The STAR Compass to Guide Future Pharmacovigilance Based on a 10-Year Review of the Strengthened EU System.

This article reflects on the 2010 pharmacovigilance legislation of the European Union (EU). Its legislative aim of better patient and public health protection through new responsibilities for pharmaceutical companies and regulatory bodies is considered to have been achieved and is well supported by the good pharmacovigilance practices 'EU-GVP'. For future progress, we set out a vision for high-quality pharmacovigilance in a world of ongoing medical, technological and social changes. To deliver this vision, four principles are proposed to guide actions for further progressing the EU pharmacovigilance system: synergistic interactions with healthcare systems; trustworthy evidence for regulatory decisions; adaptive process efficiency; and readiness for emergency situations (the 'STAR principles'). Like a compass, these principles should guide actions for building capacity, technology and methods; improving regulatory processes; and expanding policies, frameworks and research agendas. Fit for the future, the EU system should achieve further improved outputs in terms of safe, effective and trusted use of medicines and positive health outcomes within patient-centred healthcare.

Duration of Effectiveness Evaluation of Additional Risk Minimisation Measures for Centrally Authorised Medicinal Products in the EU Between 2012 and 2021.

INTRODUCTION: In studies evaluating the effectiveness of additional risk minimisation measures (aRMMs), the need for speed must be properly balanced with the quality of the study. We assessed the duration of aRMM effectiveness evaluations, using additional pharmacovigilance activities, for centrally authorised medicinal products in the European Union. METHODS: We established a cohort of medicinal products with aRMMs at marketing authorisation (MA) that were centrally authorised from July 2012-December 2021 using the European Public Assessment Reports. Evaluation studies were identified from the Risk Management Plans at the time of MA. Subsequently, we retrieved protocols, final study reports, Pharmacovigilance Risk Assessment Committee (PRAC) assessment reports, and PRAC minutes. We calculated the probability of completing an effectiveness evaluation within 60 months after MA using time-to-event analyses. Besides, we compared the planned final report with the actual final report date. RESULTS: We identified 134 medicinal products authorised with aRMMs, of which almost half (n = 63, 47.0%) had an effectiveness evaluation study. The probability of an evaluation for a medicinal product being completed within 60 months after MA was 20.7% (95% CI 6.8-32.6). Regarding study design, the probability of completing a study was higher for cross-sectional studies when compared to cohort studies (p = 0.002). Moreover, 81.0% of studies were delayed when compared to their planned final report date. CONCLUSION: The probability of completing an aRMM effectiveness evaluation at time for renewal of the MA was only one in five. Furthermore, estimates of the duration of studies around MA are too optimistic, with the majority being delayed.

An Exploratory Study of the Impact of COVID-19 Vaccine Spontaneous Reporting on Masking Signal Detection in EudraVigilance.

