Spontaneous Reporting System Research Articles

Assessing intravitreal anti-VEGF drug safety using real-world data: methodological challenges in observational research

ABSTRACT Introduction It is generally acknowledged that the ocular safety profile of intravitreal anti-VEGF drugs is acceptable, while the burden of systemic safety of these intravitreal agents is still being debated. The evaluation of the systemic safety of these drugs using real-world data (RWD), such as spontaneous reporting systems (SRS), electronic medical records (EMRs) and claims databases has several advantages, including the capture of outcomes among real-world populations over long observation periods. Nevertheless, there is a relatively small body of research exploring the post-marketing safety of these drugs. Areas covered The aim of this scoping review is to outline and discuss some of the methodological challenges to be faced when investigating the systemic safety of intravitreal anti-VEGF drugs using different sources of RWD. Expert opinion Such challenges include the selection of the most suitable data source, taking into account how well drug utilization is captured and whether the outcomes and covariates of interest can be captured. The strengths and limitations of some analytic methods that can be used to quantify risk, such as the intention-to-treat approach and the as-treated approach, complement each other, and using these together provides a more balanced analysis.

Drug-induced Urinary Retention: An Analysis of a National Spontaneous Adverse Drug Reaction Reporting Database

BackgroundNumerous drugs have been associated with urinary retention (UR), but updated information on drugs that may induce UR is limited. ObjectiveTo evaluate drug-induced UR using the Italian spontaneous adverse drug reactions (ADRs) reporting database. Design, setting, and participantsWe selected all suspected spontaneous reports of drug-induced UR collected into the Italian spontaneous reporting system (SRS) database from its inception to June 30, 2019. Outcome measurements and statistical analysisThe Mantel-Haenszel χ2 test and the Mann-Whitney U test were performed for statistical comparisons of categorical and continuous variables, respectively. As a measure of disproportionality, we calculated the reporting odds ratios (RORs) with corresponding 95% confidence intervals using a statistical case/noncase methodology. Results and limitationsA total of 506 383 ADR reports were received in the Italian SRS database during the study period. Of these, 421 reports (0.1%) included UR-related ADRs, for a total of 497 suspected drugs. The median (interquartile range [IQR]) age of patients experiencing UR was 67 (47–77) yr. Overall, 174 (41.3%) ADR reports were considered serious. One-third of male patients experiencing UR suffered from benign prostatic hyperplasia, followed by diabetes mellitus (N = 58, 13.8%), and bladder-related disorders (N = 21, 5.0%). The median lag time between the start of drug treatment and UR onset was 7 (IQR 1–47.5) d. Overall, a statistically significant ROR was reported for 39 individual drugs, and for five (12.8%) of them (dapagliflozin, gabapentin, lithium, celecoxib, and piroxicam) UR was not described in their summary of product characteristics. Limitations include under-reporting and selective over-reporting of suspected ADRs and lacking information on the number of drug users. ConclusionsA disproportionality analysis identified five potentially new UR signals for dapagliflozin, gabapentin, lithium, celecoxib, and piroxicam, requiring further evaluation. Patient summaryIn this analysis of the Italian spontaneous reporting system database, we found new urinary retention signals, requiring further evaluation, for dapagliflozin, gabapentin, lithium, celecoxib, and piroxicam.

P468 Analysis of international spontaneous reporting system databases for safety of corticosteroids in Inflammatory Bowel Disease: The Determinants, Incidence and consequences of Corticosteroid Excess (DICE)-impact study

