Comparison of the MOdified NARanjo Causality Scale (MONARCSi) for Individual Case Safety Reports vs. a Reference Standard.

INTRODUCTION: In 2018, we published the MONARCSi algorithmic decision support tool showing high inter-rater agreement, moderate sensitivity, and high specificity compared with drug-event pairs (DEPs) previously reviewed using current, industry-established approaches. Following publication, MONARCSi was implemented as a prototype system to facilitate medical review of individual case safety reports (ICSRs). This paper presents subsequent evaluation of MONARCSi-supported causality assessments against an independent, best achievable reference standard. OBJECTIVE: This paper describes the development of an independent reference standard (i.e., reference comparator) using a sample of DEPs evaluated by Roche subject matter experts (SMEs) and subsequent performance analysis for both the reference standard and MONARCSi. METHODS: Roche collected a random sample of 131 DEPs evaluated by an external vendor using the MONARCSi prototype during 2020, and collectively referred to as the VMON (Vendor using the MONARCSi system for medical review) dataset. An internal group of causality SMEs (aka CAUSMET) were recruited and trained to assess the same DEPs independently using the MONARCSi structure with Global Introspection to determine their individual assessments of causality. The CAUSMET final causality was determined using a majority voting rule. RESULTS: Binary comparison of the aggregate results showed substantial agreement (Gwet kappa = 0.81) between the VMON and reference standard CAUSMET assessments. Bayesian latent class modeling showed that both the reference standard and VMON assessments exhibited similar high posterior mean sensitivity and specificity (CAUSMET: 89 and 93%, respectively; VMON: 87 and 94%, respectively). Finally, comparison of the sensitivity and specificity suggested no obvious difference across groups. CONCLUSION: Analysis of causality results from the assessments by independent internal SMEs using MONARCSi shows there is no obvious difference in performance between the aggregate CAUSMET and VMON assessments based on the comparison of specificity and sensitivity. These results further support use of MONARCSi as a decision support tool for evaluating drug-event causality in a consistent and documentable manner.

Exploring nutrition education for migrants to Canada in Alberta's health and community sectors: Promising practices and gaps as informed by community workers and healthcare providers.

This qualitative study explored how migrant-serving agencies and healthcare providers in Alberta can support migrants to maintain healthy eating patterns. Through semi-structured interviews, respondents provided insight on their experiences working with migrant populations in the community. Observations about dietary acculturation (including food access, unfamiliar food environments, and perceptions of common foods in Canada) point to nutrition information that may be relevant for migrants. Respondents provided recommendations, noting the importance of culturally appropriate services, visual education materials, and collaboration between healthcare providers and community workers. The collective knowledge presented here could be applied by those developing programming supports for migrant communities.

Bevacizumab, temozolomide, and radiotherapy for newly diagnosed glioblastoma: comprehensive safety results during and after first-line therapy.

BACKGROUND: The proposed use of bevacizumab with radiotherapy/temozolomide for newly diagnosed glioblastoma raised potential safety concerns. Bevacizumab has been linked with stroke, bleeding events, and wound-healing complications in other tumor types; these events are of particular concern for glioblastoma (highly vascular tumors that are usually resected). Published data on the interaction of bevacizumab with radiotherapy/temozolomide are also limited. We report safety data from a phase III randomized trial (Avastin in Glioblastoma), focusing on these considerations. METHODS: Eligible patients received: radiotherapy and temozolomide plus bevacizumab/placebo, 6 cycles; a 4-week treatment break; temozolomide plus bevacizumab/placebo, 6 cycles; and bevacizumab/placebo until progression. Data on adverse events (AEs) were collected throughout. RESULTS: Bevacizumab-treated patients (n = 461) had a longer median safety follow-up time (12.3 vs 8.5 mo), and a higher proportion completed 6 cycles of maintenance temozolomide (64.6% vs 36.9%) versus placebo (n = 450). The incidences of relevant AEs (bevacizumab vs placebo, respectively) were: arterial thromboembolic events (5.9% vs 1.6%); cerebral hemorrhage (3.3% vs 2.0%); wound-healing complications (6.9% vs 4.7%); thrombocytopenia (34.1% vs 27.3%); radiotherapy-associated skin injury (8.2% vs 9.3%); alopecia (39.0% vs 36.0%); gastrointestinal perforation (including gastrointestinal abscesses and fistulae, 1.7% vs 0.4%); and radiotherapy-associated injury (0.4% vs 0.0%). Overall, 15.8% and 23.8% of bevacizumab- and placebo-treated patients had surgery (including biopsy) after progression. Within 30 days of postprogression surgery, AE incidence was 10.9% (bevacizumab) and 23.4% (placebo). CONCLUSION: The safety profile was consistent with that expected from radiotherapy/temozolomide plus bevacizumab. The increased AE incidence with bevacizumab did not impact patients' ability to receive standard-of-care treatment or to undergo further surgery.

A phase 2, double-blind, randomized, placebo-controlled, dose-escalation study to evaluate the efficacy, safety, and tolerability of naloxegol in patients with opioid-induced constipation.

Naloxegol (previously known as NKTR-118) is a peripherally acting µ-opioid receptor antagonist engineered using polymer conjugate technology in development as an oral, once-daily agent for the treatment of opioid-induced constipation (OIC). Eligible patients with OIC (n=207), defined as <3 spontaneous bowel movements (SBMs) per week with accompanying symptoms, on a stable opioid regimen of 30-1000 mg/day morphine equivalents for ≥ 2 weeks were randomized to receive 4 weeks of double-blind placebo or naloxegol (5, 25, or 50mg) once daily in sequential cohorts after a 1-week placebo run-in. The primary end point, median change from baseline in SBMs per week after week 1 of drug administration, was statistically significant for the 25- and 50-mg naloxegol cohorts vs placebo (2.9 vs 1.0 [P=0.0020] and 3.3 vs 0.5 [P=0.0001], respectively). The increase in SBMs vs placebo was maintained over 4 weeks for naloxegol 25mg (3.0 vs 0.8 [P=0.0022]) and 50mg (3.5 vs 1.0 [P<0.0001]). Naloxegol was generally well tolerated across all dosages. The most frequent adverse events (AEs) were abdominal pain, diarrhea, and nausea. Most AEs at 5 and 25mg/day were mild and transient. Similar AEs occurred with increased frequency and severity in the 50-mg cohort. There was no evidence of a statistically significant increase from baseline in pain, opioid use for the 25- and 50-mg cohorts, or centrally mediated opioid withdrawal signs and/or symptoms with naloxegol. These data demonstrate that once-daily oral naloxegol improves the frequency of SBMs compared with placebo and is generally well tolerated in this population of patients with OIC.