Development of a multivariate prediction model to identify individual case safety reports which require clinical review.

BACKGROUND: The number of Individual Case Safety Reports (ICSRs) in pharmacovigilance databases are rapidly increasing world-wide. The majority of ICSRs at the Netherlands Pharmacovigilance Centre Lareb is reviewed manually to identify potential signal triggering reports (PSTR) or ICSRs which need further clinical assessment for other reasons. OBJECTIVES: To develop a prediction model to identify ICSRs that require clinical review, including PSTRs. Secondly, to identify the most important features of these reports. METHODS: All ICSRs (n = 30 424) received by Lareb between October 1, 2017 and February 26, 2021 were included. ICSRs originating from marketing authorisation holders and ICSRs reported on vaccines were excluded. The outcome was defined as PSTR (yes/no), where PSTR 'yes' was defined as an ICSR discussed at a signal detection meeting. Nineteen features were included, concerning structured information on: patients, adverse drug reactions (ADR) or drugs. Data were divided into a training (70%) and test set (30%) using a stratified split to maintain the PSTR/no PSTR ratio. Logistic regression, elastic net logistic regression and eXtreme Gradient Boosting models were trained and tuned on a training set. Random down-sampling of negative controls was applied on the training set to adjust for the imbalanced dataset. Final models were evaluated on the test set. Model performances were assessed using the area under the curve (AUC) with 95% confidence interval of a receiver operating characteristic (ROC), and specificity and precision were assessed at a threshold for perfect sensitivity (100%, to not miss any PSTRs). Feature importance plots were inspected and a selection of features was used to re-train and test model performances with fewer features. RESULTS: 1439 (4.7%) of reports were PSTR. All three models performed equally with a highest AUC of 0.75 (0.73-0.77). Despite moderate model performances, specificity (5%) and precision (5%) were low. Most important features were: 'absence of ADR in the Summary of product characteristics', 'ADR reported as serious', 'ADR labelled as an important medical event', 'ADR reported by physician' and 'positive rechallenge'. Model performances were similar when using only nine of the most important features. CONCLUSIONS: We developed a prediction model with moderate performances to identify PSTRs with nine commonly available features. Optimisation of the model using more ICSR information (e.g., free text fields) to increase model precision is required before implementation.

An evaluation of postmarketing reports of hyperglycaemia associated with dolutegravir for treatment of HIV in Eswatini.

BACKGROUND: Dolutegravir (DTG) is an Integrase Strand Transfer Inhibitor (INSTI) indicated in combination with other antiretroviral agents for the treatment of HIV infection. It is available in a number of pharmaceutical preparations including the fixed-dose combination (TLD) containing tenofovir (300 mg) + lamivudine (300 mg) + dolutegravir (50 mg). In 2018, Eswatini adopted TLD as the preferred first-line HIV treatment regimen for adults and adolescents as per WHO recommendations. From March 2019 to March 2020, the National Pharmacovigilance Center (NPC) in Eswatini received 8 reports of hyperglycaemia associated with the use of DTG. This study was conducted to investigate if Eswatini NPC database included cases suggestive of causality between dolutegravir and hyperglycaemia. METHOD: A qualitative synthesis of information from the Eswatini national pharmacovigilance database from March 2019 to March 2020 was conducted to investigate a casual association between hyperglycaemia and dolutegravir. RESULTS: All reports with dolutegravir containing regimen and suspected Adverse Event of hyperglycaemia in the period of March 2019 to March 2020 were included in the study. Seven of the reports were serious (resulted in hospitalization and one case concerned optic neuritis, leading to blindness). Two patients had a medical history of diabetes while the rest of the patients had never experienced hyperglycaemia before starting dolutegravir. For all the reports, the time to onset of hyperglycaemia ranges from 2-5 months after the initiation of DTG. None of the patients discontinued the use of DTG. All the patients were treated with oral hypoglycaemic medication. In severe cases, patients were treated with intravenous normal saline and ringer lactate as well as rapid-acting insulins. All patients are currently stable on oral hypoglycaemic drugs. CONCLUSION: Cases that support causality between dolutegravir containing regimen and hyperglycaemia were found. These cases were mainly serious. Based on these findings it is recommended that healthcare professionals (HCPs) actively screen all patients for risk factors of hyperglycaemia before DTG initiation. In addition, it is important that HCPs are aware of the possible association between DTG and hyperglycaemia.

