Media coverage of drug regulatory agencies' safety advisories: a case study of citalopram and denosumab

AIMS: Drug regulators issue safety advisories to warn clinicians and the public about new evidence of harmful effects of medicines. It is unclear how often these messages are covered by the media. Our aim was to analyse the extent of media coverage of two medicines that were subject to safety advisories from 2007 to 2016 in Australia, Canada, the United Kingdom and the United States. METHODS: Two medicines widely used to treat mental health or physical conditions were selected: citalopram and denosumab. Media reports were identified by searching LexisNexis and Factiva. Reports were included if they stated at least one health benefit or harm. A content analysis of the reports was conducted. RESULTS: In total, 195 media reports on citalopram and 239 on denosumab were included. For citalopram, 43.1% (84/195) of the reports mentioned benefits, 85.6% (167/195) mentioned harms and 9.7% (19/195) mentioned the harm described in the advisories (cardiac arrhythmia). For denosumab, 94.1% (225/239) of the reports mentioned benefits and 39.7% (95/239) mentioned harms. The harms described in the advisories were rarely mentioned: 10.9% (26/239) of the reports mentioned osteonecrosis and ≤5% mentioned any of the other harms (atypical fractures, hypocalcaemia, serious infections and dermatologic reactions). CONCLUSIONS: We found limited media coverage of the harms highlighted in safety advisories. Almost two‐thirds of the media stories on denosumab did not include any information about harms, despite the many advisories during this time frame. Citalopram coverage covered harms more often but rarely mentioned cardiac arrhythmias. These findings raise questions about how to better ensure that regulatory risk communications reach the general public

Do Intervention Studies to Promote Physical Activity and Reduce Sedentary Behavior in Children and Adolescents Take Sex/Gender Into Account? A Systematic Review

Background: Physical inactivity is often reported in youth and differs among boys and girls. The aim of this study is to assess sex/gender considerations in intervention studies promoting physical activity and reducing sedentary behavior in youth using a sex/gender checklist. Methods: A systematic search was conducted in August 2018 to identify all relevant controlled trials. Studies screened must have reported a quantified measure of physical activity and/or sedentary behavior, and identified participants by sex/gender at baseline. For evaluation of the sex/gender consideration, the authors used a sex/gender checklist developed by expert consensus. Results: The authors reviewed sex/gender considerations in all aspects of intervention development, implementation, and evaluation in 217 studies. Sex/gender aspects were only rudimentarily taken into account, most frequently during statistical analyses, such as stratification or interaction analysis. Conclusions: Sex/gender effects are not sufficiently reported. To develop guidelines that are more inclusive of all girls and boys, future interventions need to document sex/gender differences and similarities, and explore whether sex/gender influences different phases of intervention programs. The newly developed sex/gender checklist can hereby be used as a tool and guidance to adequately consider sex/gender in the several steps of intervention planning, implementation, and evaluation

Influence of drug safety advisories on drug utilisation: an international interrupted time series and meta-analysis

OBJECTIVE: To evaluate the association between regulatory drug safety advisories and changes in drug utilisation. DESIGN: We conducted controlled, interrupted times series analyses with administrative prescription claims data to estimate changes in drug utilisation following advisories. We used random-effects meta-analysis with inverse-variance weighting to estimate the average postadvisory change in drug utilisation across advisories. STUDY POPULATION: We included advisories issued in Canada, Denmark, the UK and the USA during 2009-2015, mainly concerning drugs in common use in primary care. We excluded advisories related to over-the-counter drugs, drug-drug interactions, vaccines, drugs used primarily in hospital and advisories with co-interventions within ±6 months. MAIN OUTCOME MEASURES: Change in drug utilisation, defined as actual versus predicted percentage change in the number of prescriptions (for advisories without dose-related advice), or in the number of defined daily doses (for dose-related advisories), per 100 000 population. RESULTS: Among advisories without dose-related advice (n=20), the average change in drug utilisation was -5.83% (95% CI -10.93 to -0.73; p=0.03). Advisories with dose-related advice (n=4) were not associated with a statistically significant change in drug utilisation (-1.93%; 95% CI -17.10 to 13.23; p=0.80). In a post hoc subgroup analysis of advisories without dose-related advice, we observed no statistically significant difference between the change in drug utilisation following advisories with explicit prescribing advice, such as a recommendation to consider the risk of a drug when prescribing, and the change in drug utilisation following advisories without such advice. CONCLUSIONS: Among safety advisories issued on a wide range of drugs during 2009-2015 in 4 countries (Canada, Denmark, the UK and the USA), the association of advisories with changes in drug utilisation was variable, and the average association was modest

