From Inception to ConcePTION: Genesis of a Network to Support Better Monitoring and Communication of Medication Safety During Pregnancy and Breastfeeding

In 2019, the Innovative Medicines Initiative (IMI) funded the ConcePTION project—Building an ecosystem for better monitoring and communicating safety of medicines use in pregnancy and breastfeeding: validated and regulatory endorsed workflows for fast, optimised evidence generation—with the vision that there is a societal obligation to rapidly reduce uncertainty about the safety of medication use in pregnancy and breastfeeding. The present paper introduces the set of concepts used to describe the European data sources involved in the ConcePTION project and illustrates the ConcePTION Common Data Model (CDM), which serves as the keystone of the federated ConcePTION network. Based on data availability and content analysis of 21 European data sources, the ConcePTION CDM has been structured with six tables designed to capture data from routine healthcare, three tables for data from public health surveillance activities, three curated tables for derived data on population (e.g., observation time and mother-child linkage), plus four metadata tables. By its first anniversary, the ConcePTION CDM has enabled 13 data sources to run common scripts to contribute to major European projects, demonstrating its capacity to facilitate effective and transparent deployment of distributed analytics, and its potential to address questions about utilization, effectiveness, and safety of medicines in special populations, including during pregnancy and breastfeeding, and, more broadly, in the general population

An observational cohort study of the use of five-grass-pollen extract sublingual immunotherapy during the 2015 pollen season in France

Background:Allergic rhinitis affects around one quarter of the Western European population. Prophylactic allergen immunotherapy may be useful to reduce the risk of acute symptomatic attacks (hayfever). A five-grass pollen extract sublingual immunotherapy (5GPE-SLIT) has been developed for the treatment of allergic rhinitis to grass pollen. The objective of this study was to describe real-world treatment patterns with 5GPE-SLIT in France with respect to the prescribing information.Methods:This prospective cohort study was conducted by 90 community and hospital allergists. Adults and children (> 5 years old) starting a first treatment with 5GPE-SLIT prior to the 2015 pollen season were eligible. Data was collected at the inclusion visit and at the end of the pollen season. The primary outcome variable was compatibility of 5GPE-SLIT prescription with the prescribing information. This was determined with respect to four variables: (1) interval between 5GPE-SLIT initiation and onset of the pollen season ≥ 3 months, (2) age of patient ≥ 5 years, (3) intermittent symptoms or mild symptom severity (4) confirmatory diagnostic test. At study end, symptoms reported during the pollen season and any modifications to treatment or adverse events were documented.Results:280 adults and 203 children were enrolled. The prescribing information was respected for 82.5% of adults and 86.7% of children. A skin test was performed for all patients. 5GPE-SLIT was started 3-5 months before the pollen season for 85.3%. Treatment was discontinued before the start of the pollen season in 11.0% of patients overall, generally because of an adverse event (78.8% of discontinuations). The mean duration of treatment was 5.2 months in adults and 5.6 months in children. At the end of follow-up, symptoms during the pollen season were intermittent for 75.0% of adults and 85.7% of children, and severity was mild for 61.8 and 66.0% respectively. During 5GPE-SLIT, the following symptoms reported during the previous year were not reported again in > 50% of patients: nasal congestion, rhinorrhoea, repeated sneezing, conjunctivitis and nasal pruritus.Conclusions:5GPE-SLIT use was generally consistent with prescribing recommendations and was associated with an improvement of AR severity, with resolution of the principal AR symptoms in around half the patients treated.Trial registration EUPAS9358. Registered 13 May 2015. Not prospectively registered. http://www.encepp.eu/encepp/viewResource.htm?id=16229