Baseline assessment of pharmacovigilance activities in four sub-Saharan African countries: a perspective on tuberculosis.

BACKGROUND: New medicines have become available for the treatment of drug-resistant tuberculosis (DR-TB) and are introduced in sub-Saharan Africa (SSA) by the national TB programs (NTPs) through special access schemes. Pharmacovigilance is typically the task of national medicines regulatory agencies (NMRAs), but the active drug safety monitoring and management (aDSM) recommended for the new TB medicines and regimens was introduced through the NTPs. We assessed the strengths and challenges of pharmacovigilance systems in Eswatini, Ethiopia, Nigeria and Tanzania, focusing on their capacity to monitor safety of medicines registered and not registered by the NMRAs for the treatment of DR-TB. METHODS: Assessment visits were conducted to all four countries by a multidisciplinary team. We used a pharmacovigilance indicator tool derived from existing tools, interviewed key stakeholders, and visited health facilities where DR-TB patients were treated with new medicines. Assessment results were verified with the local NMRAs and NTPs. RESULTS: Most countries have enabling laws, regulations and guidelines for the conduct of pharmacovigilance by the NMRAs. The relative success of NTP-NMRA collaboration is much influenced by interpersonal relationships between staff. Division of roles and responsibilities is not always clear and leads to duplication and unfulfilled tasks (e.g. causality assessment). The introduction of aDSM has increased awareness among DR-TB healthcare providers. CONCLUSION: aDSM has created awareness about the importance of pharmacovigilance among NTPs. In the future, a push for conducting pharmacovigilance through public health programs seems useful, but this needs to coincide with increased collaboration with between public health programs and NMRAs with clear formulation of roles and responsibilities.

Insight in the safety profile of antidiabetic agents glucagon-like peptide-1 agonists and dipeptidyl peptidase-4 inhibitors in daily practice from the patient perspective.

PURPOSE: The primary aim of this study was to gain insight in the safety profile of the new antidiabetic agents glucagon-like peptide-1 (GLP-1) agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors in daily practice. The secondary aim was to compare reported adverse drug reactions (ADRs) with information described in the Summary of Product Characteristics (SPC) and to generate knowledge about characteristics, like time to onset and outcome of ADRs. This knowledge is important for drug regulators and clinical practice to understand and manage ADRs better. METHODS: A prospective, observational web-based cohort event monitoring study among first-time users of GLP-1 agonists and DPP-4 inhibitors. Patients were recruited through community pharmacies from 2008 to 2016. Participants were invited to complete six web-based questionnaires over a 1-year periods after start of the antidiabetic agent. Questions were posed about patient characteristics, drug use, and ADRs. Data were analyzed using descriptive statistics. RESULTS: Then, 743 patients were included. Also 62% of all GLP-1 agonist users (total n = 119) and 33% of DPP-4 inhibitor users (total n = 624) experienced an ADR. Of the 10 most reported ADRs, for GLP-1 agonist all, and for DPP-4 inhibitors 8 were described in the drug's SPC. For 45 (91%) ADRs, the patients recovered without discontinuation of the GLP-1 agonist and 79 (73%) ADRs without discontinuation of the DPP-4 inhibitor therapy. CONCLUSIONS: This study gives insight in the safety profile and ADR characteristics of the new antidiabetic agents. This study provides important knowledge for healthcare professionals in managing ADRs and can be directly applied in consultations in daily practice.

A global view of undergraduate education in pharmacovigilance.

