Search

Introduction: Published data on the safety of natural medical cannabis (MC) when used in the real-world clinical practice setting are lacking. This study aimed to describe adverse events (AEs) reported across three years following MC initiation. Methods: The Quebec Cannabis Registry (QCR) was a prospective registry of adults enrolled through participating physicians when they initiated MC between May 2015 and October 2018. Follow-up ended at MC discontinuation, loss to follow-up, three years, or end of data collection (May 2019). Data were collected at baseline and at follow-up visits every three months for the first two years, then once in the third year. Physicians filled adverse event (AE) reports, which were coded using MedDRA® preferred terms (PTs), and descriptive analyses were conducted. Results: A total of 2991 patients were enrolled (mean age 50.9 years, 50.2% females). During follow-up, 108 patients (3.6%) experienced moderate or severe AEs, yielding 111 AE reports (three patients had two reports) and 214 AEs (average 1.9 AEs per report). Mild AEs were recorded as a reason for MC discontinuation for nine patients, but no AE reports were available. The most common PTs for ingested MC (62 reports) were dizziness (12.9%), nausea (11.3%), somnolence (9.7%), and vomiting (8.1%), and for inhaled MC (23 reports), headache (13.0%) was the most common. The most frequent PTs associated with tetrahydrocannabinol (THC)-dominant MC (25 reports) were dizziness and somnolence (12.0% each); for cannabidiol (CBD)-dominant MC (20 reports), vomiting (20.0%) was most common; and dizziness (17.2%), nausea (13.8%), somnolence (10.3%), and headache (8.6%) were the most frequent for balanced MC (58 reports). Conclusion: No new safety concerns were identified relative to the published literature, although notable differences in AE profile between modes of administration and cannabinoid content ratios should be considered by health professionals. Further work identifying and managing risk factors for AEs is warranted to maintain a favorable benefit-risk balance for MC. [ABSTRACT FROM AUTHOR]

Background: The coronavirus disease 2019 (COVID-19) pandemic has led to disruptions of healthcare delivery and may thus have impacted patterns of prescription opioid use, including risk factors for long-term use. Objective: We aimed to describe changes in patterns of prescription opioid use due to the COVID-19 pandemic in community-dwelling adults without a cancer diagnosis. Methods: Using administrative claims data of the province of Quebec, Canada, a random sample of adults (aged ≥18 years) was selected. These were members of the public drug plan without a cancer diagnosis who initiated a prescription opioid in the outpatient setting between 1 January, 2018 and 28 December, 2020. We assessed the daily dose of initial prescription opioids, the number of days' supply of initial dispensing, and the total duration of opioid use over the first 6 months following initiation. We applied interrupted autoregressive integrated moving average models to examine weekly patterns of prescription opioids before and during the pandemic (starting at the lockdown). Our models included a step intervention function (immediate change) and a ramp intervention function (slope change). Results: There were 112,650 and 34,261 patients who initiated opioid therapy, respectively, in the 115-week pre-pandemic period and in the 41-week pandemic period. At the start of the lockdown, there was a significant immediate decrease in opioid treatment initiation (−326; 95% confidence interval [CI] −419 to −234) and initial daily dose (−1.7 morphine milligram equivalents; 95% CI −2.7 to −0.7). Conversely, there was a significant immediate increase in the number of days' supply of initial dispensing (1.4 days; 95% CI 1.0 to 1.8) and the total duration of opioid use over 6 months (5.7 days; 95% CI 4.6 to 6.8). All these weekly measures returned to values close to those of the pre-pandemic period 10 weeks after the start of lockdown. Conclusions: Our findings showed that the COVID-19 lockdown had an impact on initial number of days' supply, which is a risk factor for long-term use and ultimately opioid-related harm. However, over time, prescription practices and use reverted to those observed in the pre-pandemic period. [ABSTRACT FROM AUTHOR]

