'Global trigger tool' shows that adverse events in hospitals may be ten times greater than previously measured

Identification and measurement of adverse medical events is central to patient safety, forming a foundation for accountability, prioritizing problems to work on, generating ideas for safer care, and testing which interventions work. We compared three methods to detect adverse events in hospitalized patients, using the same patient sample set from three leading hospitals. We found that the adverse event detection methods commonly used to track patient safety in the United States today-voluntary reporting and the Agency for Healthcare Research and Quality's Patient Safety Indicators-fared very poorly compared to other methods and missed 90 percent of the adverse events. The Institute for Healthcare Improvement's Global Trigger Tool found at least ten times more confirmed, serious events than these other methods. Overall, adverse events occurred in one-third of hospital admissions. Reliance on voluntary reporting and the Patient Safety Indicators could produce misleading conclusions about the current safety of care in the US health care system and misdirect efforts to improve patient safety.     

Safety and acceptability with the use of a contraceptive vaginal ring after surgical or medical abortion

OBJECTIVE: The study was conducted to determine if a contraceptive vaginal ring (CVR) is a safe and acceptable method of contraception when used in the proximate postabortion period following first-trimester surgical or medical abortion. METHODS: A CVR was inserted within 1 week following a medical or surgical abortion. Participants were followed up for 3 months to determine safety and acceptability. Safety was measured by the absence of signs of infection or serious adverse events. Acceptability was assessed by the CVR satisfaction survey, completed at the 3-month follow-up visit. RESULTS: Of 81 participants enrolled in the study, 69 (85%) completed the first-month follow-up visit, and 54 (67%) completed the final 3-month follow-up visit. There were no serious adverse events and no signs of infection on physical exam. Most adverse events were mild and not specifically related to the CVR. Related adverse events were those commonly associated with hormonal contraception use. Eighty-nine percent of participants chose to continue the CVR as their birth control method. CONCLUSION: The CVR is potentially safe and has high acceptability when used in the proximate postabortion period following a first-trimester abortion.     

Our journey to zero: Reducing serious safety events by over 70% through high‐reliability techniques and workforce engagement

The techniques and best practices used to achieve a successful safety culture transformation and drive down the incidence of serious safety events are described. The Safety Transformation Initiative at Children's National resulted in national and local recognition, a financial savings of an imputed $35 million, and a greater than 70% decrease in the serious safety event rate over a 3‐year period (July 1, 2008–June 30, 2011). The results were achieved during a time of significant financial constraints and with limited resources. A blueprint detailing specifics of the implementation is presented to assist others in achieving similar results. Our safety transformation was initiated in our fiscal year 2009 as part of a 3‐year corporate goal. The work is continuing and we aspire to virtually eliminate serious safety events by 2016.     

Clinical evaluation of a polygeline-free tick-borne encephalitis vaccine for adolescents and adults

OBJECTIVE: To evaluate immunogenicity and safety of a polygeline-free tick-born encephalitis (TBE) vaccine in a clinical program. METHOD: A total of 3118 subjects aged 12-76 years were enrolled in three clinical trials. The clinical studies were conducted in 15 centers in three European countries. Evidence of neutralizing TBE antibodies was used as surrogate parameter for efficacy assessment. RESULTS: All subjects analyzed achieved levels of TBE antibodies postimmunization to fulfill the definition of seroconversion or a four-fold increase. The new TBE vaccine appeared to be well tolerated by subjects. Only very few febrile reactions, mainly 38.5 degrees C were reported. No serious or unexpected adverse events related to vaccination were reported. CONCLUSION: These successful results in terms of both immunogenicity and safety indicate that the TBE vaccination with this polygeline-free TBE vaccine can be used safely in adolescents and adults.     

Safety and reactogenicity profile of an adjuvanted H5N1 pandemic candidate vaccine in adults within a phase III safety trial

A multicentre, randomized, phase III clinical trial in 5071 healthy adults was conducted to evaluate the safety and reactogenicity of a 15 microg HA dose of a candidate oil-in-water emulsion-based adjuvant system (AS)-adjuvanted split-virion H5N1 (AS-H5N1) vaccine compared to a licensed seasonal influenza vaccine, Fluarix.(1) Stringent criteria were used to evaluate adverse events and reactogenicity profile. Overall, 96.7% of the 5071 vaccinated subjects completed the study. Significantly more participants in the AS-H5N1 vaccine group reported general or local adverse events. Pain was the most common symptom in both treatment groups. Less than 1% of subjects withdrew from the study due to adverse events and no withdrawals were due to serious adverse events related to vaccination. The safety and reactogenicity profile of the AS-H5N1 candidate vaccine can be considered clinically acceptable in the context of its use against pandemic influenza.     