Persistence of treatment as an outcome in pharmacepidemiology

En pharmaco-épidémiologie, les études visant à évaluer l’impact des médicaments sur la santé de la population en situation réelle d’utilisation à la demande des Autorités de Santé en France, sont conduites dans un contexte contraint, en l’absence de bases de données médicalisées populationnelle. Le choix des critères d’évaluation des études de terrain à mener est donc crucial. Les critères directs de mesure d’impact (mortalité, morbidité, qualité de vie) sont parfois complexes à obtenir à large échelle, aussi, l’utilisation de critères indirects est souvent nécessaire. La persistance des traitements est un critère combinant de nombreux avantages : reflet de la pratique médicale courante et simplicité de recueil. Dans le cadre de cette thèse, nous avons proposé d’étudier l’intérêt de la persistance des traitements comme critère de mesure d’impact, angle peu exploré jusque là, la persistance étant usuellement considérée comme paramètre d’exposition. Aussi, dans le Chapitre 1, nous avons précisé à quels niveaux la persistance des traitements entre dans le champ de l’évaluation de l’impact. Puis, à partir de trois études de terrain, nous avons évalué l’intérêt de la mesure de la persistance au sein de deux niveaux d’impact. La persistance comme mesure directe de l’utilisation et du respect des recommandations est illustrée dans le Chapitre 2 (prévention secondaire du post-infarctus du myocarde). La persistance comme mesure indirecte de l’efficacité en vie réelle est illustrée : dans le Chapitre 3 où la persistance signe l’échec thérapeutique (traitement curatif de la sinusite aigue) puis dans le Chapitre 4 où la persistance est considérée comme un succès thérapeutique (traitement suspensif de l’épilepsie). Pour finir, nous avons discuté l’intérêt des résultats issus de ces travaux au regard du contexte actuel des demandes d’étude requises par les Autorités de Santé avec la perspective de la mise en place de la nouvelle législation européenne d’évaluation du médicament.Pharmacoepidemiological studies requested by French Health Authorities to assess impact of treatment in real-life medical practice are performed in a restricted context, in the absence of a national health care databases. The choice of evaluation criteria for field studies is thus crucial. Direct impact measure criteria (mortality, morbidity, quality of life) are sometimes difficult to obtain on a large scale, therefore, the use of indirect criteria is often required. Treatment persistence is a criterion that combines several advantages: reflection of real-life medical practice and ease of collection. In this thesis, we studied persistence of treatment as a measure of impact, an original point of view as persistence is usually considered as a parameter of exposure. In Chapter 1, we have detailed at which level persistence of treatment is part of the field of impact evaluation. Thereafter, using three field studies, we assessed measure of persistence within two aspects of impact. Persistence as a direct measure of use and respect of recommendations is illustrated in Chapter 2 (secondary prevention in post-myocardial infarction). Persistence as an indirect measure of effectiveness is illustrated: in Chapter 3 where persistence is a sign of treatment failure (curative treatment of acute sinusitis) then in Chapter 4 where persistence is considered as treatment success (long-term treatment in epilepsy). In conclusion, we have discussed the results of this work with regards to the current context of studies requested by Health Authorities and with the forthcoming implementation of new European pharmacovigilance legislation

