically significant differences for continuous variables between drug users and non-drug users for each cohort. Descriptive statistics will be also performed for the duration of prescribed macrolides.
Incidence and prevalence
The incidence rate will be expressed as the number of prescription per 1,000 PY. The prevalence rates will be expressed as the proportion of users of the drug of interest. The prevalence and incidence rates will be stratified by age groups, sex, calendar year, and length of macrolide use (chronic versus incidental).
Other analyses
A sensitivity analysis will be performed based on the exclusion of individuals with a history of arrhythmia, an increased follow-up time (being =90, =180 and =365 days) and descriptive statistics will be performed on the reporting of an electrocardiogram procedure up to 7, 14, and 30 days before prescription of a chronic macrolide.
Software
All analyses will be performed mainly utilizing R version 4.2.1, RStudio version 2022.07.1 build 554, R-packages DrugUtilisation version 0.4.0, IncidencePrevalence version 0.5.1, CDMConnector version 1.2.0., and ggplot2 version 3.4.4. It is preferred to receive/work on data in OMOP-CDM tables suitable to be imported in a PostgreSQL database.

Expected results, applicability, relevance, and limitations
Use of macrolides will have increased in the years before the global pandemic of the coronavirus disease 2019 (COVID-19), decreased in the years 2020-2022, and increased in the year 2023. We expect that azithromycin is prescribed the most, followed by clarithromycin, and then followed by erythromycin. We expect to see an overall higher proportion of incidental use of macrolides rather than chronic use, but we also expect to see an increase in chronic use over time.

It is of high importance to understand what the real-world use is of macrolides as it contributes to i) showcasing actual real-world use of macrolides, ii) understanding user characteristics iii) making science-based public health decisions, iv) foundations for follow-up studies on efficacy- and safety studies on the topic.

Chronic use of macrolides might be underestimated, as it might be initiated by the specialist and not repeated by the general practitioner (GP). Data is not pro-actively collected for our specific research question implying that we might not obtain all covariates of interest. Hence, important effect modifiers or confounders might not be taken in to account. Disease misclassification might occur as it is based on disease codes with no further validation.

Keywords
“Asthma”, “Pulmonary Disease, Chronic Obstructive”, “Asthma-Chronic Obstructive Pulmonary Disease Overlap Syndrome”, “Macrolides”, “Drug Utilization”, “Incidence”, “Prevalence”

Background and current status of the subject
Macrolides (i.e. erythromycin, azithromycin and clarithromycin) are antibiotic agents, which also have anti-inflammatory effects.[1] Results from clinical trials showed that macrolide treatment improves health outcomes in a range of obstructive airways diseases. Chronic use of macrolides is being assessed as a treatment option for asthma and chronic obstructive pulmonary disease (COPD) as data from randomized clinical trials (RCTs) has shown that chronic use is associated with a reduced risk of exacerbations.[2,3] Data on the real-world-use of macrolides in patients with asthma and/or COPD is scarce. A recent cohort study investigating administrative data from Ontario (Canada) reported an increase in the use of macrolides in patients with COPD with a prevalence of 0.8 per 1000 people in 2004 to 13.8 per 1000 people in 2018.[4] In 2018, we reported the findings of antibiotic use in children with asthma based on data from the Dutch Integrated Primary Care Information (IPCI) database and the Health Improvement Network® (THIN®); macrolides accounted for 22% of all antibiotic prescriptions in IPCI and 15% in THIN. [5] In 2020, the British Thoracic Society published guidelines for the use of long-term macrolides in adults with respiratory disease, stating that an electrocardiogram (ECG) should be performed prior to initiation of macrolide therapy. [6] It is in our interest to assess whether ECGs are performed (or rather registered in the database). To our knowledge, further information on real-world drug utilization patterns of macrolides in patients with asthma and/or COPD is lacking. The main objective of this research is to assess the incidence, prevalence, and characteristics of macrolide users within individuals diagnosed with asthma, chronic obstructive pulmonary disease (COPD), and asthma-COPD overlap syndrome (ACOS).

Rationale and Background:
HPV vaccination programmes have been shown to reduce not only HPV infection but also the incidence of cervical cancer. However, uncertainty remains on the real-world effectiveness of different brands, and dose schedules.

Research Questions and Objectives:
To generate evidence from real-world data on the effectiveness of HPV vaccination in preventing severe disease outcomes in women, including invasive cervical cancer and CIN2+, for the different licensed HPV vaccines in Europe. This study will include data sources from UK, Spain and Germany.
More specifically the study objectives are:
Main objectives:
• To assess the effectiveness of HPV vaccination in prevention of invasive cervical cancer stratified by licenced vaccine brand
• To assess the effectiveness of HPV vaccination in prevention of CIN2+, stratified by licenced vaccine brand
• To assess the effectiveness of HPV vaccination in prevention of conization, stratified by licenced vaccine brand

Secondary objectives:
• To assess the effectiveness of HPV vaccination overall for the three outcomes (i.e. invasive cervical cancer, CIN2+ and conization)
• To assess the effectiveness of HPV vaccination in prevention of invasive cervical cancer, CIN2+ and conization in subgroups defined by number of doses, within each brand.

Results in both main and explanatory analyses will be further stratified by age group.

Research Methods
The target trial emulation approach will be used for this non-interventional study. The summary of the Target Trial is as follows:
• Study primary objective: to investigate the effectiveness of HPV vaccines to prevent cervix cancer.
• Estimand:
• Population: Women eligible for vaccination according to eligibility criteria in each country. More generally, females 9 years old or older any date after the launch of the vaccination programme in the corresponding country.
• Treatments:
• Placebo (unvaccinated).
• Vaccinated with Gardasil/Silgard.
• Vaccinated with Cervarix
• Vaccinated with Gardasil-9.
Patients are randomised to one of the above groups in a 1:1:1:1 ratio.
• Variable/outcome: incidence of invasive cervical cancer within 5, 10 and 15 years of vaccination.
• Summary measure: incidence rate. Comparison of interest is incidence rate ratio between every vaccinated group and the unvaccinated group.
• Intercurrent events:
• For the unvaccinated: vaccination, dealt with a hypothetical strategy. To implement this, data from women in the unvaccinated group that at some point get vaccinated will be included in the analysis up to the time of vaccination. (This means in the analysis these women will be censored at the time of vaccination.)
• For the vaccinated, any group: treatment discontinuation (i.e. not receiving all scheduled doses), dealt with a treatment policy strategy. To implement this strategy, all available data from these women will be included in the analysis regardless of treatment discontinuation.
f. Statistical methods: The incidence rate ratio between each vaccinated group and the unvaccinated group will be estimated.

Study Design:
New user matched cohort study

Population:
All females aged 9 years or older on any date after the launch of the vaccination programme in any of the contributing datasets and with at least 365 days of prior data availability at the beginning of vaccination programme launch date in their country of residence will be eligible. The analysis will be further restricted to matched cohorts of vaccinated and unvaccinated participants with similar baseline characteristics (see ‘Data Analysis’).

Data Sources:
– Primary care records from the UK (Clinical Practice Research Datalink (CPRD) GOLD) and Catalonia, Spain (Information System for Research in Primary Care (SIDIAP)); outpatient primary care and specialist data from Germany (IQVIA Disease Analyzer (DA) Germany)

Study Period:
HPV national vaccination programs have different start dates. For CPRD, the study period will begin on 1/1/2008. For SIDIAP and IQVIA DA Germany, the study period will begin on 1/1/2007.
For all databases, the end year of the study period is the most recent data available, sometime in 2023.

Eligibility criteria
Eligibility for vaccination in each country. More generally, females >9yo any date after the launch of the vaccination programme in the corresponding country.

Exposure
Assignment procedures: Vaccination status (brand and number of doses) is assigned as seen in the data at 15 years old. Unvaccinated will be assigned as not being vaccinated at 15 years old and censored when (and if) they get vaccinated later on.
Brand: For those vaccinated, brand will be primarily assigned as brand of all the doses administered before 15. Women with heterologous brand (not the same brand for each dose) schedules will be excluded. If this information is not available, it will be inferred, when possible, using each country’s vaccination schedules.
Schedules: Unvaccinated, vaccinated with 1 dose, vaccinated with 2 doses , and vaccinated with 3 doses.

Outcome
The main outcome of interest is invasive cervical cancer. Two secondary outcomes are also considered: CIN2+ and Conization. These outcomes will be phenotyped and diagnostics will be carried out.

Follow-up
Follow up will start at the moment of the administration of first dose before 15 years old. For unvaccinated, the follow up will start at the same date as their vaccinated matched counterpart. Follow-up will extend until another vaccine dose or outcome event, end of available follow-up, or death of any individual of the matched pair, whichever comes first.

Other variables
Year of birth, calendar year, age at vaccination, cytology results from smear test prior to the first dose of vaccine if available. For LASSO regression, all recorded features recorded in the database, including socio-demographics, geographic location, healthcare resource use, comorbidity, medicine/s use, previous smear testing, and previous vaccination/s.

Data Analysis
All analyses will be conducted separately for each database, and carried out in a federated manner, with effectiveness estimates meta-analysed and the I2 heterogeneity coefficient reported.
We will conduct a propensity score (PS) matched cohort design, where target and comparator cohort participants will be matched 1:5. Matching will be done based on PS, year of birth, year of first dose (for analyses not involving dose number) and geographic region using nearest neighbour matching, with calliper width 0.2 standard deviations as is standard for propensity score matching. Large-scale PS will be estimated using lasso regression to estimate the probability of being in the target cohorts, potentially including any of the covariates mentioned above.
The following matched cohorts will be compared:

Main comparisons:
Vaccinated vs unvaccinated per brand:
• Vaccinated with Gardasil/Silgard (target) (1 or more dose) vs unvaccinated (comparator)
• Vaccinated with Cervarix (target) (1 or more dose) vs unvaccinated (comparator)
• Vaccinated with Gardasil-9 (target) (1 or more dose) vs unvaccinated (comparator)

Secondary comparisons:
Vaccinated (target) (1 or more dose) (any brand) vs unvaccinated (comparator) overall.
Dose comparisons:
• Vaccinated with 2 or more doses (target) vs 1 dose (comparator) of the same brand.
• Vaccinated with 3 or more doses (target) vs 2 doses (comparator) of the same brand.

Vaccine effectiveness analyses
Incidence rates and incidence rate ratios (IRR) will be calculated for the matched cohorts and outcomes at 5, 10 and 15 years (if enough follow-up is available). Cox proportional hazard models will be used to calculate hazard ratios (HR) for time-to-event analyses.

Rationale and Background:
Frailty, polypharmacy, and comorbidities are common and important factors which usually coexist in older patients aged = 65. Assessment of frailty and polypharmacy is difficult, due to lack of standardized definitions. However, accounting for them is relevant, especially among older adults with cancer, due to their adverse impact on cancer outcomes and treatment. Despite this, studies reporting on the prevalence of frailty and polypharmacy specifically in older adults with cancer remain sparse.
This study intends to investigate the ability to characterise frailty and polypharmacy in EU real-world data sources, to estimate the prevalence of frailty and polypharmacy in people aged 18 and above with selected cancers at the point of diagnosis and to describe their characteristics. This will provide a benchmark to aid comparisons with evidence submitted for assessment by applicants to EMA.

Research question and Objectives:
The aim of this study is to estimate the prevalence of frailty and polypharmacy at the point of diagnosis of selected cancers in people aged 18 and above and to describe their characteristics.
The specific objectives of the study are:
1. To estimate the prevalence of frailty and polypharmacy in people aged 18 and above diagnosed with selected cancers at the point of cancer diagnosis.
2. To describe the characteristics of people aged 18 and above diagnosed with selected cancers among different frailty and polypharmacy categories at the point of cancer diagnosis.
All results will be reported by database and selected cancer type, overall and stratified by age and sex when possible.

Research Methods:
-Study design:
Population-based cohort study.

-Population:
The study population will include all individuals aged 18 years and above with a primary diagnosis of cancer (lung, breast, ovary, endometrium, prostate, pancreas, colorectal cancer, lymphoma, leukemia and myeloma) between 01/01/2017 and 31/12/2022, with at least one year of prior history available before cancer diagnosis. Individuals with a diagnosis of cancer (any, excluding non-melanoma skin cancer) any time prior to the diagnosis of one of the selected cancers will be excluded.
Additional eligibility of a minimum of 1 year of potential follow-up time will be imposed for the estimation of one-year hospitalisation and mortality rates.

-Data sources:
1. Clinical Practice Research Datalink (CPRD) GOLD, United Kingdom
2. IQVIA Disease Analyzer Germany (IQVIA DA Germany), Germany
3. IQVIA Longitudinal Patient Database Belgium (IQVIA LPD Belgium), Belgium
4. Integrated Primary Care Information Project (IPCI), The Netherlands
5. Estonian Biobank (EBB), Estonia
6. Sistema d’Informació per al Desenvolupament de la Investigació en Atenció Primària (SIDIAP), Spain

-Variables of interest:
Polypharmacy will be defined as the concomitant prescription of >= 5 or >= 10 medications (therapeutic groups) anytime during the year prior to cancer diagnosis.
A score will be created based on the presence of polypharmacy (defined as >=5 prescriptions of medications as mentioned above) and the following conditions included in frailty indexes: Mobility and transfer problems; Housebound; Activity limitation; Visual impairment; Hearing impairment; Requirement for care; Social vulnerability; Falls; Urinary incontinence; Weight loss and anorexia; Memory and cognitive problems; Dizziness; Dyspnoea; Sleep disturbance; Anaemia and haematinic deficiency; Hypertension;
Ischaemic heart disease; Heart failure; Cerebrovascular disease; Peripheral vascular disease; Atrial fibrillation; Heart valve disease; Hypotension/syncope; Diabetes; Foot problems; Arthritis; Respiratory disease; Peptic ulcer; Thyroid disease; Chronic kidney disease; Osteoporosis; Fragility fracture; Parkinsonism and tremor; Urinary system disease; Skin ulcer. Their definition will be based on diagnosis codes recorded anytime prior or at cancer diagnosis. The score will be calculated based on the number of present conditions and polypharmacy divided by the total number of conditions/polypharmacy mentioned above (35 conditions and 1 for polypharmacy prevalence), and will be further categorised accordingly into the following levels of severity: fit: 0–0.12; mild frailty: >0.12–0.24; moderate frailty= >0.24–0.36; severely frail: >=0.36.
Additionally, the Charlson Comorbidity Index at index date will be estimated also based in data recorded prior or at cancer diagnosis.
All co-morbidities and co-medications will be used for large-scale patient characterisation, identified as concept/code and descendants.
Other variables of interest will include number of hospitalisation and date of death during the year after date of cancer diagnosis.
-Sample size:
No sample size will be calculated as this is a descriptive Disease Epidemiology Study where we were interested in the characteristics of all incident cases of selected cancers.

-Data analyses:
The prevalence of an approximate score for frailty (based on the above mentioned score) and polypharmacy (objective 1) will be estimated at the time of cancer diagnosis.
Large-scale patient-level characterisation (objective 2) will be conducted for individuals with different frailty and polypharmacy categories as follows: Age and sex at time of cancer diagnosis will be described;
Medical history will assessed for anytime –and up to 365 days before index date, for 365 to 31 days before index date, for 30 to 1 day before index date, and at index date; Medication use history will be reported for 365 to 31 days before index date, for 30 to 1 day before index date, and at index date; hospitalization and mortality rates will be calculated for up to 365 days after index date.
For all analyses n and % will be reported. A minimum cell count of 5 will be used when reporting results,
with any smaller counts reported as “<5” or “0”. Overall analyses will be done separately for each database and selected cancer. Further stratification by age category (18-44, 45-64, 65-74, 75-84 and 85+) and sex will be conducted when possible (minimum cell count reached).

Rationale and Background:

Disease prevalence depends on the rate of incidence of the disease in the population as well as on the average duration of the disease. Under the assumption that both the incidence of the disease and its average duration are stable over time, a well-known mathematical relationship between prevalence (P), incidence (I) and average duration (D) is:
P/(1-P)=I·D
When P is low,(1-P)˜1 and the equation reduces to the following expression for the indirect estimated prevalence:
P=I·D
In this study direct and indirect estimated prevalence will be compared using real-world datasources.

Research question and objective:

The objective of this study is to compare direct and indirect estimations of prevalence of some rare, chronic diseases.
This will be done considering all patients with the disease as well as separately for patients with pediatric diagnosis (age 0-17 years) and for patients with adult diagnosis (age 18 and older).

Research Methods:

-Study design:
Population-level disease epidemiology to estimate point prevalence and incidence rate using the analytical pipelines from the DARWIN EU® Complete Catalogue of Standard Data Analyses.
A retrospective cohort design to estimate median disease duration using the R survival package.
Data from three databases with routinely-collected electronic healthcare records of general pratices will be used.

-Population:
All individuals present in one of the databases during the study period 01/01/2010 to 31/12/2022 will be used to estimate incidence and prevalence.
All patients with disease will be used to estimate median disease duration.

-Variables:
Presence of a diagnosis of:
•Cystic fibrosis
•Haemophilia
•Pulmonary arterial hypertension
•Pancreatic cancer
•Sickle cell disease
Age at first diagnosis.
Time from first diagnosis to death.

-Data sources:
1.Integrated Primary Care Information Project (IPCI), The Netherlands
2.Sistema d’Informació per al Desenvolupament de la Investigació en Atenció Primària (SIDIAP), Spain
3.Clinical Practice Research Datalink GOLD (CPRD GOLD), United Kingdom

-Sample size:
No sample size has been calculated.

-Data analyses:
Population-level disease epidemiology: for each disease of interest, the point prevalence at the middle of the study period, i.e. 01/01/2016, will be calculated as well as incidence rate over the total study period.
For each patient only the first diagnosis of a disease will be considered. The date of this diagnosis can be before the observation period of the patient. The disease is considered to stay present until the end of patient’s observation period. For the point prevalence, all persons with a diagnosis before 01/01/2016 and in observation in the database at this date contribute to the numerator. Denominator is the total number of persons in observation at this date. For the calculation of the incidence rate, only newly diagnosed patients (diagnosed within observation time and within the study period) contribute to the numerator. Denominator is the total number of person-years at risk, i.e. observation time of a patient within the study period or until a diagnosis occurs.
Survival estimation: Kaplan Meier estimates for survival probabilities, time axis is time since first diagnosis. Median disease duration is time where the survival probability decreases to below 50%.
For all analyses a minimum cell count of 5 will be used when reporting results, with any smaller counts obscured.
From the incidence rate and median disease duration, the indirect prevalence is calculated.
Results from the databases will be combined using random effects meta-analysis.

Rationale and background:
Atopic dermatitis (AD) is a highly prevalent, chronic, systemic inflammatory disease causing significant physical and psychological burden, as well as significant economic impact. Upadacitinib is an oral selective and reversible inhibitor of Janus Kinase (JAK)
that was approved by the European Medicines Agency (EMA) on 16 December 2019 for the treatment of moderate to severe active rheumatoid arthritis in adults and 23 August 2021 for the treatment of moderate to severe AD in patients 12 years of age
and older, who are candidates for systemic therapy.
As with other JAK inhibitors also marketed in Europe, important safety risks have been identified with upadacitinib that require additional risk minimization measures (aRMMs) such as a health care provider (HCP) educational guide and a patient card as detailed in the European Union risk management plan for RINVOQ. Following the procedure under Article 20 of Regulation (EC) No 726/2004 (concluded 10 March 2023), upadacitinib warning and precautions for use have been changed and the posology has been updated in the summary of product characteristics (SmPC). In addition, gastrointestinal (GI) perforation was added as an adverse drug reaction in upadacitinib extension indication variation procedure for Crohn’s disease (dated 17 February 2023). The HCP guide has been updated accordingly after these procedures and is focused on the targeted risks: malignancy, serious and opportunistic infections including tuberculosis (TB) and herpes zoster (HZ), major cardiovascular events (MACE), GI perforation, venous thromboembolic events (VTE), and fetal malformation following exposure in utero (pregnancy risk). The HCP educational guide also contains information on the upadacitinib use in patients 65 years of age or older and in atopic dermatitis with doses
higher than 15 mg once daily. Using electronic healthcare data from Denmark, Germany, Spain, and Sweden this drug
utilisation study will describe baseline characteristics of individuals with AD exposed to upadacitinib, and evaluate healthcare utilization in routine clinical care as an indicator of physician adherence to the aRMMs in the AD population by providing insights regarding how clinical practice patterns correspond to the listed recommendations in the SmPC and the HCP guide when using upadacitinib (RINVOQ®) for AD in routine clinical care.
Research question and objectives: The study aims to evaluate the use of upadacitinib (RINVOQ®) in individuals with AD in routine clinical care in Denmark, Germany, Spain, and Sweden. The study objectives are:
1. To describe the baseline characteristics of individuals with AD who are new users of upadacitinib
2. To the extent measurable, evaluate healthcare utilization in routine clinical care as an indicator of physician adherence to the aRMMs among individuals with AD who are new users of upadacitinib, by: a. Quantifying the compliance to recommendations for posology (average daily dose) and by describing the duration of use
b. Quantifying the compliance to recommendations for the use among individuals who have risk factors for GI perforation, serious infections, malignancy, MACE, and VTE
c. Quantifying the compliance to the recommendations for the use among patients aged 65 years and older
d. Quantifying the compliance to the recommendations for contraindicated use including pregnancy, and active TB
e. Quantifying the compliance to recommendations for patient screening and laboratory monitoring prior to and during upadacitinib treatment (Denmark, Germany, and Spain only)
3. To describe the changes in the utilization of upadacitinib following the implementation of revised aRMMs from the Article 20 referral procedure, specifically:
a. Describe the use of upadacitinib among patients with risk factors for VTE,
MACE, malignancy, and serious infections b. Describe the use of upadacitinib among patients aged 65 years and older
c. Describe the use of upadacitinib 30 mg

Study design:

The study is a drug utilization, descriptive, non-interventional, population-based, cohort
study of new users of upadacitinib (RINVOQ®) for the treatment of AD identified in
electronic healthcare data from four European countries: Denmark, Germany, Spain, and
Sweden.

Population:

The study population consists of all individuals with AD registered in the databases in the
four countries who are treated with upadacitinib. Each individual will be followed from the
initiation of upadacitinib to the end of the study period (i.e., 31 December 2024), study
withdrawal, or death.

Variables:

The exposure of interest will be the use of upadacitinib.
To describe the baseline characteristics of new users of upadacitinib the study will include
the baseline variables: demographics, socioeconomic factors, number of
prescribed/administered AD medications in the year prior to upadacitinib initiation,
number of hospitalizations and outpatient visits in the 5 years prior to upadacitinib
initiation, type of prescriber of upadacitinib, lifestyle risk factors, medical history,
comorbidities, as well as prior and concomitant medications.
To evaluate healthcare utilization in routine clinical care as an indicator of physician
adherence to the aRMMs, the study will include outcome variables related to:
malignancy, MACE, GI perforation, VTE, serious and opportunistic infections including HZ,
contraindications (pregnancy, and active TB) and posology.

Data sources:
Electronic healthcare data from Denmark, Germany, Spain, and Sweden.

Study size:

All initiators of upadacitinib during the study period, in the AD population, will be
included.

Data Analysis:

This will be a descriptive study. Upon upadacitinib initiation, baseline characteristics of
individuals will be assessed. Proportions of the aRMM outcome variables will be assessed
prior to upadacitinib initiation, at upadacitinib initiation and during continuous treatment
of upadacitinib, depending on the outcome variable being reported. The proportion of the
outcome variables will be calculated as the number of individuals for each specific
outcome variable over the total number of individuals considered for that specific
outcome. Utilization of upadacitinib will be stratified by the time period before and after
the implementation of the revised aRMMs from the Article 20 referral procedure as well
as by Coronavirus disease 2019 (COVID-19) pandemic time periods (COVID-19 pandemic
and non-COVID-19 pandemic).

Rationale and Background
A shortage of medicines containing Glucagon-Like Peptide-1 receptor agonists (GLP-1 RA) is affecting EU Member States since 2022 and will continue throughout 2024. The medicines belong to the class of GLP-1 RA are either authorised for the treatment of diabetes or authorised for weight management, with the exception of Mounjaro (tirzepatide), a glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 RA that is authorised for both indications.
The shortage is based on an increased demand for these medicines in addition to other causes, e.g. capacity constraints. Of concern has been the off-label use of GLP-1 RAs for weight management which has been mentioned frequently in the news and social media and is worsening shortages.
This study aims to provide an overview of the characteristics of patients prescribed with a GLP-1 RA medicinal product and how these have changed over the past ten years. This will help contextualise what determinants might be driving the demand for GLP-1 RA vis-à-vis the observed shortage of medicines, including exploring comparative trends of prescription of other medicinal products used in diabetes and for weight management as well as patterns of off-label use.
Research question and objectives
This study aims to provide an overview of the characteristics of patients prescribed with a GLP-1 RA medicinal product and how these have changed over the past ten years.
The specific objectives of this study are:
1) To determine the incidence and prevalence of prescriptions of GLP-1 RA medicinal products (overall and stratified by age, sex, database, indications (only for incidence), and calendar time (per month), for the past 10 years. Additionally, new drug users of GLP-1 RA with no diagnosis of diabetes mellitus II and no diagnosis of obesity will be characterised by age, sex and a list of prespecified indications.

2) To determine the incidence and prevalence of prescriptions of medicines that help contextualise exposure to GLP-1 RA, including orlistat, naltrexone/bupropion, phentermine/topiramate, phentermine and metformin (overall and stratified by age, sex, database, and calendar time (per month), for the past 10 years.
Research Methods
Study design
• Population level cohort study (Objective 1.1, Population-level drug utilisation study on GLP-1 RA)
• Patient level cohort study (Objective 1.2, Patient-level characterisation on GLP-1 RA users with no diabetes mellitus II nor obesity)
• Population level cohort study (Objective 2, Population-level drug utilisation study on medicines that help contextualise exposure to GLP-1 RA)
Population
Population-level drug utilisation of GLP-1 RA and medicines that help contextualise exposure to GLP-1 RA: All individuals present in the database in the last 10 years of available data will be included in the analysis. For this population, incidence and prevalence of use of GLP-1 RA and medicines that help contextualise exposure to GLP-1 RA will be explored.
Patient level cohort study on GLP-1 RA users with no diabetes mellitus II nor obesity: new drug users of GLP-1 RA with no diagnosis of diabetes mellitus II and no diagnosis of obesity will be characterised by age, sex and a list of prespecified indications.
Variables
Drugs of interest: list of 8 GLP-1 RA medicines (Objective 1) and 5 medicines that help contextualise exposure to GLP-1 RA (Objective 2).
Calendar month, age, sex and indications (diabetes mellitus II and obesity, and only for incidence) will be used for stratification.
Age, sex and a list of prespecified indications will be used for the characterisation.
Data sources
1) CPRD Gold (UK, Primary Care Database)
2) SIDIAP (Spain, Primary Care Database)
3) IPCI (Netherlands, Primary Care Database)
4) IQVIA DA Germany (combination of primary and secondary care (outpatient visits) database)
5) IQVIA LPD Belgium (combination of primary and secondary care (outpatient visits) database)
Sample size
No sample size has been calculated. Based on a preliminary study feasibility assessment the expected number of prescriptions in the period investigated is expected to be between <1,000 and 760,000 across the five data sources considered. Data analyses Population-level drug utilisation study on GLP-1 RA and medicines that help contextualise exposure to GLP-1 RA: monthly incidence rates of use of medicines of interest per 100,000 person-year, and monthly point prevalence rates of medicines of interest. Incidence will be stratified by age, sex and indications cohorts in each database of the study. Prevalence will be stratified by age and sex in each database of the study. Patient-level drug utilisation study: new drug users of GLP-1 RA with no diagnosis of diabetes mellitus II and no diagnosis of obesity will be characterised by age, sex and a list of prespecified indications.

NOTA PEL COMITÈ CIENTÍFIC DEL SIDIAP:
Aquest és una estudi requerit per la EMA de forma urgent (els resultats s’han de presentar a la EMA a finals d’agost). Els investigadors/es de l’estudi són conscients que les dades de suicidi no estàn disponibles al SIDIAP, però si les dades d’ansietat i depressió, així com d’altres outcomes relacionats amb suicidi com ara «self-harm» o «suicide attempt».

Rationale and background
There have been reports on a potential association between use of doxycycline and suicide. By means of a self-controlled case series and an active comparator study, the study aims to assess the association between use of doxycycline and specific outcomes of interest (i.e. suicidality events).
Research questions
1. Is there a causal association between the use of doxycycline and suicide-related events?
2. Does the association between doxycycline use and completed suicide and suicide-related events vary by indication of use, compared to active comparators?
Objectives
1. To use a self-controlled case series study to assess the association between use of doxycycline and composite suicide events (including suicide ideation, suicide attempt, self-harm), and composite outcome of depression/anxiety.
2. To use a new-use cohort study to assess the association between doxycycline and completed suicide, composite suicide-related events (suicide ideation, suicide attempt, self-harm), composite suicide-related events (completed suicide, suicide ideation and suicide attempt, self-harm), and composite outcome of depression/anxiety, compared to active comparators, stratified by indication of acne vulgaris, rosacea, chlamydia and lower respiratory tract infection (CAP or bronchitis)
Research methods
Study design
Self-controlled case series (objective 1) and new-user cohort study with active comparator (objective 2).
Population
The study population is new users of doxycycline (SCCS and cohort study) or the comparators (cohort). The new-user cohorts will be per indication: acne vulgaris: doxycycline, erythromycin or isotretinoin; rosacea: doxycycline, erythromycin or isotretinoin; chlamydia: doxycycline, azithromycin, erythromycin or amoxicillin; and lower respiratory tract infection (CAP and bronchitis): doxycycline, azithromycin, or amoxicillin.
Variables
Condition of interest
Indications of interest are acne vulgaris, rosacea, chlamydia, and lower respiratory tract infection (community-acquired pneumonia and bronchitis).
Outcomes of interest are completed suicide (cohort study only), composite (completed suicide [cohort only], suicide ideation, suicide attempting and self-harm), and composite outcome of depression or anxiety.
Data sources
1. Integrated Primary Care Information (IPCI), Netherlands
2. The Information System for Research in Primary Care (SIDIAP), Spain
3. Clinical Practice Research Datalink (CPRD) GOLD, United Kingdom
Sample size
In the SCCS to detect an IRR = 2.0 for the exposure-outcome association, the study size should be at least 245 persons. For an IRR = 1.5, the study size should include at least 828 persons. In the cohort study, with the assumption follow-up duration of 90-days and IRR = 2.0 for the exposure-outcome association (composite completed suicide, attempt, ideation or self-harm) the sample size should be at least 191,000 per group. To detect an IRR = 2.0 for the exposure-outcome association of depression/anxiety with the assumed follow-up duration of 90-days, the sample size should be at least 38,000 per exposure group.
Analytical methods
Incidence rates (IR) of the suicide-related events (suicide attempt, ideation and self-harm), depression or anxiety in people using doxycycline will be estimated and the association between doxycycline and the outcomes will be assessed using (adjusted) incidence rate ratios (IRR) in a self-controlled case series study, using the SelfControlledCaseSeries R package.
In a new-user cohort design using the CohortMethods R package, we will perform propensity-score matching of patients prescribed doxycycline to active comparators. This analysis will be conducted within cohorts of the different indication of use (acne, rosacea, chlamydia and LRTI) Cox-proportional hazards regression will estimate hazards ratios to assess the association of doxycycline with completed suicide in addition to the composite outcome of suicide-related events (suicide ideation, suicide attempt, self-harm) and the composite outcome of depression and anxiety.