Hydroxyzine Initiation Following Drug Safety Advisories on Cardiac Arrhythmias in the UK and Canada: A Longitudinal Cohort Study

INTRODUCTION: Regulatory advisories on hydroxyzine and risk of QT prolongation and Torsade de pointes (TdP) were issued in the UK in April 2015 and Canada in June 2016. We hypothesized patients with risk factors for QT prolongation and TdP, compared with those without risk factors, would be less likely to initiate hydroxyzine in the UK and in British Columbia (BC), Canada, following advisories. METHODS: We conducted a longitudinal study with repeated measures, and evaluated hydroxyzine initiation in a UK cohort and a concurrent BC control cohort (April 2013-March 2016) as well as in a BC advisory cohort (June 2014-May 2017). RESULTS: This study included 247,665 patients in the UK cohort, 297,147 patients in the BC control cohort, and 303,653 patients in the BC advisory cohort. Over a 12-month post-advisory period, hydroxyzine initiation decreased by 21% in the UK (rate ratio 0.79, 95% confidence interval 0.66-0.96) relative to the expected level of initiation based on the pre-advisory trend. Hydroxyzine initiation did not change in the BC control cohort or following the Canadian advisory in the BC advisory cohort. The decrease in hydroxyzine initiation in the UK in the 12 months after the advisories was not significantly different for patients with risk factors compared with those without risk factors. CONCLUSION: Hydroxyzine initiation decreased in the UK, but not in BC, in the 12 months following safety advisories. The decrease in hydroxyzine initiation in the UK was not significantly different for patients with versus without risk factors for QT prolongation and TdP

Protein-tyrosine kinase signalling pathways in normal hematopoiesis and leukemogenesis

grantor: University of TorontoThe reversible phosphorylation of proteins on tyrosine residues modulates protein function and is central to the regulation of hematopoiesis. Consistent with the emerging role of phosphotyrosine in normal hematopoietic processes, gain- or loss-of-function mutations in genes encoding protein-tyrosine kinases (PTKs) have been identified in a number of human hematological disorders. A well characterized example of an activating mutation is fusion of the ' abl' and 'bcr' genes which produces a chimeric Bcr-Abl protein with deregulated Abl kinase activity. The 'bcr-abl' fusion gene is the result of a reciprocal t(9;22) translocation and occurs in chronic myelogeneous leukemia and a subset of acute lymphoblastic leukemia. Identification of the targets of normal and transforming PTKs is necessary for understanding both normal signal transduction pathways and the means by which these pathways are deregulated during cellular transformation. In this thesis, proximal targets of the Bcr-Abl oncoproteins are characterized. Src homology 2 (SH2) and Src homology 3 (SH3) domains are protein interaction domains which recognize phosphotyrosine-containing and proline-rich motifs respectively, and are present in an otherwise diverse group of signalling molecules. In Chapters 2 and 3, a number of SH2/SH3-containing enzymes and adaptor molecules, along with their associated proteins, are implicated in ' bcr-abl'-mediated transformation. These include the 120 kDa Ras GTPase activating protein (p120-Gap), the Gap-associated proteins p62 and p190, Grb2, mSos1, Shc, Shc-associated p140/p145, Vav, the p85 regulatory subunit of phosphatidylinositol 3'-kinase and phospholipase C-ã1. Subsets of these proteins are substrates of Bcr-Abl (or a downstream PTK) and/or form stable complexes with Bcr-Abl 'in vivo'. A number of the identified targets are potential regulators of Ras and provide mechanisms whereby Bcr-Abl may be directly linked to Ras signalling pathways. These data are consistent with a prominent role for Ras in PTK-mediated transformation. In Chapter 4, some of these proteins, notably Shc, Shc-associated p140/p145, Grb2 and Vav, are demonstrated to participate in cytokine-stimulated pathways which control the survival, proliferation or activation of normal primary hematopoietic cells. Taken together, these data support the notion that leukemogenesis involves the constitutive stimulation of signalling molecules that are normally transiently activated in cells responding to cues within the hematopoietic microenvironment. The structural basis for the interaction of PTKs with some of their targets was also investigated. These data suggest that SH2-mediated interactions are important in hematopoietic cell signalling. In Chapter 3, the binding of Grb2 to Bcr-Abl is demonstrated to be mediated by the Grb2 SH2 domain which recognizes an autophosphorylated sequence, p.Tyr177-Val178-Asn 179-Val180, located within the N-terminal ' bcr'-encoded sequence common to all isoforms of Bcr-Abl. The Bcr element of the Bcr-Abl fusion proteins thus contributes to the target specificity of the activated Abl kinases. This is a novel function of the Bcr moiety which has not previously been defined, and provides new insight into the potential mechanisms whereby fusion of the 'abl' and 'bcr' genes is oncogenically activating.Ph.D