Persistence of treatment as an outcome in pharmacepidemiology

En pharmaco-épidémiologie, les études visant à évaluer l’impact des médicaments sur la santé de la population en situation réelle d’utilisation à la demande des Autorités de Santé en France, sont conduites dans un contexte contraint, en l’absence de bases de données médicalisées populationnelle. Le choix des critères d’évaluation des études de terrain à mener est donc crucial. Les critères directs de mesure d’impact (mortalité, morbidité, qualité de vie) sont parfois complexes à obtenir à large échelle, aussi, l’utilisation de critères indirects est souvent nécessaire. La persistance des traitements est un critère combinant de nombreux avantages : reflet de la pratique médicale courante et simplicité de recueil. Dans le cadre de cette thèse, nous avons proposé d’étudier l’intérêt de la persistance des traitements comme critère de mesure d’impact, angle peu exploré jusque là, la persistance étant usuellement considérée comme paramètre d’exposition. Aussi, dans le Chapitre 1, nous avons précisé à quels niveaux la persistance des traitements entre dans le champ de l’évaluation de l’impact. Puis, à partir de trois études de terrain, nous avons évalué l’intérêt de la mesure de la persistance au sein de deux niveaux d’impact. La persistance comme mesure directe de l’utilisation et du respect des recommandations est illustrée dans le Chapitre 2 (prévention secondaire du post-infarctus du myocarde). La persistance comme mesure indirecte de l’efficacité en vie réelle est illustrée : dans le Chapitre 3 où la persistance signe l’échec thérapeutique (traitement curatif de la sinusite aigue) puis dans le Chapitre 4 où la persistance est considérée comme un succès thérapeutique (traitement suspensif de l’épilepsie). Pour finir, nous avons discuté l’intérêt des résultats issus de ces travaux au regard du contexte actuel des demandes d’étude requises par les Autorités de Santé avec la perspective de la mise en place de la nouvelle législation européenne d’évaluation du médicament.Pharmacoepidemiological studies requested by French Health Authorities to assess impact of treatment in real-life medical practice are performed in a restricted context, in the absence of a national health care databases. The choice of evaluation criteria for field studies is thus crucial. Direct impact measure criteria (mortality, morbidity, quality of life) are sometimes difficult to obtain on a large scale, therefore, the use of indirect criteria is often required. Treatment persistence is a criterion that combines several advantages: reflection of real-life medical practice and ease of collection. In this thesis, we studied persistence of treatment as a measure of impact, an original point of view as persistence is usually considered as a parameter of exposure. In Chapter 1, we have detailed at which level persistence of treatment is part of the field of impact evaluation. Thereafter, using three field studies, we assessed measure of persistence within two aspects of impact. Persistence as a direct measure of use and respect of recommendations is illustrated in Chapter 2 (secondary prevention in post-myocardial infarction). Persistence as an indirect measure of effectiveness is illustrated: in Chapter 3 where persistence is a sign of treatment failure (curative treatment of acute sinusitis) then in Chapter 4 where persistence is considered as treatment success (long-term treatment in epilepsy). In conclusion, we have discussed the results of this work with regards to the current context of studies requested by Health Authorities and with the forthcoming implementation of new European pharmacovigilance legislation

Are traditional NSAIDs prescribed appropriately among French elderly with osteoarthritis? Results from the CADEUS cohort

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Previous Drug Exposure in Patients Hospitalised for Acute Liver Injury: A Case-Population Study in the French National Healthcare Data System

This is the accepted manuscript of this article.International audienceIntroduction: Acute liver injury (ALI) is a major reason for stopping drug development or removing drugs from the market. Hospitalisation for ALI is relatively rare for marketed drugs, justifying studies in large-scale databases such as the nationwide Système National des Données de Santé (SNDS) that covers 99% of the French population.Methods: SNDS was queried over 2010-2014 for all hospital admissions for acute toxic liver injuries not associated with a possible other cause, using a case-population approach. Exposures of interest were drugs dispensed from 7 to 60 days before date of admission. Individual drugs were analysed by their frequency (if ≥ 5 cases), and by the ratio of exposed cases to the number of exposed subjects and to exposed patient-time in the general population over the same time-frame.Results: Over 5 years, 4,807 cases of ALI were identified, mean age 54.5, 59% women, 76% exposed to at least one of 249 different drugs. Drugs most commonly identified were non-overdose paracetamol (31% of cases), esomeprazole or omeprazole (18%), phloroglucinol, domperidone, coamoxiclav, furosemide, atorvastatin (more than 250 cases each). When compared to population exposures, the highest per-person risks were observed with antimycobacterial antibiotics with 1 case for 1,000 or fewer users, followed by colestyramine and erythromycin (around 1/5,300), antiepileptic drugs, anticoagulants, anti-Alzheimer drugs (1/6,000 - 1/10,000 users). When a person-time approach is considered, the drugs with the highest per-tablet risk were still the antituberculosis drugs followed by a number of other antibiotics. Conclusions: This nationwide study describes drugs associated with ALI, according to absolute population burden, to per-patient and per-tablet risk. Some of these associations may be spurious, others causal, and others yet were unexpected. Systematic analysis of drug classes will look for outliers within each class that could raise signals of unexpected hepatic toxicity

