Post-marketing Safety Research Articles

Healthcare Professionals’ Attitudes towards Adverse Drug Reactions Reporting in Primary Healthcare Settings: A Cross-sectional Survey

Background: Spontaneous Adverse Drug Reactions (ADRs) reporting is a key to improving the post-marketing safety of medicines. The important factor of under-reporting is lack of awareness for the purpose of ADRs monitoring and reporting. Spontaneous reporting is performed by the patients or consumer to the healthcare professionals and/or industry, then the healthcare facilities and industry should report the suspected ADRs to the National Agency of Drugs and Food Control (NADFC). To date, there is a lack information and study about attitudes on ADRs reporting by healthcare professionals (HCPs), especially in primary healthcare settings.Objectives: The aim of this study was to identify the attitudes towards ADRs reporting by healthcare professionals (HCP).Methods: This research was survey study with cross-sectional design, from November 2022-March 2023. The questionnaire, that have been validated and reliable, was distributed to 3 primary healthcare facilities. demographic data questions (6 items), experiences (3 items), knowledge (4 items), and motives for reporting (1 item).Results: Total 39 HCPs completed the survey, including 14 nurses, 9 midwifes, 3 general physicians, 3 pharmacists, and 10 other professions. Most of respondents were women (84.6%), and mostly the HCPs have been working for ≥5 years (74.3%). Among 39 respondents, only 1 pharmacist have a good attitude about ADRs reporting. The other HCPs had a lack of knowledge and safety awareness. The dominant motives for reporting the ADRs was serious or severe ADRs (39.4%) and the assurance of causality assessment by suspected drugs (15.4%).Conclusion: In conclusion, the HCPs in primary healthcare settings had poor attitudes towards ADRs reporting.

Artificial intelligence for optimizing benefits and minimizing risks of pharmacological therapies: challenges and opportunities

In recent years, there has been an exponential increase in the generation and accessibility of electronic healthcare data, often referred to as “real-world data”. The landscape of data sources has significantly expanded to encompass traditional databases and newer sources such as the social media, wearables, and mobile devices. Advances in information technology, along with the growth in computational power and the evolution of analytical methods relying on bioinformatic tools and/or artificial intelligence techniques, have enhanced the potential for utilizing this data to generate real-world evidence and improve clinical practice. Indeed, these innovative analytical approaches enable the screening and analysis of large amounts of data to rapidly generate evidence. As such numerous practical uses of artificial intelligence in medicine have been successfully investigated for image processing, disease diagnosis and prediction, as well as the management of pharmacological treatments, thus highlighting the need to educate health professionals on these emerging approaches. This narrative review provides an overview of the foremost opportunities and challenges presented by artificial intelligence in pharmacology, and specifically concerning the drug post-marketing safety evaluation.

Post-marketing safety evaluation of lurbinectedin: a pharmacovigilance analysis based on the FAERS database.

Background: On 15 June 2020, the United States Food and Drug Administration (FDA) approved lurbinectedin for treating adult patients with metastatic small-cell lung cancer whose disease has progressed despite prior platinum-based chemotherapy. Following its market approval, safety data on lurbinectedin in large populations is currently lacking. Therefore, this study aims to evaluate adverse events (AEs) associated with lurbinectedin using the FDA's Adverse Event Reporting System (FAERS)database. Methods: Data concerning lurbinectedin from the FAERS database were extracted for the period from June 2020 to September 2023. Four disproportionality analysis algorithms were utilized to assess potential AEs linked to lurbinectedin: reporting odds ratio (ROR), proportional reporting ratio, disproportionate multi-item gamma Poisson shrinker, and Bayesian confidence propagation neural network. These algorithms were applied to quantify signals of lurbinectedin-related AEs. Result: A total of 5,801,535 AE reports were retrieved from the FAERS database, with 511 related to lurbinectedin. These lurbinectedin-induced AEs were observed in 23 system organ classes (SOCs). After simultaneously applying the four algorithms, 47 lurbinectedin-induced AE signals were detected in 23 SOCs. At the SOC level, blood and lymphatic system disorders (ROR, 6.70; 95% confidence interval [CI]: 5.47-8.22) were the only SOC that met all four algorithms. Lurbinectedin's most frequent adverse event was death (ROR: 6.11%, 95% CI: 4.86-7.68), while extravasation exhibited the strongest signal intensity in the ROR algorithm (ROR: 326.37%, 95% CI: 191.66-555.75). Notably, we identified a novel signals: tumor lysis syndrome (ROR: 63.22%, 95% CI: 33.87-117.99). The mean time of onset of AEs was 66 days, the median time of onset was 25days (interquartile range: 8-64days), and most AEs occurred within the first month of lurbinectedin treatment. Conclusion: Our study provided a comprehensive evaluation of lurbinectedin's safety profile in the post-marketing setting. In addition to the adverse events consistent with the existing clinical trials and labeling information, we have also identified an unreported signal related to tumor lysis syndrome. This finding will better guide the clinical practice of lurbinectedin and provide valuable evidence for future research.

