Nintedanib and ischemic colitis: Signal assessment with the integrated use of two types of real-world evidence, spontaneous reports of suspected adverse drug reactions, and observational data from large health-care databases.

PURPOSE: Statistical screening of Vigibase, the global database of individual case safety reports, highlighted an association between the MedDRA Preferred Term (PT) "colitis" and nintedanib. Nintedanib is a protein kinase inhibitor authorized in accelerated regulatory procedures for the treatment of idiopathic pulmonary fibrosis (IPF). The aim of this report is to describe the integration of two types of real-world evidence, spontaneous reports of adverse drug reactions (ADR), and observational health data (OHD) in the assessment of a post-authorization safety signal of ischemic colitis. METHODS: Assessment of the statistical signal of "nintedanib - colitis" was undertaken using data from VigiBase, OHD from the Observational Heath Data Sciences and Informatics (OHDSI) collaborative, published literature, and openly available regulatory documents. Evidence synthesis was performed to support Bradford Hill criteria in causality assessment. RESULTS: Evidence for strength of association, specificity, consistency, and analogy was found upon review of the case series. OHD was used to calculate incidence rates of colitis in new users of nintedanib across multiple populations, supportive of consistency, and further evidence for strength of association. Literature review identified support for biological plausibility and analogy. Signal assessment was supplemented with characterization of real-world users and exploration of potential risk factors using OHD. CONCLUSIONS: An integrated approach using two forms of real-world data, spontaneous reports of ADRs and data from observational databases allowed a comprehensive and efficient signal assessment of nintedanib and colitis. Further exploration of the complementary use of real-time OHD in signal assessment could inform more efficient approaches to current signal management practices.

Increased risk for aseptic meningitis after amoxicillin or amoxicillin-clavulanic acid in males: A signal revealed by subset disproportionality analysis within a global database of suspected adverse drug reactions.

PURPOSE: Drug-induced aseptic meningitis (DIAM) is an inflammation of the membranes of the central nervous system caused by certain medications. It is a rare clinical entity whose risk factors are not yet fully elucidated. A local pattern of disproportionality within a global database of suspected adverse drug reactions (ADRs) revealed an increased reporting of aseptic meningitis and amoxicillin-clavulanic acid (AC) in males. The aim of this report is to explore the clinical probability of a higher risk in males to support the use of statistical methods to identify subgroups at risk for adverse drug reactions. METHODS: Disproportionality analysis was performed for all drug-adverse event (AE) pairs in the entire database and for the subsets of males and females. AC-aseptic meningitis was highlighted for an increased disproportionality in the male subgroup in the absence of an elevated disproportionality measure for the database overall. A clinical review was undertaken. RESULTS: Clinical review revealed a similar statistical pattern of gender difference observed for amoxicillin, evidence to suggest a delayed type 4 hypersensitivity reaction with Th1 cells as a mechanism for amoxicillin-aseptic meningitis, the existence of sex differences in immune responses (Th1/Th2), and an analogous increased risk of drug-induced liver injury by AC in males. CONCLUSIONS: Subgroup disproportionality analysis has revealed a larger than expected number of reports of aseptic meningitis after amoxicillin and AC in males. Evidence synthesis supports the statistical finding. Further exploration of spontaneous databases with more extensive analyses could usher in a new era of "precision pharmacovigilance."

Benefit-risk assessment of vaccines.

Benefit-risk assessment (BRA) is critical for decision-making throughout the vaccine life cycle. It requires scientific assessment of evidence to make an informed judgment on whether the vaccine has a favourable benefit-risk profile i.e. the benefits of the vaccine outweigh its risks for use in its intended indication. The assessment must also consider data gaps and uncertainties, using sensitivity analyses to show the impact of these uncertainties in the assessment. The BRA field has advanced considerably over the past years, including the use of structured BRA frameworks, quantitative BRA models and use of the patient experience data. Analytical tools and procedures to standardize BRA implementation have become increasingly important. A Benefit-Risk Assessment Module has been prepared to enable the planning, assessment, and communication of relevant BRA information via a structured B-R framework. The module can help facilitate the conduct and communication of defensible BRAs by vaccine developers, funders, regulators and policy makers in high, middle or low-income countries, both for regulatory submissions and in public health responses to infectious diseases, including for epidemics.

