Drug Safety[JOURNAL]
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200 papers
Interplay of Spontaneous Reporting and Longitudinal Healthcare Databases for Signal Management: Position Statement from the Real-World Evidence and Big Data Special Interest Group of the International Society of Pharmacovigilance.
Crisafulli S, Bate A, Brown JS … +17 more , Candore G, Chandler RE, Hammad TA, Lane S, Maro JC, Norén GN, Pariente A, Russom M, Salas M, Segec A, Shakir S, Spini A, Toh S, Tuccori M, van Puijenbroek E, Trifirò G, Real-World Evidence and Big Data Special Interest Group of the International Society of Pharmacovigilance
Drug Saf · 2025 Sep · PMID 40223041 · Full text
Signal management, defined as the set of activities from signal detection to recommendations for action, is conducted using different data sources and leveraging data from spontaneous reporting databases (SRDs), which re...
Signal management, defined as the set of activities from signal detection to recommendations for action, is conducted using different data sources and leveraging data from spontaneous reporting databases (SRDs), which represent the cornerstone of pharmacovigilance. However, the exponentially increasing generation and availability of real-world data collected in longitudinal healthcare databases (LHDs), along with the rapid evolution of artificial intelligence-based algorithms and other advanced analytical methods, offers a wide range of opportunities to complement SRDs throughout all stages of signal management, especially signal detection. Integrating information derived from SRDs and LHDs may reduce their respective limitations, thus potentially enhancing post-marketing surveillance. The aim of this position statement is to critically evaluate the complementary role of SRDs and LHDs in signal management, exploring the potential benefits and challenges in integrating information coming from these two data sources. Furthermore, we presented successful cases of the interplay between SRDs and LHDs for signal management, along with future opportunities and directions to improve such interplay.
Risk Minimisation Measures of Advanced Therapy Medicinal Products Authorised in the EU Between 2009 and 2023: A Cross-Sectional Study.
Essink SCM, Zomerdijk IM, Straus SMJM … +2 more , Gardarsdottir H, De Bruin ML
Drug Saf · 2025 Sep · PMID 40208555 · Full text
INTRODUCTION: Because of the novelty of advanced therapy medicinal products (ATMPs), pro-active risk management is needed post-authorisation; for example, through implementation of additional risk minimisation measures (...
INTRODUCTION: Because of the novelty of advanced therapy medicinal products (ATMPs), pro-active risk management is needed post-authorisation; for example, through implementation of additional risk minimisation measures (aRMMs). OBJECTIVE: We described which aRMMs were introduced at marketing authorisation (MA) for ATMPs authorised in the European Union (EU), and for what safety concerns. METHODS: We included all ATMPs ever authorised in the EU until December 31, 2023. Data on safety concerns and aRMMs was collected from the European public assessment reports (EPARs) related to initial MA for each ATMP. Safety concerns were categorised using the Medical Dictionary for Regulatory Activities (MedDRA) or context of use, where appropriate. RESULTS: Of the 25 included ATMPs, most (n = 23, 92.0%) were authorised with aRMMs. Of these 23 ATMPs, all (100%) had educational material for healthcare professionals. Additionally, educational material for patients/caregivers was in place for 18 (78.3%) ATMPs and a controlled distribution or controlled access programme for 16 (69.6%). Safety concerns related to 'Long term effects' (n = 23, 92.0%), 'Injury, poisoning and procedural complications' (n = 22, 88.0%), and 'Use in special populations' (e.g., use in pregnancy) (n = 20, 80.0%) were common among all 25 ATMPs. ATMPs often had aRMMs introduced that addressed safety concerns related to 'Injury, poisoning and procedural complications' (n = 19/23; 82.6%), 'General disorders and administration site conditions' (n = 8, 34.8%), and/or 'Immune system disorders' (n = 8, 34.8%). CONCLUSION: The majority of ATMPs were authorised with aRMMs. Whilst educational materials were most prevalent, controlled distribution or controlled access programmes were also commonly introduced. For many ATMPs, aRMMs addressed risks related to 'Injury, poisoning and procedural complications'.
REMS Logic Model: A Pragmatic Framework for Incorporating Drug Safety into Clinical Practice.
Toyserkani GA, Robottom SB, Morrato EH
Drug Saf · 2025 Jul · PMID 40205138 · Full text
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Evaluation of Mortality in Users of Pimavanserin Compared with Other Atypical Antipsychotics in Patients with Parkinson's Disease Psychosis: An Update.
Rao S, McQuay LJ, Forns J … +6 more , MacKay R, Danysh HE, Doshi D, Abler V, Anthony MS, Layton JB
Drug Saf · 2025 Aug · PMID 40205137 · Full text
INTRODUCTION: Pimavanserin is the only antipsychotic medication approved in the USA to specifically treat hallucinations and delusions associated with Parkinson's disease psychosis (PDP). OBJECTIVE: To compare mortality...