Adverse Reactions to Evolocumab: Analysis of Real-World Data from EudraVigilance.

Evolocumab is a humanized immunoglobulin G2 monoclonal antibody, directed against Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9), prescribed in hypercholesterolemic patients. The safety profile of this drug is currently defined by the data of pre-authorization clinical trials. The purpose of this study is to update knowledge of the safety of evolocumab through an analysis of post-marketing real-world data on suspected adverse reactions (SARs), reported by the EudraVigilance database system. The public version of the EudraVigilance database has been used, and only serious SARs signals were included. Musculoskeletal system disorders, flu-like symptoms, injection-site reactions, skin reactions, and metabolism and nutrition disorders are observed in the post-marketing surveillance, as well as being found in the pre-authorization studies. Not previously signaled in the pre-marketing studies, diarrhea was reported. Furthermore, signals related to cardiac adverse reactions, more frequently at the expense of adults in comparison to elders, were found. The post-marketing safety profile of evolocumab emerging from an analysis of the EudraVigilance data system indicates it is sufficiently safe but suggests the necessity for caution when it is prescribed to hyperlipidemic patients affected by heart diseases.

Exploring Esketamine's Therapeutic Outcomes as an FDA-Designated Breakthrough for Treatment-Resistant Depression and Major Depressive Disorder With Suicidal Intent: A Narrative Review.

The expansive spectrum of major depressive disorder (MDD) continues to pose challenges for psychiatrists to treat effectively. Oral antidepressant (OAD) medications that alter monoamine neurotransmitters,mainly selective serotonin reuptake inhibitors (SSRIs) and selective norepinephrine reuptake inhibitors (SNRIs), have been the mainstay of therapy for decades. Although these drugs have been largely beneficial, a considerable subset of patients do not respond adequately to multiple conventional therapies administered for an appropriate length of time, leading to a diagnosis of treatment-resistant depression (TRD). Ketamine, a non-monoaminergic drug, has long been known for its beneficial effects on TRD when given intravenously (IV). Between 2019 and 2020, an intranasal formulation of the S (+) enantiomer of racemic ketamine, esketamine (ESK), was granted "breakthrough designation" by the FDA and approved for the indicationsof TRD and MDD patients exhibiting acute suicidal intent. The objective of this narrative review was to review the academic literature and collect clinical evidence that may corroborate intranasal ESK's effectiveness for its approved indications while addressing its safety and tolerability profile, adverse effects, andimpact on cognition. An overview ofthe drug'sorigins,pharmacology, and standard treatment regimen are provided. Theoutcomes from double-blinded randomized control trials (DB-RCTs) of ESK are outlinedto demonstrate the efficacy and safety data leading to its FDA approval, along with its long-term post-market safety outcomes. Comparative trials between ESK and ketamine are then evaluated to highlight ESK's consideration as a more practical alternative toketamine in common clinical practice. The authors further discuss currently approved and developing therapies for TRD,propose future research directions, and identify the inherent limitations of the review and further research. To conduct the research required, three digital databases (PubMed, Medline, and ClinicalTrials.gov) were queried to search for key terms, includingketamine, esketamine, treatment-resistant depression, and biomarkers,using automation toolsalong with selective search engine results.After streamlining the results by title and abstract and removing duplicates, a total of 37 results were chosen, of which 18 are clinical trials. A reduction in the Montgomery-Asberg Depression Rating Scale (MADRS) score was the primary efficacy endpoint for most of these clinical trials. In conclusion, intranasal ESK, when used as an adjunct to market OADs, shows greater efficacy in treating TRD and MDD with suicidal intent compared to OADs and placebo alone and provides a more suitable alternative to IV ketamine. It is important to note that further research is required to fully understand the novel mechanism of action of ESK, as well as the establishment of a consensus definition of TRD, which may facilitate better detection and treatment protocols. More focused quantitative and qualitative ESK studies are needed, as well as those pertaining to its use in patients with co-existing mental illnesses.

