Stella Blackburn

Evaluation of post-authorization safety studies in the first cohort of EU Risk Management Plans at time of regulatory approval.

AbstractBackgound: Since November 2005, an EU Risk Management Plan (EU-RMP) has had to be submitted as part of a marketing application for all new chemical entities in the EU. In the EU-RMP, the safety profile of the medicine has to be described and pharmacovigilance activities should be proposed to study further safety concerns during use of the drug in the real-world setting. These activities include, for example, collection of spontaneously reported adverse events and post-authorization safety studies (PASS). Since the submission of an EU-RMP is a relatively new requirement, there is limited knowledge on the quality and completeness of the study protocols of PASS at the time of approval and there are no data on the influence of certain drug characteristics on the proposed pharmacovigilance activities.n Objective: To examine the types of proposed pharmacovigilance activities in a sample of EU-RMPs, describe and evaluate the methodology of PASS, identify problems and propose remedies, and compare characteristics between biologicals and small molecules.n Methods: Eighteen EU-RMPs (nine for biologicals, nine for small molecules) given a positive decision regarding the marketing application by the Committee for Medicinal Products for Human Use between November 2005 and May 2007 were included in this descriptive cohort study. The EU-RMPs were selected over time and different therapeutic areas. Classification of the safety concerns (‘important identified risks’, ‘important potential risks’, ‘important missing information’ within the EU-RMP was studied. For PASS, data source (registry, population-based database, sponsor-owned clinical trial database), source of study population to be included in PASS and comprehensiveness of study protocol (full protocol, limited protocol, study synopsis, short description, commitment without further information) were studied.n Results: Compared to small molecules, safety concerns for biologicals were less frequently classified as important identified risks (relative risk [RR] 0.6; 95% CI 0.3, 1.0) and more frequently as important missing information (RR 1.6; 95% CI 1.0, 2.7).Forty-seven PASS were proposed; 31 for biologicals and 16 for small molecules. Compared with studies proposed in population-based databases (4 for biologicals, 8 for small molecules), studies in registries (18 for biologicals, 4 for small molecules) were more frequently proposed for biologicals than for small molecules (RR 2.5; 95% CI 1.1, 5.7). About 60% of the proposed PASS will include EU inhabitants. No full study protocols were submitted; 26% involved a limited study protocol, 33% a study synopsis, 37% a short description and 4% a commitment without further information.n Conclusion: Approximately 40% of the study proposals for PASS were classified as a short description or a commitment to perform a study without further information, precluding an adequate scientific assessment. Study ing non-EU populations may give rise to difficulties with generalizability of the results to the EU due to differences in patient characteristics, differences in the indication for the medicine and different healthcare systems. This study emphasizes the need for more complete study proposals to be submitted earlier on in the evaluation period and for the inclusion of EU inhabitants in PASS. In addition, differences in the characteristics between biologicals and small molecules, e.g. in the data source proposed, support the need for individualized tailored PASS depending on the type of drug.

European Medicines Agency review of post‐authorisation studies with implications for the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance

A review of post‐authorisation studies requested in 2007 by the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) was undertaken to determine compliance and the need for research capacity in the European Union (EU), with implications for the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP).

Risk minimization activities of centrally authorized products in the EU: A descriptive study

AbstractBackground: Since the new legislation on risk management, which came into force in November 2005, an EU Risk Management Plan (EU-RMP) is a required part of the authorization dossier of innovative drugs licensed in the EU. The EU-RMP can include additional risk minimization activities (RMAs) to strengthen the benefit-risk balance of a drug. This study describes the additional RMAs of centrally authorized medicinal products authorized between 1 January 1995 and 1 January 2010.n Methods: The European Public Assessment Reports of all centrally authorized products were analysed to identify characteristics of the product (active substance, authorization date, Anatomical Therapeutic Chemical classification), the additional RMAs and the corresponding safety concerns (classified at Medical Dictionary for Regulatory Activities (MedDRA®) System Organ Class level).n Results: Additional RMAs were identified for 58 of the 391 active substances that were authorized as of 1 January 2010. The proportion of active substances with additional RMAs was 5% among those authorized before, and 29% among those approved after the new risk management legislation. Since the new legislation, blood products and antineoplastic and immunomodulating agents most often had additional RMAs. All active substances with additional RMAs required the provision of educational material, most frequently involving healthcare professionals (n = 57) and the patient (n = 31). Thirty-three active substances required additional RMAs on top of the provision of educationalmaterial,most frequently including patientmonitoring and screening (n = 19).n Conclusions: The proactive pharmacovigilance approach is evolving and the number of products with additional RMAs is growing since the introduction of the EU-RMP. The provision of educational material is the primary additional risk minimization strategy in the EU. The effect of additional RMA implementation has to be explored.

Lessons learned on the design and the conduct of Post-Authorization Safety Studies: review of 3 years of PRAC oversight.

AIMS To describe and characterize the first cohort of Post‐Authorization Safety Study (PASS) protocols reviewed under the recent European pharmacovigilance legislation. METHODS A systematic approach was used to compile all publicly available information on PASS protocols and assessments submitted from July 2012 to July 2015 from Pharmacovigilance Risk Assessment Committee (PRAC) minutes, European Medicines Agency (EMA) and European Network of Pharmacovigilance and Pharmacoepidemiology (ENCePP) webpages. RESULTS During the study period, 189 different PASS protocols were submitted to the PRAC, half of which were entered in the ENCePP electronic register of post‐authorization studies (EU‐PAS) by July 2015. Those protocols were assessed during 353 PRAC reviews. The EMA published only 31% of the PRAC feedback, of which the main concerns were study design (37%) and feasibility (30%). Among the 189 PASS, slightly more involved primary data capture (58%). PASS assessing drug utilization mainly leveraged secondary data sources (58%). The majority of the PASS did not include a comparator (65%) and 35% of PASS also evaluated clinical effectiveness endpoints. CONCLUSIONS To the best of our knowledge this is the first comprehensive review of three years of PASS protocols submitted under the new pharmacovigilance legislation. Our results show that both EMA and PASS sponsors could respectively increase the availability of protocol assessments and documents in the EU‐PAS. Protocol content review and the high number of PRAC comments related to methodological issues and feasibility concerns should raise awareness among PASS stakeholders to design more thoughtful studies according to pharmacoepidemiological principles and existing guidelines.

Direct-to-Patient Research: Piloting a New Approach to Understanding Drug Safety During Pregnancy.

Background Little is known about the effects of human fetal exposure when a new drug is authorized unless it was specifically developed for use in pregnancy. Since many factors may contribute to adverse fetal effects, having comprehensive information about in utero exposures will enhance our ability to make correct determinations about causality. Objective The objective of the study was to assess the extent to which women, recruited without the intervention of health care professionals (HCPs), will provide information, suitable for research purposes, via the Internet or by phone on some potential risk factors in pregnancy. Methods To pilot direct-to-patient research for pharmacovigilance, we conducted a prospective, noninterventional study of medication use and lifestyle factors as part of the Pharmacoepidemiological Research on Outcomes of Therapeutics by a European ConsorTium (PROTECT) Consortium. Consenting women who self-identified as pregnant and residing in the United Kingdom (UK), Denmark (DK), The Netherlands, or Poland were recruited and could then choose to provide data every 2 or 4 weeks via the Internet or a telephonic interactive voice response system (IVRS). Self-reported drug use was compared with pharmacy register data in DK and with electronic health records in the UK. Results Recruited women were on average older and more highly educated than the general population. Most respondents chose a frequency of every 4 weeks (56.99%, 1177/2065). Only 29.83% (464/1555) of women with due dates occurring during the study provided information on pregnancy outcome. For those responding by Internet, over 90.00% (1915/2065) reported using >1 pregnancy-related medication, 83.34% (1721/2065) reported using >1 other medicine, and 23.53% (486/2065) reported only over-the-counter medications, not counting herbals and dietary supplements. Some respondents (7.16%, 148/2065) reported that they chose not to take a prescribed medication (mostly medicines for pain or inflammation, and for depression) and 1.30% (27/2065) reported using medicines that had been prescribed to a friend or family member (oxycodone, paracetamol, and medications for acid-related problems). Relatively few respondents reported using fish oil (4.60%, 95/2065), other dietary supplements (1.88%, 39/2065), herbal products (7.07%, 146/2065), or homeopathic products (1.16%, 24/2065). Most medications for chronic conditions that were listed in the Danish prescription registry were also self-reported (83.3%, 145/174 agreement), with larger discrepancies for medications indicated for short-term use (54.0%, 153/283 agreement) and pregnancy-related medications (66.1%, 78/118). Conclusions Self-reported information on medication use as well as other potential teratogenic factors can be collected via the Internet, although recruitment costs are not insubstantial and maintaining follow-up is challenging. Direct data collection from consumers adds detail, but clinical input may be needed to fully understand patients’ medical histories and capture birth outcomes.

