Therapeutic Advances in Drug Safety最新文献

Background: Underrepresentation of various populations in clinical trials limits our understanding of efficacy and safety outcomes, as individuals with diverse backgrounds can respond differently to the same interventions. Inclusion of diverse groups in device clinical trials is essential for providing innovative, patient-centric solutions and achieving health equity.

Objective: To evaluate how social determinants correlate with safety events in clinical trials with medical devices to identify safety signals, improve safety profiles, and develop risk-based safety and quality management strategies.

Design: A single-center, retrospective study was conducted for clinical trials with medical devices at a safety-net hospital.

Methods: Data obtained from 223 patients randomized into 19 device clinical trials were assessed retrospectively for correlation of social determinants of health variables and study protocol complexity with study protocol deviations, adverse events, and study dropout rates by using the Kruskal-Wallis and Spearman correlation tests.

Results: Lower median income was associated with an increased number of adverse events (r = -0.18599, p = 0.0053) and protocol deviations (r = -0.27349, p < 0.0001). Higher study protocol complexity was associated with an increased number of adverse events (r = 0.55328, p < 0.0001) and a higher number of protocol deviations (r = 0.54079, p < 0.0001). Out of 701 adverse events reported, 472 were serious adverse events, and 3.8% of serious adverse events were related to the study device. Multiple comorbidities >3 were associated with an increased number of safety events and protocol deviations (r = 0.35929, p < 0.001; r = 0.17270, p = 0.0098, respectively).

Conclusion: Examining the root causes of these outcomes, as well as patient-centric medical management, can improve data integrity and aid risk-based safety and quality management in device clinical trials.

Background: Pharmacovigilance is essential for ensuring patient safety, and hospital pharmacists play a key role in this system. However, their knowledge, attitudes, and practices (KAP) remain understudied in China.

Objectives: To evaluate the KAP of hospital pharmacists toward pharmacovigilance in China.

Design: Nationwide, cross-sectional study.

Methods: This study evaluated the KAP of 9724 hospital pharmacists from 2145 hospitals across all 31 provinces of mainland China using a structured questionnaire and a multi-stage sampling approach. Descriptive statistics were used to summarize the KAP of the participants, and multivariable logistic regression was applied to explore the influencing factors of high KAP performance.

Results: The proportions of respondents achieving high performance (score ⩾4 out of a maximum of 5) in knowledge, attitudes, and practices were 22.2%, 44.2%, and 68.0%, respectively, with significant correlations between these dimensions (p < 0.001). Misconceptions were prevalent, with 50.1% of pharmacists incorrectly attributing pharmacovigilance responsibility to medical institutions instead of marketing authorization holders (MAHs), and 36.2% misunderstanding pharmacovigilance as solely adverse drug reaction (ADR) reporting. A total of 95.5% of respondents expressed a willingness to participate in pharmacovigilance training. The reporting of ADEs/ADRs, medication errors, and drug quality problems to regulatory authorities is well-established nationwide, but 27.8% infrequently or never reported serious ADRs to pharmaceutical companies. Higher educational levels, hospital tiers, and leadership roles positively influenced knowledge and attitude, while male pharmacists showed superior practices compared to females. Clinical pharmacists and team leaders outperformed dispensing pharmacists in all KAP dimensions.

Conclusion: Our study reveals a significant scope for enhancement in the KAP of hospital pharmacists pertaining to pharmacovigilance in China. Specifically, there is a critical need to improve the understanding of pharmacovigilance's scope and responsibilities, and fostering stronger collaborative efforts between medical institutions and MAH is imperative, particularly within targeted pharmacist groups.

Background: Polypharmacy increases the risks of drug-drug interactions (DDIs), which increase the risk of adverse drug events (ADEs). Data mining techniques have described high-order (three or four) drug combinations as high risk for ADE and suggested alternative low-risk combinations, but were not able to establish clinical feasibility.

Objective: The objective of this study is to evaluate the clinical feasibility of potentially low-risk drug combinations identified in previous work through a data mining technique as substitutes for high-risk high-order drug combinations.

