Ondansetron use in nausea and vomiting during pregnancy: A descriptive analysis of prescription patterns and patient characteristics in UK general practice.

AIMS: The objective of this study was to describe ondansetron drug utilization patterns during pregnancy to treat nausea and vomiting in pregnancy (NVP). Moreover, we aimed to describe the maternal factors associated with NVP and antiemetic use. METHODS: The data consist of pregnancies with a live birth(s) within an IMRD-UK registered GP practice. Descriptive statistics were used to investigate patterns of ondansetron use in pregnancy and to describe maternal characteristics associated with NVP and antiemetic drug utilization. We differentiate first- from second-line use during pregnancy using antiemetic prescription pathways. RESULTS: The dataset included 733 633 recorded complete pregnancies from 2005 to 2019. NVP diagnosis and ondansetron prescription prevalence increased from 2.7% and 0.1% in 2005 to 4.8% and 2.5% in 2019 respectively. Over the period 2015-2019, the most common oral daily dosages were 4 mg/d (8.5%), 8 mg/d (37.1%), 12 mg/d (37.5%) and between 16 and 24 mg/d (16.9%). Prescription of ondansetron was initiated during the first trimester of pregnancy in 40% of the cases and was moderately used as a first-line therapy (2.8%), but preferred choice of second-line therapy. Women with mental health disorders, asthma and/or prescribed folic acid were more likely to experience NVP and use antiemetics in pregnancy than their counterparts. CONCLUSION: This study confirms that ondansetron is increasingly used off-label to treat NVP during pregnancy, also in the first trimester and before other prescription antiemetics have been prescribed. Several maternal comorbidities and folic acid use were more common among women experiencing NVP and using antiemetics, including ondansetron.

The Impact of Mandatory Reporting of Non-Serious Safety Reports to EudraVigilance on the Detection of Adverse Reactions.

INTRODUCTION AND OBJECTIVE: European Union legislation has mandated the submission of European Economic Area non-serious reports to the EudraVigilance database since November 2017. As spontaneous reports of suspected adverse reactions to medicines represent a key source of safety signals, the European Medicines Agency has undertaken this work to assess the effects of this requirement on the characteristics of the reports submitted to EudraVigilance and on the detection of adverse drug reactions through routine analyses of the database. METHODS: Changes in the numbers of serious and non-serious reports transmitted to EudraVigilance were examined over the period during which the legislation was implemented. The numbers and nature of potential safety signals emerging from established statistical algorithms used at the European Medicines Agency applied either to only the serious reports or to all reports in EudraVigilance were compared. RESULTS: Up to November 2017, less than 25% of European Economic Area reports in EudraVigilance were classified as non-serious, since than this figure was slightly above 60%. This change accompanied an increase in the total number of reports received. Addition of non-serious reports to the signal detection process resulted in a small overall increase in signals of disproportionate reporting with some new signals of disproportionate reporting appearing and some existing signals of disproportionate reporting disappearing; the sensitivity of the signal detection system was slightly increased and the proportion of signals of disproportionate reporting that corresponded to known adverse drug reactions (a measure of efficiency) was unchanged. CONCLUSIONS: The change in legislation has led to a small increase in sensitivity, without affecting the efficiency of the routine statistical measures used. The number of non-serious reports as a proportion of reports in EudraVigilance is likely to increase over time and further monitoring of the impact on signal detection is required. Further work is also required on the qualitative impact of non-serious reports on the nature of signals detected and on their evaluation.

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

INTRODUCTION: The analgesic metamizole, which has been withdrawn from the market in several countries due to the risk of agranulocytosis but is still available on the market in Germany and some other countries, has been associated with liver injury in published case reports; however, epidemiological studies on the risk of liver injury are limited. OBJECTIVE: The aim of this study was to compare the risk of liver injury up to 270 days after the first start of treatment with metamizole with the corresponding risk in patients starting treatment with paracetamol, using a retrospective cohort incident user design. METHODS: The first prescription for either metamizole or paracetamol in the Intercontinental Medical Statistics (IMS)® Disease Analyzer Germany database during the study period (2009-2018) was identified in patients with at least 365 days of observation and no prior diagnosis of liver events, cancer or HIV, or treatment within the last 6 months with hepatotoxic drugs typically administered for chronic conditions. Each patient was followed for specific liver events for 90 days after the prescription. In case of a new prescription within 90 days, a new 90-day observation period started, up to a maximum of 270 days. Cox regression was used to compare the risk of liver injury in the two groups. RESULTS: Metamizole was associated with a higher risk of liver injury compared with paracetamol (adjusted hazard ratio 1.69, 95% confidence interval 1.46-1.97). Sensitivity analyses were performed to evaluate the robustness of these findings. In all the sensitivity analyses, metamizole was still associated with a higher risk of liver injury, including an analysis where naproxen was used as a comparator instead of paracetamol. CONCLUSIONS: Results from this study support previous studies suggesting that metamizole is associated with a significant risk of liver injury. Nevertheless, a possible impact of residual confounding cannot be excluded.

