The Reporting of a Disproportionality Analysis for Drug Safety Signal Detection Using Individual Case Safety Reports in PharmacoVigilance (READUS-PV): Development and Statement.

BACKGROUND AND AIM: Disproportionality analyses using reports of suspected adverse drug reactions are the most commonly used quantitative methods for detecting safety signals in pharmacovigilance. However, their methods and results are generally poorly reported in published articles and existing guidelines do not capture the specific features of disproportionality analyses. We here describe the development of a guideline (REporting of A Disproportionality analysis for drUg Safety signal detection using individual case safety reports in PharmacoVigilance [READUS-PV]) for reporting the results of disproportionality analyses in articles and abstracts. METHODS: We established a group of 34 international experts from universities, the pharmaceutical industry, and regulatory agencies, with expertise in pharmacovigilance, disproportionality analyses, and assessment of safety signals. We followed a three-step process to develop the checklist: (1) an open-text survey to generate a first list of items; (2) an online Delphi method to select and rephrase the most important items; (3) a final online consensus meeting. RESULTS: Among the panel members, 33 experts responded to round 1 and 30 to round 2 of the Delphi and 25 participated to the consensus meeting. Overall, 60 recommendations for the main body of the manuscript and 13 recommendations for the abstracts were retained by participants after the Delphi method. After merging of some items together and the online consensus meeting, the READUS-PV guidelines comprise a checklist of 32 recommendations, in 14 items, for the reporting of disproportionality analyses in the main body text and four items, comprising 12 recommendations, for abstracts. CONCLUSIONS: The READUS-PV guidelines will support authors, editors, peer-reviewers, and users of disproportionality analyses using individual case safety report databases. Adopting these guidelines will lead to more transparent, comprehensive, and accurate reporting and interpretation of disproportionality analyses, facilitating the integration with other sources of evidence.

The REporting of A Disproportionality Analysis for DrUg Safety Signal Detection Using Individual Case Safety Reports in PharmacoVigilance (READUS-PV): Explanation and Elaboration.

In pharmacovigilance, disproportionality analyses based on individual case safety reports are widely used to detect safety signals. Unfortunately, publishing disproportionality analyses lacks specific guidelines, often leading to incomplete and ambiguous reporting, and carries the risk of incorrect conclusions when data are not placed in the correct context. The REporting of A Disproportionality analysis for drUg Safety signal detection using individual case safety reports in PharmacoVigilance (READUS-PV) statement was developed to address this issue by promoting transparent and comprehensive reporting of disproportionality studies. While the statement paper explains in greater detail the procedure followed to develop these guidelines, with this explanation paper we present the 14 items retained for READUS-PV guidelines, together with an in-depth explanation of their rationale and bullet points to illustrate their practical implementation. Our primary objective is to foster the adoption of the READUS-PV guidelines among authors, editors, peer reviewers, and readers of disproportionality analyses. Enhancing transparency, completeness, and accuracy of reporting, as well as proper interpretation of their results, READUS-PV guidelines will ultimately facilitate evidence-based decision making in pharmacovigilance.

Resective epilepsy surgery and its impact on depression in adults: a systematic review, meta-analysis, and implications for future research.

BACKGROUND: How epilepsy surgery influences the bidirectional relationship of epilepsy and depression remains poorly defined. METHOD: For a better understanding of this question, we conducted a systematic review and meta-analysis of risk ratio on depression prevalence before and after epilepsy surgery, using Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines. Three databases were comprehensively screened for all studies assessing depression before and after resective surgery in adult epileptic patients until 8 October 2022. Studies were included if depression was assessed before and after epilepsy surgery regardless of the time of follow-up. A total of 1917 studies were screened for eligibility and 91 full-texts up for inclusion; 35 studies were finally included, 25 studies and 2563 patients were included in main meta-analysis and 10 for exploratory analysis. Risk of bias was assessed using Risk Of Bias In Non-randomised Studies - of Interventions (ROBINS-I) from Cochrane. To derive the pooled depression rates before and after surgery, a meta-analysis with inversed-variance was performed using random-effects logistic models with Peto's correction and a 95% CI. Heterogeneity was assessed with Cochran's Q-test along with its derived measure of inconsistency I2. RESULTS: Overall, the depression rates before and after resective epilepsy surgery were 0.70 (0.53 to 0.91) 95% CI, suggesting that the rate of depression at last follow-up evaluation tends to decrease after Resective Epilepsy Surgery (RES). Subgroup analysis suggest a positive long-term effect appears with a significant lower rates of depression already 6 months (0.61 (0.38 to 0.98)), after surgery which is maintained over time after 1 year (0.53 (0.31 to 0.90)), and after 2 years (0.62 (0.42 to 0.92)). CONCLUSION: This important finding should be taken in consideration before resective surgery for drug-resistant epilepsies. However, prospective studies should be conducted to characterise which patient, at the individual level, might be at risk of de novo or worsening of depression. PROSPERO REGISTRATION NUMBER: CRD42022355386.