INTRODUCTION: During the signal detection process, statistical methods are used to identify drug-event combinations (DECs) which are disproportionately reported when compared with other drugs and events in the entire database. We hypothesise that the high volume of COVID-19 vaccine adverse drug reaction (ADR) reports transmitted to EudraVigilance may have affected the performance of disproportionality statistics used in routine signal detection, potentially resulting in signals either being masked, or false associations being flagged as potential signals. OBJECTIVE: Our aim was to study the impact of COVID-19 vaccine spontaneous reporting on statistical signal detection in EudraVigilance. METHODS: We recalculated the reporting odds ratio (ROR) for signals that were previously discussed at the level of the Pharmacovigilance Risk Assessment Committee, or signals that were retrieved from EudraVigilance, by omitting COVID-19 vaccine reports from the standard ROR calculation and then comparing the lower confidence interval (LCI) of the recalculated ROR to the LCI of the actual ROR in EudraVigilance. RESULTS: In total, 52 signals for 38 active substances were reviewed. For 35 signals, the LCI of the recalculated ROR value was lower than the LCI of the actual ROR (suggesting that COVID-19 vaccine ADR reporting had a positive effect on the strength of the signal) while for 15 signals the LCI of the recalculated ROR value was higher than the LCI of the actual ROR (suggesting that COVID-19 vaccine ADR reporting had an attenuating effect on the strength of the signal). For two signals, no change in the ROR was observed. In our analysis, six significant results were found. Five DECs were found to be masked: bleomycin and immune thrombocytopenia (actual ROR LCI = 0.94, recalculated ROR LCI = 1.02), vortioxetine and heavy menstrual bleeding (actual ROR LCI = 0.3, recalculated ROR LCI = 1.06), caplacizumab and heavy menstrual bleeding (actual ROR LCI = 0.98, recalculated ROR LCI = 3.47), ziprasidone and amenorrhoea (actual ROR LCI = 0.84, recalculated ROR LCI = 1.67), and azacitidine and pericarditis (actual ROR LCI = 0.81, recalculated ROR LCI = 2.01). For the DEC of adalimumab and immune reconstitution inflammatory syndrome, the LCI of the actual ROR value was 1.14 and removing COVID-19 vaccine reporting resulted in an LCI of the recalculated ROR value of 0.94 (below threshold). CONCLUSIONS: We demonstrated five cases of masking and one case of false-positive association due to the influence of COVID-19 vaccine spontaneous reporting on the ROR. This suggests that the high number of adverse drug reaction reports for COVID-19 vaccines in EudraVigilance has the potential to affect routine statistical signal detection activities. The impact of COVID-19 vaccine ADR reports on current signal detection practices requires further evaluation and solutions to tackle masking issues in EudraVigilance may need to be developed.

Patient Preferences for Rituximab Additional Risk Minimization Measures: Results From an International Online Survey.

OBJECTIVE: Patients' opinions are essential in optimizing risk minimization measures (RMMs) because they bring their real-life experience of disease management and medicines' use into the regulatory assessments. The aim of the survey launched in 2018 by the European Medicines Agency, in collaboration with the Pharmacovigilance Risk Assessment Committee, was to consult targeted patient groups treated with rituximab for nononcology indications to evaluate their preferences on how to receive information on progressive multifocal leukoencephalopathy and (serious) infections. Additional RMMs such as educational materials for physicians and patients including a patient alert card (PAC) and a patient brochure (PB) are in place to minimize these risks. METHODS: A question-based online survey in English created on the EU-Survey platform and disseminated primarily via relevant European patient organizations. RESULTS: Most patients (47 of 61) had knowledge of these potential adverse effects. Mostly, they were informed by a healthcare professional. Both a PAC and a PB were supported as useful tools to raise awareness of these adverse effects and thus minimize the potential risks among patients. Where the participants had to choose only 1 of these educational materials, 43 of them preferred a PAC, a shorted description that is always held by the patient and reaches the relevant healthcare professional when needed. CONCLUSIONS: Collecting patients' preferences supports periodic assessment of additional RMMs and increase transparency of regulatory processes. Considering the limitations of this initial survey, further investigation is needed to generalize the results into patients' safety outcomes.

Dissemination of Direct Healthcare Professional Communications on Medication Errors for Medicinal Products in the EU: An Explorative Study on Relevant Factors.

INTRODUCTION: When serious medication errors (ME) are identified, communication to the field may be necessary. In the EU, communication of serious safety issues, such as medication errors associated with adverse drug reactions, is done through direct healthcare professional communications (DHPCs). We aimed to identify how often DHPCs about medication errors are distributed, and we explored factors associated with these ME DHPCs. METHODS: We performed a descriptive study of all centrally authorised products (CAPs) approved before 1 May 2019 in the EU. All DHPCs issued between 1 January 2001 and 1 May 2019 were reviewed for ME content. Characteristics of CAPs were collected from the website of the European Medicines Agency. A Kaplan-Meier survival analysis was performed to estimate the 5- and 10-year probability of the occurrence of a first ME DHPC. A logistic regression was performed to explore risk factors for ME DHPCs. RESULTS: A total of 678 CAPs were included, of which 35 required an ME DHPC during the study period. The 5-year probability for a CAP to have a first ME DHPC was 2.5% (95% CI 1.1-3.9) and the 10-year probability was 4.4% (95% CI 2.2-6.5). Among products with an ME DHPC, the 5-year probability of a second ME DHPC was 21.3% (95% CI 0.2-38.0). The risk of ME DHPCs was increased for products with multiple pharmaceutical formulations, enteral liquid or parenteral injection preparations, and products classified as nervous system agents or antineoplastic and immunomodulating agents. CONCLUSIONS: The absolute number of ME DHPCs for CAPs is low and does not give rise to immediate concern. We identified potential risk factors for ME DHPCs that should be taken into account during approval procedures or line extensions.