Methods: This expert-review study utilizes potentially high-risk high-order drug combinations and complementary low-risk combinations identified in previously published work from Medicare fee-for-service (2018) and MarketScan Medicare Supplemental claims emergency department (ED) data (2012-2020). We convened a panel of clinical experts to adjudicate the list for clinical feasibility. A standard rubric was developed, and the reviewers indicated whether the data-driven substitutions were always, sometimes, or never clinically acceptable and provided comments. Two experts, not involved in the initial panel review, reviewed the results produced by the panel to determine agreement or disagreement among reviewers. The results of this clinical review are presented.

Results: Of the 1904 high-/low-risk combinations reviewed, 606 were deemed always acceptable; 588 were anticoagulant ADEs, 18 were opioid, and none were antidiabetic. The 20 most frequently observed high-risk combinations were all anticoagulant ADEs; 11 of the top 20 involved proton pump inhibitor substitution and 9 involved statin substitutions.

Conclusion: High-risk high-order DDIs with low-risk alternatives as identified in Medicare fee-for-service and MarketScan databases are identifiable, are clinically acceptable, and could decrease ADE-related ED visits.

Background: Blepharoptosis is one of the most common eyelid disorders in clinical ophthalmology. Previous evidence on drug-related blepharoptosis limited to case reports.

Objectives: This study aims to systematically evaluate the disproportionality signals of drugs associated with blepharoptosis using large-scale real-world data from the US FDA Adverse Event Reporting System (FAERS).

Design: A retrospective disproportionality analysis was conducted based on the FAERS database.

Methods: A total of 21,838,627 reports from the FAERS database, spanning 2004 to 2024, were included, with 19,541,994 reports retained after deduplication. Disproportionality analysis methods including reporting odds ratio, proportional reporting ratio, Bayesian confidence propagation neural network, and multi-item gamma Poisson shrinker were employed to detect positive signals. The therapeutic purposes of the drugs, drug-related reporting patterns, drug signals strength, and onset times of adverse reactions were comprehensively assessed.

Results: A total of 9324 cases of blepharoptosis were confirmed, involving 20 identified with significant signals. They primarily include antineoplastic and immunomodulating agents, sensory organ drugs, and neuropsychiatric drugs. Eleven drugs had previously been reported to be associated with blepharoptosis, while 9 were newly identified. Botulinum toxin A, ravulizumab, and latanoprost were found to exhibit the strongest signals. Neuropsychiatric drugs (e.g., lidocaine) had a median onset time of 1-9 days, while antineoplastic and immunomodulating agents (e.g., ravulizumab) had a median onset time of 164-912 days. Avelumab and rosuvastatin showed stronger signals for elderly males, while botulinum toxin A and bupivacaine were more significant for younger females.

Conclusion: This study validates known associations such as immune checkpoint inhibitors and neuroregulatory agents, and identifies drug-related signals. There are significant differences in the onset times of adverse reactions across drug categories, suggesting the need for targeted monitoring.

Background: Emergency departments (EDs) provide urgent care to diverse patients. Medication-related tasks, crucial for safe diagnosis and treatment, often receive inadequate attention. Clinical pharmacists, experts in medication management, can improve outcomes and reduce costs.

Objectives: To investigate how the introduction of clinical pharmacists affects ED junior physicians' work-time distribution, with particular focus on medication-related tasks.

Design: A stepped-wedge design was employed, introducing pharmacists across three Norwegian EDs over a 9-month period, with each ED starting at staggered intervals.

Methods: Using the Work Observation Method By Activity Timing (WOMBAT) methodology, we observed junior physicians' activities in three EDs. The pharmacists were encouraged to adapt to the ED setting, integrate into the team, and identify ways to apply their expertise effectively. Medication reconciliation became their primary focus. We recorded 251 h of observation in the period without pharmacists present and 287 h in the intervention period, with pharmacists present. The proportion of time spent on different tasks was compared between the two periods.

Results: Junior physicians spent 81.0% of their work time on non-medication-related tasks, 11.6% on standby/movement, and 8.7% on medication-related tasks. There was no evidence that the overall time distribution was affected by the intervention. However, in ED2, the proportion of time spent on medication-related documentation was reduced from 6.1% to 2.5%, while standby time increased from 6.1% to 13% with pharmacists present. Face-to-face interactions with pharmacists accounted for less than 2% of the junior physicians' work time in all EDs.

Conclusion: In three Norwegian EDs, junior physicians' work time was predominantly spent on non-medication-related tasks, with only 8.7% dedicated to medication-related tasks. The introduction of clinical pharmacists did not significantly impact junior physicians' overall work-time distribution. Further research should investigate pharmacists' impact on ED care quality and efficiency.