Safety of Dual Orexin Receptor Antagonist Daridorexant: A Disproportionality Analysis of Publicly Available FAERS Data.

Daridorexant (dari), as the first dual orexin receptor antagonist (DORA) marketed in Europe, offers a novel therapeutic approach to insomnia. However, data regarding its real-world safety are scarce. Thus, this study was aimed at assessing its safety profile using a large-scale pharmacovigilance database. Dari-related adverse drug reaction (ADR) reports from the Food and Drug Administration Adverse Event Reporting System were scrutinized, and ADRs were selected using reporting odds ratio (ROR) as a measure of disproportionality. Frequencies of events related to dari were compared to all other drugs (reference group, RG1) and only to other DORAs (RG2). Only significant disproportionalities to both RGs were evaluated in-depth. A total of 845 dari-related reports were selected; nightmares (n = 146; dari vs. RG1: ROR = 113.74; 95%CI [95.13, 136]; dari vs. RG2: ROR = 2.35; 95 CI% [1.93, 2.85]), depression (n = 22; dari vs. RG1: 2.13; [1.39, 3.25]; dari vs. RG2: ROR = 2.31; 95 CI% [1.45, 3.67]), and hangover (n = 20; dari vs. RG1: ROR = 127.92; 95 CI% [81.98, 199.62]; and dari vs. RG2: 3.38; [2.04, 5.61]) were considered as safety signals. These data provide valuable insights into the real-world safety profile of daridorexant, supporting the existence of safety signals related to nightmares, depression, and hangovers.

Invasive fungal infection incidence and risk factors in patients receiving ibrutinib in real-life settings: A nationwide population-based cohort study.

BACKGROUND: Data on the risk of invasive fungal infections (IFI) with ibrutinib treatment are scarce. OBJECTIVES: This study aimed to determine IFI incidence and risk factors in ibrutinib-treated patients in real-life settings. METHODS: We constituted a cohort of ibrutinib incident users in the French National Healthcare Database. All patients ≥18 years with a first dispensing of ibrutinib between 21 November 2014 and 31 December 2019 were included. Patients were followed from the cohort entry date until IFI, ibrutinib discontinuation, death, or 31 December 2020, whichever came first. The cumulative incidence function method was used to estimate the probability of IFI accounting for competing risk of death. A multivariate cause-specific Cox proportional hazards model was used to assess independent IFI risk factors. RESULTS: Among 6937 ibrutinib-treated patients, 1-year IFI cumulative incidence was 1.3%, with invasive aspergillosis being the most frequent. Allogenic or autologous stem cell transplantation (ASCT) (hazard ratio [HR] 3.59, 95% confidence interval [1.74; 7.41]), previous anticancer treatment (HR 2.12, CI 95% [1.34; 3.35]) and chronic respiratory disease (HR 1.66, [1.03; 2.67]) were associated with higher risk of IFI. Besides neutropenia and corticosteroids, use of anti-CD20 agents was significantly more frequent in patients having experienced IFI (HR 3.68, [1.82; 7.45]). CONCLUSIONS: In addition to patients with ASCT history, severe neutropenia or treated with corticosteroids, our findings support active surveillance of IFIs in those with chronic respiratory disease, previously treated, or treated with anti-CD20 agents in combination with ibrutinib. Further studies are needed to optimise IFI prophylaxis in these patient subgroups.

Analgesic switching in chronic users of dextropropoxyphene in France.