Safety and Effectiveness of Dulaglutide in the Treatment of Type 2 Diabetes Mellitus: A Korean Real-World Post-Marketing Study.

To investigate the real-world safety and effectiveness of dulaglutide in Korean adults with type 2 diabetes mellitus (T2DM). This was a real-world, prospective, non-interventional post-marketing safety study conducted from May 26, 2015 to May 25, 2021 at 85 Korean healthcare centers using electronic case data. Data on patients using dulaglutide 0.75 mg/0.5 mL or the dulaglutide 1.5 mg/0.5 mL single-use pens were collected and pooled. The primary objective was to report the frequency and proportion of adverse and serious adverse events that occurred. The secondary objective was to monitor the effectiveness of dulaglutide at 12 and 24 weeks by evaluating changes in glycosylated hemoglobin (HbA1c ), fasting plasma glucose, and body weight. Data were collected from 3,067 subjects, and 3,022 subjects who received ≥1 dose (of any strength) of dulaglutide were included in the safety analysis set (53% female, mean age 56 years; diabetes duration 11.2 years, mean HbA1c 8.8%). The number of adverse events reported was 819; of these, 68 (8.3%) were serious adverse events. One death was reported. Adverse events were mostly mild in severity; 60.81% of adverse events were considered related to dulaglutide. This study was completed by 72.73% (2,198/3,022) of subjects. At 12/24 weeks there were significant (P<0.0001) reductions from baseline in least-squares mean HbA1c (0.96%/0.95%), fasting blood glucose (26.24/24.43 mg/dL), and body weight (0.75/1.21 kg). Dulaglutide was generally well tolerated and effective in real-world Korean individuals with T2DM. The results from this study contribute to the body of evidence for dulaglutide use in this population.

Post-marketing safety surveillance study of a 9-valent human papillomavirus vaccine: Comment

Post-marketing safety surveillance study of a 9-valent human papillomavirus vaccine: Comment

Factors associated with disease control failure in acromegaly patients treated with pegvisomant: an ACROSTUDY analysis.

The aim of this study was to examine the probability of achieving acromegaly disease control according to several patient-, disease- and treatment-related factors longitudinally. We analyzed data from ACROSTUDY, an open-label, noninterventional, post-marketing safety surveillance study conducted in 15 countries. A total of 1546 patients with acromegaly and treated with pegvisomant, with available information on baseline IGF-1 level, were included. Factors influencing IGF-1 control were assessed up to 10 years of follow-up by mixed-effects logistic regression models, taking into account changing values of covariates at baseline and at yearly visits. Twenty-eight anthropometric, clinical and treatment-related covariates were examined through univariate and multivariate analyses. We tested whether the probability of non-control was different than 0.50 (50%) by computing effect sizes (ES) and the corresponding 95% CI. Univariate analysis showed that age <40 years, normal or overweight, baseline IGF-1 <300 µg/L or ranged between 300 and 500 µg/L, and all pegvisomant dose <20 mg/day were associated with a lower probability of acromegaly uncontrol. Consistently, in multivariate analyses, the probability of uncontrolled acromegaly was influenced by baseline IGF-1 value: patients with IGF-1 <300 µg/L had the lowest risk of un-controlled acromegaly (ES = 0.29, 95% CI: 0.23-0.36). The probability of acromegaly uncontrol was also lower for values 300-500 µg/L (ES = 0.37, 95% CI: 0.32-0.43), while it was higher for baseline IGF-1 values ≥700 µg/L (ES = 0.58, 95% CI: 0.53-0.64). Baseline IGF-l levels were a good predictor factor for long-term acromegaly control. On the contrary, our data did not support a role of age, sex, BMI and pegvisomant dose as predictors of long-term control of acromegaly. Among factors that could influence and predict the efficacy of pegvisomant therapy in controlling acromegaly, a central role of baseline IGF-1 values on the probability of achieving a biochemical control of acromegaly during the treatment with pegvisomant was identified, in a real-life setting.