Methodological issues arising from systematic reviews of the evidence of safety of vaccines

Adaptations to the recognized methods of systematic reviewing are required when addressing questions about safety, particularly about rare and/or long-term serious adverse events. Conducting a systematic review of vaccine safety requires the implementation of novel strategies for locating studies, the use of experimental instruments to assess the quality of non-randomized studies, and the employment of pooling methods for non-randomized data, where appropriate. Standardizing both the indexing of adverse event data on electronic libraries and their reporting would improve the potential of systematic reviews of vaccine to draw accurate conclusions about the safety of a vaccine.     

Inadequate statistical power to detect clinically significant differences in adverse event rates in randomized controlled trials

ObjectiveTo determine the statistical power to detect potentially clinically significant differences in serious adverse events between drug therapies reported in a sample of randomized controlled trials (RCTs).Study Design and SettingSystematic review of RCTs with positive efficacy endpoint and at least a twofold difference in the proportion of patients with serious adverse events between treatment groups from six major journals. The power of each study to detect statistically significant differences in serious adverse events was calculated.ResultsOf the six included trials, all performed statistical analysis on adverse events without disclosure of the statistical power for detecting the reported differences between groups. The power of each study to detect the reported differences in adverse events was calculated and yielded values ranging from 0.07 to 0.37 among trials with non–statistically significant differences.ConclusionStatistical testing for differences in the proportion of patients experiencing an adverse event is common in RCTs; non–statistically significant differences are associated with low statistical power. A high probability of type II error may lead to erroneous clinical inference resulting in harm. The statistical power for nonsignificant tests should be considered in the interpretation of results.     

Electronic health record–related safety concerns: A cross‐sectional survey

Federal electronic health record (EHR)–related initiatives are leading to rapid increases in their adoption. Despite their benefits, EHRs also introduce new risks that can lead to serious safety events. We conducted a Web‐based survey of the American Society for Healthcare Risk Management and the American Health Lawyers Association to elicit perceptions regarding the frequency and types of EHR‐related serious safety events. We received 369 responses. The majority (66%) worked for large hospitals and health systems with varying degrees of EHR adoption. More than half (53%) of respondents reported at least one EHR‐related serious safety event in the previous 5 years, and 10% reported more than 20 events. EHR workflow (63%), user familiarity with the EHR system (63%), and integration with existing systems (59%) were most frequently endorsed as variables associated with EHR‐related serious safety events. Because EHR‐related safety concerns are underreported, organizations should consider implementing robust measures of EHR safety within their institution as a key step for mitigating these concerns.     

我国药品安全定义和范畴的系统综述和定性访谈

目的：深入探讨药品安全的定义和范畴,为药品安全监管工作提供政策性建议。方法：采用系统综述方法,对近10年来相关中、英文数据库及网站中提及药品安全概念、范畴,或对保障药品安全策略和措施的文章分析、整理和综合,总结出药品安全所包含的主要内容;利用定性访谈了解药品监管人员、医务工作者和专业技术人员对于药品安全概念和范畴的认识,以及当前影响药品安全的重要问题。结果：系统综述纳入290篇文献,其中6篇给出了药品安全的定义,纳入文献对于药品安全的定义侧重于药品不良反应／事件监测、避免用药错误、风险管理以及可及性方面。药品安全的范畴主要包括药品监管、药品不良反应／事件、药品保障、药品研发、药品生产、药品流通、药品使用和药品信息获取;定性访谈结果显示,大部分受访者认为药品安全涵盖所有与药物相关的工作,现阶段质量问题和不合理用药是受访者集中反映的药品安全的主要问题。结论：通过综合分析,我们将药品安全定义为通过对药品研发、生产、流通、使用全环节进行监管所表现出来的消除或控制了外在威胁和内在隐患的综合状态,以及为达到这种状态所必要的供应保障和信息反馈。其范畴可以界定为质量符合标准、不良反应在可接受的范围内、临床无用药差错和可及性四个部分。     

Bias was reduced in an open-label trial through the removal of subjective elements from the outcome definition