BACKGROUND: The combination dextropropoxyphene/paracetamol (DXP/P) was the most prescribed opioid analgesic until its withdrawal in 2011. OBJECTIVES: This study investigated dispensations of analgesics in chronic users of DXP/P during the 18 months following its withdrawal. METHODS: A cross-sectional study repeated yearly was conducted by using the French reimbursement database from 2006 to 2015. Chronic DXP/P users were defined as patients who received at least 40 boxes of DXP/P in the year prior to withdrawal. Data on analgesic dispensing were analyzed at DXP/P withdrawal (T0) and then every 6 months for 18 months. RESULTS: A total of 63 671 subjects had a DXP/P reimbursement in the year prior to its discontinuation, of whom 7.1% were identified as chronic users (mean age: 71.5 years, women: 68.7%). Among the patients taking DXP/P alone at T0 (74.6%), one fourth switched to a peripheral analgesic, one fourth to a combination of peripheral analgesic/opioid, one fourth to another opioid, and the others mainly discontinued their treatment (14.1%) or died. During the following 12 months, most of the subjects taking only peripheral analgesics continued this treatment, while half of the subjects with a combination of opioid/peripheral analgesic or taking only an analgesic remained on this type of treatment. CONCLUSION: Eighteen months after DXP/P withdrawal, more than 10% of patients stopped taking an analgesic. Vigilance is required regarding any change in analgesics by regularly reassessing patients' pain and, in the case of opioid treatments, by monitoring the risk of use disorders.

Impact of Covid-19 Vaccination on Spontaneous Pharmacovigilance Reporting in France.

INTRODUCTION: In 2021, the massive Covid-19 vaccination campaign in France was accompanied by an intensified pharmacovigilance monitoring of their potential adverse drug reactions. The importance of this reporting might have led to an important selective reporting and overloading of Pharmacovigilance Centres, delaying the recording of some reports in the national pharmacovigilance database. In this context, we aimed to evaluate the impact of the Covid-19 vaccination campaign in France and related reports on spontaneous reporting of adverse drug reactions that were not related to the Covid-19 vaccine. METHODS: We performed time-series analyses considering the monthly number of adverse drug reactions reported between January 1, 2018 and April 30, 2022 using the French Pharmacovigilance database. The impact of the Covid-19 vaccination campaign on the monthly reporting not Covid-19 vaccine related was estimated using interrupted time-series. January 2021, marking the start of the campaign, was the intervention date in the models. Analyses were run globally first considering all adverse drug reaction reports, and second according to notifier type and to case seriousness. RESULTS: We included 170,294 reports registered in the French Pharmacovigilance database between January 1, 2018 and April 30, 2022 that were not Covid-19 vaccine-related. Among these, 77,067 (45.3%) were serious and 146,683 (86.1%) had been reported by health care professionals. The campaign start was associated with a nearly 35.0% decrease in average monthly reporting that was not Covid-19 vaccine-related, with a significant level decrease in the monthly number of reports of -658.0 (p < 10-3) immediately after the vaccination campaign start and a subsequent slope decrease of -50.0 (p < 10-3). This decrease was mainly due to a significant level and slope decrease (level: -739.2 p < 10-3; slope: -39 [p < 10-2]) for health care professional reports. A similar level decrease was found for the monthly number of both serious and non-serious reports (-402.3, p < 10-3; and -311.9, p = 10-2, respectively). According to the ATC 1 level, the decrease in the monthly number of reports showed similar patterns for all drugs. However, a potential increase in the number of serious reports suspecting antineoplastic and immunomodulating drugs (ATC L) or drugs targeting blood was observed (ATC B). CONCLUSION: Our study showed a significant impact of the Covid-19 campaign vaccination in the reporting of adverse drug reactions that were not Covid-19 vaccine-related, of roughly 35%. This leads to a loss of information regarding the monitoring of drug safety that could have impacted the system capacity to detect safety signals for drugs other than Covid-19 vaccines.

Pharmacological Evaluation of Signals of Disproportionality Reporting Related to Adverse Reactions to Antiepileptic Cannabidiol in VigiBase.

