Overview of the European post-authorisation study register post-authorization studies performed in Europe from September 2010 to December 2018.

BACKGROUND: The European post-authorisation study (EU PAS) register is a repository launched in 2010 by the European Medicines Agency (EMA). All EMA-requested PAS, commonly observational studies, must be recorded in this register. Multi-database studies (MDS) leveraging secondary data have become an important strategy to conduct PAS in recent years, as reflected by the type of studies registered in the EU PAS register. OBJECTIVES: To analyse and describe PAS in the EU PAS register, with focus on MDS. METHODS: Studies in the EU PAS register from inception to 31st December 2018 were described concerning transparency, regulatory obligations, scope, study type (e.g., observational study, clinical trial, survey, systematic review/meta-analysis), study design, type of data collection and target population. MDS were defined as studies conducted through secondary use of >1 data source not linked at patient-level. Data extraction was carried out independently by 14 centres with expertise in pharmacoepidemiology, using publicly available information in the EU PAS register including study protocol, whenever available, using a standardised data collection form. For validation purposes, a second revision of key fields for a 15% random sample of studies was carried out by a different centre. The inter-rater reliability (IRR) was then calculated. Finally, to identify predictors of primary data collection-based studies/versus those based on secondary use of healthcare databases) or MDS (vs. non-MDS), odds ratios (OR) and 95% confidence intervals (CI) were calculated fitting univariate logistic regression models. RESULTS: Overall, 1426 studies were identified. Clinical trials (N = 30; 2%), systematic reviews/meta-analyses (N = 16; 1%) and miscellaneous study designs (N = 46; 3%) were much less common than observational studies (N = 1227; 86%). The protocol was available for 63% (N = 360) of 572 observational studies requested by a competent authority. Overall, 36% (N = 446) of observational studies were based fully or partially on primary data collection. Of 757 observational studies based on secondary use of data alone, 282 (37%) were MDS. Drug utilisation was significantly more common as a study scope in MDS compared to non-MDS studies. The overall percentage agreement among collaborating centres that collected the data concerning study variables was highest for study type (93.5%) and lowest for type of secondary data (67.8%). CONCLUSIONS: Observational studies were the most common type of studies in the EU PAS register, but 30% used primary data, which is more resource-intensive. Almost half of observational studies using secondary data were MDS. Data recording in the EU PAS register may be improved further, including more widespread availability of study protocols to improve transparency.

Incidence, risk factors and re-exacerbation rate of severe asthma exacerbations in a multinational, multidatabase pediatric cohort study.

BACKGROUND: There are sparse real-world data on severe asthma exacerbations (SAE) in children. This multinational cohort study assessed the incidence of and risk factors for SAE and the incidence of asthma-related rehospitalization in children with asthma. METHODS: Asthma patients 5-17 years old with ≥1 year of follow-up were identified in six European electronic databases from the Netherlands, Italy, the UK, Denmark and Spain in 2008-2013. Asthma was defined as ≥1 asthma-specific disease code within 3 months of prescriptions/dispensing of asthma medication. Severe asthma was defined as high-dosed inhaled corticosteroids plus a second controller. SAE was defined by systemic corticosteroids, emergency department visit and/or hospitalization all for reason of asthma. Risk factors for SAE were estimated by Poisson regression analyses. RESULTS: The cohort consisted of 212 060 paediatric asthma patients contributing to 678 625 patient-years (PY). SAE rates ranged between 17 and 198/1000 PY and were higher in severe asthma and highest in severe asthma patients with a history of exacerbations. Prior SAE (incidence rate ratio 3-45) and younger age increased the SAE risk in all countries, whereas obesity, atopy and GERD were a risk factor in some but not all countries. Rehospitalization rates were up to 79% within 1 year. CONCLUSIONS: In a real-world setting, SAE rates were highest in children with severe asthma with a history of exacerbations. Many severe asthma patients were rehospitalized within 1 year. Asthma management focusing on prevention of SAE is important to reduce the burden of asthma.

Characterization of Asthma by Age of Onset: A Multi-Database Cohort Study.