Background: Considerable progress has been made in the estimation of drug safety treatment effects-particularly with observational medical claims and electronic medical record data. The use of the Target Trial framework, along with developments in statistical methodology such as doubly robust and G-estimation methods, has improved the ability to draw reliable causal inferences about drug and vaccine safety from observational data. However, such models rarely relate drug safety outcomes to other domains such as economic impacts. As shown by the COVID-19 pandemic, this is a significant limitation with potentially serious and long-term consequences.

Objective: The goal of this paper is to demonstrate that the availability of simulation tools would enable policy-makers to assess drug safety and effectiveness outcomes associated with alternative policies, as well as examine these effects in the context of other domains, such as economic outcomes.

Design: We develop an agent-based simulation model (ABM) of a peer navigator program to support engagement in HIV therapy in Tanzania. Results from the ABM are weighted to reflect the Tanzanian population and fed into the SPECTRUM model. This generates detailed demographic forecasts that are translated into macroeconomic impacts using labor force participation rates from the International Labor Organization, along with an econometric model of gross domestic product.

Results: The ABM simulation estimated that the peer navigation program increased ART participation for men and women by about 12%-15% with no strong trend over time. The impact on VLS, however, was cumulative and significant for both men and women. By year 3, VLS was improved by 33.9 percentage points for women and 32.6 percentage points for men. However, the overall impact of these estimates on mortality was modest-ranging from less than 500 lives per year at the start of the forecast period to about 2500 lives per year in 2030. Consequently, the associated macroeconomic impacts were also small. The relatively modest impacts were due to the limited opportunity for HIV control in Tanzania, which had already met its 95/95/95 goals.

Conclusion: Although the simulated macroeconomic effects of the peer navigator program in Tanzania were modest, the paper demonstrates the feasibility of linking behavioral ABM simulations of program impacts to subsequent demographic effects and, finally, macroeconomic performance. Moreover, given the clinical response in ART and VLS in the exposed population in Tanzania, it is likely that the same peer navigator intervention conducted in another country with a larger at-risk HIV population would be much larger.

Background: Dexmedetomidine may expedite recovery from acute kidney injury (AKI) in critically ill adults.

Methods: This study utilizes data from the fourth edition of the Medical Information Mart for Intensive Care (MIMIC-IV). Adult patients admitted to Beth Israel Deaconess Medical Center in Boston, Massachusetts, between 2008 and 2019 with AKI and who have at least two serum creatinine values recorded in the MIMIC-IV database meet study inclusion criteria. The primary outcome measure is the time (days) from diagnosis of AKI to recovery. Secondary outcome measures are hospital and ICU length of stay (LOS) as well as in-hospital mortality.

Results: A total of 1893 patients are included in this study. While 293 patients received dexmedetomidine, 1600 patients did not receive dexmedetomidine. Treatment with dexmedetomidine is associated with a 53.7% (95% CI: 46.8%-59.8%) decrease in the risk of recovery from AKI, on average, and this value is statistically significant (p < 0.001). Sensitivity analysis utilizing Cox regression of dexmedetomidine rate on time to AKI recovery demonstrated the opposite effect, however, with an adjusted HR of 1.42 (95% CI: 1.24-1.63, p value <0.001). Theories for this opposite effect are explored in the Discussion section of the manuscript. For patients who receive dexmedetomidine, hospital and ICU LOS, on average, increase by 18.98% and 32.56%, respectively (p value <0.001). Patients who receive dexmedetomidine have 0.6 times the odds of in-hospital mortality, on average, compared to patients who do not receive dexmedetomidine, which is statistically significant (p value 0.006).

Conclusion: Dexmedetomidine may be associated with slower recovery from AKI in critically ill adults. The prolonged hospital and ICU LOS associated with dexmedetomidine may be related to reduced mortality, but these results require additional investigation. These exploratory results warrant further investigation to better understand the clinical implications of dexmedetomidine exposure in the setting of AKI.

Background: Cholangiocarcinoma (CCA) is a cancer with a low survival rate. New drugs targeting molecular alterations, oncogenic mutations, and gene fusions are being tested as second-line treatments.

Objectives: This systematic review aims to summarize the results obtained with three new targeted therapies-pemigatinib, futibatinib, and ivosidenib-for the treatment of CCA, evaluating their safety and tolerability profiles in patients, compared to current standard therapies.