Introduction or Discontinuation of Additional Risk Minimisation Measures During the Life Cycle of Medicines in Europe.

INTRODUCTION: Additional risk minimisation measures (aRMMs) may be required to minimise important risks of medicines. aRMMs may be required at the time of authorisation, but may also be introduced or discontinued during the product life cycle as new safety information arises. The aim of this study is to describe post-authorisation introductions of new aRMMs and discontinuations of existing aRMMs for medicines authorised in the European Union (EU). METHODS: We performed a retrospective cohort study that included all new active substances authorised through the EU centralised procedure between January 1st 2006 and December 31st 2017. Data was extracted from European Public Assessment Reports available on the website of the European Medicines Agency (ema.europa.eu). Medicines were followed up from the date of marketing authorisation (MA) until first introduction or discontinuation of aRMMs, excluding Direct Healthcare Professional Communications (DHPCs), withdrawal/suspension/revocation of the MA, or July 1st 2018, when data extraction took place. Descriptive statistics were used to analyse frequency data, and survival analysis was used to calculate 5- and 10-year probability of introduction or discontinuation of aRMMs. RESULTS: A total of 476 medicines were authorised during the study period. The probability of getting aRMMs after authorisation for products authorised without aRMMs was 3.5% [95% confidence interval (CI) 1.2-5.7] within 5 years after authorisation and 6.9% (95% CI 2.6-11) within 10 years after authorisation. For products authorised with aRMMs, the probability of discontinuation of aRMMs was 0.9% (95% CI 0-2.6) within 5 years and 8.3% (95% CI 0-16.1) within 10 years after authorisation. CONCLUSIONS: We found low probabilities of introduction and discontinuation of aRMMs (excluding DHPCs) during the product life cycle for medicines authorised between 2006 and 2017. The low rate of discontinuation may potentially be due to a lack of robust data on effectiveness of aRMMs. Further research is needed to get more insight into the dynamics of aRMMs during the medicine life cycle.

Proposals for Engaging Patients and Healthcare Professionals in Risk Minimisation from an Analysis of Stakeholder Input to the EU Valproate Assessment Using the Novel Analysing Stakeholder Safety Engagement Tool (ASSET).

INTRODUCTION: Understanding the impact of regulatory actions for medicines and enablers/barriers for positive health outcomes is fundamental to effective risk minimisation measures (RMM). Therefore, the Impact Strategy of the European Union (EU) Pharmacovigilance Risk Assessment Committee (PRAC) includes engagement with patient communities and healthcare professional (HCP) bodies regarding RMM. However, there is uncertainty on how best to obtain stakeholder input. OBJECTIVES: The objectives of this study were to (1) analyse stakeholder input at a public hearing and dedicated meeting for the 2017-18 EU procedure on valproate teratogenicity and (2) draw proposals for enhancing PRAC engagement. METHODS: For the content analysis, the novel 'Analysing Stakeholder Safety Engagement Tool' (ASSET) was developed with 21 themes in six domains (appropriateness, access, audience, compatibility, integrability, time), based on implementation theories. RESULTS: Stakeholders provided a wide range of RMM proposals, some beyond the regulatory remit. Patients and most HCPs converged remarkably, but there was some divergence among HCPs on the informed choice objective, the therapeutic place of valproate, the RMM appropriateness, and RMM delivery to HCPs and patients. Ethical aspects emerged as relevant for regulatory decision making, and crucial input gaps were identified from an RMM implementation perspective. Nine pilotable proposals for PRAC were made regarding: (A) Agreeing on appropriate RMM with stakeholders and catalysing healthcare leadership for implementation; (B) Building-up stakeholder input on all elements critical to RMM implementation guided by the ASSET; and (C) Collaborating with all stakeholders for monitoring implementation and evaluating RMM. CONCLUSIONS: New implementation theory-based approaches are promising for enhancing the valuable dialogue between regulators, patients and HCPs and achieving patient safety. EU PAS REGISTER NUMBER: EUPAS35947.