Balancing the Interests of Patient Data Protection and Medication Safety Monitoring in a Public-Private Partnership

Obtaining data without the intervention of a health care provider represents an opportunity to expand understanding of the safety of medications used in difficult-to-study situations, like the first trimester of pregnancy when women may not present for medical care. While it is widely agreed that personal data, and in particular medical data, needs to be protected from unauthorized use, data protection requirements for population-based studies vary substantially by country. For public-private partnerships, the complexities are enhanced. The objective of this viewpoint paper is to illustrate the challenges related to data protection based on our experiences when performing relatively straightforward direct-to-patient noninterventional research via the Internet or telephone in four European countries. Pregnant women were invited to participate via the Internet or using an automated telephone response system in Denmark, the Netherlands, Poland, and the United Kingdom. Information was sought on medications, other factors that may cause birth defects, and pregnancy outcome. Issues relating to legal controllership of data were most problematic; assuring compliance with data protection requirements took about two years. There were also inconsistencies in the willingness to accept nonwritten informed consent. Nonetheless, enrollment and data collection have been completed, and analysis is in progress. Using direct reporting from consumers to study the safety of medicinal products allows researchers to address a myriad of research questions relating to everyday clinical practice, including treatment heterogeneity in population subgroups not traditionally included in clinical trials, like pregnant women, children, and the elderly. Nonetheless, there are a variety of administrative barriers relating to data protection and informed consent, particularly within the structure of a public-private partnership.

The European Network of Centres for Pharmacoepidemiology and Pharmacovigilance: application to diabetes and vascular disease

The European Network of Centres for Pharmacoxad epidemiology and Pharmacovigilance (ENCePP) is an initiative led by the European Medicines Agency (EMA) aimed at further strengthening the postxad authorisation monitoring of medicinal products in Europe by facilitating the undertaking of multixadcentre, independxad ent, studies focusing on safety and on benefit/risk. A key objective of ENCePP is to provide a unique point of access for all involved stakeholders, including industry or regulatory authorities, who are seeking collaboration for the commissioning or the performance of postxad authorisation studies. The 2010 EMA regulatory action relating to rosiglitazone included a pharmacoepidemioxad logical drug utilisation study to evaluate the benefit–risk profile in a realxadlife setting and has also led to the commissioning of an ENCePP study to evaluate the impact of riskxadminimisation activities. ENCePP seeks to improve the European Union capacity to conduct such studies and thus support decision making. Application of the ENCePP study concept will result in an increase in trust in medicines and their use. In addition, the ENCePP register of studies will serve as a resource to allow for ready access to study protocols and results, thereby ensuring transparency. Br J Diabetes Vasc Dis 2011;11:304-307.

Benefit Risk Management Plans

A medicinal product is authorized on the basis that in the specified indication(s), at the time of authorization, the benefit–risk balance is positive for the target population. However, it is accepted that, for many reasons, not all risks will have been identified at the time the medicine is authorized and many will only be discovered or fully characterized post-authorization. It was on this basis that the regulatory requirement for risk management plans (RMPs) was originally introduced. The safety specification of the RMP describes what is known, and not known (including missing information), about the safety profile of the medicine and summarizes the safety concerns with the product. The pharmacovigilance plan details how these safety concerns will be further identified and characterized, whilst the risk minimization plan describes measures to minimize and mitigate the risks where possible. RMPs came into regulatory use in Europe in November 2005 following the revision of the pharmaceutical legislation and the adoption of the International Conference on Harmonisation (ICH) guideline on pharmacovigilance planning—ICH E2E [1]. Although many companies had had some form of risk management in place for some years, this was the first time that companies were required to formally submit the plans for certain products to the regulatory authorities for evaluation as part of the marketing application. Whereas ICH E2E included the safety specification and the planning of post-authorization phar-macovigilance activities, the EU RMP also included risk minimization measures. The introduction of RMPs in the EU was tempered so they were required only where appropriate [2]. In practice, where appropriate approximated to all new active substances, biological medicines and significant changes to a marketing authorization. In 2010, a major revision to the EU pharmacovig-ilance legislation led to the requirement for all new marketing applications to include the risk management plan describing the risk management system which the applicant will introduce for the medicinal product concerned , together with a summary thereof [3, 4]. The new legislation is supported by an update to guidance on the conduct of pharmacovigilance in the EU. The European Medicines Agency, in cooperation with the national competent authorities, is publishing Good Phar-macovigilance Practices (GVP) in a series of modules addressing different facets of pharmacovigilance [5]. The module on risk management systems is already published and provides for the RMP also to have a modular structure consisting of seven parts [6]. Directive 2001/83 states in its recital (which explains the legally …