Abstract Background Long-term use of corticosteroids (CS) may result in significant risk of adverse events (AEs), and the true incidence of AEs in patients with inflammatory bowel disease (IBD) receiving CS is unknown.1 Such AE data may be reported in spontaneous reporting systems (SRS). Using data-mining algorithms for disproportionality, we determined the frequency of AEs of special interest (AESIs) associated with CS in patients with IBD. Methods The FDA SRS database (FAERS) was examined for AE reports associated with prednisone/prednisolone (PRED) or budesonide (BUD) use for Crohn’s disease or ulcerative colitis from Q1 2008 to Q4 2019. The incidence of key predefined AESIs was determined and the association with CS therapy was assessed using the proportional reporting ratio (PRR) criteria. Results Totals of 420,913 and 33,215 all-cause AEs were reported for PRED and BUD, respectively. The number of AE reports for each CS increased over time (Figure 1) and this was reflected in an increase in the proportion of reports of all AEs over time relating to CS. Common AEs reported with CS therapy included diarrhoea, abdominal pain, pyrexia and weight loss (Figure 2). Compared with other drugs and based on the PRR criteria, AESIs including osteonecrosis, adrenal insufficiency and Cushingoid complications were more frequently reported in patients treated with PRED; adrenal insufficiency, pancreatitis and Cushingoid complications were more frequently reported in patients treated with BUD (Table 1). There was no confounding effect from gender or disease type identified between CS and any of the AESIs in patients with IBD. Conclusion Analysis of FAERS demonstrated that steroid-treated patients with IBD report AEs that are consistent with the known safety profile for CS. Cushingoid complications and adrenal insufficiency were common signals for PRED and BUD. The increased reporting of AEs over time may reflect growth in CS prescribing, or growing awareness and reporting of CS AEs by prescribers. This analysis will be repeated in multiple international SRS systems to provide a global image of AEs for CS use in IBD. Reference

An OMOP-CDM based pharmacovigilance data-processing pipeline (PDP) providing active surveillance for ADR signal detection from real-world data sources

BackgroundAdverse drug reactions (ADRs) are regarded as a major cause of death and a major contributor to public health costs. For the active surveillance of drug safety, the use of real-world data and real-world evidence as part of the overall pharmacovigilance process is important. In this regard, many studies apply the data-driven approaches to support pharmacovigilance. We developed a pharmacovigilance data-processing pipeline (PDP) that utilized electronic health records (EHR) and spontaneous reporting system (SRS) data to explore pharmacovigilance signals.MethodsTo this end, we integrated two medical data sources: Konyang University Hospital (KYUH) EHR and the United States Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS). As part of the presented PDP, we converted EHR data on the Observation Medical Outcomes Partnership (OMOP) data model. To evaluate the ability of using the proposed PDP for pharmacovigilance purposes, we performed a statistical validation using drugs that induce ear disorders.ResultsTo validate the presented PDP, we extracted six drugs from the EHR that were significantly involved in ADRs causing ear disorders: nortriptyline, (hazard ratio [HR] 8.06, 95% CI 2.41–26.91); metoclopramide (HR 3.35, 95% CI 3.01–3.74); doxycycline (HR 1.73, 95% CI 1.14–2.62); digoxin (HR 1.60, 95% CI 1.08–2.38); acetaminophen (HR 1.59, 95% CI 1.47–1.72); and sucralfate (HR 1.21, 95% CI 1.06–1.38). In FAERS, the strongest associations were found for nortriptyline (reporting odds ratio [ROR] 1.94, 95% CI 1.73–2.16), sucralfate (ROR 1.22, 95% CI 1.01–1.45), doxycycline (ROR 1.30, 95% CI 1.20–1.40), and hydroxyzine (ROR 1.17, 95% CI 1.06–1.29). We confirmed the results in a meta-analysis using random and fixed models for doxycycline, hydroxyzine, metoclopramide, nortriptyline, and sucralfate.ConclusionsThe proposed PDP could support active surveillance and the strengthening of potential ADR signals via real-world data sources. In addition, the PDP was able to generate real-world evidence for drug safety.

Pediatric adverse reactions to antiseizure medications – An analysis of data from the Italian spontaneous reporting system (2001–2019)