Landscape review of active vaccine safety surveillance activities for COVID-19 vaccines globally.

Background: Evidence of COVID-19 vaccine safety relied upon the global vaccine monitoring infrastructure due to shortened clinical development timelines and emergency use licensure. Differences in AVSS capacity between high-income countries (HICs) versus low- and middle-income countries (LMICs) were known prior to the pandemic. Objective: To assess the global landscape of COVID-19 vaccine AVSS activities to identify gaps in safety evidence generation across vaccine products and populations with a focus on LMICs. Methods: A cross-sectional survey was conducted in January 2022 on AVSS activities evaluating adverse events following immunization (AEFI). Data collected included country, targeted population, COVID-19 vaccine product(s), design of surveillance/monitoring activities or study, and AEFIs to be monitored.To supplement these findings, we conducted a literature review of COVID-19 vaccine safety activities published in PubMed through January 2023. Observational activities assessing AEFI, specifically adverse events of special interest (AESI), following routine use of COVID-19 vaccines in medical practice were included; systematic reviews, benefit/risk assessments, clinical trials, and case reports/series were excluded. Results: The survey, completed by 34 respondents and compiled with reviews of 7 publicly available Risk Management Plans from five vaccine manufacturers, identified 79 monitoring activities in HICs, 24 in LMICs, and 9 in multiple regions. Most activities in LMICs were planned cohort event monitoring (CEM) studies (n = 18); two multi-national hospital-based sentinel surveillance studies for AESI were ongoing. Activities in LMICs evaluated multiple COVID-19 vaccine products simultaneously and were sponsored by health authorities. The literature review identified 1245 unique citations, of which 379 met inclusion criteria. The majority evaluated vaccines primarily used in high-income countries: Pfizer BioNTech (Comirnaty; n = 303), Moderna (mRNA-1273; n = 164), AstraZeneca (AZD1222; n = 126), and Janssen (Ad26.COV2.S); n = 62); 14 citations assessed vaccines used exclusively in LMICs: Sinovac (CoronaVac), Beijing CNBG (BBIBP-Corv), Bharat (Covaxin), SII (Covashield), and Gamaleya (Gam-Covid-Vac) vaccines. Conclusions: Robust safety evidence for input into benefit/risk assessments is likely unavailable for most COVID-19 vaccines used primarily in LMICs due to emphasis on cohort event monitoring methods. Goals for equitable vaccine access should be coupled with investment and support for building infrastructure and capacity for safety evidence generation to inform policy and regulatory decisions at local levels.

Collaboration within the global vaccine safety surveillance ecosystem during the COVID-19 pandemic: lessons learnt and key recommendations from the COVAX Vaccine Safety Working Group.

This analysis describes the successes, challenges and opportunities to improve global vaccine safety surveillance as observed by the Vaccine Safety Working Group from its role as a platform of exchange for stakeholders responsible for monitoring the safety of vaccines distributed through the COVAX mechanism. Three key elements considered to be essential for ongoing and future pandemic preparedness for vaccine developers in their interaction with other members of the vaccine safety ecosystem are (1) the availability of infrastructure and capacity for active vaccine safety surveillance in low-income and middle-income countries (LMICs), including the advancement of concepts of safety surveillance and risk management to vaccine developers and manufacturers from LMICs; (2) more comprehensive mechanisms to ensure timely exchange of vaccine safety data and/or knowledge gaps between public health authorities and vaccine developers and manufacturers; and (3) further implementation of the concept of regulatory reliance in pharmacovigilance. These aims would both conserve valuable resources and allow for more equitable access to vaccine safety information and for benefit/risk decision-making.

Assessing vaccine safety during a pandemic: Recent experience and lessons learned for the future.

During the roll out of vaccines during a pandemic, questions regarding vaccine safety often arise. This was surely true during the SARS-CoV-2 pandemic. Different tools and capabilities exist during the pre-authorization phase and post introduction each with its strengths and limitations. Here we review the various tools and their strengths and limitations and discuss what functioned well in high income settings and the limitations that unequal vaccine safety pharmacovigilance capacity imposed upon middle and low income countries.

Considerations for unblinding individual study participants during vaccine trials.