Direct-from-Patient Information on Medication Use

Background: One previous study of our group reported that acid suppressive drug use during pregnancy is associated with an increased risk for the development of atopic dermatitis in children. However, reported associations could have been confounded by unmeasured risk factors. Objectives: The aim of this study was to assess the association between prenatal exposure to acid-suppressive drugs and the development of atopic dermatitis in children by using a confounding minimizing crossover design. Methods: We conducted a bidirectional case-crossover study within the Clinical Practice Research Database in which 1,445 children with atopic dermatitis were randomly matched to one of their own siblings without atopic dermatitis. Children were defined as having atopic dermatitis if they had a diagnosis of atopic dermatitis and at least 3 prescriptions for ointments containing steroids or calcineurin inhibitors in the year after diagnosis. We applied conditional logistic regression to compute odds ratios (ORs) and 95% confidence intervals (95%CI). Results: The percentage of exposure to acid suppressive drugs amongst cases was 21.5% compared to 18.8% amongst controls. After adjustments for gender, birth order and maternal age at delivery the exposure to any acid suppressive drug during pregnancy increased the odds for developing atopic dermatitis by 34% (aOR 1.34; 95%CI: 1.05-1.71). Though not significant, exposure to the subgroup proton pump inhibitors conferred an increased risk of 72% (aOR 1.72 95% CI: 0.62-4.79). Conclusions: This study supports previous findings of a small association between gastric acid suppression during pregnancy and the development of atopic dermatitis in children.Background: After extensive media attention on thromboembolic adverse drug reactions (TE-ADRs) and the use of cyproterone/ethinylestradiol (CE), the Netherlands Pharmacovigilance Centre Lareb received a high number of reports about this association, which prompted for detailed analyses. Objectives: To analyse reports of thromboembolic events associated with the use of cyproterone/ ethinylestradiol submitted to Lareb, focusing on the indication of use, presence of risk factors and time between the initial symptoms and the actual diagnosis of the TE. Methods: Reports submitted to Lareb till 11 February 2014 were analysed. The analysis was focussed on reporter type, seriousness of the reaction, age of the patient, BMI, indication, ADRs classified as arterial thrombosis and venous thrombosis, pulmonary embolism, latency period, outcome of the reaction, treatment of the ADR, delay between the first symptoms and diagnosis of the ADR, presence of risk factors. Results: On 11 February 2014, Lareb had received a total of 786 reports about CE, including 41 cases with a fatal outcome. Of all reports, 438 reports considered TE-ADRs which were analysed in more detail. Reported ADRs consisted of arterial thrombosis (N = 74), venous thrombosis (N = 63), pulmonary embolism (N = 219) and thrombosis with an unspecified location (N = 172). Patients mean age was 30.5 years (range 14-57 years). The primary indications for use were acne (N = 193), oral contraceptive (N = 181), hirsutism (N = 13), other (N = 18) or the indication was unknown (N = 33). The median time to onset was 4 years, although many patients reported a longer latency period. There was no distinction between the time of onset in respect to the reported ADR. No differences in risk factors seem to exist between labeled and off-label indications. In 382 out of 438 reports (87%), the reporter was a consumer. Some reports mentioned the fact that thrombosis or embolism were not recognized in an early stage. Conclusions: The reported thromboembolic ADRs are a known risk related to the use of CE, but may be misdiagnosed initially. From the reports that Lareb received it is evident that off-label use is frequent.Background: Recent studies have reported an increased risk of asthma in children after prenatal exposure to antibiotics, notably during third trimester due to altered vaginal bacterial flora. Associations could have been influenced by unmeasured confounders. Objectives: To assess the association between antibiotic use during pregnancy and the development of toddler asthma with a confounding minimizing crossover(casesibling) design. Secondary we wanted to assess the influence of time-invariant confounding by comparing results with a case-control design. Methods: We conducted this study using a linked mother-infant subset of the University Groningen prescription database IADB.nl. We conducted both a crossover study in which 1,228 children with asthma were compared to their own siblings without asthma, and a traditional matched case-control study. Maternal exposure was defined as at least 1 day of supply of systemic antibiotics during pregnancy. Children were considered to have asthma if they received at least 3 prescriptions for anti-asthma medication within a year before the fifth birthday. Conditional logistic regression was used to estimate crude and adjusted odds ratios (aOR). Sensitivity analyses were performed to estimate the potential influence of unobserved timevarying confounders. Results: The crossover analysis only showed an increase in the toddlers asthma risk if antibiotics were used in the third trimester of pregnancy (aOR 1.37 (95%CI 1.02-1.83)). The matched case-control study yielded a similar increase in the toddlers asthma risk after exposure in the third trimester (aOR 1.40(95%CI 1.15-1.47)). In addition, use of antibiotics, independent of trimester of pregnancy, was associated with an aOR of 1.46 (95%CI 1.33-1.58) in the matched case-control study. Conclusions: Prenatal exposure to antibiotics in the third trimester of pregnancy is associated with a small increased risk of childhood asthma. This association did not appear to be influenced by time-invariant confounders such as genetic predisposition. However the influence of time-variant confounders, such as disease severity, cannot be ruled out.Background: The use of anti-epileptic drugs (AEDs) during pregnancy is associated with an increased risk of birth defects. Since epilepsy itself is also associated with potential risks for mother and child, an optimal AED treatment is needed. Over the past years, the introduction of new AEDs and the amendments of guidelines have changed the use of AEDs in this vulnerable group of patients. The extend of the changes over time in the Netherlands has not been studied before. Objectives: To compare the use of different AEDs in pregnant women over the past 10 years in the Netherlands. Methods: This retrospective cohort study data is based on data from the register that is being used to submit Dutch cases to the EURAP study. Pregnancies were included in which women were exposed to an AED between January 2003 and December 2012 either preconceptionally or during the first trimester. Binary logistic regression analysis was used to compare the proportion of various AEDs annually. Dependent variable was the year in which conception took place; the AED and type of epilepsy were covariates. In addition, the mean number of concomitantly used AEDs were calculated per year and analyzed by ANOVA. Results: A total number of 1,733 pregnancies in were included in the analysis. The proportion of use of levetiracetam and lamotrigine showed an upwards trend from 6.2 and 16.0% in 2003 till 25.0 and 33.5% in 2012, with corresponding adjusted Odds Ratio (OR) of 4.89 (95% CI 2.65-9.06) and 2.77 (95% CI 1.76-4.34) respectively. The proportion of use of valproate and carbamazepine decreased from 28.4 and 28.4% in 2003 till 9.3 and 17.3% in 2013, with an adjusted OR of 0.28 (95% CI 0.16-0.48) and from 0.44 (95%CI 0.28-0.70) respectively. The use of other miscellaneous AEDs decreased from 20.9% to 14.9%, OR 0.61 (95%CI 0.38-0.98). The average number of AEDs being used was 1.30 in 2003 and 1.24 in 2012 (p>0.05). Conclusions: The use of relatively safer AEDs gradually increased over the past 10 years compared to drugs more frequently associated with congenital defects. The mean number of AEDs used remained stable of the years. Our findings are in line with advice provided in the literature on the use of AEDs.Background: This study was part of the Pharmacoepidemiological Research on Outcomes (PROTECT) project which aims at monitoring of the benefit-risk of medicines in Europe. Few epidemiological studies have investigated the association between calcium channel blockers (CCB) and cancer, and have provided contradictory evidence. Objectives: To investigate whether CCB exposure is associated with cancer risk and whether the risk varies according to cancer subtype and duration of exposure. Methods: A population-based matched-cohort study was conducted using data from the Clinical Practice Research Datalink and National Cancer Registration System. Eligible patients (18 to 79 years, over two years primary care and prescription history) with ≥1 CCB prescription between 1996 and 2009 (CCBC) were compared with two CCB unexposed cohorts: 1) patients without CCB exposure (NCCBC), and; 2) patients with no CCB and ≥1 other antihypertensive prescription (AHTC). CCBC was compared with NCCBC and AHTC according to cancer outcomes. Conditional logistic cox-regression models estimated multivariable hazard ratios (HR) and 95% confidence intervals (CI). Results: There were 150,750 patients in the CCBC, 557,931 in the NCCBC, and 156,966 in the AHTC. Cancer rates (crude per 1000 person-years) were 16.51, 15.75 and 10.62 for the CCBC, NCCBC and AHTC respectively. Adjusted HRs (CI) of all cancer for the CCBC compared to the NCCBC and AHTC were 0.88 (0.86-0.89) and 1.01 (0.98-1.04) respectively. Adjusted HRs (CI) of breast, prostate, and colon cancer for the CCBC compared to the AHTC were 0.95 (0.87-1.04), 1.07 (0.98-1.16) and 0.89 (0.81-0.98) respectively. Adjusted HRs (CI) of all cancer for the CCBC compared to the NCCBC were 0.88 (0.85-0.91), 0.98 (0.93-1.04), and 1.11 (0.98-1.27) for 0 to 5years, 5 to 10years, and ≥10 years of cumulative drug exposure respectively. Conclusions: This study showed strong evidence that CCB use is not associated with cancer. Shorter periods of CCB exposure showed a small protective effect for cancer, as did CCB exposure for colon cancer. Results will be discussed in relation to other findings from PROTECT work package two.Background: Instrumental variable (IV) analysis with physicians prescribing preference (PPP) as an IV has been used to control for unobserved confounding in pharmacoepidemiology. PPP can be defined in several ways, but it is unclear how different PPPs perform across databases. Objectives: To assess the validity of the IV PPP in two general practice (GP) databases in the study of inhaled long-acting beta2-agonist (LABA) use and the risk of acute myocardial infarction (AMI). Methods: Information on adult patients with a diagnosis of asthma and/or COPD and at least one prescription of an inhaled short-acting beta2-agonist (SABA)/LABA/ muscarinic antagonist (MA) was extracted from the British Clinical Practice Research Datalink (CPRD, n = 490499), and the Dutch Mondriaan (n = 27459) GP databases. Conventional Cox model and two-stage IV analysis were applied to estimate the effect of LABA vs. non-LABA (SABA/MA) on the risk of AMI. PPPs were