Deoxycholic Acid for Submental Convexity: A MAUDE Database Analysis

Study Design The study was a retrospective cross-sectional database analysis. Objective Deoxycholic acid (DOC) injections are a novel, in-office procedural alternative to submental liposuction or submentoplasty to address excess submental fat. Post-market safety data regarding this treatment is currently limited. The objective of this study is to analyze adverse events reported in the Manufacturer and User Facility Device Experience (MAUDE) database. Methods The MAUDE database was queried for all reports related to adverse events involving deoxycholic acid using the search terms “KYBELLA” and “deoxycholic acid.” Reports were individually reviewed by 2 reviewers and categorized with special attention to adverse events. Results A total of 34 medical device reports were identified from the database query. Thirteen of these reports (21 total events) were included in the analysis after excluding duplicates, unrelated adverse events, or events associated with the off-label use of DOC. Reported adverse events include excessive swelling (n = 5, 24%), marginal mandibular nerve weakness (n = 4, 19%), unsatisfactory aesthetic outcome (n = 4, 19%), numbness (n = 3, 14%), dysphagia (n = 1, 5%), infection (n = 1, 5%), and skin necrosis (n = 3, 14%). Two patients required hospitalization for skin necrosis management; both had underlying systemic diseases. Conclusions Adverse events following DOC injections included excessive swelling, dysphagia, numbness, infection, unsatisfactory aesthetic outcome, facial nerve weakness, and skin necrosis requiring hospitalization and/or surgery. Patient counseling regarding these adverse events should be discussed when offering DOC injections for submental convexity.

Is pitolisant safe for clinical use? A retrospective pharmacovigilance study focus on the post-marketing safety.

Pitolisant, a novel histamine H3-receptor antagonist, holds significant promise for treating narcolepsy. However, a petition, which highlighted that pitolisant was associated with deaths during clinical trials, has propelled it into the spotlight of widespread societal attention on April 3, 2023. Till now, the clinical safety of pitolisant remains a heatedly debated topic. This study aimed to offer a comprehensive assessment of the safety profile of pitolisant in real-world clinical settings. Adverse event reports where pitolisant was the primary suspect drug were extracted from the FDA Adverse Event Reporting System database. The clinical characteristics and concomitant drugs of the pitolisant-associated adverse events were analyzed. The potential adverse event signals of pitolisant were explored using four disproportionality analysis methods. Furthermore, the difference in pitolisant-associated adverse event signals was investigated concerning sex, age, weight, and dose. A total of 526 reports and 1695 adverse events with pitolisant as the primary suspected drug were identified. The most significant adverse event signals were generally mild and of short duration. The concomitant drugs of pitolisant were highly intricate, mainly included drugs for treating narcolepsy as well as antidepressants. Seven new significant adverse event signals emerged. The safety profile of pitolisant exhibited no significant differences across age and dose groups, although slight variations were observed in relation to sex and weight. The findings from reports of death and life-threatening outcomes underscore the importance of enhanced monitoring for cardiac and respiratory adverse reactions when utilizing pitolisant. This study provided a broader understanding of the safety profile of pitolisant.