PURPOSE: The aim of this study was to gain insight in current pharmacovigilance educational activities and to gather information on which topics should be included in the undergraduate pharmacovigilance core curriculum. METHOD: A web-based questionnaire was carried out containing 45 questions divided over four sections between 28 October 2014 and 31 January 2015. Potential participants working in pharmacovigilance and/or providing training in this field were invited via email and a widespread web link and snowball sampling was used to recruit additional participants. RESULTS: The questionnaire was filled out by 307 respondents from 88 different countries with a response rate of 29.3% for the email invitation and an unknown rate for the web link. Respondents were mainly pharmacists and physicians. Currently, lectures are the largest proportion of educational activities and all healthcare profession curricula have a mode of 2 h as number of contact hours per course. Respondents rated clinical aspects as the most important subdomain to be included in the core curriculum with prevention of adverse drug reactions as the most important subtopic. This was followed by communication aspects between parties, with communication between regulatory authorities and healthcare professionals, methodological aspects with causality assessment, and regulatory aspects with benefit-risk assessment. This is similar to subjects addressed in current educational activities with little difference between medical and pharmacy curricula. CONCLUSION: This study gave a good general impression in current educational activities and the respondents' needs and wishes for future activities worldwide, which both will be used for the development of the undergraduate pharmacovigilance core curriculum.

The contribution of direct patient reported ADRs to drug safety signals in the Netherlands from 2010 to 2015.

PURPOSE: The purpose of this study was to investigate the contribution of patient reports to signals sent by the Netherlands Pharmacovigilance Centre Lareb to the Dutch Medicines Evaluation Board and to determine if there are certain types of signals where patient report add a distinct contribution. METHOD: All signals from 2010 until 2015 were included. First, we investigated how many patient reports were present in the signals and the characteristics of these reports compared to the health care professional and marketing authorization holders' reports. In addition to source, the analysis included ATC code of the drug, MedDRA® system organ class and preferred term for the adverse drug reaction (ADR), seriousness of the ADR, and 7 other factors like reports on over-the-counter medication, and how often an ADR listed in the important medical event terms list was present. Secondly, we determined the proportion of reports submitted by the individual groups to signals, in a cross-sectional manner. RESULTS: A total of 150 signals were included, including 1691 ADR reports. Our results show that 26.3% of all ADR reports in Dutch drug safety signals were reported by patients, and 30.5% of the patient reports in the signals contained one or more terms listed as important medical events. The proportion of reports by patients which were included the signals was 2% and 3.9% for health care professional reports and 0.2% for marketing authorization holders reports. CONCLUSION: Patients had an important contribution to signals overall, but especially for ADRs related to generic drug substitution and psychiatric ADRs.

Time course, outcome and management of adverse drug reactions associated with metformin from patient's perspective: a prospective, observational cohort study in the Netherlands.

PURPOSE: The aim of this study was to gather information about frequency, latency time, outcome and management of frequently occurring adverse drug reactions (ADRs) related to the use of metformin in daily practice. METHODS: A prospective, observational cohort study was performed. A total of 2490 first-time metformin users were recruited through pharmacies in the Netherlands between February 1, 2008, and April 1, 2012. Patients were invited to complete six web-based questionnaires at 2-week, 6-week, 3-month, 6-month, 9-month and 12-month intervals after starting treatment with metformin. Information was gathered about patient characteristics, ADRs and drug use. RESULTS: The occurrence of at least one possible ADR related to the use of metformin was reported by 34.5 % of the patients. A higher proportion of females reported the occurrence of an ADR (39.6 %) compared to the proportion in males (30.9 %). Some patients (11.4 %) stopped using metformin within 1 year after start. More than half of the patients (50.8 %) undertook no action regarding metformin after the occurrence of ADRs. A high number of patients (77.7 %) recovered or were still recovering from ADRs despite continuation of metformin. Most ADRs occurred shortly after the beginning of the treatment, with a median latency time of 1-6 days. The study revealed some ADR-specific differences in occurrence rate, latency time, management and outcome. CONCLUSION: This study successfully obtained information about frequency, latency time, outcome and management of frequently occurring ADRs related to the use of metformin in daily practise.

Development, assessment and educational impact of a blended e-learning training program on pharmacovigilance implemented in four African countries.

