Safety Monitoring Program Research Articles

Robust safety monitoring and signal detection using alternatives to the standard poisson distribution

ABSTRACT Proper and timely characterization of the safety profile of a pharmaceutical product under development is imperative for assessing the overall benefit-risk relationship of the product and for making key development decisions. For ongoing clinical development, a comprehensive and robust safety monitoring and safety signal detection program which is based upon quantitative statistical reasoning is critical. Methods presented here can be applied to safety signal detection and periodic safety monitoring. Various statistical properties, distributions, and models, all utilizing a Bayesian framework are considered and further examined in order to identify robust methods applicable to a broad set of scenarios and situations. Methods developed for incidence counts (including those with under-dispersed distributions) with variable time-at-risk and with underlying constant or non-constant hazard rates, are proposed and compared to traditional methods designed to assess adverse event incidence rates or binomial incidence proportions (which assume an underlying constant hazard rate and subsequent Poisson distribution for modeling event counts).

FAKTOR YANG MEMENGARUHI MORTALITAS PASIEN RAWAT INAP DI RUMAH SAKIT AKADEMIK UGM

Background: Hospital mortality indicators are an important element of a hospital patient safety monitoring program. In 2022, the record of inpatient performance at Academic Hospital UGM (RSA UGM) shows that the Net Death Rate (NDR) value has not yet reached the ideal standard, namely 34.1‰.
 Objective: Identifying factors that influence the mortality rate of adult patients ≥48 hours in inpatient care and developing a program plan to reduce hospital mortality at RSA UGM.
 Methods: An explanatory sequential design of mixed methods research was used. The medical records of adult patients admitted to RSA UGM from October 2022 to December 2022. Quantitative data analysis used chi-square, Fisher’s exact tests, and multivariate logistic regression. Qualitative data was obtained from focus group discussions with three separate groups, namely the managerial group, the doctor team, and the nurse team., while qualitative data used thematic analysis.
 Results: 388 subjects were obtained with 18 (4.64% or 46.4‰) patients who died during treatment ≥48 hours. Independently, ward type (OR 10,799, CI 95 % 3,990 – 29,233), EWS score (OR 15,644, CI 95 % 5,511 – 44,412), and some comorbidities (OR 8,603, CI 95 % 2,769 – 26,730) associated with ≥48 hours in-hospital mortality (<0.001). Multivariate analysis showed that ward type (p=0.018, aOR 4,122, CI 95 % 1,279 – 13,284) and Early Warning System (EWS) score (p=0.016, aOR 4,531, CI 95 % 1,327 – 15,469) had a strong association with ≥48 hours in-hospital mortality. The proposed program to reduce hospital mortality rates by increasing ICU capacity, improving the competency and skills of ICU nurses, adding intensivists, controlling nosocomial infections in ICU, increasing understanding regarding EWS for ward nurses, improving the EWS monitoring, and improving the competency of ward nurses in emergencies condition.
 Conclusion: The EWS score >5 and intensive care are significantly related to in-hospital mortality ≥48 hours after hospitalization so management needs to improve the quality of services at the RSA UGM by carrying out a strategy to reduce hospital mortality rates to decrease the net mortality rate in accordance with the Ministry of Health’s national standards.

Understanding radiation treatment terminations as an element of quality.