INTRODUCTION: Pimavanserin is the only antipsychotic medication approved in the USA to specifically treat hallucinations and delusions associated with Parkinson's disease psychosis (PDP). OBJECTIVE: To compare mortality risk in patients with PDP after initiation of pimavanserin or comparator atypical antipsychotics in an overall PDP cohort and in a subcohort of patients residing in long-term care or skilled nursing facilities (LTC/SNFs). METHODS: This cohort study identified patients aged ≥ 65 years with PDP initiating pimavanserin or a comparator antipsychotic in US Medicare claims (2016-2021). Cox proportional hazards models were used to estimate hazard ratios (HRs) comparing all-cause mortality in the propensity score-matched treatment groups. Cumulative incidence curves, time period-specific relative risk, and risk difference estimates evaluated risk over time. RESULTS: In this follow-up analysis, we identified 4384 pimavanserin initiators and 28,042 comparator initiators in the overall PDP cohort, and 921 pimavanserin initiators and 7963 comparator initiators in the LTC/SNF subcohort. After matching, the overall PDP cohort had 4381 patients in each treatment group, and the LTC/SNF subcohort had 905 patients in each group. The matched HR for mortality (pimavanserin versus comparator) was 0.76 (95% CI 0.68-0.85) in the overall PDP cohort and 0.90 (95% CI 0.74-1.10) in the LTC/SNF subcohort. In the overall PDP cohort, time period-specific relative risks and risk differences showed that pimavanserin initiators had a lower risk of mortality throughout the first 365 days of follow-up. CONCLUSION: In the overall PDP cohort, mortality risk was lower among pimavanserin initiators than comparator antipsychotic initiators.
IQ DILI Consensus Opinion: Best Practices for Rechallenge Following Suspected Drug-Induced Liver Injury in Clinical Trials.
Steplewski K, Walker L, Coffee N … +10 more , Fallon M, Yonemochi R, Alpers D, Rockey D, Lewis J, Cohen E, Caminis J, Hey-Hadavi J, Andrade RJ, Palmer M
Drug Saf · 2025 Aug · PMID 40178787 · Full text
Rechallenge with study drug after suspected drug-induced liver injury (DILI) during drug development requires a comprehensive assessment of risks and benefits. Lack of universal consensus or societal guidelines makes thi...
Rechallenge with study drug after suspected drug-induced liver injury (DILI) during drug development requires a comprehensive assessment of risks and benefits. Lack of universal consensus or societal guidelines makes this decision-making process more challenging and difficult to manage in clinical development. The sparse published literature is biased towards reporting cases of positive rechallenge (recurrent DILI), often with adverse outcomes. The heterogeneity of available data and inconsistent approaches to drug rechallenge likely lead to bias in our perception of the risks of rechallenge, ultimately leaving this topic controversial. The IQ DILI Causality Assessment Working Group, in collaboration with academic and regulatory experts, developed this manuscript with the following objectives: (1) understand and describe current practices via literature review and survey of practices and opinions among drug developers, academic experts, and regulators; (2) propose a consistent and structured approach to decision-making and managing the rechallenge process; (3) facilitate better understanding of the risks and benefits of rechallenge via a standardized approach to collecting rechallenge data, including outcomes and the importance of publishing rechallenge data; and (4) the role of obtaining a liver biopsy, guidance on when a biopsy might be considered, and what histologic findings can assist in making the rechallenge decision. Lastly, knowledge gaps in the drug rechallenge paradigm are highlighted alongside the proposal to standardize the collection and publication of rechallenge data to help address these gaps. This consensus expert opinion does not encourage rechallenge but provides guidance for drug developers to apply a consistent approach to rechallenge.
Major Adverse Cardiovascular Events Related to JAK Inhibitors: A Disproportionality Analysis Using the WHO Global Individual Case Safety Database.
Di Napoli R, Richez C, Scavone C … +5 more , Singier A, Demourgues M, Mascolo A, Capuano A, Salvo F
Drug Saf · 2025 Aug · PMID 40121611 · Full text
BACKGROUND: Rheumatoid arthritis (RA) is commonly treated with Janus kinase inhibitors (JAKis) and anti-tumor necrosis factor-α (anti-TNFα), but the cardiovascular safety profiles of these drugs remain unclear. OBJECTIVE...
BACKGROUND: Rheumatoid arthritis (RA) is commonly treated with Janus kinase inhibitors (JAKis) and anti-tumor necrosis factor-α (anti-TNFα), but the cardiovascular safety profiles of these drugs remain unclear. OBJECTIVE: The aim of this study was to describe the individual case safety reports of major adverse cardiac events (MACE) or stroke and to determine whether there was a difference in the frequency of reporting of cardiovascular events between JAKis and anti-TNFα used in RA. METHODS: A case/non-case study was conducted using the WHO VigiBase database. Descriptive analysis was performed, the time to onset (TTO) of MACE was calculated, and the reporting odds ratio (ROR) was used to estimate the frequency of MACE reports associated with JAKis versus anti-TNFα in RA. RESULTS: A total of 18,099 cases of MACE were identified, of which 2543 (14%) were associated with JAKis, predominantly in women (65.4%) and in patients aged ≥65 years (49.9%). The median time to onset was 210 days (IQR 60-510) for JAKis and 690 days (210-1460) for anti-TNFα. JAKis were associated with higher odds of reporting MACE (ROR 1.38 [95% CI 1.32-1.44]), mainly due to non-fatal stroke (1.65 [1.55-1.75]). Stroke as a whole showed similar results (1.62 [1.53-1.72]). The ROR of MACE was also slightly increased in patients aged <65 years treated with JAKis (1.29 [1.21-1.39]). CONCLUSIONS: Compared with anti-TNFα, JAKis were more associated with MACE, especially stroke, and with a shorter time to onset. These data support the hypothesis of a different cardiovascular reporting frequency between JAKis and anti-TNFα. In patients with identified cardiovascular risk, anti-TNFα should be preferred to JAKis until more definitive results are available.
