Transportability considerations are increasingly important to answer research questions in comparative effectiveness research (CER) to support the transfer of evidence on medicinal products across countries or settings. As drug development costs rise and healthcare systems and professionals face economic and resource pressures, leveraging existing data and evidence generated across borders or settings can improve efficiency and inform decisions in product development and decision-making (regulatory, health technology assessment [HTA] and clinical care). Differences in population characteristics, healthcare systems, and data availability, including coding discrepancies, may present significant challenges to the transportability of CER evidence. Without rigorous methodological approaches, the utility of transportability analyses is limited. This article provides a structured framework for considering transportability exercises in CER analyses. We outlined key methodological principles, when and why to use transportability exercises in CER, feasibility assessments including effect modifier identification and causal inference techniques such as weighting, outcome regression, and combined methods to guide transportability analytical approaches in CER. By synthesizing existing literature and expert insights, we identified opportunities and trade-offs in applying transportability methods to support decisions across the product lifecycle. To enhance the adoption of transportability analyses, we proposed best practices for researchers, regulators, HTA bodies, and industry stakeholders. These include early engagement with regulatory agencies and HTA bodies, transparent documentation of data assumptions, quality, fitness, and comparability assessments while ensuring robust analytical approaches. We also emphasized the need for standardized reporting guidelines and cross-country collaborations to validate transportability methods in real-world settings and communicate uncertainty in transported evidence. Transportability analyses offer a powerful tool for extending the applicability of CER findings across healthcare systems, improving evidence generation efficiency, and supporting global drug development and evaluation. By implementing best practices that promote a rigorous and transparent approach to the design and conduct of such analyses, stakeholders can maximize the value of transported treatment effects while ensuring scientific rigor and decision-making relevance. Future research should focus on empirical testing and validation of transportability methods targeting different questions across the product lifecycle and the development of harmonized regulatory and HTA methodological standards. "This manuscript is endorsed by the International Society for Pharmacoepidemiology (ISPE)." Official Endorsement was received on 5/13/26. This report explains how researchers can use data from one country or healthcare setting to help answer important questions about how well medicines work in other places where local data may be limited. The authors present a clear, step‐by‐step framework for “transportability analyses,” which are special methods that help extend research findings on medicines from one population to another (e.g., from patients in one country to similar patients in a different country). They highlight the need for careful planning, transparent reporting, and early discussions with decision‐makers like regulators and health technology assessors. It also describes best practices for choosing and analyzing data, checking assumptions, and communicating uncertainty. By following these best practices, researchers and policymakers can make better use of existing evidence to inform local decisions about medicines, especially in places where running new studies is difficult. This approach can help improve healthcare decisions worldwide by making sure that evidence is both scientifically rigorous and relevant to local needs.
Pharmacoepidemiology and population health studies using electronic health care records (EHRs) must define study variables through available electronic data. These variables are operationalized through phenotypes, which are a defined set of criteria used to identify specific traits or medical conditions. There is diversity across phenotype libraries (collections of code lists or algorithms) which intend to standardize these sets of criteria. This review aimed to characterize the landscape of phenotype libraries and how phenotypes are constructed, validated, managed, and reused across research settings. We conducted a systematic review of existing phenotype libraries to appraise their attributes. We systematically searched three databases (Scopus, PubMed, and Web of Science) up to November 2025 to identify studies on key characteristics of phenotype libraries. The search combined Medical Subject Headings (MeSH) terms related to "electronic health record," "phenotype algorithm," and "phenotype library". A structured hand search was performed to identify relevant web-based resources without accompanying publications to ensure comprehensive inclusion of libraries available to date. We extracted information on library size, vocabularies, phenotype construction methods, validation practices, management, and portability. Of 336 articles, 37 met eligibility criteria for full-text review, of which 25 were excluded because they were not EHR-based phenotype libraries (representing single algorithms, genomic resources, or study-specific phenotypes rather than reusable libraries), leaving 10 unique libraries described across 12 articles. A structured hand search identified seven more libraries. In total, 17 phenotype libraries met the inclusion criteria, including Education and Child Health Insights from Linked Data (ECHILD) Phenotype Code List Repository, Centralized Interactive Phenomics Resource (CIPHER), Chronic Condition Data Warehouse (CCW), ClinicalCodes Library, Clinical Classifications Software Refined (CCSR), ComPLy, CALIBER (Health Data Research UK (HDR UK) Phenotype Library or CALIBER), Jigsaw Algorithm Repository (JAR), Manitoba Centre for Health Policy (MCHP) Concept Dictionary, Open CodeLists, Observational Health Data Sciences and Informatics (OHDSI) ATLAS, PheCode, Phenotype KnowledgeBase (PheKB), Phenotype Execution and Modeling Architecture (PhEMA) Workbench, PheMap, Sharing and Reusing Computable Phenotype Definitions (SharePhe), Value Set Authority Center (VSAC). Libraries varied substantially in scope, size, and phenotype representation, including rule-based algorithms, probabilistic phenotypes, and standardized code groupings. Validation practices were heterogeneous and reported only for a subset of libraries. All the libraries utilized a web-based platform and met at least the minimum requirements for library management, including phenotype definitions, metadata, and version control. We observed large variations in library construction and validation across diverse libraries built in varied EHR research settings. The transparency of phenotypes and creating computable phenotypes enhance portability and streamline the effective reuse of phenotypes for different systems. Electronic health records (EHRs) contain real‐world information about patients' medical conditions, treatments, and test results. Researchers use this data to study diseases and improve patient outcomes. To this end, researchers must specify how to define specific conditions in EHR data. These definitions are called phenotypes. Phenotype libraries are platforms where such definitions are collected, documented, and shared, allowing researchers to reuse them and ensure consistency across studies. In this study, we reviewed existing phenotype libraries to understand how they are built and how they support health research. We found 17 libraries, each with unique features. Most use rule‐based methods to define conditions, and some use machine learning and natural language processing to construct phenotypes. All are accessible through web platforms and readable by both humans and computers, but not all include validation of their definitions. User interfaces vary across libraries. Our findings show that phenotype libraries play a key role in improving the reliability and reproducibility of research leveraging EHR data. We also suggest improvements to increase their accessibility, quality, and ability to work across different systems.