defined by the proportion of LABA prescriptions per practice (PLP) or previous single (PPP1), or five (PPP5), or ten (PPP10) prescriptions by a physician. Quantitative methods (e.g. correlation (r), odds ratio (OR), standardized difference (SDif)) were used to assess the validity of the IVs. 95% confidence intervals (CI) for IV estimates were estimated using bootstrapping. Results: LABA was not associated with an increased risk of AMI, adjusted hazard ratio 0.96 [95%CI 0.89-1.02] (CPRD) and 1.18 [0.97-1.43] (Mondriaan) in conventional Cox model and 0.95 [0.55-1.63], 1.24 [0.40-3.60], and 1.24 [0.47-3.09] in IV analyses with PPP10 for CPRD, and PPP5 and PPP10 for Mondriaan, respectively. PLP, PPP1 and PPP5 in the CPRD and PPP1 in Mondriaan were weakly associated with LABA (r0.10) across PLP levels in Mondriaan. Conclusions: LABA use was not associated with an increased risk of AMI compared to non-LABA. Validity of IV depends on the definition of IV and the database in which it is applied. We recommend researchers to generate several possible IVs, assess their validity, and report the estimate(s) from the most valid IV.Background: Results from several cohort studies have indicated that long-term low-dose aspirin (acetylsalicylic acid, ASA) use markedly increases the risk for neovascular age-related macular degeneration (nAMD). nAMD is a serious condition that causes rapid decline in central-field vision over the course of days to weeks. The studies currently available obtained data from questionnaires, therefore lacking high-quality information regarding exposure to low-dose ASA, and had few nAMD cases. Objectives: To quantify the risk for nAMD associated with long-term low-dose ASA use. Methods: A case-control study was conducted, including all cases of nAMD in the period 1 January 1987 - 31 December 2012 aged 50 years and older from the UK Clinical Practice Research Datalink (CPRD) database. Cases were matched to up to five controls on age, gender and general practice. Conditional logistic regression was used to estimate odds ratios for the risk of nAMD associated with increasing durations of low-dose ASA use, adjusting for smoking status, obesity, glaucoma, hypercholesterolaemia, and lipid lowering medication, and cardiovascular diseases. Results: 4,125 cases were matched to 20,173 controls. Cases had a median age of 80.1 years and were in majority female (64.7%). Overall, the risk for nAMD associated with low-dose ASA use was a small but significantly increased adjusted risk of 1.12 (95% confidence interval 1.03 - 1.21). We observed a trend for increasing risk with prolonged use: odds ratios were 1.06 (use for less than twoand- a-half years; 95% CI 0.96 - 1.17), 1.07 (twoand- a-half to five years; 95% CI 0.94 - 1.21), 1.17 (five to ten years; 95% CI 1.04 - 1.31), 1.23 (ten to fifteen years; 95% CI 1.05 - 1.45), and 1.33 (more than fifteen years; 95% CI 1.08 - 1.63), compared to no ASA use. Conclusions: Long-term use of low-dose ASA is associated with an increased risk for nAMD. This risk is lower than previously observed and small compared to other risk factors and the benefit-risk balance of low-dose ASA for the prevention of cardiovascular disease will not be impacted.Background: Current influenza vaccines mainly induce immune responses against viral membrane glycoproteins, which undergo continuous mutations through antigenic drift. To prevent immune escape, annual vaccination with the latest predicted viral strains is adopted. Such vaccination strategy is inconvenient and cost-inefficient. Moreover, poor protective effectiveness is observed when there is antigenic mismatch between vaccine strains and actual epidemic strains. This is especially of concern during a pandemic outbreak, when large populations are affected by the newly re-assorted viral strain derived from antigenic shift. Objectives: To design phase IIb studies to evaluate the safety, immunogenicity and cross-seasonal clinical efficacy of two universal influenza vaccines (Flu-v and M-001) targeting different conserved epitopes of influenza viruses. The tested epitopes are identified from the viral surface glycoproteins as well as the viral internal (structural) proteins. Moreover, these epitopes are consistently expressed on both influenza A and B viruses. Methods: In two separate trials, a total of 1500 healthy adults will be recruited from multiple centers in Europe and randomized to receive placebo or the tested influenza vaccines at low or high antigen doses through a double-blind procedure. Two parenteral administrations will be given with a 21 day interval. In one trial, additional administrations of pandemic influenza vaccine will be given 21 and 42 days after the second administration. Clinical symptom scores and adverse events (AEs) will be collected from AE diary card. Humoral and cellular immune correlates of protection will be assessed. The (severity of) incident RT-PCR-confirmed influenza infection will be recorded over two subsequent influenza seasons. Conclusions: Universal influenza vaccines are urgently needed to increase protection among vulnerable groups. Vaccine trial design needs to incorporate safety, correlates of protection and clinical efficacy.Background: In adolescents, non-adherence is a major problem and leads to uncontrolled disease. Objectives: To assess adolescents needs and preferences regarding counseling and support with focus on use of new media. Methods: Asthmatic adolescents needs and preferences were examined by means of moderated asynchronous online focus group (OFG) over a one week period. Two OFGs were created: early (age 12-13 years) and late adolescence (age 14-16 years). A new question was introduced by the researchers on each first five days. Participants were asked to respond anonymously to the questions introduced by the researcher and to each others comments. Questions concerned adherence behavior in general and needs and preferences in adherence support with focus on new digital media (mobile technology, social media, health games). Patients were recruited through community pharmacies. Results: In total, 192 adolescents were selected from 13 pharmacies and requested for participation. Fourteen returned informed consent (7.3%) of which all 14 participated in OFGs. Older participants were more actively engaged in the discussions. Forgetting was mentioned as important reason for not using medication as prescribed and some adolescents mentioned the lack of perceived need or lack of perceived effect of medicines. Participants described different supportive roles for their parents (reminding, filling prescriptions). Use of health games was not perceived useful, whilst other new media such as smartphone applications were suggested as solutions to support medication intake behavior. Furthermore, participants were generally positive about the OFG methodology and sharing of online experiences. Older participants were more actively engaged in the OFG discussion. Conclusions: It is important to find ways to improve adherence that easily fit into adolescents daily life. Adolescents are highly engaged in technology and frequently communicate through new digital media. Our findings lay the foundation for future intervention development. In order to develop patient-centered interventions to improve medication adherence in adolescents, it is important to embed these patient perspectives.Background: Unmeasured confounding is one of the principal problems in observational pharmacoepidemiologic studies. Prior event rate ratio (PERR) adjustment method has been proposed to control for unmeasured confounding. Objectives: To assess the performance of the PERR method in realistic pharmacoepidemiologic settings. Methods: Simulation studies were performed in several scenarios with varying effects of prior events on the probability of subsequent exposure, incidence rates, strength of confounders in prior and post periods, and rate of mortality/dropout. Exposure effects were estimated using conventional rate ratio (RR) and PERR adjustmentmethods. For the PERR method, the exposure effect is a ratio of two RRs: RR post exposure initiation and RR prior to initiation of exposure. In each simulation, the sample size was 100000 and each scenario was replicated 10000 times. 95% confidence intervals were estimated in a non-parametric way using the 2.5 and 97.5 percentiles of the 10000 estimates. Results: The exposure effects from the PERR adjustment method are highly biased when “prior” events influence the probability of subsequent exposure or when confounding differs considerably between prior and post periods. For example, the RR ranged from 1.52 to 1.10 (true RR= 2.00) when the effect of prior events on the exposure was RR 1.25 to 1.70, respectively. With a strong effect of prior events on the exposure (e.g. RR= 1.70), the bias of the estimates were more pronounced for PERR method than for the conventional method. In such case, even with a null exposure effect (RR = 1.00), the estimates shifted away from the null. In all settings, the confidence intervals of the estimates were wider for the PERR method than for the conventional method. Conclusions: The PERR adjustment method has significant limitations; in particular situations, e.g. when prior events strongly influence the probability of subsequent exposure, it can be more biased than conventional methods. Hence, caution should be exercised when applying this method and theoretical justification should be provided for underlying assumptions of the PERR.Background: At the time of marketing, knowledge on the safety of the use of drugs during pregnancy is still limited, as pregnant women are not included in pre-marketing research. Also after marketing, collecting information on drug use during pregnancy can be bothersome. In 2013 the pREGnant project started in order to develop and implement a national register for medical drug use during pregnancy in the Netherlands. This register will be used for signal detection and conducting epidemiological studies. In February 2014, a pilot study was started to test and validate this register. Objectives: To describe the first results of the pilot phase of the pREGnant register. Methods: In pREGnant, exposure to medical drugs and other potential risk factors are monitored prospectively. Data are collected by means of web-based questionnaires and completed by pregnant women, focusing on medical drug use, the health of the pregnant woman, pregnancy complications and outcomes, and the health of the child. In the pilot phase, different schemes for data collection are introduced in order to choose the best practice for inclusion. During the pilot phase, inclusion takes place at midwiferies and hospitals. Results: The method and approaches applied will be discussed as well as the number and type of inclusions. Based on the initial results of the validation studies and the experiences with implementing data from other data sources, possibilities for the definite system for pREGnant be discussed. Conclusions: The current lack of knowledge on the teratogenic risks of many medical drug use often hampers healthcare professionals in making evidencebased decisions on whether or not the beneficial effects of treatment outweigh the possible risks for the developing foetus and the pregnant woman. The pREGnant register will enable a systematic collection of