Interdisciplinary Safety Evaluation for Learning and Decision-Making.

The FDA IND safety reporting Final Rule (21CFR 312.32) applies to all human drugs and biological products being studied under an Investigational New Drug (IND). A sponsor must file an IND safety report for any serious unexpected suspected adverse reaction (SUSAR) of a medicinal product being investigated. Some events may be obviously drug-related (e.g., agranulocytosis, anaphylactic reaction, drug-induced hepatic injury, Stevens-Johnson Syndrome). For serious adverse events that are not interpretable as individual occurrences, additional processes and procedures need to be employed for identifying and assessing risks in the accumulating safety data. The approaches shared in this manuscript apply principally to safety reporting of events that are anticipated to occur in the patient population-regardless of study participation. For these events, the study sponsor should periodically review the data in the aggregate and make a judgment as to whether there is a reasonable possibility of an event having been caused by the study drug rather than the underlying condition of the patient or a concomitant therapy. Factors cited for consideration are the size and consistency of the difference in event frequency between the test and control groups, supportive preclinical findings, evidence of a dose response relationship, plausible mechanism of action, known class effect and occurrence of other related adverse events. Examples are provided that demonstrate the flexibility sponsors have in meeting the spirit of the Final Rule; some combination and variation of methods from the examples could be employed. The important thing, as expressed by Jacqueline Corrigan-Curay (Director of the Office of Medical Policy, Center for Drug Evaluation and Research, FDA), is to have a thoughtful process; a system in place to look for clinically important imbalances, applying the best clinical and quantitative judgment, while maintaining trial integrity (Ball et al. in Interdisciplinary aggregate assessments for IND safety reporting: a dialogue among colleagues from industry, Academia and the FDA. ASA biopharmaceutical section regulatory-industry statistics workshop, 2018).

Comparative Risk Assessment of Severe Uterine Bleeding Following Exposure to Direct Oral Anticoagulants: A Network Study Across Four Observational Databases in the USA.

BACKGROUND: Antithrombotic therapies are associated with an increased bleeding risk. Abnormal uterine bleeding data have been reported in clinical trials of patients with venous thromboembolism (VTE), but data are limited for patients with atrial fibrillation (AF). OBJECTIVE: Using real-world data from four US healthcare databases (October 2010 to December 2018), we compared the occurrence of severe uterine bleeding among women newly exposed to rivaroxaban, apixaban, dabigatran, and warfarin stratified by indication. METHODS: To reduce potential confounding, patients in comparative cohorts were matched on propensity scores. Treatment effect estimates were generated using Cox proportional hazard models for each indication, in each database, and only for pairwise comparisons that met a priori study diagnostics. If estimates were homogeneous (I2 < 40%), a meta-analysis across databases was performed and pooled hazard ratios reported. RESULTS: Data from 363,919 women newly exposed to a direct oral anticoagulant or warfarin with a prior diagnosis of AF (60.8%) or VTE (39.2%) were analyzed. Overall incidence of severe uterine bleeding was low in the populations exposed to direct oral anticoagulants, although relatively higher in the younger VTE population vs the AF population (unadjusted incidence rates: 2.8-33.7 vs 1.9-10.0 events/1000 person-years). In the propensity score-matched AF population, a suggestive, moderately increased risk of severe uterine bleeding was observed for rivaroxaban relative to warfarin [hazard ratios and 95% confidence intervals from 0.83 (0.27-2.48) to 2.84 (1.32-6.23) across databases with significant heterogeneity], apixaban [pooled hazard ratio 1.45 (0.91-2.28)], and dabigatran [2.12 (1.01-4.43)], which were sensitive to the time-at-risk period. In the propensity score-matched VTE population, a consistent increased risk of severe uterine bleeding was observed for rivaroxaban relative to warfarin [2.03 (1.19-3.27)] and apixaban [2.25 (1.45-3.41)], which were insensitive to the time-at-risk period. CONCLUSIONS: For women who need antithrombotic therapy, personalized management strategies with careful evaluation of benefits and risks are required. CLINICALTRIALS. GOV REGISTRATION: NCT04394234; registered in May 2020.

Acute pancreatitis risk in type 2 diabetes patients treated with canagliflozin versus other antihyperglycemic agents: an observational claims database study.