ObjectiveTo determine whether modifying an outcome definition to remove subjective elements reduced bias in a trial that could not use blinded outcome assessment.Study Design and SettingReanalysis of an open-label trial comparing a restrictive vs. liberal transfusion strategy for gastrointestinal bleeding. The usual definition of the primary outcome, further bleeding, allows subjective clinical symptoms to be used alone for diagnosis, whereas the definition used in the trial required more objective confirmation by endoscopy. We compared treatment effect estimates for these two definitions.ResultsFewer subjective symptom-identified events were confirmed using more objective methods in the restrictive arm (18%) than in the liberal arm (56%), indicating differential assessment between arms. An analysis using all events (both subjective and more objective) led to an odds ratio of 0.83 (95% confidence interval [CI]: 0.50–1.37). When only events confirmed using more objective methods were included, the odds ratio was 0.50 (95% CI: 0.32–0.78). The ratio of the odds ratios was 1.66, indicating that including unconfirmed events in the definition biased the treatment effect upward by 66%.ConclusionModifying the outcome definition to exclude subjective elements substantially reduced bias. This may be a useful strategy for reducing bias in trials that cannot blind outcome assessment.     

Adverse events following quadrivalent meningococcal CRM-conjugate vaccine (Menveo®) reported to the Vaccine Adverse Event Reporting system (VAERS), 2010–2015

BackgroundLimited data are available describing the post-licensure safety of meningococcal vaccines, including Menveo®. We reviewed reports of adverse events (AEs) to the Vaccine Adverse Event Reporting System (VAERS) to assess safety in all age groups.MethodsVAERS is a national spontaneous vaccine safety surveillance system co-administered by the Centers for Disease Control and Prevention and the US Food and Drug Administration. We searched the VAERS database for US reports of adverse events in persons who received Menveo from 1 January 2010 through 31 December 2015. We clinically reviewed reports and available medical records for serious AEs, selected pre-specified outcomes, and vaccination during pregnancy. We used empirical Bayesian data mining to identify AEs that were disproportionately reported after receipt of Menveo.ResultsDuring the study period, VAERS received 2614 US reports after receipt of Menveo. Of these, 67 were classified as serious, including 1 report of death. Adolescents (aged 11–18 years) accounted for 74% of reports. Most of the reported AEs were non-serious and described AEs consistent with data from pre-licensure studies. Anaphylaxis and syncope were the two most common events in the serious reports. We did not identify any new safety concerns after review of AEs that exceeded the data mining threshold, although we did observe disproportionate reporting for terms that were not associated with an adverse event (e.g., “incorrect drug dosage form administered”, “wrong technique in drug usage process”). Although reports were limited, we did not find any evidence for concern regarding the use of Menveo during pregnancy.ConclusionsIn our review of VAERS reports, findings of AEs were consistent with the data from pre-licensure studies. Vaccine providers should continue to emphasize and adhere to proper administration of the vaccine.     

Postmarketing safety surveillance of high-dose quadrivalent influenza vaccine: Reports to the Vaccine Adverse Event Reporting System

On November 4, 2019, the Food and Drug Administration approved high-dose quadrivalent influenza vaccine (Fluzone High-Dose Quadrivalent; QIV-HD) for active immunization for the prevention of influenza disease in individuals 65 years of age and older. A prelicensure randomized, active-controlled, modified double-blind trial did not reveal any major differences in adverse events following QIV-HD versus Fluzone High-Dose (trivalent). To improve our understanding of the safety profile of QIV-HD, we reviewed and summarized reports of adverse events after QIV-HD to the Vaccine Adverse Event Reporting System (VAERS). From July 30, 2020 through June 30, 2021, VAERS received 2,122 reports after QIV-HD. The vast majority (2,018; 95.1%) were non-serious and included events that had been observed in the prelicensure clinical trial, such as injection site reactions, fever, headache, and nausea. The most common serious events included Guillain-Barré syndrome, cellulitis or other local reactions, constitutional signs/symptoms (e.g., fever), and cardiovascular events. Our review did not reveal any new safety concerns. This information may enable policy makers, health officials, clinicians, and patients to make a more informed decision regarding vaccination strategies.     