408 Background: Disruptions in cancer care adversely affect clinical outcomes. The effect is magnified when treatments are not just protracted, but discontinued prematurely. The incidence of such treatment termination (TT) during radiation therapy has not been well studied. We herein present a single-institution cohort of TT at a large multi-center radiation oncology department over 10 years. Methods: As part of our ongoing departmental quality and safety monitoring program, TTs were prospectively tracked and assessed. A TT was defined as the premature discontinuation of therapy at any point following the initiation of radiation planning. The rate of TT was calculated as a percentage of all new patients who start radiation planning. Each TT between 1/2013 and 1/2023 was analyzed for a root cause, reviewed among multi-disciplinary Quality committee members, and presented monthly to the radiation department. Selected cases sparked discussion and efforts to identify interventions that may decrease the likelihood of similar TTs. Incremental departmental policy and procedure changes to critical pre-treatment evaluation, prospective contouring rounds, on-treatment management, and scheduling processes were implemented, collectively referred to as the “No-Fly” policy. Results: A total of 1,467 TTs were identified and analyzed. 688 (46.9%) involved patients treated with curative intent, 770 (52.5%) with palliative intent, and 9 (0.6%) for benign disease. The most common cause of TT was hospice and/or death (36.5%), 69.1% of which were in patients receiving palliative treatments. Other common causes identified are shown in Table 1. The overall 10-year rate of TT was 5.1% (1,467 of 28,707 planned treatment courses). The rate of TT decreased from 9.3% to 3.3% (2013 and 2022, respectively), with rates decreasing at each iteration of No-Fly from 8.8% (No-Fly 1, 2013-2014) to 5.2% (No-Fly 2, 2015-2018) to 4.0% (No-Fly 3, 2019-2022) (ANOVA p<0.001). Conclusions: Premature termination of radiation therapy can be deleterious for cancer patients. Determining the causes of TTs so that they may be mitigated is integral to effectively managing care and improving safety culture in radiation medicine departments. While some TTs may be unavoidable, open discourse and quality improvement changes are effective in reducing incidents over time. Understanding TTs is complimentary to other nationwide projects exploring how reducing missed radiation therapy appointment rates support access to high quality oncology care.[Table: see text]

Eight Years of Canadian Real-World Assessment of Tolvaptan in ADPKD: C-MAJOR Study and Safety Monitoring and Distribution Program

Eight Years of Canadian Real-World Assessment of Tolvaptan in ADPKD: C-MAJOR Study and Safety Monitoring and Distribution Program

Community pharmacists’ challenges regarding adverse drug reaction reporting: a cross-sectional study

Objective The effectiveness of the national drug safety monitoring program directly depends on the active participation of healthcare professionals in reporting suspected adverse drug reactions (ADRs). The aim of the study was to explore community pharmacists’ comprehension of pharmacovigilance, their perspectives toward reporting ADRs and investigate the current practice of ADR reporting among pharmacists in Serbia. Methods This descriptive cross-sectional study was performed on a sample of pharmacists in Serbia between November 2019 and March 2020 using a pre-tested questionnaire distributed online. Eligible participants were community pharmacists in Serbia who were willing to participate in the study during the data collection period. Non-parametric statistical tests were performed in the analysis of knowledge, perspectives and ADR reporting. The validity and reliability of the survey were measured by exploratory factor analysis. Results The median knowledge score was 6 out of 10 (interquartile range 5–7, range 2–10). No significant differences in the knowledge scores of pharmacists were found based on weekly working hours (U = 24,805, p = .374), working experience (χ 2 = 4.011, DF = 2, p = .135), being a member of a professional organization (U = 24,312, p = .209), or highest level of pharmacy qualification obtained (χ 2 = 3.233, DF = 3, p = .506). Only 28.8% of pharmacists reported ADR at least once a year, while the majority of them have never reported any ADRs. Conclusions Despite the community pharmacists’ positive attitude toward adverse drug reporting and their role in the process, they show limited knowledge regarding the issue and highly prevalent under-reporting of ADRs. Educational programs are necessary to increase ADRs reporting.

Association of Online Risk Factors With Subsequent Youth Suicide-Related Behaviors in the US