IntroductionSpontaneous reports of adverse drug reactions (ADRs) are a valuable supplement to clinical studies in informing about the safety of medications. This is especially relevant for pediatric populations, which are not often included in large-scale clinical trials. ObjectivesTo evaluate patterns of pediatric ADRs to antiseizure medications (ASMs) reported to the Italian Spontaneous Reporting System (SRS) database during the period November 1, 2001─May 31, 2019. MethodsSuspected ADRs ascribed to medications listed under ATC code N03, plus clobazam (code N05BA09), and affecting individuals below age 18 years were sourced from the Italian SRS database, categorized based on a modification of the MedDRA® high-level term, and analyzed using descriptive statistics. ResultsA total of 956 reports listing a total of 1806 ADRs ascribed to one or more ASMs were received for individuals in pediatric age. The most commonly reported ADRs were skin rashes (24.0% of all reports), epileptic seizures (12.6%), gastrointestinal disturbances (11.8%), and somnolence (10.6%). A more detailed analysis was conducted on 675 reports listing a single ASM as suspected drug and occurring in patients with a specified or presumed diagnosis of epilepsy. Adverse drug reaction patterns differed widely across ASMs. Skin rashes were the most commonly reported ADR for lamotrigine (62.3%), carbamazepine (50.3%), phenobarbital (42.3%), and oxcarbazepine (33.0%). Other most commonly reported ADRs were gastrointestinal symptoms for ethosuximide (44%), irritability/aggression for levetiracetam (25.0%), epileptic seizures for valproic acid (16.1%), fever (often associated with hypohidrosis) for topiramate (17.9%), and utilization error (mostly accidental drug administration) for clonazepam (34.6%). ConclusionsPatterns of spontaneous ADR reports are indicative of major differences in safety profile among individual ASMs. Most, but not all, frequently reported ADRs were in line with findings from clinical trials and observational studies.

Improved privacy preserving method for periodical SRS publishing.

Spontaneous reporting systems (SRSs) are used to collect adverse drug events (ADEs) for their evaluation and analysis. Periodical SRS data publication gives rise to a problem where sensitive, private data can be discovered through various attacks. The existing SRS data publishing methods are vulnerable to Medicine Discontinuation Attack(MD-attack) and Substantial symptoms-attack(SS-attack). To remedy this problem, an improved periodical SRS data publishing—PPMS(k, θ, ɑ)-bounding is proposed. This new method can recognize MD-attack by ensuring that each equivalence group contains at least k new medicine discontinuation records. The SS-attack can be thwarted using a heuristic algorithm. Theoretical analysis indicates that PPMS(k, θ, ɑ)-bounding can thwart the above-mentioned attacks. The experimental results also demonstrate that PPMS(k, θ, ɑ)-bounding can provide much better protection for privacy than the existing method and the new method dose not increase the information loss. PPMS(k, θ, ɑ)-bounding can improve the privacy, guaranteeing the information usability of the released tables.

Signals from the Dutch national spontaneous reporting system: Characteristics and regulatory actions.

The aim of the study is to characterise safety signals based on the Dutch spontaneous reporting system (SRS) and to investigate the association between signal characteristics and Product Information (PI) update stratified by approval type: centrally authorised products (CAPs) versus nationally and decentralised authorised products (NAPs). This study evaluates the full cohort of signals disseminated from the Dutch SRS in the period from 2008 to 2017. Each retrieved signal was characterised on a number of aspects. The signal management process from signal generation to a potential PI update was analysed in four steps: (1) signal characterisation; (2) proposed actions by the Dutch national competent authority (NCA) for the signals; (3) presence of PI update (yes/no) and association with signal characteristics; (4) timing from the moment the signal was issued to PI update. For step 1-3 we stratified products in CAPs and NAPs. Of all signals, 88.7% led to a proposed regulatory action by the NCA. Signals from the Dutch SRS for CAPs versus NAPs more often concerned biologicals, important medical events, class effects and shorter periods since marketing authorization. We detected PI updates for 26.2% of CAP signals and 61.3% of NAP signals. The Dutch SRSs remains an important source of signals. There are some notable differences in the characteristics of signals for CAPs versus NAPs. Signals for NAPs more frequently led to PI updates.

Relative Risk Analysis of Liver-related Adverse Drug Reactions in Children Based on China’s National Spontaneous Reporting System

