Progress in Immunization Safety Monitoring - Worldwide, 2010-2019.

High levels of coverage with safe and effective immunizations are critical to the successful control and prevention of vaccine-preventable diseases worldwide. In addition to stringent standards to regulate the safety of vaccines, robust postlicensure monitoring systems help ensure that the benefits of vaccines continue to outweigh the risks for the populations who receive them. National Expanded Programmes on Immunization (EPI) are typically responsible for identifying and investigating adverse events following immunization (AEFI), including assessment of causality. National regulatory authorities (NRAs) are mandated to perform postlicensure surveillance of adverse drug reactions, including those associated with receipt of vaccines. This report describes global progress toward meeting World Health Organization (WHO) indicators on minimal country capacity for vaccine safety surveillance and coordination of AEFI reporting between countries' EPI and NRAs. In 2019, among 194 countries, 129 (66.5%) reported having an operational national AEFI causality review committee, compared with 94 (48.5%) in 2010. During 2010-2019, the proportion of countries reporting ≥10 AEFI per 100,000 surviving infants per year (an indicator of country capacity to monitor immunization safety) increased, from 41.2% to 56.2%. In 2019, however, only 46 (23.7%) countries reported AEFI data from both EPI and NRAs. Although global progress has been made toward strengthening systems for vaccine safety monitoring over the past decade, new indicators for monitoring global immunization safety performance are needed to better reflect program functionality. Continued global efforts will be vital to address barriers to routine reporting of AEFI, build national capacity for AEFI investigation and data management, and improve sharing of AEFI data at national, regional, and global levels.

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."

Ylidenemalononitrile enamine-coated media as fluorescent "turn-on" probes for volatile primary amines.

Two ylidenemalononitrile enamines, adsorbed to various media, undergo a cyclization reaction with primary amine vapors resulting in a fluorometric and colorimetric response. After determining the media with the fastest response rate for emission "turn-on" to be aluminum oxide activated neutral (AON), we further demonstrate the sensitivity (propylamine concentrations as low as 200 ppm are detected) and selectivity to various analytes including amines, methanol, and ethanethiol. Lastly, as an alternative means of detection, the colorimetric response dye on glass filter paper was shown to detect propylamine concentrations as low as 29 ppm.

Ylidenemalononitrile enamines as fluorescent "turn-on" indicators for primary amines.

Ylidenemalononitrile enamines undergo rapid amine exchange followed by a cyclization with primary amines to yield fluorescent products with emission intensities as high as 900 times greater than the starting materials. After identifying the fluorescent species by X-ray crystallography, we demonstrate that the rate of amine exchange is substrate dependent and that by simple structural variation the fluorescence can be tuned over the entire visible spectrum. We further demonstrate their potential application in biomolecule labeling.

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.

The Brighton collaboration standardized module for vaccine benefit-risk assessment.

Vaccine Benefit-Risk (B-R) assessment consists of evaluating the benefits and risks of a vaccine and making a judgment whether the expected key benefits outweigh the potential key risks associated with its expected use. B-R supports regulatory and public health decision-making throughout the vaccine's lifecycle. In August 2021, the Brighton Collaboration's Benefit-Risk Assessment of VAccines by TechnolOgy (BRAVATO) Benefit-Risk Assessment Module working group was established to develop a standard module to support the planning, conduct and evaluation of structured B-R assessments for vaccines from different platforms, based on data from clinical trials, post-marketing studies and real-world evidence. It enables sharing of relevant information via value trees, effects tables and graphical depictions of B-R trade-offs. It is intended to support vaccine developers, funders, regulators and policy makers in high-, middle- or low-income countries to help inform decision-making and facilitate transparent communication concerning development, licensure, deployment and other lifecycle decisions.

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.

Exploring the experiences of high-risk groups during the first UK Covid-19 lockdown through creative methods.

