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This pharmacoepidemiologic study was conducted to determine whether risk factors for upper gastrointestinal bleeding influenced the prescription of cyclo-oxygenase (COX)-2 inhibitors and traditional nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) at the time when COX-2 inhibitors were first included in the formulary of reimbursed medications. A population-based case–control study was conducted in which the prevalence of risk factors and the medical histories of patients prescribed COX-2 inhibitors and traditional nonselective NSAIDs were compared. The study population consisted of a random sample of members of the Quebec drug plan (age 18 years or older) who received at least one dispensation of celecoxib (n = 42,422; cases), rofecoxib (n = 25,674; cases), or traditional nonselective NSAIDs (n = 12,418; controls) during the year 2000. All study data were obtained from the Quebec health care databases. Adjusting for income level, Chronic Disease Score, prior use of low-dose acetylsalicylic acid, acetaminophen, antidepressants, benzodiazepines, prescriber specialty, and time period, the following factors were significantly associated with the prescription of COX-2 inhibitors: age 75 years or older (odds ratio [OR] 4.22, 95% confidence interval [CI] 3.95–4.51), age 55–74 years (OR 3.23, 95% CI 3.06–3.40), female sex (OR 1.52, 95% CI 1.45–1.58), prior diagnosis of gastropathy (OR 1.21, 95% CI 1.08–1.36) and prior dispensation of gastroprotective agents (OR 1.57, 95% CI 1.47–1.67). Patients who received a traditional nonselective NSAID recently were more likely to switch to a coxib, especially first-time users (OR 2.17, 95% CI 1.93–2.43). Associations were significantly greater for celecoxib than rofecoxib for age, chronic NSAID use, and last NSAID use between 1 and 3 months before the index date. At the time of introduction of COX-2 inhibitors into the formulary, prescription channeling could confound risk comparisons across products., Affiliation: Faculté de pharmacie, Université de Montréal

The ENCePP initiative aims to strengthen post-authorisation medicines research by facilitating the conduct of multi-centre, independent and scientifically robust studies focusing on safety and the balance of benefits and risks. This includes supporting high quality research and stimulating innovation that benefits patients and public health at large. The Guide on Methodological Standards in Pharmacoepidemiology has, therefore, been developed to offer a single overview document and web resource for methodological guidance for both experienced and new researchers in pharmacoepidemiology and pharmacovigilance. For each topic covered, direct electronic access is given to internationally agreed recommendations and key points from important guidelines, published articles and textbooks after an introductory review. The focus is on scientific rather than regulatory guidance although relevant legislation and good pharmacovigilance practice are cited, where appropriate. Where relevant, gaps in guidance in areas important to collaborative pharmacoepidemiology research have been addressed with what ENCePP considers good practice. The guide has been developed by a dedicated ENCePP Working Group consisting of experts in pharmacoepidemiological and pharmacovigilance research. The original guide was published online on 17 May 2011. Both the original and the current first revision of the guide have been subject to public consultation. The guide will be updated annually by structured review to maintain its dynamic nature. It may also be amended as necessary on an ad-hoc basis in response to comments received. Researchers are therefore kindly requested to refer any additional guidance document that they consider relevant, to encepp_comments@ema.europa.eu.

This chapter focuses on the description of key commonalities and distinctions across encounter databases, illustrated with selected examples and supplemented by references to more comprehensive resources in the literature. It includes a dedicated discussion of the considerations faced by researchers when evaluating the appropriateness of a specific encounter database or deciding among multiple encounter databases for their research question. Encounter databases in South Korea, Taiwan and Australia all use Anatomical Therapeutic Chemical codes to identify individual medicines and all but Taiwan use ICD-10 codes to identify diagnoses. This allows for comparisons of similar products across different countries without the need to map individual country-specific codes. Encounter databases have a number of strengths in comparison to other data sources for pharmacoepidemiologic research, which explain their broad representation in the literature. Encounter databases are primarily intended and maintained for payment or other administrative purposes, and therefore are subject to important limitations when used for research.