To compare the risk of liver-related adverse drug reactions (ADRs) in children and adults. A case/non-case analysis on spontaneous reports based on the China National Adverse Drug Reactions Monitoring System database were conducted, focusing on events of liver-related ADRs in children younger than 14years of age. Both the relative risk of liver-related ADRs in children vs entire population and the risk stratification in children were expressed as a measure of disproportionality using the reporting odds ratio (ROR). There were 1206 cases of pediatric liver-related ADRs identified from 2012 to 2016, accounting for 2.82% of the entire population. The greatest ROR values in children from 0 to 14years vs the entire population were observed for analgesics (3.97, 95% CI 3.27-4.81), respiratory (2.60, 95% CI 1.04-6.43), antineoplastic (2.29, 95% CI 2.02-2.58), immunomodulatory (1.91, 95% CI 1.44-2.53), and antimicrobial agents (1.47, 95% CI 1.33-1.63). Notably, infants aged 0-1years showed significantly greater risk (3.14, 95% CI 2.85-3.48) of liver-related ADRs than the other age groups of children. For infants, analgesics (3.21, 95% CI 2.20-4.66) and antimicrobials (3.15, 95% CI 2.50-3.97) agents were found to have the greatest adjusted RORs than other drug categories. The highest RORs were found for meropenem, amoxicillin, fluconazole, vancomycin, cefaclor, and ceftazidime in the antimicrobial agents for infants. Children are sensitive to liver-related ADRs caused by several specific drug categories, and infants are the most sensitive.

Adverse drug reactions with oral anticoagulants: data from sicilian spontaneous reporting system database.

Direct oral anticoagulants (DOACs) were developed to avoid the limitations of vitamin K antagonists (VKAs). DOACs are associated with a greater incidence of gastrointestinal bleeding and a smaller number of intracranial haemorrhages than VKAs. Therefore, it is important to deepen our knowledge of their safety profiles. The aim of this study was thus to analyse adverse drug reaction (ADR) reports on DOACs and VKAs using the Sicilian Spontaneous Reporting System (SRS) database. All ADR reports with DOACs and VKAs as suspected drugs that were entered into the Sicilian SRS database during the period 2001-2019 were selected. In detail, all reports with the following single active substances were included: dabigatran etexilate, rivaroxaban, apixaban and edoxaban; acenocoumarol and warfarin were included as a comparator group. Descriptive statistical methodology was used to evaluate characteristics of the reported cases with a case-by-case assessment. Out of 521 reports related to anticoagulants, 444 (85.2%) and 77 (14.8%) involved DOACs and VKAs, respectively. DOAC-related reports were mainly of gastrointestinal disorders. In contrast, VKAs were mostly associated with blood and lymphatic system disorders, injury, investigations and vascular disorders. Many more cases of ADRs in the form of gastrointestinal disorders concerned dabigatran etexilate (n=179, 73.7%) than the other DOACs, while ADRs in the form of blood disorders were mainly associated with acenocoumarol (n=27, 57.4%). The most commonly reported Preferred Terms for DOACs were dyspepsia (n=89, 17.1%), upper abdominal pain (n=41, 9.2%) and pruritus (n=26, 5.8%), whereas for VKAs, they were anaemia (n=21, 27.3%) and hypocoagulable state (n=18, 3.5%). Potentially interacting concomitant medications particularly included antithrombotic agents (n=19, 4.3%) for DOACs and proton-pump inhibitors (PPIs) (n=37, 48.1%) and antithrombotic agents (n=13, 16.9%) for VKAs. The ADRs most commonly associated with DOACs, especially dabigatran, were gastrointestinal disorders, particularly gastrointestinal bleeding. Our study also highlights the potential role of drug-drug interactions in the ADRs. The cases of gastrointestinal bleeding highlight the need for careful prescribing of DOACs and use of potentially interacting concomitant drugs.

Immune Checkpoint Inhibitors and Cardiotoxicity: Reverse Translational Research by Using Real World Safety Data from the European Spontaneous Reporting System