To determine the trajectories of benzodiazepine (BZD) and Z-drug use among older adults (n = 3590) followed in a network of geriatric outpatient clinics in Brazil. This longitudinal study evaluated BZD and Z-drug use over a 24-month follow-up period. The proportion of use at baseline and at the end of the study period was compared using the McNemar test. Two trajectories were considered: started using and stopped using. Comparisons between trajectories and independent variables were performed using Pearson's chi-square test. Variables with p < 0.20 were eligible for multivariate analysis. Multivariate models were also used to identify factors associated with BZD or Z-drug use at baseline and with trajectories of initiation and discontinuation. Odds ratios (OR) with 95% confidence intervals were estimated. A small but significant reduction in overall BZD or Z-drug use was observed (17.4% to 16.0%; p = 0.007), with a marked decrease in isolated Z-drug use (6.1% to 4.0%; p < 0.001). At baseline, use was associated with female sex (OR = 1.48; 95% CI 1.19-1.84), age 60-74 years (OR = 1.64; 95% CI 1.29-2.10), having ≥ 2 fall-related conditions (OR = 2.53; 95% CI 1.94-3.31), higher frailty scores, and cognitive dysfunction (OR = 1.32; 95% CI 1.00-1.74). Initiation was associated with pharmacist consultations during follow-up (OR = 5.01; 95% CI 2.88-8.71), depression (OR = 2.59; 95% CI 1.80-3.73), insomnia (OR = 1.97; 95% CI 1.19-3.25), and panic syndrome. Pharmacist consultation was also associated with discontinuation (OR = 0.34; 95% CI 0.15-0.76). Clinical vulnerability and psychiatric conditions were associated with BZD or Z-drug use and initiation, while pharmacist consultations were associated with both initiation and discontinuation trajectories. Benzodiazepines and Z‐drugs are commonly used to treat anxiety and sleep problems, but their use in older adults is associated with risks such as falls, cognitive impairment, and dependence. Understanding how the use of these medications changes over time can help to improve the care of older patients. This study followed 3590 older adults treated in a network of geriatric outpatient clinics in Brazil for 24 months. We analyzed two patterns of medication use: individuals who started using benzodiazepines or Z‐drugs and those who stopped using them during the follow‐up. We also examined clinical and care‐related factors associated with these changes. Overall, the use of these medications decreased slightly during the study period, with a more pronounced reduction in Z‐drug use. At the beginning of the study, the use was more common among women, aged 60–74 years, with two or more conditions related to falls, higher frailty scores, and cognitive dysfunction. Starting use during follow‐up was associated with depression, insomnia, panic syndrome, and pharmacist consultations. Pharmacist consultations were also associated with stopping these medications, suggesting that contact with healthcare professionals may influence medication use among older adults.
The applicability of spontaneous reporting systems such as the US Food and Drug Administration Adverse Event Reporting System (FAERS) to detect cannabis-related safety signals remains unclear due to the potential for discrepant reporting patterns between pharmaceutical and non-pharmaceutical cannabis-derived products (CDPs). We conducted a descriptive analysis of seven groups of CDP reports submitted to FAERS between 1999 and 2023 to investigate product definitions and reporting patterns. We then performed hypothesis-free disproportionality analyses using reporting odds ratio, proportional reporting ratio, and information component for pharmaceutical cannabidiol (CBD) and non-pharmaceutical CBD reports to assess differences in signal detection profiles, potential exposure misclassification, and the influence of reporting context. We identified 42 530 reports related to CDPs, characterized by highly heterogeneous terminology and variable reporting patterns by product type, reflecting the real-world CDP usage. Epidiolex reports often involved pediatric patients, whereas non-pharmaceutical CBD reports were more frequently associated with older adults and concomitant product use. Disproportionality analysis showed divergent signal profiles, with strong seizure-related events predominating for Epidiolex and a broader range of signals, including neoplasm-related and neurological events, observed for non-pharmaceutical CBD. These differences likely reflected variations in CDP indication and utilization and reporting behaviors. This study showed that signal detection using FAERS has potential feasibility for CDP safety surveillance. However, unique challenges related to exposure definitions, reporting patterns, motivation for utilization, and the need for a robust study design must be addressed to ensure reliable safety signal detection. Self‐reports of adverse health events suspected to be related to medications are collected in the US FDA Adverse Event Reporting System (FAERS) and screened for early signals of potential side effects. The feasibility of using FAERS to monitor potential adverse drug reactions to cannabis‐derived products (CDPs) is unclear, as individual cannabinoids are utilized in different ways for varying reasons, described with different names, and include both prescription and non‐prescription forms, unlike other medications in the database. Reports concerning seven groups of CDPs submitted to FAERS from 1999 to 2023 were summarized to explore product descriptions and reporting patterns. Potential safety signals were then screened for prescription cannabidiol and non‐prescription cannabidiol using standard methods. Significant variation in product description was observed, and reporting patterns varied by product type. Signal detection profiles also differed between prescribed and non‐prescribed cannabidiol. These differences may reflect patterns of use, indications, and reporting context. We conclude that while FAERS can contribute to CDP safety surveillance, reliable interpretation requires clearer product definitions, methods of classification, and study designs that account for the unique reporting patterns, which pose challenges beyond the usual limitations of drug safety surveillance in this database.