Premature unblinding of individual participants is rarely reported in publications, but such unblinding can disrupt vaccine trials by causing worry and drop-out of other participants or "pseudo unblinding," in which participants or investigators over-interpret certain symptoms as being related to receiving an investigational product. This review summarizes appropriate reasons for unblinding in vaccine trials. Regulatory guidance could be improved by distinguishing guidance for vaccine trials from drug trials, with the recognition that unblinding individual participants in vaccine studies is rarely needed for management of adverse events following immunization.

Dispositions and Causality Assessment in Pharmacovigilance: Proposing the Dx3 Approach for Assessing Causality with Small Data Sets.

A new approach is proposed for assessing causality in pharmacovigilance. The Dx3 approach is designed to qualitatively evaluate three types of dispositions when assessing whether a particular medicine has or could have caused a certain adverse event. These are: the drug disposition; the pre-disposition of the patient taking the drug (vulnerability) and; the disposition of the patient-drug interaction (mutuality). Each of these three types of dispositions will represent valuable causally relevant evidence for assessing a potential signal of harm. A checklist is provided to guide the assessment of causality for both single individual case safety reports (ICSRs) and case series. Different types of causal information are ranked according to how well suited they are for establishing a disposition. Two case examples are used to demonstrate how the approach can be used in practice for assessment purposes. One aim of the approach is to offer a qualitative way to assess causality and to make the reasoning of different assessors more transparent. A second aim is to encourage the collection of more qualitatively rich patient narratives in the ICSRs. Crucially, we believe this approach can support the inclusion of the single ICSR as a valid and valuable form of evidence.

The Use of Subgroup Disproportionality Analyses to Explore the Sensitivity of a Global Database of Individual Case Safety Reports to Known Pharmacogenomic Risk Variants Common in Japan.

INTRODUCTION: Genetic variations of enzymes that affect the pharmacokinetics and hence effects of medications differ between ethnicities, resulting in variation in the risk of adverse drug reactions (ADR) between different populations. Previous work has demonstrated that risk-group considerations can be incorporated into approaches of statistical signal detection. It is unknown whether databases of individual case safety reports (ICSRs) are sensitive to pharmacogenomic differences between populations. OBJECTIVE: The aim of this study was to explore the sensitivity of a global database of ICSRs to known pharmacogenomic risk variants common in Japan. METHODS: The data source was VigiBase, the global database of ICSRs, including all reports entered in the version frozen on 5 January 2020. Subgroup disproportionality analysis was used to compare ICSRs of two subgroups, Japan and rest of world (RoW). Reports for UGT1A1-metabolized irinotecan and the CYP2C19-metabolized drugs voriconazole, escitalopram and clopidogrel were selected for comparison between the subgroups based upon known genetic polymorphisms with high prevalence in Japan. Contrast between the subgroups was quantified by IC delta [Formula: see text]), a robust shrinkage observed-to-expected (OE) ratio on a log scale. Harmonic mean p values (HMP) were calculated for each drug to evaluate whether a list of pre-specified ADRs were collectively significantly over- (or under-)reported as hypothesized. Daily drug dosages were calculated for ICSRs with sufficient information, and dose distributions were compared between Japan and RoW and related to differences in regionally approved doses. RESULTS: The predictions of over-reporting patterns for specific ADRs were observed and confirmed in bootstrap HMP analyses (p = 0.004 for irinotecan and p < 0.001 for each of voriconazole, escitalopram and clopidogrel) and compared with similar drugs with different metabolic pathways. The impact of proactive regulatory action, such as recommended dosing and therapeutic drug monitoring (TDM), was also observable within the global database. For irinotecan and escitalopram, there was evidence of use of lower dosages as recommended in the Japanese labels; for voriconazole, there was evidence of use of TDM with an over-reporting of terms related to drug level measurements and an under-reporting of liver toxicity. CONCLUSIONS: Pharmaco-ethnic vulnerabilities caused by pharmacogenomic differences between populations may contribute to differences in ADR reporting between countries in a global database of ICSRs. Regional analyses within a global database can inform on the effectiveness of local risk minimization measures and should be leveraged to catalyse the conversion of real-world usage into safer use of drugs in ethnically tailored ways.

Consensus clustering for case series identification and adverse event profiles in pharmacovigilance.