Background: Groups at high risk of severe illness/death from COVID-19 (older people and those identified as clinically extremely vulnerable: CEV) experienced increased restrictions, poor mental health and loneliness during the first UK lockdown. Methods: Seventeen older adults, eight CEV adults, one parent of a CEV child, and two family carers of CEV adults, shared their experiences of the first UK lockdown through various media: written reflections, interviews, poetry, videos, photographs, and visual artwork. Results: Through a positive psychology lens, five themes were identified: experiencing loss; community and connection; finding joy, hope and optimism; adapting to change; and sense- and meaning-making. Conclusion: High-risk groups fostered wellbeing and flourishing and formed a sense of coherence in a time of great loss. Engagement with artistic, creative, and cultural activities facilitated this. The arts not only provided a creative means of collecting data but was also identified as a central thread in the findings.

Practical Implementation of the Comprehensive Geriatric Assessment to Optimise Care for Older Adults with Cancer.

Whilst cancer remains a very serious health problem at any stage, cancer combined with increasing age creates an even more challenging situation for health care providers [...].

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.

Diagnostic Performance of Screening Tools for Depressive Symptoms in Vulnerable Older Patients with Cancer Undergoing Comprehensive Geriatric Assessment (CGA): Results from the SCREEN Pilot Study.

Depression is a common and disabling disorder in later life, particularly among people with poor physical health. There are many screening tools available that can be used to examine depressive symptoms; however, not all of them may be appropriate or accurate for older adults with cancer. This pilot study was designed to test the diagnostic performance of two screening tools and their short versions in a cohort of vulnerable (G8 score ≤ 14/17) older patients with cancer undergoing comprehensive geriatric assessment (CGA). The prospective analysis covered 50 vulnerable patients with cancer aged ≥70 years. The diagnostic performance of the Geriatric Depression Scale (GDS)-15, GDS-4, Patient Health Questionnaire (PHQ)-9 and PHQ-2 was compared to the 'gold standard' Structured Clinical Interview for DSM-5 Disorders (SCID-5-S) depression module A. The sensitivity and specificity in detecting depressive symptoms were the highest in the case of PHQ-2, with an area under the receiver operating characteristic curve (AUROC) of 92.7%. The AUROC for the 9-item version, PHQ-9, was 90.2%. For the GDS-15 and GDS-4, the AUROC was only 56.2% and 62.0%, respectively. The SCREEN pilot study illustrates the potential benefit of using a shorter screening tool, PHQ-2, to identify older patients with cancer who would benefit from a more in-depth emotional evaluation as part of a CGA.

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.

Psychosocial Care after Cancer Diagnosis: Recent Advances and Challenges.

Psychosocial oncology is coming of age [...].

Post-Marketing Safety Profile of Vortioxetine Using a Cluster Analysis and a Disproportionality Analysis of Global Adverse Event Reports.

INTRODUCTION: Vortioxetine, a multimodal serotonergic drug, is widely used as treatment for major depressive disorder. Although on the market since late 2013, the data of the relative safety of vortioxetine, especially compared to selective serotonin reuptake inhibitors, are still scarce. OBJECTIVE: The aim of this study was to explore the adverse event reporting pattern of vortioxetine through a cluster analysis. Furthermore, to compare the adverse event reporting pattern for vortioxetine with that of the selective serotonin reuptake inhibitors. METHODS: Individual case safety reports for vortioxetine in VigiBase up to 1 November, 2019 were subjected to consensus clustering, to identify and describe natural groupings of reports based on their reported adverse events. A vigiPoint exploratory analysis compared vortioxetine to the selective serotonin reuptake inhibitors in terms of relative frequencies for a wide range of covariates, including patient sex and age, reported drugs and adverse events, and reporting country. Important differences were identified using odds ratios with adaptive statistical shrinkage. RESULTS: Thirty-six clusters containing at least five reports were identified and analysed. The two largest clusters included 48% of the vortioxetine reports and appeared to represent gastrointestinal adverse events and hypersensitivity adverse events. Other distinct clusters were related to, respectively, fatigue, aggression/suicidality, convulsion, medication errors, arthralgia/myalgia, increased weight, paraesthesia and anticholinergic effects. Some of these clusters are not labelled for vortioxetine, such as arthralgia/myalgia and paraesthesia, but are known adverse events for selective serotonin reuptake inhibitors. A vigiPoint analysis revealed a higher proportion of reports from consumers and non-health professionals for vortioxetine as well as higher relative reporting rates of gastrointestinal symptoms, pruritus and mood-related symptoms, consistent with the cluster analysis. CONCLUSIONS: A pattern of co-reported adverse events that is consistent with labelled adverse events for vortioxetine and the safety profile for selective serotonin reuptake inhibitors in general was revealed. Clusters of unlabelled adverse events were identified that reflect clinical entities that might represent signals of previously unknown adverse events. More extensive analyses of spontaneous reports may help to further understand the reporting pattern of adverse events.

