Disproportionality Analysis and Characterisation of Medication Errors in EudraVigilance: Exploring Findings on Sexes and Age Groups.

BACKGROUND: While medication errors (MEs) have been studied in the European Medicines Agency's EudraVigilance, extensive characterisation and signal detection based on sexes and age groups have not been attempted. OBJECTIVES: The aim of this study was to characterise all ME-related individual case safety reports in EudraVigilance and explore notable signals of disproportionate reporting (SDRs) among sexes and age groups for the 30 most frequently reported drugs. METHODS: Individual case safety reports were used from EudraVigilance reported between 2002 and 2021. An ME was defined as any Preferred Term from the narrow Standardised Medical Dictionary for Regulatory Activities® Query. Signals of disproportionate reporting were selected based on a lower boundary of the 95% confidence interval ≥ 1 of the reporting odds ratio, and at least 3 individual case safety reports. Analysed subgroups were female individuals, male individuals, and age groups 0-1 month, 2 months to 2 years, 3-11 years, 12-17 years, 18-64 years, 65-85 years, and >85 years. Heatmaps were utilised as a visual aid to identify striking SDRs. RESULTS: Of the 9,662,345 EudraVigilance reports, 267,262 (2.8%) contained at least one ME, with a total of 300,324 MEs, for 429,554 drugs. The most reported ME was "Inappropriate schedule of product administration" (52,646; 17.5%), followed by "Incorrect dose administered" (32,379; 10.8%) and "Wrong technique in product usage process" (26,831; 8.9%). Individual case safety reports with MEs were most frequently related to female individuals (148,009; 55.4%), most often submitted by healthcare professionals (155,711; 58.3%), originated predominantly from the USA (98,716; 36.9%), followed by France (26,678; 10.0%), and showed a median reported age of 50 years (interquartile range: 26-68). Most ME individual case safety reports (158,991; 59.5%) were associated with a serious health outcome. A total of 847 SDRs were identified, based on the entire EudraVigilance database; for subgroups, the number of SDRs ranged from 84 for the age group 0-1 month to 749 for female individuals. Signals of disproportionate reporting for female individuals and male individuals were very similar. Most MEs were reported for the vaccine against human papillomavirus (Anatomical Therapeutic Chemical [ATC]: J07BM01; 11,086 MEs, 57% being "inappropriate schedule of product administration"), with reporting odds ratios that range from 1.5 to 47.0 among age groups. The SDR for the live-attenuated vaccine against herpes zoster (ATC: J07BK02) had a reporting odds ratio that ranged from 26.6 to 78.1 among all subgroups. Signals of disproportionate reporting for oxycodone (ATC: N02AA05; 847 cases of "Accidental overdose", 35%), risperidone (ATC: N05AX08; 469 cases "Inappropriate schedule of product administration", 22.3%) and rivaroxaban (ATC: B01AF01; 1,377 cases of "Incorrect dose administered", 34.6%) stood out with higher magnitude SDRs for the age group 2 months to 2 years, with an reporting odds ratio range between 8.2 and 10.7, while for the entire EudraVigilance the reporting odds ratio ranged between 1.3 and 1.6 for the same drugs. CONCLUSIONS: This exploratory research provides an overview of characterised ME individual case safety reports and SDRs from the EudraVigilance database. Most conspicuous SDRs were identified in specific age groups. Signals of disproportionate reporting, not described in the literature, were found for vaccines, oxycodone, rivaroxaban and risperidone, and may prompt further examination by stakeholders. Top-reported MEs ("Inappropriate schedule of product administration", "Incorrect dose administered" and "Wrong technique in product usage process") emerged as a general priority focus to perform a further root-cause analysis involving healthcare providers, manufacturers and regulatory bodies, to improve the understanding and prevention of MEs.

Descriptive analysis on disproportionate medication errors and associated patient characteristics in the Food and Drug Administration's Adverse Event Reporting System.

