Report on methods of safety signal generation in paediatrics from pharmacovigilance databases

This deliverable is based on the need to develop and test methods for safety signal detection in children. Signal detection is the mainstay of detecting safety issues, but so far very few groups have specifically looked at children. We developed reference sets for positive and negative drugevent combinations and vaccine-event combinations by a systematic literature review on all combinations. We retrieved the FDA AERS database, the CDC VAERS database and EUDRAVIGILANCE database. In order to analyse the datasets we had a stepwise approach from extraction of data, cleaning (e.g. mapping MedDRA and ATC codes) and transformation into a a common data model that we defined for the spontaneous reporting databases. A statistical analysis plan was created for the testing of methods and we provided some descriptive analyses of the FAERS data. Next steps will be to complete the analyses

Drug Safety Monitoring in Children: Performance of Signal Detection Algorithms and Impact of Age Stratification

Introduction: Spontaneous reports of suspected adverse drug reactions (ADRs) can be analyzed to yield additional drug safety evidence for the pediatric population. Signal detection algorithms (SDAs) are required for these analyses; however, the performance of SDAs in the pediatric population specifically is unknown. We tested the performance of two SDAs on pediatric data from the US FDA Adverse Event Reporting System (FAERS) and investigated the impact of age stratification and age adjustment on the performance of SDAs. Methods: We tested the performance of two established SDAs: the proportional reporting ratio (PRR) and the empirical Bayes geometric mean (EBGM) on a pediatric dataset from FAERS (2004–2012). We compared the performance of the SDAs with a published pediatric-specific reference set by calculating diagnostic test-related statistics, including the area under the curve (AUC) of receiver operating characteristics. Impact of age stratification and age-adjustment on the performance of the SDAs was assessed. Age adjustment was performed by pooling (Mantel-Hanszel) stratum-specific estimates. Results: A total of 115,674 pediatric reports (patients aged 0–18 years) comprising 893,587 drug–event combinations (DECs) were analysed. Crude values of the AUC were similar for both SDAs: 0.731 (PRR) and 0.745 (EBGM). Stratification unmasked four DECs, e.g., ‘ibuprofen and thrombocytopenia’. Age adjustment did not improve performance. Conclusion: The performance of the two tested SDAs was similar in the pediatric population. Age adjustment does not improve performance and is therefore not recommended to be performed routinely. Stratification can reveal new associations, and therefore is recommended when either drug use is age-specific or when an age-specific risk is suspected

The effect of mode of delivery on health-related quality-of-life in mothers: a systematic review and meta-analysis

Background: Previous research is inconclusive on the effects of mode of delivery on maternal health-related quality-of-life (HRQoL). We conducted a systematic review and meta-analysis to assess the current evidence for associations between mode of delivery and postpartum health-related quality-of-life. Methods: Electronic databases MEDLINE ALL (OVID), Web of Science, The Cochrane Library, CINAHL and EMBASE (OVID) were searched for English written articles investigating the relationship between mode of delivery and quality-of-life published form inception to 15th October 2020. Two reviewers independently screened titles and abstracts, assessed full texts, and extracted data. Meta-analysis was conducted where possible. Results: Twenty-one studies, including 19,879 women, met the inclusion criteria. A meta-analysis of 18 studies found HRQoL scores were significantly higher for women after vaginal delivery in comparison to caesarean (emergency and elective combined) (Effect Size (ES) 0.17, 95% CI 0.01–0.25, n = 7665) with highest scores after assisted vaginal delivery (ES 0.21, 95% CI 0.13–0.30, n = 2547). Physical functioning (ES 11.18, 95% CI = 2.29–20.06, n = 1746), physical role (ES 13.10, 95% CI = 1.16–25.05, n = 1471), vitality (ES 6.31, 95% CI = 1.14–10.29, n = 1746) and social functioning (ES 5.69, 95% CI = 1.26–10.11, n = 1746) were significantly higher after vaginal delivery compared to caesarean. Conclusions: Health-related quality-of-life scores were higher for women after vaginal delivery in comparison to caesarean section. Consequently, women should be encouraged to deliver vaginally where possible. The findings of this research should be available to the relevant population to help support informed choice

Impact of different assumptions on estimates of childhood diseases obtained from health care data: A retrospective cohort study

Purpose: Accurate estimates of disease incidence in children are required to support pediatric drug development. Analysis of electronic health care records (EHR) may yield such estimates but pediatric-specific methods are lacking. We aimed to understand the impact of assumptions regarding duration of disease episode and length of run-in period on incidence estimates from EHRs. Methods: Children aged 0 to 17 years (5-17 years for asthma) registered in the Integrated Primary Care Information database between 2002 and 2014 were studied. We tested the impact of the following: max