information and may fill this gap of knowledge.Background: There is no recent data on the epidemiology of type 1 diabetes (T1D) in Dutch children and adolescents. To assess the incidence and prevalence of T1D in children, which is reasonably rare, a large population has to be monitored. Objectives: To assess trends in the incidence and prevalence of T1D in Dutch children and adolescents aged 0-19 years. Methods: A population-based cohort study was conducted in the Dutch PHARMO-RLS that comprises community pharmacy dispensing records linked to hospital admissions (1998-2010). Insulin prescriptions were used as a proxy to identify cases of T1D. All children and adolescents aged 0-19 years with at least two insulin prescriptions were identified and the numbers of incident and prevalent cases of T1D (numerators) were calculated in each year. The incidence and prevalence of T1D were calculated overall and for different sexes and age categories (age bands: 0-4, 5-9, 10-14, 15-19, and 0-14 years) using the data from the Dutch Central Bureau of Statistics as denominator. Results: In 2010, the incidence and prevalence of T1D was 31.6/100,000 person-years and 195.2/100,000 children, respectively. From 1998 to 2010, the overall incidence and prevalence of T1D in Dutch children increased by 62.9% and 87.9%, respectively. A similar increasing pattern was observed for boys and girls. The largest increase in the incidence and prevalence of T1D was perceived for 15-19 years adolescents (140% and 93%, respectively). A sensitivity analysis restricted to children 0-14 years showed a plateau and even a gradual decrease in the incidence of T1D, mainly driven by a decreasing trend in the 0-4 year old children. Overall, there was an increase in the mean age at the onset of T1D (from 10.9 in 1999 to 13.1 years in 2010). Conclusions: Our study is the most recent populationbased study to investigate the incidence and prevalence of T1D in Dutch children and adolescents. Both incidence and prevalence of T1D nearly doubled from 1998 to 2010. The increase in the number of new cases and older age at the onset of the disease warrants further research to identify environmental triggering factors of T1D.This journal suppl. entitled: Special Issue: Abstracts of the 30th International Conference on Pharmacoepidemiology and Therapeutic Risk Management ... 2014Background: ACEI-induced ADRs are the main reason to discontinue ACEI treatment. In prescription databases, information on ADRs is not available; therefore it is necessary to identify proxies for ADRs in such databases to study risk factors for ADRs. Objectives: To study prescription patterns for ACEIs as potential marker for ACEI-induced ADRs. Methods: A cohort of patients starting ACEI from 2000 to 2011 was identified within the Rotterdam Study, (a prospective population-based cohort study of approximately 15,000 individuals aged 45 years and older). Medication dispensing data on daily basis were obtained from the fully computerized linked pharmacies. Participants were followed from the start of ACEI treatment until the end of study period, death or moving out of the area, whichever came first. Patients were classified into 4 mutually exclusive groups: continuous users, discontinued users, switchers to angiotensin receptor blockers (ARBs), and switchers to other antihypertensives. For continuous use or switching, the maximum time interval between two prescription periods was set at 3 or 6months. Patients without a prescription for antihypertensives, 3 or 6months after the end date of the last ACEI prescription were classified as discontinued users. Primary care physician files were searched for reasons of ACEI discontinuation for patients who discontinued or switched ACEIs. Clinical events were classified as definite ADRs (73.5% cough, 3% angioedema, 23.5%others), probable ADRs, possible ADRs and definite non-ADRs. Positive predictive values (PPVs) of the prescription patters of the 3 groups for ADRs were calculated. Results: Totally 1132 patients were included. The PPV for a definite ADR was 56.1% in switchers to ARBs, while the PPVs for switchers to other antihypertensives, and discontinued users were 39.5% and 19.5%. Including probable and possible ADRs, increased the PPVs for switchers to ARBs to 68.3% and 90.5%. A 6-month time interval gave slightly higher PPVs compared to a 3-month interval (maximum 6.1% higher). Conclusions: This study showed that switching from ACEI to ARB is the best marker for ACEI-induced ADRs in prescription databases.This journal suppl. entitled: Special Issue: Abstracts of the 30th International Conference on Pharmacoepidemiology and Therapeutic Risk Management ... 2014Background: Results from multiple observational studies on inhaled long-acting beta-2-agonists (LABA) and the risk of acute myocardial infarction (AMI) are conflicting, due to variations in methodological, clinical and health care characteristics. To some extent, the discrepancies in the design might limit the comparability of the results encountered. Objectives: To determine the risk of AMI in inhaled LABA users in two European electronic primary care databases using a common study protocol. Methods: Patients from the Dutch Mondriaan (1.4 Million) and the UK CPRD (5 Million) databases were included if they had a diagnosis of asthma and/or COPD, and were prescribed at least one inhaled LABA, a short-acting beta-2-agonist (SABA), or a short- or long-acting muscarinic antagonist (SAMA, LAMA) during the study period (2002 to 2009). LABA episodes were divided into current, recent (1. Effect of Statin Use on Acute Kidney Injury Following Elective Cardiothoracic Surgery: A Population Cohort Study in Denmark J Bradley Layton, Malene K Hansen, Carl-Johan Jakobsen, Jan J Andreasen, Vibeke E Hjortdal, Bodil S Rasmussen, Abhijit V Kshirsagar, Ross J Simpson, Christian F Christiansen. Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States; Clinical Epidemiology, Aarhus Univeristy Hosptial, Aarhus, Denmark; Anesthesia and Intensive Care, Aarhus University Hospital, Aarhus, Denmark; Cardiothoracic Surgery, Aalborg University Hospital, Aalborg, Denmark; Cardiothoracic and Vascular Surgery, Aarhus University Hospital, Aarhus, Denmark; Anaesthesia and Intensive Care Medicine, Aalborg University Hospital, Aalborg, Denmark; Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC,Background: Limited quantitative data exist on the burden of chronic comorbidities in children and adolescents with type 1 diabetes (T1D). Such knowledge is necessary for the development of guidelines and prevention programs. Objectives: To determine the incidence of chronic comorbidities in children and adolescents with T1D and to compare the risks with the diabetes-free children. Methods: A population-based cohort study was conducted using the Dutch PHARMO-RLS that comprises community pharmacy dispensing records linked to hospital admissions. Insulin prescriptions were used as a proxy to identify incident cases of T1D. All patients (Background: Pregnancy-induced hypertension (PIH) is possibly caused by an increased activity of the sympatic nervous system. Previous studies have suggested that inhibition of the re-uptake of serotonin and norepinephrine by selective serotonin re-uptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs) could contribute to this increased activity. Objectives: To assess the association between the use of antidepressants (ADs) and the development of pregnancyinduced hypertension. Methods: Using the prescription database IADB.nl we conducted a case-control study among pregnant women between 1995 and 2012. Cases were defined as>1 dispensed prescription of an antihypertensive drug (methyldopa, dihydralazine, ketanserin, labetalol, nifidepine) after 20weeks of gestation. Controls were matched for age at time of giving birth. Only first and singleton pregnancies of women not using any antihypertensive drug during 6months before pregnancy till 20weeks of gestation were included. Exposure was defined as>1 dispensed prescription of an antidepressant during pregnancy. Logistic regression analysis was used to estimate odds ratios (OR) and their corresponding 95% confidence intervals (95% CIs). Subanalyses were conducted for class of AD (TCA, SSRI, other) and duration of AD use (1-30, ≥ 31 Defined Daily Doses (DDDs)). As the exact duration of gestation was unknown, all analysis were conducted for 3 theoretical gestational ages (36, 38, 40weeks). Results: A total of 312 PIH cases and 12480 controls were included in the analysis (gestational age 36 weeks). The exposure rate among case and control pregnancies was 3.2% and 1.5% respectively. The use of AD increased the risk for developing PIH more than twice (OR [95% CI] 2.24 [1.17-4.27]). Significant associations (OR [95% CI]) were also found for the subgroups TCA (3.39 [1.04-11.08]), SSRI (2.23 [1.03-4.81]) and ≥ 31 DDDs (2.38 [1.16-4.90]). Increasing the theoretical gestational age showed comparable results. Conclusions: Prolonged use of ADs during pregnancy appeared to be associated with an increased risk of developing PIH. When balancing the benefit and risks of using these drugs during pregnancy, this should be taken into account.Background: In observational studies of time-varying treatment, conditioning on time-dependent confounders that are affected by previous treatment using conventional regression methods may adjust-away(indirect) treatment effects.In the presence of unmeasured common causes of confounders and outcome, it can also induce collider-stratification bias. Objectives: To compare time-dependent propensity scores, conventional Cox and marginal structural models (MSM) in a study of selective serotonin reuptake inhibitors (SSRI) and the risk of hip fracture (HF). Methods: A cohort of patients with a first prescription for antidepressants (AD, SSRI or tricyclic antidepressants, TCA) was extracted from the Dutch Mondriaan GP database in the period 2001-2009.Potential confounders were ascertained when antidepressant use changed over time or at six month intervals. Follow-up began with the first day of AD prescription and ended at the occurrence of HF, death, unregistration with the GP, or end of the study.Treatment effects were estimated using time-varying Cox regression, PS stratification, covariate adjustment, and inverse probability weighting (MSM) to control for confounding. In MSMs, censoring was accounted for by including inverse probability of censoring weights (IPCW). Results: The crude HR of HF in current SSRI users versus non-current SSRI users was 1.70 [95%CI 1.09-2.65]. Effects increased after confounder adjustment, PS stratification, and PS adjustment: HR 2.28 [1.45-3.59], 2.47 [1.54-3.95], and 2.51 [1.54-4.09], respectively.When MSMs with stabilized weights were used, the HR was 1.34 [0.65-2.76] and 1.53 [0.81-2.93] with and without accounting for censoring, respectively. After weight truncation, the HR became 2.09 [1.31-3.35] and 2.37 [1.49-3.78] with and without accounting for censoring, respectively. Conclusions: When treatment and confounders are time-varying, accounting for informative censoring can materially influence effect estimates in addition to the potential collider-stratification and confounding bias that arise due conditioning or stratification on time-dependent confounders.Hence, the use of methods such as MSMs is recommended.

