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.

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.

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.

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.

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.

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.

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.

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.

Registries in European post-marketing surveillance: a retrospective analysis of centrally approved products, 2005-2013.

PURPOSE: Regulatory agencies and other stakeholders increasingly rely on data collected through registries to support their decision-making. Data from registries are a cornerstone of post-marketing surveillance for monitoring the use of medicines in clinical practice. This study was aimed at gaining further insight into the European Medicines Agency's (EMA) requests for new registries and registry studies using existing registries and to review the experience gained in their conduct. METHODS: European Public Assessment Reports were consulted to identify products for which a request for a registry was made as a condition of the marketing authorisation. All centrally authorised products that received a positive opinion of the EMA Committee for Medicinal Products for Human Use between 1 January 2005 and 31 December 2013 were included. Data regarding registry design and experiences were collected from EMA electronic record keeping systems. RESULTS: Of 392 products that received a positive Committee for Medicinal Products for Human Use opinion during 2005-2013, 31 registries were requested for 30 products in total. Sixty-five percent were product registries whereas 35% were disease registries and 71% of the registries had a primary safety objective. Most commonly reported issues with registries were delayed time to start and low patient accrual rates. CONCLUSIONS: The delays found in getting new registries up and running support the need to improve the timeliness of data collection in the post-marketing setting. Methodological challenges met in conducting this study highlighted the need for a clarification of definitions and epidemiological concepts around patient registries. The results will inform the EMA Patient Registry initiative to support use of existing patient registries for the post-authorisation benefit-risk monitoring of medicinal products. © 2017 Commonwealth of Australia. Pharmacoepidemiology & Drug Safety © 2017 John Wiley & Sons, Ltd.

Case-only designs for studying the association of antidepressants and hip or femur fracture.

PURPOSE: The purpose of this study is to evaluate the performance and validity of the case-crossover (CCO) and self-controlled case-series (SCCS) designs when studying the association between hip/femur fracture (HF) and antidepressant (AD) use in general practitioner databases. In addition, comparability with cohort and case-control designs is discussed. METHODS: Adult patients with HF and who received an AD prescription during 2001-2009 were identified from UK's The Health Improvement Network (THIN) and the Dutch Mondriaan databases. AD exposure was classified into current, recent and past/non-use (reference). In the CCO, for each patient, a case moment (date of HF) and four prior control moments at -91, -182, -273 and -365 days were defined. In SCCS, incidence of HF was compared between exposure states. Conditional logistic regression was used in the CCO and Poisson regression in the SCCS to compute odds ratios and incidence rate ratios, respectively. In CCO, we adjusted for time-varying co-medication and in SCCS for age. RESULTS: Adjusted estimates for the effect of current AD exposure on HF were higher in the CCO (co-medication-adjusted odds ratio, THIN: 2.24, 95% confidence interval [CI]: 2.04-2.47; Mondriaan: 2.57, 95%CI [1.50, 4.43]) than in the SCCS (age-adjusted incidence rate ratio, THIN: 1.41, 95%CI [1.32, 1.49]; Mondriaan: 2.14, 95%CI [1.51, 3.03]). The latter were comparable with the traditional designs. CONCLUSION: Case-only designs confirmed the association between AD and HF. The CCO design violated assumptions in this study with regard to exchangeability and length of exposure, and transient effects on outcome. The SCCS seems to be an appropriate design for assessing AD-HF association.

Prevalence of antibiotic use: a comparison across various European health care data sources.

PURPOSE: There is widespread concern about increases in antibiotic use, but comparative data from different European countries on rates of use are lacking. This study was designed to measure and understand the variation in antibiotic utilization across five European countries. METHODS: Seven European healthcare databases with access to primary care data from Denmark, Germany, the Netherlands, Spain and the UK were used to measure and compare the point and 1-year-period prevalence of antibiotic use between 2004 and 2009. Descriptive analyses were stratified by gender, age and type of antibiotic. Separate analyses were performed to measure the most common underlying indications leading to the prescription of an antibiotic. RESULTS: The average yearly period prevalence of antibiotic use varied from 15 (Netherlands) to 30 (Spain) users per 100 patients. A higher prevalence of antibiotic use by female patients, the very young (0-9 years) and old (80+ years), was observed in all databases. The lowest point prevalence was recorded in June and September and ranged from 0.51 (Netherlands) to 1.47 (UK) per 100 patients per day. Twelve percent (Netherlands) to forty-nine (Spain) percent of all users were diagnosed with a respiratory tract infection, and the most common type of antibiotic prescribed were penicillin. CONCLUSION: Using identical methodology in seven EU databases to assess antibiotic use allowed us to compare drug usage patterns across Europe. Our results contribute quantitatively to the true understanding of similarities and differences in the use of antibiotic agents in different EU countries.

Understanding inconsistency in the results from observational pharmacoepidemiological studies: the case of antidepressant use and risk of hip/femur fractures.