The association between online activities and youth suicide is an important issue for parents, clinicians, and policy makers. However, most information exploring potential associations is drawn from survey data and mainly focuses on risk related to overall screen time. To evaluate the association between a variety of online risk factors and youth suicide-related behavior using real-world online activity data. A matched case-control study was conducted from July 27, 2019, to May 26, 2020, with the sample drawn from more than 2600 US schools participating in an online safety monitoring program via the Bark online safety tool. For 227 youths having a severe suicide/self-harm alert requiring notification of school administrators, cases were matched 1:5 to 1135 controls on location, the amount of follow-up time, and general volume of online activity. Eight potential online risk factors (cyberbullying, violence, drug-related, hate speech, profanity, sexual content, depression, and low-severity self-harm) through assessment of text, image, and video data. Severe suicide/self-harm alert requiring notification of school administrators; severe suicide alerts are statements by youths indicating imminent or recent suicide attempts and/or self-harm. The 1362 participants had a mean (SD) age of 13.3 (2.41) years; 699 (51.3%) were male. All 8 online risk factors studied exhibited differences between case and control populations and were significantly associated with subsequent severe suicide/self-harm alerts when examining total direct and indirect pathways. These associations ranged from an adjusted odds ratio (aOR) of 1.17 (95% CI, 1.09-1.26) for drug-related content to an aOR of 1.82 (95% CI, 1.63-2.03) for depression-related content. When considering the total number of different types of online risk factors among the 8 measured, there was an exponentially larger risk of severe suicide/self-harm alerts; youths with 5 or more of the 8 risk factors present in their online activity had a more than 70-fold increased odds of subsequently having a severe suicide/self-harm alert (aOR, 78.64; 95% CI, 34.39-179.84). The findings of this study suggest that many discrete types of risk factors are identifiable from online data and associated with subsequent youth suicide-related behavior. Although each risk factor carries a specific association with suicide-related behavior, the greatest risk is evident for youths demonstrating multiple types of online risk factors.

Anxiety-Related Adverse Event Clusters After Janssen COVID-19 Vaccination - Five U.S. Mass Vaccination Sites, April 2021.

On April 7, 2021, after 5 weeks' use of the Janssen COVID-19 vaccine under the Food and Drug Administration (FDA) Emergency Use Authorization (EUA), CDC received reports of clusters of anxiety-related events after administration of Janssen COVID-19 vaccine from five mass vaccination sites, all in different states. To further investigate these cases, CDC interviewed vaccination site staff members to gather additional information about the reported events and vaccination site practices. Four of the five sites temporarily closed while an investigation took place. Overall, 64 anxiety-related events, including 17 reports of syncope (fainting), an anxiety-related event, among 8,624 Janssen COVID-19 vaccine recipients, were reported from these sites for vaccines administered during April 7-9. As a follow-up to these interviews, CDC analyzed reports of syncope shortly after receipt of Janssen COVID-19 vaccine to the Vaccine Adverse Event Reporting System (VAERS), the vaccine safety monitoring program managed by CDC and FDA. To compare the occurrence of these events with those reported after receipt of other vaccines, reports of syncopal events after influenza vaccine administered in the 2019-20 influenza season were also reviewed. Syncope after Janssen COVID-19 vaccination was reported to VAERS (8.2 episodes per 100,000 doses). By comparison, after influenza vaccination, the reporting rate of syncope was 0.05 episodes per 100,000 doses. Anxiety-related events can occur after any vaccination. It is important that vaccination providers are aware that anxiety-related adverse events might be reported more frequently after receipt of the Janssen COVID-19 vaccine than after influenza vaccination and observe all COVID-19 vaccine recipients for any adverse reactions for at least 15 minutes after vaccine administration.

POS-337 CANADIAN REAL-WORLD ASSESMENT OF TOLVAPTAN IN ADPKD: C-MAJOR STUDY AND SAFETY MONITORING AND DISTRIBUTION PROGRAM