Rationale and background
The Medicines Shortages SPOC Working Party (responsible for monitoring and reporting events that could affect the supply of medications in the EU) has been monitoring shortages of different medications to treat ADHD, mainly due to an increased demand in multiple markets, production constraints related to raw material availability, new regulatory approvals for some medications, and changes in the competitive landscape. The main products under monitoring are lisdexamfetamine and methylphenidate, but 3 more have the indication in Europe (Atomoxetine, dexamfetamine and guanfacine). Currently, the situation appears to be stable in the EU and there are no critical shortages. However, some constraints in the supply could arise throughout 2024.
To better anticipate potential shortages and its impact on appropriate patient management, it would be important to assess the evolution of prescriptions over time and get an overview of how these ADHD medications are used across Europe.
Research question and objectives
The overall aim of this study is to characterise the use of ADHD medications in the period of 2010 to 2023. The specific objectives are:
1. To estimate the monthly and yearly period prevalence of use of each ADHD medicine, overall and stratified by age and gender in each database.
2. To estimate the monthly, quarterly, and yearly incidence of use of each ADHD medicine, overall and stratified by age and gender in each database.
3. Among new users of each ADHD medicine, to identify the indication at the time of the initial of the prescribing/dispensing, overall and stratified by age, sex, and quarter.
4. Among new users of each ADHD medicine, to estimate the initial dose, cumulative dose, and time on treatment of the initial medication, overall and stratified by age, sex, indication at index, and quarter.
5. Among new users of any ADHD medicine, to estimate the total treatment duration, number of prescriptions overall and by medicine. Among new users of each ADHD medicine, to estimate the time from treatment initiation to first discontinuation, stratified by initial medicine and quarter of the year.
6. To identify the treatment pathway of each individual who initiated an ADHD medicine, including treatment add-on, switch and concurrent medication/co-prescribing, stratify by calendar time of initiation.
Methods
Study design
Population-level drug utilisation study (Objectives 1 and 2)
Patient-level utilisation study (Objectives 3 – 6, new user cohort study)
Population
In the population-level utilization of ADHD medications, all individuals aged 3 years and older, registered in the respective databases since 1st of January of 2010 to the latest available data, with at least 365 days of prior data availability, will be included.
In the patient-level utilization of ADHD medications, new users will be identified using the first record of any of the ADHD medications of interest within the study period, having no previous records for any study medication during the 12 months before cohort entry.
Variables
Drugs of interest: Five approved medications for the treatment of ADHD in Europe: methylphenidate, dexamphetamine, lisdexamfetamine, atomoxetine and guanfacine.
Data source
IQVIA LPD Belgium, covering a sample of outpatient records from Belgium
IQVIA DA Germany, covering a sample of outpatient records from Germany
IPCI, covering Dutch primary care
SIDIAP Database, covering Spanish primary care
BIFAP, covering Spanish primary care
CPRD, covering UK primary care
Statistical analysis
Objectives 1 to 2 are population-level drug utilisation study, monthly, (quarterly) and yearly period prevalence and incidence use of each ADHD medications will be estimated, overall and stratified by age group and sex.
Objectives 3 to 6 are patient-level drug utilisation study. In Objectives 3 and 4, new user cohorts will be constructed for each ADHD medicine with pre-defined washout period, indication for the initial prescribing/dispensing will be estimated, overall and stratified by age, sex, and quarter of the year. Initial dose, cumulative dose and length of the treatment will be calculated. In Objective 5 and 6, we will construct new user cohorts of any ADHD medicine, estimate the total treatment duration, number of prescriptions. Treatment pathway will be defined and proportion of individuals in each path and the length of each treatment stage will be reported.
For all analyses a minimum cell counts of 5 will be used when reporting results, with any smaller counts will be noted as “<5”.

Rationale and background
Chronic skin conditions like acne and psoriasis cause significant physical and psychological distress, leading to social stigmatization and an increased risk of mental health issues, including depression and anxiety. Concerns about their link to suicidality-related events are rising. It has been discussed several signals of suicidal ideation associated with treatments for acne and/or other skin disorders. For these signals, it is difficult to estimate the extent of the confounding by indication as the underlying patient population is widely believed to be at increased risk of suicide related conditions. Despite this, there is insufficient data in the literature regarding the background rates of such outcomes in these populations and most studies focusing on broader mental health outcomes. This study aims to evaluate suicide-related drug safety signals associated with treatments for the conditions of acne and psoriasis. Understanding of the background rate of suicidality in patient with these conditions and the extent to which this differs from the general population will aid in the assessment of such signals.

Research questions
What are the background incidence rates of suicidality-related events (completed/attempted suicide, suicidal ideation, and intentional self-harm) in the general population and in patients with acne and psoriasis, overall and stratified by sex, age categories, and by calendar year? Results will further be stratified in individuals with and individuals without a medical history of mental health disorders at start of follow-up.

Objectives
1. What is the incidence rate of i) completed suicide, ii) attempted suicide, iii) suicide ideation, iv) intentional self-harm and v) composite endpoint of completed/attempted suicide, suicide ideation or intentional self-harm in patients with acne stratified by sex, age category (12-<18 years, 18-30, 31-40, 41-50 etc, >=81 years), calendar year and history of mental health disorders.
2. What is the incidence rate of i) completed suicide, ii) attempted suicide, iii) suicide ideation, iv) intentional self-harm and v) composite endpoint of completed/attempted suicide, suicide ideation or intentional self-harm in patients with psoriasis stratified by sex, age category (12-<18 years, 18-30, 31-40, 41-50 etc, >=81 years), calendar year and history of mental health disorders
3. What is the incidence rate of i) completed suicide, ii) attempted suicide, iii) suicide ideation, iv) intentional self-harm and v) composite endpoint of completed/attempted suicide, suicide ideation or intentional self-harm in the general population stratified by sex, age category (12-<18 years, 18-30, 31-40, 41-50 etc, >=81 years), calendar year and history of mental health disorders

Research methods

Study design
Population level cohort study

Population
The study population will include all individuals present in the database during the study period (2010 to 2023) and with at least one year of database history.
Within this population 2 sub-cohorts will be nested namely one on individuals newly diagnosed with acne and one consisting of individuals newly diagnosed with psoriasis.
Patients with a history of attempted suicide, suicide ideation and intentional self-harm will NOT be excluded from the study, but results will be provided, stratified by presence (or absence) of a medical history of mental health disorders prior to start of follow-up.

Outcomes
Outcomes of interest are i) completed suicide, ii) attempted suicide, iii) suicide ideation or iv) intentional self-harm and v) the composite endpoint of completed/attempted suicide, suicide ideation or intentional self-harm.

Variables
Sex, age, and calendar year.
Medical history of mental health disorders (i.e. anxiety, depression, bipolar disorder, post-traumatic stress disorder, eating disorders, and schizophrenia).

Data sources
1. Clinical Practice Research Datalink (CPRD) GOLD, United Kingdom
2. Integrated Primary Care Information (IPCI), Netherlands
3. The Information System for Research in Primary Care (SIDIAP), Spain
4. The Valencia Health System Integrated Database (VID), Spain
5. The National Public Health Information System (NAJS), Croatia

Sample size
No sample size has been calculated as this is a descriptive Disease Epidemiology Study where we are interested in the incidence rates of suicidality in patient with chronic skin conditions.

Analytical methods
For the calculation of the incidence rates of the outcomes of interest, the “IncidencePrevalence” R package will be used. A minimum cell counts of 5 will be used when reporting results, with any smaller count reported as “<5”. All analyses will be reported by country/database, overall and stratified by sex, age category and calendar year, when possible (minimum cell count reached). Incidence rates will be given together with 95% Poisson confidence intervals.

NOTA PEL COMITÈ CIENTÍFIC DEL SIDIAP:
Aquest és una estudi requerit per la EMA de forma urgent (els resultats s’han de presentar a la EMA a principis d’octtubre). Només podrem participar en aquest estudi si aconseguim aprovació dels comités com a molt tard a finals de setembre.

Rationale and background
Azathioprine is a purine analogue and prodrug of mercaptopurine that is used as an immunosuppressive medication alone or in combination with other immunosuppressive therapy to prevent rejection following organ transplantation and to treat certain autoimmune diseases, where it is considered a steroid-sparing agent. The PRAC recently discussed a signal procedure regarding the association between treatment with azathioprine and non-cirrhotic portal hypertension/porto-sinusoidal vascular disease (PSVD).
Through this study we aim to characterize patients newly treated with azathioprine, to contextualize the signal assessment.
Research question and objectives
This is a study in incident users of azathioprine aiming to characterise new users of azathioprine with respect to indications for treatment, age at treatment initiation, and sex, and to summarise the treatment durations with azathioprine for all indications combined, and for each individual treatment indication.
Study specific objectives are as following:
1. Characterise azathioprine initiators by sex and age at first prescription
2. Identify potential indications for azathioprine, and the percentage of azathioprine-treated patients for each pre-defined approved indication:
a) Organ transplantation
b) Severe rheumatoid arthritis or chronic polyarthritis
c) Inflammatory bowel disease
d) Systemic lupus erythematosus
e) Dermatomyositis
f) Polyarteritis nodosa
g) Pemphigus vulgaris and bullous pemphigoid
h) Behçet’s disease
i) Refractory autoimmune haemolytic anaemia
j) Refractory idiopathic thrombocytopenic purpura
k) Polymyositis
l) Pyoderma gangrenosum
m) Multiple sclerosis
n) Myasthenia gravis
o) None of the above/missing
3. Estimate and summarise duration of treatment with azathioprine, overall, and stratified per indication
Methods
Study design
Patient-level drug utilisation study
Study period
01/01/2000 – 31/12/2023
Population
For this study we have one cohort, namely:
• Population of individuals newly treated with Azathioprine
Data source
1. Clinical Practice Research Datalink (CPRD) GOLD, United Kingdom
2. Integrated Primary Care Information (IPCI), Netherlands
3. IQVIA Disease Analyzer Germany (IQVIA DA Germany), Germany
4. Institut Municipal Assistència Sanitària Information System (IMASIS), Spain
5. The Information System for Research in Primary Care (SIDIAP), Spain
Sample size
Based on a preliminary feasibility assessment, the expected person counts for Azathioprine were 900 for IMASIS, 6,000 for IPCI, 23,700 for IQVIA DA Germany, 24,500 for SIDIAP and 52,100 for CPRD GOLD.
Exposure of interest
Azathioprine use.
Outcomes of interest
• Characteristics (sex and age)
• Indication
o Organ transplantation
o Severe rheumatoid arthritis or chronic polyarthritis
o Inflammatory bowel diseases
o Autoimmune hepatitis
o Systemic lupus erythematosus
o Dermatomyositis
o Polyarteritis nodosa
o Pemphigus vulgaris and bullous pemphigoid
o Behcet’s disease
o Refractory autoimmune haemolytic anaemia
o Refractory idiopathic thrombocytopenic purpura
o Polymyositis
o Pyoderma gangrenosum
o Multiple sclerosis
o Myasthenia gravis
• Treatment duration, overall and by indication

Statistical analysis
Characterisation of individuals newly initiating treatment with Azathioprine will be done using the CohortCharacteristics and CohortDiagnostics R packages. For the second and third objective, we will use the DrugUtilisation package to characterise Azathioprine use including counts (%) for each indication, and treatment duration.

Rationale and background
Antipsychotic drugs have been associated with several adverse drug reactions, particularly in the elderly. Somnolence, hypotension, extrapyramidal side effects and gait abnormalities are well-recognized side effects that may in turn contribute to the risk of falls and fracture in elderly persons (1). Similarly, cardiovascular adverse effects, falls and injuries may increase mortality.
Antipsychotic drugs are indicated for the management of schizophrenia and bipolar disorder. Antipsychotics are also used to manage behavioural and psychological symptoms of dementia (BPSD) and recommendations over their use suggest they should be discontinued after BPSD symptoms resolve. Safety concerns have previously led to regulatory warnings and risk communications over their use (2,3).
Antipsychotic drugs can be classified into typical and atypical antipsychotics with different recommendations for their use. For example, guidelines recommend the preferential use of atypical antipsychotics when required for the management of BPSD (4).
The rationale of the study is to provide an overview of common antipsychotic prescribing in Europe, and to describe the characteristics of patients initiating antipsychotics. This may help to contextualize information contained in future antipsychotic periodic safety update reports.
Research question and objectives
1. To characterise older people with first use of common antipsychotics in terms of age, gender and indication/comorbidities.
2. To measure trends in the incidence of first use of common antipsychotic prescribing in older people overall, by typical/atypical grouping and by top 5 most common drug substances per database. Results will be stratified by database, calendar year, age and sex.
3. To characterise first time users of common antipsychotic drug therapy in older people after initiation by drug substance (in terms of initial dose and duration).
4. To measure survival in older people with first use of common antipsychotic overall, for typical/atypical grouping and for top 5 most common drug substances per database.
Methods
Study design
• New user cohort study (Objective 1 and 4, Patient-level antipsychotic utilisation)
• Population level cohort study (Objective 2, Population-level antipsychotic utilisation)
• New user cohort study (Objective 3, Patient-level characterisation)
Population
Population-level utilisation of antipsychotic drugs: All individuals aged = 60 years old between 01/01/2017 and 31/12/2023, with at least 365 days of prior history before the day they become eligible for study inclusion. For incidence, anyone with prior use of antipsychotic/s of interest will be excluded from the analysis.
Patient-level antipsychotic drug utilisation and patient-level characterisation: New users of antipsychotic drugs in the period between 01/01/2017 and 31/12/2023 (or latest date available), with at least 365 days of visibility prior to the date of their first antipsychotic prescription and no prior use of the respective antipsychotic drug/s.
Variables
Drugs of interest: Sulpiride, Quetiapine, Risperidone, Olanzapine, Haloperidol, Aripiprazole, Piamperone, Prothipendyl, Prochlorperazine, Chlorprothixene, Promazine, Paliperidone, Zuclopenthixol, Clozapine, Fluspirilene, Amisulpride, Fluphenazine, Perphenazine, Pimozide, and Ziprasidone
Data sources
• SIDIAP (Spain, Primary Care Database) [Objective 1 to 4]
• IPCI (Netherlands, Primary Care Database) [Objective 1 to 4]
• DK-DHR (Denmark, National Registry) [Objective 1 to 4]
• IQVIA DA Germany (Primary and Secondary care database) [Objective 1 to 3]
• IQVIA LPD Belgium (Primary and Secondary care database) [Objective 1 to 3]
• NAJS Croatia (Croatia, National Registry) [Objective 1 and 2]
Statistical analysis
Population-level drug utilisation, patient-level DUS, and patient-level characterisation will be conducted in databases based on data availability.
Population-level antipsychotic use: Annual antipsychotic use incidence rates per 100,000 person years will be estimated overall, by typical/atypical grouping and by top 5 individual drug substances per database. Results will be stratified by database, calendar year, age and sex.
Patient-level antipsychotic use: Patient-level characterization of new antipsychotic users will be conducted at index date, including patient demographics. Records of dementia, schizophrenia, bipolar disorder, depression and insomnia in the week/month or any time before antipsychotic initiation will be used as a proxy for indication and will be reported as proportions.
Initial and cumulative dose and treatment duration will be estimated for the first treatment era and the median [IQR] will be provided. Results will be stratified by drug route (restricting to antipsychotic with systemic routes).
Survival analyses using Kaplan-Meier curves for 1 year mortality will be conducted to estimate the probability of survival in new users of antipsychotic drugs overall, by typical/atypical grouping and by top 5 individual drug substances per database.
For all analyses a minimum cell counts of 5 will be used when reporting results, with any smaller counts will be noted as <5.

Rationale and background
Falls in older adults are associated with significant health outcomes, including hospitalization and increased mortality. Inappropriate prescribing, particularly in populations with multimorbidity and polypharmacy, is a recognized risk factor for falls. The prevalence of potentially inappropriate prescriptions, as outlined in Section K of the STOPP criteria, among individuals with recurrent falls remains uncertain across Europe.
Research question and objectives
What are the characteristics of patients with recurrent falls and how is STOPP Section K criteria prescribing implemented in Europe?
The study objectives are:
1.To characterise the cohort of individuals aged 65 years and older with recurrent falls in terms of age, gender, risk factors, comorbidities and concomitant prescriptions. Results will be stratified by database and where feasible by healthcare setting.
2.To estimate the overall survival of individuals aged 65 and older with recurrent falls.
3.To estimate prevalence of use of drug classes belonging to the STOPP section K criteria in individuals aged 65 and older, categorised into two cohorts: those with recurrent falls and those without recurrent falls. Results will be stratified by database, calendar year, age and sex.
4.To estimate incidence of use of drug classes belonging to the STOPP section K criteria in individuals aged 65 year and older, categorised into two cohorts: those with recurrent falls and those without recurrent falls. Results will be stratified by database, calendar year, age and sex.
5.To characterise a cohort of individuals aged 65 years and older with recurrent falls at time of their new prescription of any of the drug classes belonging to the STOPP section K criteria in terms of age, sex, comorbidities and comedication. Additionally, the proportion of individual drug substances within each drug class belonging to the STOPP section K criteria will be provided. Results will be stratified by database.
6.To determine the median duration of use the different drug classes belonging to the STOPP section K criteria at time of treatment initiation of drugs of interest in the individuals aged 65 and older, categorised into two cohorts: those with recurrent falls and those without recurrent falls. To provide product names with details on strength, formulation and volume.
Methods
Study design
Cohort analysis (Objective 1 and 2, Patient level characterisation of individuals aged 65 and older with recurrent falls in terms of age, sex, risk factors, comorbidities and concomitant medication and survival).
Population-level cohort study (Objective 3 and 4, Population-level drug utilization of drug classes belonging to the STOPP section K criteria in individuals aged 65 and older, categorised into those with recurrent falls and those without recurrent falls).
New drug user cohort study (Objective 5 and 6, Patient-level drug utilization of drug classes belonging to the STOPP section K criteria with regard to summary characterization (age, sex, comorbidities and comedication) and proportion of the individual drugs in individuals aged 65 and older with recurrent falls and duration of treatment in patients aged 65 and older, categorised into those with recurrent falls and those without recurrent falls).
Population
Patient-level characterisation: Patient-level characterisation will include individuals aged 65 years and older with a diagnosis of recurrent falls registered in the respective databases between 1st of January 2013 and 31st of December 2023, with at least 1 year of data visibility prior to the date of recurrent fall diagnosis (index date). Additional eligibility criteria, a minimum of 1 year of potential follow-up after index date, will be applied for survival analysis.
Population-level utilisation of drug classes belonging to the STOPP section K criteria: Population-level drug utilisation analyses will include individuals aged 65 and older registered in the respective databases between 1st of January 2013 and 31st of December 2023, with at least 1 year of data visibility prior becoming eligible for study inclusion. Categorisation will be done on those with recurrent falls and those without recurrent falls.
Patient-level utilisation of drug classes belonging to the STOPP section K criteria: Patient-level utilisation will include new users of drug classes belonging to STOPP section K criteria in a cohort of individuals aged 65 years and older with recurrent falls registered in the respective databases between 1st of January 2013 and 31st of December 2023, with at least 1 year of data visibility prior becoming eligible for study inclusion and no use of the respective drug classes belonging to the STOPP section K criteria in the previous 1 year prior to the index date. Product names with details on strength, formulation and volume will also be reported.
Variables
Drug classes listed in STOPP section K criteria: Benzodiazepines, Antipsychotics, Vasodilating drugs (nitrates, ACE inhibitors, ARB inhibitors, calcium channel blockers), Hypnotic z-drugs, Anti-epileptics , First generation antihistamines, Opioids, Antidepressants, Alpha-blockers, Centrally acting antihipertensives, Antimuscarinic drugs (indicated for overactive bladder)
Conditions of interest: Recurrent falls
Data sources
Clinical Practice Research Datalink GOLD (CPRD GOLD), United Kingdom
IQVIA Disease Analyzer Germany (IQVIA DA Germany), Germany
Finnish Care Register for Health Care (FinOMOP-HILMO), Finland
Croatian National Public Health Information System (NAJS), Croatia
The Information System for Research in Primary Care (SIDIAP), Spain
Statistical analysis
Patient-level characterisation: Patient-level characterisation including age, sex, comorbidities and comedication will be conducted at the date of diagnosis of recurrent falls. Comorbidities and comedication will be assessed at index date and 1 year prior to the index date. (Objective 1)
Overall survival (Objective 2) will be calculated using data on time at risk of death from any cause and the Kaplan-Meier method. Results will be reported as plots of the estimated survival curves as well as the estimated probability of survival at years 1, 3, and 5. This analysis will be conducted only for databases that collect systematically data on mortality.
Statistical analyses will be conducted using the “CohortCharacteristics”, “PatientProfiles” and “CohortSurvival”” R packages.
Population-level utilisation of drug classes belonging to the STOPP section K criteria: Annual incidence rates (expressed as number of new users per 1,000 person-years) and annual period prevalence of the use of drug classes belonging to the STOPP section K criteria will be estimated in individuals aged 65 and older,
categorised into those with recurrent falls and those without recurrent falls (objective 3 and 4). The statistical analysis will be performed based on OMOP-CDM mapped data using “IncidencePrevalence” R package. The results will also be stratified by database, calendar year, age and sex.
Patient-level utilisation of drug classes belonging to the STOPP section K criteria: Characterisation including age, sex, comorbidities and comedication will be conducted at the date of new (incident) prescription of drug classes belonging to the STOPP section K criteria for individuals aged 65 years and older with diagnosis of recurrent falls (index date). Frequency of comorbidities and comedication will be assessed at index date and in 1 year prior to the to the index date. Additionally, proportion of individual drug substances within each drug class belonging to the STOPP section K criteria will also be provided. Duration of treatment with drug classes belonging to the STOPP section K criteria will be calculated and summarized, providing minimum, quartiles and maximum for those with recurrent falls and those without recurrent falls. Statistical analyses will be conducted using the “CohortCharacteristics”, “PatientProfiles” and “DrugUtilisation” R packages based on OMOP-CDM mapped data.
For all analyses a minimum cell count of 5 will be used when reporting results, with any smaller counts obscured.

Rationale and background
Antipsychotic drugs have been associated with several adverse drug reactions, particularly in the elderly. Somnolence, hypotension, extrapyramidal side effects and gait abnormalities are well-recognised side effects that may in turn contribute to the risk of falls and fracture in elderly persons (1). Similarly, cardiovascular adverse effects, falls and injuries may increase mortality.
Antipsychotic drugs are indicated for the management of schizophrenia and bipolar disorder. Antipsychotics are also used to manage behavioural and psychological symptoms of dementia (BPSD) and recommendations over their use suggest they should be discontinued after BPSD symptoms resolve. Safety concerns have previously led to regulatory warnings and risk communications over their use (2,3).
Antipsychotic drugs can be classified into typical and atypical antipsychotics with different recommendations for their use. For example, guidelines recommend the preferential use of atypical antipsychotics when required for the management of BPSD (4).
The rationale of the study is to provide an overview of common antipsychotic prescribing in Europe among people with dementia, and to describe the characteristics of patients initiating antipsychotics. This may help to contextualize information contained in future antipsychotic periodic safety update reports.
Research question and objectives
1.
To characterise people with dementia with first use of common antipsychotics in terms of age, gender, indication and comorbidities.
2.
To measure trends in the incidence of first use of common antipsychotic prescribing overall, by typical/atypical grouping and by top 20 most common drug substances. Results will be stratified by database, calendar year, age and sex.
3.
To characterise first time users of common antipsychotic drug therapy after initiation in people with dementia by drug substance (in terms of initial dose and duration).
4.
To measure overall survival in people with dementia with first use of common antipsychotic overall, for typical/atypical grouping and for top 20 most common drug substances.
Methods
Study design
•
New user cohort study (Objective 1 and 4, Patient-level antipsychotic utilisation)
•
Population level cohort study (Objective 2, Population-level antipsychotic drug utilisation)
MODEL DE SOL·LICITUD
2 IMP-126-CT Versió 07
•
New user cohort study (Objective 3, Patient-level characterisation)
Population
Population-level antipsychotic utilisation: All individuals between 01/01/2013 and 31/12/2023, with a diagnosis of dementia and at least 365 days of prior history before the day they become eligible for study inclusion. For incidence, anyone with prior use of antipsychotic/s of interest will be excluded from the analysis.
Patient-level antipsychotic drug utilisation and patient-level characterisation: New users of antipsychotic drugs in the period between 01/01/2013 and 31/12/2023 (or latest date available), with at least 365 days of visibility prior to the date of their first antipsychotic prescription, a prior diagnosis of the condition of dementia and no prior use of the respective antipsychotic drug/s.
Variables
Drugs of interest: Sulpiride, Quetiapine, Risperidone, Olanzapine, Haloperidol, Aripiprazole, Piamperone, Prothipendyl, Prochlorperazine, Chlorprothixene, Promazine, Paliperidone, Zuclopenthixol, Clozapine, Fluspirilene, Amisulpride, Fluphenazine, Perphenazine, Pimozide, and Ziprasidone
Data sources
•
SIDIAP (Spain, Primary Care Database) [Objective 1 to 4]
•
IPCI (Netherlands, Primary Care Database) [Objective 1 to 4]
•
DK-DHR (Denmark, National Registry) [Objective 1 to 4]
•
IQVIA DA Germany (Primary and Secondary care database) [Objective 1 to 3]
•
IQVIA LPD Belgium (Primary and Secondary care database) [Objective 1 to 3]
•
NAJS Croatia (Croatia, National Registry) [Objective 1 and 2]
Statistical analysis
Population-level antipsychotic utilisation, patient-level antipsychotic drug utilisation, and patient-level characterisation will be conducted in databases based on data availability.
Population-level antipsychotic utilisation: Annual antipsychotic use incidence rates per 100,000 person years will be estimated overall, by typical/atypical grouping and by top 20 individual drug substances. Results will be stratified by database, calendar year, age and sex.
Patient-level antipsychotic use: Patient-level characterization of new antipsychotic users will be conducted at index date (date of first prescription of the antipsychotic of interest), including patient demographics. Records of schizophrenia, bipolar disorder, depression and insomnia in the week/month or any time before antipsychotic initiation will be used as a proxy for indication and will be reported as proportions.
Initial and cumulative dose and treatment duration will be estimated for the first treatment era and the median [IQR] will be provided. Results will be stratified by drug route (restricting to antipsychotic with systemic routes).
Survival analyses using Kaplan-Meier curves for 1 year mortality will be conducted to estimate the probability of overall survival in new users of antipsychotic drugs overall, by typical/atypical grouping and by top 20 individual drug substances.
For all analyses a minimum cell counts of 5 will be used when reporting results, with any smaller counts will be noted as <5.

Rationale and background
Sacubitril/valsartan (Entresto) is an angiotensin receptor-neprilysin inhibitor used to treat symptomatic chronic heart failure in both adults and children. Its dual mechanism of action involves inhibiting neprilysin and blocking the angiotensin II type-1 receptor, providing complementary cardiovascular benefits. The Pharmacovigilance Risk Assessment Committee (PRAC) is currently investigating signals on a potential association between the use of sacubitril/valsartan and myoclonus.
Through this study, we aimed to investigate the incidence rate of myoclonus in newly diagnosed heart failure patients and the general population.
Research question and objectives
This study aims to estimate myoclonus incidence rates in patients newly diagnosed with heart failure.
Specific study objectives:
1. To calculate the incidence rate of myoclonus in a newly diagnosed heart failure population and the general population, stratified by age groups and sex.
2. To calculate the incidence rate of myoclonus in incident heart failure population following first initiation of treatment cohorts: sacubitril/valsartan, angiotensin-converting enzyme inhibitors (ACEi), and angiotensin receptor blockers (ARBs) (index date being the start of the treatment).
Methods
Study design
Population-level descriptive epidemiology design.
Study Period
From January 1st, 2015 (first European Union (EU) approval) to 31st December 2023 (or last available date).
Population
For this study, patients will be required to be at least 18 years of age and have a minimum of 365 days of database history. Among them, 2 different cohorts will be defined, namely:
1. Population of newly diagnosed heart failure (HF) patients
2. General population, consisting of all patient’s observable during the study period
For objective 2, different cohorts will be defined nested in the incident heart failure cohort by the first initiation of heart failure treatments of interest, as follows:
Treatment groups:
HF + New User sacubitril/valsartan – First line Never exposed to sacubitril/valsartan or ACEi/ARB
HF + New User sacubitril/valsartan – Later line
Has been exposed to ACEi/ARB any time up to the day before the index date
MODEL DE SOL·LICITUD
2 IMP-126-CT Versió 07
No prior exposure to ACEi
No prior exposure to ARBs
• HF + New User ACEi
• HF + New User ARB
Variables
Exposure of interest: Sacubitril/valsartan, ACEi, and ARBs.
Outcomes of interest: Incident myoclonus during the study period.
Stratifications: Age, sex, and predefined heart failure treatments of interest.
Follow up
The incident heart failure population will be followed from the date of first diagnosis (index date) until the end of the study period or censoring (due to loss to follow-up, death, or the occurrence of the outcome of interest), whichever occurs first.
The general population cohort will be followed from the date of inclusion (index date) until the end of the study period or censoring.
In patients with incident heart failure, treatment cohorts will be nested in these cohorts and based on newly initiated treatments of interest: new users of sacubitril/valsartan, ACEi, and ARBs. Follow-up will begin at the time of initiation of the treatment of interest (index date) and continue until the end of follow-up or censoring (due to loss to follow-up, death, or the occurrence of the outcome of interest).
Additionally, incidence rates will be estimated at predefined time windows: 0–30 days, 0–90 days, 0–180 days, and 0–365 days post-index date. Patients will be censored at each interval if they have not experienced the event of interest, reflecting distinct periods at risk.
Data sources
• Clinical Practice Research Datalink GOLD (CPRD GOLD), United Kingdom
• IQVIA Disease Analyzer Germany (IQVIA DA Germany), Germany
• Sistema d’Informació per al Desenvolupament de la Investigació en Atenció Primària (SIDIAP), Spain
Statistical analysis
The “IncidencePrevalence” R package will be used to calculate the incidence rate of the outcome of interest (i.e. myoclonus) for objectives 1 and 2.
Incidence will be estimated at different time windows following the index date (0-30, 0-90, 0-180, 0-365 days, and the entire study period).
Incidence rate of the outcome of interest for objective 1 will be stratified by age and sex.
For objective 2, incidence rate of the event of interest will be calculated by newly initiated treatments of interest: sacubitril/valsartan, ACEi, and ARBs.
For all analyses, results will be reported by country/database. A minimum cell counts of 5 will be used when reporting results, with any smaller count reported as “n/a”.

