Long-term effectiveness of Gliadel ® implant for malignant glioma and prognostic factors for survival: 3-year results of a post-marketing surveillance in Japan

Background Adjuvant treatment with Gliadel wafers may prolong overall survival (OS) for malignant glioma patients without increasing toxicity. In Japan, the long-term OS of these patients treated with Gliadel 7.7 mg implants has not been studied. We evaluated OS and prognostic factors that might affect OS in Japanese patients with malignant glioma who received the Gliadel 7.7 mg implant. Methods This observational, long-term, post-marketing surveillance was an extension of a previous surveillance. Data were collected through case report forms at 2 and 3 years after Gliadel implant. Up to 8 Gliadel wafers (61.6 mg of carmustine) were placed over the tumor resection site. Primary endpoints were OS and prognostic factors that may influence OS. Results Among the 506 patients analyzed, 62.6% had newly diagnosed disease, and 37.4% had recurrent disease; 79.1% had glioblastoma histological type and 79.6% had World Health Organization Grade IV disease. Patients received a median of 8 wafers. The median OS was 18.0 months; OS rates were 39.8% and 31.5% at 2 and 3 years, respectively. Age ≥65 years (hazard ratio [HR]: 1.456; P = 0.002), lower resection rate (HR: 1.206; P < 0.001), recurrence (HR: 2.418; P < 0.001), and concomitant radiotherapy (HR: 0.588; P < 0.001) were identified as significant prognostic factors. Conclusions This study confirmed the 2- and 3-year OS of Japanese malignant glioma patients with varied backgrounds after Gliadel implant. With a careful interpretation of indirect comparisons with previously reported data, the results suggest that prognosis could be improved with Gliadel implants.

Initiatives for immune-related adverse events by the outpatient pharmacist clinic

Early detection is the key in managing side effects because immune-related adverse events (irAEs) are becoming more serious, and their onset time differs. In our hospital, we conducted an outpatient pharmacist clinic for early detection of irAEs by self-care practice for the cases of immune checkpoint inhibitor administration. As a result of a retrospective survey of 207 cases, the percentage of irAEs found by pharmacist’s suggestion of the outpatient pharmacist clinic increased over time, and a high detection ratio was obtained even for irAEs with a late onset time. The incidence of serious irAEs was higher than that in the immediate post-marketing surveillance, and different factors were considered. Although there were some problems, the outpatient pharmacist clinic had a certain effect.

Preventing Prescription Drug Misuse: A Regulatory Perspective in the United States, Europe, and India

Prescription medicines, such as analgesics, stimulants, steroids, anti-depressants, psychotropics, and certain antibiotics are commonly mishandled in a variety of ways, including overdosing, abuse, diversion, and drug trafficking. Because of the considerable risk to public health, they are subject to strict regulatory oversight. The drugs possess abuse potential at specific dose and hence prone to abuse therefore they are categorized as Controlled substances. Therefore, they are subject to constant vigilance over the pharmaceutical supply chain. The complete clinical data as well as post marketing surveillance study of such drugs are critical to be in place as per the regulatory requirements. The countries have kept up with the times by constantly updating the system with regulatory laws and strategies to prevent cases of misuse. The current review will give a quick summary of how prescription medications and prohibited substances are regulated in the United States, Europe, and India. It will also emphasize current trends in drug usage, as well as the issues that these countries face and the preventive policies implemented to manage and prevent drug misuse. It will also make recommendations for new regulatory initiatives to address the current drug- misuse-related concerns. As a result, a review of the regulatory system in various countries will present current challenges and new lessons for countries around the globe.

