Optimizing Safety Surveillance for COVID-19 Vaccines at the National Pharmacovigilance Centre Lareb: One Year of COVID-19 Vaccine Experience.

INTRODUCTION: Due to the COVID-19 vaccination campaign, national pharmacovigilance (PV) centres had to deal with high volumes of Individual Case Safety Reports (ICSRs) that needed to be processed and assessed in a short time span. This necessitated the development of a dedicated system to enable near real-time vaccine safety monitoring at the Dutch PV Centre Lareb. OBJECTIVES: To describe infrastructure, processes and Adverse Events Following Immunisation (AEFIs) reported for vaccine safety monitoring of COVID-19 vaccines during a large-scale vaccination campaign in the Netherlands. METHODS: A COVID-19 tailored vaccine web-based reporting form collected information on the vaccine administered, AEFIs and other (medical) information. A fully automated process for ICSRs enabled the handling of the majority of common and known reported AEFIs. All other ICSRs were triaged daily and processed separately. There were daily signal detection meetings and weekly reports for batch analysis. RESULTS: In 2021, Lareb received 184,411 ICSRs, a reporting rate of 0.67% for vaccines given in the Netherlands. 887,954 AEFIs were reported, mostly well-known, nonserious AEFIs; 2.4% were serious and 0.3% were fatal. 33.1% of all ICSRs were processed fully automatically. Based on the daily triage, 4.2% were flagged as 'high priority'; 62.7% as 'low-priority'. Twenty-seven signals and news stories about the COVID-19 vaccines were disseminated. CONCLUSIONS: Due to automatic processing of well-known AEFIs, daily triage and signal detection meetings, 99.9% of the ICSRs were processed within the compliance timeframe to Eudravigilance, and signal detection was performed during a large-scale vaccination campaign. These experiences may serve as a blueprint for future mass vaccination programs.

A tailor-made approach for causality assessment for ADR reports on drugs and vaccines.

PURPOSE: To estimate causation of adverse drug reaction (ADR) reports, causality methods were developed from a theoretical perspective. In daily practice, not all information is relevant or available, decreasing the applicability. We developed a new causality documentation tool (CausDoc) where an algorithm is combined with expert judgement. The aim of this study is to test the validity and reliability of CausDoc for ADR reports on drugs and vaccines. METHODS: CausDoc provides 9 structured relevant questions. If information is available, an answer will be chosen. If not, the question is excluded. Causality outcome is based on the sum score of all answers divided by the included questions: ≤30%: unlikely, 31% to 70%: possible, 71% to 90%: probable, and >90%: certain. Other relevant information is taken into account by expert judgement in the final step by adjusting the outcome to a limited extent. After testing face validity on 12 ADR reports, sensitivity and specificity were tested on 40 ADR reports, compared with the Naranjo algorithm and WHO AEFI criteria, using the expert panel's judgements as a standard. Inter-rater reliability was tested using weighted Cohen kappa coefficient. RESULTS: Average sensitivity and specificity with CausDoc were 47% and 83% for drugs (29% and 78% with Naranjo) and 72% and 89% for vaccines (65% and 87% with WHO AEFI criteria). Reliability between the 2 couples of assessors: κ 0.48 and 0.75. CONCLUSIONS: CausDoc shows a better performance and allows for a better documentation of ADRs in clinical practice. This approach is useful in assessing the causality of adverse drug reactions.

Characteristics, Quality and Contribution to Signal Detection of Spontaneous Reports of Adverse Drug Reactions Via the WEB-RADR Mobile Application: A Descriptive Cross-Sectional Study.

INTRODUCTION: Spontaneous reporting of suspected adverse drug reactions is key for efficient post-marketing safety surveillance. To increase usability and accessibility of reporting tools, the Web-Recognising Adverse Drug Reactions (WEB-RADR) consortium developed a smartphone application (app) based on a simplified reporting form. OBJECTIVE: The objective of this study was to evaluate the characteristics, quality and contribution to signals of reports submitted via the WEB-RADR app. METHODS: The app was launched in the UK, the Netherlands and Croatia between July 2015 and May 2016. Spontaneous reports submitted until September 2016 with a single reporter were included. For each country, app reports and reports received through conventional means in the same time period were compared to identify characteristic features. A random subset of reports was assessed for clinical quality and completeness. The contribution to signal detection was assessed by a descriptive analysis. RESULTS: Higher proportions of app reports were submitted by patients in the UK (28 vs. 18%) and Croatia (32 vs. 7%); both p < 0.01. In the Netherlands, the difference was small (60 vs. 57%; p = 0.5). The proportion of female patients and the median patient ages in app reports submitted by patients were similar to the reference. The proportion of reports of at least moderate quality was high in both samples (app: 78-85%, reference: 78-98%), for all countries. App reports contributed to detecting eight potential safety signals at the national level, four of which were eventually signalled. CONCLUSION: The WEB-RADR app offers a new route of spontaneous reporting that shows promise in attracting reports from patients and that could become an important tool in the future. Patient demographics are similar to conventional routes, report quality is sufficient despite a simplified reporting form, and app reports show potential in contributing to signal detection.