Does additional monitoring status increase the reporting of adverse drug reactions? An interrupted time series analysis of EudraVigilance data.

PURPOSE: To evaluate the impact of including a medicine in the list of medicinal products subject to additional monitoring (AM) on the reporting of adverse drug reactions (ADRs) in the european economic area (EEA). METHODS: Interrupted time series using the monthly number of EEA ADR reports in EudraVigilance during 12 months before and after the addition to AM list. The main outcome was the change (%) in reporting of ADRs with step change as the a priori impact model. Further time series analysis was performed using Joinpoint Regression. RESULTS: The analysis included 11 active substances. No significant immediate (step change) increase of reporting was identified for any product at time of addition to AM list. We identified a significant gradual increase of ADR reporting after addition to AM list (slope change) for two out of five new products-boceprevir (10% per month, 95% confidence interval (CI) 3%-18%) and denosumab-Xgeva (13% per month, 95% CI 4%-22%). No change was identified for Prolia, another denosumab-containing product not subject to AM. No significant increase was identified for any product included in the AM list due to the requirement to conduct a PASS. Conversely, a gradual decrease in reporting was identified for natalizumab (-5% per month; 95% CI -10% to -1%), rivaroxaban (-5%; -8 to -3%), and varenicline (-16%; -21 to -10%). The results were corroborated by the Joinpoint analyses, which yielded similar results. CONCLUSIONS: We identified limited evidence that reporting of ADRs increased modestly and gradually for some new products and not for products with PASS requirement.

What are the patients' and health care professionals' understanding and behaviors towards adverse drug reaction reporting and additional monitoring?

BACKGROUND: The additional monitoring (AM)/black triangle concept is aimed to enhance ADR reporting for certain types of medicinal products for which the safety profile is less well established. PURPOSE: The objective of this survey was to assess (a) attitudes towards ADR reporting and reasons for not reporting an ADR and (b) awareness of AM among HCPs, patients or their careers in EU countries. METHODS: An online questionnaire which was available in all EU languages was completed by 2918 responders coming from all EEA countries. RESULTS: The main factors motivating to report an ADR were severity or novelty of the reaction or novelty of the medicine. The main factors for not reporting an ADR was the fact that the ADR is already known (35%), the ADR was not serious (18%) or reporter was not sure if the ADR was related to the medicine (15%). Half of the respondents indicated that they have seen AM statement before. Thirty percent of the responders had correct understanding of the AM concept while 20 % misunderstood the concept. CONCLUSION: Underreporting occurs but it seems this is because of reporter's prioritisation towards certain type of ADRs. AM aims to increase reporting for certain medicines, however, approximately half of responders have seen the AM symbol before and 20% of all responders (independent of their previous awareness) misunderstood the concept.

Assessing strength of evidence for regulatory decision making in licensing: What proof do we need for observational studies of effectiveness?

Before a medicine can be recommended for a marketing authorization research must be provided to regulators that convincingly supports the benefit-risk of the product in the claimed indication. The established criteria for such research are usually expressed in terms of evidence from randomized controlled trials (RCT). If studies in real-world data (RWD) are to be accepted as all or part of the package of evidence, it is necessary to understand the relationship between information from studies of RWD and that from RCTs. The aim of this review is to consider how the strength of such evidence can be quantified in a manner that relates to the decision-making process, what research is currently available to further this understanding and what additional information will be required.