A patient safety knowledge graph supporting vaccine product development

BackgroundKnowledge graphs are well-suited for modeling complex, unstructured, and multi-source data and facilitating their analysis. During the COVID-19 pandemic, adverse event data were integrated into a knowledge graph to support vaccine safety surveillance and nimbly respond to urgent health authority questions. Here, we provide details of this post-marketing safety system using public data sources. In addition to challenges with varied data representations, adverse event reporting on the COVID-19 vaccines generated an unprecedented volume of data; an order of magnitude larger than adverse events for all previous vaccines. The Patient Safety Knowledge Graph (PSKG) is a robust data store to accommodate the volume of adverse event data and harmonize primary surveillance data sources.MethodsWe designed a semantic model to represent key safety concepts. We built an extract-transform-load (ETL) data pipeline to parse and import primary public data sources; align key elements such as vaccine names; integrated the Medical Dictionary for Regulatory Activities (MedDRA); and applied quality metrics. PSKG is deployed in a Neo4J graph database, and made available via a web interface and Application Programming Interfaces (APIs).ResultsWe import and align adverse event data and vaccine exposure data from 250 countries on a weekly basis, producing a graph with 4,340,980 nodes and 30,544,475 edges as of July 1, 2022. PSKG is used for ad-hoc analyses and periodic reporting for several widely available COVID-19 vaccines. Analysis code using the knowledge graph is 80% shorter than an equivalent implementation written entirely in Python, and runs over 200 times faster.ConclusionsOrganizing safety data into a concise model of nodes, properties, and edge relationships has greatly simplified analysis code by removing complex parsing and transformation algorithms from individual analyses and instead managing these centrally. The adoption of the knowledge graph transformed how the team answers key scientific and medical questions. Whereas previously an analysis would involve aggregating and transforming primary datasets from scratch to answer a specific question, the team can now iterate easily and respond as quickly as requests evolve (e.g., “Produce vaccine-X safety profile for adverse event-Y by country instead of age-range”).

A retrospective pharmacovigilance study of post-marketing safety concerns with cefuroxime.

Cefuroxime has played a crucial role in the prevention and treatment of bacterial infections. However, the differences in adverse events across formulations and routes remain unclear. This study aimed to investigate the post-marketing safety of cefuroxime, particularly concerning formulations and routes. A retrospective pharmacovigilance study of cefuroxime was conducted using the data from Food and Drug Administration Adverse Event Reporting System database. The clinical characteristics and concomitant drugs reported with cefuroxime were investigated. Adverse event signals of cefuroxime were identified based on four disproportionality algorithms. The signal differences of cefuroxime across formulations and routes were further examined. A total of 1810 adverse event reports associated with cefuroxime were identified, and 181 cefuroxime-associated signals were detected. Compared with tablets, injections were more likely to cause preferred terms 'blood pressure decreased' and 'anaphylactic shock'. In addition, system organ class 'eye disorders' significantly increased when cefuroxime was administered intraocularly, underscoring the importance of exercising caution regarding ocular toxicity. The adverse events associated with cefuroxime were significantly different across formulations and routes, which deserve special attention in clinical use.

Recent Trends of AI in Pharmaceutical Industries: A Review

Artificial intelligence (AI) algorithms have been used to evaluate actual knowledge, reports on unfavourable occurrences, and publications to monitor post-marketing medication safety and detect possible safety concerns concerning security and respect to standards. AI has also been helpful in signal verification, adverse event prediction, and pharmacovigilance. AI is additionally implemented in streamlining pharmaceutical supply chains, guaranteeing effective distribution, management of inventory, and output. The possibilities of AI in PKPD studies are being recognized by pharmaceutical firms more and more. AI includes significant tools and techniques that help improve the processes involved in medication development and discovery. GNS Medical Care, AstraZeneca, Atom wise, Recursion Pharmaceuticals, and Insilico Medicines are a few instances. AI has been useful in the advancement of strategies for the rapid and perfect manufacture of dosage forms. AI possesses the possibility to completely overhaul the medical industry in the future by driving up the process of medication creation and discovery. With the use of virtual screening techniques, large chemical libraries will be effectively assessed to determine therapeutic candidates with the necessary lead compound identification time. By reviewing genomes, proteomes, and health data, AI-enabled precision nursing may be able to divide up patients, determine the results of treatment, and personalize medications. Using generative models and deep learning, scientists can produce novel molecules with targetbinding properties that increase drug efficacy and decrease side effects. AI will also enable dosage formulations tailored to individual patients. AI algorithms will improve drug formulations as well as delivery systems for improving health service outcomes by accounting for factors unique to each patient, such as size, age, heritage, and medical condition disease. Security evaluations he transform as a result of AI algorithms' ability to predict the toxicity and potential negative effects of medications.

A simulation-based comparison of drug-drug interaction signal detection methods.