Tolvaptan is the only approved treatment in Canada for slowing renal function decline and kidney enlargement in ADPKD patients. As per Health Canada requirements, a patient registry evaluating long-term clinical outcomes (the C-MAJOR study) and a hepatic safety monitoring and distribution program (the HSMDP) to mitigate the risk of liver injury were implemented and have been ongoing nationally for 5 years. The aim of this interim analysis is to describe baseline characteristics of patients at initiation of tolvaptan through the C-MAJOR study and to report on rates of treatment persistence and liver test abnormalities through the HSMDP. C-MAJOR is a non-interventional, multi-centre study of Canadian ADPKD patients treated with tolvaptan. The HSMDP ensures tolvaptan is dispensed under controlled liver enzyme and function monitoring. As of April 2020, 398 patients, 51% female, were enrolled in C-MAJOR. At baseline, mean (SD) age was 45.1 (11.5) years, BP was 129.4 (13.4)/83.1 (10.0) mmHg and eGFR was 63.6 (27.8) mL/min/1.73 m2. Total kidney volume was 1949 (1562) mL, 80.7% of patients had family history of ADPKD and 39.4% had family history of early end-stage renal disease. As per Mayo classification, 90.2% were at high risk of disease progression (1C-D-E). Most common ADPKD clinical manifestations were hypertension (83.2%), hepatic cysts (69.6%) and kidney pain (24.1%). Over a mean (SD) follow-up of 2.0 (1.0) years, adverse events were reported in 82.7% of patients, most common being polyuria (19.6%), fatigue (18.6%), and nocturia (15.1%). Over a mean follow-up of 23.0 (SD = 17.6) months in the HSMDP, 2.4% (n=39) of the 1,600 patients who received at least one shipment of tolvaptan reported an elevation of transaminases >3x ULN. There were 0.3% (n=5) of patients meeting the guidelines for permanent discontinuation. No cases of drug-induced liver injury were reported. Treatment discontinuation rates at 12, 24 and 36 months were 14%, 21% and 26%, respectively. This analysis provides Canadian real-world evidence of high-risk for disease progression at tolvaptan initiation, 3-y persistence data similar to phase III studies and HSMDP data showing that tolvaptan was permanently discontinued in 0.3% of patients because of hepatic effects. This abstract was also submitted for the ASN 2020 congress.

Knowledge, attitude, and practices of pharmacovigilance among health-care professionals in a tertiary care teaching hospital in Telangana state

Background: Pharmacovigilance Program of India (PVPI) is drug safety monitoring program which aims to improve the safety and welfare of patients. Having adequate knowledge and awareness about pharmacovigilance (PV) is essential to ensure the success of PVPI. Aim and Objective: The present study was, therefore, initiated to assess the knowledge, attitude, and practices of PV among the health-care professionals. Materials and Methods: With permission from the Institutional Ethics Committee, a cross-sectional study was conducted among all the health-care professionals – doctors, nurses, and pharmacists of Malla Reddy Medical College for Women, Suraram, Hyderabad. Hard copies of pre-validated questionnaire consisting of 23 questions were administered to the study participants after taking oral informed consent. Data from completed questionnaires were entered into Excel sheet and analyzed using descriptive statistics. Results: Data of a 124 study participants were analyzed. Majority of the health-care professionals have good knowledge (knowledge score of 50–75% in 56% of the participants) and positive attitude (attitude score of >75% in 85% of the participants) toward PV but the PV practices are poor. Conclusion: There is a necessity to improve the knowledge, attitudes, and practices of PV among the health-care professionals using various educational and promotional activities to promote their active participation in the PVPI and, in turn, improve the overall quality of health care.

Canadian Real-World Assessment of Tolvaptan in ADPKD: C-MAJOR Study and Safety Monitoring and Distribution Program

Canadian Real-World Assessment of Tolvaptan in ADPKD: C-MAJOR Study and Safety Monitoring and Distribution Program

Are Patients at Risk for Recurrent Disease Activity After Switching From Remicade® to Remsima®? An Observational Study.

Background: Since the late ‘90s, infliximab (Remicade®) is being used successfully to treat patients with several non-infectious immune mediated inflammatory diseases (IMIDs). In recent years, infliximab biosimilars, including Remsima® were introduced in clinical practice.Aim: To investigate the interchangeability of Remicade® (originator infliximab) and its biosimilar Remsima® in patients with rare immune-mediated inflammatory diseases (IMIDs).Methods: This two-phased prospective open label observational study was designed to monitor the transition from Remicade® to Remsima® in patients with rare IMIDs. All included patients were followed during the first 2 years. The primary endpoint was the demonstration of non-difference in quality of life and therapeutic efficacy, as measured by parameters including a safety monitoring program, physicians perception of disease activity (PPDA) and patient self-reported outcomes (PSROs). Secondary outcomes included routine blood analysis, pre-infusion serum drug concentration values and anti-drug antibody formation.Results: Forty eight patients treated with Remicade® were switched to Remsima® in June-July 2016 and subsequently monitored during the first 2 years. The group consisted of patients with sarcoidosis (n = 17), Behçet's disease (n = 12), non-infectious uveitis (n = 11), and other diagnoses (n = 8). There were no significant differences in PPDA, PSROs, clinical and laboratory assessments and pre-infusion serum drug concentrations between the groups. De novo anti-drug antibodies were observed in two patients. Seven patients with sarcoidosis and five with another diagnosis developed a significant disease relapse (n = 7) or adverse events (n = 5) within 2 years; 10 of these patients discontinued Remsima® treatment, one withdrew from the study and one received additional corticosteroid therapy.Conclusions: We observed no significant differences in PSROs, PPDA and laboratory parameters after treatment was switched from Remicade® to Remsima®. However, disease relapse or serious events were observed in 12 out of 48 patients when treatment was switched from Remicade® to Remsima®. The choice to switch anti-TNF alpha biologics in patients with rare IMIDs, particularly in sarcoidosis, requires well-considered decision-making and accurate monitoring due to a possibly higher incidence of disease worsening.