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

Although postmarketing studies conducted in population-based databases often contain information on patients in the order of millions, they can still be underpowered if outcomes or exposure of interest is rare, or the interest is in subgroup effects. Combining several databases might provide the statistical power needed. A multi-database study (MDS) uses at least two healthcare databases, which are not linked with each other at an individual person level, with analyses carried out in parallel across each database applying a common study protocol. Although many MDSs have been performed in Europe in the past 10 years, there is a lack of clarity on the peculiarities and implications of the existing strategies to conduct them. In this review, we identify four strategies to execute MDSs, classified according to specific choices in the execution: (A) local analyses, where data are extracted and analyzed locally, with programs developed by each site; (B) sharing of raw data, where raw data are locally extracted and transferred without analysis to a central partner, where all the data are pooled and analyzed; (C) use of a common data model with study-specific data, where study-specific data are locally extracted, loaded into a common data model, and processed locally with centrally developed programs; and (D) use of general common data model, where all local data are extracted and loaded into a common data model, prior to and independent of any study protocol, and protocols are incorporated in centrally developed programs that run locally. We illustrate differences between strategies and analyze potential implications.

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

AIMS: Hydrochlorothiazide-induced photosensitivity may increase squamous cell carcinoma (SCC), basal cell carcinoma (BCC) and lip cancer risk. The aim was to quantify these risks. METHODS: Nested case-control studies using data from the UK THIN database from 01 January 1999 to 01 May 2016. Adults with incident SCC, BCC, melanoma, lip cancer and oral cancer were matched (on age, sex and calendar year of cohort entry) to controls using incidence density sampling. Incidence rate ratios (IRR) for each outcome were calculated for ever and cumulative hydrochlorothiazide exposure, measuring the impact of additionally adjusting for smoking and body mass index (BMI). Adjusted rate differences were estimated, including the number needed to harm. RESULTS: Cumulative hydrochlorothiazide doses ≥50 000 mg were associated with a significantly increased risk of SCC IRR = 3.05 (1.93-4.81) and BCC IRR = 1.34 (1.06-1.69). Using a 5-year lag-period, hydrochlorothiazide exposure was also associated with a significantly increased risk of lip cancer (IRR 2.85, 95% confidence interval 1.32-6.15). No significantly increased risk of melanoma or oral cavity cancer was observed. Following adjustment for smoking and BMI, which had inverse associations with several skin cancer types, associations for hydrochlorothiazide remained significant. The overall number needed to harm with high-dose cumulative hydrochlorothiazide exposure was: 804 for SCC; 2463 for BCC, and 200 000 for lip cancer but varied by age and sex. CONCLUSION: Hydrochlorothiazide exposure was associated with an increased risk of SCC, BCC and lip cancer that is not explained following adjustment for smoking and BMI. These findings may support clinical and regulatory decision making.

Can We Rely on Results From IQVIA Medical Research Data UK Converted to the Observational Medical Outcome Partnership Common Data Model?: A Validation Study Based on Prescribing Codeine in Children.

Exploring and combining results from more than one real-world data (RWD) source might be necessary in order to explore variability and demonstrate generalizability of the results or for regulatory requirements. However, the heterogeneous nature of RWD poses challenges when working with more than one source, some of which can be solved by analyzing databases converted into a common data model (CDM). The main objective of the study was to evaluate the implementation of the Observational Medical Outcome Partnership (OMOP) CDM on IQVIA Medical Research Data (IMRD)-UK data. A drug utilization study describing the prescribing of codeine for pain in children was used as a case study to be replicated in IMRD-UK and its corresponding OMOP CDM transformation. Differences between IMRD-UK source and OMOP CDM were identified and investigated. In IMRD-UK updated to May 2017, results were similar between source and transformed data with few discrepancies. These were the result of different conventions applied during the transformation regarding the date of birth for children younger than 15 years and the start of the observation period, and of a misclassification of two drug treatments. After the initial analysis and feedback provided, a rerun of the analysis in IMRD-UK updated to September 2018 showed almost identical results for all the measures analyzed. For this study, the conversion to OMOP CDM was adequate. Although some decisions and mapping could be improved, these impacted on the absolute results but not on the study inferences. This validation study supports six recommendations for good practice in transforming to CDMs.