OBJECTIVE: To describe and evaluate vigiGroup - a consensus clustering algorithm which can identify groups of individual case reports referring to similar suspected adverse drug reactions and describe associated adverse event profiles, accounting for co-reported adverse event terms. MATERIALS AND METHODS: Consensus clustering is achieved by grouping pairs of reports that are repeatedly placed together in the same clusters across a set of mixture model-based cluster analyses. The latter use empirical Bayes statistical shrinkage for improved performance. As baseline comparison, we considered a regular mixture model-based cluster analysis. Three randomly selected drugs in VigiBase, the World Health Organization's global database of Individual Case Safety Reports were analyzed: sumatriptan, ambroxol and tacrolimus. Clustering stability was assessed using the adjusted Rand index, ranging between -1 and +1, and clinical coherence was assessed through an intruder detection analysis. RESULTS: For the three drugs considered, vigiGroup achieved stable and coherent results with adjusted Rand indices between +0.80 and +0.92, and intruder detection rates between 86% and 94%. Consensus clustering improved both stability and clinical coherence compared to mixture model-based clustering alone. Statistical shrinkage improved the stability of clusters compared to the baseline mixture model, as well as the cross-validated log-likelihood. CONCLUSIONS: The proposed algorithm can achieve adequate stability and clinical coherence in clustering individual case reports, thereby enabling better identification of case series and associated adverse event profiles in pharmacovigilance. The use of empirical Bayes shrinkage and consensus clustering each led to meaningful improvements in performance.

Multisystem inflammatory syndrome in children and adults (MIS-C/A): Case definition & guidelines for data collection, analysis, and presentation of immunization safety data.

This is a Brighton Collaboration Case Definition of the term "Multisystem Inflammatory Syndrome in Children and Adults (MIS-C/A)" to be utilized in the evaluation of adverse events following immunization. The case definition was developed by topic experts convened by the Coalition for Epidemic Preparedness Innovations (CEPI) in the context of active development of vaccines for SARS-CoV-2. The format of the Brighton Collaboration was followed, including an exhaustive review of the literature, to develop a consensus definition and defined levels of certainty. The document underwent peer review by the Brighton Collaboration Network and by selected expert external reviewers prior to submission. The comments of the reviewers were taken into consideration and edits incorporated into this final manuscript.

Interstitial Lung Disease as an Adverse Drug Reaction in Japan: Exploration of Regulatory Actions as a Basis for High Reporting.

INTRODUCTION: Increased post-marketing reports of interstitial lung disease in Japan have been recognized. An understanding of its regional groundings can be important for the global pharmacovigilance community. OBJECTIVE: The objective of this study was to explore the correlation between high rates of interstitial lung disease reporting and regulatory actions in Japan. METHODS: Post-marketing interstitial lung disease-related label changes and interstitial lung disease reports were classified by the anatomical therapeutic chemical classification groups of the suspected drugs. Regulatory actions for the top interstitial lung disease-reporting drugs were compared. The interstitial lung disease reporting patterns of protein kinase inhibitors were compared to those of methotrexate. RESULTS: Interstitial lung disease-related label changes predominantly occurred for drugs in the anatomical therapeutic chemical classification groups L, J, C, and herbal medicines. Interstitial lung disease was reported most frequently for L group, especially for the protein kinase inhibitors. The regulatory actions for those drugs with the highest number of interstitial lung disease reports (methotrexate, protease kinase inhibitors, gemcitabine, docetaxel) plus monoclonal antibodies were analyzed. The ratio of interstitial lung disease reports to all reports over time was initially high in the re-examination period, while it was constantly low after the period expired. The increase in interstitial lung disease reporting was observed for the drugs for which interstitial lung disease was designated as a priority item in the use-results survey. Methotrexate had more interstitial lung disease reports with multiple suspected drugs and fewer reports with high completeness than the protease kinase inhibitors. CONCLUSIONS: The high rates of interstitial lung disease reporting derived from mainly the anatomical therapeutic chemical classification group L drugs. Interstitial lung disease is the targeted adverse drug reaction in the use-results survey mandated in the re-examination of those drugs. This system provides at least one explanation for the high reporting of interstitial lung disease in Japan.

Serious Neurological Adverse Events after Ivermectin-Do They Occur beyond the Indication of Onchocerciasis?