BACKGROUND: Medication errors (MEs) are a major public health concern which can cause harm and financial burden within the healthcare system. Characterizing MEs is crucial to develop strategies to mitigate MEs in the future. OBJECTIVES: To characterize ME-associated reports, and investigate signals of disproportionate reporting (SDRs) on MEs in the Food and Drug Administration's Adverse Event Reporting System (FAERS). METHODS: FAERS data from 2004 to 2020 was used. ME reports were identified with the narrow Standardised Medical Dictionary for Regulatory Activities® (MedDRA®) Query (SMQ) for MEs. Drug names were converted to the Anatomical Therapeutic Chemical (ATC) classification. SDRs were investigated using the reporting odds ratio (ROR). RESULTS: In total 488 470 ME reports were identified, mostly (59%) submitted by consumers and mainly (55%) associated with females. Median age at time of ME was 57 years (interquartile range: 37-70 years). Approximately 1 out of 3 reports stated a serious health outcome. The most prevalent reported drug class was "antineoplastic and immunomodulating agents" (25%). The most common ME type was "incorrect dose administered" (9%). Of the 1659 SDRs obtained, adalimumab was the most common drug associated with MEs, noting a ROR of 1.22 (95% confidence interval: 1.21-1.24). CONCLUSION: This study offers a first of its kind characterization of MEs as reported to FAERS. Reported MEs are frequent and may be associated with serious health outcomes. This FAERS data provides insights on ME prevention and offers possibilities for additional in-depth analyses.

Parasitic infections related to anti-type 2 immunity monoclonal antibodies: a disproportionality analysis in the food and drug administration's adverse event reporting system (FAERS).

Introduction: Monoclonal antibodies (mAbs) targeting immunoglobulin E (IgE) [omalizumab], type 2 (T2) cytokine interleukin (IL) 5 [mepolizumab, reslizumab], IL-4 Receptor (R) α [dupilumab], and IL-5R [benralizumab]), improve quality of life in patients with T2-driven inflammatory diseases. However, there is a concern for an increased risk of helminth infections. The aim was to explore safety signals of parasitic infections for omalizumab, mepolizumab, reslizumab, dupilumab, and benralizumab. Methods: Spontaneous reports were used from the Food and Drug Administration's Adverse Event Reporting System (FAERS) database from 2004 to 2021. Parasitic infections were defined as any type of parasitic infection term obtained from the Standardised Medical Dictionary for Regulatory Activities® (MedDRA®). Safety signal strength was assessed by the Reporting Odds Ratio (ROR). Results: 15,502,908 reports were eligible for analysis. Amongst 175,888 reports for omalizumab, mepolizumab, reslizumab, dupilumab, and benralizumab, there were 79 reports on parasitic infections. Median age was 55 years (interquartile range 24-63 years) and 59.5% were female. Indications were known in 26 (32.9%) reports; 14 (53.8%) biologicals were reportedly prescribed for asthma, 8 (30.7%) for various types of dermatitis, and 2 (7.6%) for urticaria. A safety signal was observed for each biological, except for reslizumab (due to lack of power), with the strongest signal attributed to benralizumab (ROR = 15.7, 95% Confidence Interval: 8.4-29.3). Conclusion: Parasitic infections were disproportionately reported for mAbs targeting IgE, T2 cytokines, or T2 cytokine receptors. While the number of adverse event reports on parasitic infections in the database was relatively low, resulting safety signals were disproportionate and warrant further investigation.

Reproducible variability: assessing investigator discordance across 9 research teams attempting to reproduce the same observational study.