Cannabidiol is the first cannabis-derived drug approved for the treatment of Lennox-Gastaut syndrome, Dravet syndrome, and Tuberous Sclerosis Complex. In the current study, we performed a descriptive analysis followed by a disproportionality analysis of potential adverse events caused by CBD extracted from the VigiBase® database. Furthermore, the biological plausibility of the association between CBD and the serotonin 5-HT1A receptor as a possible cause of adverse events was analyzed and discussed. Data were extracted from the VigiBase® database using the VigiLyze® signal detection and signal management tool. Adverse events in VigiBase® reports were coded using MedDRA, version 19 of Preferred Terms (PTs). Data were uploaded into SPSS software and analyzed via a disproportionality analysis. Statistically significant disproportionality signals for CBD were found for "weight decreased" (5.19 (95% CI: 4.54-5.70)), "hypophagia" (3.68 (95% CI: 3.22-5.27)), and "insomnia" (1.6 (95% CI: 1.40-1.83)). Positive IC025 values were found for "weight decreased" (2.2), "hypophagia" (1.3), and "insomnia" (0.5), indicating a surplus of reported cases. CBD's interactions with 5-HT1A serotonin receptors may offer a potential biological explanation for the occurrence of insomnia in patients. It is noteworthy that the risk profiles mentioned in the information for prescribing CBD as an antiepileptic agent by regulatory agencies showed disparities specifically related to the adverse event "insomnia".

Impact of Cardiovascular Comorbidities on the Effectiveness and Safety of Bevacizumab in Older Patients with Metastatic Colorectal Cancer.

BACKGROUND: Cardiovascular comorbidities are not contraindications of bevacizumab for metastatic colorectal cancer. OBJECTIVE: We aimed to evaluate the impact of cardiovascular comorbidities before bevacizumab treatment on overall survival and cardiovascular safety in older patients with metastatic colorectal cancer. METHODS: A 2009-2015 cohort of patients with metastatic colorectal cancer aged ≥ 65 years administered first-line bevacizumab was extracted from the French healthcare reimbursement claims database. Baseline heart failure, hypertension, and venous/arterial thromboembolic events were identified. The 36-month overall survival rate was evaluated using the Kaplan-Meier method, and the impact of cardiovascular comorbidities on the 36-month overall survival using a time-dependent, multivariable, Cox proportional hazards model. The 36-month cumulative incidence of cardiovascular events, and the impact of cardiovascular comorbidities on the likelihood of cardiovascular events were evaluated using the Fine and Gray model, with death as a competing risk. RESULTS: We included 9222 patients (56.4% male; median age 73 years). Two-thirds (66.7%) had baseline cardiovascular comorbidities. The median 36-month overall survival was 20.4 [95% confidence interval (CI) 19.9-21.0] and 21.8 [95% CI 21.1-22.6] months in patients with and without cardiovascular comorbidities, respectively. Age ≥ 75 years, dependency in activities of daily living, radiotherapy, and another targeted therapy were identified as death risk factors, but not cardiovascular comorbidities. At 36 months, cardiovascular events had occurred in 60.2% [95% CI 58.9-61.4] and 44.1% [95% CI 42.3-45.9] of patients with and without cardiovascular comorbidities. Baseline venous thrombosis, female, three or more cardiovascular medications, another targeted therapy, and more than six bevacizumab injections were identified as risk factors for cardiovascular events. CONCLUSIONS: In clinical practice, cardiovascular comorbidities before administering bevacizumab to older patients with metastatic colorectal cancer impacted the cardiovascular safety, but not overall survival. Unless they limit functional independency, older patients with cardiovascular comorbidities should be treated with bevacizumab under close monitoring.

Will the future of pharmacovigilance be more automated?

INTRODUCTION: Artificial intelligence (AI) based tools offer new opportunities for pharmacovigilance (PV) activities. Nevertheless, their contribution to PV needs to be tailored to preserve and strengthen medical and pharmacological expertise in drug safety. AREAS COVERED: This work aims to describe PV tasks in which the contribution of AI and intelligent automation (IA) tools is required, in the context of a continuous increase of spontaneous reporting cases and regulatory tasks. A narrative review with expert selection of pertinent references was performed through Medline. Two areas were covered, management of spontaneous reporting cases and signal detection. PERSPECTIVE: The use of AI and IA tools will assist a large spectrum of PV activities, both in public and private PV systems, in particular for tasks of low added value (e.g. initial quality check, verification of essential regulatory information, search for duplicates). Testing, validating, and integrating these tools in the PV routine are the actual challenges for modern PV systems, to guarantee high-quality standards in terms of case management and signal detection.