Objective: Observational evidence suggests that patients with type 2 diabetes mellitus (T2DM) are at increased risk for acute pancreatitis (AP) versus those without T2DM. A small number of AP events were reported in clinical trials of the sodium glucose co-transporter 2 inhibitor canagliflozin, though no imbalances were observed between treatment groups. This observational study evaluated risk of AP among new users of canagliflozin compared with new users of six classes of other antihyperglycemic agents (AHAs).Methods: Three US claims databases were analyzed based on a prespecified protocol approved by the European Medicines Agency. Propensity score adjustment controlled for imbalances in baseline covariates. Cox regression models estimated the hazard ratio of AP with canagliflozin compared with other AHAs using on-treatment (primary) and intent-to-treat approaches. Sensitivity analyses assessed robustness of findings.Results: Across the three databases, there were between 12,023-80,986 new users of canagliflozin; the unadjusted incidence rates of AP (per 1000 person-years) were between 1.5-2.2 for canagliflozin and 1.1-6.6 for other AHAs. The risk of AP was generally similar for new users of canagliflozin compared with new users of glucagon-like peptide-1 receptor agonists, dipeptidyl peptidase-4 inhibitors, sulfonylureas, thiazolidinediones, insulin, and other AHAs, with no consistent between-treatment differences observed across databases. Intent-to-treat and sensitivity analysis findings were qualitatively consistent with on-treatment findings.Conclusions: In this large observational study, incidence rates of AP in patients with T2DM treated with canagliflozin or other AHAs were generally similar, with no evidence suggesting that canagliflozin is associated with increased risk of AP compared with other AHAs.

Social isolation and loneliness: the new geriatric giants: Approach for primary care.

OBJECTIVE: To review the problems of social isolation, loneliness, and social vulnerability in older adults and the associated risks, and to help primary care providers identify patients at risk and recommend effective interventions. SOURCES OF INFORMATION: PubMed and PsycINFO searches were conducted using the terms aged, social isolation, loneliness, screening, and interventions and associated key words for relevant English-language articles. References of identified articles were also hand searched. A separate search of the gray literature using Google was conducted to find policy documents and knowledge translation materials from relevant organizations. The search covered relevant articles from the 10 years before June 2019. MAIN MESSAGE: Social isolation, loneliness, and social vulnerability are very common in older adults and are associated with considerable morbidity and mortality, comparable to established risk factors such as smoking, alcohol consumption, obesity, and frailty. Numerous interventions addressing loneliness and social isolation have been studied: social facilitation (including technology), exercise, psychological therapies, health and social services, animal therapy, befriending, and leisure and skill development. However, current evidence of effectiveness is limited. A patient-centred approach is essential to the selection of interventions. The needs of underserviced and marginalized populations, including new immigrants, older adults identifying as LGBTQ+ (lesbian, gay, bisexual, transgender, queer or questioning, and related communities), Indigenous seniors, and seniors living in poverty, as well as the needs of long-term care residents and older caregivers, require further evaluation. CONCLUSION: Social isolation, loneliness, and social vulnerability are common problems in older adults and have important health consequences. Family physicians are uniquely positioned to identify lonely and socially isolated older adults and to initiate services.

Isolement social et solitude : les nouveaux géants gériatriques: Approche à l'intention des soins primaires.