Background: Immune checkpoint inhibitors (ICIs) are widely used in the treatment of many cancers as they improve clinical outcomes. However, ICIs have also been associated with the development of immune-related adverse drug reactions (irADRs). Among irADRs, cardiac ones are rare, but also associated with higher mortality rates. Here, we evaluate the occurrence of cardiac ADRs associated with ICIs. Methods: We retrieved Individual Case Safety Reports (ICSRs) on ICIs-induced cardiac ADRs from the website of suspected ADR (www.adrreports.eu) of the European pharmacovigilance database (Eudravigilance, EV). Data were retrieved from the date of marketing authorization of each ICI (ipilimumab, nivolumab, pembrolizumab, atezolizumab, durvalumab, avelumab, and cemiplimab) to March 14th, 2020. The Reporting Odds Ratio (ROR) and its’ 95% confidence interval (95%CI) was computed to assess the reporting probability of cardiac ADRs for each ICI compared to all other ICIs. Findings: A total of 2,478 ICSRs with at least one ICI as suspected drug were retrieved from EV, of which 249 (10%) were related to combined treatments. The three most reported ICIs were nivolumab (43 . 2%), pembrolizumab (32 . 5%), and the association nivolumab and ipilimumab (9 . 4%). A total of 3,388 cardiac ADRs were identified. Cardiac ADRs were serious (99%) and associated with a fatal outcome (30 . 1%). The most reported cardiac events were myocarditis, cardiac failure, atrial fibrillation, pericardial effusion, and myocardial infarction. Nivolumab was associated with a small increased reporting probability of ICSRs with cardiac ADRs compared to all other ICIs (ROR 1 . 09, 95%CI 1 . 01–1 . 18). Interpretation: ICIs-induced cardiac ADRs were serious and associated with unfavorable outcomes. In our study, nivolumab was the only ICI associated with a small increased reporting probability of ICSRs with cardiac ADRs compared to all other ICIs. In this regards, further head-to-head studies are needed. Funding: This research was funded under grant n. 2017NR7W5K_002 (PRIN 2017) from MIUR, Italy. Declaration of Interests: No conflict to declare. Ethics Approval Statement: Safety data deriving from the spontaneous reporting system are anonymous and in compliance with the ethical standard. Therefore, no further ethical measure was required.

Machine Learning for Detection of Safety Signals From Spontaneous Reporting System Data: Example of Nivolumab and Docetaxel.

Introduction: Various methods have been implemented to detect adverse drug reaction (ADR) signals. However, the applicability of machine learning methods has not yet been fully evaluated. Objective: To evaluate the feasibility of machine learning algorithms in detecting ADR signals of nivolumab and docetaxel, new and old anticancer agents. Methods: We conducted a safety surveillance study of nivolumab and docetaxel using the Korea national spontaneous reporting database from 2009 to 2018. We constructed a novel input dataset for each study drug comprised of known ADRs that were listed in the drug labels and unknown ADRs. Given the known ADRs, we trained machine learning algorithms and evaluated predictive performance in generating safety signals of machine learning algorithms (gradient boosting machine [GBM] and random forest [RF]) compared with traditional disproportionality analysis methods (reporting odds ratio [ROR] and information component [IC]) by using the area under the curve (AUC). Each method then was implemented to detect new safety signals from the unknown ADR datasets. Results: Of all methods implemented, GBM achieved the best average predictive performance (AUC: 0.97 and 0.93 for nivolumab and docetaxel). The AUC achieved by each method was 0.95 and 0.92 (RF), 0.55 and 0.51 (ROR), and 0.49 and 0.48 (IC) for respective drug. GBM detected additional 24 and nine signals for nivolumab and 82 and 76 for docetaxel compared to ROR and IC, respectively, from the unknown ADR datasets. Conclusion: Machine learning algorithm based on GBM performed better and detected more new ADR signals than traditional disproportionality analysis methods.

Exploring the utility of a spontaneous adverse drug reaction reporting system in identifying drug–drug interactions between antiretrovirals, antitubercular drugs, and cotrimoxazole: a case/non-case analysis

Drug–drug interactions (DDIs) cause significant morbidity and mortality, especially in patients with HIV with opportunistic infections such as tuberculosis. However, the literature on quantitative signal detection analyses for DDIs within the national spontaneous reporting systems (SRSs) of countries with high HIV/tuberculosis burdens is lacking. Our objective was to explore the utility of using post-marketing SRSs in quantitative signal detection analyses of DDIs. A case/non-case analysis using the Zimbabwean adverse drug reaction (ADR) database obtained from VigiBase® was utilized for quantitative signal detection using 2 × 2 contingency table calculations. Cases were defined as individual case safety reports (ICSRs) with the ADR of interest, and non-cases included the rest of the ICSRs. The exposure of interest was the use of a drug of interest. Signals of disproportionate reporting (SDRs) were observed for hepatotoxicity for the combined use of highly active antiretroviral therapy (HAART) and antitubercular treatments (ATT) [ADR reporting odds ratio (ROR) 43.78; 95% CI 5.24–366.08], HAART and isoniazid (ROR 44.84; 95% CI 5.36–374.99), and isoniazid and nevirapine-based HAART (ROR 35.60; 95% CI 9.39–134.89). SDRs were also observed for the combined use of nevirapine-based HAART and co-trimoxazole for Stevens–Johnson syndrome (ROR 28.91; 95% CI 14.00–59.70), severe cutaneous ADRs (ROR 16.10; 95% CI 9.40–27.57), and rash (OR 2.18; 95% CI 1.69–2.81). It is feasible to conduct signal detection analyses for DDIs within relatively small SRS databases. However, the observed potential SDR for the respective DDI should be investigated further as the method is only a hypothesis-generation analysis.