Mental disorders are increasing in the last years, in particular after COVID-19 pandemic, but its prevalence and incidence is still not quantified in particular subgroups of population and comparing different countries. We aim to investigate time trends of mental disorders from 2006 to 2024 using large real-world data. We propose to conduct a descriptive study on the prevalence and incidence of common mental problems (i.e. anxiety and depression), severe mental disorders (i.e. schizophrenia and bipolar disorder) and other mental conditions, such as self-harm, sleep disorders, developmental disorders, substance abuse and eating disorders among people of all ages. Using a network of large real-world data sources of primary healthcare, we aim to determine whether the long-term trends of prevalence and incidence of several mental problems remain stable over the time.
We will conduct a population-based cohort study to investigate the temporal trends of several mental conditions and whether the patterns vary according to sex, age groups, socioeconomic deprivation, and nationality. We will calculate the prevalence and incidence rates of diagnoses, prescriptions, and sick leaves/absences due to above-mentioned mental illnesses. The present study will be conducted in multiple databases in the Observational Health Data Sciences and Informatics (OHDSI) network willing to participate, including the Information System for Research in Primary Care (SIDIAP) which contains primary care records for approximately 6 million people in Catalonia, Spain.
Our study will enable to identify temporal trends in mental disorders in Catalonia, and potentially other countries, and will inform preventive strategies targeted to specific groups that are more vulnerable, helping to address mental health disparities across different demographics.

Rationale and background
Salbutamol is essential for managing asthma and chronic obstructive pulmonary disease (COPD) due to its rapid bronchodilation effects. The rising prevalence of these conditions in Europe, driven by aging populations and worsening air quality, has led to increased demand for salbutamol, especially in urban areas. A shortage would severely impact patient care, leading to challenges in managing acute symptoms and increased strain on alternative therapies, which are not as effective for immediate relief.
The aim of the study is to understand if salbutamol (inhaled formulation) use has been increasing over the last few years in Europe which will in turn inform a potential risk of shortage. And secondly to understand the impact of the shortage of salbutamol inhaled formulations on therapeutic alternative inhalation products. This exercise falls under preparedness and prevention activities.
Research question
What is the real-world use of salbutamol (inhaled formulations)?
Objectives
The aim of this study is to determine the real-world use of salbutamol (inhaled formulations).
The specific objectives of this study are:
1. To describe the overall (i.e. all drug formulations combined) rate of prescribing inhaled salbutamol (irrespective of type of formulation) by calendar time (month, year). Monthly prescribing rates will be provided by database and healthcare setting (inpatient/outpatient).
2. To describe the rate of prescribing inhaled salbutamol by type of formulation and calendar time (year, month). Monthly prescribing rates will be provided by database and healthcare setting.
3. To describe the rate of prescribing other inhaled alternatives and oral salbutamol by calendar time (month, year). Monthly prescribing rates will be provided by database and healthcare setting.
4. To describe characteristics of individuals treated with inhaled salbutamol in terms of indication of use, sex and age (in age categories) stratified by formulation and provided by database and healthcare setting.
Methods
Study design
• Population level cohort study (Population-level drug utilisation analyses to objectives 1, 2, 3)
• New drug user cohort study (Patient-level drug utilization analyses to objective 4).
Population
The study population will include all patients presents in the databases and users of medication with inhaled salbutamol and other inhaled alternatives prescribing in the period between 01/01/2015 to the end of available data. For this population, rates of prescribing inhaled salbutamol and other inhaled alternatives and the indication for use of inhaled salbutamol will be explored. Patients need to have at least 365 days of data visibility prior to index date.
Variables
Therapeutic drug class of interest as exposures (all inhaled formulations):
Salbutamol (dry powder, pressurized metered dose inhaler, solution for inhalation), terbutaline, fenoterol, ipratropium bromide, oxitropium bromide, salbutamol + ipratropium, formoterol/budesonide, oral salbutamol
Conditions of interest: Asthma, COPD and emphysema, respiratory conditions due to inhalation of chemical substances, bronchitis, bronchospasm.
Relevant covariates: Sex, age, calendar months and years
Data source
1. Clinical Practice Research Datalink (CPRD) GOLD, United Kingdom
2. Danish Data Health Registries (DK-DHR), Denmark
3. Institut Municipal Assistència Sanitària Information System (IMASIS), Spain
4. Integrated Primary Care Information (IPCI), Netherlands
5. IQVIA Disease Analyzer Germany (IQVIA DA Germany), Germany
6. Croatian National Public Health Information System (NAJS), Croatia
7. The Information System for Research on Primary Care (SIDIAP), Spain
Sample size
No sample size has been calculated for this drug utilisation study, as our primary focus is to determine the prescribing rate of drug utilization of inhaled salbutamol products and other inhaled alternative in each database, irrespective of the sample size. Based on a preliminary feasibility assessment, the expected number of persons counts for medication with inhaled salbutamol in the databases included in this study ranged from 36,000 (IMASIS) to 3,154,200 (CPRD GOLD).
Statistical analysis
Population level drug utilisation: Monthly and yearly prescription rates of inhaled salbutamol and other inhaled alternatives (both treatment initiation and ongoing treatment episode) per 100,000 person-years will be estimated, overall and stratified by database and healthcare setting.
Patient level drug utilisation: Patient-level drug utilisation analyses will include describing the distribution of predefined indication of inhaled salbutamol use, stratified by i) type of formulation, ii) sex and iii) pre-defined age group at index date. Index date will be the date of first prescribing of salbutamol (irrespective whether incident or prevalent) during the study period.
The statistical analyses will be performed based on OMOP-CDM mapped data using “DrugUtilization” R package. A minimum cell counts of 5 will be used when reporting results, with any smaller count reported as <5.

Rationale and background
Finasteride is a specific inhibitor of 5a-reductase, an enzyme that converts testosterone into dihydrotestosterone. It is approved in Europe for treating benign prostatic hyperplasia (BPH) at 5 mg and androgenetic alopecia at 1 mg and 2.275 mg/dl. Dutasteride, another 5a-reductase inhibitor, is also approved in Europe for moderate-to-severe BPH, either alone or in combination with tamsulosin. In some non-EEA countries, dutasteride is also used for androgenetic alopecia.
Signals of mood changes, including depressed mood, depression, and rarely suicidal ideation, have been reported in patients using finasteride. Depression is listed as a side effect of finasteride, along with anxiety and suicidal thoughts, though their frequency is unknown. These psychiatric effects were not identified during clinical trials but were later explored in post-marketing observational studies. There is insufficient data in the literature regarding the background rates of suicide related events in these populations.
The aim of this study is to evaluate the background/incidence rates of suicide-related events in adult male patients exposed to finasteride or dutasteride medicines for the conditions of androgenetic alopecia and BPH. Having background rate data would be helpful to contextualise review and to give some insight into the impact of the indication on suicide-related events. Further understanding of the safety of these medicines regarding their potential psychiatric effects can help inform regulatory decisions and the assessment of the benefit/risk profile of these medicines.
Research question and objectives
Research question
What are the background/incidence rates of suicide-related events in the general adult male population, adult males with newly diagnosed androgenetic alopecia, and benign prostatic hyperplasia, overall and by age group?
Objectives
The objectives are to evaluate the background/incidence rates of suicide-related events overall and by age group (10-year age bands) in:
1. The general adult male population.
2. Adult males with newly diagnosed androgenetic alopecia.
3. Adult males with newly diagnosed androgenetic alopecia stratified by treatment (finasteride, dutasteride, topical minoxidil, spironolactone).
4. Adult males with newly diagnosed benign prostatic hyperplasia (BPH).
5. Adult males with newly diagnosed BPH stratified by treatment (finasteride, dutasteride, alpha
blockers, tadalafil, saw palmetto).
Methods
Study design
Population level cohort study.
Population
The study population will include all adult male population (= 18 years) present in the data source during the study period. (objective 1).
Within this population 2 sub-cohorts will be nested namely one of adult male patients newly diagnosed with androgenetic alopecia and one consisting of adult male patients newly diagnosed with BPH (objectives 2 and 4).
Within these cohorts of adult males newly diagnosed with androgenetic alopecia and BPH, we will nest cohorts of individuals initiating treatments of interest for the first time in the study period (objectives 3 and 5).
Study period
Study period may vary between data sources and will start at the earliest date of data-availability of the respective DP until the end of available data; and with at least 365 days of database history prior to index date.
Variables
Outcomes:
Outcomes of interest are i) completed suicide (condition record of suicide plus death date in the following 30 days), ii) attempted suicide, iii) suicide ideation, iv) intentional self-harm, v) composite outcome(combination of any of the above-mentioned events).
Relevant covariates
Age groups (10-year age bands), type of treatments (i.e. finasteride, dutasteride, topical minoxidil, alpha blockers, spironolactone, tadalafil, saw palmetto).
Data source
1. Clinical Practice Research Datalink (CPRD) GOLD, United Kingdom
2. Danish Data Health Registries (DK-DHR), Denmark
3. InGef Research Database (InGef RDB), Germany
4. Integrated Primary Care Information (IPCI), Netherlands
5. Croatian National Public Health Information System (NAJS), Croatia
6. The Information System for Research on Primary Care (SIDIAP), Spain
Sample size
No sample size has been calculated as this is a descriptive disease epidemiology study where we are interested in the incidence rates of suicide-related events in adult male patients diagnosed with androgenetic alopecia or BPH in each data source, irrespective of the sample size.
Statistical analysis
Yearly incidence rates of suicide-related events per 100,000 person-years (PYs) will be estimated in the general population of adult males, the adult male patients diagnosed with androgenetic alopecia or BPH.
Within these populations, incidence rates of suicide-related events per 100,000 PYs will also be calculated for the drug exposures of interest (i.e. respective treatment of BPH or androgenetic alopecia). Yearly incidence rates will be reported overall and stratified by age categories and type of treatments. Incidence rates will be given together with 95% Poisson confidence intervals. The statistical analyses will be performed based on OMOP-CDM mapped data using “IncidencePrevalence” R package. A minimum cell counts of 5 will
be used when reporting results, with any smaller count reported as “<5”.

Las enfermedades reumáticas inflamatorias (IRMD) incluyendo la artritis reumatoide (AR), el lupus eritematoso sistémico (LES), la artritis psoriásica (APs), la esclerosis sistémica (SSc) y las espondiloartropatías (Spa) entre otras están asociadas con un aumento significativo de la morbilidad y mortalidad. La carga de enfermedad de dichas patologías en nuestro entorno no es bien conocida. Nuestros objetivos son:
1) Evaluar la carga de enfermedad de IRMD en Cataluña, estimando su prevalencia e incidencia,
2) determinar los factores independientes asociados con las complicaciones de las IRMD en comparación a la población sana, incluyendo la enfermedad coronaria, la enfermedad tromboembólica, la diabetes mellitus, las fracturas osteoporóticas, las infecciones graves, el cáncer y la insuficiencia renal crónica y
3) Estimar el impacto de las IRMD sobre la mortalidad en comparación a la población general.
Para ello proponemos un estudio poblacional retrospectivo que incluirá todos los casos identificados mediante códigos ICD-10 del programa del Sistema de Información para el Desarrollo de la Investigación en Atención Primaria (SIDIAP) del 2006 al 2021. El SIDIAP cuenta con información de mas de 5.7 millones de habitantes e incluye datos demográficos, diagnósticos, prescripciones/dispensaciones y fecha de muerte.
Se utilizará una cohorte de control sin IRMD apareada por el año de nacimiento, género, y estado socio-económico como grupo control.

«Rationale and Background
During the evaluation of the safety results of a clinical trial in patients with severe asthma, differences in rates of serious adverse events were observed in the experimental treatment arm compared to the control arm. In order to contextualise these differences, a non-interventional study was required to generate background rates of selected health outcomes in patients with severe asthma, with a disease definition that follows recently conducted clinical trials. The results of this study may inform future drug-related safety assessments in the same population.
The present study is to produce background information on the occurrence of the health outcomes in adolescent and adult patients with severe asthma using recent data.
Research Methods
Study design
Retrospective cohort studies will be conducted using routinely-collected health data from 5 databases.
The incidence rate of mortality and the outcomes of interest will be assessed using Population Level Disease Epidemiology analytical pipelines from the DARWIN EU Complete Catalogue of Standard Data Analyses.
Population
All individuals present in the database in the period between 01/01/2015 and 31/12/2021, with at least 1 year of prior history, being diagnosed with severe asthma and fulfilling inclusion and exclusion criteria.
Variables
Variables of interest will consist of outcomes, comorbidity, lifestyle factors, measurements and drug exposure data.
Data sources
1. Integrated Primary Care Information Project (IPCI), The Netherlands
2. Sistema d’Informació per al Desenvolupament de la Investigació en Atenció Primària (SIDIAP), Spain
3. Clinical Practice Research Datalink GOLD (CPRD GOLD), United Kingdom
4. Parc Salut Mar Barcelona (PSMAR), Hospital del Mar (IMIM) (hospital database), Spain
5. University of Tartu – Estonian Biobank, Estonia»

«Background
The current COVID-19 vaccines include mRNA vaccines, non-replicating viral vector vaccines and traditional inactivated whole virus vaccines. All of them have demonstrated their effectiveness against confirmed COVID-19 infection in previous and ongoing clinical trials However, vulnerable populations, such as pregnant women, children, individuals living in nursing homes, those with cancer, autoimmune diseases, immunodeficiencies or organ transplant recipients were systematically excluded from these trials, limiting the available evidence regarding the efficacy of the COVID-19 vaccines on these patients to retrospective observational studies, and small non-randomized trials with surrogate endpoints (e.g. antibody levels).

Objectives
To estimate coverage and the effectiveness of COVID-19 vaccines against COVID-19-related outcomes in vulnerable populations, overall and by sex, age, baseline comorbidities, and socioeconomic status, using electronic health records from Catalonia, Spain.
1- To provide periodic estimates of vaccine coverage in predefined subgroups of population at risk of being excluded from the general vaccine campaigns (i.e individuals with mental disorder), stratified by vaccine type/brand, vaccine dose, sex, age groups, socioeconomic status, and nationality.
2- To assess the effectiveness of COVID-19 vaccines in vulnerable population against COVID-19 related outcomes (COVID-19 infection, hospitalisation, intensive care admission, or death) in:
2.1- pregnant women and infants up to 12 months of age;
2.2- children and adolescents from the age of 5 to 19 years;
2.3- persons living with immunodeficient conditions, namely cancer, autoimmune conditions, primary immunodeficiencies, people living with HIV infection, organ transplant recipients or people taking immunosuppressive drugs;
2.4- persons living in nursing homes.

Methods
We will conduct a population-based matched cohort study using individual-level routinely-collected electronic health records (EHR) data from the Information System for Research in Primary Care (SIDIAP; www.sidiap.org) database in Catalonia mapped to the OMOP-CDM.

Study population
We will include all women with a pregnancy episode during the study period (mother-child linkage), children and adolescents, as well as those with history of cancer, immunodeficient conditions (HIV, autoimmune diseases, organ transplant recipients) and/or use of immunosuppressive drugs (including high chronic use of corticosteroids, biological and non-biological disease modifying drugs, antineoplastic drugs), persons living in nurse home residencies or persons with mental health conditions of any age, registered for at least 365 days in the SIDIAP database prior to the 27th of December 2020 (date of initiation of the vaccination in Spain) and up to December 2022 and December 2023.

Exposures
Four COVID-19 vaccines will be included: ChAdOx1-S, BNT162b2, mRNA-1273, and Ad26.COV2.S.

Outcomes
The main outcomes to evaluate effectiveness of COVID-19 vaccination will include: 1.SARS-CoV-2 infection will be defined as any confirmed infection identified by diagnostic codes and/or a positive RT-PCR or antigen test result, 2.COVID-19-related hospitalisation will be defined as a hospital admission (at least one night) where the individual had a positive RT-PCR test result or a clinical diagnosis of COVID-19 over the 21 days prior to their admission up to the end of their hospital stay,3. COVID-19-related intensive care unit (ICU) admission in those with COVID-19 related hospitalisation, 4.COVID-19-related death will be defined as death (any cause) registered after a COVID-19-related hospitalisation or 28 days after a SARS-CoV-2 infection.

Covariates
Covariates to be considered in the analyses will include demographics, socioeconomic status, nationality and diagnosis of mental health condition (only for coverage), BMI, pre-existing comorbid conditions, history of COVID-19 infection (6 months previous), period of predominant SARS-CoV-2 variants, number of GP visits per year, pregnancy variables (gestational age at vaccination, parity, breastfeeding, maternal lifestyle behaviour factors (when available).

Follow-up
For individuals from the age of 5 and above follow up will be from their index date to occurrence of an event, end of pregnancy (for pregnancy cohort), death, or loss of visibility in the database (e.g., person leaving the practice in electronic health records data). For cohorts that had received a first vaccine dose, we also censored follow-up if a second dose was observed before 21 days for BNT162b2 and before 27 days for mRNA-1273 and ChAdOx1-S.
The index date for exposed children (up to 12 months of age) will be the date of maternal vaccination. Children will be followed from the index date until occurrence of an event of interest, exit from the database, death, end of pre-defined follow-up time (12 months after birth), or end of data availability, whichever comes first.

Statistical analysis
Vaccination uptake rate will be calculated as the number of persons receiving any COVID-19 vaccines in a certain population subgroup divided by all individuals eligible for vaccination in that group.
We will conduct a new user cohort study, to compare the effectiveness of COVID-19 vaccines against COVID-19-related outcomes. We will use propensity score (PS) matching to minimise the risk of confounding. Vaccinated individuals will be matched in a 1:3 ratio (if sample size allows) with eligible non-vaccinated individuals with no prior history of COVID-19 infection in the past 3 months. Matching will be done taking into account age group, sex, calendar time, baseline comorbidities associated with increased risks of severe COVID-19 (e.g., obesity, diabetes, immunosuppression), and smoking. We will also use a large-scale, data-driven approach to identify additional potential confounders to be included in the PS.

Background
Growth reference charts are useful tools to monitor infants growth and development. In Catalonia, national and WHO growth charts are widely used despite not being representative of the general population visited in primary care.
Objectives
To generate new growth curves for children and adolescents living in Catalonia based on data collected routinely in primary care electronic health records.
Methods
We will conduct a population-based cohort study using individual-level routinely-collected electronic health records (EHR) from primary care in Catalonia. We will include a population from 0 to 18 years of age with at least one valid weight and length/height measurement registered in their EHR between 2006 to 2019. Growth references for head circumference, weight, length/height, weight-for-length/height, and body mass index (BMI) for age will be fitted using generalized additive models for location, scale, and shape (GAMLSS). BMI percentile curves passing through BMIs 30, 25, 18.5, 17, and 16 kg/m 2 at the age of 18 years will be calculated to define limits for obesity, overweight, and various grades of thinness.
Impact
The new growth charts could be incorporated into the electronic health records system of primary care centers in Catalonia in order to facilitate the monitoring of growth and development of children and adolescents in clinical practice.

Multiple myeloma is a rare type of blood cancer with an estimated overall crude incidence rate of 3.9 cases per 100,000 and an estimated prevalence of 3 per 100,000 in 2020 in Europe. Survival rates have improved due to the better management of the disease and the development in recent years of new medicines such as immunomodulatory agents, proteasome inhibitors and monoclonal antibodies. However, there is still unmeet need for new medicines for patients who do not respond to existing therapies. The rarity of multiple myeloma makes it challenging to have a clear picture across Europe of the characteristics of these patients at the time of diagnosis, the lines of therapy they receive and their overall survival. The goal of this study is to inform these aspects, which are important from a regulatory point of view to provide context and help understand how new medicines may add value for patients.
The overall objective of this study is to characterise patients with multiple myeloma diagnosed in the period 2012-2022. The specific objectives of this study are: i) to describe demographic and clinical characteristics of patients with multiple myeloma at the time of diagnosis; ii) to describe multiple myeloma treatments; iii) to describe multiple myeloma treatment sequences; iv) to estimate the overall 1-, 5-, and 10-year survival of incident multiple myeloma cases during the study period (2012-2022).
This population-based cohort study will include all individuals identified in the database between 01/01/2012 and date of the latest data available in each database. Participants with a diagnosis of cancer (any, excluding non-melanoma skin cancer) any time prior to the diagnosis of multiple myeloma or prior to the start of the study period will be excluded. Additional eligibility criteria will be applied for each study objective. Two main outcomes of interest will be studied: treatment/s initiated at index date, 1 to 30, 1 to 90, and/or 1 to 365 days post index date, and death. For the former, a pre-specified list of multiple myeloma treatments will be generated (objectives 2-3). Overall survival in patients with multiple myeloma will also be identified based on the registered date of birth. All co-morbidities and co-medications will be used for large-scale patient characterisation, identified as concept/code and descendants. A list of pre-specified co-morbidities and co-medications will also be described. Several data sources will participate in the present study: IQVIA Diseases Analyzer Germany (IQVIA-DA Germany), Sistema d’Informació per al Desenvolupament de la Investigació en Atenció Primària (SIDIAP), Institut Municipal Assistencia Sanitaria Information System (IMASIS), Estonian Biobank, Auria Clinical Informatics (ACI), Clinical Data Warehouse of Bordeaux University Hospital (CDWBordeaux) and Netherlands Cancer Registry (IKNL). We will conduct a large-scale patient-level characterisation (objective 1). Age and sex at time of multiple myeloma diagnosis will be described. Medical history will be assessed for anytime – and up 366 days before index date, for 365 to 31 days before index date, for 30 to 1 day before index date, and at index date. Medication use history will be reported for 365 to 31 days before index date, for 30 to 1 day before index date, and at index date. We will also report medication use for 1 to 30, 1 to 90, and 1 to 365 days post index date. The number and % of patients receiving each of a pre-specified list of multiple myeloma treatments and treatment combinations (objective 2) will be described at index date, 1 to 30, 1 to 90 and 1 to 365 days post index date. When available, treatment regimen types will also be described. Additionally, sunburst plots and Sankey diagrams will be used to describe treatments patterns and sequences over time (objective 3). Overall, as well as 1-, 5-, and 10-year survival (objective 4) will be estimated as the probability of survival from any cause of death and will be reported using Kaplan-Meier plots. This analysis will be conducted only for databases with complete information on mortality. For all analyses n and % will be reported. A minimum cell counts of 5 will be used when reporting results, with many smaller counts obscured. When possible, all analyses will be stratified by age groups and sex, and data source/country. Additionally, in order to capture treatments availability and survival changes over time, sunburst plots, Sankey diagrams and KM curves will be further stratified by study periods (2012-2017 and 2018-2022).

Rationale and Background
Opioid overdoses are the primary cause of mortality among problematic drug users globally. Naloxone, an opioid antagonist, can avert such fatalities by rapidly counteracting opioid effects. To address the frequent untreated overdoses due to the lack of recognition, fear of legal consequences, and lack of naloxone access, Take-Home Naloxone (THN) programs have been established, providing naloxone to potential bystanders in 12 European countries. This study will investigate the trend of naloxone use, particularly THN, across Europe, and elucidate user profiles to augment aggregated data from existing THN programs, thereby aiding the monitoring of naloxone use and informing regulatory decisions.

Research question and Objectives
The objectives of this study are
(i) To investigate the incidence and prevalence of THN use in (1) the general population and (2) among people with a recorded history of opioid use disorder during the study period 2012-2022. Analyses will be stratified by age, sex, calendar year and country/database.
(ii) To provide summary baseline characteristics of “new” THN users including demographics and history of opioid use, overdose
(iii) To study the use of THN in ”new” users including summary statistics of number of THN packages prescribed at index date for each “new” user (e.g. mean (SD), median, q25 and q75)
Research Methods
Study design
• Population level cohort study (Objective 1, Population-level drug utilization study on THN)
• New drug user cohort study (Objective 2+3, Patient-level drug utilization analyses with regard to number of THN prescriptions and summary patient characteristics incl. history of opioid use, overdose)
Population
Population-level utilization of THN: All individuals present in the database in the period between 01/01/2012 and 31/12/2022 will be included in the analysis after 365 days of database history. Therefore, children aged <1year will be excluded. Patient-level THN utilization: All “new” users of THN in the period between 01/01/2012 and 31/12/2022, with “new” users being defined as all people with a prescription THN within the study period, with at least 365 days of visibility prior to the date of their THN prescription and no prescription of THN in the last 7 days. Therefore, the same person can be a “new” user multiple times during the study period. Variables Drug of interest: Take-Home Naloxone Data sources 1. IQVIA Disease Analyzer Germany (IQVIA DA Germany), Germany 2. IQVIA LBD Belgium, Belgium 3. Clinical Practice Research Datalink GOLD (CPRD GOLD), United Kingdom 4. The Information System for Research in Primary Care (SIDIAP), Spain Sample size No sample size has been calculated. Data analyses Population-level THN use: Annual period prevalence of THN use and annual incidence rates per 100,000 person years in (1) the general population and (2) among people with a recorded history of opioid use disorder (OUD), as described in section 9.7.5.1 – Population-level drug utilization study. Patient-level THN use: Summary baseline characteristics of “new” users incl. demographics and history of opioid use, overdose will be conducted. Index date will be the date of the respective prescription of THN for each person. Number of THN prescriptions/packages per “new” user at index date will be summarised and mean (SD), median, p25 and p75 provided. See for further description section 9.7.5.2 – Patient-level drug utilization study. For all analyses a minimum cell count of 5 will be used when reporting results, with any smaller counts obscured.

Rationale and Background
Prescription opioids, while effective for managing severe pain, have led to a public health crisis due to misuse, addiction, and overdose, particularly in the US. Recently, concerns have been growing in Europe due to increasing opioid use and related mortality. Factors such as chronic pain, mental health disorders, and advanced age can exacerbate misuse and the development of dependence. Given the potential for global spread of this issue, enhanced surveillance and in-depth research into opioid utilization patterns are imperative. A drug utilization study using the Common Data Model (CDM) is a promising approach to supplement European opioid monitoring systems, providing more granular data to inform evidence-based decisions on this complex problem.

Research question and Objectives
The objectives of this study are
(i) To investigate the annual incidence and annual period prevalence of use of opioids (overall, active drug substance, strength (weak/strong opioids) and route (oral, transdermal or parenteral)), stratified by calendar year, age, sex and country/database during the study period 2012-2022.
(ii) To determine duration of prescription opioid use, as well as characteristics of new users and indication for opioid prescribing/dispensing, all stratified by country/database.
Research Methods
Study design
• Population level cohort study (Objective 1, Population-level drug utilization study on opioids)
• New drug user cohort study (Objective 2, Patient-level drug utilization analyses regarding summary characterisation, duration, and indication of opioid use)
Population
Population-level utilization of opioids: All people registered in the respective databases on 1st of January of each year in the period 2012-2022 (or the latest available), with at least 1 year of data availability, will participate in the population-level analysis (period prevalence calculation in Objective 1). Therefore, children aged <1year will be excluded. New users of opioids in the period between 1/1/2012 and 31/12/2022 (or latest date available), with at least 1 year of data visibility, and no use of the respective opioid in the previous 6 months or 12 months, will be included for incidence rate calculations in Objective 1. Patient-level drug utilization: New users of opioids in the period between 1/1/2012 and 31/12/2022 (or latest date available), with at least 1 year of data visibility, and no use of the respective opioid in the previous 6 months or 12 months, will be included for patient-level drug utilisation analyses. Variables Drug of interest: Opioids (substances listed in ATC classes N01AH, N02A and R05DA) incl. naloxone and fixed naloxone-opioid combinations. (further details see section 9.3.1) Data sources 1. Estonian Biobank (EBB), Estonia 2. IQVIA Disease Analyzer Germany (IQVIA DA Germany), Germany 3. IQVIA LBD Belgium, Belgium 4. Integrated Primary Care Information Project (IPCI), The Netherlands 5. The Information System for Research in Primary Care (SIDIAP), Spain 6. Clinical Data Warehouse of Bordeaux University Hospital (CHUBX), France 7. Auria Clinical Informatics VARHA (ACI Varha), Finland Sample size No sample size has been calculated. Data analyses Population-level drug utilisation will be conducted in all databases, with ACI VARHA not contributing to the prevalence analyses. Patient-level DUS analyses will be conducted in all databases, with ACI VARHA not contributing to the analysis of duration of opioid prescriptions. Population-level opioid use: Annual period prevalence of opioid use and annual incidence rates per 100,000 person years will be estimated as described in section 9.7.5.1 – Population-level drug utilization study. Patient-level opioid use: Large-scale patient-level characterization will be conducted. Index date will be the date of the first prescription of the specific opioid for each person. Frequency of indication at index date, and in the immediate time before will be assessed. Cumulative treatment duration will be estimated for the first treatment era and the minimum, p25, median, p75, and maximum will be provided. See for further description section 9.7.5.2 – Patient-level drug utilization study. For all analyses a minimum cell count of 5 will be used when reporting results, with any smaller counts obscured.

Rationale and Background
Systemic lupus erythematosus (SLE) is a multisystem autoimmune disorder of connective tissue characterized by autoantibodies that target nuclear antigens, remissions and flares, and a highly variable clinical presentation, disease course, and prognosis. The disease course is more severe in childhood-onset compared to adult-onset SLE, with higher prevalence of morbidities and lower survival rates.
Therefore, to review new drug applications, it would be important for the European Medicines Agency (EMA) to understand the current clinical practice of treating SLE in paediatric population and differences with the treatment in adult population.
Research question and Objectives
The overall objective of this study is to characterise paediatric and adult patients with SLE diagnosed in the period 2013-2022, and to study the treatments they received in this same period.
Research Methods
Study design
A series of cohort studies will be conducted, including newly diagnosed SLE and new user (of SLE treatments) cohorts.
Population
The source population will include all individuals eligible in the database between 01/01/2013 and 31/12/2022. Additional eligibility criteria will be applied for each study objective: Cohort 1) at least 365 days of prior history available before date of new SLE diagnosis will be applied for large-scale characterisation (objectives 1 and 2); Cohort 2) a washout period of 365 days at the treatment ingredient level will be applied to capture new users of SLE treatment (objectives 5 and 6).
Variables
The main exposure of interest is the treatment of SLE: treatment/s initiated at index date, 1 to 30, 31 to 90, 91 to 180, 181 to 365 days, and 366 days to any time after new diagnosis of SLE. A pre-specified list of SLE treatments will be generated (objectives 3, 4, 5, and 6).
All co-morbidities and co-medications will be used for large-scale patient characterisation, identified as concept/code and descendants. A list of pre-specified co-morbidities and co-medications will also be described.
Data sources
1. IQVIA Disease Analyzer Germany (IQVIA DA Germany), Germany
2. Sistema d’Informació per al Desenvolupament de la Investigació en Atenció Primària (SIDIAP), Spain
3. Institut Municipal Assistencia Sanitaria Information System (IMASIS), Spain
4. Clinical Data Warehouse of Bordeaux University Hospital (CDWBordeaux), France
5. Clinical Practice Research Datalink (CPRD) GOLD, United Kingdom (UK)

Rationale and Background:
Gastroparesis is a medical condition characterized by delayed gastric emptying, causing symptoms like postprandial fullness, nausea, vomiting, and upper abdominal pain. It affects individuals across different age groups, encompassing both paediatric population and adults. Pharmacotherapy, particularly medication with prokinetic properties, has been used to manage symptoms, often through off-label use.

