Drug Safety最新文献

Background and objective: Missing data and unmeasured confounding may bias results of external comparator (EC) studies. Previous research quantified these effects, but there were still knowledge gaps in terms of studying a broader set of missing data-handling approaches. This knowledge gap is addressed by investigating four different ways to handle missing data for a set of four distinct marginal estimators.

Methods: An extensive simulation study was conducted based on two real EC case studies. Four different variants of missing data-handling approaches were assessed in terms of bias and other performance characteristics. Specifically, multiple imputation (MI) for the trial and EC cohorts was conducted by applying within-cohort MI, across-cohort MI and a mixed within-across-cohort MI scheme. Dropping a covariate from the analysis model if missingness exceeded a certain threshold was also added as an analysis strategy. All simulation results were generated for a set of four marginal estimators: the average treatment effect of the untreated (ATU), the average treatment effect (ATE), the average treatment effect of the treated (ATT), and the average treatment effect in the overlap population (ATO). Missingness was simulated to occur only in the EC cohort, and propensity score weighting was applied as causal inference method.

Results: Overall, within-cohort MI and the ATU showed best performance in terms of mitigating bias, while the strategy of leaving out prognostic factors (covariates) due to a higher percentage of missingness performed worst.

Conclusions: Performances of four missing data-handling strategies were assessed for a set of four different marginal estimators. Our results add clarity with regard to potential residual bias for researchers conducting EC studies when using propensity score weighting in the case of missing data or unmeasured confounding. This enables researchers to select most appropriate statistical approaches to minimise bias, potentially by including an additional bias estimation and correction step.

The evaluation of safety data by the US Food and Drug Administration (FDA) is a critical step in the review of marketing applications for drugs and biologics. It can be difficult to identify a safety signal, and important signals can be missed if not evaluated comprehensively. Adverse events reported by study participants constitute a major source of safety data, and while previously established standard term groupings have been useful for analysis (e.g., Standardised MedDRA^® Queries), the Office of New Drugs (OND) at the FDA determined a need for more clinically meaningful groupings specifically designed for use in premarket drug safety evaluation. To improve safety signal detection and analyses of adverse reactions, OND developed standard groupings of adverse event terms known as OND Custom Medical Queries (OCMQs). OCMQs are intended to capture clinically meaningful groupings (i.e., safety signals) represented in premarketing data. OND has seen great utility in OCMQs during premarket drug safety evaluations, as they have improved OND's ability to detect safety signals and to distinguish and quantify adverse reactions in clinical trial data.

Background: Preventing fetal exposure to teratogenic medications is an important target for risk mitigation efforts. Decisions about risk mitigation efforts specific to teratogenic medications are complex.

Objectives: The Teratogenic Risk Impact and Mitigation (TRIM) tool was developed as an innovative decision support tool to facilitate prioritization of teratogenic medications for risk mitigation strategies.

Methods: We employed a modified Delphi study design involving experts across teratology, obstetrics/gynecology, and medication safety. Panelists proposed decision criteria in three focus groups, followed by e-Delphi rounds to reach a consensus on criteria regarding three dimensions: (1) completeness; (2) relevance; and (3) distinctiveness. Aggregated feedback from each round was used to inform revision of the criteria in subsequent rounds.

Results: A total of 33 candidate criteria proposed by 32 focus group participants were organized into ten distinct criteria for the Delphi process. Consensus (defined as > 85% agreement on all three dimensions) was reached after three e-Delphi rounds, resulting in six criteria: (1) background use among persons of reproductive potential; (2) overall medication benefit considering severity of the indication and availability of alternatives; (3) seriousness of the teratogenic outcome; (4) risk of the teratogenic outcome; (5) certainty regarding teratogenicity; and (6) the risk of exposure during pregnancy.

Conclusions: We established measurable criteria to inform decisions when prioritizing teratogenic medications for risk mitigation programs. Criteria are consensus based and consistent with relevant regulatory guidance. Future work will operationalize these criteria and determine specific weights to facilitate medication-specific TRIM scores. Through its explicit framework, the TRIM tool may support consistent, transparent, and rational decision making and help optimize the contribution of risk mitigation programs to public health.

Background: Functional active safety surveillance is essential for post-authorization assessment and life-cycle safety evidence generation of vaccines and medicines. Data collected through active surveillance methods are routinely used for post-approval surveillance of novel vaccines and medicines. Implementing these methods in low- and middle-income countries remains challenging.