Several statistical methods have been proposed to detect adverse drug reactions induced by taking two drugs together. These suspected adverse drug reactions can be discovered through post-market drug safety surveillance, which mainly relies on spontaneous reporting system database. Most previous studies have applied statistical models to real world data, but it is not clear which method outperforms the others. We aimed to assess the performance of various detection methods by implementing simulations under various conditions. We reviewed proposed approaches to detect signals indicating drug-drug interactions (DDIs) including the Ω shrinkage measure, the chi-square statistic, the proportional reporting ratio, the concomitant signal score, the additive model and the multiplicative model. Under various scenarios, we conducted a simulation study to examine the performances of the methods. We also applied the methods to Korea Adverse Event Reporting System (KAERS) data. Of the six methods considered in the simulation study, the Ω shrinkage measure and the chi-square statistic with threshold = 2 had higher sensitivity for detecting the true signals than the other methods in most scenarios while controlling the false positive rate below 0.05. When applied to the KAERS data, the two methods detected one known DDI for QT prolongation and one unknown (suspected) DDI for hyperkalemia. The performance of various signal detection methods for DDI may vary. It is recommended to use several methods together, rather than just one, to make a reasonable decision.

Post-Market Safety Measures for Cybersecurity Vulnerabilities in Medical Devices: International Perspectives

Post-Market Safety Measures for Cybersecurity Vulnerabilities in Medical Devices: International Perspectives

Time series analysis of using the PDCA method combined with the Teach-back method to improve spontaneous reports of adverse drug reactions in a grade IIIA hospital in China.

Spontaneous reporting of adverse drug reactions (ADRs) is essential for the post-marketing safety evaluation of drugs. Therefore, good monitoring of ADRs is vital for strengthening drug supervision, management, and guiding rational drug use. Chinese medical institutions are the primary source of ADR case reports, but the proportion of the reports in grade IIIA hospitals is still low due to serious under-reporting. The 3rd Affiliated Hospital of Chengdu Medical College, Chengdu Pidu District People's Hospital, also has such a problem. To improve the quantity and quality of ADR reports and enhance the level of pharmacovigilance in hospitals, the Third Affiliated Hospital of Chengdu Medical College, People's Hospital of Chengdu Pidu District experienced 10years to gradually establish a management model to improve the medical staff's reporting rate of spontaneous reporting of ADRs. The management model is led by clinical pharmacists and combines the PDCA with Teach-back methods. The purpose of this paper is to introduce the management model and discuss its advantages and shortcomings of this model. This study was conducted at the Third Affiliated Hospital of Chengdu Medical College-Chengdu Pidu District People's Hospital. From 2016, the daily management of reporting, auditing, and data improvement of adverse drug reactions in the hospital was carried out by clinical pharmacists, who used the PDCA method combined with the Teach-back method to continuously improve the reporting program of ADRs in the hospital during 2016-2021. Then, the proportion of spontaneous reports of total, new, and serious ADRs was compared before and after the intervention. Also, we performed a time series analysis using an autoregressive moving average model to assess changes in the total number of spontaneous ADR reports before the intervention (2013-2015), the first intervention (2016-2018), and the second intervention (2019-2021). After the combined PDCA and Teach-back method intervention, the median number of reported ADRs per year increased from 50 (range 37-55) in the pre-intervention period to 88 (range 83-162) in the first intervention period and to 374 in the second (range 312-566). Breakpoint regression analysis of the spontaneous reporting rate of ADRs showed that the instantaneous increase after the first intervention was not statistically significant (P = 0.526). However, the reporting rate of ADRs increased at a month-by-month growth rate during the second intervention compared to the first intervention. Its spontaneous reporting rate improved 1.034 times (P = 0.002). After the second intervention, the spontaneous reporting rate of ADRs transiently increased 6.111-fold (P < 0.001), and the month-to-month growth rate increased 1.024-fold (P < 0.001) again. The management model that combines the PDCA and the Teach-back method significantly improves the reporting rate of adverse drug reactions.