Putative Abscopal Effect in Three Patients Treated by Combined Radiotherapy and Modulated Electrohyperthermia.

Purpose: True abscopal responses from radiation therapy are extremely rare; the combination of immune checkpoint inhibitors with radiation therapy has led to more reports of the abscopal effect, but even in this setting, the genuine magnitude remains unknown and is still considered generally uncommon. We report the occurrence of what appears to be putative, durable abscopal tumor responses with associated auto-immune systemic reactions resulting from the combination of local radiotherapy (RT) and modulated electrohyperthermia (mEHT).Materials and Methods: Data from advanced cancer patients treated palliatively with RT and mEHT between January and December 2017 were collected as part of a post-marketing safety monitoring program of mEHT therapy. We specified a minimum RT dose of 30 Gy and at least four mEHT treatments for reporting toxicities, which was the primary aim of the larger study.Results: Thirty-three patients treated with RT and mEHT, both applied to the same lesion, were included. The median RT dose was 45.5 Gy in 20 fractions (fxs) and the median number of mEHT treatments was 12 (range, 4–20). Most patients had subsequent systemic therapy after one course of RT and mEHT. Three patients (9.1%) developed autoimmune toxicities. Case number 1 received RT and mEHT only; case number 2 had two cycles of concurrent low dose chemotherapy during RT; and case number 3 received concurrent immune checkpoint inhibitors. None of the three patients received any further systemic treatment due to obvious treatment-related autoimmune reactions which occurred rapidly after RT; one had autoimmune hepatitis, one had dermatitis herpetiformis and the third developed severe myasthenia gravis. Interestingly, what we surmise to be long-lasting abscopal responses outside the irradiated area, were noted in all three patients.Conclusion: RT combined with mEHT could putatively result in enhancing immune responsiveness. These preliminary observational findings lead to the generation of a hypothesis that this combination induces both an in-situ, tumor-specific immune reaction and an anti-self-autoimmune reaction, in at least a small proportion of patients, and of those who experience the auto-immune response, tumor response is a concomitant finding. Mechanisms underlying this phenomenon need to be investigated further.

Anhydrous Ammonia Chemical Release - Lake County, Illinois, April 2019.

On April 25, 2019, a farm tractor towing two 2-ton ammonia tanks on a county road in Lake County, Illinois, experienced a mechanical failure that resulted in the release of anhydrous ammonia, a colorless, pungent, irritating gas that can cause severe respiratory and ocular damage (1). Approximately 80% of anhydrous ammonia produced in the United States is used as a fertilizer in agriculture (1). Eighty-three persons, including first responders, motorists, and neighborhood residents, were evaluated at area hospitals because of exposure to the gas. Two weeks after the release, the Agency for Toxic Substances and Disease Registry (ATSDR) and CDC's National Center for Environmental Health (NCEH) collaborated with the Lake County Health Department and the Illinois Department of Public Health on an investigation using ATSDR's Assessment of Chemical Exposures program to describe the release, review the emergency response, and determine health effects associated with the exposure. First responders, community residents, and hospital personnel reported communication challenges related to the nature of the gas release and effective protective measures. Among the 83 persons evaluated at six area hospitals for effects of the chemical release, 14 (17%) were hospitalized, including eight (10%) who were admitted to the intensive care unit (ICU), seven (8%) of whom required endotracheal intubation and mechanical ventilation; no deaths occurred. In addition, ICU health care providers experienced symptoms of secondary exposure. The National Institute for Occupational Safety and Health's Emergency Responder Health Monitoring and Surveillance Program has specific recommendations and tools to protect responders during all phases of a response (2). Hospitals also need to review institutional policies and procedures for chemical mass casualty events, including decontamination (3). Prompt and correct identification of hazardous material (hazmat) events, and clear communication among responding entities, including on-scene and hospital responders, is important to ensure effective response after a chemical release.