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Background: One previous study of our group reported that acid suppressive drug use during pregnancy is associated with an increased risk for the development of atopic dermatitis in children. However, reported associations could have been confounded by unmeasured risk factors. Objectives: The aim of this study was to assess the association between prenatal exposure to acid-suppressive drugs and the development of atopic dermatitis in children by using a confounding minimizing crossover design. Methods: We conducted a bidirectional case-crossover study within the Clinical Practice Research Database in which 1,445 children with atopic dermatitis were randomly matched to one of their own siblings without atopic dermatitis. Children were defined as having atopic dermatitis if they had a diagnosis of atopic dermatitis and at least 3 prescriptions for ointments containing steroids or calcineurin inhibitors in the year after diagnosis. We applied conditional logistic regression to compute odds ratios (ORs) and 95% confidence intervals (95%CI). Results: The percentage of exposure to acid suppressive drugs amongst cases was 21.5% compared to 18.8% amongst controls. After adjustments for gender, birth order and maternal age at delivery the exposure to any acid suppressive drug during pregnancy increased the odds for developing atopic dermatitis by 34% (aOR 1.34; 95%CI: 1.05-1.71). Though not significant, exposure to the subgroup proton pump inhibitors conferred an increased risk of 72% (aOR 1.72 95% CI: 0.62-4.79). Conclusions: This study supports previous findings of a small association between gastric acid suppression during pregnancy and the development of atopic dermatitis in children.Background: After extensive media attention on thromboembolic adverse drug reactions (TE-ADRs) and the use of cyproterone/ethinylestradiol (CE), the Netherlands Pharmacovigilance Centre Lareb received a high number of reports about this association, which prompted for detailed analyses. Objectives: To analyse reports of thromboembolic events associated with the use of cyproterone/ ethinylestradiol submitted to Lareb, focusing on the indication of use, presence of risk factors and time between the initial symptoms and the actual diagnosis of the TE. Methods: Reports submitted to Lareb till 11 February 2014 were analysed. The analysis was focussed on reporter type, seriousness of the reaction, age of the patient, BMI, indication, ADRs classified as arterial thrombosis and venous thrombosis, pulmonary embolism, latency period, outcome of the reaction, treatment of the ADR, delay between the first symptoms and diagnosis of the ADR, presence of risk factors. Results: On 11 February 2014, Lareb had received a total of 786 reports about CE, including 41 cases with a fatal outcome. Of all reports, 438 reports considered TE-ADRs which were analysed in more detail. Reported ADRs consisted of arterial thrombosis (N = 74), venous thrombosis (N = 63), pulmonary embolism (N = 219) and thrombosis with an unspecified location (N = 172). Patients mean age was 30.5 years (range 14-57 years). The primary indications for use were acne (N = 193), oral contraceptive (N = 181), hirsutism (N = 13), other (N = 18) or the indication was unknown (N = 33). The median time to onset was 4 years, although many patients reported a longer latency period. There was no distinction between the time of onset in respect to the reported ADR. No differences in risk factors seem to exist between labeled and off-label indications. In 382 out of 438 reports (87%), the reporter was a consumer. Some reports mentioned the fact that thrombosis or embolism were not recognized in an early stage. Conclusions: The reported thromboembolic ADRs are a known risk related to the use of CE, but may be misdiagnosed initially. From the reports that Lareb received it is evident that off-label use is frequent.Background: Recent studies have reported an increased risk of asthma in children after prenatal exposure to antibiotics, notably during third trimester due to altered vaginal bacterial flora. Associations could have been influenced by unmeasured confounders. Objectives: To assess the association between antibiotic use during pregnancy and the development of toddler asthma with a confounding minimizing crossover(casesibling) design. Secondary we wanted to assess the influence of time-invariant confounding by comparing results with a case-control design. Methods: We conducted this study using a linked mother-infant subset of the University Groningen prescription database IADB.nl. We conducted both a crossover study in which 1,228 children with asthma were compared to their own siblings without asthma, and a traditional matched case-control study. Maternal exposure was defined as at least 1 day of supply of systemic antibiotics during pregnancy. Children were considered to have asthma if they received at least 3 prescriptions for anti-asthma medication within a year before the fifth birthday. Conditional logistic regression was used to estimate crude and adjusted odds ratios (aOR). Sensitivity analyses were performed to estimate the potential influence of unobserved timevarying confounders. Results: The crossover analysis only showed an increase in the toddlers asthma risk if antibiotics were used in the third trimester of pregnancy (aOR 1.37 (95%CI 1.02-1.83)). The matched case-control study yielded a similar increase in the toddlers asthma risk after exposure in the third trimester (aOR 1.40(95%CI 1.15-1.47)). In addition, use of antibiotics, independent of trimester of pregnancy, was associated with an aOR of 1.46 (95%CI 1.33-1.58) in the matched case-control study. Conclusions: Prenatal exposure to antibiotics in the third trimester of pregnancy is associated with a small increased risk of childhood asthma. This association did not appear to be influenced by time-invariant confounders such as genetic predisposition. However the influence of time-variant confounders, such as disease severity, cannot be ruled out.Background: The use of anti-epileptic drugs (AEDs) during pregnancy is associated with an increased risk of birth defects. Since epilepsy itself is also associated with potential risks for mother and child, an optimal AED treatment is needed. Over the past years, the introduction of new AEDs and the amendments of guidelines have changed the use of AEDs in this vulnerable group of patients. The extend of the changes over time in the Netherlands has not been studied before. Objectives: To compare the use of different AEDs in pregnant women over the past 10 years in the Netherlands. Methods: This retrospective cohort study data is based on data from the register that is being used to submit Dutch cases to the EURAP study. Pregnancies were included in which women were exposed to an AED between January 2003 and December 2012 either preconceptionally or during the first trimester. Binary logistic regression analysis was used to compare the proportion of various AEDs annually. Dependent variable was the year in which conception took place; the AED and type of epilepsy were covariates. In addition, the mean number of concomitantly used AEDs were calculated per year and analyzed by ANOVA. Results: A total number of 1,733 pregnancies in were included in the analysis. The proportion of use of levetiracetam and lamotrigine showed an upwards trend from 6.2 and 16.0% in 2003 till 25.0 and 33.5% in 2012, with corresponding adjusted Odds Ratio (OR) of 4.89 (95% CI 2.65-9.06) and 2.77 (95% CI 1.76-4.34) respectively. The proportion of use of valproate and carbamazepine decreased from 28.4 and 28.4% in 2003 till 9.3 and 17.3% in 2013, with an adjusted OR of 0.28 (95% CI 0.16-0.48) and from 0.44 (95%CI 0.28-0.70) respectively. The use of other miscellaneous AEDs decreased from 20.9% to 14.9%, OR 0.61 (95%CI 0.38-0.98). The average number of AEDs being used was 1.30 in 2003 and 1.24 in 2012 (p>0.05). Conclusions: The use of relatively safer AEDs gradually increased over the past 10 years compared to drugs more frequently associated with congenital defects. The mean number of AEDs used remained stable of the years. Our findings are in line with advice provided in the literature on the use of AEDs.Background: This study was part of the Pharmacoepidemiological Research on Outcomes (PROTECT) project which aims at monitoring of the benefit-risk of medicines in Europe. Few epidemiological studies have investigated the association between calcium channel blockers (CCB) and cancer, and have provided contradictory evidence. Objectives: To investigate whether CCB exposure is associated with cancer risk and whether the risk varies according to cancer subtype and duration of exposure. Methods: A population-based matched-cohort study was conducted using data from the Clinical Practice Research Datalink and National Cancer Registration System. Eligible patients (18 to 79 years, over two years primary care and prescription history) with ≥1 CCB prescription between 1996 and 2009 (CCBC) were compared with two CCB unexposed cohorts: 1) patients without CCB exposure (NCCBC), and; 2) patients with no CCB and ≥1 other antihypertensive prescription (AHTC). CCBC was compared with NCCBC and AHTC according to cancer outcomes. Conditional logistic cox-regression models estimated multivariable hazard ratios (HR) and 95% confidence intervals (CI). Results: There were 150,750 patients in the CCBC, 557,931 in the NCCBC, and 156,966 in the AHTC. Cancer rates (crude per 1000 person-years) were 16.51, 15.75 and 10.62 for the CCBC, NCCBC and AHTC respectively. Adjusted HRs (CI) of all cancer for the CCBC compared to the NCCBC and AHTC were 0.88 (0.86-0.89) and 1.01 (0.98-1.04) respectively. Adjusted HRs (CI) of breast, prostate, and colon cancer for the CCBC compared to the AHTC were 0.95 (0.87-1.04), 1.07 (0.98-1.16) and 0.89 (0.81-0.98) respectively. Adjusted HRs (CI) of all cancer for the CCBC compared to the NCCBC were 0.88 (0.85-0.91), 0.98 (0.93-1.04), and 1.11 (0.98-1.27) for 0 to 5years, 5 to 10years, and ≥10 years of cumulative drug exposure respectively. Conclusions: This study showed strong evidence that CCB use is not associated with cancer. Shorter periods of CCB exposure showed a small protective effect for cancer, as did CCB exposure for colon cancer. Results will be discussed in relation to other findings from PROTECT work package two.Background: Instrumental variable (IV) analysis with physicians prescribing preference (PPP) as an IV has been used to control for unobserved confounding in pharmacoepidemiology. PPP can be defined in several ways, but it is unclear how different PPPs perform across databases. Objectives: To assess the validity of the IV PPP in two general practice (GP) databases in the study of inhaled long-acting beta2-agonist (LABA) use and the risk of acute myocardial infarction (AMI). Methods: Information on adult patients with a diagnosis of asthma and/or COPD and at least one prescription of an inhaled short-acting beta2-agonist (SABA)/LABA/ muscarinic antagonist (MA) was extracted from the British Clinical Practice Research Datalink (CPRD, n = 490499), and the Dutch Mondriaan (n = 27459) GP databases. Conventional Cox model and two-stage IV analysis were applied to estimate the effect of LABA vs. non-LABA (SABA/MA) on the risk of AMI. PPPs were