Pharmacovigilance in the era of social media: Discovering adverse drug events cross-relating Twitter and PubMed

In pharmacovigilance, post-marketing surveillance is mainly supported by spontaneous reporting systems (SRS) collecting adverse drug events explicitly submitted by physicians alerted by their patients. Nowadays, this activity could leverage on mining opinions and experiences of individuals from social media by monitoring users’ posts citing symptoms, drugs, etc. The most critical problem is the reliability of the information sources. In order to address this challenge, the proposed method tries to cross-relate heterogeneous data sources with correspondingly different levels of trustworthiness. It filters out assertions quoted on social media on the basis of data validated by official information sources. The method adopts the Fuzzy Formal Concept Analysis (Fuzzy FCA) to evaluate the reliability of adverse drug events extracted on Twitter and PubMed. It keeps track of the difference between the co-citation frequencies by calculating a residual thresholdτ. The main outcome is that with τ in the range [−4,+4], 91% of drug and side effect correlations extracted from tweets can be considered reliable, according to the official site (we used http://sideeffects.embl.de).

ADR/AE early warning analysis of Shujin Jianyao Pills based on spontaneous reporting system

To explore the general characteristics of adverse drug reactions/adverse events(ADR/AE) in patients after using Shujin Jianyao Pills, and explore risk warning signals, this study analyzed 166 cases of ADR/AE reports of Shujin Jianyao Pills collected from 2005 to 2017 based on the National Center for ADR Monitoring spontaneous reporting system(SRS). And the descriptive statistical method was used to analyze general characteristics. The results showed that among the 166 ADR/AE cases, 106 cases were female patients, accounting for 63.86%. Middle-aged and elderly people aged 45 to 64 accounted for the largest proportion(82 cases, 49.40%), which were followed by elderly aged 65 and over(48 cases, 28.91%). ADR/AE involved a wide range of systems and organs, of which skin and its accessories were the most damaged(30 cases, 12.93%), which were followed by systemic damage(27 cases, 11.64%). The top 10 ADR/AE manifestations were rash(15 cases, 6.33%), nausea(14 cases, 5.91%), dizziness(14 cases, 5.91%), abdominal pain(12 cases, 5.06%), pruritus(11 cases, 4.64%), low back pain(11 cases, 4.64%), vomiting(10 cases, 4.22%), hepatocyte damage(9 cases, 3.80%), headache(9 cases, 3.80%), and diarrhea(7 cases, 2.95%). Bayesian confidence propagation neural network(BCPNN) was used to mine the ADR/AE risk early warning signal of Shujin Jianyao Pills, and the propensity score method was used to control the balance of confounding factors. The results suggested warning signs for nausea, diarrhea, rash, and dizziness, vomiting, abdominal pain, headache, liver cell damage. This study provides a basis for the post-marke-ting safety evaluation of Shujin Jianyao Pills, and can provide guidance for its rational clinical use and risk management.

Current status of the spontaneous reporting and classification/coding system for herbal and traditional medicine in pharmacovigilance

BackgroundWhile the use of herbal and traditional medicine (H&TM) has been extensive worldwide, the current status of H&TM management in pharmacovigilance remains to be investigated. To date, there is little information regarding the use of the classification/coding system (CCS) to detect signals for certain drugs within databases built on the basis of the spontaneous reporting system (SRS). The purpose of this study is to investigate the status of the SRS and CCS for H&TM in the pharmacovigilance systems of various countries around the world. MethodsAn e-mail survey was performed from late December 2018 to early January 2019 with 54 experts in pharmacovigilance. The results based on the information provided by the respondents were summarized. ResultsFourteen experts from 13 countries responded to the survey. Eleven countries/regions were found to already include H&TM in their SRSs, managing only limited range of H&TM. Of the 9 countries/regions that provided the information on the status of CCS for H&TM in their domestic pharmacovigilance systems, only China had a separate CCS for H&TM. ConclusionRevising the current pharmacovigilance systems to include or expand the range of H&TM, and developing an internationally harmonized system to classify and code H&TM suitable to the unique characteristics of H&TM are critical and overall beneficial.