BACKGROUND: Asthma can occur at any age but the differences in patient characteristics between childhood-, adult-, and late-onset asthma are not well understood. OBJECTIVE: To investigate differences in patients' characteristics by age at asthma onset. METHODS: From 5 European electronic databases, we created a cohort encompassing adult patients with doctor-diagnosed asthma in 2008 to 2013. Patients were categorized based on their age at asthma onset: childhood-onset (age at onset < 18 y), adult-onset (age at onset 18-40 y), and late-onset asthma (age at onset ≥ 40 y). Comorbidities were assessed at study entry. For each characteristic and comorbidity, odds ratios and age- and sex-adjusted odds ratios (ORadj) comparing asthma-onset categories were estimated per database and combined in a meta-analysis using a random effect model. RESULTS: In total, 586,436 adult asthma patients were included, 81,691 had childhood-onset, 218,184 adult-onset, and 286,561 late-onset asthma. Overall, 7.3% had severe asthma. Subjects with adult-onset compared with childhood-asthma had higher risks for overweight/obesity (ORadj 1.4; 95% CI 1.1-1.8) and lower risks for atopic disorders (ORadj 0.8; 95% CI 0.7-0.95). Patients with late-onset compared with adult-onset asthma had higher risks for nasal polyposis (ORadj 1.8; 95% CI 1.2-2.6), overweight/obesity (ORadj 1.3; 95% CI 1.2-1.4), gastroesophageal reflux disease (ORadj 1.4; 95% CI 1.2-1.7), and diabetes (ORadj 2.3; 95% CI 1.8-2.9). A significant association between late-onset asthma and uncontrolled asthma was observed (ORadj 2.8; 95% CI 1.7-4.5). CONCLUSIONS: This international study demonstrates clear differences in comorbidities between childhood-, adult-, and late-onset asthma phenotypes in adults. Furthermore, patients with late-onset asthma had more frequent uncontrolled asthma.

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

INTRODUCTION: As asthma medications are frequently prescribed for children, knowledge of the safety of these drugs in the paediatric population is important. Although spontaneous reports cannot be used to prove causality of adverse events, they are important in the detection of safety signals. OBJECTIVE: Our objective was to provide an overview of adverse drug events associated with asthma medications in children from a spontaneous reports database and to identify new signals. METHODS: Spontaneous reports concerning asthma drugs were obtained from EudraVigilance, the European Medicine Agency's database for suspected adverse drug reactions. For each drug-event combination, we calculated the proportional reporting ratio (PRR) in the study period 2011-2017. Signals in children (aged 0-17 years) were compared with signals in the whole population. Analyses were repeated for different age categories, by sex and by therapeutic area. RESULTS: In total, 372,345 reports in children resulted in 385 different signals concerning asthma therapy. The largest group consisted of psychiatric events (65 signals). Only 30 signals were new, with seven, including herpes viral infections, associated with omalizumab. Stratification by age, sex and therapeutic area provided additional new signals, such as hypertrichoses with budesonide and encephalopathies with theophylline. Of all signals in children, 60 (16%) did not appear in the whole population. CONCLUSIONS: The majority of signals regarding asthma therapy in children were already known, but we also identified new signals. We showed that signals can be masked if age stratification is not conducted. Further exploration is needed to investigate the risk and causality of the newly found signals.

Hair cortisol and inhaled corticosteroid use in asthmatic children.

BACKGROUND: Adrenal suppression is a side effect of long-term use of inhaled corticosteroids (ICS). Hair cortisol concentration (HCC) measurement is a noninvasive tool for measuring adrenal function that may be useful for asthmatic patients who are on long-term ICS treatment. The aim of this study was to compare HCC between children with and without asthma and to explore the association between HCC and ICS dose in asthmatic children. METHODS: A cross-sectional observational study in subjects with or without asthma (n = 72 and 226, respectively, age 6-21 years). Hair samples were obtained from the posterior vertex for each subject and data on medication use were collected using questionnaires. HCC was analyzed by liquid chromatography-mass spectrometry in the most proximal 3 cm of hair. RESULTS: Median HCC was significantly lower in subjects with asthma than in subjects without asthma: 1.83 pg/mg and 2.39 pg/mg, respectively (P value after adjustment for age, sex, and body mass index: .036). Median HCC was 1.98 pg/mg in asthmatics using no ICS, 1.84 pg/mg in those using a low dose, 1.75 pg/mg in those on a medium dose, and 1.46 in those using a high ICS dose (P = .54). CONCLUSION: We observed a significantly lower HCC in asthmatics than in healthy controls and a nonsignificant trend of lower HCC with increasing ICS dose. Whether HCC measurement may be used to detect individuals at risk for hypocortisolism and may be useful to monitor adrenal function in asthmatic children using ICS needs to be further investigated.

Trends of prescribing antimicrobial drugs for urinary tract infections in primary care in the Netherlands: a population-based cohort study.