The objective of this analysis was to determine the contribution to the understanding of product benefit/risk made by non-randomized, observational post-marketing surveillance (PMS) studies previously required by the Ministry of Food and Drug Safety (MFDS) re-examination system and conducted by Pfizer in Korea over 2000-2024. A retrospective analysis of all Pfizer Korea PMS studies during 2000-2024 was performed, covering a wide range of therapy areas. Available Pfizer clinical study reports and re-examination reports were reviewed for sample sizes, study periods, and key safety and effectiveness findings. Twenty-four studies that enrolled 21 179 Korean participants were identified. Original sample sizes assigned by MFDS were typically either 600 or 3000 participants, but enrollment challenges were common and approximately half of the PMS studies were permitted to reduce sample size. Mean study duration (FSFV-LSLV) was 3.8 years. Safety findings were consistent with existing global safety data, with no clinically significant new safety information being generated from the PMS studies. PMS conducted by Pfizer in Korea were often challenging to recruit and generated data that were consistent with prior global data, with no evidence of clinically meaningful differences in Korean patients. These findings support MFDS's recent transition to a risk management plan (RMP) framework, with PMS only as needed, reducing mandatory requirements for newly approved drug products. Furthermore, when a PMS study is necessary to address a specific scientific uncertainty, MFDS allows individual determination of the sample size, which will improve the feasibility of conducting the study. Until 2025, a re‐examination procedure for each new drug was scheduled by the Korean Ministry of Food and Drug Safety (MFDS) to determine if new information existed that needed to be included in the product label. The procedure took place 4 or 6 years after approval and included a mandatory observational post‐marketing surveillance (PMS) study, completed by the Sponsor within that re‐examination period. The present study analyzed all Pfizer PMS studies in Korea during 2000–2024 to determine if they had generated important new safety or effectiveness information. Most of the 24 Pfizer PMS studies in Korea were completed within the assigned re‐examination period (4 or 6 years) while some required an extension (range +1.4 to +3.3 years) due to enrollment difficulties. No effectiveness findings were identified that warranted changes to the product information. For all studies, safety findings were consistent with the current global safety data for the product. No significant new safety risks were identified by any study. It was concluded that these findings lend support to the decision by MFDS to discontinue the previous re‐examination system with mandatory PMS study in favor of a more flexible approach to safety monitoring based on the risk management plan.
The length of the time window used to assess "current drug use" or "number of medications used" will influence the estimates hereof; however, no consensus exists on the optimal width of such time windows. We aimed to explore how the estimated prevalence of drug use in general, and of polypharmacy in particular, is affected by definitions used. We conducted a drug-utilization study divided into two parts. In the first part, we focused on current drug use. Using population-based registries from Denmark, we identified adults (i.e., individuals aged ≥ 18) during 2020-2022, and among them, current use of different drugs, including those with typically chronic or episodic patterns of use. The second part of the study focused on polypharmacy. We estimated its prevalence, based on different definitions, using population-based registries from Denmark in a cohort of older adults (i.e., individuals aged ≥ 65) in 2022. We also evaluated the accuracy of different criteria for predicting polypharmacy using simulations. Evaluating current drug use, the proportion of individuals classified as exposed increased with the length of the time window for all drugs, reaching a plateau considering a 120-150-day window for statins, glucose-lowering drugs, and selective serotonin reuptake inhibitors, and a 180-300-day window for opioids, whereas no plateau was reached for non-steroidal anti-inflammatory drugs within 360 days. The prevalence of polypharmacy ranged from 21% (10 different 4th level Anatomical Therapeutic Chemical (ATC) groups in 1 year) to 92% (two different 4th level ATC groups in 1 year) depending on the applied definition. In the simulation, the best criterion for identifying polypharmacy required at least two dispensations during the one-year study period for each of at least five drugs, with sensitivity ranging between 0.93 and 1.0, and specificity between 0.72 and 1.0. Time windows up to 120 days are too short to identify baseline drug use in the Danish setting. How polypharmacy is defined significantly influences its estimate, suggesting a need to use multiple definitions in each study. “Current drug use” is estimated in most pharmacoepidemiological studies. However, the impact of using different time window lengths is rarely investigated. The definition of such baseline drug use itself varies substantially—for example it may be based on prescriptions filled within the last 60, 90 or 120 days prior to, for example, cohort entry. In this study, we explored how the length of the time window considered influences the estimated prevalence of “current drug use” using Danish registry data. We observed that such prevalence was considerably underestimated when time windows shorter than 120 days were considered. We also investigated how both the number of different concomitant drugs and the time window considered affected the estimated prevalence of polypharmacy. Our findings show that these factors substantially influence the estimated prevalence, underscoring the need to include multiple definitions of polypharmacy within each study.
The dispense of methylphenidate (MPH) for attention-deficit hyperactivity disorder (ADHD) treatment often raises concerns about overdiagnosis, over-, mis-, and abuse. However, in-depth temporal analyses on dispensing and reimbursement data are lacking in Belgium and globally. Longitudinal trends in the dispensing of MPH and its alternatives, including atomoxetine (ATO), modafinil (MOD), and guanfacine (GUA), were analyzed from 2011 to 2022 in Belgium using data from IFSTAT and IQVIA databanks. The dataset uniquely separates MPH and MOD into reimbursed and non-reimbursed categories across age groups (6-17 and > 17 years). These trends were further examined in the context of international literature to provide a comprehensive framework for comparison. MPH is the most prescribed ADHD medication. Over the 12-year study period, all included drugs showed an increasing trend. For MPH and MOD, this rise is driven by non-reimbursed dispensing, while reimbursed dispensing remained stable. During summer months, a seasonal drop in MPH dispensing for the 6-17Y age group suggests an annual 'MPH drug holiday' to evaluate the necessity of continued use. While comprehensive pharmacovigilance is currently limited by insufficient demographic data and specific prescription indications, addressing these gaps presents an opportunity to better understand the underlying causes of observed dispensing trends. Differentiating between reimbursed and non-reimbursed dispensing is crucial to accurately describe the increasing use of this group of ADHD medication. More granular data is needed to assess whether changes to prescribing practices are necessary and to inform future development of guidelines. The dispensing of methylphenidate for ADHD treatment raises concerns about overdiagnosis, misuse, and abuse. However, comprehensive temporal analyses of dispensing and reimbursement data remain limited in Belgium and internationally. The dataset uniquely separates MPH and MOD into reimbursed and non‐reimbursed categories across age groups (6–17 and > 17 years). Over the 12‐year study period, all included drugs showed an increasing trend. For methylphenidate and modafinil, this rise is driven by non‐reimbursed dispensing, while reimbursed dispensing remained stable. Differentiating between reimbursed and non‐reimbursed dispensing is crucial to accurately describe the increasing use of this group of ADHD medication and to fully understand the effect of specific reimbursement policies. The distinction between both forms of dispensing is essential for comprehensive pharmacovigilance and for identifying usage trends of partially reimbursed medication since patterns could be concealed without this differentiation.