Purpose of Review: To quantify the prevalence of asymptomatic pre-heart failure (pre-HF), progression to more severe stages, and associated mortality. Recent Findings: A systematic review was conducted between 01 January 2010 and 12 March 2020 (PROSPERO: CRD42020176141). Data of interest included prevalence, disease progression, and mortality rates. In total, 1030 sources were identified, of which, 12 reported on pre-HF (using the ACC/AHA definition for stage B HF) and were eligible. Prevalence estimates of pre-HF ranged from 11 to 42.7% (10 sources) with higher estimates found in the elderly, in patients with hypertension, and in men. Three studies reported on disease progression with follow-up ranging from 13 months to 7 years. The incidence of symptomatic HF (HF/advanced HF) ranged from 0.63 to 9.8%, and all-cause mortality from 1.6 to 5.4%. Summary: Further research is required to investigate whether early detection and intervention can slow or stop the progression from asymptomatic to symptomatic HF. [ABSTRACT FROM AUTHOR]

Introduction: There have been public health concerns about a potential association between human papillomavirus (HPV) vaccines and premature ovarian failure (POF) in young women. Objective: To identify a potential safety signal of POF after HPV vaccination using the United States (US) Vaccine Adverse Event Reporting System (VAERS) database. Methods: We manually selected relevant MedDRA preferred terms related to POF and identified in VAERS all POF reports in women less than 40 years of age between 2 July 1990 and 14 May 2018, followed by a review of narratives to confirm the cases. We conducted descriptive analyses on age, POF type, HPV vaccine type (HPV2, HPV4, HPV9), time to onset of POF, and dose rank. We described trends in reporting over time and assessed a potential safety signal using the proportional reporting ratio (PRR). Results: Of the 228,341 eligible POF reports, 281 (0.1%) were suspected to be associated with HPV vaccines. Median patient age was 15 years (range 11–39 years). POF events consisted mainly of amenorrhea (80.4%) and premature menopause (15.3%). Mean number of reported POF events significantly increased after the first HPV vaccine launch in 2006 with 22.2 POF cases/year up from 1.4 POF cases/year before the launch. PRR was 46.1 (95% confidence interval: 31.7–67.2) and sensitivity analyses yielded similar estimates. Conclusion: Our study suggests the presence of a potential safety signal of POF associated with HPV vaccination, which may only be partly attributed to notoriety bias. Due to the well-known limitations of spontaneous reporting data, further investigations are warranted. [ABSTRACT FROM AUTHOR]

Global adoption of risk management principles outlined in the International Conference on Harmonisation (ICH) E2E guideline and the Council for International Organizations of Medical Sciences (CIOMS) Working Group VI guidance introduced greater proactivity and consistency into the practice of pharmacovigilance and benefit–risk management throughout the lifecycle of a drug. However, following the release of these guidelines there have been important advances in the science and practice of risk minimisation itself, especially in terms of how risk minimisation measures (RMMs) are designed, implemented, disseminated and evaluated for effectiveness in real-world healthcare settings. In this article, we describe how the field of design, implementation, dissemination and evaluation of RMMs has advanced in recent years while highlighting current areas of challenge and possible solutions. Where possible we cite global examples to demonstrate how evidence-based approaches have informed the development of RMMs. In this context, while taking into consideration local healthcare system policies and national legislations, we conclude with a call for a global effort to harmonise certain areas that focus on, but are not limited to, standardising certain terms and definitions, consistent application of robust methodologies, and outline of best practices for risk minimisation design, implementation, and dissemination. [ABSTRACT FROM AUTHOR]