Research question and Objectives:
Research question
What is the real-life use of medicines with prokinetic properties in children and adults diagnosed with gastroparesis?
Study objectives
1.To determine the incidence and prevalence of use of medications with prokinetics properties in the paediatric population stratified by calendar year, age categories, sex and country/database during the study period (2012 – 2022)
2.To determine the incidence and prevalence of use of medications with prokinetics properties in adults, stratified by calendar year, age categories, sex and country/database during the study period (2012 – 2022)
3.To describe the characteristics (in terms of age, sex) of children and adults initiating treatment with any of the prokinetic drugs of interest stratified by indication of use.
4.To determine the dose, formulation, route of administration , indication of use and setting (inpatient vs outpatient ) at time of treatment initiation of any of the prokinetic drugs of interest. In addition, the cumulative treatment duration will be estimated.

Research Methods:
Study design
-Population-level cohort study (Objective 1 and 2, Population-level drug utilization study of medication with prokinetic properties)
-New drug user cohort study (Objective 3 and 4, Patient-level drug utilization analyses regarding summary characterization, dose, formulation, route of administration (oral or parenteral), duration and indication of use of medication with prokinetic properties)
Population
-Population-level utilization of medication with prokinetic properties: Population-level drug utilization analyses will include all individuals registered in the respective databases between 2012 and 2022, with at least 1 year of data visibility prior they become eligible for study inclusion. This requirement of at least 1 year of data history will not hold for children < 1 year. -Patient-level drug utilization: Patent-level drug utilization analyses will include new users of medication with prokinetic properties in the period between 2012 and 2022 (or latest date available, whatever comes first), with at least 1 year of data visibility prior to index date, and no use of the respective medication with prokinetic properties in the previous 1 year. This requirement of at least 1 year of data history will not hold for children < 1 year. Variables: Drug of interest -Macrolide antibiotics: Erythromycin (not used for the treatment of infection – i.e. prescriptions with code for infection in the +7/-7 days around the prescription date will be excluded) -Prokinetic agents: Metoclopramide, Cisapride, Domperidone, Clebopride, Itopride and Cinitapride Condition of interest: -Gastroparesis and other conditions/indications Data sources: 1.Clinical Data Warehouse of Bordeaux University Hospital (CHUBX), France 2.Clinical Practice Research Datalink GOLD (CPRD GOLD), United Kingdom 3.IQVIA Disease Analyzer Germany (IQVIA DA Germany), Germany 4.IQVIA LBD Belgium, Belgium 5.Institut Municipal Assistencia Sanitaria Information System (IMASIS), Spain 6.Integrated Primary Care Information Project (IPCI), The Netherlands 7.The Information System for Research in Primary Care (SIDIAP), Spain Sample size: No sample size has been calculated for this drug utilization study, as our primary focus is to examine drug utilization of medications with prokinetics properties, irrespective of the sample size. Based on a preliminary feasibility assessment, the expected number of records for medication with prokinetic properties in the databases included in this study will be approximately up to 276,000 in children and up to 1,655,000 in adults. Data analyses: Population-level utilization of medication with prokinetic properties: Annual period prevalence of medications with prokinetics properties use and annual incidence rates per 100,000 person years will be estimated in the paediatric population and in adults. The statistical analyses will be performed based on OMOP-CDM mapped data using the “IncidencePrevalence” R package. Patient-level drug utilization: Large-scale patient-level characterization will be conducted at index date including patient demographics and co-medication. Index date will be the date of the first prescription of the specific medications with prokinetics properties for each person. Frequency of indication/comorbidities will be assessed at index date and for any time up to 2 years for infants/toddlers and any time up to 5 years for the other age categories. Treatment duration will be estimated for the first treatment era and the minimum, p25, median, p75, and maximum will be provided. Dose/strength of prescribed or dispensed medication with prokinetic properties will be expressed as the minimum, p25, median, p75 and maximum. Route of administration will be estimated for the first treatment era and provided as proportion. The statistical analyses will be performed based on OMOP-CDM mapped data using the “DrugUtilization” R package. For all analyses a minimum cell count of 5 will be used when reporting results, with any smaller counts obscured.

Rationale and Background:

In clinical trials involving patients with major depressive disorder, participants who start treatment may experience intercurrent events (IEs) during follow-up, such as treatment discontinuation, switch to alternative therapies, or changes in background/concomitant therapies (e.g., sleep aids). The ICH E9(R1) guideline defines these IEs as events that occur after treatment initiation and influence the interpretation of the outcome of interest or after which the outcome no longer exists (e.g., death).
While target estimands in these trials may adopt a treatment policy or composite strategy to handle these IEs, it is crucial to recognize that the rate at which these intercurrent events occur significantly impacts the interpretation of estimated treatment effects.
To gain a more comprehensive understanding of the external validity of clinical trials in this indication, it is essential to assess whether the rate of occurrence of these IEs is similar in real-life settings compared to what is observed in the clinical trials. By obtaining such insights, the results of this study aim to provide valuable information regarding the generalizability of clinical trial findings to real-world scenarios.

Research question and Objectives:

Research question
What is the incidence of treatment-related intercurrent events (IEs) common in clinical trials in patients with major depressive disorder?

Study objectives
1. To examine the proportion of patients with newly diagnosed major depressive disorder who start treatment with antidepressants (NSRIs, SSRIs, or other anti-depressants), as well as those who switch or discontinue treatment at specific intervals (4, 6, 8, 12, and 24 weeks after treatment initiation), stratified by age, sex, and country/database during the study period (2013 – 2022).
2. To estimate the duration of antidepressant use in patients with newly diagnosed major depressive disorder who initiate treatment with antidepressants (NSRIs, SSRIs, or other antidepressants), stratified by age, sex, and country/database during the study period (2013 – 2022).
3. To assess the proportions of patients with newly diagnosed major depressive disorder who initiate, switch, or discontinue treatment with psycholeptics (antipsychotics, anxiolytics, hypnotics, and sedatives) at specific intervals (4, 6, 8, 12, and 24 weeks) after starting antidepressant therapy, stratified by age, sex, and country/database during the study period (2013 – 2022).

Research Methods:

Study design
•Patient-level characterisation (Objective 1 and 3, Patient-level characterization of use patterns and sequences, including initiation, discontinuation, and switching, of antidepressants and psycholeptics in patients with newly diagnosed major depressive disorder).
•Patient-level drug utilization (Objective 2, Patient-level drug utilization analyses to assess the duration of antidepressant use in patients with newly diagnosed major depressive disorder).

Population
Patient-level characterisation: Patient-level characterisation analyses will include all patients with newly diagnosed with major depressive disorder who are aged 12 years and above in the respective databases from 2013 to 2022 (or the latest available date if earlier), with a minimum of 1 year of data visibility before their diagnosis, and no previous record of major depressive disorder in the year preceding their diagnosis.

Patient-level utilization: Patient-level drug utilization analyses will include all patients aged 12 years and above with newly diagnosed major depressive disorder who are new users of any of the antidepressant class of interest in the respective databases from 2013 to 2022 (or the latest available date if earlier), with a minimum of 1 year of data visibility before the index date, and no record of using the respective antidepressants in the year preceding the index date.

Variables
Drug class of interest:
•Non-selective monoamine reuptake inhibitors
•Selective serotonin reuptake inhibitors
•Other antidepressants (excluding esketamine and Hyperici herba)
•Concomitant medications – Psycholeptics
-Antipsychotics
-Anxiolytics
-Hypnotics and sedatives
Condition of interest:
•Major depressive disorder (MDD)

Data sources
1.Clinical Practice Research Datalink GOLD (CPRD GOLD), United Kingdom
2.IQVIA Disease Analyzer Germany (IQVIA DA Germany), Germany
3.Institut Municipal Assistencia Sanitaria Information System (IMASIS), Spain
4.Integrated Primary Care Information Project (IPCI), The Netherlands
5.The Information System for Research in Primary Care (SIDIAP), Spain

Sample size
No sample size was calculated for this study, as our primary focus is to examine the use pattern of antidepressants and psycholeptics in adolescents/adults with newly diagnosed MDD, regardless of the sample size. Based on a preliminary feasibility assessment, the expected number of MDD records in the included databases for this study will be approximately 380,000.

Data analyses
Patient-level characterisation of incident MDD: The number and percentage of patients with newly diagnosed MDD initiating, switching, or discontinuing treatment with antidepressants (objective 1) and psycholeptics (objective 3) following date of MDD diagnosis (for treatment initiation of antidepressants and at 4, 6, 8, 12, and 24 weeks after starting antidepressant therapy will be depicted using Sunburst plots and Sankey diagrams. The statistical analyses will be performed based on OMOP-CDM mapped data using the “TreatmentPatterns” R package.

Patient-level drug utilization of antidepressants: The patient-level drug utilization of antidepressants will involve estimating the duration (mean, median, quantiles 25% and 75%, minimum and maximum) of antidepressant use in patients with newly diagnosed MDD during the first treatment era. The index date will be determined as the date of the first prescription of the specific antidepressant class for each individual. Statistical analyses will be conducted using the «DrugUtilization» R package based on OMOP-CDM mapped data.
For all analyses, results will be reported with a minimum cell count of 5, and any counts smaller than 5 will be obscured to ensure privacy and confidentiality.

Rationale and Background:

Idiopathic inflammatory myopathies (IIM) are rare and diverse autoimmune disorders characterized by muscle inflammation, weakness, and extramuscular manifestations affecting organs like skin, lungs, heart, and joints (Lundberg 2021, Sasaki 2018). The subgroups include dermatomyositis, antisynthetase syndrome, immune-mediated necrotizing myopathy, inclusion body myositis, polymyositis, and overlap myositis (Lundberg 2021). Despite their rarity, understanding the epidemiology of these disorders is essential to identify patterns and determinants.
Currently, there are no approved specific therapies for dermatomyositis (DM) and polymyositis (PM) based on randomized controlled trials. These diseases are challenging because of their associated morbidity and mortality (Aggarwal et al., 2017). Classification criteria developed by the European League Against Rheumatism (EULAR) and the American College of Rheumatology (ACR) help identify major IIM subgroups. Diagnostic tools involve elevated muscle-derived enzymes in serum, antinuclear antibodies, muscle biopsy, electromyography, and MRI (Lundberg 2021, Papadopoulo 2023).
The pathogenesis, treatment responses, and organ involvement vary among IIM subtypes, necessitating a deeper understanding of molecular pathways and auto-antigens (Lundberg 2021, Findlay 2015). Glucocorticoids are commonly used as first-line treatment, often combined with immunosuppressive agents like methotrexate, azathioprine, and others (Oldroyd 2022, Sasaki 2018). Rituximab shows promise in refractory cases (Valiyil R 2010-, Mok 2007). Although TNF’s role is implicated, anti-TNF treatments’ efficacy is limited (Lundberg 2021).
Pediatric cases require special consideration. Juvenile idiopathic inflammatory myopathies affect children and young individuals, involving muscles, skin, and other organs. Differences exist between juvenile and adult forms in terms of pathogenesis, autoantibody profiles, and treatment responses. Consensus guidelines help guide diagnosis and management (Belluti et al.).
In conclusion, idiopathic inflammatory myopathies encompass a spectrum of rare autoimmune disorders affecting muscles and various organs. Understanding their epidemiology, classification, diagnostic criteria, and treatment approaches is essential for improving patient outcomes and tailoring treatments, especially in paediatric cases.

Research question and Objectives:

The overall objective of this study is to describe and characterise dermatomyositis (DM), polymyositis (PM) and their juvenile forms (JDM and JPM), in terms of prevalence, natural history of the disease, disease severity, and treatment.

The specific objectives of this study are:
1. To estimate the yearly prevalence of DM and PM in adult (18+ years) and paediatric populations (less than 2 years, 2 to less than 6 years, 6 to less than 12 years, 12 to less than 18 years) overall and by sex.
2. To characterise patients and describe age at disease onset, for DM, PM, JDM and JPM.
3. To describe the occurrence in adults and children of biomarker measurements (e.g. creatinine kinase, tests for myositis auto-antibodies – INF-b levels, INF type I gene signature) before, at the time, and after a diagnosis of DM, PM, JDM and JPM.
4. To describe the occurrence of clinical manifestations (muscle inflammation, muscle weakness, connective tissue disease overlap, presence of calcinosis in children) before, at the time, and after a diagnosis of DM, PM, JDM and JPM.
5. To describe disease severity including organ involvement (skin, joints, lung, heart, GI tract) before, at the time, and after a diagnosis of DM, PM, JDM and JPM.
6. To describe treatment administered (including combinations and sequences) after a diagnosis of DM, PM, JDM and JPM

All results will be reported by database, overall, and by study periods (2006-2013, 2013-2020, and 2020-2022), and stratified by age and sex when possible.

Research Methods:

-Study design
Cohort study. We will include cohorts of first diagnosed DM, PM, JDM, JPM and new user cohorts of their treatments (for objective 6).

-Population
The source population will include all individuals eligible in the database between 01/01/2006 and end of the available date in each database. For objective 1, all patients active in the database at the start of all calendar year will be included. For objectives 2-5, two cohorts with be characterised, one with a 90-day prior history requirement from diagnosis date, and one without this requirement. For objective 6, a washout period of 365 days at the treatment ingredient level will be applied to capture new users of DM, PM, JDM and JPM treatment.

-Variables
DM, PM, JDM and JPM will be assessed as first occurrence of the codes specified in Annex 1. Additional age criteria, <18 year old at time of first diagnosis will be applied for JDM and JPM and >18 at time of first diagnosis for DM and PM. Co-morbidities and co-medications will be used for large-scale patient characterisation, identified as concept/code and descendants. A list of pre-specified co-morbidities, measurements, clinical manifestations, and severity markers will also be characterised and is included in Annex 1. Treatments of DM, PM, JDM, JPM will be identified using the codes included in Annex 1.

-Data sources
1. IQVIA Disease Analyzer Germany (IQVIA DA Germany), Germany
2. Sistema d’Informació per al Desenvolupament de la Investigació en Atenció Primària (SIDIAP), Spain
3. Clinical Data Warehouse of Bordeaux University Hospital (CDW Bordeaux), France
4. Clinical Practice Research Datalink (CPRD) GOLD, United Kingdom (UK)
5. Estonian Biobank (EBB), Estonia

-Sample size
No sample size has been calculated as this is a descriptive Disease Epidemiology Study where we are interested in the characteristics of all incident DM, PM, JDM and JPM patients. Based on a preliminary feasibility assessment the expected number of patients in the included databases for this study will be approximately 6,000 for DM, and 5,000 for PM. We will define JDM and JPM based on codes and age at diagnosis as they are likely to not be coded specifically as juvenile, so we are not able to determine a concrete sample size for the juvenile forms (we expect around 3-10% of them to be juvenile).

-Data analyses
Point prevalence of each outcome of interest (DM, PM, JDM, JPM), with every individual deemed to have the diagnosis from first occurrence until end of follow-up calculated on an annual basis as of the 1st January for each year, estimated overall and stratified by age and sex.
Age and sex at time of DM, PM, JDM, JPM diagnosis (index date) will be described for each of the generated study cohorts (Objective 2). Large-scale patient-level characterisation will be conducted for objectives 3 to 5. Occurrence of co-morbidities, measurements, clinical manifestations, and severity markers will be assessed for anytime –and up to 365 days before index date, for 364 to 91, for 90 to 31, and for 30 to 1 day before index date, and at index date. We will also report them for 1 to 90, 91 to 180, 181 to 365 days, 366 to 1095, 1096 to 1825 days, and 1826 days to any time post index date.
The number and percentage of patients receiving each of a pre-specified list of DM, PM, JDM and JPM treatments (see Appendix 1) and treatment combinations will be described at index date, 1 to 90, 91 to 180, 181 to 365 days, 366 to 1095, 1096 to 1825 days, and 1826 days to any time post index date. Additionally, sunburst plots and Sankey diagrams will be used to describe treatment patterns and sequences over time (objective 6).
For all continuous variables, mean with standard deviation and median with interquartile range will be reported. For all categorical analyses, number and percentages will be reported. A minimum cell count of 5 will be used when reporting results, with any smaller counts reported as “<5”. All analyses will be reported by country/database, overall and stratified by age groups and sex when possible (minimum cell count reached). Additionally, to capture treatments availability and changes over time, analyses will be further stratified by study periods (2006-2013, 2013-2020, and 2020-2022).

Rationale and background: Coronavirus disease-2019 (COVID-19) patients are at increased risk of venous and arterial thromboembolic events. SARS-CoV-2 variants have evolved during the COVID-19 pandemic with the dominant variant being Omicron now (as of December 2021). Information relating to thromboembolic risk and its impact on COVID-19 largely relates to COVID-19 variants occurring earlier during the pandemic. Therefore, evidence used to contextualize coagulopathy risk in light of vaccination may now differ. There is a need to better understand the risks of thromboembolic events among patients with COVID-19 associated with the Omicron variant, their impact on prognosis, and whether risk factors for such events remain the same, overall and in the context of prior COVID-19 infection, SARS-CoV-2 vaccination and among certain subgroups.
This study is one of the five use cases selected in the pilot project to test and inform HealthData@EU frameworks. HealthData@EU pilot project is the European Health Data Space (EHDS) Pilot project that aims to investigate and establish an infrastructure and data ecosystem for the secondary use of health data to facilitate research, innovation and better policy making; and assess the ability to scale towards a Union-wide infrastructure, as a core component of the EHDS.

Objectives:
1. To estimate the background incidence rate of venous and arterial thromboembolic events among the general population pre-pandemic population.
2. To estimate the incidence rate of venous and arterial thromboembolic events among patients with COVID-19 within 30-, 60-, 90- and 180-days during the Omicron period, stratified by prior SARS-CoV-2 vaccination and prior infection status.
3. To estimate the incidence rate of venous and arterial thromboembolic events among patients with SARS-CoV-2 vaccination within 30-, 60-, 90- and 180-days, stratified by prior infection status.
4. To estimate a) the association between clinical risk factors and prior SARS-CoV-2 vaccination on the incidence rate of venous and arterial events among people with COVID-19 and b) the impact that thromboembolic events have on worsening severity of COVID-19 during the Omicron period.
5. To estimate incidence rate ratios for venous and arterial thromboembolic events among patients with COVID-19 and different SARS-CoV-2 vaccine doses compared to the background population, using incidence rates estimated in objectives 1 to3.

Study type: population-level cohort
Study population:
1) Pre-pandemic cohort to calculate background rates of venous and arterial thromboembolic events in the general population (year 2017-2019).
2) People with COVID-19 during the time when OMICRON was the dominant variant (coded or test positive). All participants are required to be visible in the data source since 1st January 2020 to have full records on infection and vaccination history.
3) People vaccinated against SARS-CoV-2 (+/- during the period when OMICRON was the dominant variant). All participants are required to be visible in the data source since 1st January 2020 to have full records on infection and vaccination history.
For allcohorts, individuals with recent VTE or ATE event (defined as having a diagnosis of VTE or ATE within 183 days prior to index date, with sensitivity analysis of using any time prior and 91-days as wash-out periods.) will be excluded.

Analysis:
Standardized incidence rate ratio (SIR) compared to the background population will be estimated using indirect standardization.
Cohorts will be stratified by prior COVID-19 infection occurrence and prior SARS-CoV-2 vaccination (COVID-19 and vaccine cohorts only), age, sex. All cohorts will additionally be stratified by whether patients are immunocompromised on the index date.

Rationale and Background:

The extended mandate of EMA reinforcing the role of the Agency in crisis preparedness and management of medicinal products and medical devices became applicable on 1st March 2022 (Regulation on EMA’s extended mandate becomes applicable | European Medicines Agency (europa.eu)).
EMA is now responsible for monitoring medicine shortages that might lead to a crisis situation, as well as reporting shortages of critical medicines during public health emergencies (PHE). Such shortages would make it difficult or impossible to meet the treatment needs of individual patients or populations. The Agency has also the mandate to coordinate responses of EU / EEA countries to shortages of critical medical devices and in-vitro diagnostics in crisis situations.
Scientific and commercial data on monthly prescriptions of medicines that may be critical in PHE can help understanding trends and seasonal variations. In conjunction with time series and forecasting models, as well as data on medicines supply, such data will contribute to the on-going efforts of the Agency to better monitor and coordinate its response to shortages of critical medicines.
This study aims at generating monthly prescription rates of selected medicines over the last 10 years and to fit Autoregressive Integrated Moving Average (ARIMA) prediction models to such data.

Research question and objectives:

This study aims to characterise the incidence of use (prescription or dispensation) of 11 antibiotics used for public health emergencies that are considered at risk of shortages in order to understand trends, cycles and seasonality in the use of those medicines; and to forecast short-term prescription rates of such medicines under assumed scenarios, which could help anticipate and prevent potential shortages, or manage them.
The general research question is: What are the monthly prescription rates of selected medicines of importance for public health emergencies over the last 10 years?
The specific objectives of this study are:
(i) To estimate monthly incidence rates of use (prescription or dispensation) of the 11 selected medicines during a 10-year period from the most recent data available, stratified by age and sex, in each of the databases.
(ii) To conduct time series modelling by fitting an ARIMA model to data generated in objective 1 for short-term (6-month) forecasting.

Research Methods:

Study design
• Population level cohort study (Objective 1, Population-level drug utilisation study on antibiotics)
• Population level cohort study (Objective 2, Time series modelling based on the Population-level drug utilisation study on antibiotics)
Population
Population-level drug utilisation of antibiotics: All individuals present in the database in the last 10 years of available data will be included in the analysis after 30 days of database history. For this population, incidence of use of antibiotics will be explored.

Variables
Drugs of interest: list of 11 antibiotics that may be critical in PHE
Calendar month, age, and sex will be used for stratification.

Data sources
1) IQVIA LPD Belgium (Primary Care Database)
2) CPRD Gold (UK, Primary Care Database)
3) SIDIAP (Spain, Primary Care Database)
4) IMASIS (Spain, Secondary Care Database)
5) IQVIA DA (Germany, combination of primary and secondary care (outpatient visits) database).

Sample size
No sample size has been calculated. Based on a preliminary study feasibility assessment the expected number of prescriptions in the period investigated is expected to be between <1Kand 25M across the five data sources considered. Data analyses Population-level drug utilisation study on antibiotics: monthly incidence rates of antibiotic use per 100,000 person-year, as described in section 8.7.5.1 – Population-level drug utilisation study. Time series modelling: forecast of the 6-month incidence rates of antibiotic use after the end of available data in the data source using AutoRegressive Integrated Moving Average (ARIMA) models for time series analysis, as described in section 8.7.5.2.

Ranitidine is a competitive and reversible inhibitor of the action of histamine and indicated for the management of peptic ulceration (with or without Helicobacter Pylori), Gastro-Esophageal Reflux Disease (GERD), reflux oesophagitis and Zollinger-Ellison syndrome. In 2019, results of a preliminary laboratory analysis have shown the presence of NNitrosodimethylamine (NDMA), a human carcinogen, in ranitidine.
The European Commission triggered on 12 September 2019 a referral procedure to evaluate the relevance of these findings, the potential root causes and their impact on the benefit-risk balance of medicinal products containing ranitidine. Based on this evaluation, in April 2020 EMA’s Committee for Medicinal Products for Human Use (CHMP) has recommended the suspension of all ranitidine-containing medicines in the
EU due to the presence of low levels of NDMA impurities.
Many ranitidine-containing medicines have not been available in the EU for several months since the initiation of the referral, because national competent authorities have recalled them either due to levels of NDMA found in the products or as a precaution while the EMA review is ongoing. Healthcare professionals have been asked to advise patients on alternative medicines. In addition, in some Member States the outcome of the referral was communicated at national level through media campaigns,
involving learned societies and medical associations to inform prescribing physicians and health care organisations about these changes.
The unavailability of ranitidine-containing medicines is expected to cause patients to switch treatment to alternative medicines or alternative treatment strategies. The extent of switches to alternative medicines remains unknown as well as the rate of patients permanently discontinuing treatment following unavailability of ranitidine-containing medicines.

The overall aim of this study is to evaluate the impact of the regulatory actions taken for ranitidine containing medicinal products following the 2019 referral procedure, using healthcare databases of six European countries.

Background and Significance: Type 2 diabetes mellitus (T2DM) is a major cause of morbidity and mortality globally and is associated with an elevated risk of cardiovascular events. Therapeutic options for T2DM have expanded over the last decade with the emergence of sodium-glucose co-transporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP1) receptor agonists, which reduced the risk of major cardiovascular events in randomized controlled trials (RCTs). Cardiovascular evidence for older second-line agents, such as sulfonylureas, and direct head-to-head comparisons, including with dipeptidyl peptidase 4 (DPP4) inhibitors, are lacking, leaving a critical gap in our understanding of the relative effects of T2DM agents on cardiovascular risk and on patient-centered safety outcomes.

Study Aims: To determine real-world comparative effectiveness and safety of traditionally second-line T2DM agents using health information encompassing millions of patients with T2DM, with a focus on individuals at moderate cardiovascular risk and other key subgroups.
Study Description: We will conduct three large-scale, systematic, observational studies to make pairwise comparisons of all SGLT2 inhibitor, GLP1 receptor agonist, DPP4 inhibitor and sulfonylurea agents at the drug-, class- and population subgroup-level within our proposed Large-Scale Evidence Generations Across a Network of Databases for T2DM (LEGEND-T2DM) initiative. LEGEND-T2DM will leverage the ObservationalHealth Data Science and Informatics (OHDSI) community that provides access to a standing global network of administrative claims and electronic health record (EHR) data sources. The 13 data sources already committed to LEGEND-T2DM cover > 190 million patients in the US and about 50 million internationally, and include two academic medical centers, IBM MarketScan and Optum databases, and the US Department of Veterans Affairs. LEGEND-T2DM will study invite other OHDSI data custodians around the world to participate in the study.

Population: Adult, T2DM patients who newly initiate a traditionally second-line T2DM agent, including individuals with and without established cardiovascular disease.

Our systematic framework will address residual confounding, publication bias and ?-hacking using data-driven, large-scale propensity adjustment for measured confounding, a large set of negative control outcome experiments to address unmeasured and systematic bias, prespecification and full disclosure of hypotheses tested and their results. These approaches capitalize on mature OHDSI open source resources and a large body of clinical and quantitative research that the LEGEND-T2DM investigators originated and continue to drive. Finally, LEGEND-T2DM is dedicated to open science and transparency and will publicly share all our analytic code from reproducible cohort definitions through turn-key software, enabling other research groups to leverage our methods, data, and results in order to verify and extend our findings.

El cáncer es responsable de una proporción importante de la carga total de morbilidad en la población mundial. Sin embargo, no afecta a todas las subpoblaciones por igual. Para la mayoría de los tipos de cáncer, los países desarrollados tienen tasas de incidencia más altas, aunque las tasas aumentan desproporcionadamente en los países en desarrollo. En España, la incidencia del cáncer varía en función de una serie de factores. Actualmente existe un vacío en el conocimiento sobre las tendencias temporales de la incidencia del cáncer en España y, más concretamente, en Catalunya. Nuestro objetivo es describir las tasas de incidencia anual de cáncer de los 5 tipos de cáncer sólido más incidentes en España (cáncer de mama, próstata, colorrectal, pulmón y vejiga) desde 2009 hasta 2018 utilizando la base de datos SIDIAP. SIDIAP es una recopilación de historias clínicas longitudinales pseudoanonimizadas de casi seis millones de pacientes de Catalunya (80% de la población) registrados en 370 centros de atención primaria, y es representativa del total de la población catalana por sexo, edad y distribución geográfica. Las tasas de incidencia del cáncer se estratificarán por sexo y niveles de privación del índice MEDEA para investigar las subpoblaciones que son más vulnerables a los tipos de cáncer especificados. Esto ayudará a planificar futuras intervenciones que puedan ser más específicas y efectivas para las poblaciones con un mayor riesgo.

Serious adverse events have been reported among antidementia drug users. We aim to analyse the use and comparative safety of the antidementia drugs in primary care centres in Catalonia (Spain).
Design: A population-based cohort study using real-world primary health care data (SIDIAP database), standardized to the Common Data Model OMOP with hospital linkage (CMBD database). A nested case-control approach will be adopted to assess risk of adverse events (AE) during the study period (2007-2020). Inclusion criteria: for the drug utilization study (DUS) we will include individuals with at least 40 year or older with dementia, registered for at least 1 year before cohort entry and with at least 1 prescription of rivastigmine, galantamine, donepezil or memantine during study period. For the safety study we will include patients from the DUS with an incident use (no previous 365 days use) of any of the study drugs. For the nested case control analysis, we will create a cohort of patients with dementia without treatment (anytime). Exposure (DUS/Safety): prescription of rivastigmine, donepezil, galantamine or memantine. Outcomes: (DUS) demographics, comorbidities, prescriber-type, prescribing pattern and proportion of ‘prescription cascade’ drugs (prescriptions generated to alleviate adverse events). Outcomes (safety study): AEs related to disorders of the skin, cardiovascular, gastrointestinal, neurological, psychiatric, sleep, urinary and respiratory disorders, falls, hospitalizations and all-cause mortality.
Statistics: Yearly age-sex incidence rates (IR) and Kaplan Meier curves to assess the duration and drug discontinuation. Adjusted and unadjusted IR of AEs, Hazard Ratios (95% confidence intervals (CI)) using Cox proportional hazard models, and Odds Ratios (95% CI) using nested case-control analysis with conditional logistic regression will be assessed. Each case will be matched (age, sex, Charlson Comorbidity Index and socioeconomic status) with up to 10 controls.
Expected results: With this large population-based cohort study based on routinely collected primary care data with hospital linkage we expect to provide an in-depth characterization of the population that uses any of the currently commercialised antidementia drugs. Because we are using routinely collected real-world information, which differs from the information gathered in randomized controlled trials, we will be able to provide a more accurate picture of the patients that finally receive the drugs to treat dementia. We will also analyse the proportion of patients with a ‘prescription cascade’ and this will contribute to the identification of adverse events that have been misclassified as new medical conditions. Finally, the comparative safety study carried out will inform us about the risk of adverse events between users and non-users of antidementia drugs. Given the increasing availability of non-pharmacological treatments to treat dementia, this information will help clinicians to assess the risk-benefit of these drugs. The other comparative safety studies, between acetylcholinesterase inhibitors versus N-methyl-D-aspartate receptor antagonists and between galantamine and donepezil versus rivastigmine will also contribute to decision making of clinicians and can be the base of other prospective head-to-head comparison studies.
Relevance and aplicability: Population-based cohort studies that use routinely collected health care data have gained importance in the last years because of their ability to provide evidence that could not be generated through randomized controlled trials. This is more important in pharmacoepidemiology given that subjects that are included in the pivotal trials of the drugs usually differ greatly from the overall population that finally receives the medication. The ageing of the populations foresees an increase in the cognitive related disorders including dementia and Alzheimer disease. Although the actual medications to treat dementia (rivastigmine, galantamine, donepezil and memantine) were commercialized more than a decade ago, few are the studies that have analysed their real-world adverse effects at a population level, none of them in Spain, and even fewer are the ones that have done this comparing the different medications. Regardless of the new therapies that are being recently developed to treat dementia the great burden of the treatment still relies on these four medications and therefore is it necessary to fully identify, describe in depth the patients that are using these drugs. The comparative safety analysis results will help health care providers and clinicians to assess the risk-benefits of these drugs to avoid future adverse events or better target patients who receive medication. At last, this can also be a hypothesis generating study given that it will help identify the characteristics of the population at an increased risk of adverse events which could help design future antidementia drug studies.