Introduction: Efforts to improve medication access in low-and middle-income countries, particularly in Sub-Saharan Africa, have made progress, especially in the fight against infectious diseases such as tuberculosis. However, challenges exist in establishing effective pharmacovigilance systems. The PhArmacoVIgilance Africa (PAVIA) project was committed to enhancing pharmacovigilance in Tanzania, Eswatini, Nigeria, and Ethiopia, with an emphasis on anti-tuberculosis drugs, utilizing various methods, including training. This study evaluates the PAVIA training program's effectiveness and its adaptation during the COVID-19 pandemic. Methods: A blended e-learning program, incorporating two courses and a platform for educational materials, was developed. This program, designed to train healthcare professionals in pharmacovigilance, was incorporated into a Training of Trainers model. To evaluate the program effectiveness, we used multiple measures such as assessing knowledge gain through pre-and post-test scores, assessing learners' satisfaction and attitudes via questionnaires, and analyzing Individual Case Safety Reports (ICSRs) in VigiBase to determine the impact on spontaneous reporting systems in the PAVIA countries. Results: 121 learners enrolled in the pilot trainings, including 36 from Tanzania, 34 from Eswatini, 25 from Nigeria, and 26 from Ethiopia. Notably, post-test scores were significantly higher than pre-test scores in all four countries. Following the pilot trainings, multiple step-down training sessions were held in Tanzania, Eswatini, and Nigeria, with a total of 827 learners registering and 421 successfully completing the program. Learners' scores on the post-tests were significantly higher than on the pre-tests for both courses in all three countries. Learners' feedback on the training was overwhelmingly positive. Additionally, a qualitative analysis of ICSRs revealed a substantial increase in reports after the training in Tanzania, Eswatini, and Nigeria. Discussion: An innovative e-learning program trained healthcare professionals in pharmacovigilance and anti-tuberculosis drug safety over 3 years in four PAVIA countries. The program effectively improved participants' knowledge, received positive feedback, and likely had an impact on reporting rates in Tanzania, Eswatini, and Nigeria, although a direct causal link could not be definitively established due to data limitations and other factors, such as the heightened reporting rates associated with COVID-19 vaccines, that could have contributed to the notable increase in ICSRs.

Neuropsychiatric adverse events of varenicline: a systematic review of published reports.

INTRODUCTION: Over the past years, the impact of varenicline in patients with mental illness has been debated as serious neuropsychiatric adverse events (AEs) have been reported with varenicline use. AIM: To identify and summarize published case reports of neuropsychiatric AEs ascribed to varenicline and to determine potential risk factors for these AEs. METHODS: A literature search of MEDLINE, the Cochrane Library, EMBASE, and PsychInfo database was conducted for case reports concerning the neuropsychiatric AEs of varenicline published in English from 2006 (approval year by the US Food and Drug Administration and the Dutch Medicines Evaluation Board) to January 1, 2012. RESULTS: We identified 25 published cases. In most reports, patients had been admitted to psychiatric hospitals with serious neuropsychiatric AEs due to varenicline. The average patient age was 46.4 years, and 56% were men; 68% of patients had a psychiatric history. The onset of symptoms started 2 days to 3 months after the initiation of varenicline. One report described completed suicide in a man with no psychiatric history. In most cases (84%), the neuropsychiatric symptoms resolved after the discontinuation of varenicline. Analysis of all reports using the Naranjo causality scale, a method for estimating the probability of adverse drug reactions, indicated probable causality in 76% of the cases and definite causality in 12% of cases. CONCLUSION: Varenicline is associated with an increased risk of serious neuropsychiatric AEs, especially in patients with a psychiatric illness. It is strongly recommended that varenicline be administered only to mentally stable patients and under close monitoring.

Intensive monitoring of duloxetine: results of a web-based intensive monitoring study.

PURPOSE: Duloxetine (Cymbalta(®)) is a serotonin (5-HT) and norepinephrine (NE) re-uptake inhibitor indicated for the treatment of depression, diabetic peripheral neuropathic pain and general anxiety disorder. The aim of this study is to gain insight in the user and safety profile of duloxetine in daily practice, reported by patients via a web-based intensive monitoring system during their first 6 months of use. METHODS: First-time users of duloxetine were identified through the first dispensing signal in the pharmacy. Patient demographics and information about drug use and adverse drug reactions, ADRs, were collected through electronic questionnaires sent 2 and 6 weeks, 3 and 6 months after the start of duloxetine administration. ADRs were quantified and signal detection was performed on a case by case basis. RESULTS: Three hundred and ninety-eight patients registered for the study; 69.1 % were female. Depression was the main indication. Three hundred and three patients (76.1 %) filled in at least one questionnaire and 78.9 % of these reported an ADR. Serious ADRs were reported by 4 patients. Three new signals were identified, amenorrhea, shock-like paraesthesias and micturition problems. CONCLUSIONS: Web-based intensive monitoring is an observational prospective cohort study mirroring the use and ADRs of duloxetine in daily practice. This study indicates that duloxetine is a relatively safe drug as used by patients for six months in daily practice, but the aforementioned signals need to be evaluated in more detail.