Fatal outcomes following immunization errors as reported to the EudraVigilance: A case series.

BACKGROUND: Serious adverse reactions after immunization are rare but do occur. In very rare instances, cases with fatal outcome have been reported. These reports can have a huge impact and even more so when due to an immunization error. The aim of this study is to systematically review immunization errors with fatal outcomes in EudraVigilance. METHODS: This was a case-series analysis of Individual Case Safety Reports (ICSRs) reporting immunization errors and a fatal outcome. To determine the level of certainty of a causal association between the immunization errors and fatal outcomes two independent reviewers assessed all ICSRs using the WHO tool "Causality assessment of an Adverse Event Following Immunization (AEFI)". In accordance with the tool, the ICSRs were classified as consistent, indeterminate, inconsistent/coincidental, or unclassifiable. In addition, we estimated the contribution of reported errors to the fatal outcomes as large, moderate, small, none, or unclassifiable using a classification developed for this study. RESULTS: A total of 154 ICSRs met the inclusion criteria. Vaccines reported most frequently were pneumococcal (33), rabies (27) and influenza vaccines (24). Most frequently reported errors were non-compliance with recommended schedules of immunization (63). The most frequently reported vaccine-error combination was rabies vaccines and non-compliance with a recommended schedule of immunization (23). Twelve cases were classified as consistent with causal association and had a large error contribution. These cases concerned a cluster of six cases reporting incorrect handling of multi-dose vials containing measles vaccine and six cases reporting administration of live-attenuated vaccines to immunocompromised patients. DISCUSSION: In this study, we showed that fatal outcomes following immunization errors are very rare. Four key issues were the importance of: (1) quality control of multi-dose vaccines, (2) screening patients for immunocompromising factors, (3) education on the importance of adherence, and (4) measures to improve distinction between vaccines and medicines.

Description of the Risk Management of Medication Errors for Centrally Authorised Products in the European Union.

INTRODUCTION: Medication errors can have serious consequences for patients. To prevent the occurrence of medication errors in clinical practice, safety concerns may be included in the risk management plan and subsequently be addressed with routine and/or additional risk minimisation measures. OBJECTIVE: This study aims to describe safety concerns around medication errors and the risk minimisation measures for centrally authorised products in the European Union. METHODS: All safety concerns included in the risk management plans of originator centrally authorised products, authorised between 1 January, 2010 and 31 December, 2017, were collected from the European Public Assessment Report registry. Medication error safety concerns were categorised by Anatomical Therapeutic Classification code, year of authorisation, type of medication error and type of risk minimisation measure. RESULTS: During the study period, 311 centrally authorised products were approved, of which 84 had at least one medication error safety concern. The proportion of centrally authorised products with medication error safety concerns showed variation between 2010 and 2017 ranging from 15.2% to 36.4%. In total, 95 medication error safety concerns were identified. The type of medication error was highly variable, drug administration error was listed most frequently (n = 17). For 27 out of 95 medication error safety concerns, corresponding to 23 centrally authorised products, additional risk minimisation measures were required. All additional risk minimisation measures consisted of educational material targeted at healthcare professionals (85.2%) and/or patients (51.9%). For 78.3% of centrally authorised products with additional risk minimisation measures for medication errors, studies to evaluate the effectiveness of the additional risk minimisation measures were agreed upon. CONCLUSIONS: Medication error safety concerns were listed for almost a quarter of centrally authorised products approved during the study period. Further research is needed to evaluate the effectiveness and continued need for additional risk minimisation measures for medication errors.

Spontaneous reports of vaccination errors in the European regulatory database EudraVigilance: A descriptive study.

