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Purpose: Metadata for data dIscoverability aNd study rEplicability in obseRVAtional studies (MINERVA), a European Medicines Agency–funded project (EUPAS39322), defined a set of metadata to describe real‐world data sources (RWDSs) and piloted metadata collection in a prototype catalogue to assist investigators from data source discoverability through study conduct. Methods: A list of metadata was created from a review of existing metadata catalogues and recommendations, structured interviews, a stakeholder survey, and a technical workshop. The prototype was designed to comply with the FAIR principles (findable, accessible, interoperable, reusable), using MOLGENIS software. Metadata collection was piloted by 15 data access partners (DAPs) from across Europe. Results: A total of 442 metadata variables were defined in six domains: institutions (organizations connected to a data source); data banks (data collections sustained by an organization); data sources (collections of linkable data banks covering a common underlying population); studies; networks (of institutions); and common data models (CDMs). A total of 26 institutions were recorded in the prototype. Each DAP populated the metadata of one data source and its selected data banks. The number of data banks varied by data source; the most common data banks were hospital administrative records and pharmacy dispensation records (10 data sources each). Quantitative metadata were successfully extracted from three data sources conforming to different CDMs and entered into the prototype. Conclusions: A metadata list was finalized, a prototype was successfully populated, and a good practice guide was developed. Setting up and maintaining a metadata catalogue on RWDSs will require substantial effort to support discoverability of data sources and reproducibility of studies in Europe. [ABSTRACT FROM AUTHOR]

Purpose: This paper aims to introduce an algorithm designed to identify Venous Thromboembolism (VTE) in the French National Healthcare Database (SNDS) and to estimate its positive predictive value. Methods: A case‐identifying algorithm was designed using SNDS inpatient and outpatient encounters, including hospital stays with discharge diagnoses, imaging procedures and drugs dispensed, of French patients aged at least 18 years old to whom baricitinib or Tumor Necrosis Factor Inhibitors (TNFi) were dispensed between September 1, 2017, and December 31, 2018. An intra‐database validation study was then conducted, drawing 150 cases identified as VTE by the algorithm and requesting four vascular specialists to assess them. Patient profiles used to conduct the case adjudication were reconstituted from de‐identified pooled and formatted SNDS data (i.e., reconstituted electronic health records—rEHR) with a 6‐month look‐back period prior to the supposed VTE onset and a 12‐month follow‐up period after. The positive predictive value (PPV) with its 95% confidence interval (95% CI) was calculated as the number of expert‐confirmed VTE divided by the number of algorithm‐identified VTE. The PPV and its 95% CI were then recomputed among the same patient set initially drawn, once the VTE‐identifying algorithm was updated based on expert recommendation. Results: For the 150 patients identified with the first VTE‐identifying algorithm, the adjudication committee confirmed 92 cases, resulting in a PPV of 61% (95% CI = [54–69]). The final VTE‐identifying algorithm including expert suggestions showed a PPV of 92% (95% CI = [86–98]) with a total of 87 algorithm‐identified cases, including 80 retrieved from the 92 confirmed by experts. Conclusion: The identification of VTE in the SNDS is possible with a good PPV. [ABSTRACT FROM AUTHOR]

Background: The combination dextropropoxyphene/paracetamol (DXP/P) was the most prescribed opioid analgesic until its withdrawal in 2011. Objectives: This study investigated dispensations of analgesics in chronic users of DXP/P during the 18 months following its withdrawal. Methods: A cross‐sectional study repeated yearly was conducted by using the French reimbursement database from 2006 to 2015. Chronic DXP/P users were defined as patients who received at least 40 boxes of DXP/P in the year prior to withdrawal. Data on analgesic dispensing were analyzed at DXP/P withdrawal (T0) and then every 6 months for 18 months. Results: A total of 63 671 subjects had a DXP/P reimbursement in the year prior to its discontinuation, of whom 7.1% were identified as chronic users (mean age: 71.5 years, women: 68.7%). Among the patients taking DXP/P alone at T0 (74.6%), one fourth switched to a peripheral analgesic, one fourth to a combination of peripheral analgesic/opioid, one fourth to another opioid, and the others mainly discontinued their treatment (14.1%) or died. During the following 12 months, most of the subjects taking only peripheral analgesics continued this treatment, while half of the subjects with a combination of opioid/peripheral analgesic or taking only an analgesic remained on this type of treatment. Conclusion: Eighteen months after DXP/P withdrawal, more than 10% of patients stopped taking an analgesic. Vigilance is required regarding any change in analgesics by regularly reassessing patients' pain and, in the case of opioid treatments, by monitoring the risk of use disorders. [ABSTRACT FROM AUTHOR]