Mitigation and Management of Common Toxicities Associated with the Administration of CAR-T Therapies in Oncology Patients.
Renninger J, Kurz L, Stein H
Drug Saf · 2025 Jul · PMID 40108072 · Full text
Chimeric antigen receptor T-cell (CAR-T) therapies are one of the main approaches among targeted cellular therapies. Despite the potential benefit and durable responses observed in some patients receiving CAR-T therapies...
Chimeric antigen receptor T-cell (CAR-T) therapies are one of the main approaches among targeted cellular therapies. Despite the potential benefit and durable responses observed in some patients receiving CAR-T therapies, serious and potentially fatal toxicities remain a major challenge. The most common CAR-T-associated toxicities include cytokine release syndrome (CRS), neurotoxicity, cytopenias, and infections. While CRS and neurotoxicity are generally managed with tocilizumab and corticosteroids, respectively, high-grade toxicities can be life-threatening. Close postinfusion monitoring and assessment of clinical laboratory parameters, patient-related and clinical risk factors (e.g., age, tumor burden, comorbidities, baseline laboratory parameters, and underlying abnormalities), and therapy-related risk factors (e.g., CAR-T type, dose, and CAR-T-induced toxicity) are effective strategies to mitigate the toxicities. Clinical laboratory parameters, including various cytokines, have been identified for CRS (interleukin [IL]-1, IL-2, IL-5, IL-6, IL-8, IL-10, C-reactive protein [CRP], interferon [IFN]-γ, ferritin, granulocyte-macrophage colony-stimulating factor [GM-CSF], and monocyte chemoattractant protein-1), neurotoxicity (IL-1, IL-2, IL-6, IL-15, tumor necrosis factor [TNF]-α, GM-CSF, and IFN-γ), cytopenias (IL-2, IL-4, IL-6, IL-10, IFN-γ, ferritin, and CRP), and infections (IL-8, IL-1β, CRP, IFN-γ, and procalcitonin). CAR-T-associated toxicities can be monitored and treated to mitigate the risk to patients. Assessment of alterations in clinical laboratory parameter values that are correlated with CAR-T-associated toxicities may predict development and/or severity of a given toxicity, which can improve patient management strategies and ultimately enable the patients to better tolerate these therapies.
Pregnancy and Infant Outcomes in Women with Multiple Sclerosis Exposed to Glatiramer Acetate Therapy: An Extended 4-Year Safety Update.
Kaplan S, Ghimpeteanu A, Dragut CF
Drug Saf · 2025 Jun · PMID 40106171 · Publisher ↗
BACKGROUND AND OBJECTIVES: While glatiramer acetate (GA) is generally considered safe during pregnancy and breastfeeding, long-term data, particularly for the 40 mg/mL dose, are limited. Previous research found GA exposu...
BACKGROUND AND OBJECTIVES: While glatiramer acetate (GA) is generally considered safe during pregnancy and breastfeeding, long-term data, particularly for the 40 mg/mL dose, are limited. Previous research found GA exposure rates and pregnancy outcomes comparable to the general population. This study evaluates pregnancy, fetal, and infant outcomes following maternal exposure to GA 20 and 40 mg/mL to provide a cumulative four-year update. METHODS: Post-marketing pregnancy data reported between April 1, 2019 to March 31, 2023 were searched in Teva's Global Safety database and supplemented with 1- and 12-month post-delivery questionnaires. Prospective pregnancy data, collected prior to known pregnancy outcomes or congenital malformations, were used to estimate pregnancy and infant outcomes for GA 20 and 40 mg/mL exposure. Rates of major congenital malformations (MCM) and other pregnancy and infant outcomes were estimated. RESULTS: Among 3514 pregnancies, multiple sclerosis (MS) was the primary indication (62.4%), with most exposure to GA 40 mg/mL (72.2%), in the first trimester (94.9%). Of these, 2455 (69.9%) had known pregnancy outcomes. Of 1211 prospective pregnancies (1239 fetuses) with known outcomes, 1138 (91.8%) resulted in live births. Fetal loss occurred in 101 cases (8.2%), including spontaneous abortion (6.7%), elective termination (0.8%), ectopic pregnancy (0.3%), stillbirth (0.2%), and other (0.2%). The prevalence of MCM was 1.5% overall (95% CI, 0.9-2.4) and 1.9% during organogenesis (95% CI, 1.1-3.1), comparable to background rates. Minor congenital malformations were less frequent (0.7%). Prospective pregnancies with completed questionnaires (n = 539) reported preterm birth (9.8%), low/very low birth weight (7.3%), neonatal intensive care unit (NICU) admission (8.8%), and adverse events (17.4%). Infant growth remained within normal ranges. Of 384 women completing the 12-month questionnaire, 146 reported breastfeeding with GA (average 8 months). Among these, 14/125 (11.2%) respondents reported infant hospitalization. Growth parameters for 55 breastfed infants were within normal limits. Overall, pregnancy and infant outcomes were similar across GA doses. DISCUSSION: Despite limitations of post-marketing data, this four-year study found no increased risk of adverse pregnancy, fetal, or infant outcomes associated with GA exposure. The MCM rates aligned with the general population, and infant outcomes during breastfeeding were within normal ranges. These findings support the safety of both 20 and 40 mg/mL GA during pregnancy and breastfeeding.