BACKGROUND: Among all post-marketing medication error reports submitted to EudraVigilance, vaccines are the most frequently reported medicinal products. This study aims to describe the characteristics of vaccination errors submitted to Eudravigilance between 2001 and 2016. METHODS: EudraVigilance is a spontaneous reporting database for adverse events maintained by the European Medicines Agency. We extracted Individual Case Safety Reports (ICSRs) submitted to EudraVigilance between 1 January 2001 and 31 December 2016. Reports were included for analysis if a vaccine was reported as interacting or suspect drug and at least one medication error term was listed as an adverse reaction. ICSRs were stratified by age and gender, by year of reporting, region of origin, reporter profession, seriousness of outcome, ATC, and type of error. RESULTS: In total, 7097 ICSRs were included in the study. We observed a yearly increase in the reporting of vaccination errors, with the proportion to all vaccine ICSRs increasing from 0.4% to 4.0% between 2001 and 2016. The majority of reports was classified as serious (4248, 59.9%), but non-serious reports were increasingly reported since 2012. The mean age of patients was 24.1 years. The most frequently reported vaccines were influenza (13.5%), bacterial and viral combined (12.3%), and hepatitis vaccines (11.8%). A total of 8167 medication error terms were reported. The most frequently reported terms were "Inappropriate schedule of drug administration" (27.2%), "Incorrect route of drug administration" (12.5%) and "Drug administered to patient of inappropriate age" (10.0%). For infants and children, the error "Drug administered to patient of inappropriate age" was reported more often than for all other age categories. DISCUSSION: Vaccination errors are increasingly submitted to EudraVigilance. Errors related to the schedule are the most common errors reported with vaccines. However, consequences of vaccination errors appear to be relatively mild.

Measuring the impact of the 2012 European pharmacovigilance legislation on additional risk minimization measures.

AIMS: Additional risk minimization measures (aRMMs) may be needed to ensure that the benefits continue to outweigh the risks for medicines associated with serious risks. Prior research showed an increasing trend in medicines with aRMMs. We assessed whether the European pharmacovigilance legislation may have impacted the number and type of aRMMs. METHODS: We included new active substances approved between 1 January 2010 and 31 December 2015. Information extracted from the summary of the Risk Management Plan at the time of licensing included date and type of marketing authorization, presence and type of aRMMs. We tested for differences using Pearson's Χ2 test and segmented Poisson regression. RESULTS: We identified 231 medicines approved during the study period, of which 30% had aRMMs at the time of licensing. ARMMs were in place for 38% of medicines before July 2012 and for 28% after (p = 0.16). Segmented Poisson regression did not show changes in trend or level of medicines with aRMMs. DISCUSSION AND CONCLUSION: During the study period, no significant differences in the proportion or trend of products with aRMMs at the time of licensing before and after the pharmacovigilance legislation were identified.

Is patient exposure preapproval and postapproval a determinant of the timing and frequency of occurrence of safety issues?

BACKGROUND: The amount of drug exposure, pre and post approval, is considered to be a direct determinant of knowledge about the safety of a drug. A larger pre-approval exposed population is supposed to reduce the risk of unanticipated safety issues post-approval. The amount of use in the postapproval population is also expected to influence the occurrence and timing of safety issues. We investigated how the amount of pre and post approval exposure influences the detection of post-approval safety issues. METHODS: A cohort of innovative drugs approved in Europe was followed for the period of 2012-2016. The main outcome of interest was a new safety issue in the period. Post-approval exposure was collected at 6 month intervals, and pre-approval exposure was collected at the moment of authorisation. Other characteristics collected for the included drugs were anatomical therapeutical chemical (ATC) class, biological status, orphan status and type of approval. We used Cox proportional hazards regression to investigate the association between exposure and the hazard of having a first safety issue. RESULTS: The pre-approval exposure was not associated with the risk of safety issues after adjusting for ATC class, biological status, and treatment duration. Higher post-approval exposure was associated with more new safety issues identified (HR = 2.44 (95% CI = 1.12-5.31)) for drugs with more than 1,000 patient-years of cumulative exposure compared to drugs with less than 1,000 patient years of exposure. CONCLUSION: Our results suggest that postapproval exposure influences the detection of safety issues.

Study Design and Evaluation of Risk Minimization Measures: A Review of Studies Submitted to the European Medicines Agency for Cardiovascular, Endocrinology, and Metabolic Drugs.