Representativeness of diabetes patients participating in a web-based adverse drug reaction monitoring system.

PURPOSE: Lareb Intensive Monitoring, LIM, is a non-interventional observational cohort method which follows first-time users of certain drugs during a certain period of time and collects information about adverse drug reactions, ADRs. In order for LIM to be a useful pharmacovigilance tool, it is important to know whether the LIM population is comparable to the whole population using the drug. The aim of this study is to compare the LIM diabetes population with an external diabetes reference population on characteristics that may influence the patient's susceptibility for ADRs. METHODS: In this study, a LIM diabetes population was compared to a reference diabetes population derived from The Groningen Initiative to ANalyse Type 2 diabetes Treatment project. Comparisons were made regarding age, gender, body mass index and polypharmacy, as well as diabetes medication used and disease/treatment duration. RESULTS: LIM patients were more often men (58.5% vs 50.8%) and in general younger (59.1 vs 64.7 years) and healthier, by that meaning they had a higher percentage of de novo treated patients (55.5% vs 53.2%), a shorter diabetes treatment duration (3.7 vs 5.5 years) and used less co-medication than patients in the reference population. CONCLUSIONS: This study shows that diabetes patients participating in a web-based intensive monitoring system differ from a reference population. The observed differences might lead to an underestimation of ADRs, but it is not clear whether this would also influence the type or time-course of the reported ADRs. When interpreting results from LIM studies, one should take these differences into account.

Patients' motives for participating in active post-marketing surveillance.

PURPOSE: Web-based intensive monitoring is a method to actively collect information about adverse drug reactions (ADRs) using patients as a source of information. To date, little is known about patients' motivation to participate in this kind of active post-marketing surveillance (PMS). Increased insight in this matter can help us to better understand and interpret patient reported information, and it can be used for developing and improving patient-based pharmacovigilance tools. The aim of this study is to gain insight into patients' motives for participating in active PMS and investigate their experiences with such a system. METHOD: A mixed model approach combining qualitative and quantitative research methods was used. For both parts, patients participating in a web-based intensive monitoring study about the safety of anti-diabetic drugs (excluding insulins) were used. A questionnaire was developed based on the results from qualitative interviews. The data collected through the questionnaires was analysed with descriptive statistics. Relations between patient characteristics and motives were analysed using a t-test or a Chi-squared test. RESULTS: 1332 (54.6%) patients responded to the questionnaire. The main motive for participation was altruism. Often experiencing ADRs or negative experiences with drugs were not important motives. The patient's gender played a role in the different motives for participation. For men, potential future personal benefit from the results was more important than for women. The overall opinion about the system was positive. CONCLUSION: The knowledge that patients participate in this kind of research from an altruistic point of view may strengthen patient involvement in pharmacovigilance.

Funding and financial sustainability of pharmacovigilance: suggested models for funding pharmacovigilance in resource-limited African countries.

Background: An important factor hindering the growth of pharmacovigilance (PV) in resource-limited settings is the lack of adequate funds to establish a functional National Pharmacovigilance System. Consequently, the crucial function of monitoring and ensuring the availability of safe medicines in these settings cannot be guaranteed considering the peculiarities of diseases and medicines used. Objectives: The objective of this paper is to provide an overview as to the availability of potential sources of funds, which could be explored to ensure Medicine Safety and to proffer a potential framework likely to ensure sustainable funding of PV in Africa. Methods/processes: The process of developing this framework entailed a review of PV financing in some developed economies, a landscape study of funding of PV in some African countries, an in-depth understanding of the PV system and the organisational structure and nexus between the regulatory agencies and National Pharmacovigilance Centre. Critical points for consideration included the sources of funds, revenue pool, the disbursement of funds, budgeting and expenditure profile and the legal framework. Consultative meetings, webinars and interviews with experts were carried out. Results: The findings showed that most of the PV systems were mainly integrated into the regulatory agencies regarding operational and fiscal governance with few facilities being independent of the regulatory agencies. The main source of funding was from the government with significant donor funding which is ad hoc and non-sustainable. Several potential sources were identified but yet to be exploited. There were no legal provisions for PV financing. A framework likely to ensure sustainable PV financing is suggested to capture all available sources of funding, mine the potential sources providing a sizeable pool of revenue to address its activities and enabling legal framework which will engender autonomy. Furthermore, it will address the nexus between the regulatory agencies and the PV outfits, thus enabling appropriate share of resources and blockage of diversions. Conclusion: In all, addressing the various elements identified in this study and providing the legal provisions which guarantees some degree of autonomy will provide a sustainable mechanism for PV funding in the resource-limited setting of Africa.