Narrative Search Engine for Case Series Assessment Supported by Artificial Intelligence Query Suggestions.
Zekarias A, Meldau EL, Bista S … +2 more , Félix China J, Sandberg L
Drug Saf · 2025 Jul · PMID 40088342 · Full text
INTRODUCTION: Manual identification of case narratives with specific relevant information can be challenging when working with large numbers of adverse event reports (case series). The process can be supported with a sea...
INTRODUCTION: Manual identification of case narratives with specific relevant information can be challenging when working with large numbers of adverse event reports (case series). The process can be supported with a search engine, but building search queries often remains a manual task. Suggesting terms to add to the search query could support assessors in the identification of case narratives within a case series. OBJECTIVE: The aim of this study is to explore the feasibility of identifying case narratives containing specific characteristics with a narrative search engine supported by artificial intelligence (AI) query suggestions. METHODS: The narrative search engine uses Best Match 25 (BM25) and suggests additional query terms from two word embedding models providing English and biomedical words to a human in the loop. We calculated the percentage of relevant narratives retrieved by the system (recall) and the percentage of retrieved narratives relevant to the search (precision) on an evaluation dataset including narratives from VigiBase, the World Health Organization global database of adverse event reports for medicines and vaccines. Exact-match search and BM25 search with the Relevance Model (RM3), an alternative way to expand queries, were used as comparators. RESULTS: The gold standard included 55/750 narratives labelled as relevant. Our narrative search engine retrieved on average 56.4% of the relevant narratives (recall), which is higher when compared with exact-match search (21.8%), without a significant drop in precision (54.5% to 43.1%). The recall is also higher as compared with RM3 (34.4%). CONCLUSIONS: Our study demonstrates that a narrative search engine supported by AI query suggestions can be a viable alternative to an exact-match search and BM25 search with RM3, since it can facilitate the retrieval of additional relevant narratives during signal assessments.
QT Interval, Antipsychotics and Correlates Among Patients with Schizophrenia: Cross-Sectional Data from the Multicentric Real-World FACE-SZ.
Gerentes M, Lajnef M, Szöke A … +27 more , Aouizerate B, Berna F, Cléry M, Chéreau I, Coulon N, Clauss-Kobayashi J, Fakra E, Dorey JM, Dubertret C, Fond G, Godin O, Goze T, Lançon C, Leboyer M, Leignier S, Llorca PM, Mallet J, Misdrahi D, Oriol N, Rey R, Roux P, Schorr B, Urbach M, Véry E, FACE-SZ (FondaMental Academic Centers of Expertise-Schizophrenia) Group, Schürhoff F, Pignon B
Drug Saf · 2025 Jul · PMID 40088341 · Publisher ↗
BACKGROUND: The life expectancy of patients with schizophrenia is reduced, partly due to cardiovascular diseases. Antipsychotics are associated with QT interval prolongation, which is a risk factor for arrhythmia and car...
BACKGROUND: The life expectancy of patients with schizophrenia is reduced, partly due to cardiovascular diseases. Antipsychotics are associated with QT interval prolongation, which is a risk factor for arrhythmia and cardiac arrest. The differences between antipsychotic with regard to QT interval prolongation are not well understood. OBJECTIVE: The aim was to compare the QT values associated with different antipsychotics within a real-world population of subjects with clinically stable forms of schizophrenia. METHODS: The FACE-SZ cohort comprises subjects with psychotic disorders, referred to schizophrenia expert cents. QT interval was measured, as well as all treatments (psychotropic and others). The following maintenance treatment for schizophrenia was analysed cross-sectionally: aripiprazole, clozapine, haloperidol, amisulpride, olanzapine, quetiapine, risperidone. Age, sex, smoking status, body mass index, blood potassium levels, and the co-prescription of another QT-prolonging treatment were used as adjustment factors in multivariable linear regression analyses. RESULTS: Among 792 patients, the mean corrected QT (QTc) interval in the sample of patients under monotherapy was 407 ms. The mean age was 31.7 years, and the majority were male (73.3 %). In comparison to the rest of the sample, clozapine was associated with a longer QTc interval (β = 0.012, 95% CI [0.006-0.018]), while aripiprazole was significantly associated with a shorter QTc interval (β = - 0.010, 95% CI [- 0.016 to - 0.005]). Other antipsychotics were not associated with significant variations of the QTc. CONCLUSIONS: The prescription of antipsychotics should always be accompanied by close monitoring of the QTc interval to prevent the risk of severe cardiac arrhythmia, particularly concerning clozapine.