Abstract 28: Feasibility and Safety of Pre-Hospital Resuscitative Endovascular Balloon Occlusion of the Aorta (REBOA) in Non-Traumatic Out-Of-Hospital Cardiac Arrest

Introduction: The proportion of patients surviving to hospital discharge after out of hospital cardiac arrest (OHCA) is low and any measure that may improve circulation to vital organs during cardiopulmonary resuscitation (CPR) is beneficial. The use of resuscitative endovascular balloon occlusion of the aorta (REBOA) will redistribute cardiac output to the organs proximal to the occlusion. Animal studies supports that aortic occlusion during CPR might benefit patients suffering from OHCA, but human data are scarce. Methods: We performed an observational study at the helicopter emergency medical service in Trondheim (Norway) to assess the feasibility and safety of establishing REBOA in OHCA patients. The femoral artery was identified by ultrasound and a REBOA catheter was placed in the thoracic aorta. All patients received advanced cardiac life support (ACLS) during the procedure. REBOA eligibility, procedural success and time intervals were registered. A safety monitoring program was conducted to ensure that the procedure did not interfere with the quality of ACLS. Results: REBOA was initiated in ten of 98 OHCA patients. The mean age was 63 years (55-71) and 7 were male. The REBOA procedure was successful in all cases (100%), with 80% success rate on first cannulation attempt. Mean REBOA procedural time was 11,7 minutes (8-16, SD 3,2). End-tidal CO2 (EtCO2) increased by a mean of 1.9 kPa at 60 seconds after inflation compared to baseline (p < 0.001). Six of 10 patients (60%) achieved return of spontaneous circulation, 3 (30%) was admitted to hospital. 30-day survival was 10%. The mean width of the femoral artery and vein during CPR was 5,9 mm (3,6 - 7,4, SD 1,2) and 9,4 mm (5,0 - 12,9, SD 2,9), respectively. The safety monitoring group identified no negative influence on the ACLS quality. Conclusions: This is the first study to assess the pre-hospital use of REBOA in patients with non-traumatic cardiac arrest. The REBOA procedure does not interfere with the quality of the ACLS. REBOA is a feasible adjunct treatment in OHCA. The significant increase in EtCO2 after occlusion suggests improved organ circulation during CPR.

First occurrence and composition assessment of microplastics in native mussels collected from coastal and offshore areas of the northern and central Adriatic Sea.

In recent years, the occurrence of microplastics in the aquatic environment has gathered increasing scientific interest. Several studies have shown that the ingestion of microplastics may negatively influence the physiology of marine organisms having different feeding strategies, particularly in those species which cannot discriminate between food sources. Recent studies highlighted the potential for such particles to accumulate in the food web, posing risks to human health via the consumption of seafood. Furthermore, early findings also indicated the role of microplastics as vectors of chemical pollutants either used as additives during synthesis of the plastics or adsorbed directly from seawater, i.e., PAHs, PCB, and surfactants. Despite the importance of microplastics in adsorption and transport of hydrophobic pollutants, little is known about their distribution and accumulation in marine food webs, or their direct and indirect harmful effects. The Adriatic Sea represents a semi-enclosed basin with a low water recirculation rate and high anthropogenic pressures associated with unsustainable fishing and inputs of contaminants. The body burden, accumulation rates, polymer composition, and recurring morphotypes of microplastics in native blue mussels (M. galloprovincialis) were examined. Organisms collected offshore were compared to those collected in coastal areas. Microplastics were recovered from the soft tissues of all analyzed mussels. Coastal organisms showed a load of 1.06-1.33 fragments g-1 (wet weight) and 0.62-0.63 fibers g-1 (wet weight) while offshore organisms showed an accumulation of 0.65-0.66 fragments g-1 (wet weight) and 0.24-0.35 fibers g-1 (wet weight). The size class distribution revealed a marked prevalence of smaller particles (20 μm to 40 μm range) and the most recurring polymer type in analyzed organisms was PE followed by PP, PET, and equal amounts of PS, PLY, and PVC. A significant site-, time-, and oceanographic-related distribution trend was observed. Based on the findings presented here, there is a clear need to implement a seafood safety monitoring program to better understand actual human health-related risks.

