Assessing the Sensitivity of the Canadian Adverse Event Following Immunization Surveillance System ( CAEFISS)

Background: Vaccines are important to public health, but because of the way they are manufactured, their mechanism of action, and their indicated population, careful monitoring of their adverse events is necessary. Canada has a national surveillance system that collects reports on adverse events that may be associated with vaccine administration. Sensitivity is one of the tools used with surveillance systems to study the extent and characteristics of reporting of a surveillance system. To date, the sensitivity of the Canadian system has not been assessed. Purpose: To assess the sensitivity of the Canadian Adverse Event Following Immunization Surveillance System (CAEFISS). Methods: Based on specific adverse events following immunization (AEFI) and vaccines chosen for the study, a thorough literature search was completed to find the best source which identifies expected rates of AEFI. Studies used were assessed based on quality and sample size. The expected rates of AEFI, in combination with public health estimates of vaccine coverage rates, were used to estimate the expected number of reports. The reports provided the actual number of events used to calculate the sensitivity. Sensitivity was compared based on year of administration, age group, and type of AEFI. Results: The overall sensitivity of the CAEFISS varied from 1.0% to 136.6% for various AEFI for the years 1997 to 2008. For influenza the sensitivity was found to be 93.6% and 136.3% for GBS and anaphylaxis respectively. For DTaP, the rates were found to be 15.0%, 1.0%, and 21.2% for anaphylaxis, HHE, and seizures respectively, and for MMR the rates were 16.5%, 52.7%, and 12.7% in relation to anaphylaxis, thrombocytopenia, and seizures respectively. Conclusions: This is the first assessment of the sensitivity of the CAEFISS, and this study found that the system has reasonable ability to detect AEFI on a national level. CAEFISS had comparable senstivity to other vaccine reporting systems. Many of the AEFI had sensitivity values higher than the 5%-10% range traditionally seen in other passive surveillance systems related to adverse events. The greatest variation of sensitivity was seen between vaccines. Rarity and timing of the AEFI may also impact the sensitivity. Variation of sensitivity and the variation found in the sensitivity analysis lend to the further development and implementations of case definitions for rarer adverse events, especially anaphylaxis. Further research of other factors that impact reporting is necessary

Disease risk score as a confounder summary method: systematic review and recommendations: DRS AS A CONFOUNDER SUMMARY METHOD

To systematically examine trends and applications of the disease risk score (DRS) as a confounder summary method

Characteristics of Opioid-Related Deaths in Ontario, Canada: Leveraging the Drug and Drug/Alcohol Related Death (DDARD) Database

Introduction Review of post-mortem toxicological results is the gold standard for identifying whether a death is opioid-related. The Drug and Drug/Alcohol Related Death (DDARD) database contains abstracted information from the Office of the Chief Coroner of Ontario, for all opioid-related deaths that occurred in Ontario, Canada between 1991 and 2016. Objectives and Approach The DDARD, which contains manner of death and drug concentrations from post-mortem toxicology results for opioids-related deaths in Ontario, was linked to the data repository housed at ICES. The objective of this project was to examine demographic characteristics and the type of opioid contributing to opioid-related deaths in FY2015/16. Individuals identified within DDARD who died from an opioid-related cause were linked to demographic, hospitalization and prescription drug databases to report on age, gender, neighbourhood income quintile, past health services utilization for opioid-toxicity, alcohol use disorders (AUD), mental health emergency department (ED) visits, and opioid(s) present at time of death. Results We identified 737 opioid-related deaths in FY2015/16, the majority of which involved men (n=497; 67.4%), those living in lower socioeconomic status areas (n=395; 53.6%), and those residing in urban regions (n=655; 88.9%). Nearly half (n=325; 44.1%) of opioid-related deaths occurred among those aged 45 to 65 years. We found 9.5% (n=70) of individuals had a previous hospital visit for opioid toxicity, 25.4% (n=187) had previously diagnosed AUD, and 42.5% (n=313) had a previous mental health ED visit. Overall, 250 (33.9%) individuals had an active opioid prescription at time of death with oxycodone (n=92; 36.8%) the most commonly dispensed. Among those who didn’t have an active opioid prescription at time of death (n=484; 66%), fentanyl (n=184; 37.8%) was the most commonly found opioid on post-mortem toxicology. Conclusion/Implications This project demonstrates how data obtained through chart abstractions can be used to enhance existing administrative health datasets. Given the concern around the safety of opioids, it is important to examine the characteristics and type of opioid(s) involved at time of opioid-related death in order to develop targeted preventative strategies

Linking the Narcotics Monitoring System Database to Quantify the Contribution of Prescribed and Non-Prescribed Opioids to Opioid Overdoses in Ontario, Canada