defined by the proportion of LABA prescriptions per practice (PLP) or previous single (PPP1), or five (PPP5), or ten (PPP10) prescriptions by a physician. Quantitative methods (e.g. correlation (r), odds ratio (OR), standardized difference (SDif)) were used to assess the validity of the IVs. 95% confidence intervals (CI) for IV estimates were estimated using bootstrapping. Results: LABA was not associated with an increased risk of AMI, adjusted hazard ratio 0.96 [95%CI 0.89-1.02] (CPRD) and 1.18 [0.97-1.43] (Mondriaan) in conventional Cox model and 0.95 [0.55-1.63], 1.24 [0.40-3.60], and 1.24 [0.47-3.09] in IV analyses with PPP10 for CPRD, and PPP5 and PPP10 for Mondriaan, respectively. PLP, PPP1 and PPP5 in the CPRD and PPP1 in Mondriaan were weakly associated with LABA (r0.10) across PLP levels in Mondriaan. Conclusions: LABA use was not associated with an increased risk of AMI compared to non-LABA. Validity of IV depends on the definition of IV and the database in which it is applied. We recommend researchers to generate several possible IVs, assess their validity, and report the estimate(s) from the most valid IV.Background: Results from several cohort studies have indicated that long-term low-dose aspirin (acetylsalicylic acid, ASA) use markedly increases the risk for neovascular age-related macular degeneration (nAMD). nAMD is a serious condition that causes rapid decline in central-field vision over the course of days to weeks. The studies currently available obtained data from questionnaires, therefore lacking high-quality information regarding exposure to low-dose ASA, and had few nAMD cases. Objectives: To quantify the risk for nAMD associated with long-term low-dose ASA use. Methods: A case-control study was conducted, including all cases of nAMD in the period 1 January 1987 - 31 December 2012 aged 50 years and older from the UK Clinical Practice Research Datalink (CPRD) database. Cases were matched to up to five controls on age, gender and general practice. Conditional logistic regression was used to estimate odds ratios for the risk of nAMD associated with increasing durations of low-dose ASA use, adjusting for smoking status, obesity, glaucoma, hypercholesterolaemia, and lipid lowering medication, and cardiovascular diseases. Results: 4,125 cases were matched to 20,173 controls. Cases had a median age of 80.1 years and were in majority female (64.7%). Overall, the risk for nAMD associated with low-dose ASA use was a small but significantly increased adjusted risk of 1.12 (95% confidence interval 1.03 - 1.21). We observed a trend for increasing risk with prolonged use: odds ratios were 1.06 (use for less than twoand- a-half years; 95% CI 0.96 - 1.17), 1.07 (twoand- a-half to five years; 95% CI 0.94 - 1.21), 1.17 (five to ten years; 95% CI 1.04 - 1.31), 1.23 (ten to fifteen years; 95% CI 1.05 - 1.45), and 1.33 (more than fifteen years; 95% CI 1.08 - 1.63), compared to no ASA use. Conclusions: Long-term use of low-dose ASA is associated with an increased risk for nAMD. This risk is lower than previously observed and small compared to other risk factors and the benefit-risk balance of low-dose ASA for the prevention of cardiovascular disease will not be impacted.Background: Current influenza vaccines mainly induce immune responses against viral membrane glycoproteins, which undergo continuous mutations through antigenic drift. To prevent immune escape, annual vaccination with the latest predicted viral strains is adopted. Such vaccination strategy is inconvenient and cost-inefficient. Moreover, poor protective effectiveness is observed when there is antigenic mismatch between vaccine strains and actual epidemic strains. This is especially of concern during a pandemic outbreak, when large populations are affected by the newly re-assorted viral strain derived from antigenic shift. Objectives: To design phase IIb studies to evaluate the safety, immunogenicity and cross-seasonal clinical efficacy of two universal influenza vaccines (Flu-v and M-001) targeting different conserved epitopes of influenza viruses. The tested epitopes are identified from the viral surface glycoproteins as well as the viral internal (structural) proteins. Moreover, these epitopes are consistently expressed on both influenza A and B viruses. Methods: In two separate trials, a total of 1500 healthy adults will be recruited from multiple centers in Europe and randomized to receive placebo or the tested influenza vaccines at low or high antigen doses through a double-blind procedure. Two parenteral administrations will be given with a 21 day interval. In one trial, additional administrations of pandemic influenza vaccine will be given 21 and 42 days after the second administration. Clinical symptom scores and adverse events (AEs) will be collected from AE diary card. Humoral and cellular immune correlates of protection will be assessed. The (severity of) incident RT-PCR-confirmed influenza infection will be recorded over two subsequent influenza seasons. Conclusions: Universal influenza vaccines are urgently needed to increase protection among vulnerable groups. Vaccine trial design needs to incorporate safety, correlates of protection and clinical efficacy.Background: In adolescents, non-adherence is a major problem and leads to uncontrolled disease. Objectives: To assess adolescents needs and preferences regarding counseling and support with focus on use of new media. Methods: Asthmatic adolescents needs and preferences were examined by means of moderated asynchronous online focus group (OFG) over a one week period. Two OFGs were created: early (age 12-13 years) and late adolescence (age 14-16 years). A new question was introduced by the researchers on each first five days. Participants were asked to respond anonymously to the questions introduced by the researcher and to each others comments. Questions concerned adherence behavior in general and needs and preferences in adherence support with focus on new digital media (mobile technology, social media, health games). Patients were recruited through community pharmacies. Results: In total, 192 adolescents were selected from 13 pharmacies and requested for participation. Fourteen returned informed consent (7.3%) of which all 14 participated in OFGs. Older participants were more actively engaged in the discussions. Forgetting was mentioned as important reason for not using medication as prescribed and some adolescents mentioned the lack of perceived need or lack of perceived effect of medicines. Participants described different supportive roles for their parents (reminding, filling prescriptions). Use of health games was not perceived useful, whilst other new media such as smartphone applications were suggested as solutions to support medication intake behavior. Furthermore, participants were generally positive about the OFG methodology and sharing of online experiences. Older participants were more actively engaged in the OFG discussion. Conclusions: It is important to find ways to improve adherence that easily fit into adolescents daily life. Adolescents are highly engaged in technology and frequently communicate through new digital media. Our findings lay the foundation for future intervention development. In order to develop patient-centered interventions to improve medication adherence in adolescents, it is important to embed these patient perspectives.Background: Unmeasured confounding is one of the principal problems in observational pharmacoepidemiologic studies. Prior event rate ratio (PERR) adjustment method has been proposed to control for unmeasured confounding. Objectives: To assess the performance of the PERR method in realistic pharmacoepidemiologic settings. Methods: Simulation studies were performed in several scenarios with varying effects of prior events on the probability of subsequent exposure, incidence rates, strength of confounders in prior and post periods, and rate of mortality/dropout. Exposure effects were estimated using conventional rate ratio (RR) and PERR adjustmentmethods. For the PERR method, the exposure effect is a ratio of two RRs: RR post exposure initiation and RR prior to initiation of exposure. In each simulation, the sample size was 100000 and each scenario was replicated 10000 times. 95% confidence intervals were estimated in a non-parametric way using the 2.5 and 97.5 percentiles of the 10000 estimates. Results: The exposure effects from the PERR adjustment method are highly biased when “prior” events influence the probability of subsequent exposure or when confounding differs considerably between prior and post periods. For example, the RR ranged from 1.52 to 1.10 (true RR= 2.00) when the effect of prior events on the exposure was RR 1.25 to 1.70, respectively. With a strong effect of prior events on the exposure (e.g. RR= 1.70), the bias of the estimates were more pronounced for PERR method than for the conventional method. In such case, even with a null exposure effect (RR = 1.00), the estimates shifted away from the null. In all settings, the confidence intervals of the estimates were wider for the PERR method than for the conventional method. Conclusions: The PERR adjustment method has significant limitations; in particular situations, e.g. when prior events strongly influence the probability of subsequent exposure, it can be more biased than conventional methods. Hence, caution should be exercised when applying this method and theoretical justification should be provided for underlying assumptions of the PERR.Background: At the time of marketing, knowledge on the safety of the use of drugs during pregnancy is still limited, as pregnant women are not included in pre-marketing research. Also after marketing, collecting information on drug use during pregnancy can be bothersome. In 2013 the pREGnant project started in order to develop and implement a national register for medical drug use during pregnancy in the Netherlands. This register will be used for signal detection and conducting epidemiological studies. In February 2014, a pilot study was started to test and validate this register. Objectives: To describe the first results of the pilot phase of the pREGnant register. Methods: In pREGnant, exposure to medical drugs and other potential risk factors are monitored prospectively. Data are collected by means of web-based questionnaires and completed by pregnant women, focusing on medical drug use, the health of the pregnant woman, pregnancy complications and outcomes, and the health of the child. In the pilot phase, different schemes for data collection are introduced in order to choose the best practice for inclusion. During the pilot phase, inclusion takes place at midwiferies and hospitals. Results: The method and approaches applied will be discussed as well as the number and type of inclusions. Based on the initial results of the validation studies and the experiences with implementing data from other data sources, possibilities for the definite system for pREGnant be discussed. Conclusions: The current lack of knowledge on the teratogenic risks of many medical drug use often hampers healthcare professionals in making evidencebased decisions on whether or not the beneficial effects of treatment outweigh the possible risks for the developing foetus and the pregnant woman. The pREGnant register will enable a systematic collection of