Intensive safety monitoring program of antineoplastic medicines: A pilot study in a Portuguese oncology hospital.

The aim of this study was to test the feasibility and the usefulness of an intensive safety monitoring program to identify adverse drug reactions for medicines under additional monitoring that are used to treat cancer patients within a Portuguese oncology hospital. This pilot intensive safety monitoring program was a three-month prospective, observational study. Patients undergoing treatment with one of the following medicines were included: nivolumab, olaparib, palbociclib, pembrolizumab, pertuzumab, ramucirumab, ribociclib, trastuzumab emtansine, or trifluridine/tipiracil. Potential eligible patients were identified by pharmacists based on prescription data. Clinicians used proper paper-based reporting forms to record adverse drug reactions. Clinical secretariats sent those reports through an electronic platform to the pharmacovigilance department for analysis. Seventy-five patients were on treatment with selected medicines. Of those, 33 (44%) experienced adverse drug reactions: 23 (69.7%) cases were serious and 5 (15.2%) unexpected. Considering the number of patients exposed to each medicine and the number of patients experiencing adverse drug reactions, trifluridine/tipiracil (72.7%; 8/11) was associated with the highest rate of toxicity, followed by olaparib (66.7%; 2/3), trastuzumab emtansine (50.0%; 3/6), pertuzumab (47.8%; 11/23), pembrolizumab (45.5%; 5/11), palbociclib (25.0%; 1/4), and nivolumab (18.8%; 3/16). A total of 59 adverse drug reactions were identified (i.e. 1.8 adverse drug reactions/patient), mainly gastrointestinal disorders (n = 15; 25.4%), and blood and lymphatic system disorders (n = 14; 23.7%). This intensive safety monitoring program was feasible and allowed identifying serious and unexpected adverse drug reactions, adding value to pharmacovigilance and therefore contributing to improve patient safety. Further research is needed to confirm the findings of this pilot study.

Seasonal heavy metals accumulation in the soft tissue of <i>Anadara granosa</i> mollusc form Tanjung Balai, Indonesia

A problem of food safety may rise in benthic estuary organisms such as the bivalve mollusc of Anadara granosa, as dangerous metals in environment may accumulate in their soft tissue. Fluctuation of accumulation may also happen, as there are factors that influence the amount of pollutants in water environment. This research aimed to analyze the seasonal pattern (Indonesian east, intermediate, and west monsoon season) of heavy metals (Cr, Co, As, Cd, Hg and Pb) accumulation factor in the soft tissue A. granosa and evaluate the use of mollusc as bio-indicator in metals pollution. The study had been done on the estuary of Tanjung Balai, North Sumatra, Indonesia. Heavy metal from water, sediment, and soft tissue of A. granosa were extracted by microwave digestion and analyzed by ICP-MS (Inductively Coupled Plasma-Mass Spectrometer). Result of the study showed that the heavy metals accumulation in the soft tissue of A. granosa was as follow Cd > As > Hg > Pb > Cr > Co and between 0.01–0.31 mg/kg. The concentration may consider as safe, which is below the maximum allowable limits for marine products. Meanwhile, a significant (P < 0.05) heavy metals contamination was detected higher in the beginning east monsoon season. Thus, temporal variation should be considered in food safety monitoring program on fisheries products, which usually only collected once per year. Moreover, BWAF (bio-water accumulation factor) was detected significantly (P < 0.05) higher than BSAF (bio-sediment accumulation factor). The results also showed only Cr and Pb had a significant relation (P < 0.05) between their accumulation in environment and in the mollusc. Therefore, environmental parameters need to take into account when using bivalves as indicator of heavy metal pollution since seasonality could affect the absorption of heavy metals.