Combining Social Media and FDA Adverse Event Reporting System to Detect Adverse Drug Reactions.

IntroductionAdverse drug reactions (ADRs) are unintended reactions caused by a drug or combination of drugs taken by a patient. The current safety surveillance system relies on spontaneous reporting systems (SRSs) and more recently on observational health data; however, ADR detection may be delayed and lack geographic diversity. The broad scope of social media conversations, such as those on Twitter, can include health-related topics. Consequently, these data could be used to detect potentially novel ADRs with less latency. Although research regarding ADR detection using social media has made progress, findings are based on single information sources, and no study has yet integrated drug safety evidence from both an SRS and Twitter.ObjectiveThe aim of this study was to combine signals from an SRS and Twitter to facilitate the detection of safety signals and compare the performance of the combined system with signals generated by individual data sources.MethodsWe extracted potential drug–ADR posts from Twitter, used Monte Carlo expectation maximization to generate drug safety signals from both the US FDA Adverse Event Reporting System and posts from Twitter, and then integrated these signals using a Bayesian hierarchical model. The results from the integrated system and two individual sources were evaluated using a reference standard derived from drug labels. Area under the receiver operating characteristics curve (AUC) was computed to measure performance.ResultsWe observed a significant improvement in the AUC of the combined system when comparing it with Twitter alone, and no improvement when comparing with the SRS alone. The AUCs ranged from 0.587 to 0.637 for the combined SRS and Twitter, from 0.525 to 0.534 for Twitter alone, and from 0.612 to 0.642 for the SRS alone. The results varied because different preprocessing procedures were applied to Twitter.ConclusionThe accuracy of signal detection using social media can be improved by combining signals with those from SRSs. However, the combined system cannot achieve better AUC performance than data from FAERS alone, which may indicate that Twitter data are not ready to be integrated into a purely data-driven combination system.

Safety of Anticancer Agents Used in Children: A Focus on Their Off-Label Use Through Data From the Spontaneous Reporting System.

BackgroundAmong factors influencing the higher risk of developing unknown or rare adverse drug reactions (ADRs) among children and adolescents, there is the frequent off-label use of drugs that seems to be very common in pediatric oncological patients. Our study aim to collect and evaluate data on the safety profile of antineoplastic drugs and their off-label use in the pediatrics population using real life data.MethodsWe retrieved Individual Case Safety Reports (ICSRs) with an anticancer agent as suspected drug among those reported through the Campania spontaneous reporting system from 1 January 2013 to 30 September 2019. We classified ICSRs into four off-label categories: “age,” “route of administration,” “weight,” and “therapeutic indication.” We defined an ICSR as an off-label case if it met at least one of the aforementioned categories for at least one of the reported suspected antineoplastic drugs.ResultsA total of 18 ICSRs (7.6%) out of 236 were classified as off-label cases. The median age of patients was 13 years (interquartile range, IQR: 6–16), with 94.4% of cases occurring in male patients. In the classification of the off-label category, 16 ICSRs were categorized according to the “therapeutic indication” and two for the “age.” No case was categorized for the off-label categories “route of administration” and “weight.” The two off-label cases categorized as “age” were both related to the use of brentuximab vedotin for Hodgkin’s lymphoma in patients aged 16 years. Twenty-nine ADRs (1.6 suspected adverse drug reactions per ICSR) were identified among off-label cases. Among ADRs, those reported more than one were diarrhea (N = 3), neutropenia (N = 3), nausea (N = 2), pyrexia (N = 2), and vomit (N = 2).ConclusionsOur findings showed a low number of ICSRs classified as off-label. The majority of off-label ICSRs were categorized for the “therapeutic indication.” This low number of off-label ICSRs might be largely due to the underreporting phenomenon, which is a major limit in pharmacovigilance. Therefore, we believe that spreading pharmacovigilance knowledge and awareness might improve this aspect.