INTRODUCTION: Studies measuring the effectiveness of risk minimization measures (RMMs) submitted by pharmaceutical companies to the European Medicines Agency are part of the post-authorization regulatory requirements and represent an important source of data covering a range of medicinal products and safety-related issues. Their objectives, design, and the associated regulatory outcomes were reviewed, and conclusions were drawn that may support future progress in risk minimization evaluation. METHODS: Information was obtained from risk management plans, study protocols, clinical study reports, and assessment reports of 157 medicinal products authorized for cardiovascular, endocrinology, and metabolic indications. We selected observational studies measuring, as outcomes of interest, the relationship between the RMMs in place and (1) implementation measures, such as clinical knowledge or physicians` compliance to recommendations contained in the RMMs; and (2) occurrence or reduced severity of the adverse drug reactions for which the RMMs were required. RESULTS: Of 59 eligible studies (24 completed, 35 ongoing), 44 assessed implementation measures, whereas only 15 assessed safety outcomes (1 study as a single endpoint and 14 studies with other endpoints). Fifty-one studies used non-experimental designs and 25 studies employed electronic healthcare databases for analysis. Of the 24 completed studies, 17 were considered satisfactory and supported immediate regulatory decision making, 6 were considered inconclusive and required new evaluations, and 1 was terminated early because new safety restrictions were required, thereby necessitating a new evaluation. Compliance with agreed deadlines was considered acceptable in 21 of 24 completed studies; the average time for a submission was 37 months (standard deviation ± 17), with differences observed by type of data source employed. CONCLUSIONS: Three important gaps in the evaluation plans of RMMs were identified: lack of early feedback on implementation, limited evaluation of safety outcomes, and inability to provide information on the effectiveness from an integrated measurement of different elements of a set of risk minimization tools. More robust evidence is needed to advance regulatory science and support more rapid adjustment of risk minimization strategies as needed.

Decision making in drug safety-a literature review of criteria used to prioritize newly detected safety issues.

PURPOSE: In drug safety, there is a lack of guidance on how prioritization of safety issues should be performed. The aim of this literature review is to provide an overview of criteria used for signal prioritization and of the associated decision support frameworks. METHODS: A search strategy was constructed to identify relevant articles in Medline/Embase databases from the period from 1 January 1995 to 31 August 2015. The prioritization criteria were extracted and classified in relevant categories. RESULTS: From an initial set of 63 articles, 11 were retained for full review. The articles mentioned 48 criteria used in the prioritization process, with a median of six criteria per study [range: 1-16]. More than half of the criteria (63%), referred to strength of evidence while 19% related to public health impact, 14% to general public and media attention and 4% to novelty of the drug event association. Fifteen criteria were tested for predictive value with 11 showing positive results, most of them from the strength of evidence category. Six decision-making frameworks are presented, which incorporate criteria from various categories. Five of these frameworks were tested against expert decisions or by other means, but only in one database each and for a limited set of products. CONCLUSIONS: There is a wide range of prioritization criteria described in the literature; however, few of them demonstrated predictive value. Many criteria with predictive value were related to strength of evidence category and to novelty. There were few attempts at integrating different criteria in decision support frameworks. Five of the frameworks were tested for validity and showed usefulness, while at least three are already in use for prioritization. Copyright © 2016 John Wiley & Sons, Ltd.

Using Prescription Patterns in Primary Care to Derive New Quality Indicators for Childhood Community Antibiotic Prescribing.