Bleeding risk with concurrent use of anticoagulants and ibrutinib: A population-based nested case-control study.

Data regarding the safety of co-administration of ibrutinib with anticoagulants in real-life settings are scarce. Using a nationwide database, we conducted a nested case-control study in a cohort of new users of ibrutinib to assess the risk of clinically relevant bleeding (CRB) associated with anticoagulation. Cases were patients with a diagnosis of CRB, defined as hospitalization with a diagnosis of bleeding. The date of CRB constituted the index date. Up to four controls were matched on sex, age at index date and duration of follow-up. The risk of CRB associated with anticoagulation in patients receiving ibrutinib was estimated using conditional logistic regression models, providing odds ratios (OR) adjusted for risk factors of bleeding. Among 614 cases and 2407 matched controls, the risk of CRB was significantly higher in patients receiving both ibrutinib and anticoagulants (adjusted OR [aOR] 2.54, confidence interval [CI] 95% [1.94; 3.32]). When considering anticoagulant class, aOR was 1.99 (CI 95% [1.19; 3.33]) for VKA, 2.48 (CI 95% [1.76; 3.47]) for direct oral anticoagulants and 3.40 (CI 95% [2.01; 5.75]) for parenteral anticoagulants. In conclusion, this study found a 2.5-fold increased risk of CRB in patients receiving both ibrutinib and anticoagulants in real-life settings, and similar aOR among oral anticoagulants.

Mapping Strategies to Assess and Increase the Validity of Published Disproportionality Signals: A Meta-Research Study.

BACKGROUND AND AIM: Disproportionality analysis is traditionally used in spontaneous reporting systems to generate working hypotheses about potential adverse drug reactions: the so-called disproportionality signals. We aim to map the methods used by researchers to assess and increase the validity of their published disproportionality signals. METHODS: From a systematic literature search of published disproportionality analyses up until 1 January 2020, we randomly selected and analyzed 100 studies. We considered five domains: (1) rationale for the study, (2) design of disproportionality analyses, (3) case-by-case assessment, (4) use of complementary data sources, and (5) contextualization of the results within existing evidence. RESULTS: Among the articles, multiple strategies were adopted to assess and enhance the results validity. The rationale, in 95 articles, was explicitly referred to the accrued evidence, mostly observational data (n = 46) and regulatory documents (n = 45). A statistical adjustment was performed in 34 studies, and specific strategies to correct for biases were implemented in 33 studies. A case-by-case assessment was complementarily performed in 35 studies, most often by investigating temporal plausibility (n = 26). Complementary data sources were used in 25 articles. In 78 articles, results were contextualized using accrued evidence from the literature and regulatory documents, the most important sources being observational (n = 45), other disproportionalities (n = 37), and case reports (n = 36). CONCLUSIONS: This meta-research study highlighted the heterogeneity in methods and strategies used by researchers to assess the validity of disproportionality signals. Mapping these strategies is a first step towards testing their utility in different scenarios and developing guidelines for designing future disproportionality analysis.

Safety of antituberculosis agents used for multidrug-resistant tuberculosis among patients attending the Jamot Hospital of Yaounde, Cameroon.

Background: Recognized in 1994 as a global emergency by the World Health Organization, tuberculosis (TB) remains an ongoing health threat. In Cameroon, the mortality rate is estimated at 2.9%. Treatment of multidrug-resistant TB (MDR-TB) defined as the resistance to the two most effective antiTB drugs, and requires therapy of more than 7 drugs taken on a daily basis during 9-12 months. This study aimed to evaluate the safety profile of treatment regimens used for MDR-TB at Jamot Hospital of Yaounde (JHY). Methods: This was a retrospective cohort study of patients treated for MDR-TB at HJY from January 1, 2017, to December 31, 2019. Patients characteristics of the cohort, drugs regimen were collected and described. All possible adverse drug reactions (ADR) were described clinically and by severity grade. Results: During the study period, 107 patients were included, and 96 (89.7%) experienced at least one ADR. Most parts of the patients (90) experienced mild or moderate ADR. Hearing loss was the most frequent ADR, and led mostly in aminoglycosides dose reduction (n = 30, 96.7%). Gastrointestinal events were commonly observed during the study period. Conclusion: Our findings suggested that ototoxicity was a prominent safety issue during the study period. The implementation of the new short treatment regimen could be effective in reducing the burden of ototoxicity among MDR-TB patients. Nevertheless, new safety issues could emerge.