Although isolated reports indicate widespread use of benzodiazepines and benzodiazepine-related drugs (BZRDs) in the Baltic States, utilisation patterns remain poorly described. We examined utilisation patterns of benzodiazepines and BZRDs in Estonia, Latvia, and Lithuania. A drug utilisation study was conducted using nationwide prescription databases from the Baltic states between 2019 and 2023. Dispensed benzodiazepine and BZRD prescriptions were identified using Anatomical Therapeutic Chemical codes: anxiolytic benzodiazepines (N05BA); hypnotic benzodiazepines (N05CD); antiepileptic benzodiazepines (N03AE); and BZRDs (N05CF). Annual incidence and prevalence per 1,000 inhabitants were calculated. Therapeutic intensity was assessed as defined daily doses (DDDs) per user per year. Between 2019 and 2023, incidence of benzodiazepine and BZRD use declined in Estonia (from 40.8 to 32.8 users/1,000 inhabitants), remained stable in Latvia (46.5-48.9 users/1,000 inhabitants), and fluctuated in Lithuania (44.4-56.8 users/1,000 inhabitants). Prevalence decreased in Estonia from 103.0 to 94.0 users/1,000 inhabitants, but increased in Latvia and Lithuania until 2022, followed by a decline in 2023 to 102.0 and 117.6 users/1,000 inhabitants. Incidence and prevalence of all benzodiazepine and BZRD classes declined in Estonia. Although antiepileptic benzodiazepine use declined in Latvia and Lithuania, BZRD use increased. In Lithuania, prevalence of hypnotic and anxiolytic benzodiazepines increased. In 2023, therapeutic intensity reached 121 DDDs/user in Estonia, 92 DDDs/user in Latvia, and 97 DDDs/user in Lithuania. Benzodiazepine and BZRD use remained high in the Baltic states. Estonia showed the lowest prevalence but highest therapeutic intensity. In Latvia and Lithuania, overall use changed little. Continuous monitoring of prescribing practices is warranted.
To extend the Chronic Hypertension and Pregnancy (CHAP) trial findings, this study compared labetalol, nifedipine, and methyldopa initiation at or before 23 weeks' gestation in pregnant patients with chronic hypertension, examining effects on a composite effectiveness outcome and on small for gestational age birth (SGA). We used California Medicaid claims from deliveries between 2016 and 2020, linked to the California Study of Outcomes in Mothers and Infants (SOMI). The exposure was defined as ≥ 1 paid Medicaid fill for labetalol, extended-release nifedipine, or methyldopa in the first 23 weeks of pregnancy among women who did not use oral antihypertensive therapy in the period starting 90 days prior to last menstrual period (LMP) through LMP. Like CHAP, the composite outcome was preeclampsia with severe features, preterm birth < 35 weeks (PTB), placental abruption, and/or fetal or neonatal death. SGA was modeled as a safety outcome. The analysis included 2281 singleton births: 1496 labetalol initiators, 653 methyldopa initiators, and 132 nifedipine initiators. Composite outcome incidence varied by medication (labetalol: 23%; methyldopa: 19%; nifedipine: 24%). The adjusted risk ratio (aRR) comparing methyldopa versus labetalol was 0.82 (95% CI: 0.68, 1.00); nifedipine versus labetalol was 1.01 (95% CI: 0.72, 1.41); and nifedipine versus methyldopa was 1.22 (95% CI: 0.85, 1.76). For SGA, results were similar (aRR (95% CI): methyldopa vs. labetalol: 0.81 (0.62, 1.05); nifedipine vs. labetalol: 1.07 (0.65, 1.75); nifedipine vs. methyldopa: 1.32 (0.78, 2.24)). Nifedipine and labetalol were equivalent in effectiveness and safety. Methyldopa was associated with lower risks of adverse outcomes. Potential residual confounding and limited overlap between treatment groups warrant caution in interpretation of our findings. Future research is needed to clarify whether the apparent advantages of methyldopa reflect true therapeutic benefit or underlying biases. There is currently no international consensus on which drug is preferable in treating chronic hypertension in pregnancy. Thus, we aimed to compare labetalol, nifedipine, and methyldopa initiation prior to 23 weeks of pregnancy to treat chronic hypertension in pregnancy. Using California Medicaid data linked with birth and hospital records from women who delivered between 2016 and 2020, we examined risks of preterm birth before 35 weeks, preeclampsia with severe features, placental abruption, fetal or newborn death, and small‐for‐gestational‐age (SGA) birth. We found that all outcomes were similar between nifedipine and labetalol users. Contrastingly, we found that people who started methyldopa had lower risks of these complications than those who started nifedipine or labetalol, largely because of lower risk of preterm birth occurring before 35 weeks. Methyldopa users also had a lower risk of SGA infants. Although these results show methyldopa may offer advantages in preventing these outcomes, differences in patient characteristics, lack of baseline blood pressure data, and potential increased side effects mean the findings should be interpreted cautiously. Further studies with detailed clinical data, such as blood pressure readings, are needed to confirm whether methyldopa truly provides better outcomes during pregnancy.