Background: Fentanyl buccal tablet (FBT), a potent opioid, was approved in Canada in 2013 for breakthrough pain in opioid-tolerant adult cancer patients. Additional risk minimization measures (aRMMs), consisting of communications to patients and healthcare providers (HCPs), were implemented from November 2014 through September 2015.Objectives: The aim of this study was to assess the effectiveness of FBT aRMMs as measured by prescriber knowledge, understanding, and behavior regarding key safety concerns (off-label use, use in non-opioid-tolerant patients, misuse/abuse/diversion, and drug-drug interaction) and to evaluate illicit FBT use.Methods: The study included three components: (1) a knowledge and understanding (KAU) survey of FBT prescribers conducted in two waves: November 2016-February 2017 and April-September 2018; (2) a retrospective prescription study of medical records of patients treated with FBT by a subgroup of prescribers from the KAU survey; and (3) Web surveillance of illicit FBT use in Canada using the search term FENTORA (May 2014-September 2018). The aRMMs were considered effective if the lower bound of the 95% confidence interval indicated that at least 65% of respondents met or partly met the knowledge objective for each key safety concern.Results: KAU survey: Of 46 eligible HCPs, 97.8% met or partly met the knowledge objective on use in breakthrough pain cancer patients, 97.8% on use in opioid-tolerant patients, 89.1% on dose and titration, 100% on abuse/addiction, and 58.7% on drug-drug interaction. Retrospective prescription study: Of 22 FBT-treated patients identified from 14 HCPs, 45.5% had cancer, 50.0% recorded a breakthrough pain indication, and 36.4% reported opioid tolerance; however, only 13.6% of patients were prescribed FBT according to the approved indication. Web surveillance: Of 932 FBT posts in Canada, only 40 (4.3%) mentioned illicit use.Conclusions: The aRMMs as measured by the prescriber KAU were effective for most key safety messages; however, not all key messages of the aRMMs were stringently followed in routine practice. [ABSTRACT FROM AUTHOR]

Introduction: Some adverse drug reactions (ADRs) may involve direct social issues, such as impaired quality of life, work productivity, or social functioning, as opposed to being social consequences of medical adverse events. Data on ADRs with a direct social impact remain scarce in the literature.Objective: Our objective was to describe the ADRs consisting of direct social issues that have been recorded in the Canadian national spontaneous reporting system (Canada Vigilance).Methods: We conducted an analysis of the online Canada Vigilance spontaneous reporting database from 1 January 1965 (inception) to 31 December 2015 (last date available). We manually examined all Medical Dictionary for Regulatory Activities (MedDRA) preferred terms (PTs) found in the Canada Vigilance database to identify those that involved direct social issues. We then used those PTs to search for relevant individual case safety reports (ICSRs). We conducted a descriptive analysis of the following ICSR characteristics: patient and reporter characteristics, type of ADR, seriousness (as assessed by the reporter and according to the International Conference on Harmonisation criteria of seriousness), and suspected drug(s). We compared the characteristics of ADRs with and without direct social impact.Results: Among the 11,946 MedDRA PTs recorded in Canada Vigilance, we retained 40 that had a direct social impact. Using these PTs, we identified 9557 relevant ICSRs (corresponding to 6670 patients). The proportion of ADRs consisting of direct social issues increased over time, with a sharp transient peak in 2008. The majority were reported by healthcare professionals and consumers (56.7 and 37.8%, respectively). The mean age of patients was 45.4 years, and 53.3% were females. Direct social issues consisted of personality disorders and behaviour disturbances (41.6%) followed by neurological disorders (34.2%). The majority of ADRs were considered serious by reporters (76.5%), with 26.8% resulting in hospitalization. Commonly suspected health products included nervous system drugs (63.3%) and antineoplastic and immunomodulating agents (23.6%). Compared with other ADRs, those with a direct social impact were more often reported by consumers, involved patients who were on average 5 years younger, and were more frequently assessed as being serious by the reporters.Conclusions: Findings from this study support the consideration of direct social issues as ADRs in the detection of drug safety signals. [ABSTRACT FROM AUTHOR]