Safety Profile of Medicines Used for the Treatment of Drug-Resistant Tuberculosis: A Descriptive Study Based on the WHO Database (VigiBase®).

BACKGROUND: The introduction of new drugs that increase the usage of repurposed medicines for managing drug-resistant tuberculosis (DR-TB) comes with challenges of understanding, properly managing, and predicting adverse drug reactions (ADRs). In addition to the health consequences of ADRs for the individual, ADRs can reduce treatment adherence, thus contributing to resistance. This study aimed to describe the magnitude and characteristics of DR-TB-related ADRs through an analysis of ADRs reported to the WHO database (VigiBase) in the period from January 2018 to December 2020. METHODS: A descriptive analysis was performed on selected reports from VigiBase on the basis of medicine-potential ADR pairs. The ADRs were stratified by sex, age group, reporting country, seriousness, outcome of the reaction, and dechallenge and rechallenge. RESULTS: In total, 25 medicines reported to be suspected individual medicines or as a fixed-dose combination in the study period were included the study. Pyrazinamide (n = 836; 11.2%) was the most commonly reported medicine associated with ADRs, followed by ethionamide (n = 783; 10.5%) and cycloserine (n = 696; 9.3%). From the report included in this analysis, 2334 (31.2%) required complete withdrawal of the suspected medicine(s), followed by reduction of the dose (77; 1.0%) and an increased dose (4; 0.1%). Almost half of the reports were serious ADRs mainly caused by bedaquiline, delamanid, clofazimine, linezolid, and cycloserine that are the backbone of the DR-TB treatment currently in use. CONCLUSIONS: A third of the reports required medication withdrawal, which impacts treatment adherence and ultimately leads to drug resistance. Additionally, more than 40% of the reports indicated that ADRs appeared two months after the commencement of treatment, thus it's important to remain alert for the potential ADRs for the entire duration of the treatment.

Pharmacovigilance signals from active surveillance of mRNA platform vaccines (tozinameran and elasomeran).

INTRODUCTION: Two severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) messenger RNA (mRNA) vaccines, tozinameran/BNT162b2 (Comirnaty®, Pfizer-BioNTech) and elasomeran/mRNA-1273 (Spikevax®, Moderna), were approved by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) at the end of 2020, less than a year after the start of the coronavirus disease 2019 (COVID-19) pandemic. In France, the health authorities have requested an intensive vaccination campaign, accompanied by a reinforced and active pharmacovigilance surveillance. This surveillance and analysis of real-life data, based on spontaneous reports received by the French Network of Regional PharmacoVigilance Centers (RFCRPV), has enabled to identify numerous pharmacovigilance signals. Some of them, such as myocarditis and heavy menstrual bleeding, have been confirmed as adverse effects of these vaccines. METHOD: We propose a descriptive review of the main pharmacovigilance signals identified by the RFCRPV concerning vaccines from the mRNA platform. RESULTS: Most pharmacovigilance signals were common to both mRNA vaccines: myocarditis, menstrual disorders, acquired haemophilia, Parsonage-Turner syndrome, rhizomelic pseudo-polyarthritis and hearing disorders. Other signals were more specific, such as arterial hypertension with tozinameran or delayed reaction site injection with elasomeran. CONCLUSION: This non-exhaustive review illustrates the experience of RFCRPV in identifying and monitoring pharmacovigilance signals related to mRNA vaccines in France during the COVID-19 pandemics, and the crucial role of pharmacological and clinical expertise in this area. It also highlights the predominant contribution of spontaneous reporting in the generation of pharmacovigilance signals, particularly for serious and rare adverse events not detected before marketing.