Kidney Injury Following Ibuprofen and Acetaminophen: A Real-World Analysis of Post-Marketing Surveillance Data

Background: Although kidney injury has been reported as a serious adverse effect in patients treated with ibuprofen or acetaminophen (APAP), there are still few real-world studies to compare the specific differences in the adverse effects of nephrotoxicity.Methods: Disproportionality analysis and Bayesian analysis were devoted to data-mining of the suspected kidney injury after using ibuprofen and APAP based on the FDA’s Adverse Event Reporting System (FAERS) from January 2004 to March 2021. The times to onset, fatality, and hospitalization rates of ibuprofen-associated kidney injury and APAP-associated kidney injury were also investigated.Results: 2,453 reports of ibuprofen-associated kidney injury and 1,288 reports of APAP-associated kidney injury were identified. Ibuprofen appeared to affected more middle-aged patients than elderly ones (27.76 vs 16.53%) while APAP appeared to affected more young patients than middle-aged patients (45.24 vs 29.10%) and elderly patients were fewer (13.99%). Compared to ibuprofen, APAP had the higher association with renal injury based on the higher reporting odds ratio (ROR = 2.45, 95% two-sided CI = 2.36–2.56), proportional reporting ratio (PRR = 2.39, χ2 = 2002.94) and empirical Bayes geometric mean (EBGM = 2.38, 95% one-sided CI = 2.3). In addition, APAP-associated kidney injury had earlier onset (32.74 vs 115.82 days, p < 0.0001) and a higher fatality rate (44.43 vs 7.36%, p < 0.001) than those of ibuprofen-associated kidney injury.Conclusion: The analysis of FAERS data provides a more accurate profile on the incidence and prognosis of kidney injury after ibuprofen and acetaminophen treatment, enabling continued surveillance and timely intervention in patients at risk of kidney injury using these drugs.

Long-term safety and effectiveness of velaglucerase alfa in Gaucher disease: 6-year interim analysis of a post-marketing surveillance in Japan

Background Gaucher disease (GD) is caused by reduced lysosomal enzyme β-glucocerebrosidase activity. Heterogeneous genotypes and phenotypes have been observed within GD types and across ethnicities. Enzyme replacement therapy is generally recommended for patients with type 1 GD, the least severe form of GD. In Japan, velaglucerase alfa has a broad indication covering type 1, 2 or 3 GD. Methods All patients with type 1, 2, or 3 GD administered velaglucerase alfa 60 U/kg every 2 weeks via intravenous infusion after its launch date in Japan in 2014, were enrolled in a non-interventional, observational post-marketing surveillance (PMS). Individual patient data were reported via case report forms (CRFs). Key safety endpoints investigated included the incidence of infusion-related reactions (IRRs), the safety of velaglucerase alfa in patients with types 2 and 3 GD, from patients under one year of age to elderly patients (≥ 65 years of age). Long-term efficacy was also assessed. Results In total, 53 patients with GD were registered. CRFs were available for 41 (77.4%) patients at the 6-year interim analysis. Fourteen adverse drug reactions (ADRs) were reported in seven patients. All reported ADRs occurred in patients with type 2 GD. ADRs were reported by 63.6% (7/11) of patients with type 2 GD. Ten ADRs were reported in five patients aged < 4 years. No elderly patients experienced any ADR during the surveillance period. Five ADRs occurring in three (10.0%) patients were classified as IRRs, with one case of vomiting (moderate severity) resulting in treatment discontinuation. Ten serious adverse events were reported in five (16.7%) patients. Three fatal events were considered to be unrelated to treatment with velaglucerase alfa. Platelet counts increased after the administration of velaglucerase alfa and were generally maintained within the normal range over the administration period. Among eleven patients tested for neutralizing anti-velaglucerase alfa antibodies, two (18.2%) were assessed as positive results. Conclusion PMS data from patients with types 1–3 GD in Japan indicate that long-term treatment with velaglucerase alfa was well-tolerated and associated with increased platelet counts, which is consistent with observations made in studies outside of Japan. Trial registration: NCT03625882 registered July 2014.