information and may fill this gap of knowledge.Background: There is no recent data on the epidemiology of type 1 diabetes (T1D) in Dutch children and adolescents. To assess the incidence and prevalence of T1D in children, which is reasonably rare, a large population has to be monitored. Objectives: To assess trends in the incidence and prevalence of T1D in Dutch children and adolescents aged 0-19 years. Methods: A population-based cohort study was conducted in the Dutch PHARMO-RLS that comprises community pharmacy dispensing records linked to hospital admissions (1998-2010). Insulin prescriptions were used as a proxy to identify cases of T1D. All children and adolescents aged 0-19 years with at least two insulin prescriptions were identified and the numbers of incident and prevalent cases of T1D (numerators) were calculated in each year. The incidence and prevalence of T1D were calculated overall and for different sexes and age categories (age bands: 0-4, 5-9, 10-14, 15-19, and 0-14 years) using the data from the Dutch Central Bureau of Statistics as denominator. Results: In 2010, the incidence and prevalence of T1D was 31.6/100,000 person-years and 195.2/100,000 children, respectively. From 1998 to 2010, the overall incidence and prevalence of T1D in Dutch children increased by 62.9% and 87.9%, respectively. A similar increasing pattern was observed for boys and girls. The largest increase in the incidence and prevalence of T1D was perceived for 15-19 years adolescents (140% and 93%, respectively). A sensitivity analysis restricted to children 0-14 years showed a plateau and even a gradual decrease in the incidence of T1D, mainly driven by a decreasing trend in the 0-4 year old children. Overall, there was an increase in the mean age at the onset of T1D (from 10.9 in 1999 to 13.1 years in 2010). Conclusions: Our study is the most recent populationbased study to investigate the incidence and prevalence of T1D in Dutch children and adolescents. Both incidence and prevalence of T1D nearly doubled from 1998 to 2010. The increase in the number of new cases and older age at the onset of the disease warrants further research to identify environmental triggering factors of T1D.This journal suppl. entitled: Special Issue: Abstracts of the 30th International Conference on Pharmacoepidemiology and Therapeutic Risk Management ... 2014Background: ACEI-induced ADRs are the main reason to discontinue ACEI treatment. In prescription databases, information on ADRs is not available; therefore it is necessary to identify proxies for ADRs in such databases to study risk factors for ADRs. Objectives: To study prescription patterns for ACEIs as potential marker for ACEI-induced ADRs. Methods: A cohort of patients starting ACEI from 2000 to 2011 was identified within the Rotterdam Study, (a prospective population-based cohort study of approximately 15,000 individuals aged 45 years and older). Medication dispensing data on daily basis were obtained from the fully computerized linked pharmacies. Participants were followed from the start of ACEI treatment until the end of study period, death or moving out of the area, whichever came first. Patients were classified into 4 mutually exclusive groups: continuous users, discontinued users, switchers to angiotensin receptor blockers (ARBs), and switchers to other antihypertensives. For continuous use or switching, the maximum time interval between two prescription periods was set at 3 or 6months. Patients without a prescription for antihypertensives, 3 or 6months after the end date of the last ACEI prescription were classified as discontinued users. Primary care physician files were searched for reasons of ACEI discontinuation for patients who discontinued or switched ACEIs. Clinical events were classified as definite ADRs (73.5% cough, 3% angioedema, 23.5%others), probable ADRs, possible ADRs and definite non-ADRs. Positive predictive values (PPVs) of the prescription patters of the 3 groups for ADRs were calculated. Results: Totally 1132 patients were included. The PPV for a definite ADR was 56.1% in switchers to ARBs, while the PPVs for switchers to other antihypertensives, and discontinued users were 39.5% and 19.5%. Including probable and possible ADRs, increased the PPVs for switchers to ARBs to 68.3% and 90.5%. A 6-month time interval gave slightly higher PPVs compared to a 3-month interval (maximum 6.1% higher). Conclusions: This study showed that switching from ACEI to ARB is the best marker for ACEI-induced ADRs in prescription databases.This journal suppl. entitled: Special Issue: Abstracts of the 30th International Conference on Pharmacoepidemiology and Therapeutic Risk Management ... 2014Background: Results from multiple observational studies on inhaled long-acting beta-2-agonists (LABA) and the risk of acute myocardial infarction (AMI) are conflicting, due to variations in methodological, clinical and health care characteristics. To some extent, the discrepancies in the design might limit the comparability of the results encountered. Objectives: To determine the risk of AMI in inhaled LABA users in two European electronic primary care databases using a common study protocol. Methods: Patients from the Dutch Mondriaan (1.4 Million) and the UK CPRD (5 Million) databases were included if they had a diagnosis of asthma and/or COPD, and were prescribed at least one inhaled LABA, a short-acting beta-2-agonist (SABA), or a short- or long-acting muscarinic antagonist (SAMA, LAMA) during the study period (2002 to 2009). LABA episodes were divided into current, recent (1. Effect of Statin Use on Acute Kidney Injury Following Elective Cardiothoracic Surgery: A Population Cohort Study in Denmark J Bradley Layton, Malene K Hansen, Carl-Johan Jakobsen, Jan J Andreasen, Vibeke E Hjortdal, Bodil S Rasmussen, Abhijit V Kshirsagar, Ross J Simpson, Christian F Christiansen. Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States; Clinical Epidemiology, Aarhus Univeristy Hosptial, Aarhus, Denmark; Anesthesia and Intensive Care, Aarhus University Hospital, Aarhus, Denmark; Cardiothoracic Surgery, Aalborg University Hospital, Aalborg, Denmark; Cardiothoracic and Vascular Surgery, Aarhus University Hospital, Aarhus, Denmark; Anaesthesia and Intensive Care Medicine, Aalborg University Hospital, Aalborg, Denmark; Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC,Background: Limited quantitative data exist on the burden of chronic comorbidities in children and adolescents with type 1 diabetes (T1D). Such knowledge is necessary for the development of guidelines and prevention programs. Objectives: To determine the incidence of chronic comorbidities in children and adolescents with T1D and to compare the risks with the diabetes-free children. Methods: A population-based cohort study was conducted using the Dutch PHARMO-RLS that comprises community pharmacy dispensing records linked to hospital admissions. Insulin prescriptions were used as a proxy to identify incident cases of T1D. All patients (Background: Pregnancy-induced hypertension (PIH) is possibly caused by an increased activity of the sympatic nervous system. Previous studies have suggested that inhibition of the re-uptake of serotonin and norepinephrine by selective serotonin re-uptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs) could contribute to this increased activity. Objectives: To assess the association between the use of antidepressants (ADs) and the development of pregnancyinduced hypertension. Methods: Using the prescription database IADB.nl we conducted a case-control study among pregnant women between 1995 and 2012. Cases were defined as>1 dispensed prescription of an antihypertensive drug (methyldopa, dihydralazine, ketanserin, labetalol, nifidepine) after 20weeks of gestation. Controls were matched for age at time of giving birth. Only first and singleton pregnancies of women not using any antihypertensive drug during 6months before pregnancy till 20weeks of gestation were included. Exposure was defined as>1 dispensed prescription of an antidepressant during pregnancy. Logistic regression analysis was used to estimate odds ratios (OR) and their corresponding 95% confidence intervals (95% CIs). Subanalyses were conducted for class of AD (TCA, SSRI, other) and duration of AD use (1-30, ≥ 31 Defined Daily Doses (DDDs)). As the exact duration of gestation was unknown, all analysis were conducted for 3 theoretical gestational ages (36, 38, 40weeks). Results: A total of 312 PIH cases and 12480 controls were included in the analysis (gestational age 36 weeks). The exposure rate among case and control pregnancies was 3.2% and 1.5% respectively. The use of AD increased the risk for developing PIH more than twice (OR [95% CI] 2.24 [1.17-4.27]). Significant associations (OR [95% CI]) were also found for the subgroups TCA (3.39 [1.04-11.08]), SSRI (2.23 [1.03-4.81]) and ≥ 31 DDDs (2.38 [1.16-4.90]). Increasing the theoretical gestational age showed comparable results. Conclusions: Prolonged use of ADs during pregnancy appeared to be associated with an increased risk of developing PIH. When balancing the benefit and risks of using these drugs during pregnancy, this should be taken into account.Background: In observational studies of time-varying treatment, conditioning on time-dependent confounders that are affected by previous treatment using conventional regression methods may adjust-away(indirect) treatment effects.In the presence of unmeasured common causes of confounders and outcome, it can also induce collider-stratification bias. Objectives: To compare time-dependent propensity scores, conventional Cox and marginal structural models (MSM) in a study of selective serotonin reuptake inhibitors (SSRI) and the risk of hip fracture (HF). Methods: A cohort of patients with a first prescription for antidepressants (AD, SSRI or tricyclic antidepressants, TCA) was extracted from the Dutch Mondriaan GP database in the period 2001-2009.Potential confounders were ascertained when antidepressant use changed over time or at six month intervals. Follow-up began with the first day of AD prescription and ended at the occurrence of HF, death, unregistration with the GP, or end of the study.Treatment effects were estimated using time-varying Cox regression, PS stratification, covariate adjustment, and inverse probability weighting (MSM) to control for confounding. In MSMs, censoring was accounted for by including inverse probability of censoring weights (IPCW). Results: The crude HR of HF in current SSRI users versus non-current SSRI users was 1.70 [95%CI 1.09-2.65]. Effects increased after confounder adjustment, PS stratification, and PS adjustment: HR 2.28 [1.45-3.59], 2.47 [1.54-3.95], and 2.51 [1.54-4.09], respectively.When MSMs with stabilized weights were used, the HR was 1.34 [0.65-2.76] and 1.53 [0.81-2.93] with and without accounting for censoring, respectively. After weight truncation, the HR became 2.09 [1.31-3.35] and 2.37 [1.49-3.78] with and without accounting for censoring, respectively. Conclusions: When treatment and confounders are time-varying, accounting for informative censoring can materially influence effect estimates in addition to the potential collider-stratification and confounding bias that arise due conditioning or stratification on time-dependent confounders.Hence, the use of methods such as MSMs is recommended.