Funding models for pharmacovigilance in resource-limited African countries An important factor hindering the growth of pharmacovigilance (PV) in resource-limited settings following their entry into the WHO Programme of International Drug Monitoring is the lack of adequate funds to establish a functional National Pharmacovigilance System. This article provides an overview of various potential sources of funds in these settings and how they can be harnessed to fund PV. We undertook a review of PV financing in developed settings and carried out a landscape study of funding of PV in some African countries, as well as having an in-depth understanding of the PV system and the organisational structure. The nexus between the regulatory agencies and National Pharmacovigilance Centre was noted. We took into account the sources of funds, revenue pool, the disbursement of funds, budgeting and expenditure profile and the legal framework for the different African countries. We also identified the prevalent and potential sources of funds for PV. Consultative meetings, webinars and interviews with experts in PV were carried out as well. We discovered that most of the PV facilities were mainly integrated into the regulatory agencies regarding operational and fiscal governance with few facilities being independent of the regulatory agencies. The main source of funding was from the government with significant donor funding which is ad hoc and non-sustainable. Several potential sources were identified but yet to be exploited. There were no legal provisions for PV financing. We have now proposed funding models that may lead to increased revenue for PV in these countries as well as suggesting that a legal framework be provided to guarantee sustainability and address the nexus between the regulatory agencies and the PV outfits to ensure an appropriate share of resources and blocking diversions.

Epistaxis and other haemorrhagic events associated with the smoking cessation medicine varenicline: a case series from two national pharmacovigilance centres.

PURPOSE: To present a case series of haemorrhagic events associated with varenicline identified from the New Zealand (NZ) and Netherlands national pharmacovigilance centres and propose a possible mechanism for these adverse events. METHODS: Reports of epistaxis and other haemorrhagic events (in all system organ classes excluding gynaecological) associated with varenicline were identified and assessed in both the NZ Intensive Medicines Monitoring Programme (IMMP) and the Netherlands Pharmacovigilance Centre Lareb (Lareb). Additional reports were identified from the World Health Organisation Uppsala Monitoring Centre (WHO-UMC) datasets, and these also underwent causality assessment. RESULTS: A total of 30 reports of haemorrhagic events were identified by the NZ IMMP (16 reports) and Lareb (14 reports). Six cases of epistaxis were identified, and four patients had a positive dechallenge on withdrawal of varenicline, suggesting a causal association. Another five reports of gingival bleeding were identified, with three patients having a positive dechallenge. Another patient who experienced haemoptysis while taking varenicline had a positive dechallenge and a positive rechallenge. In the WHO datasets, a further 49 reports of epistaxis, 39 reports of haemoptysis and 21 reports of thrombocytopenia were identified. A plausible mechanism for haemorrhagic events associated with varenicline may be a result of interaction with the serotonin (5-HT) receptor system and transporter. CONCLUSIONS: This is the first specific investigation of haemorrhagic events associated with varenicline. The results of our assessment of reports identified by two national pharmacovigilance centres suggest that there may be causal relationship between varenicline and these adverse events.

COVID-19 vaccine reactogenicity - A cohort event monitoring study in the Netherlands using patient reported outcomes.

