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

INTRODUCTION: 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. OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Remdesivir in the COVID-19 Pandemic: An Analysis of Spontaneous Reports in VigiBase During 2020.

INTRODUCTION: The safety profile of remdesivir, conditionally approved for COVID-19, was limited at its 2020 introduction. Adverse drug reactions (ADRs) for medicines are collected in VigiBase, the WHO Global Database of Individual Case Safety Reports (ICSRs). OBJECTIVE: This study aimed to provide a descriptive analysis of COVID-19 ICSR data focusing on remdesivir, including a disproportionality analysis (DA) of ADRs. METHODS: A dedicated algorithm enabled retrieval of all COVID-19 treatment-specific ICSRs. A severity algorithm based on co-reported medicines and symptoms enabled selection of tocilizumab with its well established safety profile as comparator for remdesivir. Descriptive statistics were used for general ICSR demographics for all COVID-19-specific medicines, remdesivir and tocilizumab individually and furthermore to present treatment patterns of medicines co-reported with remdesivir. A COVID-19 indication-focused DA was deployed to minimize confounding from underlying polysymptomatic disease. RESULTS: 14,574 COVID-19-related ICSRs were entered into VigiBase during 2020. Remdesivir was the most common medicine reported. Of 4944 remdesivir ICSRs, where tocilizumab was not co-reported, 93% described remdesivir as the sole suspect medicine. Sixty percent of ICSRs concerned males, median age was 63 years and the majority originated from the Americas (72%). In 1089 (21%) of remdesivir ICSRs, data indicated severe/critical disease. Co-reported medicines peaked during the first 3 days of remdesivir treatment. The DA for the established tocilizumab and the new remdesivir were mainly in line with the safety profiles for both medicines but suggested new safety concerns. The most reported ADRs for remdesivir represented liver dysfunction, kidney injury, death and bradycardia. CONCLUSION: Global COVID-19-related ADR reporting proved useful in providing information on ADRs as well as on treatment patterns in this patient group. Indication-focused disproportionality analysis, together with the use of a comparator with a known safety profile, proved effective in identifying known safety information and suggested new safety concerns for remdesivir.

Sex Differences in Reported Adverse Drug Reactions to COVID-19 Drugs in a Global Database of Individual Case Safety Reports.

INTRODUCTION: In late 2019, a new coronavirus-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-was discovered in Wuhan, China, and the World Health Organization later declared coronavirus disease 2019 (COVID-19) a pandemic. Numerous drugs have been repurposed and investigated for therapeutic effectiveness in the disease, including those from "Solidarity," an international clinical trial (azithromycin, chloroquine, hydroxychloroquine, the fixed combination lopinavir/ritonavir, and remdesivir). OBJECTIVE: Our objective was to evaluate adverse drug reaction (ADR) reporting for drugs when used in the treatment of COVID-19 compared with use for other indications, specifically focussing on sex differences. METHOD: We extracted reports on COVID-19-specific treatments from the global ADR database, VigiBase, using an algorithm developed to identify reports that listed COVID-19 as the indication. The Solidarity trial drugs were included, as were any drugs reported ≥ 100 times. We performed a descriptive comparison of reports for the same drugs used in non-COVID-19 indications. The data lock point date was 7 June 2020. RESULTS: In total, 2573 reports were identified for drugs used in the treatment of COVID-19. In order of frequency, the most reported ADRs were electrocardiogram QT-prolonged, diarrhoea, nausea, hepatitis, and vomiting in males and diarrhoea, electrocardiogram QT-prolonged, nausea, vomiting, and upper abdominal pain in females. Other hepatic and kidney-related events were included in the top ten ADRs in males, whereas no hepatic or renal terms were reported for females. COVID-19-related reporting patterns differed from non-pandemic reporting for these drugs. CONCLUSION: Review of a global database of suspected ADR reports revealed sex differences in the reporting patterns for drugs used in the treatment of COVID-19. Patterns of ADR sex differences need further elucidation.