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

Importance: Peripheral neuropathy has been associated with systemic fluoroquinolone exposure, but risk has been poorly quantified. Objective: To calculate relative and absolute risk estimates for the association of fluoroquinolone exposure with peripheral neuropathy and to examine how risk may be affected by timing of fluoroquinolone exposure and by other risk factors. Design, Setting, and Participants: This nested case-control study used anonymized data from all patients routinely registered with general practices in The Health Improvement Network database, a large primary care population database in the United Kingdom, from January 1, 1999, to December 31, 2015. Data analyses were conducted January 8, 2018. The cohort consisted of 1 338 900 adults issued 1 or more prescriptions of fluoroquinolone (34.3%) or amoxicillin-clavulanate (65.7%) antibiotics. Adults with incident peripheral neuropathy were matched (on age, sex, general practice, and calendar time) with up to 4 controls by using incidence density sampling selected from a cohort prescribed oral fluoroquinolone or amoxicillin-clavulanate antibiotics. Incidence rate ratios of peripheral neuropathy were calculated for fluoroquinolone and for amoxicillin-clavulanate exposure and compared with nonexposure among patients without diabetes, with sensitivity analyses testing the consistency of the results. Population mean-adjusted rate differences were then estimated, including the number needed to harm for various durations of fluoroquinolone therapy. Exposures: Current and cumulative exposure to oral fluoroquinolone or amoxicillin-clavulanate antibiotics. Main Outcomes and Measures: Incident peripheral neuropathy cases recorded in electronic medical records. Results: In total, 5357 patients with incident peripheral neuropathy (mean [SD] age, 65.6 [14.7] years; 2809 women [52.4%]) were matched to 17 285 controls (mean [SD] age, 64.4 [15.2] years; 9485 women [54.9%]) without diabetes. Current oral fluoroquinolone exposure was associated with an increased relative incidence of peripheral neuropathy compared with nonexposure (adjusted incident rate ratio, 1.47; 95% CI, 1.13-1.92). Risk increased by approximately 3% for each additional day of current fluoroquinolone exposure and persisted for up to 180 days following exposure. No significant increased risk was observed with oral amoxicillin-clavulanate exposure. The absolute risk with current oral fluoroquinolone exposure was 2.4 (95% CI, 1.8-3.1) per 10 000 patients per year of current use. The number needed to harm for a 10-day course was 152 083 patients (95% CI, 117 742-202 778) and was greatest among men and among patients older than 60 years. Conclusions and Relevance: The results of the present study suggested that oral fluoroquinolone therapy was associated with an increased risk of incident peripheral neuropathy that may depend on the timing of the exposure and the cumulative dose. Health care professionals should consider these potential risks when prescribing fluoroquinolone antibiotics.

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

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

Prescribing patterns of tramadol in adults in IMS® primary care databases in France and Germany between 1 January 2006 and 30 June 2016.

PURPOSE: There is increasing concern with regard to fatal intoxications with prescription opioids and tramadol poisonings. This study aimed to characterise prescribing patterns for tramadol in primary care in France and Germany and identify long-term treatment and potential risk factors for such treatment. METHODS: Adult patients-prescribed tramadol between January 2006 and June 2016 in GP practices in IMS® Disease Analyzer databases in France and Germany were identified. Six-monthly prevalence and mean doses and durations were calculated by gender, age group and type of tramadol product. The proportion of incident use that resulted in treatment ≥ 366 days was calculated. The odds for long-term treatment was analysed in relation to gender, age group, type of tramadol product, start dose, indication and a diagnosis of abuse or misuse. RESULTS: Overall prescribing of tramadol decreased in Germany and increased, then plateaued in France. Prescribing was higher in females. Predominantly prescribed products were tramadol in combination with paracetamol (COMB) in France and slow release formulations of tramadol (SR-TRAM) in Germany. SR-TRAM had the highest mean doses and durations, followed by immediate release formulations of tramadol (IR-TRAM) and COMB. Around 1.5% of incident tramadol use in France and 8.2% in Germany resulted in long-term treatment. Long-term treatment was associated with increasing age, SR-TRAM and a diagnosis of abuse or misuse. CONCLUSIONS: The risk of long-term treatment appeared to increase with increasing age. Potential risk factors for long-term treatment included initiating treatment with SR-TRAM and a diagnosis of abuse or misuse.