OBJECTIVES: To explore factors that are associated with reactogenicity in general and systemic after the first dose of COVID-19 vaccine in the Netherlands. DESIGN: A web-based prospective cohort design using patient reported outcomes (PROs). SETTING: Any person who has been vaccinated with any brand of COVID-19 vaccine in the Dutch COVID immunization programme. PARTICIPANTS: 22,184 participants. Of these, 13,959 (62.9%) experienced reactogenicity in general and 11,979 (54.0%) systemic reactogenicity within 7 days after vaccination. MAIN OUTCOME MEASURES: Factors that are associated with the occurrence of reactogenicity after COVID-19 vaccination. RESULTS: Compared to the Comirnaty® vaccine, the highest odds ratio (OR) for developing reactogenicity was for the Vaxzevria® vaccine (OR 5.18) followed by Spikevax® (OR 2.16), and Janssen (OR 1.65). Participants with a history of COVID-19 disease had a 3.10 increased odds for reactogenicity. Women had a 2.08 increased odds compared to men. Older participants experienced less reactogenicity. Compared to the age group < 50, the ORs for the age groups 50-60, 61-79, and ≥80 were 0.36, 0.15, and 0.10 respectively. The use of an antipyretic drug, or a drug for nervous system disorders gave an increased odds of 1.34 and 1.16 respectively. A body mass index of 25.0-29.9 and over 30 was negatively associated with reactogenicity (OR 0.87 and OR 0.72 respectively). Comorbidities that were associated with reactogenicity were cardiac disorders (OR 1.26), respiratory disorders (OR 1.31), psychiatric disorders (1.37), reproductive disorders (OR 1.54), and eye disorders (OR 1.55). The factors associated with systemic reactogenicity were mostly comparable, but there were differences for comorbidities, drug use, and the strength of the regression coefficient. CONCLUSIONS: This extensive study with over 22,000 vaccine recipients in the Netherlands demonstrated that, taken into account all factors in the model, the Comirnaty® vaccine gave the least and the Vaxzevria® vaccine the most reactogenicity in general and systemic after the first dose. Also a person with a history of COVID-19 disease, female sex and younger age had an increased odds for experiencing reactogenicity after vaccination.

Factors Contributing to Best Practices for Patient Involvement in Pharmacovigilance in Europe: A Stakeholder Analysis.

INTRODUCTION: Involving patients in decision making adds value in the context of pharmacovigilance (PV). This added value goes beyond participation in spontaneous reporting systems for adverse drug reactions. However, there is a gap between allowing patients to report and actual patient involvement. Views regarding best practices from regulators, patient organizations and pharmaceutical companies could help increase and improve patient involvement in PV. OBJECTIVE: The aim of this study was to investigate the factors contributing to best practices for patient involvement in PV and to develop a definition of patient involvement based on a qualitative multistakeholder study across Europe. METHODS: A literature review was conducted to map the field of study and obtain insights for the elaboration of an interview guide. Subsequently, patient representatives, members of the pharmaceutical industry and regulators were invited to participate in interviews. These interviews were analyzed using NVIVO® software and employing reflective thematic analysis. RESULTS: A total of 20 interviews were conducted with representatives at both the national and European levels. The best practices identified were engagement from the start, face-to-face communication, a full circle of feedback, same-level partners, structured involvement and guidelines, establishing common goals, patient education and empowerment, and developing trust and balance. These activities can be implemented via deep collaboration among stakeholders. A definition of patient involvement was constructed in accordance with the input of all stakeholder groups, which reflects the involvement of all types of patients at all levels of the decision-making process. CONCLUSION: In this study, we developed a definition for patient involvement based on qualitative interviews. The factors contributing to best practices for patient involvement were mentioned across stakeholder groups and aimed to stimulate patient involvement in PV. Patients are eager to become equal partners and to engage effortlessly in the same manner as other stakeholders.

Development and validation of a machine-learning algorithm to predict the relevance of scientific articles within the field of teratology.