Purpose: The objective was to compare the risk of malignancies in real‐world settings between exclusive immunosuppressant (IS) and immunomodulator (IM) use in multiple sclerosis (MS). Methods: A nested case–control study was designed within a new‐user cohort of all patients with MS who initiated a first IM or IS between 2008 and 2014, and without cancer history, using the information of the SNDS nationwide French claims database. Incident cancer cases were matched with up to six controls on year of birth, sex, initiation date, and disease risk score of cancer. A conditional logistic regression (odds ratio [95% confidence interval]) was used to compare exclusive IS versus IM use during follow‐up and according to three use durations. Results: From 28 720 newly treated patients with MS, 407 incident cancers were observed during the follow‐up with 2324 matched controls. A significant increase in cancer risk was observed for IS compared with IM (1.36 [1.05, 1.77]), with similar increases for the first 2 years of use but not for ≥2 years (1.06 [0.65, 1.75]). Similar increase was also observed for IS with indications other than MS (1.37 [1.04, 1.81]) but not for IS indicated only in MS (1.03 [0.45, 2.34]). Conclusions: Compared with IM, a 37% increase in cancer risk was observed for IS with indications other than MS and used for a short duration (≤2 years) but not for IS indicated only in MS. The absence of risk for prolonged exposure of IS with indications other than MS is not in favor of a causal relation with these drugs. [ABSTRACT FROM AUTHOR]

Although drugs for osteoporosis have been demonstrated to be effective in reducing fracture risk in placebo‐controlled clinical trials, data on effectiveness in real‐world practice is limited. Data from the French national health insurance claims database (SNDS) were used to follow five cohorts of women aged ≥55 years after initiating treatment for ≥6 months with either denosumab, zoledronic acid, oral bisphosphonates, raloxifene, or teriparatide in 2014–2016. Fracture incidence was compared within each cohort between the 3 months following initiation (baseline fracture risk) and the 12month, 18month, and 24 month postinitiation periods. Data are presented as incidence rate ratios (IRRs) with their 95% confidence intervals (CIs)s. Overall, 67,046 women were included in the denosumab cohort, 52,914 in the oral bisphosphonate cohort, 41,700 in the zoledronic acid cohort, 11,600 in the raloxifene cohort, and 7510 in the teriparatide cohort. The baseline vertebral fracture rate ranged from 1.74 per 1000 person years (‰PY) in the raloxifene cohort to 34.75‰PY in the teriparatide cohort, and the baseline hip fracture rate from 0.70‰PY in the raloxifene cohort to 10.52‰PY in the zoledronic acid cohort. Compared with the baseline fracture rate, vertebral fractures involving hospitalization were significantly reduced in the 3–24–month postinitiation period with denosumab (IRR 0.6; 95% CI, 0.5–0.7), zoledronic acid (IRR 0.4; 95% CI, 0.3–0.4), teriparatide (IRR 0.3; 95% CI, 0.2–0.5), and oral bisphosphonates (IRR 0.6; 95% CI, 0.4–0.8). Hip fracture incidence was reduced with denosumab (IRR 0.8; 95% CI, 0.6–0.9), but higher for oral bisphosphonates (IRR 1.7; 95% CI, 1.2–2.3); no significant change in hip fracture rate was observed for zoledronic acid, teriparatide, or raloxifene. A reduction in nonvertebral, non‐hip fracture incidence was observed only in the denosumab cohort (IRR 0.8; 95% CI, 0.7–0.9). These findings indicate that treatment with osteoporosis drugs is effective in the real‐world setting. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research. [ABSTRACT FROM AUTHOR]