Prescription stimulant use among the United States' (US) older adult population is increasing, yet little is known about the cardiovascular safety profiles of the two major prescription stimulant classes, methylphenidate (MPD) and amphetamine (AMP). To compare the hazard of major adverse cardiovascular (CV) events between new users of prescription MPD and AMP products in US older adults. We employed a new user comparative safety study from a 5% random sample of fee-for-service Medicare beneficiaries. Continuously enrolled beneficiaries (Parts A/B/D) aged ≥ 66 years who initiated MPD or AMP (1/1/17-12/31/21) were included. We required a 1-year washout before the first prescription claim (index date) and excluded those with contraindications based on diagnosis codes. The primary outcome was incident modified 4-Point Major Adverse Cardiovascular Event (4-P MACE), including acute myocardial infarction, stroke or transient ischemic attack, ventricular arrhythmia, or all-cause mortality; secondary outcomes included all-cause mortality and CV events (all MACE excluding death). We used a 1-year follow up after index date that was censored at change in insurance coverage, therapeutic switch, addition of the comparator drug, or end of the study (12/31/21). Confounders included demographics, healthcare utilization indicators, comorbidities, and other medications. We used trimmed propensity scores (PS) to create stabilized inverse probability of treatment weights (IPTW) and Cox proportional hazard regression to estimate the effect of MPD vs. AMP initiation on the first occurrence of 4-P MACE. We identified 2526 Medicare beneficiaries initiating MPD (N = 1340, mean [SD] age = 76.7 [7.4] years, 54.3% female sex) or AMP (N = 1186, mean [SD] age = 72.3 [5.4] years, 60.6% female sex). After PS trimming and applying IPTW, the groups were well-balanced based on absolute standardized mean differences. During 2021.6 person-years follow up (MPD [1009.9 years] vs. AMP [1011.8 years]), 339 4-P MACE events occurred (MPD [N = 280] vs. AMP [N = 59]), of which 225 were deaths (MPD [N = 192] vs. AMP [N = 33]), and 114 were CV events (MPD [N = 88] vs. AMP [N = 26]). In the primary analysis, MPD vs. AMP initiation was associated with an increased risk of 4-P MACE (HR = 1.73, 95% CI [1.36, 2.19]). The secondary analysis showed a statistically significant increased risk of all-cause mortality (HR = 2.20, 95% CI [1.62, 3.00]), but not adverse CV events (HR = 1.14, 95% CI [0.77, 1.67]). Initiation of MPD vs. AMP among older adults was associated with an increase in the hazard of 4-P MACE. Secondary analysis suggested that this increase was driven by all-cause mortality as opposed to adverse CV events. Use of prescription stimulants is growing among older adults in the United States, but we know little about how safe these medications are for the heart. This study looked at two commonly used stimulant types—methylphenidate (MPD) and amphetamine (AMP)—to see if one is linked to more heart‐related problems. Using data from Medicare, we studied people aged 66 and older who started taking either MPD or AMP between 2017 and 2021. We tracked serious heart events like heart attacks, strokes, irregular heartbeats, and all‐cause deaths. The study included over 2500 people and followed them for about a year. We found that those who started MPD had a 73% higher risk of these serious events compared to those who took AMP. Specifically, MPD users had a significantly higher chance of dying during the study period, while the difference in other heart‐related events was not as clear. These results suggest that starting MPD may carry more risk than starting AMP for older adults, especially when it comes to overall survival. Doctors and patients should consider these findings when choosing between these medications.
Digital databases such as pharmacovigilance (PV) databases could provide unique opportunities to monitor trends in suspected antibiotic resistance, ineffectiveness, and misuse, extending beyond their traditional role of tracking adverse drug reactions (ADRs). This approach is potentially valuable globally but particularly advantageous in lower-middle-income countries (LMICs) where formal resistance surveillance systems are often insufficiently developed. Leveraging PV data could help generate early signals of resistance and inappropriate antibiotic use and support antimicrobial stewardship in resource-constrained settings. To explore the potential use of PV databases in monitoring suspected antibiotic resistance trends and inappropriate use in LMICs. A retrospective cross-sectional study was conducted using VigiBase. Data were extracted in October 2024 from inception to January 1, 2024. Reports involving antibacterials for systemic use, Anatomical Therapeutic Chemical (ATC) codes J01 and J04 from LMICs were included. Selected Medical Dictionary for Regulatory Activities (MedDRA) preferred terms were mapped according to RIOLE classification to the "resistance," "ineffectiveness," "off-label use," and "error" categories to identify reporting patterns. Descriptive statistics were used to summarize reports' characteristics, and associations between categorical variables were examined using chi-squared tests. A total of 1570 ICSRs from 37 LMICs were identified, yielding 2958 drug-adverse event pairs, with reporting increasing markedly after 2016. The "off-label use" (38.6%) and "ineffectiveness" (37.0%) were the dominant RIOLE categories, driven mainly by the preferred terms (PTs) of Off-label use (795; 26.4%) and Drug ineffective (751; 25.4%). Resistance-related PTs accounted for 12.7% of pairs, most frequently Drug resistance (210; 7.0%) and Pathogen resistance (132; 4.5%), while "error" category (11.7%) was led by Product use issue (60; 2.0%) and Medication error (44; 1.5%). Watch antibiotics predominated, especially azithromycin, ceftriaxone, and meropenem, with significant associations observed between RIOLE categories and age, reporter type, ATC class, reaction outcome, AWaRe category, and WHO region. These findings demonstrate that PV databases can provide valuable insights into suspected antibiotic resistance and inappropriate use patterns in LMICs, supporting their potential role as additional data sources in antimicrobial stewardship. Antibiotics sometimes fail to work as expected, either because the bacteria are resistant, the wrong antibiotic was chosen, or the medicine was used incorrectly. In this study, we analyzed reports from lower‐ middle‐income countries (LMICs) submitted to the World Health Organization's global safety database (VigiBase) to understand why antibiotic treatments go wrong. We found that most reports were related to antibiotics being used for the wrong indication or not working as intended, while only a smaller number described confirmed resistance. These patterns likely reflect challenges in LMICs' health systems, such as limited access to diagnostic tests and the need to make treatment decisions based on symptoms alone. The study also shows that safety reporting systems, originally designed to detect side effects, can provide important early warnings about possible antimicrobial resistance, especially in places where laboratory testing is limited. Strengthening antibiotic prescribing practices, improving how health workers report treatment failures, and integrating pharmacovigilance data into national antimicrobial resistance programs could help countries identify problems sooner and support safer, more effective use of antibiotics.
Guidance from the American Academy of Pediatrics on generic drugs was last published in 1987. The regulatory process for development of a new generic product in place of the reference brand-name drug requires extensive Food Drug and Administration (FDA) standards for similarity to expect the same safety and effectiveness profiles. Since the last guidance, the growth in biologic agents and the development of biosimilars as alternatives to the originator have become more common across the United States. As with generics, FDA requires extensive evidence of biosimilar agents as compared to the originator drug. Generic drugs are identical to the brand name drug and must meet the regulatory standard of bioequivalence whereas biosimilars are "highly similar" but may differ clinically inactive components and even molecular structure, as long as these differences are not "clinically meaningful." Confidence in the development and approval of generic and biosimilar medications should guide providers toward generic and biosimilar substitution. This technical report summarizes domestic and global regulations, development of generic and biosimilar drugs, and the literature review of a variety of generic products and biosimilars.