136例国际医疗器械严重不良事件的统计与分析

为了探明医疗器械不良事件发生的规律及特点,为减少同类不良事件的再发生提供研究方法和思路,该研究收集了国际上具有代表性的5个国家的医疗器械安全信息,并对事件类别、管理类别和事件原因进行统计与分析。结果显示,136例严重不良事件中,召回原因占比位居前三位的分别是产品设计因素、软件因素和组件缺损。为降低医疗器械的应用风险,建议产品设计者、操作使用者和所在医疗机构正确实施医疗器械监测评价体系。     

An algorithm developed using the Brighton Collaboration case definitions is more efficient for determining diagnostic certainty

The Brighton Collaboration is a global research network focused on vaccine safety. The Collaboration has created case definitions to determine diagnostic certainty for several adverse events. Currently nested within multi-page publications, these definitions can be cumbersome for use. We report the results of a randomized trial in which the case definition for anaphylaxis was converted into a user-friendly algorithm and compared the algorithm with the standard case definition. The primary outcomes were efficiency and accuracy. Forty medical students determined the Brighton Level of diagnostic certainty of a sample case of anaphylaxis using either the algorithm or the original case definition. Most participants in both groups selected the correct Brighton Level. Participants using the algorithm required significantly less time to review the case and determine the level of diagnostic certainty [mean difference = 107 s (95% CI: 13–200; p = 0.026)], supporting that the algorithm was more efficient without impacting accuracy.     

2008 - 2017年湖北省乙型脑炎减毒活疫苗疑似预防接种异常反应监测分析

目的 分析2008 - 2017年湖北省乙型脑炎减毒活疫苗（Japanese Encephalitis Attenuated Live Vaccine,JEV - L）接种后疑似预防接种异常反应（Adverse Events Following Immunization,AEFI）的发生特征,评价JEV-L疫苗安全性。方法 采用描述流行病学方法对湖北省2008 - 2017年AEFI 信息管理系统JEV-L接种后AEFI个案数据进行分析。结果 湖北省2008 - 2017年共报告JEV-L接种后AEFI个案5 738例,报告发生率51.54/10万剂。一般反应占95.09%,异常反应占4.43%;男女性别比为1.23∶1, 1岁以下和2岁组儿童分别占59.41%和24.82%,夏、秋2季报告病例分别占34.47%和33.13%;83.17%的AEFI病例接种至反应发生时间间隔＜1 d;所有AEFI中仅有1例（脑炎和脑膜炎病例）有后遗症。一般反应以发热、红肿、硬结为主;异常反应以过敏性皮疹为主,严重异常反应以热性惊厥为主,其他严重异常反应报告发生率均较低;近年来热性惊厥报告发生率有逐年升高趋势。结论 AEFI以一般反应为主,异常反应占比较低,严重异常反应较少见,湖北省JEV - L疫苗安全性良好,但仍需关注热性惊厥、神经系统脑病等严重异常反应的发生。     

COVID-19 vaccine safety monitoring in Republic of Korea from February 26, 2021 to October 31, 2021

ObjectivesThis study aimed to present data on reported adverse events following coronavirus disease 2019 (COVID-19) vaccination in Republic of Korea from February 26 to October 31, 2021, and to determine whether any significant patterns emerged from an analysis of the characteristics of suspected adverse event cases for each type of vaccine.MethodsAdverse events following COVID-19 vaccination reported by medical doctors and forensic pathologists were analyzed. Cases of suspected anaphylaxis were classified using the Brighton Collaboration definition.ResultsBy October 31, 2021, a total of 353,535 (0.45%) adverse events were reported after 78,416,802 COVID-19 vaccine doses. Of the adverse events, 96.4% were non-serious and 3.6% were serious. The most frequently reported adverse events were headache, myalgia, and dizziness. Of the 835 reported deaths after COVID-19 vaccination, 2 vaccine-related deaths were confirmed. Suspected anaphylaxis was confirmed in 454 cases using the Brighton Collaboration definition.ConclusionThe commonly reported symptoms were similar to those described in clinical trials. Most reported adverse events were non-serious, and the reporting rate of adverse events following COVID-19 vaccination was higher in women than in men (581 vs. 315 per 100,000 vaccinations). Confirmed anaphylaxis was reported in 5.8 cases per 1,000,000 vaccinations.     

2010年石家庄市麻疹疫苗强化免疫疑似预防接种异常反应监测分析

目的分析石家庄市麻疹疫苗强化免疫活动后,疑似预防接种异常反应(adverse events following immunization,AEFI)的发生状况,探讨麻疹疫苗强化免疫活动的安全性。方法采用描述分析方法对监测数据进行分析。结果石家庄市2010年麻疹强化免疫期间共报告AEFI 181例,发生率12.02/10万剂次。其中一般反应161例,异常反应16例,偶合症4例;绝大多数病例转归良好。结论 AEFI监测敏感性高,麻疹疫苗安全性好,未发现严重疑似预防接种异常反应。     

Safety monitoring of COVID-19 vaccination among adolescents aged 12 to 17 years old in the Republic of Korea