BACKGROUND: To describe patterns of antibiotic outpatient use in 3 European countries, including 2 new pediatric-specific quality indicators (QIs). METHODS: A cohort study was conducted, 2001-2010, using electronic primary care records of 2,196,312 children up to 14 (Pedianet, Italy) or 18 years (The Health Improvement Network, United Kingdom; Integrated Primary Care Information database, The Netherlands) contributing 12,079,620 person-years. Prevalence rates of antibiotic prescribing per year were calculated and antibiotics accounting (drug utilization) for 90% of all antibiotic prescriptions were identified (drug utilization 90% method). The ratio between users of broad to narrow-spectrum penicillins, cephalosporins and macrolides (B/N ratio) and 2 pediatric-specific QIs: the proportion of amoxicillin users (amoxicillin index) and the ratio between users of amoxicillin to broad-spectrum penicillins, cephalosporins and macrolides (A/B ratio) were determined. RESULTS: The overall annual prevalence of antibiotic prescriptions was 18.0% in the Netherlands, 36.2% in the United Kingdom and 52.0% in Italy. Use was maximal in the first years of life. The number of antibiotics accounting for the drug utilization 90% was comparable. The B/N ratio varied widely from 0.3 to 74.7. The amoxicillin index was highest in the Netherlands and the United Kingdom (50-60%), lowest in Italy (30%) and worsened over time in the United Kingdom and Italy. The A/B ratio in 2010 was 0.3 in Italy, 1.7 in the Netherlands and 5.4 in the United Kingdom. CONCLUSIONS: The patterns of antibiotic prescribing varied highly with age and country. The pediatric-specific QIs combined with the total prevalence rate of use provide a clear picture of the trends of community childhood antibiotic prescribing, allowing monitoring of the impact of policy interventions.

Patterns of spontaneous reports on narcolepsy following administration of pandemic influenza vaccine; a case series of individual case safety reports in Eudravigilance.

OBJECTIVE: This study aims to describe the frequency and quality of spontaneous narcolepsy case reports following administration of pandemic influenza vaccine as captured in the Eudravigilance database. METHODS: We conducted a retrospective descriptive study of spontaneous Individual Case Safety Reports (ICSRs), reporting narcolepsy following administration of pandemic influenza vaccine as received by Eudravigilance until July 2014. De-duplication was carried out by Eudravigilance. Frequency of reporting is described as number of ICSRs received per month over time. The quality of the ICSRs was evaluated by completeness of information and diagnostic certainty using the Automated Brighton Collaboration case definition tool (ABC-tool) for narcolepsy. RESULTS: After de-duplication, a total of 1333 ICSRs of narcolepsy and/or cataplexy following pandemic influenza vaccine were identified, originating from 18 countries worldwide. Most of the ICSRs (61.9%) originated from the signaling countries, Sweden and Finland. Although de-duplication of case reports was carried out, it is suspected that many duplicates exist, in particular from Sweden. The majority of the ICSRs (95.3%), reported exposure to Pandemrix®. Only few reports were received for Arepanrix® (1.6%) or Focetria® (0.5%), and Celvapan® (0.1%). Of those ICSRs reporting age, 73.1% concerned persons below age of 20years. When using the ABC-tool, all ICSRs were classified as having insufficient information to meet the Brighton Collaboration case definition of narcolepsy. CONCLUSION: An increase in reporting of narcolepsy appeared in Eudravigilance only after awareness was raised by the national authorities. Most narcolepsy reports were received from countries where the signal initially occurred, and were related to Pandemrix® in children/adolescents. Basic information about the patient and the exposure was present in most of the ICSRs. The ICSRs captured by Eudravigilance however, do not collect enough information to assess the diagnostic certainty according to the Brighton Collaboration case definition.

The effect of exposure misclassification in spontaneous ADR reports on the time to detection of product-specific risks for biologicals: a simulation study.

BACKGROUND AND OBJECTIVE: The availability of accurate product-specific exposure information is essential in the pharmacovigilance of biologicals, because differences in the safety profile may emerge between products containing the same active substance. In spontaneous adverse drug reaction (ADR) reports, drug exposure may, however, be misclassified, that is, attributed to the incorrect product. The aim of this study was to explore the effect of exposure misclassification on the time to detection of product-specific risks in spontaneous reporting systems. METHODS: We used data simulations to explore the effect of exposure misclassification. We simulated an active substance-specific subset of a spontaneous reporting system and used the proportional reporting ratio for signal detection. The effect of exposure misclassification was evaluated in three test cases representing product-specific ADRs that may occur for biologicals and studied in relative terms by varying the model parameters (market share and relative risk). RESULTS: We found that exposure misclassification results in the largest delay in identification of risks that have a weak association (relative risk < 2 or 3) with the product of interest and in situations where the product associated with the unique risk has a large (>50%) market share. The absolute public health impact of exposure misclassification, in terms of cases/time to detection, varied considerably across the test cases. CONCLUSION: Exposure misclassification in ADR reports may result in a delayed detection of product-specific risks, particularly in the detection of weak drug-event associations. Our findings can help inform the future implementation and refinement of product-specific and batch-specific signal detection procedures.