Serious neurological adverse events have been reported from large scale community-based ivermectin treatment campaigns against Onchocerciasis volvulus in Africa. The mechanism of these events has been debated in the literature, largely focusing on the role of concomitant infection with Loa loa versus the presence of mdr-1 gene variants in humans allowing ivermectin penetration into the central nervous system. A case series of serious neurological adverse events occurring with the use of ivermectin outside of the onchocerciasis indication has been identified in VigiBase, an international database of suspected adverse drug reactions. Forty-eight cases have been reported from multiple countries in which ivermectin has been prescribed for multiple indications; clinical review excluded 20 cases with more probable explanations or other exclusion criteria. Within the remaining 28 cases, there is supportive evidence for a causative role of ivermectin including presence of the drug in brain tissue in one case and recurrence of symptoms on repeated exposure in three cases. This series suggests that serious neurological adverse events observed with the use of ivermectin in the treatment of onchocerciasis may not be entirely explained by concomitant high burden loiasis infections. By comparison with the extensive post marketing experience with ivermectin in the successful treatment of parasitic infections, the number of reported cases suggests that such events are likely rare. However, elucidation of individual-level risk factors could contribute to therapeutic decisions that can minimize harms. Further investigation into the potential for drug-drug interactions and explorations of polymorphisms in the mdr-1 gene are recommended.

Safety Concerns Reported by Patients Identified in a Collaborative Signal Detection Workshop using VigiBase: Results and Reflections from Lareb and Uppsala Monitoring Centre.

INTRODUCTION: Patient reporting in pharmacovigilance is important and contributes to signal detection. However, descriptions of methodologies for using patient reports in signal detection are scarce, and published experiences of how patient reports are used in pharmacovigilance are limited to a few individual countries. OBJECTIVE: Our objective was to explore the contribution of patient reports to global signal detection in VigiBase. METHODS: Data were retrieved from VigiBase in September 2016. Drug-event-combination series were restricted to those with >50% patient reports, defined as reporter type "Consumer/non-health professional" per E2B reporting standard. vigiRank was applied to patient reports to prioritize combinations for assessment. Product information for healthcare professionals (HCPs) as well as patient information leaflets (PILs) were used as reference for information on adverse drug reactions (ADRs). Staff from the Uppsala Monitoring Centre and the Netherlands Pharmacovigilance Centre Lareb categorized the combinations. Potential signals proceeded to a more in-depth clinical review to determine whether the safety concern should be communicated as a "signal." RESULTS: Of the 212 combinations assessed, 20 (9%) resulted in eight signals communicated within the World Health Organization (WHO) programme for international drug monitoring. Review of PILs revealed insufficient ADR descriptions for patients and examples of poor consistency with product information for HCPs. Patient narratives provided details regarding the experience and impact of ADRs and evidence that patients make causality and personal risk assessments. CONCLUSIONS: Safety concerns described in patient reports can be identified in a global database including previously unknown ADRs as well as new aspects of known ADRs. Patient reports provide unique information valuable in signal assessment and should be included in signal detection. Novel approaches to highlighting patient reports in statistical signal detection can further improve the contribution of patient reports to pharmacovigilance.

Clostridium difficile-associated disease in Oregon: increasing incidence and hospital-level risk factors.

BACKGROUND: The incidence of Clostridium difficile-associated disease (CDAD) appears to be increasing. Population-based estimates of disease have been limited, and analyses of hospital-level risk factors for CDAD are lacking. We sought to determine the incidence and trends of CDAD in Oregon and to identify hospital-level factors associated with increases in disease. METHODS: We analyzed hospital discharge data to calculate the incidence and to describe trends of CDAD in Oregon from 1995 through 2002. We administered questionnaires to hospital laboratory directors, infection control practitioners, and pharmacists to determine the status of laboratory, infection control, and pharmacy policies over time. RESULTS: The overall incidence of CDAD in Oregon was 3.5 case patients per 10,000 residents in 2002. Incidence increased from 1.4 to 3.3 cases per 1,000 hospital discharges from 1995 to 2002. Rates of disease increased most in hospitals with licensed bed capacity of more than 250 beds and more than 5 intensive care unit beds. Few laboratories, infection control practitioners, and pharmacists were able to identify changes in specific policies over the study period. CONCLUSIONS: This is the first study to determine a statewide population-based incidence of CDAD. Incidence of CDAD in Oregon has more than doubled over the past decade; larger hospitals experienced the greatest increase in disease rates. We did not identify hospital-level policies that could explain the increase. A study of patients with CDAD at the hospitals with the largest increases is underway to further identify risk factors.