COVID-19 in cardiac arrest and infection risk to rescuers : a systematic review

Background There may be a risk of COVID-19 transmission to rescuers delivering treatment for cardiac arrest. The aim of this review was to identify the potential risk of transmission associated with key interventions (chest compressions, defibrillation, cardiopulmonary resuscitation) to inform international treatment recommendations. Methods We undertook a systematic review comprising three questions: (1) aerosol generation associated with key interventions; (2) risk of airborne infection transmission associated with key interventions; and (3) the effect of different personal protective equipment strategies. We searched MEDLINE, Embase, Cochrane Central Register of Controlled Trials, and the World Health Organization COVID-19 database on 24th March 2020. Eligibility criteria were developed individually for each question. We assessed risk of bias for individual studies, and used the GRADE process to assess evidence certainty by outcome. Results We included eleven studies: two cohort studies, one case control study, five case reports, and three manikin randomised controlled trials. We did not find any direct evidence that chest compressions or defibrillation either are or are not associated with aerosol generation or transmission of infection. Data from manikin studies indicates that donning of personal protective equipment delays treatment delivery. Studies provided only indirect evidence, with no study describing patients with COVID-19. Evidence certainty was low or very low for all outcomes. Conclusion It is uncertain whether chest compressions or defibrillation cause aerosol generation or transmission of COVID-19 to rescuers. There is very limited evidence and a rapid need for further studies

Association between vitamin D supplementation or serum vitamin D level and susceptibility to SARS-CoV-2 infection or COVID-19 including clinical course, morbidity and mortality outcomes? A systematic review

Objective To systemically review and critically appraise published studies of the association between vitamin D supplementation or serum vitamin D level and susceptibility to SARS-CoV-2 infection or COVID-19, including clinical course, morbidity and mortality outcomes. Design Systematic review. Data sources MEDLINE (OVID), Embase (OVID), Cochrane Central Register of Controlled Trials, MedRxiv and BioRxiv preprint databases. COVID-19 databases of the WHO, Cochrane, CEBM Oxford and Bern University up to 10 June 2020. Study selection Studies that assessed vitamin D supplementation and/or low serum vitamin D in patients acutely ill with, or at risk of, severe betacoronavirus infection (SARS-CoV, MERS-CoV, SARS-CoV-2). Data extraction Two authors independently extracted data using a predefined data extraction form and assessed risk of bias using the Downs and Black Quality Assessment Checklist. Results Searches elicited 449 papers, 59 studies were eligible full-text assessment and 4 met the eligibility criteria of this review. The four studies were narratively synthesised and included (1) a cross-sectional study (n=107) suggesting an inverse association between serum vitamin D and SARS-CoV-2; (2) a retrospective cohort study (348 598 participants, 449 cases) in which univariable analysis showed that vitamin D protects against COVID-19; (3) an ecological country level study demonstrating a negative correlation between vitamin D and COVID-19 case numbers and mortality; and (4) a case–control survey (n=1486) showing cases with confirmed/probable COVID-19 reported lower vitamin D supplementation. All studies were at high/unclear risk of bias. Conclusion There is no robust evidence of a negative association between vitamin D and COVID-19. No relevant randomised controlled trials were identified and there is no robust peer-reviewed published evidence of association between vitamin D levels and severity of symptoms or mortality due to COVID-19. Guideline producers should acknowledge that benefits of vitamin D supplementation in COVID-19 are as yet unproven despite increasing interest

Pediatric drug safety signal detection: a new drug-event reference set for performance testing of data-mining methods and systems

BACKGROUND: Better evidence regarding drug safety in the pediatric population might be generated from existing data sources such as spontaneous reporting systems and electronic healthcare records. The Global Research in Paediatrics (GRiP)-Network of Excellence aims to develop pediatric-specific methods that can be applied to these data sources. A reference set of positive and negative drug-event associations is required. OBJECTIVE: The aim of this study was to develop a pediatric-specific reference set of positive and negative drug-event associations. METHODS: Considering user patterns and expert opinion, 16 drugs that are used in individuals aged 0-18 years were selected and evaluated against 16 events, regarded as important safety outcomes. A cross-table of unique drug-event pairs was created. Each pair was classified as potential positive or negative control based on information from the drug's Summary of Product Characteristics and Micromedex. If both information sources consistently listed the event as an adverse event, the combination was reviewed as potential positive control. If both did not, the combination was evaluated as potential negative control. Further evaluation was based on published literature. RESULTS: Selected drugs include ibuprofen, flucloxacillin, domperidone, methylphenidate, montelukast, quinine, and cyproterone/ethinylestradiol. Selected events include bullous eruption, aplastic anemia, ventricular arrhythmia, sudden death, acute kidney injury, psychosis, and seizure. Altogether, 256 unique combinations were reviewed, yielding 37 positive (17 with evidence from the pediatric population and 20 with evidence from adults only) and 90 negative control pairs, with the remainder being unclassifiable. CONCLUSION: We propose a drug-event reference set that can be used to compare different signal detection methods in the pediatric population