Strong instrumental variables biased propensity scores in comparative effectiveness research: A case study in oncology

International audienceBackground and Objectives: Some medications require specific medical procedures in the weeks before their start. Such procedures may meet the definition of instrumental variables (IVs). We examined how they may influence treatment effect estimation in propensity score (PS)-adjusted comparative studies, and how to remedy. Study Design and Setting: Different covariate assessment periods (CAPs) did and did not include the month preceding treatment start were used to compute PS in the French claims database (Syt eme National des Donn ees de Sant e-SNDS), and 1:1 match patients with metastatic castration resistant prostate cancer initiating abiraterone acetate or docetaxel. The 36-month survival was assessed. Results: Among 1, 213 docetaxel and 2, 442 abiraterone initiators, the PS distribution resulting from the CAP [-12; 0 months] distinctly separated populations (c 5 0.93; 273 matched pairs). The CAPs [-12;-1 months] identified 765 pairs (c 5 0.81). Strong docetaxel treatment predictors during the month before treatment start were implantable delivery systems (1% vs. 59%), which fulfilled IV conditions. The 36-month survival was not meaningfully different under the [-12; 0 months] CAP but differed by 10% points (38% vs. 28%) after excluding month À1. Conclusion: In the setting of highly predictive pretreatment procedures, excluding the immediate pre-exposure time from the CAP will reduce the risk of including potential IVs in PS models and may reduce bias

Idarucizumab for Reversion of Anticoagulant Effect in Daily Practice

International audienceBackground and Purpose— We compared the 1-year safety and effectiveness of rivaroxaban 15 mg (R15) or rivaroxaban 20 mg (R20) to vitamin K antagonists (VKAs) in patients with nonvalvular atrial fibrillation. Methods— New user cohort study of patients dispensed R15 or R20 versus VKA in 2013 or 2014 for nonvalvular atrial fibrillation, followed 1 year in the French Système National des Données de Santé (66 million people). R15 and R20 users were matched 1:1 with VKA users on sex, age, date of first drug dispensing, and high-dimensional propensity score. Hazard ratios (95% CIs) for stroke and systemic embolism, major bleeding, and death were computed using Cox proportional hazards or models by Fine and Gray during exposure. Results— In 31 171 matched R20 and VKA, mean age, 71; 62% men; 76% with CHA 2 DS 2 -VASc ≥2; 5% HAS-BLED >3 (hypertension, abnormal renal and liver function, stroke, bleeding, labile INR, elderly, drugs or alcohol); incidence rates for stroke and systemic embolism were 1.5% and 1.9% (hazard ratio, 0.79 [0.69–0.90]); major bleeding, 1.5% and 2.2% (0.67 [0.59–0.77]); death, 3.9% and 5.8% (0.67 [0.61–0.73]). In 23 314 matched R15 and VKA patients, mean age, 80; 47% men; 93% with CHA 2 DS 2 -VASc ≥2 and 9% with HAS-BLED >3; incidence rates of stroke and systemic embolism were 2.3% and 2.1% (1.05 [0.92–1.21]); major bleeding, 2.4% and 2.9% (0.84 [0.74–0.96]); death, 9.1% and 10.8% (0.85 [0.79–0.90]). Numbers needed to treat to observe one fewer death (NNT) were 46 for R15 and 61 for R20. Conclusions— In real life in France over 2013 to 2015, R15 and R20 were at least as effective and safer than VKA. Clinical Trial Registration— URL: http://www.encepp.eu . Unique identifier: EUPAS14567