Evidence-Based Design of Prescription Medication Information: An Updated Scoping Review.
Russell AM, Lovett R, Vogeley A … +4 more , Nunes DA, McKelvie C, Middleton W, Wolf M
Drug Saf · 2025 Jun · PMID 40075034 · Full text
BACKGROUND: Well-designed prescription medication information (PMI), defined as materials which communicate the essential information needed for a patient to safely and accurately self-administer a medication at or near...
BACKGROUND: Well-designed prescription medication information (PMI), defined as materials which communicate the essential information needed for a patient to safely and accurately self-administer a medication at or near the time of prescribing, is important for patient education. A previous review identifying best practices in the design of PMI was last completed using studies published through 2015. OBJECTIVE: The aim of this review was to present an updated description of studies comparing one or more types of PMI, including details of if or how patients were involved in PMI design, and to consolidate design elements associated with positive outcomes. METHODS: Four databases (Ovid, Embase, CINAHL, and Cochrane) were searched for studies comparing one or more types of PMI using a specified literature search with follow-up citation searching of included articles. Eligible studies were (1) conducted in English-speaking countries, (2) randomized controlled trials, and (3) published in 2016 or later. Consistent findings from at least two well-conducted studies were deemed 'strong' evidence and inconsistency in study findings or quality were deemed 'moderate' evidence. RESULTS: Thirty-two articles were included and most had some risk (n = 24) or high risk of bias (n = 4). Two-thirds of articles (n = 21) reported on the details of PMI development, and over half (n = 14) conducted formal pilot testing or obtained feedback from patients. Findings suggested benefits when patients were involved in PMI development. Twelve studies examined written medication information (e.g., leaflets), ten examined pharmacy-generated contained labelling (e.g., instructions printed on pill bottles), two examined supplemental information (e.g., medication regimen charts), and fourteen examined PMI delivered using technology-supported tools (e.g., text message instructions). The most prevalent assessed outcomes were knowledge (n = 19), behaviors (n = 17), attitudes/beliefs (n = 11), and clinical outcomes, such as blood pressure (n = 3). Several studies demonstrated positive outcomes when PMI was designed according to health literacy principles of plain language, typographic cues, actionable instructions, large font, and white space. Multiple trials of pictograms and illustrations alongside paired text and text messages to deliver PMI also had positive outcomes. Although there were several studies that examined interactive websites, audio, and video delivery of PMI, mixed findings resulted in moderate evidence. Novel methods of PMI delivery were identified: a plain language label for as-needed medications, strategic memory training, inclusion of patient photos and quotes, Quick Response codes, and electronic health record strategies. CONCLUSIONS: Overall, a high proportion of studies included patients in the development of PMI and focused on behavioral outcomes. However, clinical outcomes appear to be understudied. In addition to health literacy principles, there is strong evidence for pictograms with paired text when used in written medication information and pharmacy-generated labels. There is moderate evidence for using text messages to deliver PMI. Novel methods require additional study to determine best practices in design.
Navigating Diverging Perspectives: Reasoning, Evidence, and Decision-Making in Drug Safety.
Hammad TA, Davies S
Drug Saf · 2025 Jun · PMID 40075033 · Full text
Decision making in drug safety is a complex and iterative process that requires the integration of diverse evidence sources, scientific reasoning, and clinical judgment. Diverging opinions among stakeholders-including ph...
Decision making in drug safety is a complex and iterative process that requires the integration of diverse evidence sources, scientific reasoning, and clinical judgment. Diverging opinions among stakeholders-including pharmacovigilance professionals, regulatory authorities, clinical researchers, statisticians, and epidemiologists-often stem from differences in data interpretation, methodological approaches, and thresholds for concern or action. This paper examines the key sources of these divergences and presents a structured framework to enhance alignment in drug safety decision making. The proposed framework outlines three core dimensions: evidence assessment, interpretation, and action. It distinguishes between quantitative aspects, such as effect magnitude and measurement error, and qualitative considerations, including contextual interpretation and risk thresholds. The framework also underscores the importance of multidisciplinary collaboration, as safety professionals must actively engage with other scientific and regulatory stakeholders to ensure a comprehensive evaluation of the evidence. A fundamental challenge in pharmacovigilance is the need to communicate the complexities of drug safety assessment to a broader audience, including those who may not be familiar with the nuances of safety decision making. This paper aims to serve not only as a resource for new pharmacovigilance professionals, but also as a tool to facilitate clearer communication between disciplines. By adopting a structured approach and fostering open dialogue, drug safety professionals can enhance transparency and improve regulatory and clinical decision-making processes.