We aim to estimate the risks of long-term COVID-19 outcomes among individuals with COVID-19 or exposed to COVID-19 during pregnancy, as well as the effect of vaccines on the development of long COVID and long-term COVID-19 outcomes.
Data will be obtained from SIDIAP, which includes primary care records for approximately 6 million people in Catalonia. To estimate long-term COVID-19 outcomes (Objective 1), we will conduct three population-based matched cohort studies using a target trial emulation design from September 2020 to December 2023. We will match COVID-19 infections to uninfected controls in a 1:5 ratio using propensity score (PS) matching. Cases/controls matched cohorts will include: Objective 1.1: people not vaccinated against COVID-19; Objective 1.2: people vaccinated against COVID-19; and Objective 1.3: newborns (cases: exposed to COVID-19 infection during pregnancy, controls: unexposed). Cohorts will be followed for 2 years. Our outcomes will include autoimmune, cardiovascular, mental, neurological, renal and early-life complications. We will estimate cause-specific Hazard Ratios (HR) for each outcome.To estimate vaccine effectiveness on the development of long COVID, we will first characterise long COVID based on persistent symptoms for >28 days (Objective 2.1). We will then estimate the effect of vaccines on the development of long COVID (Objective 2.2) using a staggered cohort study design. Vaccinated and unvaccinated cohorts will be compared using different PS techniques. We will then calculate HR for long COVID and long-term outcomes.
Our findings will inform preventive strategies and post-acute care pathways, thus contribute to prevent long COVID and improve COVID-19 survivors’ health.

Background:
Understanding the determinants of childhood health inequity has never been more urgent, given its influence on life-long health and lifestyle. It is increasingly recognized that the environment plays an important role in health in/equity and that it provides important potential for community-level intervention. However there are important gaps in the knowledge about the impact of changing environment on childhood health e.g. moving from urban to rural environments and vice versa.

Objectives:
The overarching objective is to examine how changes in the environment (air pollution, green spaces, social environment, built environment, unhealthy food environment) influence childhood health equity by applying artificial intelligence methods to analyse a unique and complex electronic record database of 1.6 million children living in urban and rural environments.

Dataset:
The project will use already existing ECOHCAT dataset, therefore there will be no need to make a new data extraction.

Methodology: The study will exploit the large resource of available primary care data of 1.6 million children (80% of the population) and the extensive individual data already available in a mother-child cohort in Catalonia. It will also collect new data on school children (10-12 years) in one Catalan city, Sabadell, where anthropometric measurements will be combined with questionnaires to obtain data on obesity and important risk factors. Geographical information system technologies will be used to estimate exposure to the different urban environment indicators at census tract level for the whole Catalonia and at home and school address level for Sabadell city. Individual-level mediators including diet, physical activity, and psychological well-being will be evaluated for their role in the association between urban environment indicators and childhood obesity. A health impact assessment will be developed based on this study and available literature. Machine learning methods will be considered to complement epimiology study designs and statistical approaches to uncover spatial and temporal movement patterns and associations with child health outcomes.

Expected results: The study will be novel in modelling multiple community-level urban environment
indicators and by evaluating potential individual-level mediators. A final impact assessment will help decision makers to develop urban environment policies aimed at reducing and preventing childhood obesity in
Catalonia.

Rationale and Background:
Vaproic acid/valproate-containing medicine (VPA) are first-line treatment for generalised tonic-clonic seizures (epilepsy) and adjunctive therapies in other types of seizures. They are also used as second-line treatments or adjuncts for the treatment of bipolar disorder, and for migraine prevention. Valproic acid is a teratogen, with prenatal exposure carrying a substantial risk of neurodevelopmental impairment and congenital malformations in the child. Therefore, its use in women of childbearing age is restricted to prevent valproate exposure during conception and pregnancy.
The European Medicines Agency (EMA) has issued risk minimisation measures in 2014 and 2018 including a compulsory pregnancy prevention program. Timely information on the use of VPA in young women across Europe is important.

Research question and Objectives:
The objectives of this study are
1. To estimate the population-level use (incidence rate and prevalence) of VPA in women between 12 and 55 years of age
2. To characterise patient-level VPA use in women between 12 and 55 years of age initiating treatment with VPA.

Research Methods:
Study design
• Population level cohort study (Objective 1, Population-level VPA utilisation)
• New user cohort study (Objective 2, Patient-level VPA utilisation)
Population:
Population-level utilisation of VPA and alternative treatments: All women aged between 12 years and =55 years between 01/01/2010 and 31/12/2022, with at least 365 days of prior history before the day they become eligible for study inclusion (study period: 2009-2022 including 1 year of previous data). For incidence, anyone with prior use of VPA will be excluded from the analysis.
Patient-level VPA utilisation: New users of VPA in the period between 01/01/2010 and 31/12/2021 (or latest date available), with at least 365 days of visibility prior to the date of their first VPA prescription, and no used VPA in the previous 365 days.
Variables
Drug of interest: Valproic acid, Sodium valproate, Magnesium valproate, Valproate semisodium and Valpromide
Alternative treatments: Carbamazepine, Phenobarbital, Phenytoin, Primidone, Clobazam, Clonazepam, Eslicarbazepine acetate, Lamotrigine, Oxcarbazepine, Perampanel, Rufinamide, Topiramate, Zonisamide, Brivaracetam, Ethosuximide, Gabapentin, Lacosamide, Levetiracetam, Pregabalin, Tiagabine, Vigabatrin, Lithium, Quetiapine, Olanzapine, Lamotrigine, Propranolol, Metoprolol, Atenolol, Nadolol, Timolol, Bisprolol, Topiramate, Amitriptyline, Flunarizine, Pizotifen, Clonidine
Data sources
1. Integrated Primary Care Information Project (IPCI), The Netherlands
2. Sistema d’Informació per al Desenvolupament de la Investigació en Atenció Primària (SIDIAP), Spain
3. IQVIA Longitudinal Patient Database Belgium (IQVIA LPD Belgium), Belgium
4. IQVIA Disease Analyzer Germany (IQVIA DA Germany), Germany
5. Hospital District of Helsinki and Uusimaa (HUS), Finland
6. Clinical Practice Research Datalink GOLD (CPRD GOLD), United Kingdom
Sample size
No sample size has been calculated. Feasibility counts have been generated in the general population in each databases.
Data analyses
For all analyses a minimum cell count of 5 will be used when reporting results, with any smaller counts obscured.
Population-level VPA utilisation: Annual period prevalence of VPA use and alternative treatments will be estimated, as will annual incidence rates per 100,000 person years.
Patient-level VPA utilisation: Large-scale patient-level characterisation will be conducted. Medical History will be assessed for anytime – 366 days before index date, for 365 to 31 days before index date, for 30 to 1 day before index date, and at index date. Medication use will be reported for 365 to 31 days before index date , for 30 to 1 day before index date, and at index date. Frequency of indication, namely epilepsy, bipolar disorder and migraine at index date will be assessed. Initial dose/strength and treatment duration will be estimated and the minimum, p25, median, p75, and maximum will be provided.

Rationale and Background
Substantial uncertainty surrounds the prevalence of rare blood cancers. Using real-world data, brought together as part of DARWIN EU®, we aim to estimate the prevalence of rare blood cancers in order to see if they still meet the condition to be classified as a rare disease.
Research question and Objectives
Research question
What is the prevalence of rare blood cancers in Europe?
Study objectives
Objective 1: To estimate the prevalence of follicular lymphoma between 1st January 2010 and the end of available data in data sources from across Europe, stratified by age and sex
Objective 2: To estimate the prevalence of diffuse Large B-Cell Lymphoma between 1st January 2010 and the end of available data in data sources from across Europe, stratified by age and sex
Objective 3: To estimate the prevalence of multiple myeloma between 1st January 2010 and the end of available data in data sources from across Europe, stratified by age and sex
Objective 4: To estimate the prevalence of chronic lymphocytic leukaemia between 1st January 2010 and the end of available data in data sources from across Europe, stratified by age and sex
Objective 5: To estimate the prevalence of acute myeloid leukaemia between 1st January 2010 and the end of available data in data sources from across Europe, stratified by age and sex
Objective 6: To estimate the prevalence of acute lymphocytic leukaemia between 1st January 2010 and the end of available data in data sources from across Europe, stratified by age and sex
Research Methods
Study design
Population-based cohort
Population
All people in a database will be eligible for inclusion in the study. Included study participants will need to have some observation time during the study period and, for the primary analysis, have a year of prior history available. In sensitivity analyses the requirement for prior history will first be removed, and then increased to three years.
Variables
Two age groupings will be used in the study: 1) 0-9; 10-19; 20-29; 30-39; 40-49; 50-59; 60-69; 70-79; 80-89; 90-99; 100+, and 2) 0-44; 45-64; 65 and over. The sex (male/ female) of study participants will also be identified.
Study outcomes will be identified based on the presence of a relevant diagnosis or observation. For the primary analysis, 5-year partial prevalence will be estimated and so individuals will be considered as a prevalent case if they have had a such a record in the prior 5 years. In sensitivity analyses, 2-year partial prevalence and complete prevalence will be estimated. For the latter, once identified as a case, an individual will remain so until their exit from the study (i.e. considering people diagnosed with malignancies to always be affected by the condition).
Data sources
1. Integrated Primary Care Information Project (IPCI), The Netherlands
2. Sistema d’Informació per al Desenvolupament de la Investigació en Atenció Primària (SIDIAP), Spain
3. The Clinical Practice Research Datalink (CPRD) GOLD database
4. IQVIA LPD Belgium
5. IQVIA DA Germany
Sample size
No sample size has been calculated as this is a Disease Epidemiology Study where we are interested in the prevalence of haematological cancers in as large and representative a denominator population as possible.
Data analyses
In line with EMA guidelines for the estimation of the prevalence of rare disease, point prevalence will be used for the primary analysis. The prevalence of each outcome of interest calculated on an annual basis as of the 1st January for each year, estimated overall and stratified by age and sex. As a sensitivity analysis annual period prevalence will also be estimated. A minimum cell count of 5 will be used when reporting results, with any smaller counts obscured.

Rationale and Background
The WHO 2021 AWaRe classification (who.int) of antibiotics for evaluation and monitoring of use classifies 258 antibiotics into 3 categories (Access/Watch/Reserve) according to their impact on antimicrobial resistance. The Watch list includes antibiotic classes that have higher resistance potential and includes most of the highest priority agents among the Critically Important Antimicrobials for Human Medicine and/or antibiotics that are at relatively high risk of selection of bacterial resistance. These medicines should be prioritized as key targets of stewardship programs and monitoring. This study will improve our understanding of the use of antibiotics in the Watch category in routine health care delivery, including indication, treatment duration and trends over time. The results will contribute to the EU efforts to monitor use of antibiotics as part of the global fight against antimicrobial resistance.
Research question and Objectives
The objectives of this study are (i) To investigate the incidence and prevalence of use of antibiotics (from the WHO Watch list) stratified by calendar year, age, sex and country/database during the study period 2012-2021. (ii) To explore duration of antibiotic use as well as indication for antibiotic prescribing/dispensing.
Research Methods
Study design: ? Population level cohort study (Objective 1, Population-level drug utilisation study on antibiotics) ? New drug user cohort study (Objective 2, Patient-level drug utilisation analysis with regard to duration and indication of antibiotic use)
Population
Population-level utilisation of antibiotics: All individuals present in the database in the period between 01/01/2012 and 31/12/2021 will be included in the analysis after 365 days of database history. For this population, incidence of use of antibiotics will be explored.
Patient-level antibiotic utilisation: All new users of antibiotics after not using the antibiotic of interest for 30 days in the period between 01/01/2012 and 31/12/2021, with at least 365 days of visibility prior to the date of their first antibiotic prescription.
Variables
Drug of interest: All antibiotics from the WHO Watch list (see also section 9.3.1 – exposure)
Data sources
1. Integrated Primary Care Information Project (IPCI), The Netherlands 2. Bordeaux University Hospital France 3. Sistema d’Informació per al Desenvolupament de la Investigació en Atenció Primària (SIDIAP)-OMOP, Spain 4. Parc Salut Mar Barcelona, Hospital del Mar (IMIM) (hospital database), Spain 5. IQVIA Disease Analyzer Germany (IQVIA DA Germany), Germany, 6. Clinical Practice Research Datalink GOLD (CPRD GOLD), United Kingdom
For all analyses a minimum cell count of 5 will be used when reporting results, with any smaller counts obscured.

Rationale and background: DKP-TRAM is a pharmacologi¬cal fixed association with analgesic activity, which has been registered for treatment of acute pain in 2017 in several European Countries. In Spain and Italy, the product has been launched in January 2017 and March 2017, respectively. The safety and efficacy of DKP-TRAM (25 mg – 75 mg) combination has been extensively demonstrated in the clinical development program in more than 1800 patients, especially from randomized clinical trials (RCTs) in post-operative pain. However, there is limited evidence in the real-life use of the product in the primary care settings particularly in elderly patients where the use of the 75 mg dose (with no possibility of dose titration) of tramadol contained in the combination could be a source of safety concerns for the prescribers.
In the light of this background, the evaluation of the patterns of use and the safety profile of DKP-TRAM combination will be investigated through a real-world study involving an Italian and a Spanish database.
Furthermore, we will test the potential effect modification exerted by age (75 years or older vs. younger patient) or frailty (mild, moderate, severe) among elderly patients (aged 65 or older) on the risk of adverse events (AEs) likely due to DKP-TRAM.
Research question and objectives:
Primary objectives: To evaluate pattern of drug use (i.e. indication, dosage, and duration) of DKP-TRAM.

Secondary objectives:
? To assess the risk of AEs (nausea, vomiting, diarrhoea, vertigo, hallucinations, somnolence, and constipation) in incident users of DKP-TRAM vs. incident users of tramadol as monotherapy and fixed combination tramadol-paracetamol.
? To evaluate the effect modification exerted by age (75 or older vs. 74 or younger) on the risk of adverse events in DKP-TRAM vs. tramadol monotherapy and tramadol-paracetamol combinations users.
? To evaluate the effect modification exerted by frailty (mild, moderate or severe) on the risk of adverse events in DKP-TRAM vs. tramadol monotherapy and tramadol-paracetamol combinations users aged 65 years or older.

Background: The global burden of mental and behavioral health disorders has been increasing in the last 30 years. These disorders cause premature mortality and pose an important public health burden. As the world population becomes more urbanized, the metropolitan environment continues to result in negative physical and mental health effects; however, green spaces have been shown to act as a buffer to these negative health effects. Although the relationship between mental health and green spaces has been investigated in previous studies, there are still gaps, especially with regards to the relationship between green spaces and specific mental and behavioral disorders.
Objective: To determine the association between green space (NDVI, percentage of green spaces) and the risk of developing depression, anxiety, stress, OCD and eating disorders in adults in Catalonia.
Methods: We will conduct a cohort study using data from the Information System for Research in Primary Care (SIDIAP). We will include all persons registered in the SIDIAP who are aged ?18 years between January 1, 2009 and December 31, 2018. The exposure of interest will be the availability of green spaces (measured using NDVI and the percentage of green space at the census tract level). Outcomes will be captured through diagnostic codes (ICD-10) of each mental and behavioral disorder. To evaluate the association between green spaces and the risk of each specific mental and behavioral disorder, cox proportional hazard models will be fitted to estimate cause specific hazard ratios (HR) and 95% confidence intervals (CIs).

The global pandemic of COVID-19 has resulted in over 50 million reported cases and over 1.2 million deaths globally. Meanwhile, hundreds of clinical trials of vaccines are ongoing and some of them show clinical efficacy. While planning for the large-scale immunization program, it is important to understand the potential adverse events after vaccination or viral infections. Electronic health records have been increasingly used in safety study, including SIDIAP. The ability to and the reliability of capturing the adverse events using suitable phenotyping algorithms in such databases is the foundation in conducting these studies. We will firstly identify the phenotyping algorithms of the AESI used in other studies, or develop the phenotypes if no existing one is found. Then we will evaluate the performance of these phenotypes using the diagnostic and evaluation tool that had been previously developed. The second objective is to estimate the background incidence rates (IR) of the AESI among the general population from year 2006 to 2019. Individuals who were observed for at least 365 days in the dataset during the study period will be included. The numerator of the incidence rate will be the total number of incident cases in a given year, and the denominator will be person-time at risk in each year. We will also estimate the IR among patients who were diagnosed or received a positive test for COVID-19 (after February 2020) or seasonal influenza. We will apply different algorithms in identifying both the exposures and the outcomes. We will also conduct a self-control case series analysis to explore the association between developing the AESI and COVID-19 or influenza infections.

Approximately 10-20% of COVID-19 positive patients, many of whom are older or have co-morbidities, suffer from pneumonia and acute respiratory distress syndrome (ARDS), requiring hospitalization and ventilatory support. It has been suggested that this population is also at higher risk of inflammatory immune system disorders. As a result, current treatment recommendations are to combine anti-viral therapy with immunosuppressive or immunomodulatory drugs to mitigate these immunologic complications, reducing COVID-19 associated morbidity and mortality. While the search for appropriate anti-viral therapy is ongoing, there have been some positive results with respect to systemic glucocorticoid use, such as dexamethasone, which has been associated with reduced mortality in ventilated patients and those on supplemental oxygen therapy. This has mobilised efforts to repurpose some of these steroids for the treatment of severe COVID-19 cases. That said, a lot of information on steroid use in COVID-19 patients is currently missing. Treatment type, dosage, timing of administration, as well as identification of patient risk groups that will benefit most from the treatments, is inadequately explored. To partially address these research gaps, this protocol describes a non-comparative study to explore patterns of systemic glucocorticoid use and administration in patients with either a first confirmed diagnosis for COVID-19 (diagCOVID-19) or a first positive PCR test for SARS-CoV-2 (labCOVID-19) using healthcare databases from seven European countries. The aim of this study is to describe patterns of systemic glucocorticoid use, as well as the risks of adverse events associated with these medications, in diagCOVID-19 or labCOVID-19 patients across seven European countries in ambulatory and hospital inpatient care settings.

Fluoroquinolones, are broad spectrum antibiotics that are active against both Gram-negative and Gram-positive bacteria and are indicated in the management of certain bacterial infections. The use of Fluoroquinolones has been associated with the risk of some serious adverse events, which involve the peripheral and central nervous system as well as tendons, muscles and joints. The concerns of the persistence of side effects resulted in the European Medicines Agency (EMA) conducting a pharmacovigilance referral procedure focused on assessing the severity and persistence of long lasting, disabling and potentially irreversible adverse drug reactions, and the benefit-risk balance of Fluoroquinolones for systemic and inhalational use. In November 2018, the EMA concluded that serious adverse reactions including tendon, muscle and joint disorders, neurologic and psychiatric disorders listed in the product information of different fluoroquinolones could in rare cases become long-lasting, and recommended cessation of prescriptions for milder, non-severe or self-limiting infections, and restrictions for other indications.

The overall aim of this study is to evaluate the impact of the regulatory actions taken for fluoroquinolone containing medicinal products following the 2018 referral procedure. The study objectives are:
1. To determine the drug utilisation and prescription patterns of fluoroquinolone containing medicinal products over the period 2016 and 2020 by
a) estimating monthly incident drug use, stratified by on label indications (which includes first line and last line indications) and off label indications (mild infections for which fluoroquinolones are not indicated for).
b) Estimation of early discontinuation proportion (prescribed courses that were discontinued prior to intended treatment end date)
2. Evaluate the impact of regulatory interventions on fluoroquinolone prescribing patterns using time series analysis.
3. To determine prescribers’ compliance with warnings as described in fluoroquinolones SmPC section 4.4, in particular on tendinitis and tendon rupture as well as on aortic aneurysm/dissection specifically by calculation of monthly incident prescription rates in the subgroups at risk:
a) risk groups for tendinitis and tendon rupture
b) risk groups for aortic aneurysm/dissection
c) patients with recent (within 30 days prior) or concomitant prescribing of systemic corticosteroids
4. To determine monthly incident prescription rates for alternative antibiotics prescribed in patients where systemic or inhalation use fluoroquinolones have previously been prescribed and discontinued

In contrast to declining incidence and mortality rates for older men and women, since the mid-1980s, rates of early-onset colorectal cancer (EOCRC, diagnosed before age 50 years) have increased in many high-income countries. Increasing trends in EOCRC are unexplained but may reflect secular changes that began in the 1960s and 1970s in exposure to putative risk factors including obesity, diabetes, metabolic dysfunction, and use of certain medications (including antibiotics). Few epidemiological studies have adequately examined the etiology of EOCRC. Most prior evidence is from case-control studies or small-scale cohort analyses (<150 EOCRC cases). We propose to leverage data from electronic primary care records in the Information System for Research in Primary Care (SIDIAP database; www.sidiap.org) to examine the role of obesity, diabetes and metabolic factors, aspirin/NSAID use, statin use, oral antibiotics, and tobacco smoking in EOCRC development. Hazard ratios (HR) and 95% confidence intervals (CI) for the risk factors and colorectal cancer (CRC) will be estimated using multivariable adjusted flexible parametric survival models. Risk factor associations for EOCRC will also be compared with those for CRC diagnoses at older ages (50-64 and >=65 years at diagnosis) using interaction terms. We expect to robustly identify a selection of modifiable risk factors associated with EOCRC development. Such evidence informs on the etiology of EOCRC, sheds light on possible lifestyle behaviours that can be intervened upon, and could be used by clinicians to risk stratify young-adults presenting with non-specific CRC symptoms for early screening.

Childhood overweight and obesity is an unprecedented public health challenge with immediate and adulthood effects. Findings on the relationship between playspace and overweight and obesity are mixed and studies limited, as mainly are cross-sectional and focused on green spaces. Some studies have explored how individual or area-based characteristics moderate the relationship between playspaces and overweight and obesity, finding lower effects for girls or younger children and mixed effects by race. Also, higher playspaces exposure has been linked to lower body mass index for low socioeconomic families, but higher outcome for high socioeconomic ones. Differential effects by area characteristics have been less explored, despite links between deprivation and higher risk of overweight and playspaces only benefiting privileged residents in gentrifying neighborhoods.
This study aims to assess the associations between the exposure of playspaces and overweight and obesity incidences and explore the role of individual and area-level characteristics. We will use a retrospective open longitudinal study with children aged between 2 and 5, identified as normal weight and registered in a primary healthcare record (SIDIAP database) between 2011 and 2018 in Barcelona (Spain). Overweight and obesity will be defined following the international reference and based on height and weight measures. We will estimate residential proximity to playspaces based on a local data from 2014.
We will estimate the risk of developing overweight and obesity per playspace exposure with Cox proportional hazard models by sex. To explore effect modification, interactions will be tested for individual and area-level characteristics, and stratification will be conducted for significant interaction.

Estudis epidemiològics mostren que diversos factors materns com ara l’obesitat, l’augment de pes durant la gestació, la diabetis gestacional, la preeclàmpsia i la hipertensió s’associen amb un perfil cardiometabòlic desfavorable en la descendència i amb un major risc d’obesitat infantil.
La relació dels nivells de tensió arterial (TA) durant la gestació en mares sanes, sense patologia hipertensa, amb el risc de sobrepès/obesitat i els nivells de TA en la descendència és desconegut.

Mitjançant l’anàlisi de la base de dades Sistema d’Informació per el Desenvolupament de la Investigació en Atenció Primària (SIDIAP), que inclou dades clíniques de 500.000 parelles mare-fill de Catalunya , s’estudiarà: 1) l’associació entre la TA durant l’embaràs, en mares sanes [tensió arterial sistòlica (TAS), tensió arterial diastòlica (TAD) i pressió de pols (PP) al 2n i 3er trimestre] i el fenotip de la descendència al naixement [pes, talla, índex de massa corporal (IMC)] i als 6 i 12 anys de vida [pes, talla, IMC, TAS i TAD], i 2) es determinaran punts de tall i/o trajectòries de TA durant l’embaràs que s’associïn al risc de sobrepès/obesitat en la descendència.

El coneixement d’aquestes associacions pot tenir importants implicacions clíniques i permetre el desenvolupament d’estratègies de prevenció primària durant l’embaràs i/o en la descendència i frenar l’epidèmia d’obesitat infantil actual i els problemes cardiometabòlics associats.

In the past decades, our increasing understanding of the complex biology of cancer has spurred the development of higher-resolution diagnostic technologies, numerous innovative therapeutic oncologic agents as well as vast knowledge regarding how treatment outcomes vary with a wide range of factors. Whilst this has already greatly improved the standard of care in oncology, it is also accompanied by a myriad of challenges. If we are to address these challenges, we must build on the huge potential of the large volumes of continuously updated real-world data that are now available through Electronic Health Records (EHR) across Europe, and the promise of Artificial Intelligence (AI).

Our vision is that every patient should have access to the most up-to-date individualised treatments and to innovative therapies. By strengthening shared decision-making based on dynamic computer-interpretable guidelines (CIGs), innovative broad data access and AI-driven technology and tools, we envision revolutionizing oncology care in Europe.
Our mission is to design, develop and deliver the first interoperable and GDPR-compliant European real-world oncology data and evidence generation platform from the onset based on the needs of the clinicians and patients, in an inclusive and sustainable way. It will be built on a combination of federated and centralised access to a vast network of European data providers to help answer the highest priority research questions in prostate, breast and lung cancer, especially where current existing evidence underpinning clinical practice guidelines is weak or not covered at all in current guidelines. In parallel, comprehensive decision support toolsets based on national and international guidelines with approved regular updates of guideline recommendations underpinned by evidence from advanced statistical analysis and AI will be made available to fill the guidelines gaps and better support shared decision making by clinicians and patients.

*This is a new IMI2 project in which IDIAPJGol is participating as full partner and will have an important role in WP6 ((Non)interventional study data and real-world data gathering, preparation and Integration; for more details, please check page 41 of the proposal). The presented document is not a study protocol but the project submitted to IMI2. Different study protocols will be submitted to this committee as part of this project in the next 5 years. Data used in SIDIAP will be data mapped to the OMOP-CDM. The study will be focused on patients with breast, prostate, or lung cancer, and thevariable sused in each study is still to be defined.

Background: The overwhelming numbers of COVID-19 infections have led to an unprecedented crisis for healthcare systems worldwide. Understanding the impact of this pandemic on health is an urgent priority.
Objectives: UNCOVER aims to unravel the mid- and long-term effects of the pandemic on COVID-19 and non-COVID-19 morbidity and mortality through the use of large real-world databases from Catalonia and the UK.
Methods: UNCOVER will conduct a cohort study using longitudinal electronic health records from Catalonia (SIDIAP) and the UK (CPRD). These databases have been transformed to an international common data model (CDM), and when possible, the study will be replicated in other databases around the world. COVID-19 testing, diagnosis in primary care, hospitalisations, and deaths will be identified from March 1st 2020. Study periods will be defined as pre-COVID-19, COVID-19-pre-vaccine, and COVID-19-vaccination. Different periods will be defined for the study of non-pharmaceutical interventions by country. Mid- and long-term symptoms and outcomes will be identified. Time-series and multi-state models will be used for data analyses.
Expected results: UNCOVER will provide novel scientific knowledge aimed at helping decision-makers and clinicians in the control and management of the pandemic on a national and international level, whilst improving populations’ health and quality of life.

Background
To further monitor COVID-19 vaccine safety and complement pharmacovigilance measures, multi-national observational studies have been requested by the EMA: Incidences of patient-reported side effects after COVID-19 vaccination and adverse events of special interest are closely being monitored. The Covid-Vaccine-Monitor project will facilitate the rapid signal assessment of emerging safety concerns.

Hypothesis
These existing initiatives will provide important data on the incidence of adverse outcomes reported after vaccination and on potential risk factors for thromboembolic events in COVID-19 patients.

Objectives:
1-a)To quantify the association between the administration of a COVID-19 vaccine and the occurrence of thrombosis with thrombocytopenia syndrome/s (TTS) within pre-specified risk periods, stratified by vaccine type/brand, age and gender, while controlling for relevant confounding factors.
1b) To quantify the association between different COVID-19 vaccine types/brand (where possible/applicable), while controlling for relevant confounding factors.
2a) To quantify the association between the administration of a COVID-19 vaccine and the occurrence of thromboembolic events (TE) within pre-specified risk periods, stratified by vaccine type/brand, age and gender, while controlling for relevant confounding factors.
2b) To quantify the association between different COVID-19 vaccine types/brands (where possible/applicable), while controlling for relevant confounding factors.
3) To study the association between pre-specified potential risk factors and TTS in people receiving COVID-19 vaccine/s
4) To characterize the treatments used in patients with TTS, including the use of anticoagulants and other therapeutic products
Exploratory objective:
5) To develop a proof-of-concept study to support future genetic and pharmacogenomic analyses of the association between COVID-19 vaccines and thromboembolic events and TTS. The three specific subobjectives are:
Objective 5.1. To identify genetic variations associated with TE based on previous literature and a review of previous GWAS studies
Objective 5.2. To investigate whether the risk of TE following COVID vaccination is modified by genetic susceptibility
Objective 5.3. To assess the feasibility of identifying TTS in UK Biobank using linked hospital and primary care records to inform future pharmacogenetic studies

Methods:
Data will be obtained from five European primary care records, two outpatient records, and one inpatient records databases (UK,Spain,The Netherlands, France, Denmak). In addition, one US claims and one large US hospital records database will be accessed to maximise sample size and exposure to vaccines currently under-represented in European data.All of the data sources are previously mapped to the Observational Medical Outcomes Partnership (OMOP) common data model (CDM).

Distributed network cohort studies will be conducted to answer objectives 1-4. Propensity score matching based on large-scale propensity scores will be used to minimise confounding by indication for objectives 1-2 and 5

The study period will cover from Dec 2020 (first vaccine users) until the latest data extraction available in each of the contributing databases. For objectives 1-3, lags in hospital linkage will result in two different study periods for analyses based on primary care vs linked data in both CPRD AURUM, GOLD and SIDIAP.
For other objectives and data sources the study period will be unique and will go from cohort-specific index date to the latest data available.
Cohort-specific index dates are: For vaccinated people (and matched unvaccinated) [Objectives 1a-2a, 3, 5.2 and 5.3]: date of first dose vaccine (and same date for matched unvaccinated);For comparative cohorts [Objective 1b and 2b]: date of first dose of the corresponding vaccine type/Brand; For TTS cohorts [Objective 4]: date of TTS diagnosis.