Le biais de confusion est un défi majeur des études observationnelles, surtout s'ils sont induits par des caractéristiques difficiles, voire impossibles, à mesurer dans les banques de données administratives de soins de santé. Un des biais de confusion souvent présents dans les études pharmacoépidémiologiques est la prescription sélective (en anglais « prescription channeling »), qui se manifeste lorsque le choix du traitement dépend de l'état de santé du patient et/ou de son expérience antérieure avec diverses options thérapeutiques. Parmi les méthodes de contrôle de ce biais, on retrouve le score de comorbidité, qui caractérise l'état de santé d'un patient à partir de médicaments délivrés ou de diagnostics médicaux rapportés dans les données de facturations des médecins. La performance des scores de comorbidité fait cependant l'objet de controverses car elle semble varier de façon importante selon la population d'intérêt. Les objectifs de cette thèse étaient de développer, valider, et comparer les performances de deux scores de comorbidité (un qui prédit le décès et l’autre qui prédit l’institutionnalisation), développés à partir des banques de services pharmaceutiques de la Régie de l'assurance-maladie du Québec (RAMQ) pour leur utilisation dans la population âgée. Cette thèse vise également à déterminer si l'inclusion de caractéristiques non rapportées ou peu valides dans les banques de données administratives (caractéristiques socio-démographiques, troubles mentaux ou du sommeil), améliore la performance des scores de comorbidité dans la population âgée. Une étude cas-témoins intra-cohorte fut réalisée. La cohorte source consistait en un échantillon aléatoire de 87 389 personnes âgées vivant à domicile, répartie en une cohorte de développement (n=61 172; 70%) et une cohorte de validation (n=26 217; 30%). Les données ont été obtenues à partir des banques de données de la RAMQ. Pour être inclus dans l’étude, les sujets devaient être âgés de 66 ans et plus, et être membres du régime public d'assurance-médicaments du Québec entre le 1er janvier 2000 et le 31 décembre 2009. Les scores ont été développés à partir de la méthode du Framingham Heart Study, et leur performance évaluée par la c-statistique et l’aire sous les courbes « Receiver Operating Curves ». Pour le dernier objectif qui est de documenter l’impact de l’ajout de variables non-mesurées ou peu valides dans les banques de données au score de comorbidité développé, une étude de cohorte prospective (2005-2008) a été réalisée. La population à l'étude, de même que les données, sont issues de l'Étude sur la Santé des Aînés (n=1 494). Les variables d'intérêt incluaient statut marital, soutien social, présence de troubles de santé mentale ainsi que troubles du sommeil. Tel que décrit dans l'article 1, le Geriatric Comorbidity Score (GCS) basé sur le décès, a été développé et a présenté une bonne performance (c-statistique=0.75; IC95% 0.73-0.78). Cette performance s'est avérée supérieure à celle du Chronic Disease Score (CDS) lorsqu'appliqué dans la population à l'étude (c-statistique du CDS : 0.47; IC 95%: 0.45-0.49). Une revue de littérature exhaustive a montré que les facteurs associés au décès étaient très différents de ceux associés à l’institutionnalisation, justifiant ainsi le développement d'un score spécifique pour prédire le risque d'institutionnalisation. La performance de ce dernier s'est avérée non statistiquement différente de celle du score de décès (c-statistique institutionnalisation : 0.79 IC95% 0.77-0.81). L'inclusion de variables non rapportées dans les banques de données administratives n'a amélioré que de 11% la performance du score de décès; le statut marital et le soutien social ayant le plus contribué à l'amélioration observée. En conclusion, de cette thèse, sont issues trois contributions majeures. D'une part, il a été démontré que la performance des scores de comorbidité basés sur le décès dépend de la population cible, d'où l'intérêt du Geriatric Comorbidity Score, qui fut développé pour la population âgée vivant à domicile. D'autre part, les médicaments associés au risque d'institutionnalisation diffèrent de ceux associés au risque de décès dans la population âgé, justifiant ainsi le développement de deux scores distincts. Cependant, les performances des deux scores sont semblables. Enfin, les résultats indiquent que, dans la population âgée, l'absence de certaines caractéristiques ne compromet pas de façon importante la performance des scores de comorbidité déterminés à partir de banques de données d'ordonnances. Par conséquent, les scores de comorbidité demeurent un outil de recherche important pour les études observationnelles., Confounding is an important challenge in observational studies given that they are induced by characteristics difficult, if not impossible, to measure in administrative claims databases. Prescription channelling is a frequent source of confounding in pharmacoepidemiologic studies, and occurs when the selection of one treatment over another is influenced by overall health status and patient's experience with other treatment options. Among the methods available to control for this bias, comorbidity scores are frequently used. Most of the comorbidity scores published in the literature assess the patients’ health status through drug dispensing or diagnostic codes included in physicians’ billings. These comorbidity scores, however, are controversial since their performance appears to vary according to the population of interest ( example: elderly vs. adult). The objectives of this thesis were to develop, validate and compare the performance of two comorbidity scores (the Geriatric Comorbidity Score based on death, and a comorbidity score based on institutionalization) derived from dispensing data for use in the community-dwelling elderly population. Furthermore, this thesis aimed to evaluate whether the inclusion of characteristics not usually