Knowledge, Attitude and Practice of Community Pharmacists towards Adverse Drug Reactions Reporting

: Background: Spontaneous reporting systems (SRSs) play an important role in identifying adverse drug reactions. In most of the developed countries, community pharmacists contribute to the pharmacovigilance system to a greater deal. Objectives: Present investigation is designed to evaluate the impact of clinical pharmacists’ educational intervention on ADRs and pharmacovigilance program of India (PvPI) among community pharmacists in Anantapur district, Andhra Pradesh, India. Methods: It was a single group, pre – post interventional trial. A ‘KAP’ questionnaire regarding ADRs in accordance with the PvPI was prepared and validated by experts. The initial phase of survey was conducted by approaching the community pharmacists at their premises. A total of 58 practicing community pharmacists in Anantapur district of south India were included in the study. All the participated community pharmacists were invited for an education session with an aim to improve ADR reporting and to make aware of PvPI. Results: After the educational intervention, a significant improvement in knowledge, attitude and practice towards ADRs identification and reporting and PvPI among the study participants was evident. In addition, age and educational level were impactful on KAP of community pharmacists for the same. Conclusion: Based on the results of this study, it is necessary to offer continuous educational programs and hands-on training for spontaneous reporting of ADRs until we reach the point that voluntary reporting of ADRs becomes accessible and habitual among the community pharmacists.Key words: Community Pharmacists, ADR reporting, KAP, Pharmacovigilance, ADE, Continuous Pharmacy Education.

Quinolones-Induced Musculoskeletal, Neurological, and Psychiatric ADRs: A Pharmacovigilance Study Based on Data From the Italian Spontaneous Reporting System.

BackgroundThe use of quinolones has been associated with the development of serious and persistent adverse drug reaction (ADR) mainly affecting muscles, joints and the nervous system. This risk has led the European Medicines Agency (EMA) to endorse some restrictions on the use of this class of antibiotic. Therefore, we performed a study to primary estimate the reporting probability of musculoskeletal, neurological, and psychiatric ADRs among quinolone generations using national data.MethodsWe retrieved Individual Case Safety Reports (ICSRs) with a quinolone as suspected drug among those reported through the Campania spontaneous reporting system from January 1st, 2001 to April 30th 2019. Moreover, we retrieved national aggregated safety data from the online public report system (RAM system) for the period from January 1st, 2002 to March 31st, 2019. Risk factors were classified as “age greater than 60 years,” “therapeutic indication,” “renal failure,” “organ transplantation,” “use of corticosteroid,” and “history of side effects”. Reporting odds ratio (ROR) was computed to evaluate the reporting probability of musculoskeletal, neurological, or psychiatric events among quinolones generations.ResultsA total of 87 ICSRs with a quinolone as suspected drug that reported at least one musculoskeletal, neurological, and psychiatric adverse event were identified in the Campania spontaneous reporting system. Forty-nine (56.3%) ICSRs reported risk factors (total risk factors 59). The most reported risk factor was “age greater than 60 years” (69.5%), followed by “therapeutic indication” (16.9%), “renal failure” (5.1%), “organ transplantation” (3.4%), “use of corticosteroid” (3.4%), and “history of side effects” (1.7%). Second-generation quinolones were associated with a lower reporting probability of musculoskeletal (ROR 0.70; 95% CI 0.63–0.79), neurological (ROR 0.81; 95% CI 0.73–0.90), and psychiatric (ROR 0.55; 95% CI 0.44–0.63) ADRs compared to the third generation of quinolones.ConclusionsOur findings showed that third-generation quinolones were always associated with a higher reporting probability of musculoskeletal, neurological, and psychiatric ADRs compared to the second generation ones. Moreover, we described risk factors in more than half of our cases suggesting that the inappropriate use of quinolones is a phenomenon that may frequently predispose patients to the occurrence of these ADRs.

自発報告に基づくシグナル検出ができること，できないこと:―その理論と実践―

自発報告に基づくシグナル検出ができること，できないこと:―その理論と実践―