Men with castration-resistant prostate cancer (CRPC) who have a pre-existing history of cardiovascular disease (CVD) or other comorbidities are often excluded from clinical trials involving oral androgen receptor pathway inhibitors (ARPi). In this study, we compared all-cause and prostate cancer-specific mortality among CRPC patients, with and without a pre-existing history of CVD, receiving ARPi compared to chemotherapy. Men with CRPC were identified using the Surveillance, Epidemiology, and End Results-Medicare Linked Database from 2004 to 2015. Patients were grouped into two analytical cohorts by drug use. Inverse probability treatment weights (IPTW)-adjusted Cox models and Fine-Gray subdistribution hazards models were used to evaluate associations between ARPi and chemotherapy, and between ENZ and AA for all-cause mortality and cancer-specific mortality separately. The study cohort included 1438 men with CRPC. Nearly 54.4% of patients had a pre-existing history of CVD. Patients with a pre-existing history of CVD had a higher incidence of all-cause and prostate cancer-specific mortality compared to patients without a history of CVD (all-cause mortality: 69.7% vs. 59.3%, prostate cancer-specific mortality: 56.0% vs. 49.5%, respectively). In the pre-existing history of CVD cohort, the IPTW-adjusted Cox model showed a significantly lower all-cause mortality in patients who received APRi, enzalutamide, and abiraterone, versus chemotherapy (IPTW-adjusted hazard ratio [AHR], 0.56; 95% Confidence Interval [CI], 0.48-0.64; p-value < 0.001). Further, the IPTW-adjusted competing risk model showed significantly lower prostate cancer-specific mortality in patients who received ARPi compared with those who received chemotherapy (IPTW-AHR, 0.48; 95% CI, 0.41 to 0.57; p-value < 0.001). In the without pre-existing history of CVD cohort, the adjusted Cox model showed significantly lower all-cause mortality in patients who received APRi than those who received chemotherapy (IPTW-AHR, 0.49; 95% CI, 0.41-0.60; p-value < 0.001). Whereas the IPTW-adjusted competing risk model showed significantly lower prostate cancer-specific mortality in patients who received ARPi compared with those who received chemotherapy (IPTW-AHR, 0.52; 95% CI, 0.42-0.64; p-value < 0.001). In this population-based cohort of older men with castration-resistant prostate cancer, treatment with oral androgen receptor pathway inhibitors was associated with lower estimated risks of all-cause and prostate cancer-specific mortality compared with chemotherapy in patients with and without pre-existing CVD. These findings add real-world comparative effectiveness evidence for patient populations not well represented in randomized clinical trials; however, given the observational design and limitations of administrative data, residual confounding and unmeasured clinical differences may have influenced the results. Prostate cancer that no longer responds to hormone therapy is called castration‐resistant prostate cancer (CRPC). Two commonly used treatments for CRPC are oral androgen receptor pathway inhibitors (ARPis), which are pills, and chemotherapy, which is given by infusion. Many older men with CRPC also have cardiovascular disease (CVD) (such as heart disease or prior stroke), but these patients are often underrepresented in clinical trials. In this study, we used national Medicare data linked with cancer registry records to examine survival outcomes among 1438 older men with CRPC who received either ARPis or chemotherapy between 2012 and 2014. About half of the patients had pre‐existing CVD. After accounting for differences in patient characteristics between treatment groups, men who received ARPis had lower overall mortality and lower prostate cancer–specific mortality compared with those who received chemotherapy. These patterns were similar among patients with and without CVD. Because this was an observational study using administrative data, unmeasured differences between groups may still have influenced the results. Nonetheless, the findings provide real‐world evidence to help inform treatment decisions for older men with advanced prostate cancer.
Quantification of prescription of antimicrobial agents and use of paediatric outpatient services before, during and after the COVID-19 pandemic. We conducted a population-based study using Norwegian linked health registries and Japanese claims (2018-2023). Paediatric antibiotic prescription rates, broad-spectrum use, and proportion of antibiotic prescriptions with prior presumed bacterial infection diagnoses were analysed monthly, overall and by age groups and sex. Interrupted time series analyses were performed to evaluate pandemic-related changes, expressed in rate ratio (RR) and its CI, using March 2020 as the interruption point and the pre-pandemic trend/level as reference. Data on 5.5 million children and 19.5 million antibiotic prescriptions were analysed. Before the pandemic, antibiotic prescribing was higher in Japan (120-200/1000 children/month) than in Norway (10-20/1000). At pandemic onset, rates fell by 45% in Norway (RR = 0.55; 95% CI, 0.45-0.67) and by 53% in Japan (RR = 0.47; 95% CI, 0.41-0.55), then by 2023 had returned to expected levels. Broad-spectrum antibiotic use was much higher in Japan (70%) compared with Norway (10%) before the pandemic. However, Norway experienced a sharp 20% increase whereas Japan remained largely unchanged post-pandemic. The proportion of prescriptions with a prior presumed bacterial diagnosis was between 50% and 65% before the pandemic then decreased modestly by 5%-10% at pandemic onset, followed by gradual rebound in both countries. The COVID-19 pandemic significantly altered paediatric antibiotic prescribing in both countries. Sustained antibiotic stewardship efforts are needed to ensure appropriate paediatric antibiotic use in the post-pandemic era.
The incidence of attention-deficit hyperactivity disorder (ADHD) in children and young people has increased in recent years. Disease frequency varies according to sociodemographic characteristics. There are seasonal patterns in ADHD diagnosis and prescribing with rates falling during school holidays. COVID-19 societal restrictions may have exacerbated ADHD symptoms. Electronic health records were utilised to examine temporal trends throughout the pandemic in the diagnosis and treatment of ADHD by ethnicity and social deprivation in Greater Manchester, England. We conducted a time-series analysis of all diagnosed episodes of ADHD and associated medication prescribing among patients aged 1-24 years using the Greater Manchester Care Record (GMCR). The 60-month observation period was split into four temporal phases: Pre-pandemic (1/2019-2/2020); Pandemic Phase 1 (3/2020-6/2021); Pandemic Phase 2 (7/2021-12/2022) and Post-Pandemic (1/2023-12/2023). Rate ratios by sex, age, ethnicity, and neighbourhood-level Indices of Multiple Deprivation (IMD) quintile were modelled using negative binomial regression. Overall, ADHD incidence and medication prescribing rates increased throughout the study period. Rates of increase were much higher in females than in males. Particularly large increases in ADHD incidence and medication prescribing were observed in Asian females, with post-pandemic incidence rates being seven times higher compared to the Pre-Pandemic phase. In addition, the ADHD medication prescribing rate was 90% higher for Asian females than for White females. Results showed a large increase in incidence and prescribing rates in the least deprived group, particularly in males where incidence rates increased by 83% compared to the most deprived quintile. ADHD incidence and prescribing rates differ between sociodemographic groups, plausibly due to cultural and behavioural differences in the way ADHD symptoms are presented or perceived. It is therefore important that there is greater understanding of how different demographic subgroups exhibit ADHD behaviour to help ensure timely diagnosis and access to the required support.