Off-the-Shelf Large Language Models for Causality Assessment of Individual Case Safety Reports: A Proof-of-Concept with COVID-19 Vaccines.
Abate A, Poncato E, Barbieri MA … +6 more , Powell G, Rossi A, Peker S, Hviid A, Bate A, Sessa M
Drug Saf · 2025 Jul · PMID 40075032 · Full text
BACKGROUND: This study evaluated the feasibility of ChatGPT and Gemini, two off-the-shelf large language models (LLMs), to automate causality assessments, focusing on Adverse Events Following Immunizations (AEFIs) of myo...
BACKGROUND: This study evaluated the feasibility of ChatGPT and Gemini, two off-the-shelf large language models (LLMs), to automate causality assessments, focusing on Adverse Events Following Immunizations (AEFIs) of myocarditis and pericarditis related to COVID-19 vaccines. METHODS: We assessed 150 COVID-19-related cases of myocarditis and pericarditis reported to the Vaccine Adverse Event Reporting System (VAERS) in the United States of America (USA). Both LLMs and human experts conducted the World Health Organization (WHO) algorithm for vaccine causality assessments, and inter-rater agreement was measured using percentage agreement. Adherence to the WHO algorithm was evaluated by comparing LLM responses to the expected sequence of the algorithm. Statistical analyses, including descriptive statistics and Random Forest modeling, explored case complexity (e.g., string length measurements) and factors affecting LLM performance and adherence. RESULTS: ChatGPT showed higher adherence to the WHO algorithm (34%) compared to Gemini (7%) and had moderate agreement (71%) with human experts, whereas Gemini had fair agreement (53%). Both LLMs often failed to recognize listed AEFIs, with ChatGPT and Gemini incorrectly identifying 6.7% and 13.3% of AEFIs, respectively. ChatGPT showed inconsistencies in 8.0% of cases and Gemini in 46.7%. For ChatGPT, adherence to the algorithm was associated with lower string complexity in prompt sections. The random forest analysis achieved an accuracy of 55% (95% confidence interval: 35.7-73.5) for predicting adherence to the WHO algorithm for ChatGPT. CONCLUSION: Notable limitations of ChatGPT and Gemini have been identified in their use for aiding causality assessments in vaccine safety. ChatGPT performed better, with higher adherence and agreement with human experts. In the investigated scenario, both models are better suited as complementary tools to human expertise.
Using Mixed Methods to Evaluate Risk Minimisation Programs in Europe and the USA: An Innovative Blueprint.
Smith MY, Davis R, Bahri P … +4 more , Saragoussi D, Nguyen V, Toyserkani GA, Hamilton A
Drug Saf · 2025 Jul · PMID 40075031 · Full text
BACKGROUND: Significant methodological shortcomings have been documented to date in risk minimisation program evaluations for medicinal products, including overreliance on survey methods alone. Recently updated guidances...
BACKGROUND: Significant methodological shortcomings have been documented to date in risk minimisation program evaluations for medicinal products, including overreliance on survey methods alone. Recently updated guidances from the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) recommend the use of frameworks and mixed methods designs to improve the rigor of these assessments. OBJECTIVE: The purpose of this paper was to exemplify how a mixed methods approach, guided by an implementation science framework, can be used to design the evaluation of a risk minimisation program. METHODS: We selected the Practical, Robust, Implementation and Sustainability Model (PRISM) as the implementation science framework to guide our mixed methods approach. PRISM provides a comprehensive and systematic approach to measuring the key domains relevant to the implementation and outcomes of a risk minimisation program. We mapped the PRISM domains to the evaluation dimensions described in the EMA and FDA guidances. We then specified a mixed methods evaluation design and data collection methods using a fictitious risk minimisation program as a case study for illustrative purposes. RESULTS: On the basis of our case study, we developed quantitative and qualitative measures, including specific items for surveys and interviews, for both formative and summative evaluations. For both the formative and summative evaluations, measures focussed on assessing (1) contextual factors that could affect program implementation and impact and (2) outcomes including implementability and acceptability as well as degree of program reach, adoption, implementation, effectiveness and maintenance. CONCLUSIONS: Mixed methods, guided by a well-established implementation science framework, can be applied to ensure comprehensive formative and summative evaluations that provide fit-for-purpose information that may inform regulatory decision-making.
The Frequency of Drug-Induced Liver Injury Due to Antibiotics Among Hospitalised Patients.
Björnsson RA, Sigurdsson SS, Arnarson DT … +2 more , Logason E, Björnsson ES
Drug Saf · 2025 Jul · PMID 40072769 · Publisher ↗
INTRODUCTION: Most epidemiological studies have found antibiotics to be the most common cause of drug-induced liver injury (DILI). It is unclear what the risk of DILI is associated with different antibiotics. OBJECTIVE:...