Source and study population:
Target population: All persons registered in any of the contributing databases within the study period and with at least one year of data visibility before December 2020 will be eligible.
Study population for Objectives 1a-2a, 5.2 and5.3: Of these, people with at least one exposure to any COVID vaccine in the study period will be included in the ‘exposed’ cohort/s, with 1st and 2nd dose vaccine date as time-varying index dates. Unexposed matched groups will be pooled from the Target population.
Study populations for Objective 1b & 2b: Those with at least one exposure to viral vector-based vaccines will be included in the exposed group/s and those with at least one exposure to mRNA COVID-19 vaccines in the active comparator group/s. Similarly, those with Vaxzevria vaccine will be included in the exposed group and those with Comirnaty as the active comparator in the vaccine brand comparative safety analyses based on CPRD AURUM, GOLD, RCGP, and SIDIAP.
Study population for Objective 3: Those with at least one exposure to any COVID vaccine in the study period will be included in this cohort for the analysis of risk factors of post-vaccine TTS.
Study population for Objectives 4: Those with a TTS event in the up to 28 days post vaccination of any dose will be included as ‘TTS cases’ for Objective 4, with TTS date as index date.
Study population for Objective 5: UKBB participants with linkage to primary care and HES data and vaccine exposure identified in the primary care records will be included in the exposed group. Unexposed matched participants will be pooled from those with linked primary care and HES data

Data analysis
All the analyses detailed below will be conducted stratified by database and by age, gender and vaccine type/brand

The use of healthcare data, generated through the delivery of normal clinical care is increasingly being proposed as a source of evidence to support not only drug development and regulatory decision-making but also to understand the physiology and pathogenesis of diseases.
Use of multiple electronic health care databases is important not only to increase sample size but also to investigate country specific differences, differences by type of databases (e.g. primary vs. secondary care) or to replicate findings. One of the challenges however are the differences between the databases with regard to the underlying structures and semantic mapping. A common data model could help harmonise healthcare data across multiple data sets and provide a mechanism to allow the conduct of multi-database, international studies.
The European Health Data and Evidence Network (EHDEN) project (https://www.ehden.eu/) is an international project supported by the Innovative Medicines Initiative (IMI) aiming to standardize health care data to the Observational Medical Outcomes Partnership Common Data Model (OMOP CDM) and to develop and implement tools to facilitate research on large electronic health care databases.
One of the objectives of the EHDEN project is to test existing methodologies but also to develop new methodologies and analytical tools to conduct (pharmaco)epidemiological research using electronic health care databases mapped to the OMOP CDM. To investigate the validity and functionality of this approach, we want to conduct a drug-utilisation study using EHR data. As proof of concept study we want to conduct a drug utilisation studies on respiratory drug use in patients with asthma and chronic obstructive pulmonary disease (COPD). This research is important and relevant as asthma and COPD are prevalent conditions, primarily treated in primary care.

This is a study protocol for an observational health data analysis, submitted as a preprint to facilitate transparency and open science. Watchful waiting (WW) represents a deferred treatment option for prostate cancer (PCa) patients when curative treatment seems overtreatment right from the outset. Patients are ‘watched’ for the development of local or systemic progression with disease-related symptoms, at which stage they are then treated palliatively according to their symptoms, in order to maintain quality of life. When choosing WW, it is important to adequately assess life expectancy of patients. Although previous studies reported the outcomes of PCa patients managed with WW, which is the impact of individual patient characteristics and comorbidities on long-term outcomes is still largely unknown. The PIONEER, which is a novel project of the Innovative Medicine Initiative’s (IMI’s) «»Big Data for Better Outcomes»» program
with the mission to transform PCa care with particular focus on improving cancer related outcomes, health system efficiency and the quality of health and social care across Europe, aims at assessing which are the long-term outcomes of PCa patients undergoing WW overall and after stratification according to disease characteristics, comorbidities and life expectancy. This topic emerged as the second one with the
highest agreement score among different stakeholders after an international consensus to identify and prioritize the most important questions in the field of PCa. This study aims to describe demographics, clinical characteristics and estimate outcomes of PCa patients under WW across a network of databases in the overall
population and subgroups of patients identified by individual disease characteristics, demographics and comorbidities. The study will rely on large observational data, namely population-based registries, electronic health records and insurance claims data. The study will be an observational cohort study based on routinely collected health care data which has been mapped to the Observational Medical Outcomes Partnership (OMOP) Common Data Model (CDM).

*In SIDIAP, the study will be performed in the data mapped to OMOP. Not all the objectives presented in the protocol will be studies in SIDIAP, data availability will be taken into account. For example, cause-specific survival or cancer treatment are not available in SIDIAP and therefore will not be investigated.

Urbanization is one of the leading global trends of the 21st century. Childhood obesity is a key health outcome in childhood and for lifelong health. World-wide childhood obesity rates are alarmingly high. The urban environment provides important opportunities for interventions aimed at alleviating the childhood obesity epidemic. It is increasingly recognized that the urban environment may affect childhood growth and obesity and that it provides important opportunities for community-level prevention.
The aim of UrbanKids is to evaluate how changes in the urban and social environment affect weight gain and obesity in children. For this we will use a large longitudinal cohort of 1 million children and adolescents (aged 0-18 years) in Catalonia, with repeat measures of height and weight, registered in the electronic health records (EHRs) from primary care data between 2011 and 2019. The moving2health approach will focus on children who changed address and who thus provide a unique natural experiment design by changing their neighbourhood environment from one day to the next.
The UrbanKids will tackle key societal changes regarding childhood obesity by identifying which urban exposures could be modified to reduce the obesity epidemic, and by identifying how socioeconomic status may drive environmental health disparities.

Antecedentes. Se estima que la endometriosis afecta al 10% de mujeres, estando el 60% de los casos sin diagnosticar. A pesar de estas estimaciones se desconoce la prevalencia e incidencia de la endometriosis en Cataluña. Tampoco, cómo mejorar el sistema sanitario para reducir su diagnóstico tardío y mejorar la calidad asistencial. Objetivos. Este proyecto tiene como objetivo determinar la prevalencia, incidencia y factores de riesgo asociados a la endometriosis, así como identificar y explorar los factores relacionados con el diagnóstico tardío. Metodología. Esta propuesta incluye un un proyecto de metodología mixta, integrando un estudio observacional de cohorte retrospectivo con «real world data», utilizando la base de datos SIDIAP (Estudio 1) y de dos estudios de metodología cualitativa con pacientes, profesionales sanitarios, gestores y otros agentes del sistema sanitario (Estudios 2 y 3). Este es un proyecto participativo que cuenta con la colaboración activa de la Asociación de Afectadas por la Endometriosis de Cataluña. Análisis de datos. Los datos se analizarán diferencialmente para cada estudio. Se llevará a cabo un análisis descriptivo y análisis de series temporales usando una regresión de Poisson (Estudio 1). Los datos cualitativos se analizarán a través del método-técnica Fotovoz (Estudio 2) y utilizando el Análisis de Contenido Temático (Estudio 3). Aplicabilidad y relevancia. El estudio permitirá conocer la magnitud de la afectación de la endometriosis en Cataluña, así como la detección de necesidades para su diagnóstico y abordaje temprano. Con ello, se generarán recomendaciones para la mejora del circuito diagnóstico de la endometriosis en Cataluña, aplicables al sistema sanitario catalán.?

Objectives: First, to describe the features and characteristics of the complications of viral infections, with a particular focus on viral pneumoniae. Second, to assess the predictors of adverse outcomes amongst patients with virus-related hospitalization and generate algorithms to identify subjects most at risk of complications and/or morbi-mortality. Third, to compare the safety of treatments being considered/used for potential use in COVID-19 (including hydroxychloroquine, systemic steroids, and ACE inhibitors (angiotensin converting enzyme inhibitors)/ ARBs (angiotensin-receptor blockers)).
Design: This study will use SIDIAP data linked to ICS CMBD hospital data, and mapped to the Observational Medical Outcomes Partnership (OMOP) Common Data Model (CDM). Study cohorts will be generated, descriptive statistics will be used for the first research question, prediction modelling will be used for the second research question, and a propensity-score adjusted analysis will be used in the third question.
Setting: Population-based, electronic health records from primary and secondary care in Catalonia.
Participants: Individuals diagnosed with a viral infection.
Exposure: For research questions 1 and 2, exposures will be a record of a viral infection. For research question 3, exposures will be incident use of a medication of interest.
Outcomes: Viral infection, viral pneumonia, adult distress respiratory syndrome, advanced life support including ICU and/or mechanical ventilation or intubation, all-cause death.
Applicability: The results of this study will have an immediate impact on the response of COVID19.
Limitations: Selection bias could affect the first two analyses and confounding by indication could affect the third. Appropriate analytical methods will be employed to minimize such issues.

Background
Conventional synthetic disease modifying anti-rheumatic drugs (csDMARDs) are usually the first line of treatment of rheumatoid arthritis (RA). This study has the following research objectives: 1) to characterise treatment patterns in rheumatoid arthritis, 2) to predict the risk of safety outcomes for individuals initiating treatment with csDMARDs, and 3) to assess the comparative safety of alternative first-line csDMARD treatment strategies commonly used in rheumatoid arthritis.

Methods
Study participants will have a drug utilisation record of csDMARD after a diagnosis of RA, with the first such record taken as their index event.
First, individuals’ treatment pathway involving csDMARDs after a diagnosis of rheumatoid arthritis will be characterised. Second, prediction models will be developed for the 5-year risk for safety outcomes of interest. A range of algorithms will be used to develop these prediction models (for example, regularised logistic regression and Random Forest). Lastly, the relative safety of common first-line csDMARD treatment strategies will be compared. Cox models will be estimated, with propensity score adjustment used to control for confounding by indication.

Relevance and limitations
The results from this study will help to improve our understanding of current prescribing practice in RA and help to inform shared decision making. However, a limitation of the study on treatment pathways will be that biological DMARDs are not expected to be observable in SIDIAP. Meanwhile, with factors such as radiographic evidence also unavailable in SIDIAP, it will not be possible to include these unobserved factors in the generation of propensity scores.

Background: Despite efforts to reduce and prevent excessive weight gain among healthy adults, the worldwide prevalence of obesity continues to increase. The development of overweight and obesity is due to many factors, both individual and contextual, and increases the risk of comorbid conditions such as cardiovascular diseases, diabetes, and hypertension. Recent studies have observed associations between various factors of the built environment and the development of overweight and obesity, though specific results have been inconsistent across studies. Additionally, most studies have been cross-sectional and have focused on a single built environment indicator at a time. To our knowledge, this is the first longitudinal study to assess the association between multiple indicators of the built environment and the development of overweight and obesity in Southern Europe (specifically Catalonia, Spain).
Objective: To evaluate the association between the built environment (measured by population density, green spaces, street connectivity, and facility richness) and the development of adult overweight and obesity in Catalonia, Spain.
Methods: This mega-longitudinal study will use data from the Information System for Research in Primary Care (SIDIAP), an electronic primary care health record database from Catalonia (Spain), including all adults identified as normal weight between January 1, 2006 and December 31, 2016. Adults will be followed until developing overweight or obesity, the end of the study (December 31, 2018), passing away, or transferring out. Overweight will be categorized as having a BMI of ? 25 kg/m2. The urban built environment indicators will be calculated at census tract level and include population density, green spaces, street connectivity, and facility richness. Hazard ratios (HRs) will be calculated using a multivariable Cox proportional hazards model to explore the association between the built environment environment and the risk of developing overweight/obesity.

Background: Nowadays, two thirds of the world’s population lives in urban areas. Air pollution and green spaces are two of the most-used indicators to measure the impact of urban environment on health. These indicators have been associated with different health outcomes such as lung cancer or premature mortality. A recent case-control publication has suggested that an increase in green spaces may decrease the incidence of breast cancer. Although this study is extremely relevant to the field, these results need to be replicated in longitudinal studies. Therefore, our objective is to determine whether air pollution and green spaces are associated with the risk of developing breast cancer in women living in Catalonia.
Methods: With data from the Information System on the Development of Research in Primary Care (SIDIAP), a cohort study will be carried out in women over 18 years of age between 2006 and 2018. At the census tract level, they will be assigned a level of air pollution and green spaces at the time of entry into the database until they have a diagnosis of breast cancer, die, emigrate or the study ends. We will use Cox models to investigate the association between the exposures and breast cancer, adjusting for possible confounding factors.

Gastric cancer incidence has been falling during the last century due to several factors such as the reduction of helicobacter pylori infection and the regulation on food and water treatment. However, it still persists as one of the most incident cancers worldwide.
It usually entails a poor prognosis. Evidence so far has pointed out the need for gastric cancer prevention strategies since treatment options are ineffective and limited. Due to the lack of screening techniques for finding gastric cancer in early stages, public health services might look at geographic analysis and environment study to perform gastric cancer prevention.
Green spaces exposure might reduce the likelihood to develop gastric cancer through increasing healthy lifestyles. Outdoor air pollution exposure has been found in relation with throat and mouth cancer and it might be related to gastric cancer. The goal of this study is to assess the associations between green spaces, air pollution, and gastric cancer risk.
It will be done through a nested case-control design with data obtained from a large population-based database in the Information System for Research in Primary Care (Sistema de Información para el Desarrollo de la Investigación en Atención Primária (SIDIAP)) in Catalonia. At the same time, the exposures to green spaces and air pollution will be attributed from other technological sources which collected data in a census tract level. We will carry out multivariable conditional logistic regression models using STATA v14. The findings from this study might help policymakers to develop better gastric cancer prevention strategies.

El projecte inclou dos estudis:
El primer estudi, ja fet fa una setmana durant 4 dies amb diverses bases de dades internacionals online, ha estudiat el comportament d’infeccions víriques similars que hi ha hagut en el passat: s’han descrit les característiques de les persones amb complicacions d’infeccions víriques com la grip, s’han valorat els predictors de resultats adversos entre els pacients hospitalitzats amb pneumònies virals, s’han generat algoritmes per identificar els pacients amb més risc de complicacions i/o morbimortalitat, i s’ha avaluat la seguretat dels tractaments utilitzats per a un ús potencial en Covid-19.
El segon estudi vol descriure les característiques de les persones amb Covid-19 a Catalunya, així com desenvolupar models predictius de les complicacions de la Covid-19 fent servir els mètodes i resultats obtinguts en el primer estudi. Per això, es farà la integració de la informació dels pacients infectats amb Covid-19 a Catalunya, la transformació de la nova informació a un model de dades internacional, i després de contrastar les dades amb altres bases de dades d’altres països, s’elaboraran uns criteris pronòstic aplicables a les polítiques de control de pandèmia de Covid-19 al nostre país.
Els models predictius de casos greus d’infecció vírica permetran classificar els pacients amb Covid-19 per gestionar-los adequadament, avaluant la necessitat de que el malalt vagi a l’hospital o es quedi a casa, i les condicions necessàries per al seu tractament.

A goal of Discovery and Translational Sciences is to implement new technology platforms to accelerate research. This grant allows the rapid acquisition and analysis of emerging data from the ongoing global outbreak of Covid-19. The clinical and epidemiological data will inform the foundation’s response to the outbreak including expanding our understanding of risk factors for disease progression and the design of efficient clinical trials.

Objectives: To investigate the association between bariatric surgery (BS) and the risk of obesity-related cancers (esophagus, liver, pancreas, colorectal, breast (postmenopausal), endometrium, kidney, stomach, gallbladder, ovary, thyroid, meningioma, and multiple myeloma) and to examine the association between BS with all-cause mortality.

Design: This study will be a matched cohort using SIDIAP and CMBD-PADRIS source data and data been mapped to the Observational Medical Outcomes Partnership (OMOP) Common Data Model (CDM).

Setting: Population-based, electronic health records from primary and secondary care in Catalonia.

Participants: Individuals aged ?18 years, with a record of BMI ?35 kg/m2 or an Obesity diagnosis, without history of bariatric surgery nor cancer, who have been on the database for 1 year before study entry and have at least 1 year of follow-up.

Exposure: Bariatric surgery procedure.

Outcomes: Incident diagnoses of obesity-related cancers and date of death.

Expected Results: Participants who undergo BS have a decreased risk of obesity-related cancers and improved survival compared to morbidly obese participants who do not undergo bariatric surgery.

Applicability: The results of this study will be valuable for policymakers (decision-making about financing this procedure), for surgeons (surgery recommendation), for patients (knowing the risks and benefits of this procedure) and for general practitioners (advising patients to consult a surgeon).

Limitations: Insufficient statistical power to study less frequent cancer types or to find suitable matches of cases and possible unmeasured confounding due to variables that might be lacking in the SIDIAP database.

Stratification of Obese Phenotypes to Optimize Future Obesity Therapy (SOPHIA) ha sido del proyecto ganador de la 17 convocatoria The Innovative Medicines Initiative 2 Joint Undertaking (IMI2 JU) (H2020-JTI-IMI2-2019-17-two-stage), una asociación financiada conjuntamente entre la Unión Europea, representada por la Comisión Europea, y la Federación Europea de Industrias y Asociaciones Farmacéuticas (EFPIA). En este proyecto, la Fundació Institut d’investigació Biomèdica de Girona Doctor Josep Trueta (IDIBGI) participa como socio, a través del grupo Nutrición, Eumetabolismo y Salud, liderado por el Dr. José Manuel Fernándes-Real Lemos. El Dr. Rafel Ramos, quién participa en este proyecto como un investigador del IDIAP Jordi Gol y del IDIBGI, ha sido designado como investigador principal de las cohortes denominadas dentro de la memoria CAT-DM1 y SIDIAP-DM2.

SOPHIA optimizará el futuro tratamiento de la obesidad. El reto es que los médicos, los pagadores y los pacientes vean la obesidad como una falta de autocontrol, más que como una enfermedad.

Se pretende cambiar esta perspectiva definiendo a las subpoblaciones en términos de:
1. los riesgos de complicaciones relacionadas con la obesidad
2. la respuesta a los diversos tratamientos de la obesidad

Las subpoblaciones se caracterizarán en términos de variables operacionales (fenotípicas, genéticas, conductuales, ambientales y ómicas). Estas variables predictivas facilitarán el diagnóstico y sustentarán la atención personalizada y protocolizada de la obesidad.

Las prioridades de los pacientes en cuanto al riesgo y la respuesta influirán en todos los aspectos del trabajo de este proyecto.

SOPHIA comenzará creando una base de datos federada y brindando acceso seguro a conjuntos de datos claves relacionados con obesidad de toda Europa (WP2). Se definirán subpoblaciones clínicamente relevantes de pacientes con obesidad, en términos de riesgo y respuesta al tratamiento, e identificarán las variables operativas que los caracterizan (WP3). Se aplicará este enfoque a DM1 (WP4) y DM2 (WP5), aclarando sus relaciones con los riesgos de obesidad y las respuestas al tratamiento y comparando estos riesgos en los pacientes con y sin obesidad. Las variables operativas se validarán contra cohortes independientes, y se crearán algoritmos predictivos, mediante el aprendizaje automático, con indicadores de riesgo y respuesta al tratamiento (WP6). Los resultados científicos se combinarán con las perspectivas y prioridades del paciente (WP7).

Se validará el valor predictivo de estas variables antes de crear algoritmos clínicamente útiles para decidir «»cuándo tratar»» y «»cómo tratar»». Las variables de los biomarcadores alimentarán los ensayos innovadores, las pruebas y los objetivos de investigación. Se interpretarán y analizarán los resultados obtenidos para identificar el valor compartido por todas las partes interesadas (pacientes, médicos, industria, pagadores).

SOPHIA cambiará las actitudes y la experiencia de la obesidad mediante:
1. la demostración de la heterogeneidad de la enfermedad,
2. la identificación de las personas con riesgo de complicaciones,
3. la identificación del mejor tratamiento para cada individuo,
4. la entrega de un vocabulario común y una comprensión compartida de la obesidad,
5. la demostración de un valor compartido, que combina la oportunidad comercial con el beneficio social.

Esta ambición sólo se hará realidad si:
1. los pagadores aceptan financiar el tratamiento,
2. la industria genera tratamientos eficaces,
3. los médicos están preparados para prescribir tratamientos, y
4. los pacientes están preparados para recibirlos.

La base de pruebas no existe actualmente. SOPHIA entregará esta evidencia y el análisis de valor compartido para impulsar esta revolución en el cuidado de la obesidad.

Background
Clinical trials have shown an association between aromatase inhibitor (AI) use for the treatment of breast cancer and adverse musculoskeletal disease when compared with tamoxifen. This has not been investigated in routine clinical practice.

Hypothesis
In comparison to tamoxifen, AI use is associated with an increased incidence of carpal tunnel syndrome (CTS), tendinopathy, osteoarthritis and related procedures/surgery in post menopausal women with hormone receptor positive breast cancer.

Methodology
Cohort study design, using non identifiable SIDIAP OHDSI CDM mapped data in order to enable replication of the study internationally within the OHDSI network. All post-menopausal (defined >55 years) women with an incident diagnosis of breast cancer, with 6 months continous enrolment prior to diagnosis, and incident use of AI, tamoxifen, or both within 1 year of diagnosis. Those with a prevalent cancer, or outcome prior to breast cancer diagnosis are excluded. Incidence of fracture (vertebral and appendicular fractures) to be used as a positive control outcome.

Variables & Measurements
The date of exposure will be identified from the first drug exposure; outcomes defined as the first incident record of an outcome, each outcome assessed independently, identified using OMOP CDM ATLAS generated definitions.

Statistical Analysis
Propensity score adjustment to minimise confounding. Cumulative Incidence of outcome; cox proportional hazards modelling to estimate hazard ratios for each of the outcomes.

Expected results
Incidence of adverse musculoskeletal outcomes at a population level in Catalonia, with replication worldwide to enable international comparison.

Applicability
To counsel women at the beginning of treatment; consider earlier identification and surveillance during treatment.

Strengths & Limitations
The study is based upon drug dispensation rather than adherence, and only contains information from clinical services, leading to the potential to underreport an association. The study aims to increase generalisability through using OMOP CDM mapped data, to ensure the study can be replicated within the international OHDSI community.

Dietary N-nitrosodimethylamine (NDMA) has been shown to be carcinogenic in animals, however, evidence from population-based studies is inconlusive. The U.S. Food and Drug Administration has issued a statement on ranitidine because they may contain unacceptable levels of NDMA in 2019.
To date, there have been several studies regarding association between NDMA exposure and risk of cancer, however, real-world evidence of cancer risk in relation with ranitidine is scarce. We aim to evaluate the comparative risk of incident cancer in patients exposed to various H2 receptor antagonists (H2RAs).
We will conduct systematic, multinational study to estimate the relative risk of primary outcome (overall cancer except thyroid cancer) and secondary outcomes (overall cancer, 16 types of cancer, and cancer mortality) in ranitidine cohort. We will compare the target cohort with the comparator cohort for the hazards of outcome during the time-at-risk by applying a Cox proportional hazards model after propensity score adjustment.

Background
The use of hydrochlorothiazide (HCTZ) has been linked to skin cancer, and especially to non-melanoma skin cancer. However, the association has not been evaluated in a Mediterranean-origin population specifically, which has a phototype and sun exposure different from those of the Nordic populations.
Hypothesis
HCTZ exposure might be associated to an increased risk of skin cancer in non-Nordic European population.
Objectives
To assess the association between HCTZ exposure and risk of malignant melanoma (MM) and non-melanoma skin cancer (NMSC) in Spain using electronic health care data.
Methodology
Two independent case-control studies using data from BIFAP an SIDIAP datasets will be carried out.
Determinations and Statistical Analysis
Comparing MM and NMSC cases to disease-free population controls, the use and cumulative use of HCTZ will be assessed and odds ratios for the association will be estimated using conditional logistic regression.
Expected results and Applicability
The study will either confirm of disprove an association between HCTZ use and MM and NMSC in European people other than Nordic-origin.
Relevance and limitations
Knowledge of an increased skin cancer risk would allow prescribers to take appropriate measures, such as increased focus on UV protection or would even motivate regulatory actions on the use of HCTZ in the EU. Conversely, a disproved risk would reassure prescribers in the safety of the use of the drug.
The main limitation is the lack of direct measures of UV exposure history. However, there is no reason to suspect that HCTZ users will display markedly different sun exposure habits than the background population.

Antecedentes:
Se informa que los espacios de juego urbanos mejoran la salud de los niños, incluida la salud mental. A pesar de las sugerencias de esta asociación, hay poca evidencia disponible sobre el impacto de los espacios de juego (particularmente los no verdes) en la salud mental y del comportamiento infantil.

Hipótesis y objetivos:
Planteamos la hipótesis de que un mayor acceso a los espacios de juego residenciales se asocia con menores probabilidades de resultados de salud mental y conductual y que estas asociaciones serán más fuertes para las personas de características socioeconómicas marginadas.
Investigaremos las asociaciones entre la proximidad residencial a los espacios de juego (en general, verde y diversidad) y los resultados de salud mental y conductual diagnosticados. También exploraremos si estas asociaciones difieren según las características sociodemográficas a nivel individual y de área.

Métodos:
Probaremos la relación entre la exposición residencial a los espacios de juego y los resultados de los trastornos mentales y del comportamiento diagnosticados para 151110 niños que viven en la ciudad de Barcelona y que forman parte del conjunto de datos SIDIAP. Usaremos amortiguadores de área de servicio de 300 m alrededor de cada espacio de juego para estimar la proximidad residencial de los niños a los espacios de juego en general, los espacios verdes de juego y la diversidad del paisaje de juego en la zona de residencia del censo.
Usaremos modelos de regresión logística para investigar la asociación entre los espacios de juego y los resultados de salud. Además, para probar las diferencias en las relaciones por características sociodemográficas individuales y de nivel de área, probaremos términos de interacción para indicadores de espacios de juego y dos indicadores socioeconómicos (privación a nivel de área y etnia individual). Para aquellas características que muestren términos de interacción significativos, luego realizaremos modelos estratificados

Background: Coronavirus disease-2019 (COVID-19) patients appear to be at an increased risk of venous and arterial thromboembolic events. There is a need to better understand the risks of thromboembolic events among patients with COVID-19, their impact on prognosis, the risk factors for such events, and whether individuals’ risks can be predicted given their demographic characteristics and medical history.
Objectives: To estimate the incidence of thromboembolic events among patients with COVID-19, to calculate the risks of worsening of COVID-19 stratified by the occurrence of a thromboembolic event, to assess the impact of risk factors on the rates of thromboembolic events among patients with COVID-19, and to develop patient-level prediction models for venous thromboembolic events for patients with COVID-19.
Design: This study will use SIDIAP data mapped to the Observational Medical Outcomes Partnership (OMOP) Common Data Model (CDM) as part of a European international network cohort study.
Setting: Population-based, electronic health records from primary and secondary care in Catalonia.
Participants: Individuals diagnosed with COVID-19 or tested positive for SARS-CoV-2.
Exposure: A recorded diagnosis of COVID-19 or positive test for SARS-CoV-2.
Outcomes: Venous thromboembolic events, arterial thromboembolic events, cardiovascular events, mortality.
Applicability: The results of this study will have an immediate impact on the management of COVID-19.
Limitations: Ascertainment bias may make any comparisons with estimated rates for historical comparators from the literature difficult.

1. Aprender y comprender los datos de salud disponibles en el estudio de cohorte de 100 millones de brasileños.
2. Conocer cuáles son las áreas principales de los proyectos de investigación desarrollados por los investigadores de CIDACS para identificar áreas comunes de interés para futuras colaboraciones.
3. Presentar SIDIAP y las principales áreas de investigación de IDIAPJGol en CIDACS.
4. Generar ideas de nuevos proyectos e identificar convocatorias de subvenciones para las que podríamos aplicar juntos.

There is currently a lack of knowledge on the factors associated with the COVID19 pandemic, including disease severity and/or morbi-mortality. In this proposal we aim to describe the baseline characteristics of the COVID19 infected population, including the symptoms and complications related to the infections, as well as to validate prediction models for the identification of COVID19 infectees at high risk of poor outcomes, and determine the influence of previous disease trajectories in the COVID19 disease progression. All analyses will be performed with a special focus on specific population groups including pregnant women and their newborns, children/adolescents, persons with overweight/obesity, cancer history or mental health disorders. We will use routinely-collected healthcare data from Catalonia, and we will participate in the international OHDSI network in collaboration with other databases around the world.

Background: As women diagnosed with breast cancer are living longer, attention to the impact of known and suspected cardiotoxicities associated with breast cancer treatment is increasing. Large scale, long duration observational studies are needed for research in this area. SIDIAP is planning to link primary and secondary clinical data to cancer treatment data for this purpose.
Hypotheses and objectives: We aim to compare use of systemic chemotherapies in breast cancer patients with prior cardiovascular disease or risk factors to patients at lower risk of cardiovascular disease. We will also characterise the new linked data resource.
Methodology (design, setting, participants): This cross-sectional observational study will link primary care health records for female breast cancer patients in the SIDIAP database with hospital discharge and cancer treatment data. The study period is 2011 to 2017.
Measurements:
Exposure: cardiovascular disease risk (low vs. prior cardiovascular disease; low vs. primary)
Analysis populations: Analysis populations will be defined according to treatment guidelines ICOPraxis in Institut Català d?Oncologia (ICO) in Catalonia
Primary outcomes: Systemic chemotherapy agents administered in first year
Secondary outcomes: dose at initiation, cumulative dose
Covariates: age at diagnosis, socioeconomic status, cardiovascular risk factors (secondary risk analysis), type of prior cardiovascular disease (secondary risk analysis), calendar time
Statistical analysis: Descriptive analyses and logistic regression models will be performed.
Expected outcomes: Peer reviewed journal publication. Linkage of SIDIAP and ESPOQ data bases.
Applicability and relevance: Our study will improve understanding of how knowledge and guidelines relating to the toxicity of systemic chemotherapies is being translated into practice, and inform future studies investigating the likely future burden of CVD in breast cancer patients. It will also provide the basis for future studies needing both SIDIAP and cancer treatment data.

Antecedentes: aunque se sabe que la osteoartritis (OA) está relacionada con varias comorbilidades, la asociación entre la OA y el cáncer rara vez se ha estudiado.

Hipótesis: la OA puede tener asociaciones heterogéneas con cánceres comunes.

Objetivos: Estimar la asociación entre la OA de rodilla y cadera y los cánceres específicos en adultos.

? Study Title
Estimating Short-Term and Long-Term Direct Economic Burden Associated with Osteoporotic Fractures
? Background and Rationale
Osteoporotic fractures (OFs) among adults are considered an important public health concern, with up to 50% of women and 22% of men over the age of 50 years experiencing at least one fragility fracture in their lifetime. Additionally, the risk of osteoporotic fractures increases with age, especially in postmenopausal women among whom decreased estrogen levels are associated with decreased bone mineral density (BMD). Osteoporotic fractures are associated with significant burden both in formal (e.g. hospitalizations, rehabilitative services, long-term care) and informal (e.g. care provided by family and friends) care settings, and increased mortality. Considering the total burden of OFs to both patient and society, it is important to better understand the short- and long-term direct healthcare impact in order to enhance osteoporosis management in the contemporary care setting. This study will focus on evaluating the direct economic burden of OFs, while a companion protocol will evaluate the indirect and humanistic burden of OFs. Moreover, the outputs from the proposed study will inform policy makers, clinicians, and patients about the multi-national burden of OFs in women, and help payers and clinicians understand the importance of treatment advances that can reduce the risk of osteoporotic fractures. This study will have the advantage of estimating the direct economic burden in six countries using the same study population composition and same time period rather than previous studies that have varying study population characteristics at varying time periods.