Studying Disease Occurrence and Drug Effects in Children: A global approach

markdownabstractChildhood diseases result from different causes and exhibit different characteristics. The occurrence of such diseases can be estimated from electronic healthcare records but the characteristics of both the diseases and the databases should be considered. Licensed drugs have limited or no direct evidence of safety and effectiveness in children, resulting in high levels of unlicensed and off-label drug use. To address this unfairness, evidence on safety and effectiveness should be generated using ‘real-world’ data in children. Methods need to be made ‘child-proof’. In this thesis, we studied and developed methods for assessing the occurrence of disease, and drug safety and effectiveness in children. Based on our findings, we made appropriate recommendations. In the studies that comprise this thesis, we utilized different types/sources of data including the published literature, spontaneous reporting (suspected adverse drug reactions) data and electronic health records (data from general practitioners). We found that disease occurrence can be estimated from electronic health care databases. Also, we demonstrated that both left censoring and the choice of episode duration impact the incidence and prevalence estimates of childhood diseases. For the common and recurrent diseases like acute otitis media (AOM), increasing the assumed length of an episode decreases the incidence but increases the prevalence estimates. For the chronic diseases, increasing the length of the run-in period prior to start of follow-up decreases the incidence rate with negligible effect on the prevalence. Of note, the length of the run-in period impacts both common and rare diseases. In order to test the performance of signal detection algorithms when applied to pediatric data specifically, we created a pediatric-specific reference set comprising 37 known (positive controls - PC) and 90 ‘unknown’ (negative controls - NC) DECs. We found that age-stratified analysis is important when performing pediatric-specific drug safety surveillance. Regarding pediatric pharmacoepidemiological safety studies, we discovered that such studies are few and the studies are almost exclusively conducted in high income countries and receive limited funding from pharmaceutical companies and other private sources. Designs differed a lot between drug and vaccine studies. Focus in these studies was only on a small fraction of registered drugs and mainly intermediate outcomes (signs/symptoms). Regarding the quality of the studies, cohort studies were most likely to be biased because historical time prior to study start was not considered for the identification of prevalent cases of the outcome of interest and because follow-up time after study start was not long enough to observe occurrence of the outcome(s). Case control studies were most likely to be of poor quality because of differences in non-response rate (regarding ascertainment of the exposure) between the cases and controls, and because the authors did not specifically report that the controls did not experience the outcome of interest. Regarding published pediatric comparative drug effectiveness studies, we found that studies were few, mainly conducted in North America and Europe and mainly based on public funding. Studies in newborns were rare. Regarding study design, the cohort design was the most commonly applied, probably also because it allows studying multiple outcomes. Regarding outcome, intermediate outcomes were often used. The investigated drugs did not always reflect routine drug utilization in paediatrics. Regarding the use of propensity scores to control confounding by indication in pediatric comparative drug effectiveness studies in asthmatic children; compared to ICS+LABA loose combination for treating asthma, ICS+LABA fixed protected against exacerbation. Calliper matching without replacement resulted in the largest adjustments of the crude hazard ratio (HR) especially in the 1 month prior to treatment start. Based on a survey of the current needs in pediatric pharmacoepidemiology, we found that different researchers used different databases to study the effects of different drug classes, perhaps reflecting the wide range of interests. Based on our findings, we made several recommendations for the improvement of pediatric pharmacoepidemiology

Pharmacoepidemiology in pediatrics : needs, challenges and future directions for research

Despite international initiatives to promote clinical research in pediatrics, there are still many gaps of knowledge in the use of drugs to treat this specific population. When important information cannot be derived only from clinical trials, use of available observational research tools is required. In this paper, we provide an overview of the particular interest of pharmacoepidemiological research into the evaluation of drug effects in children and adolescents. We also sought to underline the unique challenges and specific needs regarding this research. Implementation of innovative methodologies and expansion of database networks to perform necessary studies could further improve performances of observational research. (C) 2018 Societe francaise de pharmacologie et de therapeutique