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

BACKGROUND AND OBJECTIVE: Tendon rupture can result from fluoroquinolone exposure. The objective of this study was to quantify relative and absolute risk and determine how risk is affected by timing of exposure. METHODS: The UK Health Improvement Network primary care database was used to perform a nested case-control study measuring the association between fluoroquinolone exposure and tendon rupture. Adults with tendon rupture were matched on age, sex, general practice and calendar time to four controls selected from a cohort prescribed systemic fluoroquinolone or co-amoxiclav antibiotics. The relative and absolute risk of tendon rupture with fluoroquinolone exposure was calculated. RESULTS: Current fluoroquinolone exposure was associated with an increased risk of any tendon rupture (adjusted incidence rate ratio [aIRR] 1.61, 95% CI 1.25-2.09) and Achilles tendon rupture (aIRR 3.14, 95% CI 2.11-4.65) that persisted for 60 days. Risk increased with cumulative exposure and was greatest when co-prescribed with oral corticosteroids (aIRR 19.36, 95% CI 7.78-48.19 for Achilles tendon rupture). The adjusted rate difference (aRD) with fluoroquinolone exposure was 2.9 and 2.1 per 10,000 patients for any and Achilles tendon rupture, respectively, and was greatest in people aged ≥ 60 years prescribed concomitant oral corticosteroid therapy (aDR 19.6 for any tendon and 6.6 Achilles tendon rupture per 10,000). No association was seen with co-amoxiclav or statin exposure, or with biceps or other tendon ruptures. CONCLUSIONS: Risk of tendon rupture with fluoroquinolones depends on timing, cumulative dose and concomitant exposure to oral corticosteroids. Absolute risk significantly varied by age and concomitant corticosteroid exposure, affecting elderly patients the greatest.

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

OBJECTIVE: Electronic healthcare databases (EHDs) are useful tools for drug development and safety evaluation but their heterogeneity of structure, validity and access across Europe complicates the conduct of multidatabase studies. In this paper, we provide insight into available EHDs to support regulatory decisions on medicines. METHODS: EHDs were identified from publicly available information from the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance resources database, textbooks and web-based searches. Databases were selected using criteria related to accessibility, longitudinal dimension, recording of exposure and outcomes, and generalisability. Extracted information was verified with the database owners. RESULTS: A total of 34 EHDs were selected after applying key criteria relevant for regulatory purposes. The most represented regions were Northern, Central and Western Europe. The most frequent types of data source were electronic medical records (44.1%) and record linkage systems (29.4%). The median number of patients registered in the 34 data sources was 5 million (range 0.07-15 million) while the median time covered by a database was 18.5 years. Paediatric patients were included in 32 databases (94%). Completeness of information on drug exposure was variable. Published validation studies were found for only 17 databases (50%). Some level of access exists for 25 databases (73.5%), and 23 databases (67.6%) can be linked through a personal identification number to other databases with parent-child linkage possible in 7 (21%) databases. Eight databases (23.5%) were already transformed or were in the process of being transformed into a common data model that could facilitate multidatabase studies. CONCLUSION: A Few European databases meet minimal regulatory requirements and are readily available to be used in a regulatory context. Accessibility and validity information of the included information needs to be improved. This study confirmed the fragmentation, heterogeneity and lack of transparency existing in many European EHDs.

Indications for Systemic Fluoroquinolone Therapy in Europe and Prevalence of Primary-Care Prescribing in France, Germany and the UK: Descriptive Population-Based Study.

BACKGROUND AND OBJECTIVES: In the USA the benefit-risk profile of fluoroquinolones for treating patients with acute bacterial sinusitis, acute bacterial exacerbation of chronic bronchitis, and uncomplicated urinary tract infections (uUTIs) is considered unfavorable. However, the number of fluoroquinolone products in the EU indicated and prescribed for these infections is uncertain. The objective of this study was to provide data on indications for fluoroquinolones in Europe and examine the prevalence of prescribing in France, Germany and the UK. METHODS: Descriptive analysis of indications for systemic fluoroquinolone antibiotics across the European Economic Area (EEA) and descriptive analysis of systemic fluoroquinolone antibiotic prescribing in France, Germany and UK electronic health records (2000-2015). RESULTS: All EEA countries had fluoroquinolone products indicated for acute sinusitis, acute bronchitis, or uUTIs, with differences in the number of products between countries for: acute sinusitis (19.5-51.9%), acute bronchitis (22.2-73.4%), and uUTIs (52.0-89.1%). The prevalence of fluoroquinolone prescribing for the treatment of respiratory tract infections (RTIs) appeared to fall with time in all countries and for UTI in France and UK only. Changes were greatest in the UK. In France, Germany, and the UK, respectively: acute sinusitis accounted for 29.5, 20.6, and 40.7% of all oral fluoroquinolone prescriptions for upper RTIs; acute bronchitis accounted for 63.0, 83.0, and 89.9% of all fluoroquinolone prescriptions for lower RTIs; uUTIs accounted for 83.3, 89.9, and 32.2% of all fluoroquinolone prescriptions for UTIs. CONCLUSION: Large numbers of fluoroquinolone products in Europe are listed for the treatment of milder infections such as acute bronchitis, acute sinusitis and uUTIs. Among the countries assessed, fluoroquinolones were commonly prescribed for these conditions and potentially should lead to a review of therapeutic guidelines.