OBJECTIVE: Urinary tract infections (UTIs) are an important reason to consult a general practitioner (GP). Here, we describe antimicrobial drug prescribing patterns for UTIs by GPs in relation to the Dutch primary care guidelines. METHODS: We conducted a population-based cohort study in the Dutch Integrated Primary Care Information (IPCI)database, which encompasses approximately 2.5 million patients. All patients aged ≥12 years with at least 1 year of follow-up from 1996 to 2014 were extracted from the database. The number of prescriptions and choice of drug type were investigated over time and in different age categories. The choice of antimicrobial drug classes for UTIs and the duration of nitrofurantoin use in women were compared with the Dutch primary care guidelines of 1989, 1999, 2005 and 2013. RESULTS: The source population comprised 1 755 085 patients who received 2 019 335 antimicrobial drug prescriptions; 401 655 (35.1%) prescriptions were for UTIs (45.2% in women and 12.6% in men). The proportion of prescriptions for UTIs within all prescriptions with an indication code increased from 5.2% in 1996 to 14% in 2014 in men and from 28% in 1996 to 50% in 2014 in women. In men, UTIs were most frequently treated with fluoroquinolones during the entire study period, whereas fluoroquinolones were only advised as first choice in the latest guideline of 2013. In women, UTIs were increasingly (p<0.05) treated with nitrofuran derivatives with a statistically significant difference after implementation of the guideline of 2005. Compliance to the advised duration of nitrofurantoin prescriptions in women has increased since the guideline of 2005. CONCLUSIONS: Antimicrobial drug prescribing for UTIs seemed to have increased over time. Prescribing in line with the UTI guidelines increased with regard to choice and duration of antimicrobial drugs. We showed that databases like IPCI, in which prescription and indication are monitored, can be valuable antibiotic stewardship tools.

Antibiotic use in children with asthma: cohort study in UK and Dutch primary care databases.

OBJECTIVES: To compare the rate, indications and type of antibiotic prescriptions in children with and without asthma. DESIGN: A retrospective cohort study. SETTING: Two population-based primary care databases: Integrated Primary Care Information database (IPCI; the Netherlands) and The Health Improvement Network (THIN; the UK). PARTICIPANTS: Children aged 5-18 years were included from January 2000 to December 2014. A child was categorised as having asthma if there were ≥2 prescriptions of respiratory drugs in the year following a code for asthma. Children were labelled as non-asthmatic if no asthma code was recorded in the patient file. MAIN OUTCOME MEASURES: Rate of antibiotic prescriptions, related indications and type of antibiotic drugs. RESULTS: The cohorts in IPCI and THIN consisted of 946 143 and 7 241 271 person years (PY), respectively. In both cohorts, antibiotic use was significantly higher in asthmatic children (IPCI: 197vs126 users/1000 PY, THIN: 374vs250 users/1000 PY). In children with asthma, part of antibiotic prescriptions were for an asthma exacerbation only (IPCI: 14%, THIN: 4%) and prescriptions were more often due to lower respiratory tract infections then in non-asthmatic children (IPCI: 18%vs13%, THIN: 21%vs12%). Drug type and quality indicators depended more on age, gender and database than on asthma status. CONCLUSIONS: Use of antibiotics was higher in asthmatic children compared with non-asthmatic children. This was mostly due to diseases for which antibiotics are normally not indicated according to guidelines. Further awareness among physicians and patients is needed to minimise antibiotic overuse and limit antibiotic resistance.

Sex-specific differences in fetal and infant growth patterns: a prospective population-based cohort study.

BACKGROUND: The objective of this study was to assess whether sex-specific differences in fetal and infant growth exist. METHODS: This study was embedded in the Generation R Study, a population-based prospective birth cohort. In total, 8556 live singleton births were included. Fetal growth was assessed by ultrasound. During the first trimester, crown-rump-length (CRL) was measured. In the second and third trimester of pregnancy head circumference (HC), abdominal circumference (AC) and femur length (FL) were assessed. Information on infant growth during the first 2 years of life was obtained from Community Health Centers and included HC, body weight and length. RESULTS: In the first trimester, male CRL was larger than female CRL (0.12 SD [95% CI 0.03,0.22]). From the second trimester onwards, HC and AC were larger in males than in females (0.30 SD [95% CI 0.26,0.34] and 0.09 SD [95% CI 0.05,0.014], respectively). However, FL in males was smaller compared to female fetuses (0.21 SD [95% CI 0.17,0.26]). Repeated measurement analyses showed a different prenatal as well as postnatal HC growth pattern between males and females. A different pattern in body weight was observed with a higher body weight in males until the age of 12 months where after females have a higher body weight. CONCLUSIONS: Sex affects both fetal as well as infant growth. Besides body size, also body proportions differ between males and females with different growth patterns. This sexual dimorphism might arise from differences in fetal programming with sex specific health differences as a consequence in later life.