Correction to: Safety Concerns with HPV Vaccines Continue to Linger: Are Current Vaccine Pharmacovigilance Practices Sufficient?

The following disclaimer was missing from the article.

Current Safety Concerns with Human Papillomavirus Vaccine: A Cluster Analysis of Reports in VigiBase®.

INTRODUCTION: A number of safety signals-complex regional pain syndrome (CRPS), postural orthostatic tachycardia syndrome (POTS), and chronic fatigue syndrome (CFS)-have emerged with human papillomavirus (HPV) vaccines, which share a similar pattern of symptomatology. Previous signal evaluations and epidemiological studies have largely relied on traditional methodologies and signals have been considered individually. OBJECTIVE: The aim of this study was to explore global reporting patterns for HPV vaccine for subgroups of reports with similar adverse event (AE) profiles. METHODS: All individual case safety reports (reports) for HPV vaccines in VigiBase® until 1 January 2015 were identified. A statistical cluster analysis algorithm was used to identify natural groupings based on AE profiles in a data-driven exploratory analysis. Clinical assessment of the clusters was performed to identify clusters relevant to current safety concerns. RESULTS: Overall, 54 clusters containing at least five reports were identified. The four largest clusters included 71 % of the analysed HPV reports and described AEs included in the product label. Four smaller clusters were identified to include case reports relevant to ongoing safety concerns (total of 694 cases). In all four of these clusters, the most commonly reported AE terms were headache and dizziness and fatigue or syncope; three of these four AE terms were reported in >50 % of the reports included in the clusters. These clusters had a higher proportion of serious cases compared with HPV reports overall (44-89 % in the clusters compared with 24 %). Furthermore, only a minority of reports included in these clusters included AE terms of diagnoses to explain these symptoms. Using proportional reporting ratios, the combination of headache and dizziness with either fatigue or syncope was found to be more commonly reported in HPV vaccine reports compared with non-HPV vaccine reports for females aged 9-25 years. This disproportionality remained when results were stratified by age and when those countries reporting the signals of CRPS (Japan) and POTS (Denmark) were excluded. CONCLUSIONS: Cluster analysis reveals additional reports of AEs following HPV vaccination that are serious in nature and describe symptoms that overlap those reported in cases from the recent safety signals (POTS, CRPS, and CFS), but which do not report explicit diagnoses. While the causal association between HPV vaccination and these AEs remains uncertain, more extensive analyses of spontaneous reports can better identify the relevant case series for thorough signal evaluation.

Transmission of group A Streptococcus limited to healthcare workers with exposure in the operating room.

BACKGROUND: Nosocomial transmission of group A Streptococcus (GAS) has been well described. A recent report of an outbreak investigation suggested that transmission can be extensive and that standard infection control measures may not be adequate to prevent transmission from patients with severe, invasive disease to healthcare workers (HCWs). OBJECTIVE: A case of pharyngitis in an HCW caring for a patient with GAS pharyngitis and necrotizing fasciitis prompted an investigation of the extent and risk factors for nosocomial transmission of GAS. SETTING: A 509-bed, tertiary care center in Portland, Oregon with 631,100 patient visits (hospital and clinic) and 11,500 employees in the year 2003. METHODS: HCWs with exposure to the index patient ("contacts") were identified for streptococcal screening and culture and completion of a questionnaire regarding the location and duration of exposure, use of personal protective equipment, and symptoms of GAS infection. RESULTS: We identified 103 contacts of the index patient; 89 (86%) submitted oropharyngeal swabs for screening and culture. Only 3 (3.4%) of contacts had a culture that yielded GAS; emm typing results and pulsed-field gel electrophoresis patterns of GAS isolates from 2 HCWs were identical to those for the isolate from the index patient. Both HCWs were symptomatic, with febrile pharyngitis and reported prolonged contact with the open wound of the patient in the operating room. CONCLUSIONS: In this investigation, nosocomial transmission was not extensive, and standard precautions provided adequate protection for the majority of HCWs. Transmission was restricted to individuals with prolonged intraoperative exposure to open wounds. As a result, infection control policy for individuals was modified only for HCWs with exposure to GAS in the operating room.