Aims: To assess the effectiveness of dimethyl fumarate (DMF) on annual rate of relapse subject to treatment (ARRt) and disability progression in multiple sclerosis (MS) compared to injectable immunomodulators (IMM), teriflunomide (TERI) and fingolimob (FTY), in real‐life setting. Methods: A population‐based cohort study was conducted using data of the French nationwide claims database, SNDS. All patients initiating IMM, TERI, FTY or DMF between 1 July 2015 and 12 December 2017, with 4.5 years of database history and 1–3.5 years of follow‐up were included in this study. DMF patients were 1:1 matched to IMM, TERI or FTY using a high dimensional propensity score. Negative binomial regression and a logistic regression model were used to estimate the relative risk (RR ± [95% CI]) of ARRt and the odds ratio (OR ± [95% CI]) of disability progression, respectively. Results: Overall, 9304 subjects were identified: 29.0% initiated DMF, 33.2% TERI, 5.6% FTY and 32.2% an IMM. The matched cohorts consisted of 1779 DMF‐IMM patients, 1679 DMF‐TERI patients, and 376 DMF‐FTY patients. DMF significantly reduced ARRt compared to IMM (RR 0.72 [0.61–0.86]) and TERI (0.81 [0.68–0.96]) and did not show any significant difference when compared with FTY. The risk of the progression of MS‐specific disability was not significantly different for any matched cohorts. Conclusion: DMF is associated with lower risk of treated relapse for patients with RRMS than other first‐line RRMS agents (TERI and IIM). [ABSTRACT FROM AUTHOR]

Purpose This post‐authorisation safety study estimated the risk of anaphylaxis in patients receiving intravenous (IV) iron in Europe, with interest in iron dextran and iron non‐dextrans. Studies conducted in the United States have reported risk of anaphylaxis to IV iron ranging from 2.0 to 6.8 per 10 000 first treatments. Methods: Cohort study of IV iron new users, captured mostly through pharmacy ambulatory dispensing, from populations covered by health and administrative data sources in five European countries from 1999 to 2017. Anaphylaxis events were identified through an algorithm that used parenteral penicillin as a positive control. Results: A total of 304 210 patients with a first IV iron treatment (6367 iron dextran), among whom 13–16 anaphylaxis cases were identified and reported as a range to comply with data protection regulations. The pooled unadjusted incidence proportion (IP) ranged from 0.4 (95% confidence interval [CI], 0.2–0.9) to 0.5 (95% CI, 0.3–1.0) per 10 000 first treatments. No events were identified at first dextran treatments. There were 231 294 first penicillin treatments with 30 potential cases of anaphylaxis (IP = 1.2; 95% CI, 0.8–1.7 per 10 000 treatments). Conclusion: We found an IP of anaphylaxis from 0.4 to 0.5 per 10 000 first IV iron treatments. The study captured only a fraction of IV iron treatments administered in hospitals, where most first treatments are likely to happen. Due to this limitation, the study could not exclude a differential risk of anaphylaxis between iron dextran and iron non‐dextrans. The IP of anaphylaxis in users of penicillin was consistent with incidences reported in the literature. [ABSTRACT FROM AUTHOR]

Aims: Poor efficacy has been reported for patients with BRAF mutations for metastatic colorectal cancer (mCRC). Methods: EREBUS is a French cohort study of wild‐type (wt) KRAS unresectable mCRC patients initiating a first‐line treatment with cetuximab from 2009 to 2010, followed for two years (five years for vital status). Molecular genetics platforms have provided additional RAS and BRAF mutation testing results. Progression‐free survival (PFS) and overall survival (OS) were assessed according to tumour mutation (mt) status: RASmt/BRAFany, RASwt/BRAFmt and RASwt/BRAFwt. Multivariate Cox analyses were used to evaluate association between mutation status and death or progression. Results: A total of 389 patients were included in 65 centres and with a known tumour mutation status: 64 RASmt/BRAFany (21%), 33 RASwt/BRAFmt (13%) and 213 RASwt/BRAFwt (87%). Respective baseline characteristics were: median age 65, 64 and 63 years, male gender 63%, 64% and 69%, Eastern Cooperative Oncology Group performance status ≤ 1 75%, 76% and 79%, and liver‐only metastases 39%, 33% and 40%. Median progression‐free survival was 8.0 months [5.9–9.3] for patients with RASmt/BRAFany, 6.0 months [2.3–7.2] for patients with RASwt/BRAFmt, and 10.4 months [9.5–11.0] for patients with RASwt/BRAFwt. Respectively, median overall survival was 18.4 months [10.9–23.3], 9.7 months [6.9–16.6] and 29.3 months [26.3–36.1]. In multivariate analyses, progression (HR = 2.71 [1.79–4.10]) and death (HR = 2.79 [1.81–4.30]) were more likely for RASwt/BRAFmt vs RASwt/BRAFwt patients. Conclusions: BRAF mutations were associated with markedly poorer outcomes in initially unresectable RASwt mCRC patients treated by cetuximab in first‐line treatment. [ABSTRACT FROM AUTHOR]