PURPOSE: Results from observational studies on the same exposure-outcome association may be inconsistent because of variations in methodological factors, clinical factors or health care systems. We evaluated the consistency of results assessing the association between antidepressant use and the risk of hip/femur fractures in three European primary care databases using two different study designs. METHODS: Cohort and nested case control studies were conducted in three European primary care databases (Spanish BIFAP, Dutch Mondriaan and UK THIN) to assess the association between use of antidepressants and hip/femur fracture. A common protocol and statistical analysis plan was applied to harmonize study design and conduct between data sources. RESULTS: Current use of antidepressants was consistently associated with a 1.5 to 2.5-fold increased risk of hip/femur fractures in all data sources with both designs, with estimates for SSRIs generally higher than those for TCAs. In general, risk estimates in Mondriaan, the smallest data source, were higher compared to the other data sources. This difference may be partially explained by an interaction between SSRI and age in Mondriaan. Adjustment for GP-recorded lifestyle factors and matching on general practice had negligible impact on adjusted relative risk estimates. CONCLUSION: We found a consistent increased risk of hip/femur fracture with current use of antidepressants across different databases and different designs. Applying similar pharmacoepidemiological study methods resulted in similar risks for TCA use and some variation for SSRI use. Some of these differences may express real (or natural) variance in the exposure-outcome co-occurrences.

Exposure to benzodiazepines (anxiolytics, hypnotics and related drugs) in seven European electronic healthcare databases: a cross-national descriptive study from the PROTECT-EU Project.

PURPOSE: Studies on drug utilization usually do not allow direct cross-national comparisons because of differences in the respective applied methods. This study aimed to compare time trends in BZDs prescribing by applying a common protocol and analyses plan in seven European electronic healthcare databases. METHODS: Crude and standardized prevalence rates of drug prescribing from 2001-2009 were calculated in databases from Spain, United Kingdon (UK), The Netherlands, Germany and Denmark. Prevalence was stratified by age, sex, BZD type [(using ATC codes), i.e. BZD-anxiolytics BZD-hypnotics, BZD-related drugs and clomethiazole], indication and number of prescription. RESULTS: Crude prevalence rates of BZDs prescribing ranged from 570 to 1700 per 10,000 person-years over the study period. Standardization by age and sex did not substantially change the differences. Standardized prevalence rates increased in the Spanish (+13%) and UK databases (+2% and +8%) over the study period, while they decreased in the Dutch databases (-4% and -22%), the German (-12%) and Danish (-26%) database. Prevalence of anxiolytics outweighed that of hypnotics in the Spanish, Dutch and Bavarian databases, but the reverse was shown in the UK and Danish databases. Prevalence rates consistently increased with age and were two-fold higher in women than in men in all databases. A median of 18% of users received 10 or more prescriptions in 2008. CONCLUSION: Although similar methods were applied, the prevalence of BZD prescribing varied considerably across different populations. Clinical factors related to BZDs and characteristics of the databases may explain these differences.

Sharing clinical trial data on patient level: opportunities and challenges.

In recent months one of the most controversially discussed topics among regulatory agencies, the pharmaceutical industry, journal editors, and academia has been the sharing of patient-level clinical trial data. Several projects have been started such as the European Medicines Agency´s (EMA) "proactive publication of clinical trial data", the BMJ open data campaign, or the AllTrials initiative. The executive director of the EMA, Dr. Guido Rasi, has recently announced that clinical trial data on patient level will be published from 2014 onwards (although it has since been delayed). The EMA draft policy on proactive access to clinical trial data was published at the end of June 2013 and open for public consultation until the end of September 2013. These initiatives will change the landscape of drug development and publication of medical research. They provide unprecedented opportunities for research and research synthesis, but pose new challenges for regulatory authorities, sponsors, scientific journals, and the public. Besides these general aspects, data sharing also entails intricate biostatistical questions such as problems of multiplicity. An important issue in this respect is the interpretation of multiple statistical analyses, both prospective and retrospective. Expertise in biostatistics is needed to assess the interpretation of such multiple analyses, for example, in the context of regulatory decision-making by optimizing procedural guidance and sophisticated analysis methods.

Antiepileptic drug use in seven electronic health record databases in Europe: a methodologic comparison.

OBJECTIVE: The annual prevalence of antiepileptic drug (AED) prescribing reported in the literature differs considerably among European countries due to use of different type of data sources, time periods, population distribution, and methodologic differences. This study aimed to measure prevalence of AED prescribing across seven European routine health care databases in Spain, Denmark, The Netherlands, the United Kingdom, and Germany using a standardized methodology and to investigate sources of variation. METHODS: Analyses on the annual prevalence of AEDs were stratified by sex, age, and AED. Overall prevalences were standardized to the European 2008 reference population. RESULTS: Prevalence of any AED varied from 88 per 10,000 persons (The Netherlands) to 144 per 10,000 in Spain and Denmark in 2001. In all databases, prevalence increased linearly: from 6% in Denmark to 15% in Spain each year since 2001. This increase could be attributed entirely to an increase in "new," recently marketed AEDs while prevalence of AEDs that have been available since the mid-1990s, hardly changed. AED use increased with age for both female and male patients up to the ages of 80 to 89 years old and tended to be somewhat higher in female than in male patients between the ages of 40 and 70. No differences between databases in the number of AEDs used simultaneously by a patient were found. SIGNIFICANCE: We showed that during the study period of 2001-2009, AED prescribing increased in five European Union (EU) countries and that this increase was due entirely to the newer AEDs marketed since the 1990s. Using a standardized methodology, we showed consistent trends across databases and countries over time. Differences in age and sex distribution explained only part of the variation between countries. Therefore, remaining variation in AED use must originate from other differences in national health care systems.

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.

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.

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.