? Research Question and Objectives
The study aims to evaluate the direct economic burden of OFs in women aged 50 years or older in the short-term (index fracture date to 12 months) and long-term (one year to five years) following the date of the first recorded osteoporotic fracture.
Study Objectives
1. Estimate the short-term and long-term direct, post-index healthcare resource utilization (HCRU) and costs in women who experienced an incident OF and in a matched cohort of women free of any OF.
2. Estimate the short-term and long-term direct HCRU and costs pre- versus post-fracture (before and after osteoporotic fracture) in women who experienced an incident OF.
? Study Design/Type
This is a multi-national, retrospective cohort study to assess direct economic burden of OF between 2013-2018 in women aged 50 years or older in 6 countries (Australia, France, Germany, Japan, Spain, and USA). The direct all-cause HCRU and cost experience of women with an incident OF in each country will be compared with matched women without an OF (i.e. non-OF cohort) during the study period. Because of differences in healthcare systems, provision of services and costs across countries, outcomes will be reported by individual country. Women with an osteoporotic fracture will initially be matched to women in the non-OF cohort using the same birth month and year as the women with an osteoporotic fracture, then matched 1:1 on selected variables as described in Section 9.1.3. Additionally, among women with an OF, pre-fracture and post-fracture HCRU and costs will be compared. Regional or national electronic medical records (EMR), registries, or claims databases will be used in each country as described in section 10.1. For example, the PharMetrics Plus, anonymised patient-level claims database including primary and secondary care data from US commercial payers, will be used for the USA.
The study design is depicted in Figure 1 above; the following time periods/dates have been defined:
1. Index date: The index date for the OF cohort corresponds to the calendar date of the first record of an OF (i.e. incident OF) between January 1, 2013 and November 30, 2018. The index dates of the women with osteoporotic fracture will then be assigned to the corresponding matched non-OF women, in order to ensure there are no temporal differences in the comparisons between the populations.
2. Pre-index period: The pre-index period (i.e. baseline period) corresponds to the 18 months preceding the index date for both the OF and the non-OF cohort. Women must have 18 months of continuous enrollment in the database pre-index to ascertain osteoporotic fracture-free status and comorbidity and medication history.
3. Follow-up period: The follow-up period corresponds to the period extending from the earliest of index date up to December 31, 2018 (study end date), death, fracture event in non-OF woman, or lost to follow-up (drop out of the database). For woman included in the study, the follow-up period can range from a minimum of one month up to six years from the index date.
? Study Population
The study population is women aged ?50 years with or without an osteoporotic fracture. This study will be conducted in six countries: United States, Australia, France, Germany, Spain and Japan.

? Patient Eligibility
Inclusion Criteria:
OF cohort:
1. Women aged ?50 years when experiencing an incident osteoporotic fracture at the following skeletal sites: hip, vertebral (spine), forearm (radius, ulna), humerus, pelvis, proximal femur, tibia, fibula, ribs, clavicle, scapula, and ankle between January 1, 2013 and November 30, 2018.
2. Continuously enrolled in the database for at least 18 months prior to index date and at least 1 month after index date.
3. No osteoporotic fracture in the pre-index period (i.e. 18 months prior to index fracture)
Non-OF cohort:
1. Women aged ?50 years and with no record of osteoporotic fracture in the pre-index period (i.e. 18 months prior to assigned index date).
2. Continuously enrolled in the database for at least 18 months prior to index date and at least 1 month after assigned index date.
Exclusion Criteria for both cohorts:
1. Record of participation in a clinical trial pertaining to an osteoporotic treatment ?18 months before the index date.
2. Cancer (except non-melanoma skin cancer) during the study period (July 1, 2011-December 31, 2018). Patients with cancer will be excluded because of the high healthcare resource utilization and costs of cancer care as well as effect of cancer and chemotherapeutic agents on bone.
3. Paget’s disease of the bone, osteitis deformans, and osteopathies or metabolic bone diseases (e.g., osteomalacia, hyperparathyroidism, osteogenesis imperfecta) during the study period (July 1, 2011-December 31, 2018). Patients with other bone conditions will be excluded to ensure that the outcomes are associated with osteoporosis and not other bone diseases.

? Matching criteria
Women without OF will be matched to women with OF. Women in the non-OF cohort will first be matched to women with OF using their birth month and year. The index date of the women with fracture (i.e. fracture date) will then be assigned to the corresponding matched non-OF women. After identifying an age-matched group of non-OF patients for each OF patient, the closest matching non-OF woman will be identified through propensity score matching using important confounders (e.g. geographic region, race/ethnicity, total months since index date (fracture date), pre-index glucocorticoid use, pre-index hormone replacement therapy, pre-index anti-osteoporosis drug use, selected comorbidities, and pre-index hospitalizations. The OF and non-OF women will be matched 1:3. If a non-OF woman has a fracture during follow-up, then she will be censored on the date of her fracture. A 1:3 matching will be used to optimize follow-up time of women with OF because a non-OF woman may fracture and be censored before the end of follow-up of the matched woman with OF.
? Variables
Study Outcomes
? Direct all-cause healthcare resource utilization: HCRU will include any resource/services directly provided by the healthcare system in each relevant country, including hospitalisations, emergency room (ER) visits, physician visits, diagnostic and/or reimbursed procedures, and prescriptions. Physical and/or occupational therapy services also will be reported.
? Direct all-cause healthcare costs will be estimated using country-specific costs, and include total direct costs (medical + pharmacy), total medical costs (inpatient + outpatient), hospitalizations, ER, physician, and outpatient pharmacy costs.
? Study Sample Size
The half-length of the 95% confidence intervals (CI) for estimated direct costs was calculated based on mean total costs from the multi-national study of Svedbom et al 2013. The half length of the CI was estimated to be 536 for a sample size of 2,000 and 107 for a sample size of 50,000 for the first year cost of approximately $14,335. The half length of the CI was estimated to be 160 (sample size of 2,000) and 71 (sample size of 50,000) for the fifth year cost of approximately $4,421. The half length for the intervening years since fracture (i.e. 2-4 years) fell between the ranges for the first and fifth year. It is estimated that the number of incident fractures may range from about a low of 16,000 in Australia to more than 140,000 in Spain. Due to the large sample size, the CIs will be narrow, and it is believed that the estimate of direct costs will be with very small estimate error and reliable.
? Data Analysis:
All analyses will be country-specific and will not be combined across countries due to differences in healthcare systems. Demographics, baseline clinical characteristics, and pre-index direct all-cause HCRU and costs will be reported for OF and non-OF groups using number and percent within category for categorical variables, and mean (standard deviation [SD]) with 95% confidence interval or median (interquartile range [IQR]), minimum and maximum values for continuous variables as appropriate. Methods for dealing with missing data such as multiple imputation or last observation carried forward (LOCF) will not be applied, and the number with missing data reported.
To evaluate direct all-cause HCRU and costs among the propensity score matched women who experienced an OF and those who did not, descriptive measures including the mean (SD), median (IQR), and range (minimum, maximum) will be reported. Costs will be log-transformed to diminish the effect of outliers. Direct HCRU and costs will be reported by the year since index date (fracture date) (e.g. ?1 year, >1 to ?2 years, >2 to ?3 years, >3 to ?4 years, >4 to ?5 years since index date) and include all patients alive at the start of each annual period to assess short-term and long-term economic burden of OF. The main outcome is the difference between direct all-cause HCRU and costs in OF and non-OF cohorts (incremental costs). Likewise, the mean HCRU and costs among women with an OF will be compared between 1-year pre-fracture versus each year (1 to 5) post-fracture. Rate of HCRU will be calculated for each year since index date (fracture date) as the number of utilizations divided by follow-up time in the year. The rate will be reported for each individual healthcare resource type. Also, the proportion of women with at least 1 utilization for each resource type (e.g. had at least 1 hospitalization, at least 1 ER visit) will be reported
Comparisons will be made for all osteoporotic fracture types combined as well as by individual osteoporotic fracture types. Differences in HCRU and costs between OF and non-OF cohorts and pre-index versus post-index among OF women will be assessed using regression modelling. A linear regression model with log-transformed costs or gamma regression will be considered. Outcomes will be stratified by residence (i.e. community-dwelling or not) at index date, and also by occurrence of subsequent osteoporotic fracture among OF women during follow-up (yes/no).

Background:
While obesity is an established risk factor for a number of common cancers,1 the predictive power of BMI (body mass index) and other adiposity indices in cancer risk prediction remains moderate in the general population.2 This suggests that some heterogeneity might exist regarding the increased risk of cancer related to adiposity.
Cancer and other chronic diseases often share common risk factors including adiposity, and tend to co-occur within the same individuals.3 Four in ten patients with cancer have at least one other chronic condition; the most common comorbid conditions include cardiovascular disease (CVD) and type-2 diabetes (T2D).4
One hallmark of obesity is systemic inflammation, a well-described pathway for the development of cancer,5 CVD,6 and T2D.7 Comorbid conditions may modify cancer processes associated with obesity through shared pathways, for example, by synergistically stimulating inflammation, but also through additionally activated pathways or external factors such as disease treatment.
The extent to which a comorbidity might contribute to cancer risk among overweight individuals is unclear.
Obesity has also been linked to poorer survival in cancer patients.8 Similarly, patients diagnosed with cancer who have pre-existing comorbidities such as diabetes are at increased risk for all-cause mortality compared with those without diabetes.9
However, the interplay between obesity and comorbidities on cancer development and survival is uncertain.

Hypothesis and objectives:
Our hypothesis is that the occurrence of a major comorbidity, CVD and/or T2D, prior to cancer modifies associations between obesity and risk of cancer development and cancer mortality.

Specific objectives:
1. To investigate whether incident CVD or T2D modifies the association between obesity and the risk of developing ‘obesity-related’ cancers, and specifically of the colorectum, pancreas, postmenopausal breast, and endometrium;
2. To investigate causal associations of in turn, CVD and T2D, by obesity status with cancers of the colorectum, pancreas, postmenopausal breast, and endometrium using Mendelian randomization (MR) approaches;
3. To investigate the role of obesity in cancer progression in relation to pre-existing comorbidities.

Settings and methods:
We will use individual-level data from large cohorts in Europe and Asia, complemented with a population-based primary care database and data from genetic consortia. Requirements include the availability of incident data on CVD and/or T2D. Treatment data for comorbidities and cancer will also be incorporated.
For risk of cancers, we will use survival models with age as the main time scale, time-varying variables for incident CVD/T2D, and an interaction with obesity (BMI).
Among cancer patients, survival models with time since diagnosis of cancer as the main time scale will be used with interactions between obesity and the presence of comorbidities prior to cancer.
Cancer risks will be related to obesity in the presence/absence of comorbidity in objective 1, while for objective 2, we will compare cancer risk related to comorbidity (using MR and GWAS data for susceptibility to CVD/T2D and related traits) in the presence/absence of obesity. The evaluation will address the question whether obesity and comorbidities interact in relation to cancer risk.

Impact:
This project could identify important pathways/modifiers of cancer risk among overweight individuals and lead to a more stratified approach to preventive or management strategies.

The European Health Data and Evidence Network (EHDEN) invites Data partners in Europe to apply for funding to map their health data to the OMOP common data model (CDM). The ambitions of the EHDEN project are high. We aim to standardise more than 100 million patient records across Europe from different geographic areas and different data sources. Mapping of such data to the OMOP CDM will facilitate their use for a variety of purposes, enhancing and accelerating research and healthcare decision-making for global benefit.

The Agency considers it requires a study to investigate exposure and use patterns of H2-receptor antagonists-containing medicinal products authorised in the European Union (EU).
The study should be carried out in at least five European countries with ideally equal spread across Western, Southern, Northern and Eastern countries and balanced representation of European healthcare services and setting with the following objectives:
1. To determine drug utilisation and prescription patterns of medicinal products containing H2-receptor antagonists (ATC codes: A02BA01 (cimetidine), A02BA02 (ranitidine), A02BA03 (famotidine), A02BA04 (nizatidine), A02BA06 (roxatidine), A02BA07 (ranitidine bismuth citrate), A02BA08 (lafutidine), A02BA51 (cimetidine, combinations) and A02BA53 (famotidine, combinations) by substance over a minimum period of five years (preferably more) including up to 2018 or more recent data. This study should give particular focus to:
a. Prescribing of medicinal products containing H2-receptor antagonists by incident and prevalent use by year, by indication (i.e. gastro-oesophageal reflux disease (GERD), gastric and duodenal ulcer, ulcer associated with H. pylori, Zollinger-Ellison syndrome), by age group, by gender, by dose, by formulation, by duration, by cumulative exposure and by country and data source;
b. To determine, in so far as is possible, comorbidity of renal impairment in patients using H2-receptor antagonist containing medicinal products.

El subproyecto CONCEPT-SURBCAN es parte de un proyecto coordinado denominado Efectividad y eficiencia de la atención crónica en el Sistema Nacional de Salud español: un estudio de múltiples cohortes con datos del mundo real [estudio CONCEPT]. El objetivo de este subproyecto es evaluar la efectividad y eficiencia de la atención sanitaria en largas supervivientes de cáncer de mama e identificar las preferencias y necesidades no cubiertas de pacientes y profesionales para mejorar la atención prestada durante la supervivencia de cáncer de mama.
Los datos de mundo real (RWD) de una cohorte retrospectiva de supervivientes de cáncer de mama (n = 7241 mujeres; 5 millones de contactos sanitarios) tratadas en hospitales y centros de atención primaria de cinco regiones de España (cohorte SURBCAN) se analizarán con métodos mixtos para describir las trayectorias asistenciales y el cumplimiento de las recomendaciones, utilizando técnicas de minería de datos y de procesos.
Se realizarán grupos focales con pacientes y profesionales para estudiar las preferencias y necesidades no cubiertas. La identificación de discrepancias en el cumplimiento de recomendaciones para el seguimiento de pacientes que han sobrevivido al cáncer es fundamental para identificar oportunidades para mejorar tanto la prestación de servicios como los resultados de las pacientes.

Background: Use of the antiarrhythmic flecainide have been linked to an increased risk of melanoma in a hypothesis-generating study from Denmark.
Hypothesis: Flecainide exposure might be associated to an increased risk of melanoma but also non-melanoma skin cancer.
Objectives: To assess the association between flecainide exposure and risk of melanoma and non-melanoma skin cancer in Denmark and Spain using health care data.
Methodology: Two independent case-control studies will be carried out.
Determinations and Statistical Analysis: Comparing melanoma and non-melanoma skin cancer cases to disease-free population controls, the use and cumulative use of flecainide will be assessed and odds ratios for the association will be estimated using conditional logistic regression.
Expected results and Applicability: The study will either confirm of disprove an association between flecainide use and non-melanoma and melanoma skin cancer.
Relevance and limitations: Knowledge of an increased skin cancer risk would allow prescribers to take appropriate measures, such as increased focus on UV protection. Conversely, a disproved risk would reassure prescribers in the safety of the use of the drug.
The main limitation is the lack of direct measures of UV exposure history. However, there is no reason to suspect that flecainide users will display markedly different sun exposure habits than the background population.

Scientific background
Cancer patients often have other health-related conditions that existed before diagnosis and are referred to as cancer comorbidities. Studies have shown poorer survival among cancer patients with comorbidities, but it is unknown whether the negative impact of comorbidities on cancer survival affects primarily comorbidity-related deaths or cancer-specific mortality. Comorbidities can affect cancer survival also through detection and treatment, but associations have been shown to vary by cancer and by type, duration and severity of comorbidities, factors that have not been considered previously.
– Project objectives and brief description of the methods which will be used to achieve them
1. To describe presence of comorbidities in patients with overall and cancer-specific sites, by age, sex, and education, and to compare these patterns with those of cancer-free subjects;
2. To investigate whether pre-existing comorbidities are associated with stage of cancer;
3. To investigate the impact of pre-existing comorbidities on overall and cancer-specific survival;
4. To explore how treatments for pre-existing comorbidities or for cancer explain the prognostic impact of comorbidities.
In a prospective cohort study design, we define comorbidity as the occurrence of one or more chronic conditions among obesity, hypertension, coronary heart disease, stroke, and type 2 diabetes prior to a first cancer diagnosis. The main data source will be the EPIC study with ~89,000 cancer patients of which 35% died after cancer diagnosis. In the French E3N study (~15,000 women with cancer), data on drug reimbursement, cancer treatments, and additional comorbidities will be available for refined analysis. Analyses will be replicated using a primary care database (SIDIAP), representative of the Catalan population, with ~490,000 cancer patients.
– Expected results
Contribution to refined clinical guidelines for cancer treatment accounting for comorbidities and improved prognostic stratification.

Antecedentes: La enfermedad de Parkinson (EP) es el trastorno del movimiento neurodegenerativo más frecuente del cual se desconoce la etiopatogenia pero se sugiere la concurrencia de una base genética compleja y factores ambientales. Se han realizado diversos trabajos epidemiológicos sobre la relación entre las alteraciones del metabolismo de la glucosa y la EP observando datos contradictorios, por lo que la existencia de una asociación entre EP y la diabetes mellitus tipo 2 (DM2) permanece motivo de controversia.
Objetivos: Considerando una mayor prevalencia de EP en relación a la DM2 se quiere explotar y analizar la base de datos de Atención Primaria de Cataluña con el fin de establecer el riesgo relativo de tener EP en relación a la presencia o ausencia de DM2.
Métodos: Estudio epidemiológico retrospectivo de cohorte de la población atendida en Atención Primaria del Instituto Catalán de la Salud en Cataluña entre 2006 al 2017 determinando la incidencia de EP en pacientes con y sin un diagnóstico de DM2. Se obtendrá los datos a partir del Sistema de Información para el Desarrollo de la Investigación en Atención Primaria (SIDIAP).
Determinaciones: A través de la codificación diagnóstica del CIE-10, formar una cohorte de casos de DM2 entre 2006-2010 y una cohorte de controles de no-DM2 y determinar entre 2011-2017 la proporción de EP en cada grupo ayudándonos de variables como temblor, fármacos dopaminérgicos, antidopaminérgicos y antidiabéticos para la definición de los casos de EP y DM2.
Análisis estadístico: Se calculará el riesgo relativo y los intervalos de confianza del 95% de EP asociado a la DM2 a partir de modelos de riesgo proporcional de Cox.
Resultados esperados: Evaluar la posibilidad de que la DM2 sea factor de riesgo para la EP en nuestro medio a través de una gran cohorte representativa de la población catalana.
Aplicabilidad y relevancia: Aportar datos sobre la asociación entre la EP y la DM2 pudiendo tratarse esta última de ser factor de riesgo para la EP y desarrollar nuevas investigaciones dirigidas a esclarecer la etiopatogenia de la enfermedad y nuevas estrategias terapéuticas.

Background:
An imbalance in the incidence of serious CV events, driven by events of MI and stroke, was observed with romosozumab in the alendronate ( ALN) – controlled study 20110142 ( ARCH) after 12 months of treatment. No imbalance was observed in the placebo-controlled study 20070337 ( FRAME) after 12 months of treatment. Serious CV events of MI and stroke are determinded an identified risk in the European Union ( EU) – Risk Management Plan ( RMP).
Research questions and objectives: The overarching objective of this study is to characterize the risk of serious CV events of MI and stroke and all-cause mortality including CV death associated with the use o romosozumab, in comparison with other available OP medications in routine clinical practice in Europe.
Specifically, the study will provide further understanding on the following objectives: 1- to assess the incidence rate (IR) of serious CV events ( MI and stroke) and all-cause mortality including CV death in romosozumab users in the indicated population in Europe as per the summary of products characteristics ( SmPC), and in cohorts of users of other OP medications who would also fulfil the indication (contraindications for romosozumab in Europe; 2- to assess the IR of serious CV events ( MI and stroke) and all-cause mortality including CV death in romosozumab users in the indicated population in Europe spoer the SmPC and amongst users of other OP medications similar to the indicated population for romosozumab in Europe as per the SmPC, stratified by age, previous use of OP medications and by prespecified key CV risk factors; 3- to assess the comparative risk of CV events ( MI and stroke) and all-cause mortality including CV death in romosozumab users in the indicated population in Europe as per the SmPC to users of ALN ( active comparator) with similar baselien characteristics.
Methodology: study design: multinational-multidatabase cohort study of new users of romosozumab and new users of other OP medications. study period is expected to last 6 years ( 2020-2026).
Population: the study population comprises all women from the 7 participating databases with severe OP who are dispensed or prescribed an OP medication of interest for the first time ( new users ) during the study period, have been continiously registered in the data source for at least 12 months prior the the first recorded dispensing/prescription of the OP medication of interst, and are at least 50 years of age on the date of the first dispensing/prescription of the OP medication of interest. Women with diagnosis of cancer ( any except basal cell skin cancer) or paget disease at any time before treatment initiation will be excluded. New users will be followed for a maxium of 24 months from index therapy inititation ( index date). Two Follow-up periods will be included for the estimation of CV IRs: an Exposure-based follow-up period and a fixed ( first exposure carried forward) follow-up period.
For the exposure-based analysis, participants will be followed until the occurrence of the CV event of interest, discontinuation of the study drug of interest, switch or addition of any otherOP medication ( except Calcium/vitamin D supplements), lost to follow-up, death, end of the 12 months after therapy initiation (as per the romosozumab SmPC), or end of the study period/data extraction date. For the Fixed Follow-up Period, participants will be followed in their respective cohorts until lost to follow-up, CV event of interest, death or end of the study period. Variables: the OP medication of interest include romosozumab and other OP medications, such as ALN (primary active comparator), other oral bihposphonates (ibandronate or risedronate at doses indicated for OP treatment), intravenous (iv) biphosphonates (zoledronate or ibandronate at doses indicated for OP treatment), denosumab (at the dose indicated for OP treatment) and teripartide.
Primary outcome is major adverse cardiac event(s) (MACE-2) (first occurrence of death [all cause], MI or stroke). Secondary outcomes are MI, stroke, death due to CV cause, all-cause mortality and MACE-1 (first occurrence of death due to CV causes, MI or stroke). Other covariates and potential confounding factors will be identified at cohort entry (index date) based on the patients’ records in the previous 12 months (baseline period), and will include general patient characteristics, CV risk facgtors, markers of OP severity, and use of other medications.
Data sources: This study will be conducted using routinely collected data from different data sources that participate in the EU-ADR Alliance, with the addition of databases from the UK (Clinical Practice Research Datalink [CPRD] GOLD), Germany (German PHarmacoepidemiological Research Database [GePard]), and France (Système National Des Données de Santé [SNDS] database). Participants form 7 European countries will provide heterogeneous and representative data on the safety of romosozumab as well as ensuring sufficient statistical power for the study.
Study size: Feasibility estimates demostrate the capability of the ocnsortium and the data sources to capture a sufficient sample of patients in each OP medication group. The number of romosozumab users and comparator users needed to obtain an alpha risk of 0.05 with 90% power in a 1:3 (romosozumab:comparator) matched cohort analysis for different scerarios of incidence of CV events and hazard ratio (HR) were calculated. In the worst-case scenario of IRs of 1 per 100 person-year and a 2-fold relative increase in risk, 1,450 romosozumab users (and 4,350 users of the active comparator) would be required.
Data analysis: The IRs of CV events of interest for each OP medication will be calculated for the 2 Follow-up Periods. Incidence rates and 95% conficence intervals (CIs) of CV events of interest will be calculated for each study drug using a Poisson model.
For the Fixed Follow-up Period, IR of patients with CV events of interest will also be reported.
The CV event/s rates (as in objective 1 and 2) for each study drug will be provided stratified by key CV risk factors. For objective 3 (the comparative safety analysis), the Cox regression model stratified by matched sets will be used to calculate HRs and 95% CIs for eath safety endpoint (MI, stroke, MACE-1 and MACE-2).
Measures for reducing confounding by indication will be implemented including propensity score matching as well as negative control outcome analyses to identify unobserved confounding. If required, additional analysis will be conducted to assess the effects of potential biases related to insufficient control for confounding/channeling bias: (i) empirical calibration using negative control outcomes; (ii) self-controlled case series (SCCS) and (iii) instrumental variable analysis.

Rationale and Background: POC1.2 aims to test near real-time and visual monitoring of coverage, benefits and risks of acellular pertussis (aP) vaccination. POC1.2 is designed as a continuation of POC1 to leverage previously completed work. POC1.2 will use near real-time visual monitoring of aP vaccines in Europe as a test case, aiming to mimic the introduction of a new vaccine. The interactive dashboard developed as an additional analysis to POC1 will be regularly updated for monitoring.

Research Question and Objectives:
The overall objective of the ADVANCE POC studies is to build and test a system (including data availability) for the benefit-risk monitoring of vaccines in Europe. The objective of POC1.2 is to determine the feasibility of periodic and rapid assessments of vaccine coverage, benefits and risks using electronic healthcare databases, while displaying these data using a dashboard.

Target Population: All children from their start of follow-up in the database until school-entry pertussis booster, 6 years of age or any periodic data lock point within the eligible ADVANCE databases.

Observation Period:
The total observation period consists of two distinct periods. The first period starts from 01 January 2014 until the start of the near real-time monitoring upon approval of the protocol and has as objective to establish a baseline. The second period has the objective of near real-time monitoring and will cover a few months. This period will start upon protocol approval until last periodic data lock point (DLP) (i.e. the time the last periodic database extract is produced) and will cover a few months.

Study design: A dynamic cohort study
Exposure: The exposure of interest is vaccination with any acellular pertussis-containing (aP) vaccine recorded in the study population covered by the ADVANCE databases participating in POC1.2
Outcomes: The risk outcomes are hypotonic hypo-responsive episodes (HHE), febrile convulsions/seizures, fever, somnolence and persistent crying. The benefit outcome is pertussis, confirmed or probable.

Data analyses
The test case is near real-time (weekly or bi-weekly/monthly, depending on the database) visual monitoring of vaccination coverage, benefits and risks of pertussis vaccination. The monitoring will be facilitated through the use of an interactive dashboard developed based on the POC1 data. The dashboard contains three monitoring tabs with visualizations:
-Coverage: number of administered doses per week over calendar time and vaccination coverage within specific age groups by calendar time
-Benefits: observed pertussis incidence in the total population by calendar time
-Risks: incidence rates in event specific risk windows and in control periods (out of risk windows) at vaccination eligible ages, separately for each risk outcome by dose, estimated cumulatively over calendar time.

Data Sources:
The potential data sources were selected from all databases available from ADVANCE partners and associated partners, based on the following eligibility criteria:
-Successful database quality assessment based on database fingerprinting and benchmarking for the events and vaccine of interest
-Theoretical ability to generate periodic data, with a target of weekly refresh of data, as recovered based on a detailed survey
Based on these two criteria the following six data sources remained: ASLCR, ARS, PEDIANET, RCGP, SIDIAP and SSI/AUH.

Sample size: Entire eligible study population from the six eligible databases.

Dosing errors are one of the most common types of medication issues and contribute to the mortality and morbidity within the paediatric population. Paediatric patients are at a higher risk than adults of experiencing such problems because of the need for a dose calculation based on the patient?s age, weight (mg/kg), body surface area (mg/m2), and clinical condition.
Antibiotics are the medications most widely prescribed in the paediatric population and one of the drug classes most commonly reported to be involved in paediatric dosing errors.
Despite a number of studies conducted about antibiotics usage in different European countries, the appropriateness of antibiotic dosing (prescribed by doctors in primary or secondary care, dispensed by community or hospital pharmacies, or administered in hospital settings) according to the child?s age, weight and height (and other related parameters, as Body Mass Index – BMI, Body Surface Area – BSA) has not yet been investigated.
In this study, we would like to assess in European Medical Information Framework (EMIF) Electronic Healthcare Records (EHR) databases (DBs) the relationship between dosing of antibiotics prescribed, administered or dispensed (either for outpatients or inpatient settings) to children (age 0-18 yr), and their weight, age and height.

Antecedents: Una de les línies de treball interna prioritàries del Sistema d’informació per al Desenvolupament de la Investigació en Atenció Primària (SIDIAP) és la validació dels diagnòstics de patologies registrats a l?historia clínica electrònica (HCE) d?atenció primària. El Registre de Càncer de Girona (RCG) recull informació sobre tots els casos de càncer diagnosticats a la Regió Sanitària Girona i és la millor font de dades disponible per a la validació de casos de càncer registrats al SIDIAP així com per a la realització de futurs estudis de recerca que necessitin informació detallada dels tumors.
Hipòtesis: El registre dels diagnòstics de càncers a l?HCE per part dels professionals d?atenció primària de l?ICS a la Regió Sanitària de Girona és vàlid.
Objectius: L?objectiu principal és validar el registre dels diagnòstics de càncer a la població del SIDIAP a la regió sanitària de Girona, fent servir les dades del RCG com a estàndard d?or. Els objectius específics són: 1) vincular les dades del SIDIAP amb les dades del RCG; 2) validar els diagnòstics de càncers registrats a l?HCE d?atenció primària a la població SIDIAP de la Regió Sanitària de Girona; 3) descriure els indicadors de validació en funció de l’edat, el sexe, la zona geogràfica (i/o centre d?atenció primària si és possible), nacionalitat, nivell socioeconòmic, la data de registre del diagnòstic i la localització tumoral; i 4) investigar l?associació entre el nivell socioeconòmic de les persones amb càncer i l?estadificació dels tumors (quan disponible) en el moment del diagnòstic.
Mètodes: Estudi de validació transversal. S?identificaran els casos de càncer registrats amb codis CIM-10 al SIDIAP i al RCG a la regió sanitària de Girona entre l?1 de gener de 2005 al 31 de desembre del 2015. Les variables d?estudi són: edat, sexe, codi CIM-10 pels diagnòstics de càncer i la data de registre del diagnòstic, l?estadificació dels tumors (RCG; pels tumors amb aquesta informació disponible), la zona geogràfica, nivell socioeconòmic (índex MEDEA), nacionalitat, realització de proves de cribratge per la detecció de casos de càncer i els seus resultats si està disponible, consum d?alcohol, tabaquisme, activitat física, índex de massa corporal, índex de comorbiditat de Charlson, variables de salut reproductiva (paritat, edat primer embaràs, menopausa i teràpia hormonal), diabetis, hipertensió, colesterol, i els antecedents familiars de neoplasmes malignes. Per cada localització de tumor, es calcularà la sensibilitat, l?especificitat, el valor predictiu positiu (VPP) i el negatiu (VPN). Aquests indicadors de validació es descriuran segons els grups d?edat, sexe, zona geogràfica, equip d?atenció primària, any de diagnòstic, nacionalitat i índex MEDEA. L?associació entre el nivell socioeconòmic i l?estadificació dels tumors s?avaluarà a partir de models de regressió logística.
Aplicabilitat i rellevància: La validació dels diagnòstics de càncer al SIDIAP i la col·laboració amb el RCG facilitarà la realització de futurs estudis de recerca. A més a més, el SIDIAP podria ser una nova font d?informació del RCG.

Les bases de dades electròniques dissenyades primàriament per a l’assistència i que, posteriorment, es trasnformen en bases de dades per a la recerca necessiten validar la informació disponible. Una de les línies estratègiques de l’IDIAP Jordi Gol és la qualitat de SIDIAP i, per tant, la necessitat de validació de la informació que conté. L’objectiu d’aquest projecte és la la validació, en termes de valor predictiu positiu, dels codis de cardiopatia isquèmica de SIDIAP. Addicionalment, s’analitzarà descriptivament la concordança entre el motiu d’ingrés i d’alta dels registres hospitalaris que no estiguin registrats a SIDIAP, així com els motius pel qual no s’ha registrat.