OBJECTIF: Examiner les problèmes de l'isolement social, de la solitude et de la vulnérabilité sociale chez les adultes plus âgés, de même que les risques qui leur sont associés, et aider les professionnels des soins primaires à identifier les patients à risque et à recommander des interventions efficaces. SOURCES DE L'INFORMATION: Une recherche documentaire a été effectuée dans PubMed et PsycINFO en se servant des expressions aged, social isolation, loneliness, screening et interventions, de même que des mots clés associés pour trouver des articles pertinents en anglais. Les références des articles cernés ont aussi fait l'objet d'une recherche manuelle. Une recension distincte dans la littérature grise à l'aide de Google a aussi été faite pour trouver des documents de politiques et du matériel de transfert des connaissances provenant d'organisations appropriées. La recherche portait sur les articles publiés durant les 10 années précédant juin 2019. MESSAGE PRINCIPAL: L'isolement social, la solitude et la vulnérabilité sociale sont très fréquents chez les adultes plus âgés; ils sont liés à une morbidité et à une mortalité considérables, et sont comparables à des facteurs de risque établis comme le tabagisme, la consommation d'alcool, l'obésité et la fragilité. De nombreuses interventions pour lutter contre la solitude et l'isolement social ont fait l'objet d'études : la facilitation sociale (y compris avec la technologie), l'exercice, les psychothérapies, les services sociaux et de santé, la zoothérapie, les programmes d'amitié, les loisirs et le perfectionnement des compétences. Par ailleurs, les données scientifiques actuelles sur leur efficacité sont limitées. Les besoins des populations mal desservies et marginalisées, y compris les nouveaux immigrants, les adultes plus âgés s'identifiant comme LGBTQ+ (lesbienne, gai, bisexuel, transgenre, queer ou en questionnement, et les communautés connexes), les personnes âgées autochtones et les aînés qui vivent dans la pauvreté, de même que les besoins des bénéficiaires de soins de longue durée et des aidants plus âgés, doivent être évalués de manière plus approfondie. CONCLUSION: L'isolement social, la solitude et la vulnérabilité sociale sont des problèmes fréquents chez les adultes plus âgés, et ils ont des répercussions importantes sur la santé. Les médecins de famille sont bien placés pour identifier les aînés esseulés ou socialement isolés et enclencher l'amorce des services voulus.

Diabetic ketoacidosis in patients with type 2 diabetes treated with sodium glucose co-transporter 2 inhibitors versus other antihyperglycemic agents: An observational study of four US administrative claims databases.

PURPOSE: To compare the incidence of diabetic ketoacidosis (DKA) among patients with type 2 diabetes mellitus (T2DM) who were new users of sodium glucose co-transporter 2 inhibitors (SGLT2i) versus other classes of antihyperglycemic agents (AHAs). METHODS: Patients were identified from four large US claims databases using broad (all T2DM patients) and narrow (intended to exclude patients with type 1 diabetes or secondary diabetes misclassified as T2DM) definitions of T2DM. New users of SGLT2i and seven groups of comparator AHAs were matched (1:1) on exposure propensity scores to adjust for imbalances in baseline covariates. Cox proportional hazards regression models, conditioned on propensity score-matched pairs, were used to estimate hazard ratios (HRs) of DKA for new users of SGLT2i versus other AHAs. When I2 <40%, a combined HR across the four databases was estimated. RESULTS: Using the broad definition of T2DM, new users of SGLT2i had an increased risk of DKA versus sulfonylureas (HR [95% CI]: 1.53 [1.31-1.79]), DPP-4i (1.28 [1.11-1.47]), GLP-1 receptor agonists (1.34 [1.12-1.60]), metformin (1.31 [1.11-1.54]), and insulinotropic AHAs (1.38 [1.15-1.66]). Using the narrow definition of T2DM, new users of SGLT2i had an increased risk of DKA versus sulfonylureas (1.43 [1.01-2.01]). New users of SGLT2i had a lower risk of DKA versus insulin and a similar risk as thiazolidinediones, regardless of T2DM definition. CONCLUSIONS: Increased risk of DKA was observed for new users of SGLT2i versus several non-SGLT2i AHAs when T2DM was defined broadly. When T2DM was defined narrowly to exclude possible misclassified patients, an increased risk of DKA with SGLT2i was observed compared with sulfonylureas.

Five-weekend care of the elderly certificate course: continuing professional development activity for family physicians.

PROBLEM ADDRESSED: Primary care practitioners have unique clinical challenges in caring for elderly patients and require educational courses that are specifically designed for their needs in caring for this patient population. OBJECTIVE OF PROGRAM: To improve family physicians' knowledge of and confidence in managing common geriatric problems. PROGRAM DESCRIPTION: The accredited course curriculum is delivered on 5 weekends over approximately 6 months.Each weekend focuses on a different theme including cognitive impairment, gait disorders, mental health and pain management, geriatric medical problems, and failure to thrive. Participants complete written assignments between weekend sessions, which involve self-reflection on how the new knowledge and skills gained through the course will be incorporated in the management of elderly patients in their practices. CONCLUSION: The 5-Weekend Care of the Elderly Certificate Course is an accredited continuing professional development program for primary care practitioners. Preliminary evaluation suggests improvement in participants' self-rated knowledge of and confidence in managing geriatric problems. Qualitative data show positive changes in clinical practice.