INTRODUCTION: Most epidemiological studies have found antibiotics to be the most common cause of drug-induced liver injury (DILI). It is unclear what the risk of DILI is associated with different antibiotics. OBJECTIVE: The aim of the study was to assess the frequency of DILI due to the most commonly used antibiotics among inpatients, in a population-based setting. METHODS: Patients who were treated with the 14 most-used antibiotics at Landspitali University Hospital Iceland 2012-2023, with concomitant: > 5 × upper limit of normal (ULN) of alanine aminotransferase (ALT) and/or > 2 × ULN of alkaline phosphatase (ALP), were identified. If DILI was a potential cause, the Revised Electronic Causality Assessment Method (RECAM) method was used to determine likelihood of DILI. RESULTS: Overall 2292 patients fulfilled the inclusion criteria, 52 of whom were found to have DILI, median age 67 (range 21-93) years, 58% females, 17 (33%) with jaundice and three (5.8%) died of liver failure. The most commonly implicated agent was amoxicillin/clavulanate (n = 23) in 1:1327 users (0.075%), ceftriaxone (n = 8) 1:3779 (0.02%), cefazolin (n = 7) 1: 6363 (0.016%), cloxacillin 1:6024 (n = 4) (0.017%), piperacillin/tazobactam (n = 2) 1:1551 (0.097%), vancomycin (n = 2) 1:1966 (0.076%), trimethoprim-sulfamethoxazole (TMP/SMX) (n = 3) 1:1096 (0.091%) and ciprofloxacin (n = 1) 1:10,938 (0.009%). In two cases, more than one antibiotic was considered likely. CONCLUSIONS: Drug-induced liver injury was found to be a rare adverse effect of antibiotics in a population-based setting. Overall, 33% presented with jaundice but three died of liver failure, all due to amoxicillin/clavulanate, which was the most common cause occurring in around 1 in 1300 users. However, TMP/SMX was associated with the highest proportional risk of DILI.
Might We Come Together on a Paradigm Shift to Manage ICSRs with a Decentralized Data Model?
Smith L, Glaser M, Kempf D … +4 more , Roman X, Artlich C, Patel MA, Bate A
Drug Saf · 2025 Aug · PMID 40056291 · Full text
The current practice of managing and sharing individual case safety reports (ICSRs) across the patient safety ecosystem, established in the 1960s, has become burdened with ICSR duplication and replication and can result...
The current practice of managing and sharing individual case safety reports (ICSRs) across the patient safety ecosystem, established in the 1960s, has become burdened with ICSR duplication and replication and can result in a fragmented understanding of product safety profiles. For this article, we have defined duplication as multiple representations of the same case within the same database and replication as various representations of the same case across numerous databases. Evolving safety regulations and increasing case volumes signal a need for a new path forward that is sustainable and enhances public health. While there is no question that ICSRs are a crucial component of safety surveillance, stakeholders must evaluate their management to ensure they are fit for purpose in a modern ecosystem. This article aims to embark on that path by proposing a conceptual decentralized ICSR management model to facilitate multi-stakeholder collaboration around new working models to mitigate duplication and replication, allow ecosystem stakeholders to access the latest source of truth on demand, facilitate more meaningful safety analysis and interpretation, and ultimately enable a real-time learning healthcare system to improve patient safety and health outcomes. It describes the feasibility analysis results and subsequently conducted proof of concept (PoC) based on a decentralized system architecture supporting such a decentralized model. It outlines considerations, challenges, and opportunities compared with the current state related to case management and signal management processes.
Opinion Mining of Erowid's Experience Reports on LSD and Psilocybin-Containing Mushrooms.
Al-Imam A, Lora R, Motyka MA … +5 more , Marletta E, Vezzaro M, Moczko J, Younus M, Michalak M
Drug Saf · 2025 May · PMID 40032797 · Publisher ↗
BACKGROUND: Psychedelics are gaining attention for their therapeutic potential in modern and personalized medicine. Online forums such as Erowid provide valuable user insights, but analyses of these experiences using nat...