OBJECTIVE: Observational studies can impact patient care but must be robust and reproducible. Nonreproducibility is primarily caused by unclear reporting of design choices and analytic procedures. This study aimed to: (1) assess how the study logic described in an observational study could be interpreted by independent researchers and (2) quantify the impact of interpretations' variability on patient characteristics. MATERIALS AND METHODS: Nine teams of highly qualified researchers reproduced a cohort from a study by Albogami et al. The teams were provided the clinical codes and access to the tools to create cohort definitions such that the only variable part was their logic choices. We executed teams' cohort definitions against the database and compared the number of subjects, patient overlap, and patient characteristics. RESULTS: On average, the teams' interpretations fully aligned with the master implementation in 4 out of 10 inclusion criteria with at least 4 deviations per team. Cohorts' size varied from one-third of the master cohort size to 10 times the cohort size (2159-63 619 subjects compared to 6196 subjects). Median agreement was 9.4% (interquartile range 15.3-16.2%). The teams' cohorts significantly differed from the master implementation by at least 2 baseline characteristics, and most of the teams differed by at least 5. CONCLUSIONS: Independent research teams attempting to reproduce the study based on its free-text description alone produce different implementations that vary in the population size and composition. Sharing analytical code supported by a common data model and open-source tools allows reproducing a study unambiguously thereby preserving initial design choices.

Use of unstructured text in prognostic clinical prediction models: a systematic review.

OBJECTIVE: This systematic review aims to assess how information from unstructured text is used to develop and validate clinical prognostic prediction models. We summarize the prediction problems and methodological landscape and determine whether using text data in addition to more commonly used structured data improves the prediction performance. MATERIALS AND METHODS: We searched Embase, MEDLINE, Web of Science, and Google Scholar to identify studies that developed prognostic prediction models using information extracted from unstructured text in a data-driven manner, published in the period from January 2005 to March 2021. Data items were extracted, analyzed, and a meta-analysis of the model performance was carried out to assess the added value of text to structured-data models. RESULTS: We identified 126 studies that described 145 clinical prediction problems. Combining text and structured data improved model performance, compared with using only text or only structured data. In these studies, a wide variety of dense and sparse numeric text representations were combined with both deep learning and more traditional machine learning methods. External validation, public availability, and attention for the explainability of the developed models were limited. CONCLUSION: The use of unstructured text in the development of prognostic prediction models has been found beneficial in addition to structured data in most studies. The text data are source of valuable information for prediction model development and should not be neglected. We suggest a future focus on explainability and external validation of the developed models, promoting robust and trustworthy prediction models in clinical practice.

Real-World Effects of Antibiotic Treatment on Acute COPD Exacerbations in Outpatients: A Cohort Study under the PharmLines Initiative.

BACKGROUND: Although antibiotic treatment is recommended for acute exacerbations of chronic obstructive pulmonary disease (AECOPD), its value in real-world settings is still controversial. OBJECTIVES: This study aimed to evaluate the short- and long-term effects of antibiotic treatment on AECOPD outpatients. METHODS: A cohort study was conducted under the PharmLines Initiative. We included participants with a first recorded diagnosis of COPD who received systemic glucocorticoid treatment for an AECOPD episode. The exposed and reference groups were defined based on any antibiotic prescription during the AECOPD treatment. The short-term outcome was AECOPD treatment failure within 14-30 days after the index date. The long-term outcome was time to the next exacerbation. Adjustment for confounding was made using propensity scores. RESULTS: Of the 1,105 AECOPD patients, antibiotics were prescribed to 518 patients (46.9%) while 587 patients (53.1%) received no antibiotics. The overall antibiotic use was associated with a relative risk reduction of AECOPD treatment failure by 37% compared with the reference group (adjusted odds ratio [aOR] 0.63 [95% CI: 0.40-0.99]). Protective effects were similar for doxycycline, macrolides, and co-amoxiclav, although only the effect of doxycycline was statistically significant (aOR 0.53 [95% CI: 0.28-0.99]). No protective effect was seen for amoxicillin (aOR 1.49 [95% CI: 0.78-2.84]). The risk of and time to the next exacerbation was similar for both groups. CONCLUSION: Overall, antibiotic treatment, notably with doxycycline, supplementing systemic glucocorticoids reduces short-term AECOPD treatment failure in real-world outpatient settings. No long-term beneficial effects of antibiotic treatment on AECOPD were found for the prevention of subsequent exacerbations.