ObjectivesThis study aimed to disseminate information on coronavirus disease 2019 (COVID-19) vaccine safety among adolescents aged 12 to 17 years in the Republic of Korea.Methods Two databases were used to assess COVID-19 vaccine safety in adolescents aged 12 to 17 years who completed the primary Pfizer-BioNTech vaccination series. Adverse events reported to the web-based COVID-19 vaccination management system (CVMS) and collected in the text message-based system were analyzed.Results From March 5, 2021 to February 13, 2022, 12,216 adverse events among 12- to 17-year-olds were reported to the CVMS, of which 97.1% were non-serious adverse events and 2.9% were serious adverse events, including 85 suspected cases of anaphylaxis, 74 suspected cases of myocarditis and/or pericarditis, and 2 deaths. From December 13, 2021 to January 26, 2022, 10,389 adolescents responded to a text message survey, and local/systemic adverse events were more common after dose 2 than after dose 1. The most commonly reported events following either vaccine dose were pain at the injection site, headache, fatigue/tiredness, and myalgia.ConclusionThe overall results are consistent with previous findings; the great majority of adverse events were non-serious, and serious adverse events were rare among adolescents aged 12 to 17 years following Pfizer-BioNTech COVID-19 vaccination.     

Reports of cell-based influenza vaccine administered during pregnancy in the Vaccine Adverse Event Reporting System (VAERS), 2013–2020

BackgroundIn November 2012, the first cell cultured influenza vaccine, a trivalent subunit inactivated influenza vaccine (Flucelvax(®), ccIIV3), was approved in the United States for adults aged ≥18 years. A quadrivalent version (ccIIV4) was later approved in 2016 and replaced ccIIV3. The safety of ccIIV3 or ccIIV4 (ccIIV) was not assessed for pregnant women or their infants during pre-licensure studies.ObjectiveTo assess the safety of ccIIV administered during pregnancy in pregnant women and their infants whose reports were submitted to VAERS during 2013–2020.Material and methodsWe searched VAERS for United States reports of adverse events (AEs) in pregnant women who received ccIIV from 1 July 2013 through 31 May 2020. Clinicians reviewed reports and available medical records and assigned a primary clinical category for each report. Reports were coded as serious based on the Code of Federal Regulations definition.ResultsVAERS received 391 reports following ccIIV administered to pregnant women. Twenty-four (6.1%) were serious. Two neonatal deaths were reported. No maternal deaths occurred. Among reports with trimester information (n = 340), ccIIV was administered during the second trimester in 170 (50%). The most frequent pregnancy-specific AE was premature delivery in 85 (21.7%) reports, followed by dysmature placenta in 13 (3.3%) and pre-eclampsia/eclampsia in ten (2.3%). The most common non-pregnancy specific conditions were infectious conditions in 32 (8.2%). Among infant conditions, low birth weight was reported in 62 (15.9%) reports. Fifteen birth defects were reported; in 12 with gestational age information, administration of the vaccine occurred late in the second trimester or later.ConclusionsReview of maternal ccIIV reports in VAERS was not unexpectedly different from other maternal influenza vaccine safety VAERS reviews.     

Simulation study comparing exposure matching with regression adjustment in an observational safety setting with group sequential monitoring

Sequential methods are well established for randomized clinical trials (RCTs), and their use in observational settings has increased with the development of national vaccine and drug safety surveillance systems that monitor large healthcare databases. Observational safety monitoring requires that sequential testing methods be better equipped to incorporate confounder adjustment and accommodate rare adverse events. New methods designed specifically for observational surveillance include a group sequential likelihood ratio test that uses exposure matching and generalized estimating equations approach that involves regression adjustment. However, little is known about the statistical performance of these methods or how they compare to RCT methods in both observational and rare outcome settings. We conducted a simulation study to determine the type I error, power and time‐to‐surveillance‐end of group sequential likelihood ratio test, generalized estimating equations and RCT methods that construct group sequential Lan–DeMets boundaries using data from a matched (group sequential Lan–DeMets‐matching) or unmatched regression (group sequential Lan–DeMets‐regression) setting. We also compared the methods using data from a multisite vaccine safety study. All methods had acceptable type I error, but regression methods were more powerful, faster at detecting true safety signals and less prone to implementation difficulties with rare events than exposure matching methods. Method performance also depended on the distribution of information and extent of confounding by site. Our results suggest that choice of sequential method, especially the confounder control strategy, is critical in rare event observational settings. These findings provide guidance for choosing methods in this context and, in particular, suggest caution when conducting exposure matching. Copyright © 2014 John Wiley & Sons, Ltd.