To explore the opioid decision-making process of prescribers in primary care, surgery, and subspecialty pain management. This was a multistage qualitative-qualitative study with clinicians involved in opioid prescribing and management from a single healthcare organization with locations in Minnesota, Florida, Arizona, and Wisconsin. Clinicians in this study included physicians, nurse practitioners (NPs), and physician assistants (PAs) practicing in primary care, surgery, or pain medicine. The interview guide was organized in three domains of a conceptual model for opioid use: (1) prescriber characteristics, (2) patient characteristics, and (3) practice environment characteristics. Individual interviews (N = 20) were performed first, and data were summarized using a rapid template-based approach. Subsequently, focus groups (FGs) (N = 4) were conducted with an additional 21 clinicians to confirm and explore interview results. Data from interviews and FGs were analyzed using a common codebook. Findings were organized as decision factors into the three domains. Factors in the prescriber domain included characteristics such as formal pain management training, as well as factors that influenced knowledge and beliefs (e.g., advice from or observation of supervising clinicians and expert colleagues). Decision factors in the patient domain included patient pain etiology, comorbid medical or mental health conditions, and demographic characteristics. Clinicians' perceptions of these factors, such as viewing older age as having lesser risk for opioid misuse, influenced prescribing decisions. Clinicians also described challenges associated with "legacy patients" whose therapy was previously managed by a different clinician. Primary care clinicians, in particular, expressed difficulties managing post-surgical or trauma-related pain after care transition. Relevant decision factors reported by prescribers in the practice environment domain included guidelines and practice oversight. Most participants reported practicing in an environment that promoted conservative opioid use and having access to standardized institutional guidelines that reduced perceived decision-making burden. Clinicians described how they used prescribing guidelines to help them communicate with patients about opioid use and prescribing decisions. Intersecting prescriber, patient, and practice environment factors shape opioid analgesic prescribing decisions. Available resources in the practice environment, including peer input and institutional guidelines, may support clinician decision-making and conversations with patients at the point of care, including in cases where patients have complex histories or personal characteristics that influence decision making. The purpose of this qualitative study was to understand how physicians and advanced practice providers from primary care, surgery, and pain management practices decide whether to prescribe opioids. Researchers conducted interviews and focus groups with 41 individuals to discuss their experiences with opioid prescribing. Researchers identified the types of things that influence how clinicians decide whether to prescribe opioids. These include the patient's pain source, medical conditions, mental health, and age. They also include the provider's training in pain management and advice from experienced colleagues. Finally, organizational policies and guidelines play a role. Understanding how healthcare clinicians make opioid prescribing decisions can inform efforts to prevent opioid use disorder and promote high‐quality care for individuals in pain.
Hormonal contraceptives (HCs) contain synthetic gonadal hormones that act on receptors widely distributed throughout the brain, thereby altering the body's endogenous hormonal milieu in ways that may influence brain and behavior. Although HCs are among the most commonly prescribed medications for female adolescents, their effects on the developing brain and mental health remain poorly understood. This gap is concerning given that adolescence is marked by substantial hormonal change, neurodevelopment, and a sharp rise in depression risk among female youth. In this review, we synthesize current evidence on associations between adolescent HC use, depression risk, and brain structure and function. Epidemiological studies have consistently reported associations between HC use during adolescence and increased depression risk, but causal interpretation is limited by residual confounding. Neuroimaging research remains scarce, particularly in adolescents, and rarely accounts for heterogeneity in HC formulations and characteristics of use or for endogenous hormonal variation related to puberty or the menstrual cycle. We outline 3 considerations to guide future research: accounting for HC heterogeneity, incorporating developmental features of adolescent menstrual cycles, and situating HC use within its broader developmental and sociocultural context. We conclude by emphasizing the need for rigorous developmentally sensitive research to counter misinformation and better support adolescents' reproductive and mental health care needs. Hormonal contraceptives (HCs) are widely used by adolescent girls, but their potential effects on the developing brain and mental health are not well understood. This matters because puberty brings major hormonal and brain changes, and depression risk rises for girls during adolescence. Many population studies link adolescent HC use to higher depression risk, but these findings may reflect other differences between users and nonusers. In this review, we evaluate evidence linking adolescent HC use with depression risk and with brain structure and function. We highlight key research gaps and priorities to reduce misinformation about HCs and better support adolescents’ reproductive and mental health.
Janus kinase inhibitors (JAKi) are medicines used to treat inflammatory rheumatic musculoskeletal diseases (IRMDs) and inflammatory bowel diseases (IBDs). In Europe, JAKis received marketing authorisation in 2017 for rheumatoid arthritis. Subsequently, the European Medicines Agency (EMA) issued multiple safety alerts concerning this drug class. We aimed to examine how the use of JAKis developed in Finland. We conducted a retrospective time series analysis on the initiations and use of JAKis in the treatment of IRMD and IBD, utilising the national medicines reimbursement registry 2018-2023, including nearly all JAKi prescriptions. We assessed the initiators' age, line of treatment and atherosclerotic risk factors. Between 2018 and 2023, the prevalence of JAKi use increased from 0.14 to 0.43/1000 inhabitants, from 756 to 1740 among IRMD patients and from 11 to 672 among IBD patients. In IRMD, JAKis were rapidly adopted with 677 initiations in 2018, declining to 328 initiations in 2023. The corresponding numbers in IBD were 11 in 2018 and 358 in 2023. The mean age of IRMD patients initiating JAKis decreased from 54 years in 2021 to 41 years in 2023, while IBD patients' mean age changed from 42 to 39 years. In 2020, 52% of IRMD Patients Initiated JAKi in second-line of treatment but by 2023, this decreased to 31%. Prevalence of atherosclerotic risk factors declined. The uptake of JAKis among IRMD patients were initially fast. After safety alerts, initiation rates declined and shifted towards younger patients with fewer atherosclerotic risk factors. In contrast, the uptake of JAKis among IBD patients increased steadily. JAK inhibitors are a new group of medicines to treat autoimmune diseases, such as rheumatic conditions or inflammatory bowel disease. In Europe, the first JAK inhibitors were approved in 2017. Since then, the European Medicines Authority has issued several warnings concerning the use of JAK inhibitors among patients with an increased risk of cardiovascular diseases or cancer. Utilising Finnish register data, this study assessed the use of JAK inhibitors in Finland following the safety alerts between 2018 and 2023. The study found that in Finland, the use of JAK inhibitors increased especially among patients with inflammatory bowel disease and shifted towards the treatment of younger patients. Initiating JAK inhibitor therapy before previous treatment with biologic medicines decreased from half to one‐third of all JAK inhibitor initiations. The proportion of patients with atherosclerotic risk factors initiating JAK inhibitor therapy decreased among both rheumatic disease patients and inflammatory bowel disease patients. The study showed that following the publication of the safety alerts, JAK inhibitor initiations decreased among older patients and those with a higher atherosclerotic risk, while the overall use of JAK inhibitors increased.