included in administrative claims databases or with a low validity (such as sociodemographic characteristics, sleep or mental disorders) improves the performance of the Geriatric Comorbidity Score. A nested case-control analysis was conducted within a cohort that consisted of a random sample of 87,389 elderly distributed into a construction cohort (n=61,172; 70%) and a validation cohort (n=26,217; 30%). Sources of data consisted of the databases of the Régie de l’assurance maladie du Québec (RAMQ). To be included in the study, subjects had to be 66 years and older and covered by the public drug insurance program of Quebec between 1st January 2000 and 31st December 2009. Scores were developed using the Framingham Heart Study method, and their performances were assessed using the c-statistics and receiver operating curves (ROC). For the last objective, a prospective cohort study was performed using the participants in the Étude sur la Santé des Aînés (ESA) (n=1,494) which covered the period ranging from 2005 to 2008. Study variables included marital status, social support, mental health as well as sleep disorders. The comprehensive literature review conducted in the thesis and our results revealed that factors associated with death greatly differed from those associated with institutionalization, which supported the need to develop two distinct scores. Performances of the institutionalization score were, however, not statistically different from the death score (institutionalization c-statistic = 0.79; 95% CI: 0.77-0.81; death c-statistic= 0.75; 95% CI: 0.73-0.78). The Geriatric Comorbidity Score (death score) revealed a better performance than the Chronic Disease Score, which has been widely used in the literature (c-statistic= 0.47; 95%CI: 0.45-0.49). The inclusion of variables not recorded in claims databases yielded an improvement of the death score of only 11%, with marital status and social support being mainly responsible for the improvement. In terms of achievement, this thesis made three contributions. First, it was shown that the performance of comorbidity scores based on death vary according to the study population, reinforcing the need for specific scores, such as the Geriatric Comorbidity Score which was developed here. Second, factors associated with the risk of institutionalization were different than those associated with the risk of death in the elderly population, which supported the development of an institutionalization score. Even if the performance of death and institutionalization scores were similar, the latter would be preferred in studies that aim at assessing the effect of drugs on institutionalisation in the elderly. Lastly, the results indicate that the absence of some characteristics in the administrative databases do not appear to have a major impact on the performance of scores based on claims data. Consequently, comorbidity scores based on drug dispensing data remain important research tools for pharmacoepidemiologic studies conducted through health claims databases.

The improvement of the surveillance of the drug safety by using healthcare databases is waited with hope for a decade. The objective of this thesis was to develop an automated system combining detection and prioritization of safety signals from healthcare databases, for the surveillance of drugs used in chronic diseases. Noninsulin glucose-lowering drugs (NIGLDs) were selected as a case study for the development and the assessment of the system. Firstly, we studied the patterns of use of the NIGLDs in France, and we found a large misuse with the dipeptidylpeptidase-4 (DPP-4) inhibitors and a higher risk of non-observance with their use. Secondly, we conducted two literature review, which allows us to select the sequence symmetry analysis for the detection and to develop our algorithm for the prioritization that we based on strength, novelty, impact of the safety signal, and patterns of drug use. Thirdly, we assessed the performance of the system, in a pilot study on NIGLDs that showed satisfying results and identified a new safety signal with the use of DPP-4 inhibitors and venous thromboembolic events, as well as its acceptability among stakeholders that judged it positively. These results invite us to pursue our researches to improve and to validate the developed system.; L’amélioration de la surveillance de la sécurité des médicaments grâce à l’utilisation des bases de données médico-administratives est source de nombreuses promesses. L’objectif de cette thèse était de développer un système automatisé de détection et de priorisation des signaux de sécurité adapté aux bases de données médico-administratives, pour la surveillance de la sécurité des médicaments des maladies chroniques. Les antidiabétiques non insuliniques (ANI) ont été sélectionnés comme cas d’étude pour le développement et l’évaluation de ce système. Nous avons d’abord étudié le profil d’utilisation des ANI en France, et avons retrouvé un fort mésusage des inhibiteurs de la dipeptidylpeptidase-4 (DPP-4) ainsi qu’un risque accru de non observance avec ces derniers. Nous avons ensuite réalisé deux revues de la littérature qui nous ont permis de sélectionner, pour la détection, la méthode sequence symmetry analysis, et de construire, pour la priorisation, notre algorithme que nous avons structuré autour de la force, la nouveauté, l’impact du signal de sécurité, et les modalités d’utilisation du médicament. Nous avons enfin évalué, d’une part, les performances du système développé, dans une étude pilote sur les ANI qui a montré des résultats satisfaisants et permis d’identifier un nouveau signal de sécurité entre les inhibiteurs de la DPP-4 et les événements thromboemboliques veineux, et d’autre part, son acceptabilité auprès des décideurs de santé qui l’ont jugé positivement. Ces résultats nous invitent à poursuivre nos recherches sur l’amélioration et la validation du système développé.