First experiences with a tool to measure the level of clinical information present in adverse drug reaction reports.

BACKGROUND: To make a proper causality assessment of an adverse drug reaction (ADR) report, a certain level of clinical information is necessary. A tool was developed to measure the level of clinical information present in ADR reports. The aim of this study was to test the validity and reliability of the clinical documentation tool (ClinDoc) in an international setting. METHODS: The tool was developed by a panel of pharmacovigilance experts. It includes four domains: ADR, chronology of the ADR, suspected drug and patient characteristics. The final score categorizes reports into: excellent, well, moderately or poorly documented. In two rounds, eight pharmacovigilance assessors of different countries made a total of 224 assessments using the tool, with the expert panels judgement as a standard. Sensitivity and specificity were calculated. RESULTS: The tool with four outcome-categories demonstrated low sensitivity. A lack of distinctiveness was demonstrated between the categories moderate and well. Results for the second round were re-analysed using three categories. This demonstrated a better validity. CONCLUSION: This is the first tool to give insight in the level of relevant clinical information present in ADR reports. It can be used internationally to compare reports coming from different reporting methods and different types of reporters in pharmacovigilance.

Experiences with the use of varenicline in daily practice in the Netherlands: a prospective, observational cohort study.

BACKGROUND: Although a concise overview of adverse drug reactions (ADRs) to varenicline is available, little is known about the use of varenicline in daily practice and time-related information about ADRs. OBJECTIVE: The aim of this study was to gain insight in the safety and use of varenicline in daily practice. METHODS: A prospective, observational, non-interventional cohort study was performed. The study population was defined as first-time users recruited through participating pharmacies between 1 December 2008 and 31 March 2012. Patients could sign up for the study on a dedicated website. Web-based questionnaires were sent after 1, 2 and 6 weeks, 3 months and 4 months after patients started to use varenicline. Questions were asked about drug use and ADRs. Information about the ADR, its seriousness and the action taken when experiencing an ADR was gathered. RESULTS: A total of 1,418 patients signed up for the study. The response rates for the various questionnaires varied from 31.3 to 62.5 %. At least one ADR was reported by 58.8 % of the patients. The most frequently reported ADRs were nausea (30.8 %), abdominal pain (11.2 %) and abnormal dreaming (10.4 %). Most patients did not stop taking varenicline when they experienced these ADRs. The median latency times for ADRs reported more than 50 times were 3-7 days, with an exception for depressed mood, which had a latency time of 10 days. CONCLUSION: This prospective cohort study has given insight into latency time and action taken with varenicline when ADRs occur during treatment with varenicline in daily practice. It confirms the ADR pattern detected prior to marketing of the drug.

Expectations for feedback in adverse drug reporting by healthcare professionals in the Netherlands.

BACKGROUND: In 2010, the Netherlands Pharmacovigilance Centre Lareb received more than 4000 reports from healthcare professionals (HCPs). All HCPs received individual personal feedback containing information about the reported drug-adverse drug reaction (ADR) association. It is unclear what type of information HCPs expect in this feedback letter. OBJECTIVE: The aim of the study was to examine the expectations of the personal feedback of HCPs who reported an ADR to the Netherlands Pharmacovigilance Centre Lareb. METHODS: A questionnaire survey was conducted among a random sample of 1200 pharmacists, general practitioners (GPs) and medical specialists who reported an ADR to the Netherlands Pharmacovigilance Centre Lareb between 1 January 2009 and 27 January 2010. Responders and non-responders were compared on the basis of profession, number of reports submitted to the pharmacovigilance since 2007 and their last report being serious or not. Questions were asked about the importance of personal feedback and the type of information reporters would like to see in their personal feedback. Both linear and logistic regression analysis were performed, with correction for possible confounding factors. RESULTS: The response rate to the questionnaire was 34.6% (n = 399). The type of information the respondents generally would like to see in their personal feedback is information about the time course of the ADR and information about the pharmacological mechanism. However, GPs were, in general, less interested in receiving feedback than pharmacists and medical specialists. Most of the respondents were (very) unsatisfied if they received only a confirmation letter instead of personal feedback. Personalized feedback was considered to be (very) important for reporting an ADR in the future. Most of the respondents (80.3%) stated that the personal feedback increased their knowledge. Only 0.6% of respondents had not read the personalized feedback. No differences were found between responders and non-responders, with the exception that responders had reported statistically more often to the Netherlands Pharmacovigilance Centre Lareb in the past 3 years. CONCLUSIONS: Most of the respondents would like personal feedback instead of a standard confirmation letter. In general, pharmacists and medical specialists would like more information than GPs. The information in this study is useful in generating more customized personal feedback in the future, and could be useful for other pharmacovigilance centres that are interested in writing personalized feedback to make available to reporters.