Risk prediction models for lung cancer in people who have never smoked: a protocol of a systematic review

Abstract Background Lung cancer is one of the most commonly diagnosed cancers and the leading cause of cancer-related death worldwide. Although smoking is the primary cause of the cancer, lung cancer is also commonly diagnosed in people who have never smoked. Currently, the proportion of people who have never smoked diagnosed with lung cancer is increasing. Despite this alarming trend, this population is ineligible for lung screening. With the increasing proportion of people who have never smoked among lung cancer cases, there is a pressing need to develop prediction models to identify high-risk people who have never smoked and include them in lung cancer screening programs. Thus, our systematic review is intended to provide a comprehensive summary of the evidence on existing risk prediction models for lung cancer in people who have never smoked. Methods Electronic searches will be conducted in MEDLINE (Ovid), Embase (Ovid), Web of Science Core Collection (Clarivate Analytics), Scopus, and Europe PMC and Open-Access Theses and Dissertations databases. Two reviewers will independently perform title and abstract screening, full-text review, and data extraction using the Covidence review platform. Data extraction will be performed based on the Checklist for Critical Appraisal and Data Extraction for Systematic Reviews of Prediction Modeling Studies (CHARMS). The risk of bias will be evaluated independently by two reviewers using the Prediction model Risk-of-Bias Assessment Tool (PROBAST) tool. If a sufficient number of studies are identified to have externally validated the same prediction model, we will combine model performance measures to evaluate the model’s average predictive accuracy (e.g., calibration, discrimination) across diverse settings and populations and explore sources of heterogeneity. Discussion The results of the review will identify risk prediction models for lung cancer in people who have never smoked. These will be useful for researchers planning to develop novel prediction models, and for clinical practitioners and policy makers seeking guidance for clinical decision-making and the formulation of future lung cancer screening strategies for people who have never smoked. Systematic review registration This protocol has been registered in PROSPERO under the registration number CRD42023483824

A sex/gender perspective on interventions to promote children’s and adolescents’ overall physical activity: results from genEffects systematic review

Background: To evaluate the effects of interventions on children’s and adolescents’ overall physical activity (PA) for boys and girls separately and to appraise the extent to which the studies haven taken sex/gender into account. Methods: Systematic review and semi-quantitative analysis. Eleven electronic databases were searched to identify all relevant randomized and non-randomized controlled trials. Studies had to report overall PA as the main outcome to be eligible for inclusion in the review. The main outcomes of the studies is a quantified measure of overall PA. Additionally, all studies had to report sex/gender disaggregated overall PA at baseline and/or follow up and/or explain how they dealt with sex/gender during outcome analysis (i.e., sex/gender adjusted analyses) and/or report that there were no differences in the outcome when looking at sex/gender. PRISMA guidelines were followed. Two authors independently screened studies for eligibility and assessed the risk of bias. Semi-quantitative analyses were conducted to evaluate intervention effects, taking into account the extent to which studies have considered sex/gender aspects. To evaluate sex/gender considerations in primary studies, a newly developed sex/gender checklist was used. The study was registered previously (registration number CRD42018109528). Results: In total, 97 articles reporting 94 unique studies with 164 outcomes for overall PA were included in the present review. Average sample size was 829 participants, ranging from five to 9839. Participants’ ages ranged from three to 19 years. Our review shows that overall 35% of PA outcomes had significant effects in increasing overall PA of children and adolescents. Not including single sex/gender studies, 105 out of 120 PA outcomes resulted in same intervention effects for boys and girls. The interventions reported to have similar effects on PA outcomes for boys and girls showed higher quality of reporting sex/gender aspects of measurement instruments, participant flow and intervention content and materials than PA outcomes with effects only in boys or only in girls. Overall, consideration of sex/gender aspects in intervention studies is low. Conclusions: There is still a need to address sufficient consideration of sex/gender aspects in developing and implementing interventions in the context of PA.Medicine, Faculty ofNon UBCAnesthesiology, Pharmacology and Therapeutics, Department ofReviewedFacult

Unbranded advertising of prescription medicines to the public by pharmaceutical companies

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: To assess the effects of unbranded advertising of prescription medicines, conducted by or on behalf of pharmaceutical companies, on consumers' attitudes, knowledge, behaviour, health services use, health outcomes and costs

Protocol for the the validation of search strategies for retrieval of Clinical Practice Guidelines in MEDLINE, Embase and PubMed

Procedures, including required equipment, instruments, safety precautions, and reporting standards