Introduction The Ontario Narcotics Monitoring System (NMS) captures information on all prescriptions for controlled medications dispensed from outpatient pharmacies in Ontario, Canada, regardless of payer. This system was introduced in 2012, as a strategy to promote appropriate prescribing and dispensing practices. Objectives and Approach We sought to explore the degree to which prescriptions in the NMS can be linked to other health claims databases, and describe the types of medications dispensed between July 2012 and December 2016. We also linked opioid prescriptions to hospitalization and mortality data to examine the relative contributions of prescribed and non-prescribed opioids to opioid toxicity events in 2016. A recent opioid prescription was defined as a prescription with a days’ supply that overlapped the opioid toxicity event. Analyses were stratified by gender and age. Results We examined 1.3 million prescriptions in the NMS during the study period: 72.8% for opioids, 21% for benzodiazepines, 4.4% for stimulants and <2% for other medications. Approximately 97% of prescriptions in the NMS could be linked because an Ontario health card was used at the time of dispensing. In 2016, we found that 52.8% of individuals with an opioid-related hospitalization (N=804/1,524) and 32.5% of those with an opioid-related death (N=278/855) had a recent opioid prescription. The proportion of opioid-related hospitalizations and deaths with a recent opioid prescription was significantly higher among females vs. males (57.2% vs. 48.0% and 45.6% vs. 26.4%, respectively; p<.001), and older (aged 45-64) vs. younger (aged 0-24) individuals (66.9% vs 9.9% and 46.4% vs 11.6% respectively; p<.001). Conclusion/Implications Linkage was possible for the majority of prescriptions in the NMS. We found that a large proportion of opioid overdoses involved a non-prescribed opioid, particularly among men and younger individuals. These findings highlight an important difference in patterns of opioid use and toxicities in the population that policy-makers should consider

Developing a framework to incorporate real-world evidence in cancer drug funding decisions : The Canadian Real-world Evidence for Value of Cancer Drugs (CanREValue) collaboration

Background Oncology therapy is becoming increasingly more expensive and challenging the affordability and sustainability of drug programmes around the world. When new drugs are evaluated, health technology assessment organisations rely on clinical trials to inform funding decisions. However, clinical trials are not able to assess overall survival and generalises evidence in a real-world setting. As a result, policy makers have little information on whether drug funding decisions based on clinical trials ultimately yield the outcomes and value for money that might be expected. Objective The Canadian Real-world Evidence for Value of Cancer Drugs (CanREValue) collaboration, consisting of researchers, recommendation-makers, decision makers, payers, patients and caregivers, are developing and testing a framework for Canadian provinces to generate and use real-world evidence (RWE) for cancer drug funding in a consistent and integrated manner. Strategy The CanREValue collaboration has established five formal working groups (WGs) to focus on specific processes in the generation and use of RWE for cancer drug funding decisions in Canada. The different RWE WGs are: (1) Planning and Drug Selection; (2) Methods; (3) Data; (4) Reassessment and Uptake; (5) Engagement. These WGs are acting collaboratively to develop a framework for RWE evaluation, validate the framework through the multiprovince RWE projects and help to integrate the final RWE framework into the Canadian healthcare system. Outcomes The framework will enable the reassessment of cancer drugs, refinement of funding recommendations and use of novel funding mechanisms by decision-makers/payers across Canada to ensure the healthcare system is providing clinical benefits and value for money

Impact of the COVID-19 pandemic on antidepressant and antipsychotic use among children and adolescents: a population-based study

BackgroundThe COVID-19 pandemic was associated with increases in the prevalence of depression, anxiety and behavioural problems among children and youth. Less well understood is the influence of the pandemic on antidepressant and antipsychotic use among children. This is important, as it is possible that antidepressants and antipsychotics were used as a “stop-gap” measure to treat mental health symptoms when in-person access to outpatient care and school-based supportive services was disrupted. Furthermore, antipsychotics and antidepressants have been associated with harm in children and youth. We examined trends in dispensing of these medications two years following the pandemic among children 18 years of age and under in Ontario, Canada.MethodsWe conducted a population-based time-series study of antidepressant and antipsychotic medication dispensing to children and adolescents ≤18 years old between September 1, 2014, and March 31, 2022. We measured monthly population-adjusted rates of antidepressant and antipsychotics obtained from the IQVIA Geographic Prescription Monitor (GPM) database. We used structural break analyses to identify the pandemic month(s) when changes in the dispensing of antidepressants and antipsychotics occurred. We used interrupted time series models to quantify changes in dispensing following the structural break and compare observed and expected use of these drugs.ResultsOverall, we found higher-than-expected dispensing of antidepressants and antipsychotics in children and youth. Specifically, we observed an immediate step decrease in antidepressant dispensing associated with a structural break in April 2020 (−55.8 units per 1,000 individuals; 95% confidence intervals [CI] CI: −117.4 to 5.8), followed by an increased monthly trend in the rate of antidepressant dispensing of 13.0 units per 1,000 individuals (95% CI: 10.2–15.9). Antidepressant dispensing was consistently greater than predicted from September 2020 onward. Antipsychotic dispensing increased immediately following a June 2020 structural break (26.4 units per 1,000 individuals; 95% CI: 15.8–36.9) and did not change appreciably thereafter. Antipsychotic dispensing was higher than predicted at all time points from June 2020 onward.ConclusionWe found higher-than-expected dispensing of antidepressants and antipsychotics in children and youth. These increases were sustained through nearly two years of observation and are especially concerning in light of the potential for harm with the long-term use of antipsychotics in children. Further research is required to understand the clinical implications of these findings

