title: Design considerations in an active medical product safety monitoring system.
abstract: Active medical product monitoring systems, such as the Sentinel System, will utilize electronic healthcare data captured during routine health care. Safety signals that arise from these data may be spurious because of chance or bias, particularly confounding bias, given the observational nature of the data. Applying appropriate monitoring designs can filter out many false-positive and false-negative associations from the outset. Designs can be classified by whether they produce estimates based on between-person or within-person comparisons. In deciding which approach is more suitable for a given monitoring scenario, stakeholders must consider the characteristics of the monitored product, characteristics of the health outcome of interest (HOI), and characteristics of the potential link between these. Specifically, three factors drive design decisions: (i) strength of within-person and between-person confounding; (ii) whether circumstances exist that may predispose to misclassification of exposure or misclassification of the timing of the HOI; and (iii) whether the exposure of interest is predominantly transient or sustained. Additional design considerations include whether to focus on new users, the availability of appropriate active comparators, the presence of an exposure time trend, and the measure of association of interest. When the key assumptions of self-controlled designs are fulfilled (i.e., lack of within-person, time-varying confounding; abrupt HOI onset; and transient exposure), within-person comparisons are preferred because they inherently avoid confounding by fixed factors. The cohort approach generally is preferred in other situations and particularly when timing of exposure or outcome is uncertain because cohort approaches are less vulnerable to biases resulting from misclassification.
authors.affiliation: Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02120, USA. jgagne1@partners.org
authors.forename: Joshua J
authors.initials: JJ
authors.lastname: Gagne
authors.forename: Bruce
authors.initials: B
authors.lastname: Fireman
authors.forename: Patrick B
authors.initials: PB
authors.lastname: Ryan
authors.forename: Malcolm
authors.initials: M
authors.lastname: Maclure
authors.forename: Tobias
authors.initials: T
authors.lastname: Gerhard
authors.forename: Sengwee
authors.initials: S
authors.lastname: Toh
authors.forename: Jeremy A
authors.initials: JA
authors.lastname: Rassen
authors.forename: Jennifer C
authors.initials: JC
authors.lastname: Nelson
authors.forename: Sebastian
authors.initials: S
authors.lastname: Schneeweiss
mesh_terms: D015982:Bias; D015986:Confounding Factors, Epidemiologic; D016208:Databases, Factual; D003657:Decision Making; D064420:Drug-Related Side Effects and Adverse Reactions; D057286:Electronic Health Records / Q000706:statistics & numerical data; D015340:Epidemiologic Research Design; D004864:Equipment and Supplies / Q000009:adverse effects; D006801:Humans; D017063:Outcome Assessment, Health Care; D011358:Product Surveillance, Postmarketing / Q000379:methods*; D016730:Program Development