Introduction: An often key component to coordinating surveillance activities across distributed networks is the design and implementation of a common data model (CDM). The purpose of this study was to evaluate two drug safety surveillance CDMs from an ecosystem perspective to better understand how differences in CDMs and analytic tools affect usability and interpretation of results.Methods: Humana claims data from 2007 to 2012 were mapped to Observational Medical Outcomes Partnership (OMOP) and Mini-Sentinel CDMs. Data were described and compared at the patient level by source code and mapped concepts. Study cohort construction and effect estimates were also compared using two different analytical methods--one based on a new user design implementing a high-dimensional propensity score (HDPS) algorithm and the other based on univariate self-controlled case series (SCCS) design--across six established positive drug-outcome pairs to learn how differences in CDMs and analytics influence steps in the database analytic process and results.Results: Claims data for approximately 7.7 million Humana health plan members were transformed into the two CDMs. Three health outcome cohorts and two drug cohorts showed differences in cohort size and constituency between Mini-Sentinel and OMOP CDMs, which was a result of multiple factors. Overall, the implementation of the HDPS procedure on Mini-Sentinel CDM detected more known positive associations than that on OMOP CDM. The SCCS method results were comparable on both CDMs. Differences in the implementation of the HDPS procedure between the two CDMs were identified; analytic model and risk period specification had a significant impact on the performance of the HDPS procedure on OMOP CDM.Conclusions: Differences were observed between OMOP and Mini-Sentinel CDMs. The analysis of both CDMs at the data model level indicated that such conceptual differences had only a slight but not significant impact on identifying known safety associations. Our results show that differences at the ecosystem level of analyses across the CDMs can lead to strikingly different risk estimations, but this can be primarily attributed to the choices of analytic approach and their implementation in the community-developed analytic tools. The opportunities of using CDMs are clear, but our study shows the need for judicious comparison of analyses across the CDMs. Our work emphasizes the need for ongoing efforts to ensure sustainable transparent platforms to maintain and develop CDMs and associated tools for effective safety surveillance. [ABSTRACT FROM AUTHOR]

Background Comorbidity scores based on medical or prescription claims data are frequently used to control for confounding in pharmacoepidemiological studies. Performance of such scores in predicting the risk of death in community-dwelling elderly adults may be compromised by the absence of mental health and socioeconomic characteristics not captured in claims data. Objective The aim of the study was to assess the impact of adding mental health status and sociodemographic characteristics to the Geriatric Comorbidity Score (GCS), a score derived from prescription claims data in the Quebec community-dwelling elderly population. Methods We used the cohort study from the longitudinal Quebec Seniors' Health Survey (n = 1,494) conducted between 2005 and 2006. For each participant, we obtained mental health and socioeconomic characteristics through validated questionnaires, which we linked with the medical and prescription claims databases of the Quebec Health Insurance Agency [Régie de l'assurance maladie du Québec (RAMQ)]. The main study outcome was death within 1 year, ascertained using the Quebec death registry. The GCS was calculated from prescription claims data, with the c statistic as a measure of performance. Using backward stepwise selection, external variables (marital status, region, family income, social support, daily hassles, perceived physical and mental health status, presence of mental health disorders) were added to the logistic regression model and the marginal effect assessed by comparing the c statistic with and without each covariate. Results Over 1 year, 77 deaths (5.15 %) were reported. The c statistic for the GCS was calculated as 0.67 (95 % confidence interval 0.64, 0.70). Addition of sex and age to the score yielded a 2.4 % increase. The variable with the greatest impact on the c statistic was marital status (6.1 % increase). Though important contributors, social support and perceived mental health status did not significantly improve performance of the score. Conclusions While sex, age and marital status significantly improved performance of a predictive score in the community-dwelling elderly population, the absence of data on mental and physical health status did not appear to compromise the validity of claims-based scores. Combining comorbidity scores with other methods to control for confounding thus remains a useful tool in pharmacoepidemiological research. [ABSTRACT FROM AUTHOR]