Useful Interplay Between Spontaneous ADR Reports and Electronic Healthcare Records in Signal Detection.

BACKGROUND AND OBJECTIVE: Spontaneous reporting systems (SRSs) remain the cornerstone of post-marketing drug safety surveillance despite their well-known limitations. Judicious use of other available data sources is essential to enable better detection, strengthening and validation of signals. In this study, we investigated the potential of electronic healthcare records (EHRs) to be used alongside an SRS as an independent system, with the aim of improving signal detection. METHODS: A signal detection strategy, focused on a limited set of adverse events deemed important in pharmacovigilance, was performed retrospectively in two data sources-(1) the Exploring and Understanding Adverse Drug Reactions (EU-ADR) database network and (2) the EudraVigilance database-using data between 2000 and 2010. Five events were considered for analysis: (1) acute myocardial infarction (AMI); (2) bullous eruption; (3) hip fracture; (4) acute pancreatitis; and (5) upper gastrointestinal bleeding (UGIB). Potential signals identified in each system were verified using the current published literature. The complementarity of the two systems to detect signals was expressed as the percentage of the unilaterally identified signals out of the total number of confirmed signals. As a proxy for the associated costs, the number of signals that needed to be reviewed to detect one true signal (number needed to detect [NND]) was calculated. The relationship between the background frequency of the events and the capability of each system to detect signals was also investigated. RESULTS: The contribution of each system to signal detection appeared to be correlated with the background incidence of the events, being directly proportional to the incidence in EU-ADR and inversely proportional in EudraVigilance. EudraVigilance was particularly valuable in identifying bullous eruption and acute pancreatitis (71 and 42 % of signals were correctly identified from the total pool of known associations, respectively), while EU-ADR was most useful in identifying hip fractures (60 %). Both systems contributed reasonably well to identification of signals related to UGIB (45 % in EudraVigilance, 40 % in EU-ADR) but only fairly for signals related to AMI (25 % in EU-ADR, 20 % in EudraVigilance). The costs associated with detection of signals were variable across events; however, it was often more costly to detect safety signals in EU-ADR than in EudraVigilance (median NNDs: 7 versus 5). CONCLUSION: An EHR-based system may have additional value for signal detection, alongside already established systems, especially in the presence of adverse events with a high background incidence. While the SRS appeared to be more cost effective overall, for some events the costs associated with signal detection in the EHR might be justifiable.

Pediatric Drug Safety Surveillance in FDA-AERS: A Description of Adverse Events from GRiP Project.

Individual case safety reports (ICSRs) are a cornerstone in drug safety surveillance. The knowledge on using these data specifically for children is limited. We studied characteristics of pediatric ICSRs reported to the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS). Public available ICSRs reported in children (0-18 years) to FAERS were downloaded from the FDA-website for the period Jan 2004-Dec 2011. Characteristics of these ICSRs, including the reported drugs and events, were described and stratified by age-groups. We included 106,122 pediatric ICSRs (55% boys and 58% from United States) with a median of 1 drug [range 1-3] and 1 event [1-2] per ICSR. Mean age was 9.1 years. 90% was submitted through expedited (15-days) (65%) or periodic reporting (25%) and 10% by non-manufacturers. The proportion and type of pediatric ICSRs reported were relatively stable over time. Most commonly reported drug classes by decreasing frequency were 'nervous system drugs' (58%), 'antineoplastics' (32%) and 'anti-infectives' (25%). Most commonly reported system organ classes were 'general' (13%), 'nervous system' (12%) and 'psychiatric' (11%) disorders. Duration of use could be calculated for 19.7% of the reported drugs, of which 14.5% concerned drugs being used long-term (>6 months). Knowledge on the distribution of the drug classes and events within FAERS is a key first step in developing pediatric specific methods for drug safety surveillance. Because of several differences in terms of drugs and events among age-categories, drug safety signal detection analysis in children needs to be stratified by each age group.