Cohort Study of Psychiatric Adverse Events Following Exposure to Levonorgestrel-Containing Intrauterine Devices in UK General Practice.

INTRODUCTION: Intrauterine devices are implantable contraceptives of which some brands steadily release levonorgestrel over an extended time period. Exposure to a levonorgestrel-releasing intrauterine device has been associated with depression and, more recently, a connection to anxiety, panic attacks, sleep problems and restlessness has been suggested. This study uses data from the THIN database of UK general practice to investigate these suggestions. METHODS: A cohort study was performed to compare the incidence of psychiatric adverse events between groups of women who were new users of levonorgestrel-releasing and non-hormonal intrauterine devices. Hazard ratios for the first occurrence of psychiatric symptoms or prescriptions of disease-specific treatments were calculated on an intention-to-treat basis using a proportional hazards model. RESULTS: Significant associations were found between levonorgestrel exposure and records of anxiety (hazard ratio = 1.18; 95% confidence interval 1.08-1.29) and sleep problems (hazard ratio = 1.22; 95% confidence interval 1.08-1.38) in women without a prior record of these events. No significant associations were found for panic attacks or restlessness. Clear baseline differences in clinical characteristics and age between the groups were present. These were included in the model as potential confounding factors. CONCLUSION: Statistically significant associations of levonorgestrel exposure with anxiety and sleep problems were observed. Substantive differences in baseline characteristics of the treated groups make robust conclusions difficult but the results strongly suggest that additional studies are warranted.

EudraVigilance Medicines Safety Database: Publicly Accessible Data for Research and Public Health Protection.

The analysis of safety data from spontaneous reporting systems has a proven value for the detection and analysis of the risks of medicines following their placement on the market and use in medical practice. EudraVigilance is the pharmacovigilance database to manage the collection and analysis of suspected adverse reactions to medicines authorised in the European Economic Area. EudraVigilance first operated in December 2001, with access to the database being governed by the EudraVigilance access policy. We performed a literature search including data up to December 2016 to demonstrate how the data from EudraVigilance has been used in scientific publications. We describe the results, including by type of publication, research topics and drugs involved. In 50% of the publications, the data are used to describe safety issues, in 44% to analyse methodologies used in pharmacovigilance activities and in 6% to support clinical perspectives. We also outline a description of the use of the database by the European Union regulatory network. Driven by the full implementation of the 2010 pharmacovigilance legislation, EudraVigilance has undergone further enhancements together with a major revision of its access policy, taking into account the use of the new individual case safety report standard developed by the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use and the International Organization for Standardization. The aim of the broadened access is to facilitate more effective safety monitoring of authorised medicines, to make more data available for research and to provide better access to information on suspected adverse reactions for healthcare professionals and patients. In November 2017, the new full functionalities of EudraVigilance were launched, including the extensive web access to data on suspected adverse drug reactions and the possibilities for academic research institutions to request a more extensive dataset for the purposes of health research. The main objective of this article is to describe the new access to the database together with the opportunities that this new access can bring for research. It is intended to promote an appropriate use of the data to support the safe and effective use of medicines.

Antidepressant use during pregnancy and risk of autism spectrum disorder and attention deficit hyperactivity disorder: systematic review of observational studies and methodological considerations.