A Case Study of Safety Monitoring Program for Existing Bridge Crossing a Twin Tower Construction Project

A Case Study of Safety Monitoring Program for Existing Bridge Crossing a Twin Tower Construction Project

Understanding the positive benefit:risk profile of alemtuzumab in relapsing multiple sclerosis: perspectives from the Alemtuzumab Clinical Development Program.

The introduction of high-efficacy therapies for relapsing–remitting multiple sclerosis has driven re-evaluation of treatment goals and benefit:risk considerations in treatment choice. In the alemtuzumab Phase II and III clinical trials, patients treated with alemtuzumab 12 mg versus subcutaneous interferon beta-1a demonstrated significantly reduced annualized relapse rates and improved magnetic resonance imaging outcomes, and were significantly more likely to achieve no evidence of disease activity and reduction in brain volume loss. In two of the studies, alemtuzumab-treated patients had a significantly reduced risk of 6-month confirmed disease worsening, compared with subcutaneous interferon beta-1a. Benefits were maintained throughout 5 years, with a majority of patients receiving no alemtuzumab retreatment or other disease-modifying therapy. Trial results support alemtuzumab’s manageable, consistent safety profile in relapsing–remitting multiple sclerosis. Infusion-associated reactions, the most frequent adverse events (AEs), can be minimized by corticosteroid pretreatment, monitoring, and symptomatic management. Other AEs include infections and autoimmune events. Oral anti-herpes prophylaxis should be initiated on the first day of each alemtuzumab treatment course and continued according to local guidelines. Overall cancer risk was lower in the alemtuzumab clinical trials than in a reference population; however, continuing surveillance will determine if alemtuzumab may be associated with certain malignancies such as thyroid papillary carcinoma and melanoma, which are currently identified as potential risks. The post-approval risk management strategy includes a safety monitoring program. Autoimmune AEs (thyroid events, immune thrombocytopenia, nephropathies) can be detected in a timely manner with the monitoring program, which includes physician and patient education about the signs and symptoms, monthly renal and hematologic monitoring, and quarterly thyroid function monitoring for 48 months after the last alemtuzumab course. Education, vigilance by physicians and patients, and monthly laboratory monitoring are recommended to maintain alemtuzumab’s positive benefit:risk profile.

Daclizumab: Development, Clinical Trials, and Practical Aspects of Use in Multiple Sclerosis.

Daclizumab is a humanized monoclonal antibody directed towards CD25, the alpha subunit of the high-affinity interleukin (IL)-2 receptor. Daclizumab exerts its effects via multiple mechanisms, including reduction of IL-2-mediated lymphocyte activation and upregulation of CD56-bright natural killer cells. Intravenous daclizumab (Zenapax™) was initially approved for prevention of rejection in renal transplant. In subsequent early testing, followed by larger-scale phase II and phase III trials, both intravenous and subcutaneous daclizumab have demonstrated clinical efficacy in the treatment of multiple sclerosis. The subcutaneous daclizumab prepared by high-yield process was utilized in the advanced phase II and phase III trials (SELECT and DECIDE). High-yield process daclizumab is now approved by the US Food and Drug Administration for relapsing-remitting multiple sclerosis, and is now formally termed daclizumab beta (DAC-beta; Zinbryta™). In this review, the early development of anti-IL-2 receptor alpha monoclonal antibodies and the properties of IL-2 and its receptor are discussed, and diverse mechanisms of action for daclizumab are presented. Results of the CHOICE, SELECT, and DECIDE clinical trials are discussed in detail. Adverse events observed in clinical trials included cutaneous reactions, liver enzyme elevations, infections, and autoimmune phenomena. DAC-beta is a monthly, patient-administered subcutaneous injection that requires enrollment in a safety monitoring (REMS) program for monthly liver function testing. Prescribers should be aware of the potential adverse events, as early recognition and management is important, particularly in cutaneous and hepatic reactions. Continued clinical experience with DAC-beta, including observations from the REMS program, will define its place in the armamentarium of immunotherapeutics for relapsing-remitting multiple sclerosis.