Purposes Drug induced acute liver injury (ALI) is a frequent cause of liver failure. Case‐based designs were empirically assessed and calibrated in the French National claims database (SNDS), aiming to identify the optimum design for drug safety alert generation associated with ALI. Methods: All cases of ALI were extracted from SNDS (2009‐2014) using specific and sensitive definitions. Positive and negative drug controls were used to compare 196 self‐controlled case series (SCCS), case‐control (CC), and case‐population (CP) design variants, using area under the receiver operating curve (AUC), mean square error (MSE) and coverage probability. Parameters that had major impacts on results were identified through logistic regression. Results: Using a specific ALI definition, AUCs ranged from 0.78 to 0.94, 0.64 to 0.92 and 0.48 to 0.85, for SCCS, CC and CP, respectively. MSE ranged from 0.12 to 0.40, 0.22 to 0.39 and 1.03 to 5.29, respectively. Variants adjusting for multiple drug use had higher coverage probabilities. Univariate regressions showed that high AUCs were achieved with SCCS using exposed time as the risk window. The top SCCS variant yielded an AUC = 0.93 and MSE = 0.22 and coverage = 86%, with 1/7 negative and 13/18 positive controls presenting significant estimates. Conclusions: SCCS adjusting for multiple drugs and using exposed time as the risk window performed best in generating ALI‐related drug safety alert and providing estimates of the magnitude of the risk. This approach may be useful for ad‐hoc pharmacoepidemiology studies to support regulatory actions. [ABSTRACT FROM AUTHOR]

Aims: Pictograms on medicine boxes warn of potential drug‐related driving hazard; we studied their association with serious accidents. Methods: Prospective study in emergency departments of the hospitals in Bordeaux and Périgueux (France), of drivers with serious (admitted at least 24 hours) or nonserious vehicular accidents. Minors, passengers, pedestrians or subjects incapable of answering an interview were excluded. Interviews ascertained driver and accident characteristics, use of drugs with or without pictograms, use of alcohol and abuse substances, sleepiness, distractions, and mind wandering at the time of the accident, Results: Between 18 October 2016 and 26 December 2018, 1200 of the 6212 drivers admitted to the hospital emergency rooms, 741 nonserious, 459 serious, were interviewed. Serious accidents were associated with male sex (odds ratio 1.89, 95% confidence interval [1.36–2.64]), age above 60 years (3.64 [2.21–6.00]), driving on local roads (3.34 [2.34–4.76]), driving a motorcycle (3.39 [2.29–5.00]), having drunk alcohol within 6 hours (2.89 [1.85–4.51]) and using a drug with a pictogram during the 24 hours previous to the accident (1.57 [1.06–2.32]). From 207 police reports, 101 drivers were not responsible, and 106 were responsible, associated with age below 40 years, driving in overcast or rainy weather (2.62 [1.29–5.33]), on local roads (3.89 [1.90–7.95]), and use of at least 1 pictogram drug in the previous week (3.12 [1.31–7.41]). Conclusion: The known risks of alcohol and pictogram drugs, of riding motorcycles and using local roads were confirmed. As measured, behavioural sleepiness did not predict accidents. [ABSTRACT FROM AUTHOR]

Aims: Analgesics are the most widely used medicines worldwide. In parallel, opioid abuse has increased and is of major concern. The accessibility of pharmacologically powerful medicines and the addictovigilance signals in France about the risk of opiates addiction call for an overview of analgesic use. The objective of this study was to investigate the use of analgesics reimbursed in France over a 10‐year period through its prevalence. Methods: A cross‐sectional study repeated yearly was conducted by using data from the French reimbursement database from 2006 to 2015. Analgesics were classified according to their pharmacological potency: prevalence of use for each category and sociodemographic characteristics of patients treated were analysed. Results: The annual prevalence of analgesic use was high and increased during the study period (59.8%, 253 976 users in 2015). In 2015, prevalence was always higher in women and increased with age, except for those older than 84 years. Peripheral analgesics were the most used (55.3%, 234 739 users). The prevalence of weak analgesic use decreased (21.3%, 90 257 users), mainly due to the definitive withdrawal of dextropropoxyphene in France in 2011, which was not offset by an increase in the consumption of other weak analgesics. For strong analgesics (1.2%, 5129 users), morphine was the most widely used, with a dramatic increase in oxycodone use, especially in the elderly. Conclusion: The prevalence of analgesic use is high: approximately 31 million adults had at least 1 analgesic reimbursed in 2015. The most widely used analgesics were peripheral analgesics, far ahead of opioid analgesics. [ABSTRACT FROM AUTHOR]