Objective: This systematic review identified and assessed existing active safety surveillance in low- and middle-income countries, including key features, strengths, and limitations.

Methods: A search of EMBASE and PubMed Google Scholar databases was conducted. The protocol was registered with PROSPERO and adhered to Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) guidelines. Findings were synthesized narratively and categorized by surveillance systems characteristics.

Results: Of 13,027 records identified, 423 publications met inclusion criteria. Articles spanned 96 low- and middle-income countries, with India (96), China (57), Brazil (30), Iran (26), Ethiopia (21), Indonesia (20), Uganda (18), Kenya (17), and Ghana (16), most represented. The majority focused on vaccines (211). A total of 127 articles utilized mobile technologies for follow-up, online data collection, and/or adverse event reporting. Fifteen percent of vaccine surveillance systems described in articles demonstrated flexibility to incorporate new vaccines, 34% reported multi-sectoral collaborations, and 10% involved multiple countries. Gaps identified include small sample sizes, lack of sustainability, limited flexible surveillance, staffing challenges, and limited use of standard case definitions and digital technologies.

Conclusions: Active safety surveillance in low- and middle-income countries has made progress but still faces challenges. The capture and management of safety data through harmonized digital tools that promote consistency in recording and reporting and cross-country collaborations are crucial in further strengthening active safety surveillance in low- and middle-income countries.

Background: The US Food and Drug Administration (FDA)-mandates Risk Evaluation and Mitigation Strategy (REMS) programs for certain drugs with serious side effects help ensure that the benefits of use outweigh the risks. REMS materials-including enrollment forms, fact sheets, and medication guides-inform patients and caregivers about drug risks and program requirements.

Objective: To explore how effectively REMS materials communicate drug risk information and program requirements to patients and caregivers and to identify patients' and caregivers' preferences for risk communication.

Methods: Interviews with patients and caregivers of patients prescribed REMS-covered drugs focused on REMS materials. Transcripts were coded manually, with answers to closed-ended questions tabulated in Excel.

Results: The study included 43 patients and six caregivers across eight REMS-covered drugs: alemtuzumab, ambrisentan, clozapine, isotretinoin, lenalidomide, pegvaliase, pomalidomide, and sodium oxybate. Most participants were female (N = 42, 86%), white/non-Hispanic (N = 40, 82%), and college educated (N = 37, 76%). The average age was 40 years, with 27 (55%) having annual family incomes over $100,000. Most participants learned about REMS-covered drugs via printed information (N = 36, 73%), mostly REMS materials; conversations with providers about drug risks and benefits (N = 29, 59%); and websites found on their own (N = 42, 86%). Nearly all participants (N = 47, 96%) felt well-informed about drug risks and benefits, and most participants taking self-administered drugs (N = 28, 67%) reported understanding safe use "very well." However, knowledge gaps emerged around REMS-related risks and reasons for safe use measures; some participants misunderstood REMS enrollment forms as legal protections, not safety measures. Patients also widely varied in their valuations of REMS materials, with some feeling informed and empowered and others confused or intimidated. Preferences for risk communication varied; most participants (N = 36, 73%) wanted to receive information verbally from providers, with several wanting visual aids, summaries, and other resources.

Discussion: Gaps in patients' and caregivers' understanding of REMS programs and drug risks highlight the merits of reviewing communication materials and strategies. Clear, concise, and comprehensive educational documents could promote understanding and adherence to REMS requirements.

Background: Sulfonylureas (SU) are widely used for diabetes management in older adults but can cause hypoglycemia, which may be worsened by drug interactions. We applied high-throughput data mining to identify medications that could increase hypoglycemia risk when taken with SU.

Methods: Using Medicare, MarketScan, and Optum Clinformatics (2003-2022), we identified patients aged ≥ 65 years who experienced a severe hypoglycemic event after at least 90 days on SU. We evaluated all medications dispensed in the 90 days before the event using a case-crossover (CCO) design. We adjusted for time-varying confounding and direct effect of the evaluated medications (precipitant) using a case-case time-control (CCTC) approach and metformin as control. We computed odds ratios (ORs) for its association with hypoglycemia. The false discovery rate (FDR) was controlled at 0.05 to adjust for multiple testing. To reduce confounding from other diabetes medications, we analyzed non-diabetes and diabetes medications separately.