544 Two cases of constrictive pericarditis temporally associated with mRNA-1273 COVID-19 vaccination

Aims The SARS-CoV-2 pandemic has led to the development of the mRNA vaccines in humans which are well tolerated, safe, and highly efficacious; however, post-marketing surveillance is revealing potential rare cardiac adverse effects as acute pericarditis. We herein report two cases of symptomatic constrictive pericarditis following administration of the second dose of mRNA-1273 (Moderna) SARS-CoV-2 vaccine. Methods and results Case summary: A 75 years old male with history of hypertension and COPD presented to our Hospital approximately one month after the second dose of mRNA-1273 SARS-CoV-2 Vaccine with dyspnoea and leg oedema. Routine analysis resulted normal, no increasing of inflammatory markers or ECG abnormalities. Echocardiogram showed circumferential fibrinous pericardial effusion without tamponade and typical features of constrictive pericarditis: annulus reversus, ventricular interdependence, expiratory diastolic flow reversal in hepatic vein, inferior vena cava plethora. Pleural ultrasound showed bilateral pleural effusion that was sampled and showed a transudate fluid. Tumoral marker and a CT Scan, autoimmunity panel, blood tests for bacteraemia and Quantiferon were negative. Cardiac magnetic resonance imaging confirmed thickening of pericardium. A 68 years old male with history of ischaemic heart disease with previous CABG, hypertension, dyslipidaemia and chronic kidney disease presented with palpitations and mild legs swelling. Approximately, 2 months before he received the second dose of mRNA-1273 SARS-CoV-2 vaccine. Routine blood examinations resulted normal, ECG showed a right bundle branch block. Echocardiogram showed a mild enlargement of LV with normal systolic function, a moderate primary mitral regurgitation and a circumferential pericardial effusion, showing signs of constrictive syndrome. CT Scan demonstrated pericardium thickness. Constrictive pericarditis may represent a subacute complication of an asymptomatic exudative acute pericarditis. Although cases of acute pericarditis have been reported after SARS-CoV-2 vaccine, to our knowledge, the association with constrictive pericarditis has not been described. The temporal link between vaccination and symptoms development as the biological plausibility of autoimmune or cross-reaction response to vaccination in predisposed subjects could suggest a possible correlation as an adverse event, even if causality could not be established. Conclusions We present two cases of constrictive pericarditis occurring after mRNA-1273 SARS-CoV-2 vaccination, aiming further data to confirm a causal role.

PEDT-9 A study of NovoTTF-100A to expand the regulatory indication for childhood glioblastoma through a pediatric clinical trial based on the Advanced Medical Care system

Background: Tumor-treating fields (TTF) are alternating electric fields applied continuously to the brain by attaching 2-pair arrays on the scalp. Although TTF therapy has demonstrated efficacy against supratentorial glioblastoma (GBM) in adults, its safety and efficacy in children have not been confirmed. In Japan, off-label use of medical devices is almost impossible because the national health insurance system does not cover the cost of off-label use of drugs and medical devices. Therefore, TTF therapy cannot be applied to the treatment of pediatric GBM. [Objectives] The investigator-initiated clinical trial aims to expand regulatory approval of TTF therapy for pediatric GBM treatment based on safety and exploratory efficacy data. Methods: Patients aging between 5 and 17 years with histopathological diagnosis of GBM (either newly diagnosed or first-recurrence), which located in the supratentorial region would be included. All the patients will receive TTF therapy for 28 days per course for up to 26 courses until the end-of-therapy criteria are met. The primary endpoint is the adverse event rate with causality. The secondary endpoints include various time-to-event measures and QoL. In total ten patients will be enrolled. Current Status: Discussions with the Pharmaceuticals and Medical Devices Agency (PMDA) led to a tentative consensus that the accumulated data on the efficacy of NovoTTF-100A for adult GBM may be extrapolatable to pediatric GBM if the trial is able to demonstrate efficacy equivalent to that found in previous, adult studies. On the other hand, the combination of the pediatric safety data gathered in this trial and the findings of international studies, including clinical trials and post-marketing surveillance studies, may expedite approval of the device for pediatric GBM treatment. The trial started patient enrollment in April, 2021 with the supervision of the Advanced Medical Care administration system and is currently awaiting the first eligible patient.