Data sources and methods: A systematic literature search was performed with a cutoff date of July 24, 2023, in MEDLINE, Embase, and the Cochrane Library. The authors also conducted an advanced search in the ClinicalTrials.gov database, evaluated conference abstracts, article bibliographies, and drug monographs. Studies involving the treatment of patients with pemigatinib, futibatinib, and ivosidenib were considered. The selected studies had to report adverse events (AEs) that occurred during treatment with these therapies.

Results: The most common AEs observed with pemigatinib, futibatinib, and ivosidenib were alopecia, diarrhea, fatigue, and dysgeusia. In addition, hyperphosphatemia, hypophosphatemia, and ocular disorders were observed with fibroblast growth factor receptor (FGFR) inhibitors, while the isocitrate dehydrogenase 1 (IDH1) inhibitor was associated with dose-dependent prolongation of the corrected QT interval (QTc). These AEs were effectively managed through dose adjustments.

Conclusion: FGFR2 and IDH1 inhibitors have good tolerability in the population examined. All AEs were optimally managed with dose modulation. Future studies should focus on identifying the most effective dosages to further enhance treatment safety.

Background: Pharmacovigilance (PV) inspections are critical regulatory assessments that evaluate the robustness and compliance of a company's drug safety system. Despite their significance, there is limited published guidance on how organizations-particularly Medical Safety functions-can prepare operationally for such inspections.

Objectives: To share practical, experience-based insights and organizational strategies for inspection readiness, execution, and follow-up, based on a recent large-scale European Medicines Agency PV inspection.

Design: Descriptive case-based manuscript outlining the stepwise activities undertaken before, during, and after a regulatory PV inspection, with a focus on Medical Safety coordination.

Methods: An internally coordinated approach was implemented, including preparatory meetings, document request management, cross-functional mock inspections, role assignments, and communication planning. A structured system was established for Medical Safety responses involving on-site and remote collaboration among safety leaders.

Results: The inspection was successfully completed. The coordinated system enabled timely, consistent, and quality-controlled responses. Visual tools, including timelines and workflows, supported operational efficiency and stakeholder alignment. Post-inspection debriefs further informed process improvements across Medical Safety functions.

Conclusion: This manuscript provides a practical, case-based framework for PV teams to approach regulatory inspections with strategic foresight and cross-functional coordination. The experience shared can serve as a useful reference, particularly for Medical Safety professionals and organizations seeking to strengthen inspection readiness and compliance operations.

Background: Statins have been demonstrated to decrease cardiovascular events in high-risk patients. Statin-induced myotoxicity is a major contributor to statin intolerance and often the leading cause of statin discontinuation. Studies on the association between statin use and rhabdomyolysis risk remain limited.

Objectives: This study aimed to compare the risk of rhabdomyolysis in patients who used statins versus those who did not.

Design: A population-based case-control study was conducted.

Methods: Data were collected from the Taiwan National Health Insurance Research Database between 2011 and 2020, involving 186,604 individuals with rhabdomyolysis and 746,416 without. Each patient with rhabdomyolysis (case group) was matched with four control patients based on the index year. Statins were assessed in both groups.

Results: Approximately 50% of study participants were male, with an average age of 53 years. After confounding variables were adjusted for, patients who used statins exhibited a higher risk of rhabdomyolysis than those who did not (adjusted odds ratio (OR): 1.70, 95% confidence interval (CI): 1.68-1.73). Psychiatric disorders, alcoholism, generalized epileptic seizure, heat stroke, and crush injury were independent risk factors of rhabdomyolysis. Patients with psychiatric disorders who used statins exhibited a substantial risk of rhabdomyolysis (adjusted OR: 2.30, 95% CI: 1.95-2.71) compared with the reference group of patients without psychiatric disorders who did not use statins.

Conclusion: Statin use was associated with a higher risk of rhabdomyolysis, and patients with psychiatric disorders who used statins exhibited an additive risk of rhabdomyolysis. These findings emphasize the need for clinicians to remain attentive to the potential risk of rhabdomyolysis in patients prescribed statins, especially in those with psychiatric disorders. Proactive monitoring, early recognition of symptoms, and individualized risk-benefit assessments are crucial to optimize treatment outcomes while minimizing adverse effects.