Post-marketing safety surveillance study of a 9-valent human papillomavirus vaccine in individuals aged 16–26 years in Chongqing, China

ABSTRACT The safety of human papillomavirus (HPV) vaccines, one of the major challenges to public vaccination, has been controversial. This study assessed the adverse reactions of 9-valent HPV (9vHPV) vaccines. This open-label, observational, multi-center, post-marketing study assessed the safety of 9vHPV administered according to local clinical practice. All post-marketing adverse events (AEs) reports received between December 2019 and November 2021 in Chongqing were analyzed. A total of 1000 individuals aged 16–26 years provided safety data post-vaccination; The most common AEs (60.1%) experienced by 9vHPV vaccine recipients were vaccination-site AEs (pain, swelling, induration) and non-vaccination-site AEs (dizzy, weak, fever). Vaccination-site AEs most were mild-to-moderate in intensity. Discontinuations and HPV 9-related serious AEs were rare (0.3% and 0.0%, respectively). Eight SAEs were reported during the study but none were considered as related to the study vaccine. The 9vHPV vaccine was generally well tolerated in subjects aged 16–26 years; Vaccination-site AEs were more common with 9vHPV.

Nationwide safety surveillance of COVID-19 mRNA vaccines following primary series and first booster vaccination in Singapore

BackgroundThe real-world safety profile ofCOVID-19 mRNA vaccines remains incompletely elucidated. MethodsWe performed a nationwide post-market safety surveillance analysis in Singapore, on vacinees aged 5 years and older, through mid-September 2022. Observed-over-expected (O/E) analyses were performed to identify potential safety signals among eight shortlisted adverse events of special interest (AESIs): strokes, cerebral venous thrombosis (CVT), acute myocardial infarction, myocarditis/pericarditis, pulmonary embolism, immune thrombocytopenia, convulsions and appendicitis. Self-controlled case series analyses (SCCS) were performed to validate signals of concern, occurring within 42 days of vaccination. FindingsElevated risks were observed on O/E analyses for the following AESIs: myocarditis/pericarditis, [rate ratio (RR): 3.66, 95 % confidence interval (95 % CI): 2.71 to 4.94], appendicitis [RR: 1.14 (1.02 to 1.27)] and CVT [RR: 2.11 (1.18 to 3.77)]. SCCS analyses generated corroborative findings: myocarditis/pericarditis, [relative incidence (RI): 6.96 (3.95 to 12.27) at 1 to 7 days post-dose 2], CVT [RI: 4.30 (1.30 to 14.20) at 22 to 42 days post-dose 1] and appendicitis [RI: 1.31 (1.03 to 1.67) at 1 to 7 days post-dose 1]. Booster dose 1 continued to be associated with higher rates of myocarditis/pericarditis on O/E analysis [RR: 2.30, (1.39 to 3.80) and 1.69, (1.11 to 2.59)] at 21- and 42-days post-booster dose 1, respectively. Males aged 12 to 17 exhibited highest risks of both myocarditis/pericarditis [RI: 6.31 (1.36 to 29.3)] and appendicitis [RI: 2.01 (1.12 to 3.64)] after primary vaccination. Similarly, CVT was also predominantly observed in males aged above 50 (11 out of 16 cases), within 42-days of vaccination. InterpretationOur data suggest that myocarditis/pericarditis, appendicitis and CVT are associated with primary vaccination using COVID-19 mRNA vaccines. Males at specific ages exhibit higher risks for all three AEs identified. The risk of myocarditis/pericarditis continues to be elevated after booster dose 1.

Post-marketing safety surveillance and re-evaluaiton of Shu-Xue-Ning injection: a real-world study based on 30,122 cases

Objective: This study aims to investigate the safety of Shu-Xue-Ning injection (SXNI) in real-world clinical applications.Methods: A prospective, multi-center, large-sample intensive monitoring method was used to monitor the use of SXNI in several medical institutions across China while collecting patients’ dosing and adverse event information. Patients who suspected as adverse reactions made comparisons with patients who did not report adverse reactions to calculate the correlation between relevant risk factors and suspected adverse reactions. Statistical analysis software SAS 9.1 was used for data analysis.Results: A total of 48 hospitals participated in this intensive monitoring study of SXNI, and 30,122 patients were monitored from July 2015 to December 2018. A total of 1,908 adverse events were reported during the use of SXNI, with an adverse event rate of 6.33% and a 95% confidence interval (CI) of 6.06%–6.61%. Association assessment showed that 54 cases presented with SXNI-related adverse reactions with an incidence of 0.18% and a 95% CI of 0.13%–0.23%, thereby indicating that the incidence of SXNI-related adverse reactions was occasional. SXNI-related adverse reactions involved 9 systems-organs with 20 clinical manifestations, and the most common adverse reactions were rash, pruritus, and other damages of skin and its appendages. No serious adverse reactions were observed; 27.78% of the adverse reactions occurred within 30 min of drug administration and more than half of them occurred within 2 h of drug administration; 96.3% of the adverse reactions were cured or improved. Causal analysis showed that women, long dispensing time, and slow dripping speed rate were considered as risk factors.Conclusion: The incidence of SXNI-related adverse reactions in real-world clinical applications is occasional and in a reasonable range with a good prognosis.

