Supporting Pharmacovigilance Signal Validation and Prioritization with Analyses of Routinely Collected Health Data: Lessons Learned from an EHDEN Network Study

Oskar Gauffin, Judith S. Brand, Sara Hedfors Vidlin, Daniele Sartori, Suvi Asikainen, Martí Català, Etir Chalabi, Daniel Dedman, Ana Danilovic, Talita Duarte-Salles, Maria Teresa García Morales, Saara Hiltunen, Annika M. Jödicke, Milan Lazarevic, Miguel A. Mayer, Jelena Miladinovic, Joseph Mitchell, Andrea Pistillo, Juan Manuel Ramírez-Anguita, Carlen Reyes, Annette Rudolph, Lovisa Sandberg, Ruth Savage, Martijn Schuemie, Dimitrije Spasic, Nhung T. H. Trinh, Nevena Veljkovic, Ankica Vujovic, Marcel de Wilde, Alem Zekarias, Peter Rijnbeek, Patrick Ryan, Daniel Prieto-Alhambra, G. Niklas Norén

Individual case reports are the main asset in pharmacovigilance signal management. Signal validation is the first stage after signal detection and aims to determine if there is sufficient evidence to justify further assessment. Throughout signal management, a prioritization of signals is continually made. Routinely collected health data can provide relevant contextual information but are primarily used at a later stage in pharmacoepidemiological studies to assess communicated signals. The aim of this study was to examine the feasibility and utility of analysing routine health data from a multinational distributed network to support signal validation and prioritization and to reflect on key user requirements for these analyses to become an integral part of this process. Statistical signal detection was performed in VigiBase, the WHO global database of individual case safety reports, targeting generic manufacturer drugs and 16 prespecified adverse events. During a 5-day study-a-thon, signal validation and prioritization were performed using information from VigiBase, regulatory documents and the scientific literature alongside descriptive analyses of routine health data from 10 partners of the European Health Data and Evidence Network (EHDEN). Databases included in the study were from the UK, Spain, Norway, the Netherlands and Serbia, capturing records from primary care and/or hospitals. Ninety-five statistical signals were subjected to signal validation, of which eight were considered for descriptive analyses in the routine health data. Design, execution and interpretation of results from these analyses took up to a few hours for each signal (of which 15-60 minutes were for execution) and informed decisions for five out of eight signals. The impact of insights from the routine health data varied and included possible alternative explanations, potential public health and clinical impact and feasibility of follow-up pharmacoepidemiological studies. Three signals were selected for signal assessment, two of these decisions were supported by insights from the routine health data. Standardization of analytical code, availability of adverse event phenotypes including bridges between different source vocabularies, and governance around the access and use of routine health data were identified as important aspects for future development. Analyses of routine health data from a distributed network to support signal validation and prioritization are feasible in the given time limits and can inform decision making. The cost-benefit of integrating these analyses at this stage of signal management requires further research.