BACKGROUND: Antidepressant exposure during pregnancy has been associated with an increased risk of autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) in several observational studies. We performed a systematic review of these studies to highlight the effect that important methodological limitations have on such analyses and to consider approaches to the conduct, reporting and interpretation of future studies. METHODS: A review of MEDLINE and EMBASE identified case-control, cohort and sibling studies assessing the risk of ASD and ADHD with antidepressant use during pregnancy. Approaches to confounding adjustment were described. Crude and adjusted effect estimates for comparisons between antidepressant exposure during pregnancy vs. all unexposed women were first meta-analysed using a generic inverse variance method of analysis, followed by effect estimates for alternative pre-selected comparison groups. RESULTS: A total of 15 studies measuring ASD as an outcome (involving 3,585,686 children and 40,585 cases) and seven studies measuring ADHD as an outcome (involving 2,765,723 patients and 52,313 cases) were identified. Variation in confounding adjustment existed between studies. Updated effect estimates for the association between maternal antidepressant exposure during pregnancy vs. all unexposed women remained statistically significant for ASD (adjusted random-effects risk ratio [RaRR] 1.53, 95% confidence interval [CI] 1.31-1.78). Similar significant associations were observed using pre-pregnancy maternal antidepressant exposure (RaRR 1.48, 95% CI 1.29-1.71) and paternal antidepressant exposure during pregnancy (1.29, 95% CI 1.08-1.53), but analyses restricted to using women with a history of affective disorder (1.18, 95% CI 0.91-1.52) and sibling studies (0.96, 95% CI 0.65-1.42) were not statistically significant. Corresponding associations for risk of ADHD with exposure were: RaRR 1.38, 95% CI 1.13-1.69 (during pregnancy), RaRR 1.38, 95% CI 1.14-1.69 (during pre-pregnancy), RaRR 1.71, 95% CI 1.31-2.23 (paternal exposure), RaRR 0.98, 95% CI 0.77-1.24 (women with a history of affective disorder) and RaRR 0.88, 95% CI 0.70-1.11 (sibling studies). CONCLUSIONS: Existing observational studies measuring the risk of ASD and ADHD with antidepressant exposure are heterogeneous in their design. Classical comparisons between exposed and unexposed women during pregnancy are at high risk of residual confounding. Alternative comparisons and sibling designs may aid the interpretation of causality and their utility requires further evaluation, including understanding potential limitations of undertaking meta-analyses with such data.

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

BACKGROUND: The amount of drug exposure, pre and post approval, is considered to be a direct determinant of knowledge about the safety of a drug. A larger pre-approval exposed population is supposed to reduce the risk of unanticipated safety issues post-approval. The amount of use in the postapproval population is also expected to influence the occurrence and timing of safety issues. We investigated how the amount of pre and post approval exposure influences the detection of post-approval safety issues. METHODS: A cohort of innovative drugs approved in Europe was followed for the period of 2012-2016. The main outcome of interest was a new safety issue in the period. Post-approval exposure was collected at 6 month intervals, and pre-approval exposure was collected at the moment of authorisation. Other characteristics collected for the included drugs were anatomical therapeutical chemical (ATC) class, biological status, orphan status and type of approval. We used Cox proportional hazards regression to investigate the association between exposure and the hazard of having a first safety issue. RESULTS: The pre-approval exposure was not associated with the risk of safety issues after adjusting for ATC class, biological status, and treatment duration. Higher post-approval exposure was associated with more new safety issues identified (HR = 2.44 (95% CI = 1.12-5.31)) for drugs with more than 1,000 patient-years of cumulative exposure compared to drugs with less than 1,000 patient years of exposure. CONCLUSION: Our results suggest that postapproval exposure influences the detection of safety issues.

An algorithm to detect unexpected increases in frequency of reports of adverse events in EudraVigilance.

PURPOSE: The European Medicines Agency developed an algorithm to detect unexpected increases in frequency of reports, to enhance the ability to detect adverse events that manifest as increases in frequency, in particular quality defects, medication errors, and cases of abuse or misuse. METHODS: An algorithm based on a negative binomial time-series regression model run on 6 sequential observations prior to the monitored period was developed to forecast monthly counts of reports. A heuristic model to capture increases in counts when the previous 4 observations were null supplemented the regression. Count data were determined at drug-event combination. Sensitivity analyses were run to determine the effect of different methods of pooling or stratifying count data. Positive retrospective detections and positive predictive values (PPVs) were determined. RESULTS: The algorithm detected 8 of the 13 historical concerns, including all concerns of quality defects. The highest PPV (1.29%) resulted from increasing the lower count threshold from 3 to 5 and including literature reports in the counts. Both the regression model and the heuristic model components to the algorithm contributed to the detection of concerns. Sensitivity analysis indicates that stratification by commercial product reduces the PPV but suggests that pooling counts of related events may improve it. CONCLUSION: The results are encouraging and suggest that the algorithm could be useful for the detection of concerns that manifest as changes in frequency of reporting; however, further testing, including in prospective use, is warranted.