Advancing Comparative Effectiveness Research: Filling in the Gaps for Bisphosphonates

Drug approval regulations for market-entry often only require that medications be proven efficacious compared to placebo. This drug approval policy creates a gap in information for clinicians and policy makers to make informed decisions between treatment options. Comparative effectiveness research seeks to address these knowledge gaps, primarily through the use of administrative data and network meta-analysis (NMA). The use of bisphosphonates for the treatment of osteoporosis is representative of this problem. In Canada, there are currently four approved bisphosphonates indicated for the treatment of osteoporosis. This thesis is comprised of three unique projects contributing to comparative effectiveness research of bisphosphonate therapy. The projects address methodological gaps in the development and uses of the disease risk score (DRS), a confounder summary score, and clinical gaps in the comparative safety of bisphosphonates leveraging NMA methodology. The methodological findings of the thesis raise caution towards the standard practice of applying the DRS in situations where policy-induced bias is present, suggest the need for more consistent nomenclature for the DRS, and points to future areas for development of the DRS. The clinical findings of the thesis demonstrate little difference in serious adverse events between oral bisphosphonates. Future research should address questions related to the impact of comparative safety and adherence of bisphosphonates. Overall, this dissertation addresses important gaps in utilization and applications of the DRS, implications of policy-induced selection bias, and comparative safety and adherence of bisphosphonate therapy.  Ph.D.2018-06-09 00:00:0

Editorial: Shaping with data: Using pharmacoepidemiology to shape pharmaceutical policy and clinical decision-making

ISSN:1663-981

Nationwide Trends in Dispensing of Sodium Glucose Cotransporter 2 Inhibitors

Background: Three large cardiovascular outcome trials have investigated the safety of sodium glucose cotransporter 2 (SGLT2) inhibitors.  Objective: To analyze the nationwide dispensing of SGLT2 inhibitors before and after the publication of these trials.  Methods: A cross-sectional study was conducted of monthly prescription dispensing of SGLT2 inhibitors from May 23, 2014, to April 30, 2019, using nationwide data for Canada. An autoregressive integrated moving average (ARIMA) model was fitted to the monthly number of tablets dispensed for each SGLT2 inhibitor; the model included a ramp intervention function at the publication dates of interest to estimate the impact on SGLT2 inhibitor dispensing patterns.  Results: The rate of canagliflozin and dapagliflozin dispensing declined after publication of results of the empagliflozin cardiovascular trial in September 2015. After publication of results of the canagliflozin trial in June 2017, which indicated a reduction in cardiovascular events and an increase in the risk of lower-limb amputation, canagliflozin remained the most commonly dispensed SGLT2 inhibitor, but its rate of dispensing declined further. In contrast, the rate of empagliflozin dispensing increased, while the rate of dapagliflozin dispensing was unchanged. After publication of the dapagliflozin trial in November 2018, which indicated no clear reduction in cardiovascular events, short-term trends in dispensing of canagliflozin, empagliflozin, and dapagliflozin were largely unaffected.  Conclusions: The cardiovascular outcome trials appeared to have an important impact on the dispensing of SGLT2 inhibitors in Canada.  RÉSUMÉ  Contexte : Trois grands essais portant sur les résultats cardiovasculaires avaient pour objet l’étude de l’innocuité des inhibiteurs du cotransporteur sodium-glucose de type 2 (SGLT2).  Objectif : Analyser la délivrance nationale des inhibiteurs du SGLT2 avant et après la publication de ces essais.  Méthodes : Une étude transversale a été menée sur la délivrance d’ordonnances mensuelles d’inhibiteurs du SGLT2 du 23 mai 2014 au 30 avril 2019, à l’aide de données nationales pour le Canada. Un modèle de moyenne mobile intégrée autorégressive (ARIMA) a été adapté au nombre mensuel de comprimés distribués pour chaque inhibiteur du SGLT2; le modèle comprenait une fonction d’intervention progressive aux dates de publication d’intérêt pour estimer l’effet sur les schémas de délivrance d’inhibiteurs du SGLT2.  Résultats : Le taux de délivrance de canagliflozine et de dapagliflozine a diminué après la publication des résultats de l’essai cardiovasculaire empagliflozine en septembre 2015. Après la publication des résultats de l’essai cardiovasculaire canagliflozine en juin 2017, qui indiquaient une réduction des événements cardiovasculaires et une augmentation du risque d’amputation des membres inférieurs, la canagliflozine est restée l’inhibiteur du SGLT2 le plus couramment délivré, mais son taux de délivrance a encore diminué. En revanche, le taux d’empagliflozine délivré a augmenté, tandis que le taux de délivrance de dapagliflozine est resté identique. Après la publication de l’essai sur la dapagliflozine en novembre 2018, qui n’indiquait aucune réduction nette des événements cardiovasculaires, les tendances à court terme de la délivrance de la canagliflozine, de l’empagliflozine et de la dapagliflozine n’ont pratiquement pas changé.  Conclusions : Les essais portant sur les résultats cardiovasculaires semblaient avoir un effet important sur la délivrance des inhibiteurs du SGLT2 au Canada.