The evidence gap relating to the risk of congenital anomalies (CA) associated with first trimester medication exposure in pregnancy is well recognized. We describe the EUROmediCAT network and databases, and the methodological approach to pregnancy pharmacovigilance. Multidisciplinary expertise includes CA diagnosis and epidemiology, pharmacoepidemiology, pharmacology and teratology. The EUROmediCAT central database comprises standardized data from 19 EUROCAT CA registries in 14 countries, including more than 40 000 CA cases 1995-2021 with first trimester medication exposure data recorded, and a population coverage of 14.6 million births, growing by more than 650 000 births per year. The distributed database enables federated data analysis across eight countries which can link data from CA registries to electronic healthcare data, with population coverage of up to 900 000 births per year for linkage to maternal prescriptions, of which 300 000 births per year for linkage also to data on all births. The databases have enabled a variety of study designs: case-malformed control studies, cohort studies, disease cohort studies, signal detection studies, prevalence and ecological studies, and medication utilization studies. A key strength is that studies of CA risk can address accurately the specificity of risk by type of CA. EUROmediCAT presents a unique data and expert resource for tackling the enormous evidence gap regarding the safety of medication during pregnancy. There is a well‐recognized need for more evidence about the safety of medication use in early pregnancy to guide optimal medication choice. This paper describes the EUROmediCAT network and its databases, and how these databases can be used to generate evidence about medication safety in pregnancy. A single central database includes data from congenital anomaly registries in 14 countries of Europe, with information on medication exposure of each case. This covers a population of 14.6 million births 1995–2021, and is growing by more than 650 000 births per year. Databases accessible in eight countries link congenital anomaly registries to prescription data (covering over 900 000 births per year), and to all births (covering over 300 000 births per year). These data can also be shared for large scale research. A key strength of the EUROmediCAT network and databases is that particular attention is paid to accurate information on the risk of specific types of congenital anomaly. EUROmediCAT presents a unique data and expert resource for tackling the enormous evidence gap regarding the safety of medication during pregnancy.
There has been a growing trend of combining traditional Chinese medicine and Western medicine, but the safety of co-prescribing Salvia miltiorrhiza (Danshen) and anticoagulants remains uncertain. This study aimed to evaluate the bleeding risk following the concurrent prescribing of S. miltiorrhiza and anticoagulants in a real-world setting. A self-controlled case series study was conducted. This study used the Chang Gung Research Database to identify adult patients co-prescribed oral anticoagulants and S. miltiorrhiza, and having records of bleeding events. Bleeding events included any bleeding event (gastrointestinal, intracranial, or urogenital bleeding) and major bleeding events (hemorrhages requiring hospitalization or transfusion). Exposure periods were defined as days of concurrent prescribing of S. miltiorrhiza and anticoagulants, while control periods included days of anticoagulant use without S. miltiorrhiza. Conditional Poisson regression was applied to estimate bleeding risk during exposure periods relative to control periods, and results were presented as adjusted incidence rate ratio (aIRR) and 95% confidence interval (95%CI). Among 525 patients receiving both medications, 146 experienced bleeding events. The risk of any bleeding increased significantly during days 1-14 (aIRR: 3.98; 95% CI: 3.29-4.77) and days 15-28 (aIRR: 3.99; 95% CI: 3.23-4.79) after concurrent prescribing of S. miltiorrhiza and anticoagulants. Elevated risks of gastrointestinal bleeding (aIRR: 3.79; 95% CI: 2.95-4.53) and intracranial hemorrhage (aIRR: 3.59; 95% CI: 2.79-5.03) were observed within the first 14 days. Concurrent use of S. miltiorrhiza and anticoagulants significantly increased bleeding risk, particularly during the first 28 days of coadministration. These findings highlight the need for careful monitoring during the initial period of combined therapy. Concurrent use of Danshen (a Chinese herbal medicine) and anticoagulants may increase bleeding risk Danshen, also known as Salvia miltiorrhiza, is a traditional Chinese medicine that is commonly used for heart and circulation problems. In Taiwan, Danshen is frequently prescribed together with modern Western medications. One group of these medicines, called anticoagulants, are commonly used to prevent blood clots in people with conditions such as atrial fibrillation or heart disease. While anticoagulants are effective, they can increase the risk of bleeding. It has been uncertain whether using Danshen at the same time might make this risk even greater. In this study, we used a large medical records database to investigate the real-world safety of taking Danshen together with anticoagulants. We included 525 adults who were prescribed both treatments and 146 of them had records of bleeding events. To minimize differences between individuals, we applied a self-controlled case series (SCCS) study design, where each patient served as their own control. We found that the risk of bleeding was significantly higher during the first 28 days after patients started taking Danshen with an anticoagulant. The risk was especially high for gastrointestinal and intracranial bleeding. On average, the first bleeding event happened about 16 days after starting combined treatment. Importantly, most patients in our study already had a high baseline risk of bleeding, but even after adjusting for other factors, the increased risk remained clear. These findings suggest that patients who take Danshen alongside anticoagulants should be monitored carefully, particularly during the first few weeks of combined use. This study highlights the need for careful communication about herbal and conventional medicine use.