Background: Therapeutic risk management has received growing interest in recent years, particularly since the publication of regulatory guidances in 2005 and 2006, paralleled with a change in drug regulation. The characteristics of risk minimization interventions (RMIs) that have been implemented or approved remain inadequately explored.Objective: The aim of this study was to review RMIs published in the literature or posted on regulatory agency websites over the past 10 years, and to assess whether publication of regulatory guidances on risk management is associated with changes in the number and types of interventions.Methods: Sources were searched for RMIs published/posted between 1 January 2000 and 31 December 2009. For the literature search, MEDLINE and EMBASE databases were used using key words related to drug safety (i.e. 'drug toxicity') and the individual RMI names. The website review involved searches of major regulatory authority websites such as the European Medicines Agency, US FDA, Health Canada, the UK's Medicines and Healthcare products Regulatory Agency, Japan's Pharmaceutical and Medical Devices Agency and Australia's Therapeutic Goods Administration. The following eligibility criteria were applied for inclusion in the review: published/posted between the years 2000 and 2009, inclusive; involving drug products; use in humans; and involving RMIs, or tools used to increase the reporting of adverse events (AEs). Natural healthcare products, devices, diagnostic chemicals, pregnancy registries without follow-up, medication errors and products not used as therapy for illness were not retained. For each source, the following characteristics were extracted: nature of the intervention, target population, therapeutic area, AE(s) of special interest, country/regulatory agency and year of publication.Results: A total of 119 unique interventions were identified in the literature (54 published in 2000-4 and 65 published in 2005-9). Interventions included educational material (n = 37; 31%), black-box warnings (n = 22; 19%) and therapeutic drug monitoring (n = 11; 9%). The website review produced a total of 1112 interventions: 326 posted between the years 2000 and 2004, and 786 between the years 2005 and 2009. The main interventions observed were: educational material (n = 956; 86%), black-box warnings (n = 45; 4%) and withdrawals (n = 39; 4%).Limitations: Additional regulatory resource websites were available in the post-guidances periods that were not available in the earlier years of the pre-guidances periods, and may bias the post-guidances results. Also, not all global regulatory websites were searched. Finally, only English-language websites were searched, limiting the variation of RMIs observed. Classification and categorizing for this particular review may not be consistent with future reviews by other researchers.Conclusion: The US is the sole region with a substantial increase in published RMIs during the post-guidances period, while the EU, Japan and the US all indicated an increase in the number of interventions on their websites. [ABSTRACT FROM AUTHOR]

Case series and case reports are a cornerstone of drug safety research; however, the characteristics of case series published in the literature remain poorly examined. A narrative review of case series addressing drug safety, published in the literature between 1 January 2003 and 15 July 2009, and identified through a PubMed search, was conducted in order to determine their characteristics and quality according to the criteria found in the US FDA Pharmacovigilance Guidance 2005. Of 130 publications that met the search criteria, 11.5% included an analytical component and 88.5% were descriptive. The median number of cases included in a given case series was 7 (range 2-2195) and the median time period for recruitment of the cases was 23 months (range 0.5-96). Overall, 43.1% of case series consisted of individual case reports, while 24.6% originated from cohorts and 21% from pharmacovigilance databases. Of the case series, 65.1% concerned adults (age ≥18 years), 11.6% elderly (age ≥65 years) and 8.5% youth (<18 years). Adverse effects involved mainly the skin (18.5%) and the circulatory system (13.8%). The main suspected drug classes (Anatomical Therapeutic Chemical classification) were nervous system drugs (23.1%) and antineoplastic and immunomodulating agents (20.0%). On average, six out of the possible nine US FDA Pharmacovigilance Guidance Criteria were fulfilled, with 27% of publications fulfilling at least seven criteria. Only 10% reported data on co-morbidity. In conclusion, this review highlights the reporting gaps and heterogeneity in published case series with respect to size, recruitment period and quality. [ABSTRACT FROM AUTHOR]

Presents a letter to the editor about the delusion of reducing sample size in clinical trials.