Results: Among 1607 candidate drugs received before experiencing hypoglycemia, 86 non-diabetes medications showed a CCO OR ≥ 1.00. With metformin as control, sulfamethoxazole/trimethoprim (CCTC OR 1.76, p < 0.01, FDR q < 0.01) and metronidazole (CCTC OR 2.17, p < 0.01, FDR q = 0.04) were associated with severe hypoglycemia. Among 10 diabetes medications, insulin showed increased association (CCO OR 1.22, p < 0.01); however, once adjusted for the drug's direct effects, CCTC OR was 1.03 (p = 0.47, FDR q = 0.47).

Conclusions: Using a high-throughput data mining approach, we identified two antibiotics (sulfamethoxazole/trimethoprim and metronidazole) that may increase hypoglycemia risk in older adults on sulfonylureas. Given the exploratory nature of this study, these findings warrant further investigation.

Introduction: Sexual side effects of serotonergic drugs are well documented. However, observational evidence comparing specific antidepressants remains sparse.

Objective: The aim of this study was to compare the risk of developing healthcare-recorded sexual dysfunction among male patients after initiating treatment with citalopram, sertraline, venlafaxine, or mirtazapine.

Methods: We conducted a new-user, active comparator cohort study of adult males in Denmark who started treatment with any of the study drugs between 2001 and 2015, allowing multiple cohort entries per person. Data from Danish national healthcare registers included 170,580 new treatment episodes of citalopram, 67,721 of mirtazapine, 51,984 of sertraline, and 19,820 of venlafaxine. A separate analysis examined patients with prior depression-related hospital visits. Results were reported as incidence rates as well as unmatched and propensity score-matched hazard ratios.

Results: In our primary analysis with 1-year follow-up and washout periods, incidence rates ranged from 18.80 (95% CI 17.60-20.00) to 28.5 (95% CI 26.00-31.30) per 1000 person-years. Venlafaxine was associated with the highest risk of healthcare-recorded sexual dysfunction compared with citalopram (hazard ratio [HR] 1.27; 95% CI 1.02-1.46), which was particularly pronounced among those with previous hospital contact for depression (HR 1.93; 95% CI 1.14-1.27). No significant difference was observed for sertraline (HR 0.99; 95% CI 0.90-1.09), while mirtazapine demonstrated modest evidence of a lower risk relative to citalopram (HR 0.87; 95% CI 0.81-0.93). Findings remained consistent across all analyses.

Conclusions: The risk of developing sexual dysfunction varies across antidepressant treatment. Healthcare providers should discuss the potential for sexual side effects, particularly when multiple treatment options are available.

Background: Medicine shortages are an increasing threat to medicine safety and access. In Australia, a 7-month shortage of Coumadin 5-mg tablets (Dec 2022-Jul 2023) prompted Therapeutic Goods Administration (TGA) intervention via the Serious Scarcity Substitution Instrument (SSSI), allowing pharmacists to substitute 5-mg warfarin tablets with lower-strength tablets. Understanding the impact of this shortage on anticoagulant use and safety is essential for informing future regulatory responses.

Aims: The aim of this study was to assess the impact of the 2023 warfarin shortage in Australia on dispensing of warfarin and direct oral anticoagulants (DOACs), International Normalised Ratio (INR) testing, and adverse event reporting.

Methods: Monthly national dispensing data (January 2020-August 2024) were obtained from Pharmaceutical Benefits Scheme (PBS) Date of Supply data. INR pathology data were sourced from Services Australia. The TGA Medicines Shortages Database identified relevant shortage periods. Warfarin-related adverse events were extracted from the TGA Database of Adverse Event Notifications. Interrupted time series assessed changes in dispensing and INR testing trends over time.

Results: Warfarin dispensing declined by 1094 prescriptions per month prior to March 2023 (p < 0.0001). A short-term increase occurred in March 2023 (+ 8625 prescriptions; p = 0.0017) following implementation of the SSSI, although this was not sustained. At the warfarin strength level, dispensing rose for warfarin 1 mg and 2 mg but fell for 5 mg, with subsequent compensatory increases; 3 mg remained stable. DOAC dispensing increased steadily before March 2023 (+ 3771 prescriptions per month; p < 0.0001) but declined thereafter (- 3056 per month; p < 0.0001), most notably for rivaroxaban and dabigatran, while apixaban decreased non-significantly. INR testing briefly increased during the shortage and SSSI. A modest rise in haemorrhage-related adverse events was observed.

Conclusion: Warfarin supply was maintained during the 2023 shortage through strength-based substitution under the SSSI, with limited impact on DOAC dispensing.