The Dutch Teratology Information Service Lareb counsels healthcare professionals and patients about medication use during pregnancy and lactation. To keep the evidence up to date, employees perform a standardized weekly PubMed query where relevant literature is identified manually. We aimed to develop an accurate machine-learning algorithm to predict the relevance of PubMed entries, thereby reducing the labor-intensive task of manually screening the articles. We fine-tuned a pre-trained natural language processing transformer model to identify relevant entries. We split 15,540 labeled entries into case-control-balanced train, validation, and test datasets. Additionally, we externally validated the model prospectively with 1288 labeled entries obtained from weekly queries after developing the model. This dataset was also independently labeled by a team of six experienced human raters to evaluate our model's performance. The validation of our machine learning model on the retrospectively collected outheld dataset obtained an area under the sensitivity-versus-specificity curve of 89.3 % (CI: 88.2- 90.4). In the prospective external validation of the model, our model classified relevant literature with a sensitivity versus specificity curve area of 87.4 % (CI: 85.0-89.8). Our model achieved a higher sensitivity than the human raters' team without sacrificing too much specificity. The team of human raters showed weak to moderate levels of agreement in their article classifications (kappa range 0.40-0.64). The human selection of the latest relevant literature is indispensable to keep the teratology information up to date. We show that automatic preselection of relevant abstracts using machine learning is possible without sacrificing the selection performance.

Longitudinal monitoring of the safety of drugs by using a web-based system: the case of pregabalin.

PURPOSE: Information about the time course of adverse drug reactions (ADRs) is often lacking. If this information would be available, it could help increase patient's adherence to drugs when experiencing an ADR. The aim of this study was to demonstrate how a web-based intensive monitoring system using the patient as a source of information can be used to gather longitudinal safety data of a drug. In this study, pregabalin was used as an example. METHODS: First-time users of pregabalin were approached in Dutch pharmacies between 1 August 2006 and 31 January 2008. After online registration, patients received questionnaires by email 2 weeks, 6 weeks, 3 months and 6 months after the start of the drug use. Data on patient characteristics, drug use and ADRs were collected and analysed. RESULTS: A total of 1373 patients registered for the pregabalin study. Of these patients, 1051 (76.5%) filled in at least one questionnaire. On an aggregated level, the ADR profile remained relatively stable over time. Incidence densities showed that the five most frequently reported reactions occurred early in the treatment. Initially, the majority of the patients did not undertake any action when experiencing an ADR. Recovery did not seem to be completely dependent of drug cessation. CONCLUSIONS: With web-based intensive monitoring, it is possible to study the time course of ADRs. This method can be a valuable addition to pharmacovigilance because it can generate other types of information as compared with spontaneous reporting and other intensive monitoring methodologies.

Pharmacovigilance Data as a Trigger to Identify Antimicrobial Resistance and Inappropriate Use of Antibiotics: A Study Using Reports from The Netherlands Pharmacovigilance Centre.

(1) Background: Antimicrobial resistance (AMR) requires urgent multidisciplinary solutions, and pharmacovigilance has the potential to strengthen current antimicrobial stewardship strategies. This study aimed to characterize AMR-relevant adverse drug reaction (ADR) reports submitted to The Netherlands Pharmacovigilance Centre; (2) Methods: We carried out a descriptive analysis of ADR reports submitted to Lareb, coded with AMR-relevant MedDRA Preferred Terms (PTs); (3) Results: Between 1998 and January 2019, 252 AMR-relevant ADR reports were submitted to Lareb. The most frequent antibiotics were tobramycin (n = 89; 35%), colistin (n = 30; 11.9%), cipro-floxacin (n = 16; 6.3%), doxycycline (n = 14; 5.5%), and aztreonam (n = 12; 4.8%). The PTs used included off label use (n = 91; 36.1%), drug ineffective (n = 71; 28.2%), product use in unapproved indication (n = 28; 11.1%), pathogen resistance (n = 14; 5.6%), and drug resistance (n = 13; 5.2%). 54% of the reports were on Watch antibiotics and 19% were involved in the Reserve group. In the Watch group, "off label use" and "product use in unapproved indication" were the most frequent PTs and the majority of reports on Reserve antibiotics were coded as "Off label". A sharp increase in the number of reports was observed in the three consecutive years with 21 in 2013, 54 in 2014, and 83 in 2015; (4) Conclusions: In addition to existing AMR monitoring strategies, pharmacovigilance databases can serve as a source of data on suspected resistance and inappropriate use. Future research should explore how these AMR-relevant MedDRA Terms are used in resource-limited settings with less capacity to generate laboratory-confirmed resistance data.