BACKGROUND: Psychedelics are gaining attention for their therapeutic potential in modern and personalized medicine. Online forums such as Erowid provide valuable user insights, but analyses of these experiences using natural language processing (NLP) remain scarce. OBJECTIVE: This study aims to utilize NLP, including sentiment and lexicon analysis, to examine user-generated experience reports on psilocybin-containing mushrooms and LSD from the Erowid forum. METHODS: Data from 2188 Erowid users (1161 psilocybin mushrooms and 1027 LSD) was collected via automated web scraping with XPath, CSS selectors, and Selenium WebDriver. The dataset included report titles, substances, and demographics. Sentiment analysis utilized BERT, RoBERTa, and VADER models. Preprocessing involved tokenization, lemmatization, part-of-speech tagging, and stop-word filtering. Lexicon analysis identified themes through recurring n-grams, visualized using Python. RESULTS: User demographics revealed comparable ages for psilocybin mushrooms (23.8 ± 0.9 years) and LSD users (20.0 ± 0.6 years), with a predominance of male users. The BERT model predominantly labeled experiences as negative (unfavorable), particularly for mushroom users (p = 0.001). VADER indicated more positive experiences for mushroom users (p < 0.001), while RoBERTa mainly classified experiences as negative or neutral. Significant gender differences were found only with VADER, where more male users expressed positive opinions about psilocybin mushrooms (74.09% versus 65.52%, p < 0.021). The VADER model yielded more polarized results, whereas RoBERTa's cautious classifications indicate its suitability for analyzing lengthy and complex psychedelic reports. Further, RoBERTa outperformed other transformer-based models, achieving the highest accuracy. Lexicon analysis revealed emotional, sensory, and temporal themes, with psilocybin reports emphasizing introspection and time dilation phenomenon, while LSD reports highlighted memory issues and cognitive disorientation. CONCLUSIONS: Sentiment analysis showed that VADER produced more polarized results, while RoBERTa offered cautious classifications with the highest accuracy. Lexicon analysis revealed shared themes, with mushroom reports focusing on introspection and time dilation perception, while those of LSD emphasized cognitive disturbances. This study highlights the value of these analyses in understanding psychedelic experiences, informing harm reduction, and guiding policy-making.
Comment on: "The Use of Multiple Medications During Pregnancy Among an Ethnically Diverse Population in South-Eastern Melbourne: A Retrospective Analysis to Explore Potential Risks and Complications".
Tran MH, Truong-Nguyen KH
Drug Saf · 2025 Apr · PMID 40029575 · Publisher ↗
Abstract loading — click title to view on PubMed.
Authors' response to Tran et al.'s comment on "The Use of Multiple Medications During Pregnancy Among an Ethnically Diverse Population in South-Eastern Melbourne: A Retrospective Analysis to Explore Potential Risks and Complications".
Belsti Y, Mousa A, Jackson H … +7 more , Moran LJ, Palmer KR, Dhungana RR, Callander E, Rolnik DL, Teede H, Enticott J
Drug Saf · 2025 Apr · PMID 40029574 · Publisher ↗
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Understanding the Work of the Pharmacovigilance Risk Assessment Committee (PRAC): A Quantitative Review of the Post-Authorisation Safety Evaluation of Antidiabetic Drugs from 2012 to 2022.
Le H, Sindahl P, Andersen M … +1 more , Hallgreen CE
Drug Saf · 2025 Jul · PMID 40024970 · Full text
BACKGROUND: The Pharmacovigilance Risk Assessment Committee (PRAC) plays a central role in the European Union's pharmacovigilance system, evaluating drug safety through several procedures and activities. Despite its cent...
BACKGROUND: The Pharmacovigilance Risk Assessment Committee (PRAC) plays a central role in the European Union's pharmacovigilance system, evaluating drug safety through several procedures and activities. Despite its central role, few studies have quantitatively investigated the PRAC's activities from a system's perspective. OBJECTIVE: This study aims to map PRAC's evaluation of safety signals and concerns using antidiabetic products as a case. It characterises the drugs and adverse events involved, analyses the PRAC-led regulatory procedures where the safety signals and concerns were evaluated, and provides a comprehensive review of PRAC meeting minutes. METHODS: From PRAC meeting minutes, we retrieved information on all antidiabetic drug-related adverse events discussed from 2012 to 2022. We identified drug-adverse event evaluations based on the discussion content. These were described by drug classes, System Organ Classes, PRAC procedures, and the evaluation outcomes corresponding to recommendations for regulatory actions. We also analysed the sequence of PRAC-led procedures and activities addressing drug-adverse event pairs across meeting minutes. RESULTS: A total of 321 drug-adverse event pairs were identified, with 14 pairs associated with drug classes. Second-generation antidiabetic agents, including sodium-glucose transport protein-2 inhibitors, glucagon-like peptide-1 receptor agonists, and dipeptidyl peptidase 4 inhibitors, were the most frequently discussed. Of these, 62 pairs underwent multiple evaluations, resulting in a total of 413 evaluations. In 48% of evaluations, no regulatory action was required. Most evaluations (97%) were concluded in a single procedure, and 66% were concluded in one meeting. Periodic safety update reports accounted for 54% of drug-adverse event evaluations and updates to product information were the most frequent outcome. Signal assessment and prioritisation procedures, while less common, resulted in more diverse recommendations for regulatory action. Referrals were infrequent (N = 5) and were often triggered by the signal assessment and prioritisation procedure. CONCLUSIONS: Periodic safety update reports are the primary source for PRAC evaluations of safety signals although they are not intended for notification of new urgent safety information. Compared with periodic safety update reports, the signal assessment and prioritisation procedure evaluates fewer signals but leads to a wider range of regulatory actions, from risk minimisation measures to referrals. This difference may be attributed to the fact that signals detected in periodic safety update reports are not intended for urgent safety issues, these should be assessed through the signal assessment and prioritisation procedure, as the latter involves real-time signal management, whereas the periodic safety update reports are conducted at predefined intervals.
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