A Real-World Evidence Review of Post-Marketing Safety and Compliance with Pegcetacoplan in Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH) in the US

Introduction: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired hematologic condition characterized by complement-mediated, life-threatening hemolysis and thrombosis which are associated with significant impacts on health-related quality of life (HRQoL). Pegcetacoplan is the first targeted complement component 3 (C3) therapy approved for adults with PNH (US) and adults with PNH plus anemia despite receiving a complement component 5 inhibitor (C5i) for ≥3 months (EU). In clinical trials including patients with PNH who were C5i-experienced or -naive, pegcetacoplan significantly improved levels of hemoglobin (Hb) and lactate dehydrogenase (LDH) and reduced transfusion burden. Pegcetacoplan had a favorable safety profile in parent studies and an ongoing long-term, rollover, open-label extension study (NCT03531255). Compliance with pegcetacoplan treatment was high across all clinical studies. In the US real-world OPERA and Adelphi PNH Disease Specific Programme™ (DSP) patient-reported outcomes (PRO) studies, improvements in levels of Hb and LDH, along with self-reported fatigue and cognitive outcomes, were observed. Pegcetacoplan treatment also led to reductions in the frequency and severity of PNH symptoms (including shortness of breath and fatigue) and improvements in social, physical, and emotional HRQoL domains in the US real-world Voice of the Patient PRO study. Further, both patient and physician satisfaction with pegcetacoplan treatment was high in the Adelphi PNH DSP study. However, to date, compliance and safety with pegcetacoplan treatment in the real-world setting have not been described. The objective of this real-world evidence review study was to evaluate compliance and safety with pegcetacoplan treatment in patients with PNH in the US post-marketing setting. Methods: Post-marketing data from the US, including the number of patients who received pegcetacoplan and reported safety events, were collected and analyzed from the pegcetacoplan Risk Evaluation and Mitigation Strategies (REMS) program which controls the distribution of pegcetacoplan and the pharmacovigilance safety database through May 13, 2023. Treatment compliance was calculated as the proportion of days a patient had the drug in possession, divided by the total number of days of follow-up, using central pharmacy prescription refill data. Thrombosis (a leading cause of death in patients with PNH prior to the availability of complement inhibitors) and meningococcal infections (a potential risk with complement inhibitors) were safety events of interest. To reduce the risk of serious meningococcal infections, clinical trial protocols and pegcetacoplan labeling required vaccination against Streptococcus pneumoniae; N meningitidis types A, C, W, Y, and B; and Haemophilus influenzae type B before starting treatment with pegcetacoplan. If pegcetacoplan treatment must be initiated before vaccination, the US label mandates prophylactic antibiotic use. In this study, the rates of thrombosis and meningococcal infection per 100 patient-years were estimated based on the total number of thrombosis and meningococcal infection events reported in the REMS program. Results: As of May 13, 2023, the cumulative pegcetacoplan exposure was 273.10 patient-years in the US post-marketing setting. Based on prescription refill data, compliance with pegcetacoplan treatment was ~98%. There were 2 confirmed thrombotic events reported and the incidence of thrombotic events was 0.73 events/100 patient-years in 273.10 patient-years. Similar to clinical trials, no meningococcal infections were reported in the US post-marketing setting. Conclusions: The high compliance rate and favorable safety profile of pegcetacoplan in the US post-marketing setting were consistent with clinical trial observations. These data, coupled with the effectiveness on hematologic parameters and improvements in symptoms and HRQoL reported in pegcetacoplan real-world PRO studies, support a positive benefit:risk profile for pegcetacoplan in the real-world setting.