Clinical evaluation and management of a 45-year-old man with confusion, psychosis, agitation, stereotyped behavior, and impaired speech.

Our patient Mr. A is a mentally and physically disabled gentleman. He was first diagnosed with bipolar disorder as a teenager. He incurred a lumbar spinal injury due to a motor vehicle incident in his 20s which led to weakness, numbness, and frequent infection over both of his lower extremities. He also developed alcohol addiction over the course of his life. Mr. A presented to our facility with complicated neuropsychiatric symptoms. By adopting various clinical strategies, we were able to control his symptoms of agitation, self-harm, mood swings, and stereotyped behavior. However, we were not able to improve his neurocognitive functioning or speech impairment which seemed to become severe and irreversible in a period of a few months. We felt disappointed and perplexed by the mixed treatment responses. To understand Mr. A's clinical presentation, various laboratory tests and imaging studies were performed. Different psychotropic medications were used to manage his symptoms. Gradually, we felt that we were able to understand this case better clinically and etiologically. His bipolar disorder, alcohol addiction, and physical injury had likely all contributed to his neuropsychiatric symptoms, directly or indirectly. It is highly possible that an alcohol-related progressive dementia along with his chronic bipolar disorder played a key role in the progression of his brain neurodegeneration. Also, Wernicke-Korsakoff syndrome could reasonably be considered having developed during his clinical course. Moreover, the fluctuation of the patient's neuropsychiatric symptoms we observed during his hospitalization reflects the increased vulnerability of the human brain under sustained neurodegeneration.

Developing and evaluating a participatory arts programme for cancer patients and their caregivers.

OBJECTIVES: Cancer patients, survivors and caregivers often encounter severe distress, having significant consequences to wellbeing, functionality and physical health. This study developed and evaluated a participatory arts programme to determine if such could help to improve the wellbeing of cancer patients and their caregivers. METHODS: To inform the development of a participatory arts programme, cancer patients and their caregivers at an Organisation of European Cancer Institute (OECI)-designated cancer centre were asked which activities they would wish to engage in (anonymous survey one). A programme was then developed and trialled for 1 year. Following participation, we explored the satisfaction and any benefits of taking part (anonymous survey two). RESULTS: Survey one had a participation rate of 70%. In this survey, participants indicated they preferred group-based activities (61%) over an individual approachto take place on a monthly basis (46%). The developed programme ran from December 2018 to December 2019, with 435 patients and caregivers taking part. Two hundred and eighteen completed survey two and revealed a positive response to both the structure and content of the programme and its impact on the wellbeing of patients and caregivers. The majority indicated they felt (much) betterfrom participating in the participatory arts programme. CONCLUSION: This study points out the interest and potential value of a participatory arts programme to the perceived wellbeing. This suggests such programmes could be incorporated into cancer care provision, to serve as psychosocial support. The latter is particularly relevant for improving the lives, wellbeing and health of cancer patients and those supporting them.

Evidence-based clinical practice guidelines on the management of pain in older people - a summary report.

OBJECTIVE: The objective of this study is to develop an update of the evidence-based guidelines for the management of pain in older people. DESIGN: Review of evidence since 2010 using a systematic and consensus approach is performed. RESULTS: Recognition of the type of pain and routine assessment of pain should inform the use of specific environmental, behavioural and pharmacological interventions. Individualised care plans and analgesic protocols for specific clinical situations, patients and health care settings can be developed from these guidelines. CONCLUSION: Management of pain must be considered as an important component of the health care provided to all people, regardless of their chronological age or severity of illness. By clearly outlining areas where evidence is not available, these guidelines may also stimulate further research. To use the recommended therapeutic approaches, clinicians must be familiar with adverse effects of treatment and the potential for drug interactions.