L’any 2014 es van iniciar a Catalunya els primers tractaments dels pacients infectats pel virus
de l’hepatitis C (VHC) amb agents antivirals directes (AAD). Aquests fàrmacs tenen eficàcies
superiors i un millor perfil de seguretat que els tractaments previs basats en interferó (IFN).
L’efectivitat i la seguretat a curt termini dels tractaments en condicions de pràctica clínica ha
mostrat ser similar a la descrita en els assaigs clínics, però la seguretat a llarg termini o en
poblacions especials està poc establerta. Recentment s’han descrit alguns senyals de seguretat
que inclouen riscos de descompensació hepàtica en pacients amb fibrosi avançada, reactivació
de la infecció per hepatitis B i un possible augment del risc de recidiva d’carcinoma
hepatocel·lular després del tractament amb AAD. Fisiopatològicament és plausible que
augmenti el risc de qualsevol càncer, no només de l?carcinoma hepatocel·lular. Aquestes
comunicacions han generat recentment una alerta de seguretat regulatòria a nivell europeu.
El present estudi de cohorts retrospectiu pretén valorar a nivell poblacional la incidència de
qualsevol càncer no hepàtic en pacients tractats amb AAD per a la infecció per VHC, i
comparar-la amb la incidència en controls infectats per VHC tractats amb pautes basades en
interferó abans del 2014, i amb pacients no infectats per VHC, per tal de valorar possibles
diferències i factors que puguin influir en les mateixes. L?establiment d?inicidències i de risc
relatius per als AAD mitjançant models de Poisson ajustats permetrà descriure si existeixen
aquests riscs, i en cas afirmatiu, establir-ne el risc atribuïble i dissenyar un pla de gestió dels
mateixos.

Background:
Increased body mass index (BMI), indicating general adiposity, is an established risk factor for several cancers. There is convincing evidence for associations between BMI and cancers of the oesophagus (adenocarcinoma), pancreas, colon, rectum, breast (postmenopausal), endometrium, liver, kidney and probable evidence for gallbladder, ovary, and prostate. However, data are currently limited for many other cancer sites. Recently, a population-based cohort study of 5.24 million UK adults reported associations between BMI and 17 cancers, suggesting wider-ranging associations. These observations are important and need replication in other populations. Furthermore, BMI alone may not fully capture the complex biology underlying associations between adiposity and cancer risk, and individuals with similar BMI may have distinct disease risks depending on their body fat distribution. Waist circumference (WC) is often used as an indicator of central adiposity and have even been suggested to be a superior predictor of cancer risk. Furthermore, there is still a crucial need for better characterisation of existing obesity-cancer links to determine dose-response relationships and effect modification by important individual level factors across a wide range of cancer sites.
Hypothesis and Objectives:
The main objective of this project is to investigate the relationships between adiposity and 22 major cancers using measured BMI and outcome data from prospectively collected primary care records in 6 million individuals from a Mediterranean population.
Specific objectives are to investigate (1) non-linear dose-response associations and effect modification by individual level factors (e.g., age group, smoking, hormone use); (2) relations of duration of overweight/obesity to site-specific cancer using repeated measures of BMI; and (3) to derive standardized risk estimates for general (BMI) and central (WC) adiposity in relation to site-specific cancers.
Setting and Methods:
The proposed study will use comprehensive data from a prospective population-based database from the Information System for the Development of Research in Primary Care (SIDIAP). SIDIAP includes data of anonymized patient records for nearly six million people throughout Catalonia since 2006. SIDIAP includes all data collected by health professionals during routine visits, including anthropometric measurements, clinical diagnoses, as well as demographic and lifestyle information. The quality of these data has been previously documented.
All people in SIDIAP aged 15 years or older with BMI data and subsequent follow-up will be included. Baseline measured BMI will be calculated and assigned as the earliest BMI recorded. Repeated weight measurements will be used to predict individual BMI trajectories for each study participant. Approximately 260,900 first primary cancers have been recorded from 2006-2014. Hazard ratios will be calculated using Cox models, and spline models will be fitted to investigate the dose-response nature of the observed associations. Overweight/obesity duration will be estimated using quadratic growth models.
Impact:
This project will represent one of the largest studies in this area of research to date and will substantially advance our understanding of the impact of obesity on cancer risk, including rarer cancers and cancer at younger age. It will strengthen the rationale to implement strategies of obesity prevention and mitigating the public health effects of cancer due to obesity.

El objetivo principal del estudio es el de comparar la asociación entre Síndrome Metabólico (SM) y cáncer versus el hecho de presentar 1 o 2 componentes individuales del propio SM. Se seleccionarán 14 tipos de cáncer incidentes diagnosticados a partir de las historias electrónicas de Atención Primaria (base de datos SIDIAP).
El objetivo secundario es el de evaluar el tiempo transcurrido desde la exposición a SM y la posterior aparición de cáncer dentro del periodo 2006-16.

Metodología: estudio caso-control para el objetivo principal y seguimiento de una cohorte de expuestos a SM para la evaluación del segundo objetivo. Se seleccionarán pacientes ?40 años incluidos en SIDIAP recogidos desde 01/01/2006 hasta 31/12/2016. La base de datos SIDIAP incluye datos anónimos de 6 millones de personas (80% de la población catalana) registradas en 274 centros de primaria. El apareamiento se hará siguiendo la técnica de propensity score, poniendo la condición previa que cada control (4 por caso) apareado tiene que tener la misma fecha de inclusión, el mismo sexo y una edad similar (± 1 año) del caso al que se aparea. Para el análisis estadístico, se realizará la regresión logística y un análisis de supervivencia.

Los análisis serán estratificados por tipo de cáncer. El análisis principal será ajustado por: sexo, edad, índice de privación MEDEA, tabaco, alcohol, actividad física, consumo de fármacos, características del centro, índice de Charlson, embarazos previos y presencia de menopausia.

La población de mujeres que sobreviven a un cáncer de mama está aumentando como consecuencia de las mejoras en el diagnóstico y tratamiento. Este fenómeno está ligado a la edad y asociado a la comorbilidad. Se conoce muy poco sobre cuál es el seguimiento que hacen estas mujeres de la enfermedad, sobre su patrón de uso de servicios de salud y sobre sus necesidades. El proyecto tiene como objetivos principales conocer las comorbilidades y el patrón de uso de atención primaria y especializada en mujeres que han sobrevivido al cáncer de mama cinco años o más, compararlo con el de las mujeres sin diagnóstico de cáncer y estimar modelos de consumo de recursos ajustando por tiempo de supervivencia y comorbilidades. A partir de la historia clínica informatizada (HCI) de áreas básicas de salud de cinco Comunidades Autónomas de España se identificarán mujeres que hayan hecho uso de servicios de salud. Se identificarán aquellas con diagnóstico de cáncer de mama y una supervivencia superior a cinco años en el periodo de estudio (1 de enero de 2012 hasta 31 de diciembre de 2016) y mujeres sin diagnóstico de cáncer. Con técnicas de regresión logística, regresión de Poisson y modelos de simulación de eventos discretos se dará respuesta a los objetivos planteados. Este proyecto combina experiencia de grupos expertos en evaluación de servicios de salud, en análisis de comorbilidades y de enfermedades crónicas, pertenecientes a la Red de Investigación en Servicios de Salud en Enfermedades Crónicas (REDISSEC).

L’objectiu de la proposta és la incorporació de la Dr. Talita Duarte-Salles, infermera i epidemiòloga postdoc, al Grup de Recerca en Malalties Prevalents de l?Aparell Locomotor en Atenció Primària (GREMPAL), liderat pel Dr. Daniel Prieto-Alhambra. La candidata desenvoluparà les següents tasques:
1) Epidemiologia de les malalties més prevalents de l?aparell locomotor a l?Atenció Primària i la seva relació amb malalties oncològiques: estudi sobre l?associació entre l?obesitat, l?artrosi, i el càncer (de diferents tipus/localització); estudi de validació dels diagnòstics de malalties oncològiques registrats a l?HCE d?atenció primària.
2) Estudi de l?obesitat infantil com a factor de risc per l?aparició d?artrosi precoç: estudi amb dades de l?historia clínica electrònica anonimitzada -base de dades SIDIAP- per descriure l?obesitat, així com a problemes de salut relacionats, en la població infantil (0-14 anys) a Catalunya, i investigar l?impacte del sobrepès/obesitat infantil sobre el desenvolupament d?artrosi en edats precoces.
3) Real world big data solutions: liderar estudis de validació de la informació registrada a SIDIAP necessaris per la realització dels estudis de recerca proposats; vinculació de les dades del SIDIAP amb fonts externes (p.e. registre de càncer i/o d?artroplàsties); estandardització de les variables del SIDIAP a un model comú de dades a Europa per tal de facilitar futurs estudis col·laboratius del GREMPAL amb altres bases de dades europees; i vinculació mare-fill a SIDIAP a partir d?algoritmes per la realització de futurs estudis de seguretat de fàrmacs anti-inflamatoris, analgèsics i anti-osteoporosi utilitzats durant l?embaràs i post-part/lactància

Non-alcoholic fatty liver disease (NAFLD) is an important clinical syndrome related to ectopic deposition of fat in the liver, known as simple steatosis. Several researchers have encouraged further exploration of the relation of NAFLD and other chronic liver diseases with the development of cognitive impairment and dementia.
We hypothesize that patients with NAFLD are at increased risk of developing cognitive impairment including dementia. The scientific aim of this study is to evaluate whether risk of dementia differs in patients with versus those without a previous diagnosis of NAFLD.
In this study, we will request access to the THIN, HSD, IPCI and SIDIAP databases that were previously analysed in other EMIF projects called Use Cases (UC) on NAFLD (UC 10) or dementia (UC 6, 11 and 12). We will utilize the standardized processes developed by the EMIF-Platform to conduct protocol-based studies in multiple routine health care data across Europe. This will enable us to access the largest cohort assembled to date of patients with dementia and to investigate heterogeneity across country and primary care systems. A pragmatic objective of this study is to further develop the Platform by streamlining already existing processes and experimenting on new ways of working.

Background: Understanding the determinants of childhood obesity has never been more urgent, given the rapid rise in obesity worldwide. Individual-level interventions, focused on changing dietary and physical activity behaviours, have had limited success. It is increasingly recognized that the urban environment contributes to the obesity epidemic and that it provides important potential for community-level intervention.

There are important gaps, though, in knowledge about multiple urban exposures and mediators, and there is no data in Catalonia on which to base impact assessments.

Main objective: ECHOCAT aims to examine whether the urban environment (air pollution, green spaces, social environment, built environment, unhealthy food environment) influences childhood obesity across Catalonia in three unique and complementary study populations.

Methodology: ECHOCAT will exploit the large resource of available primary care data of 1.6 million children (80% of the population) and the extensive individual data already available in a mother-child cohort in Catalonia. ECHOCAT will also collect new data on school children (10-12 years) in one Catalan city, Sabadell, where anthropometric measurements will be combined with questionnaires to obtain data on obesity and important risk factors. Geographical information system technologies will be used to estimate exposure to the different urban environment indicators at census tract level for the whole Catalonia and at home and school address level for Sabadell city. Individual-level mediators including diet, physical activity, and psychological well-being will be evaluated for their role in the association between urban environment indicators and childhood obesity. A health impact assessment will be developed based on this study and available literature.

Expected results: ECHOCAT will be novel in modelling multiple community-level urban environment
indicators and by evaluating potential individual-level mediators. A final impact assessment will help decision makers to develop urban environment policies aimed at reducing and preventing childhood obesity in
Catalonia.

Resumen: En el contexto actual de la obesidad y la diabetes epidemias en el mundo desarrollado, hay un interés por los médicos, académicos y empresas farmacéuticas a comprender mejor la epidemiología de la enfermedad de hígado graso no alcohólica (EHNA) y enfermedad hepática no alcohólica (EHNA ). NAFLD y NASH tienen una alta prevalencia en estas poblaciones, y pueden aumentar aún más el riesgo de enfermedades cardiovasculares futuros, así como las complicaciones del hígado, como la cirrosis y carcinoma hepatocelular.
los datos de historiales médicos electrónicos para mantener los registros médicos en poblaciones de pacientes a gran escala, y los datos de atención primaria generalmente tiene acceso a los registros médicos durante varios años de seguimiento. Este protocolo se propone indagar hígado graso no alcohólico y la EHNA y sus complicaciones en las bases de datos de atención primaria disponibles dentro EMIF. Este protocolo pretende primera estimación de la incidencia de hígado graso no alcohólico y la EHNA en la población general. Además, el protocolo tiene como objetivo evaluar el exceso de riesgo de las enfermedades cardiovasculares y hepáticas morbilidad en pacientes con diagnóstico de hígado graso no alcohólico o EHNA en comparación con los individuos con edad y sexo similares y sin diagnóstico, utilizando un diseño de cohortes emparejado. Un objetivo adicional es evaluar si la gravedad de la fibrosis hepática, según las estimaciones de la puntuación no invasiva en pacientes con NAFLD o NASH, está también asociada con los resultados cardiovasculares y hepáticas. Debido a las diferencias en los sistemas de codificación y la información disponible en cada una de las bases de datos, este protocolo reconoce que algunos de los objetivos pueden no ser posibles en todas las bases de datos seleccionadas.
Este protocolo corresponde con el caso de la EMIF usuario 10 – Paquete de trabajo 7 y se prevé que ayudará a apoyar el desarrollo de herramientas para la EMIF-plataforma, y ??las capacidades de la EMIF prueba en la realización de un estudio epidemiológico de forma simultánea en varias bases de datos.

Comentario general: Este es un proyecto de varios objetivos utilizando varias bases de datos y de este protocolo reconoce que algunos de los objetivos puede no ser realizable en todas las bases de datos debido a las diferencias en los sistemas y el nivel de detalle de la información registrada de codificación.
Vamos a colaborar con los custodios de datos para mejorar nuestra comprensión de estos datos; por ejemplo, con respecto a la EHGNA y la EHNA grabación por los médicos de atención primaria en un país en particular, la representatividad de la población de pacientes inscritos, la grabación del uso del alcohol y de las mediciones de laboratorio.
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El proyecto europeo Marco de Información Médica (EMIF) tiene el objetivo principal de la construcción de una infraestructura para la reutilización eficiente de los datos de salud existentes para la investigación epidemiológica. Dentro del proyecto, la Plataforma EMIF
representa una federación de fuentes heterogéneas de datos de salud (por ejemplo administrativa, bases de datos hospitalarias o de atención primaria, los registros de enfermedades, biobancos). Uno de los principales retos para el proyecto EMIF es para hacer frente a las diferentes características de las fuentes de datos de participantes con el fin de facilitar la ejecución de los grandes, de múltiples datos multinacional
fuente estudios de observación y generan pruebas de alta calidad. Para este propósito, una plantilla de procedimiento de derivación de datos fue desarrollada específicamente. En este estudio de prueba de concepto, el procedimiento estándar será aplicado para la identificación de los pacientes con infarto agudo de miocardio (IAM) en un conjunto de fuentes heterogéneas de datos de salud de observación.
Índices de validez (sensibilidad, PPV) de los algoritmos de detección de casos de origen a la medida de datos se estimaron a partir de pruebas disponibles, y la prevalencia ajustada y la incidencia de IAM se estimaron a partir de las fuentes de datos que participan.

Rationale and Background: The overall ADVANCE proof-of-concept (POC) question is to test the system for benefit-risk monitoring of vaccines in Europe. This will first be done by using test cases. For this POC, the following research question is used: ?Has the initial benefit-risk profile in children prior to school-entry booster been maintained after the switch from whole-cell pertussis (wP) vaccines to acellular pertussis (aP) vaccines??
This protocol will test the system related to the estimation of coverage data as they are required for the performance and interpretation of the benefit-risk analysis.
Research Question and Objective: To assess the system capability to estimate aP and wP vaccine coverage.
Study Design: The main study design is a retrospective dynamic cohort study.
Population: Children from birth until 6 years of age (until 6th birthday) during the study period.
Outcome Parameters: Vaccine coverage is the proportion of individuals within the target population
having received the vaccine.
For Objective 1 the following parameters are needed: Number of databases with adequate data for coverage estimates; Number of children vaccinated; Number of children within the target population; Proportion of vaccinated children; Coverage rates overall, wP and aP immunization by database, birth cohort, , age in months and per dose; The variability of vaccine administration over time; Changes of coverage rates over time.
Data Sources: Electronic health care databases (record linkage, surveillance and GP based databases)
currently available in the ADVANCE consortium and eligible are located in Denmark, Spain, Italy, and UK.
Study Size: Total population (0-6 year of age) of all eligible ADVANCE databases.
Data Analysis: Frequencies and distributions are measured by general descriptive statistics. Coverage rates and timeliness of immunization are calculated according to the Kaplan-Meier method. Changes of coverage rates will be assessed by the cumulative sum (CUSUM) method.
Informed Consent and Ethical Approval: This study will be conducted on the basis of secondary use of electronic healthcare records. Each database will apply local governance and privacy rules prior to aggregating and sharing anonymized data.

Rationale and Background: The overall ADVANCE proof-of-concept (POC) objective is to test the system for benefit-risk monitoring of vaccines in Europe. This will first be done by using test cases. For this POC analysis, the following research question is used: ?Has the initial benefit-risk profile in children prior to school-entry booster been maintained after the switch from whole-cell pertussis (wP) vaccines to acellular pertussis (aP) vaccines??
This protocol aims to obtain the data on the benefits that will feed into the benefit-risk model.
Research Question and Objectives: 1. To assess the feasibility of healthcare databases to estimate the incidence rates of pertussis following pertussis vaccination; 2. To estimate the incidence rate of diagnosed pertussis in infants and children up to school-entry or age 6 years ? any case at, or between, any dose of primary or booster vaccine, dose-specific; 3. To estimate the risk of non-fatal pertussis-related complications leading to hospitalizations, i.e. seizures and pneumonia in infants and children up to age 6 years; 4. To assess the risk of deaths following pertussis in infants and children up to age 6 years; 5. To calculate calendar month-specific incidence rates which will also allow for time sequential monitoring of effectiveness in the methods development.
Design: The main design is a retrospective dynamic cohort analysis.
The analysis will be conducted utilizing electronic health care data from ADVANCE partners in Denmark,
UK, Netherlands, Spain and Italy.
Population: The source population for this analysis will comprise all children registered in any of the participating databases during the study period and for whom an adequate start and end of follow-up and date of birth can be defined.
Data Sources: Electronic health care databases (record linkage, surveillance and GP-based databases) currently available in the ADVANCE consortium and eligible are located in Denmark, Spain, Italy, The Netherlands and UK. Short descriptions of databases and their full names will be included in this protocol upon final decisions of inclusions.
Data Analysis: Incidence rates of pertussis will be calculated by age in months, sex, country, calendar
time (year and month) and wP/aP type and dose.
The risk of complications and death will be calculated within the 30 days after occurrence of pertussis
disease in all subjects with a recorded diagnosis of pertussis. Risk will be stratified by age in months, sex, country, calendar time and wP/aP type and dose.

Obesity is an important and well known risk factor for cardiovascular diseases (CVD) and all-cause mortality with prevalence across the world continuing to increase (Europe PMC Funders Goup 2014) with the economic cost estimated to be £50 billion by the year 2050 (Morgan & Monica 2010). Currently, the associations with obesity and CVD have not been extensively studied in the electronic health record (EHR) setting. EHRs are an invaluable resource allowing population-level research on large representative scales; they include information captured on patients? medical records such as diagnoses and prescribed treatments that are deemed relevant for patient care. Body mass index (BMI) is recorded on a number of EHR systems; however there are concerns about its completeness and representativeness particularly since BMI may be recorded as a risk based measure.

This study seeks to evaluate the relationship between obesity (as measured by BMI) with cardiovascular disease and all-cause mortality using data from EHR primary care databases in the UK, Spain, Netherlands and Italy through the European Medical Information Framework (EMIF) platform. Characteristics such as demographics, morbidity burden and history of healthcare utilization will be compared between individuals with BMI recorded and those without a BMI recorded on their health records in order to better understand whether any key differences exist between the two groups. In addition, sensitivities about the timing of the recording of BMI on any observed relationships will be explored.

It is anticipated that this study of a well characterized association between obesity (as measured by BMI) and CVD will support future EMIF studies and the development of Platform tools.

Title of Study: Testing new approaches to monitoring benefit/risk with pertussis vaccines as test case: Incidence rates of safety outcomes of whole-cell pertussis and acellular pertussis vaccines in pre-school children.
Study Period: 01 January 1990 ? 31 December 2015
Rationale and Background: The overall ADVANCE proof-of-concept (POC) question is to test the system for benefit-risk monitoring of vaccines in Europe. This will first be done by using test cases. For this POC feasibility study, the following research question is used: ?Has the initial benefit-risk profile in children prior to school-entry booster been maintained after the switch from whole-cell pertussis (wP) vaccines to acellular pertussis (aP) vaccines??
This protocol aims to create the safety data for a benefit-risk analysis of aP versus wP vaccines.
Research Question and Objectives:
The objectives of this specific POC feasibility study focusing on the incidence rates of safety outcomes of pertussis vaccines are:
1. To evaluate participating databases on quality criteria for inclusion in the study (i.e. vaccination data on pertussis vaccine available, at least one of the outcomes available, data access and clearance of protocol possible within timelines of POC feasibility study).
2. To provide safety information for a benefit/risk analysis model.
The safety information required for the model is: incidence rates of specific events (i.e. injection site reactions, fever, somnolence, persistent crying, irritability, febrile or afebrile seizure/convulsion, hypotonic-hyporesponsive episode [HHE], extensive limb swelling) in risk and baseline periods. Incidence rates will be estimated within specific risk windows after each dose of wP or aP vaccine in pre-school children and within the periods outside the risk windows (baseline).
3. To provide calendar time specific incidence data as test for methods development in ADVANCE WP4.
Study Design: The main study design is a retrospective dynamic cohort study.
The study will be conducted utilizing electronic health care data from ADVANCE partners in different countries (i.e., Short descriptions of databases in respective coutries and their full names will be included in this protocol upon final decisions of inclusions).
In databases that cover the period in which wP was still provided, the incidence rate (IR) ratio for wP versus baseline risk will be calculated using a self-controlled case series (SCCS) design. This IR ratio will be applied to baseline rates for the aP period in databases that do not capture the wP period, to estimate the rate of events during wP in each specific database.
Population: The study population will comprise all children registered in any of the participating databases during the study period and for whom an adequate start and end of follow-up and date of birth can be defined.
Children will be followed from start of the study period, one month after date of birth (i.e. to allow for pre-vaccination time for the SCCS design and to avoid pre-term related or birth-induced increase in incidence rates), or date of valid data in the database (whichever is the latest) until the end of study period (31-12-2015, the school-entry pertussis booster, transferring out of the database, death, reaching age 6 years: whichever is the earliest).
Variables:
Exposure of interest
Any wP vaccines and aP pertussis-containing vaccines and their doses in the vaccine schedule (D1, D2, D3, D4, D5)
Outcomes
? Injection site reactions: erythema, edema, induration/nodule/sterile abscess, pain/tenderness
? Fever
? Somnolence
? Persistent crying, irritability
? Generalized convulsive seizures
? HHE
? Extensive limb swelling
Data Sources:
? Electronic health care databases (record linkage, surveillance and GP-based databases) currently available in the ADVANCE consortium and eligible are located in Denmark, Spain, Italy, The Netherlands and UK. Short descriptions of databases and their full names will be included in this protocol upon final decisions of inclusions.
Study Size: Total population (0-6 year of age) of all eligible ADVANCE databases
Data Analysis: The purpose of this study is to provide incidence rates (i.e. baseline and risk-window specific) of known adverse reactions following vaccination with pertussis-containing vaccines for use in a multi-criteria decision analysis (MCDA) model of benefits and risks of wP versus aP pertussis vaccines (models are described in a separate benefit-risk study protocol). In some more recent databases, wP information will not be captured. To generate risk-window specific incidence rates for the wP period in these databases, the IR ratio originating from an SCCS analysis of wP versus baseline in other databases will be multiplied by the baseline IR.
Informed Consent and Ethical Approval: This study will be conducted on the basis of secondary use of electronic healthcare records. Each database will apply local governance and privacy rules prior to aggregating and sharing anonymized data.
Milestones:
Draft protocol: July 31 2015
Submission to SC: August 6, 2015
Comments from SC: August 31, 2015
Submission for consortium review: September 2015
Submission to in house clearances/ governance boards: January 2016
Updated protocol after review: April 15, 2016
Final data extraction to CDM: Nov 1, 2016
Running scripts and submission to RRE: Nov 7, 2016
Data analysis: Nov 2016
Data interpretation and reporting: 30 Nov 2016
Final report of study results: January 2017

Introduction: Until now, estimates of the Global Burden of Disease have mainly been produced on national or regional levels. These estimates, however, are less useful for city governments who have to take decisions on local scales. We conducted a burden of disease (BoD) assessment and applied the Urban and Transport Planning Health Impact Assessment (UTOPHIA) tool to estimate annual preventable morbidity by complying with international exposure recommendations for the performance of physical activity, exposure to air pollution, noise, heat and access to green spaces in Barcelona.
Methods: Exposure estimates and morbidity data were available for 1357361 Barcelona residents ?20 years. We compared recommended with current exposure levels. We quantified the associations between exposures and morbidity and calculated population attributable fractions to estimate the number of morbidity cases. We also quantified the BoD attributable to non-compliant exposure levels by calculating disability-adjusted life-years (DALYs).
Results: Our estimations show that a large morbidity burden is attributable to current urban and transport planning practices in Barcelona. Non-compliance of recommended exposure levels for physical activity, air pollution, noise, heat and access to green spaces were estimated to generate almost 40,000 DALYs annually. Almost 50% of the BoD was due to road traffic noise with especially sleep disturbance and annoyance contributing largely.
Conclusions: The estimated BoD could be modified by changes to urban and transport planning related practices. We emphasize the need for (1) the reduction of motorized traffic and (2) the provision of green infrastructure to provide mitigation of noise, air pollution and heat as well as opportunities for physical activity engagement.

El presente proyecto tiene por objetivo evaluar el impacto de las actividades preventivas del cáncer de cuello uterino en Cataluña para el periodo 2008-16. Por una parte, se evaluará el impacto del programa de vacunación frente al virus del papiloma humano (VPH) a través de la monitorización de las coberturas de vacunación VPH y de la incidencia de las verrugas anogenitales y, por otra, se evaluará la cobertura del cribado del cáncer de cuello uterino en Cataluña, sus determinantes, y el impacto en las lesiones precursoras de este cáncer para el
periodo de estudio. Para evaluar el impacto de la vacunación frente al VPH en la incidencia de las verrugas anogenitales se ha diseñado un estudio de incidencia y para evaluar las estrategias de cribado frente al cáncer de cuello uterino un estudio longitudinal. Los sujetos de estudio serán aquellos asignados a los equipos de atención primaria del ICS a nivel de toda Cataluña. Debido a la introducción de la vacuna VPH, en los próximos años se espera una disminución en la incidencia de las verrugas anogenitales, y, posteriormente, una disminución de las lesiones preneoplásicas asociadas al VPH. Este proyecto permitirá, por un lado, evaluar el impacto de esta medida de salud pública en la carga de enfermedad por verrugas anogenitales y, por otro lado, evaluar la cobertura de las estrategias de cribado de cáncer de cuello uterino en Cataluña y su impacto en las lesiones precursoras de este cáncer.

EMIF plans to address the logistical challenges of developing a sustainable and scalable information framework which has the potential to access data on a scale and at a level of detail not currently available which will completely re-shape the way researchers currently approach key scientific questions and also to open avenues of research that so far have been out of reach. The current project will focus on two such research questions to provide focus and some guidance for the framework development:

Study Design & Population Method of Assessment Index period: 1st Jan 2013 – 31st Dec 2013 Study Population: Patients diagnosed with MI* and/or PAD* Index Date: Diagnosis of MI or PAD recorded during the index period Inclusion Criteria (MI patients): At least 12 months of history prior to index date (=diagnosis of 1st MI) and 12 months of follow-up post index date Inclusion Criteria (PAD patients): At least 12 months of history prior to index date (=diagnosis of 1st PAD) and 12 months of follow-up post index date Comments/Limitations For patients with both MI and PAD conditions patients will be counted in both groups Date of first MI or PAD diagnosis recorded in the EMR data by the physician during the index period (Note: this may not be the date of the acute event)

The IMI ADVANCE specific objectives guiding this POC for pertussis are:
1. Establish the feasibility of continuously updating the information on the B/R of a vaccine from the first day after a vaccine is marketed
2. Assess IMI ADVANCE platform for data availability on a routinely used vaccine in established vaccination programs covering different populations, and different schedules across countries.
3. To test and assess the level of collaboration between different stakeholders in collecting evidence and integrating evidence on the benefits and risks of vaccines
4. To assess the methods for evidence generation on safety, effectiveness, preferences and vaccination coverage using a near real-time scenario.
5. To evaluate the acceptability of the results by stakeholders for decision making on B/R.

Vaccines are one of the most effective public health measures out, saving some two to three million lives worldwide every year. However, in Europe, public distrust in immunisation programs is limiting high vaccine uptake, resulting in outbreaks of vaccine-preventable infectious diseases that had almost disappeared. Bringing together the European Centre for Disease Prevention and Control and the European Medicines Agency, as well as national public health and regulatory bodies, vaccine manufacturers and academic experts, the ADVANCE project will develop and test methods and guidelines in order to pave the way for a framework capable of rapidly delivering reliable data on the benefits and risks of vaccines that are on the market. This framework should both help regulators and public health authorities make decisions on vaccination strategies, and help maintain public confidence in immunisation as an effective public health tool to control infectious disease.

Immunisation prevents two to three million deaths worldwide every year from diseases such as diphtheria, tetanus, pertussis (whooping cough) and measles. Millions more are spared the long-term health consequences of vaccine-preventable infectious diseases; the WHO estimates that due to the Global Polio Eradication Initiative, five million people are walking today who would otherwise have been paralysed by the virus.

In Europe, one of the greatest barriers to the wider uptake of immunisation is distrust, among some sections of the public, of immunisation programmes. This is due largely to fears surrounding vaccine safety. In fact, serious side effects are very rare. Nevertheless, as vaccines are given to healthy people, public acceptance of the risk of any adverse reaction is much lower than for medicines designed to treat sick people; the trade-off between benefit and risk is different.
At the same time, some vaccines have been around for so long that many people have no personal experience of the diseases prevented, and so are unaware of just how serious the illness can be.

Una de les línies de treball interna de SIDIAP és la validació dels diagnòstics de les patologies registrades en la plataforma. Alguns diagnòstics, com ara algunes patologies cardiovasculars o de l’aparell musculoesquelètic han estat validades mitjançant la comparació amb registres poblacionals (REGICOR) o amb el Registre d’Artroplàsties de Catalunya, respectivament.
En el context dels processos de validació interna de SIDIAP s’adjunta aquest projecte, que és la tercera fase de la validació de diversos tipus de càncer de la plataforma SIDIAP. Es proposa una metodologia de validació directa amb els metges de capaçalera (feed-back).
En el projecte participarien dos centres d’Atenció Primària que pertanyen a l’àrea de captació de casos de càncer del Regsitre del Hospital del Mar: el CAP Clot i el CAP Ciutat Vella. La metodologia proposada seria que els metges d’atenció primària, mitjançant, una pregunta en la història clínica electrònica, validessin el diagnòstic registrat de càncer dels pacients de SIDIAP que no van creuar amb el Registre de l’Hospital del Mar. La informació es recollirà de manera agregada i en cap moment es transmetrà dades de tipus individual al Registre de Càncer de l’Hospital del Mar.
Es preveu utiiltzar el suport tècnic i el procediment estàndar que disposa SISAP per tal de reclutar individus amb l’objectiu de participar en assajos clínics.